WO2025111547A1 - 2,3-dihydropyrollopyridine carboxamide compounds and methods of use thereof - Google Patents

Abstract

The present disclosure relates to compounds of Formula (I) or subformulas thereof: (I) and pharmaceutically acceptable salts thereof, and their uses in treating PMS1 -associated diseases and disorders.

Description

2,3-DIHYDROPYROLLOPYRIDINE CARBOXAMIDE COMPOUNDS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATION [001] This application claims the benefit of and priority to U.S. Provisional Patent Application No.63/601,947, filed on November 22, 2023, which is incorporated by reference in its entirety herein. BACKGROUND [002] More than 90% of human genes produce multiple mature transcripts via alternative splicing. This process is essential for generating different transcripts in different cell and tissue types, during the developmental process, and in response to internal and external signals. Alternative splicing are prevalent not only for protein-coding genes but also for most other kinds of genes including microRNA genes and long noncoding genes. Splicing is carried out by the spliceosome. Small nuclear RNAs (snRNAs) are key components of the spliceosome. The major spliceosome comprises the U1, U2, U4, U5, and U6 snRNAs, and it catalyzes the removal of ~95% of human introns, while the remaining introns (called the U12-type of introns) are removed by the minor spliceosome, comprising the U11, U12, U4atac, U5, and U6atac snRNAs. These snRNAs are in complex with their respective protein partners to form the functional unit of small nuclear ribonucleoproteins (snRNPs). [003] Splicing is a highly regulated process, with the regulation exerted by both cis- elements and trans-factors. The cis-elements that are recognized by the snRNAs include the 5’-splice site, 3’-splice site, and the branchpoint, each of these associating with a sequence motif that is recognized by a component of the spliceosome. In addition, there are intronic splicing enhancers (ISE), intronic splicing silencer (ISS), exonic splicing enhancer (ESE), and exonic splicing enhancer (ESS), which are recognized by a myriad of trans-factors commonly known as RNA-binding proteins (RBPs). Some of these RBPs directly bind to the cis-elements in a sequencing-specific way, while other RBPs recognize RNA structures (e.g., RNA duplex or unpaired loop region), yet others function via protein-protein interaction. There are ~1600 RBPs annotated in the human genome, and they are expressed in a cell-type- specific manner and form an extensive regulatory network for splicing regulation. [004] Dysregulation of splicing is implicated in roughly half of human diseases. Some diseases are caused by mutations in the spliceosome components or RBPs, while others by mutations in the cis-elements such as splice sites, branchpoint, or the various splicing enhancers and silencers. Although current approaches to treating these diseases, such as CRISPR-based genome editing, virus-aided gene therapy, or a variety of oligonucleotide- based technologies, continue to improve, they still suffer major technical and clinical challenges. In particular, oligonucleotide-based therapeutics show unfavorable pharmacokinetics, can not be orally administered, and can not be delivered effectively to many tissues, especially the brain. Small-molecule drugs have excellent pharmacokinetics, effective delivery, and bioavailability, and have only recently become available for modulating RNA splicing. Yet, the currently molecules come from a few limited chemical series. Thus, there is a great need to develop additional small molecule splicing modulators (SMSMs). [005] Almost 50 inherited disorders in humans result from an increase in the number of copies of single repeats in genomic DNA. These DNA repeats appear to be predisposed to such expansion because they have unusual structural characteristics, which disrupt cellular replication, repair, and recombination machinery. The presence of expanding DNA repeats alters gene expression in human cells, leading to disease. [006] One of these inherited disorders is Huntington's disease (HD). HD is a deadly neurodegenerative disorder with no cure associated with cognitive impairment, dementia, and loss of motor coordination. It is characterized by the progressive and hereditary increase in the length of the CAG trinucleotide repeats that encode a stretch of polyglutamine, in the Huntington gene (HTT) coding region. These repeats can increase in number from one generation to the next. The normal allele of the HTT gene contains fewer than 36 CAG repeats, while the mutant allele contains more than 36 repeats. Most HD patients carry one normal allele and one mutant allele that causes the disease. Functionally, the aberrant accumulation of CAG repeats is believed to confer a toxic gain of function on the mutant HD protein, causing it to aggregate, form protein deposits (ie, inclusion bodies), and induce cell death. The severity of the disease generally reflects the extent of repeat expansion in the mutant HTT protein. [007] Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are associated with long repeats of polyCUG and polyCCUG in the 3'-UTR and intron 1 regions of the transcription of myotonic dystrophy protein kinase (DMPK) and protein 9 of zinc finger (ZNF9), respectively. While normal individuals have up to 30 CTG repeats, DMI patients have a higher number of repeats ranging from 50 to thousands. The severity of the disease and the age of onset correlate with the number of repetitions. Adult-onset patients show milder symptoms and have fewer than 100 repeats, juvenile-onset DM1 patients have up to 500 repeats, and congenital cases typically have around 1,000 CTG repeats. Expanded transcripts containing CUG repeats form a secondary structure, accumulate in the nucleus as nuclear foci, and sequester RNA-binding proteins (RNA-BP). [008] Besides the extra copies of repeats inherited at birth, for many repeat expansion diseases, repeats are highly unstable and their repeat numbers continue to expand throughout the life time of patients. This repeat instability has been shown experimentally to be mediated by proteins in DNA mismatch repair (MMR) processes including PMS1, MLH1, MSH3. Human genetics data from genome-wide association studies has indicated that variants in MMR proteins are associated with clinically relevant HD symptomatology including age at motor onset, rate of progression and somatic instability. Knocking down and knocking out MMR genes have been shown to stall or slow the somatic repeat expansion in various preclinical models of repeat expansion diseases. SUMMARY [009] Provided herein are small molecule splicing modulators (SMSMs), which can be used to treat a wide variety of diseases, including neurodegenerative and repeat expansion diseases. These SMSMs target regions of a primary RNA transcript that are cis-elements, such as splice sites, branch points, splicing enhancers, or splicing silencers. These regions may contain unpaired nucleotides in an RNA duplex, called bulges, which may occur naturally or result from disease. [010] When the SMSMs come into contact with an RNA transcript, the RNA transcript may be bound by the spliceosome or the other trans-factors, most notably RNA-binding proteins (RBPs). The SMSMs reported herein may cause an alteration in the sequence or abundance of the mature transcript, which may, in turn, alter the sequence or abundance of the functional protein should the transcript be protein-coding, or the sequence or abundance of the functional RNA should the transcript be non-coding. [011] In one aspect, provided herein is a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3-12 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted 8-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R¹ is independently selected from halogen, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_{3- 6}cycloalkyl, and 5-8 memebered heteroaryl; each R² is independently selected from halogen and C_1-6alkyl; R³ is selected from H and C_1-6alkyl; each R^a is independently selected from the group consisting of halogen, -OH, C_1-6alkyl, C_{1- 6}haloalkyl, oxo, C_3-6cycloalkyl, -C(O)O-C_1-6alkyl, -C(O)C_1-6haloalkyl, -C(O)O-C_{1- 6}alkylene-OC(O)-C_1-6alkyl, and -N(R^cR^d), wherein the C_1-6alkyl is optionally substituted with -OH, C_1-6alkoxy, C_3-6cycloalkyl, -N(R^cR^d), or -S(O)₂C_1-6alkyl, or two R^a attached to the same carbon atom, together with carbon atom to which they are attached, combine to form a C_3-6cycloalkyl; each R^b is independently selected from the group consisting of halogen, -OH, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6 alkoxy, C_1-6haloalkoxy, and C_3-6cycloalkyl, wherein the C_1-6 alkoxy is optionally substituted with C_3-6cycloalkyl; each R^c is independently selected from H, C_1-6alkyl, and C_3-6cycloalkyl, wherein the C_1-6alkyl is optionally substituted with -OH; each R^d is independently selected from H and C_1-6alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. [012] In some embodiments, the compound is a compound of formula (Ia),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3; and the rest of the variables are as defined herein. [013] In some embodiments, the compound is a compound of formula (Ib),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined herein. [014] In some embodiments, the compound is a compound of formula (Ic),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined herein. [015] In some embodiments, the compound is a compound formula (Id),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in herein. [016] In another aspect, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described here (e.g., a method comprising one or more steps described in herein). [017] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. [018] In another aspect, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described herein). [019] In another aspect, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [020] In another aspet, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [021] In another aspect, the present disclosure provides a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein. [022] In another aspect, the present disclosure provides a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein. [023] In another aspect, the present disclosure provides use of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof for treating or preventing a disease or disorder disclosed herein. [024] In another aspect, the present disclosure provides use of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof for treating a disease or disorder disclosed herein. [025] In another aspect, the present disclosure provides use of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [026] In another aspect, the present disclosure provides use of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. [027] In another aspect, the present disclosure provides a method of preparing a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)). [028] In another aspect, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein. [029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. [030] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION [031] Compounds described herein are generally designed to treat diseases and disorders disclosed herein. Definitions [032] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. [033] As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅, C₆ alkyl” or “C_1-6 alkyl” is intended to include C₁, C₂, C₃, C₄, C₅, or C₆ straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C₁-₆ alkyl is intended to include C₁, C₂, C₃, C₄, C_5, and C₆ alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has four or fewer carbon atoms. [034] As used herein, the term “alkoxy” refers to the group -OR where R is linear or branched alkyl. When the term “alkoxy” is modified with a designated number of carbon atoms (e.g., C_1-6 alkoxy) the number of carbon atoms refers to the number of carbon atoms in the linear or branched alkyl R. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 6 carbon atoms (“C_1-6 alkoxy”). [035] As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3- ₁₂, C₃-₁₀, or C_3-8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl. Particular cycloalkyl groups are lower cycloalkyl, e.g., with between 3 and 6 carbon atoms (“C_3-6 cycloalkyl”). [036] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated 3- 8 membered monocyclic (e.g., 4-7 membered monocyclic) or 7-12 membered bicyclic (fused, bridged, or spiro rings) having one or more heteroatoms e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or _{1-6 heteroatoms, or e.g. ̧1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the} group consisting of nitrogen, oxygen and sulphur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1- azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane- 1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl- 2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). [037] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring (e.g., an 8-12 membered bicyclic aromatic heterocyclic ring) which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or _{e.g. ̧1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of} nitrogen, oxygen and sulphur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulphur heteroatoms may optionally be oxidised (i.e., N→O and S(O)_r, where r = 1 or 2). Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7- tetrahydrobenzo[c]isoxazolyl). [038] Furthermore, the term “heteroaryl” includes multicyclic heteroaryl groups, e.g., tricyclic, bicyclic, e.g., benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine. [039] Bicyclic and tricyclic systems can be edge-fused, spiro-fused, or bridged systems. [040] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. For substituted groups containing one or more heteroatoms (e.g., substituted heterocyclyl or substituted heteroaryl), the heteroatoms may be substituted provided that the heteroatoms’ normal valencies are not exceeded. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. [041] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any carbon atom or heteroatom in the ring, provided that the carbon atom or heteroatom’s normal valency is not exceeded. Unless specified otherwise, it is assumed that the substituent replaces a hydrogen atom of the substituted atom. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. [042] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. [043] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O-. [044] As used herein, the term “cyano” refers to the group -CN. [045] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. [046] As used herein, the term “haloalkyl” refers to a branched or unbranched alkyl substituted with one or more halogens. For example, a C_1-6 haloalkyl is an alkyl group of from one to six carbons wherein at least one H is substituted by a halogen. Examples of haloalkyl include but are not limited to CFH₂, CF₂H, CF₃, CH₂CF₃, CF₂CF₃, C(F)(CH₃)₂, CH₂CH₂Br, CH(I)CH₂F, and CH₂Cl. [_{47] As used herein, the term “haloalkoxy” refers to alkoxy structures that are substituted} with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" are haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine. [_{48] As used herein, the term “amino” refers to the radical -NH2. In certain embodiments} as specified herein, one or both hydrogen atoms of -NH₂ may be replaced with a different group, e.g., amino-C1-7alkyl. [_{49] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or} C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise. [_{50] It is to be understood that the present disclosure provides methods for the synthesis of} the compounds of any of the Formulae described herein (e.g., compounds formula (I), (Ia), (Ib), (Ic), or (Id)). The present disclosure also provides detailed methods for the synthesis of various disclosed compounds e.g., those shown in the Examples. [_{51] It is to be understood that, throughout the description, where compositions are} described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously. [_{52] It is to be understood that the synthetic processes of the disclosure can tolerate a wide} variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. [_{53] It is to be understood that compounds of the present disclosure (e.g., compounds} formula (I), (Ia), (Ib), (Ic), and (Id)) can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3^rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art _{[054] One of ordinary skill in the art will note that, during the reaction sequences and} synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3^rd edition, John Wiley & Sons: New York, 1999. _{[055] It is to be understood that, unless otherwise stated, any description of a method of} treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. _{[056] As used herein, the terms “individual,” “patient,” or “subject” are used} interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). _{[057] As used herein, the term “treating” or “treat” includes any effect, e.g., lessening,} reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like. _{[058] It is to be understood that a compound of the present disclosure, or a pharmaceutically} acceptable salt or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. _{[059] As used herein, the term “preventing,” “prevent,” or “protecting against” describes} reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. _{[060] It is to be understood that one skilled in the art may refer to general reference texts for} detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3^rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18^th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure. _{[061] It is to be understood that the present disclosure also provides pharmaceutical} compositions comprising any compound described herein (e.g., a compound formula (I), (Ia), (Ib), or (Ic)) in combination with at least one pharmaceutically acceptable excipient or carrier. _{[062] As used herein, the term “pharmaceutical composition” is a formulation containing} the compounds of the present disclosure (e.g., compounds formula (I), (Ia), (Ib), or (Ic)) in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the subject. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. _{[063] As used herein, the term “pharmaceutically acceptable” refers to those compounds,} anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. _{[064] As used herein, the term “pharmaceutically acceptable excipient” means an excipient} that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. _{[065] It is to be understood that a pharmaceutical composition of the disclosure is} formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. _{[066] It is to be understood that a compound or pharmaceutical composition of the} disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the subject should preferably be closely monitored during and for a reasonable period after treatment. _{[067] As used herein, the term “therapeutically effective amount” means the amount of the} subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Altneratively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect. _{[068] It is to be understood that, for any compound, the therapeutically effective amount can} be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the subject, and the route of administration. _{[069] Dosage and administration are adjusted to provide sufficient levels of the active} agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. _{[070] The pharmaceutical compositions containing active compounds of the present} disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen. _{[071] Pharmaceutical compositions suitable for injectable use include sterile aqueous} solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. _{[072] Sterile injectable solutions can be prepared by incorporating the active compound in} the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. _{[073] Oral compositions generally include an inert diluent or an edible pharmaceutically} acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. _{[074] For administration by inhalation, the compounds are delivered in the form of an} aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser. _{[075] Systemic administration can also be by transmucosal or transdermal means. For} transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. _{[076] The active compounds can be prepared with pharmaceutically acceptable carriers that} will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811. _{[077] It is especially advantageous to formulate oral or parenteral compositions in dosage} unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved. _{[078] In therapeutic applications, the dosages of the pharmaceutical compositions used in} accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell. _{[079] It is to be understood that the pharmaceutical compositions can be included in a} container, pack, or dispenser together with instructions for administration. _{[080] It is to be understood that, for the compounds of the present disclosure being capable} of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure. _{[081] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of} the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulphonic, 1,2-ethane sulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulphamic, sulphanilic, sulphuric, tannic, tartaric, toluene sulphonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. _{[082] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a} potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt. _{[083] Other examples of pharmaceutically acceptable salts include hexanoic acid,} cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulphonic acid, 2-naphthalenesulphonic acid, 4- toluenesulphonic acid, camphorsulphonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1- carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. _{[084] It is to be understood that all references to pharmaceutically acceptable salts include} solvent addition forms (solvates) as defined herein, of the same salt. _{[085] The compounds, or pharmaceutically acceptable salts thereof, are administered orally,} nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration. _{[086] A salt, for example, can be formed between an anion and a positively charged group} (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulphate, bisulphate, sulphamate, nitrate, phosphate, citrate, methanesulphonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulphonate, and acetate (e.g., trifluoroacetate). [_{87] It is to be understood that the compounds of the present disclosure, for example, the} salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. [_{88] As used herein, the term “solvate” means solvent addition forms that contain either} stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H₂O. [_{89] As used herein, the term “derivative” refers to compounds that have a common core} structure and are substituted with various groups as described herein. [_{90] It is also to be understood that certain compounds of any one of the Formulae} disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. [_{91] Compounds of any one of the Formulae disclosed herein may exist in a number of} different tautomeric forms and references to compounds of formula (I), (Ia), (Ib),(Ic), and (Id) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by formula (I), (Ia), (Ib), and (Ic). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/ oxime, thioketone/enethiol, and nitro/aci-nitro.

k_{eto enol enolate} [092] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of formula (I), (Ia), (Ib), (Ic), and (Id) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N- oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. _{[093] The compounds of any one of the Formulae disclosed herein may be administered in} the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substitutents at the ester or amide group in any one of the Formulae disclosed herein. _{[094] As used herein, the term “isomerism” means compounds that have identical molecular} formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” _{[095] As used herein, the term “chiral centre” refers to a carbon atom bonded to four} nonidentical substituents. _{[096] As used herein, the term “chiral isomer” means a compound with at least one chiral} centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). [097] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. [098] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity. [099] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity. [0100] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases. [0101] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. [0102] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. [0103] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [0104] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). [0105] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound. [0106] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the subject without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro- Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987. [0107] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the subject to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C₁-C₁₀ alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C₁-C₁₀ alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C₁-C₆ alkyl)₂carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(C₁-C₄ alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. [0108] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C_{1- 4}alkylamine such as methylamine, a (C₁-C₄ alkyl)₂amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a C₁-C₄ alkoxy-C₂-C₄ alkylamine such as 2-methoxyethylamine, a phenyl-C₁-C₄ alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. [0109] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C₁-C₁₀ alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4- (C₁-C₄ alkyl)piperazin-1-ylmethyl. [0110] The dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the subject; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition. [0111] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19^th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. [0112] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. [0113] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer. [0114] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The present disclosure having now been described by way of written description, those of skill in the art will recognize that the present disclosure can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. [0115] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein (e.g., compounds of formula (I), (Ia), (Ib), and (Ic)), both generically and specifically.

Compounds of the Present Disclosure [0116] In one aspect, provided herein is a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3-12 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted 8-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R¹ is independently selected from halogen, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_{3- 6}cycloalkyl, and 5-8 memebered heteroaryl; each R² is independently selected from halogen and C_1-6alkyl; R³ is selected from H and C_1-6alkyl; each R^a is independently selected from the group consisting of halogen, -OH, C_1-6alkyl, C_{1- 6}haloalkyl, oxo, C_3-6cycloalkyl, -C(O)O-C_1-6alkyl, -C(O)C_1-6haloalkyl, -C(O)O-C_{1- 6}alkylene-OC(O)-C_1-6alkyl, and -N(R^cR^d), wherein the C_1-6alkyl is optionally substituted with -OH, C_1-6alkoxy, C_3-6cycloalkyl, -N(R^cR^d), or -S(O)₂C_1-6alkyl, or two R^a attached to the same carbon atom, together with carbon atom to which they are attached, combine to form a C_3-6cycloalkyl; each R^b is independently selected from the group consisting of halogen, -OH, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6 alkoxy, C_1-6haloalkoxy, and C_3-6cycloalkyl, wherein the C_1-6 alkoxy is optionally substituted with C_3-6cycloalkyl; each R^c is independently selected from H, C_1-6alkyl, and C_3-6cycloalkyl, wherein the C_1-6alkyl is optionally substituted with -OH; each R^d is independently selected from H and C_1-6alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. [0117] In some embodiments, m is 0. In some embodiments, n is 0. In some embodiments, m and n are each 0. [0118] In some embodiments, Ring A is an optionally substituted 5-6 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 5-6 membered heterocyclyl comprising 1-2 nitrogen atoms. [0119] In some embodiments, Ring A is selected from optionally substituted piperidinyl and optionally substituted pyrrolidinyl. In some embodiments, Ring A is optionally substituted piperazinyl. In some embodiments, Ring A is optionally substituted piperidinyl. In some embodiments, Ring A is optionally substituted pyrrolidinyl. [0120] In some embodiments, each R^a is independently selected from C_1-6alkyl and -N(R^cR^d). In some embodiments, each R^a is independently C_1-6alkyl. In certain embodiments, each R^a is methyl. In some embodiments, each R^a is independently -N(R^cR^d). In some embodiments, each R^c is methyl. In some embodiments, each R^d is H. In certain embodiments, each R^c is methyl and each R^d is H. In certain embodiments, each R^a is -N(H)CH₃. In certain embodiments, each R^a is independently selected from methyl and -N(H)CH₃. [0121] In some embodiments, p is 1 or 2. In certain embodiments, p is 1. In certain embodiments, p is 2. [0122] In some embodiments, the portion of the compound represented

is selected from the group consisting

[0123] In some embodiments, the portion of the compound represented

[0125] In some embodiments, the portion of the compound represented

is selected from the group consisting of

, , , ,

[0126] In some embodiments, the portion of the compound represented

is selected from the group consisting

[0127] In some embodiments, the compound is a compound of formula (Ia),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3; and the rest of the variables are as defined herein. [0128] In some embodiments, p is 0. In some embodiments, p is 1 or 2. [0129] In some embodiments, R^a is methyl. [0130] In some embodiments, the compound is a compound of formula (Ib),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined herein. [0131] In some embodiments, each R^a is -N(H)CH₃. [0132] In some embodiments, p is 1. [0133] In some embodiments, the compound is a compound formula (Ic),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined herein. [0134] In some embodiments, the compound is a compound formula (Id),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined herein. [0135] In some embodiments, p is 0. [0136] In some embodiments, Ring B is an optionally substituted 9 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted 9 membered bicyclic heteroaryl comprising 1-2 heteratoms independently selected from nitrogen and oxygen. [0137] In some embodiments, Ring B is selected from the group consisting of optionally substituted indazolyl, optionally substituted imidazo[1,2-a]pyridyl, and optionally substituted 2,7a-dihyrdobenzo[d]oxazolyl. [0138] In some embodiments, each R^b is independently selected from the group consisting of halogen, C_1-6alkyl, C_1-6haloalkyl, and C_1-6alkoxy. In some embodiments, each R^b is independently selected from the group consisting of fluoro, methyl, methoxy, ethoxy, -CHF₂, and -CF₃. In some embodiments, R^b is halogen. In some embodiments, R^b is C_1-3alkyl. In some embodiments, R^b is C_1-3haloalkyl. In some embodiments, R^b is C_1-3alkoxy. [0139] In some embodiments, q is 2 or 3. In certain embodiments, q is 2. In certain embodiments, q is 3. [0140] In some embodiments, the portion of the compound represented by

_{selected from the group consisting of}

, ^Rb , H _{, N} NH , _N , R^{b b b b} q R q R q _b N R N ^b N _{N R q} N q H R H N N N N N N , N , N _, ^N NH , ^N R^b , N R^b R^{b b} q R N _Rb q q q NH N N N N N N N _N R^b N N N , ^q , N , N ^Rb , N , R^{b b} q R q R^{b b} q R N q N N N _N NH N N N _{N N N N} R _N R^b N ^b , _N , ^Rb , ^Rb _, ^q ,

[0141] In some embodiments, the portion of the compound represented by

[0142] In some embodiments, the portion of the compound represented by

[0143] In some embodiments, the portion of the compound represented by

[0144] In some embodiments, the portion of the compound represented by

[0145] In some embodiments, the portion of the compound represented by

[0146] In some embodiments, the portion of the compound represented by

F N N , O N N N N , F N N _{N ,} N N , F N N N ,

F F O F N N N N N O _, ^O _{, O , S ,} ^S , F O O N _{N N N N N N N N N} , , , , ,

[0147] To clarify, in all embodiments where two variable groups together form an alkylene, those groups along with the atoms they are attached to and possible intervening atoms, form a ring. This ring can be cycloalkyl or heterocyclyl depending on the attachment point of the variables, but the variable groups themselves are alkylene and thus contain no heteroatoms of their own. [0148] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0149] In some embodiments, the compound is selected from the compounds described in Table 1, or from the disclosure. [0150] In some embodiments, the compound is selected from the compounds described in Table 1.

[0151] Table 1. Exemplary compounds of the disclosure

[0152] In some embodiments, the compound is a therapeutically active substance. In some embodiments, the compound is a small molecule splicing modulator. [0153] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group. [0154] The various functional groups and substituents making up the compounds of formulae (I), (Ia), (Ib), (Ic), and (Id) are typically chosen such that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 daltons or less. [0155] It will be understood that the compounds of any one of formulae (I), (Ia), (Ib), (Ic), and (Id) disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers and mixtures of stereoisomers of all isomeric forms of said compounds. [0156] It is to be understood that the compounds of formulae (I), (Ia), (Ib), (Ic), and (Id) described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. [0157] The in vivo effects of a compound of any one of formulae (I), (Ia), (Ib), (Ic), and (Id) disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of formulae (I), (Ia), (Ib), (Ic), and (Id) disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). [0158] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Alternative Embodiments [0159] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be ²H (D or deuterium) or ³H (T or tritium); carbon may be, for example, ¹³C or ¹⁴C; oxygen may be, for example, ¹⁸O; nitrogen may be, for example, ¹⁵N, and the like. In other embodiments, a particular isotope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸O, or ¹⁵N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. Methods of Synthesis [0160] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure (e.g., a compound of formula (I), (Ia), (Ib), or (Ic)). [0161] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein. [0162] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein (e.g., a compound of formula (I), (Ia), (Ib), or (Ic)). [0163] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., a compound of formula (I), (Ia), (Ib), or (Ic)). [0164] The compounds of the present disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. [0165] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. [0166] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized. [0167] It will be appreciated that during the synthesis of the compounds of the disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. [0168] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. [0169] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. [0170] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. [0171] Once a compound of formula (I), (Ia), (Ib), (Ic), or (Id) has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of a formula (I),(Ia), (Ib), (Ic), or (Id) into another compound of formula (I), (Ia), (Ib), (Ic), or (Id) ; and/or (iii) forming a pharmaceutically acceptable salt thereof. [0172] The resultant compounds of formula (I), (Ia), (Ib), (Ic), or (Id) can be isolated and purified using techniques well known in the art. [0173] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulphoxides, such as dimethyl sulphoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water. [0174] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used. [0175] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours. [0176] Moreover, by utilising the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. [0177] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons). [0178] General routes for the preparation of a compound of the application are described herein. Biological Assays [0179] Compounds designed, selected and/or optimised by methods described above, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. Pharmaceutical Compositions [0180] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1, or from the disclosure. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1. [0181] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. [0182] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts. [0183] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof. [0184] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulphated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulphobutyl ether, branched-β- cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof. [0185] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. [0186] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof. [0187] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. [0188] The aqueous vehicle may also contain a viscosity/suspending agent. Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof. [0189] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range. [0190] The aqueous vehicle may also contain a buffering agent to stabilise the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof. [0191] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene- polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof. [0192] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. [0193] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing). [0194] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. [0195] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a disease or disorder referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0196] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a disease or disorder referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0197] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) or (II) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well- known principles of medicine. Methods of Use [0198] Provided herein is a method of treating a a disorder related to a nucleotide repeat expansion in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition described herein. [0199] In some embidmments, the nucleotide repeat expansion comprises a nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CNN, ANN, TNN, and GNN, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C). [0200] In some embodiments, the nucleotide repeat expansion comprises a nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CAG, CAG/CTG, GCG, GCN, CGG, CCG, CCCCGCCCCGCG, GCA, GGGGCC, CTG, GAA, ATTCT, TGGAA, GGCCTG, AAGGG, CCCTCT, ATTTT/ATTTC, and CCCTCT, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C). [0201] In certain embodiments, the nucleotide repeat expansion comprises a trinucleotide sequence repeated two or more times, wherein the trinucleotide sequence is selected from the group consisting of CAG, CTG, CGG, and GCN. [0202] Also provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition described herein, wherein the disease is selected from the group consisting of Dentatorubropallidoluysian atrophy, Huntington's disease, Spinal and bulbar muscular atrophy, SCA1 (Spinocerebellar ataxia Type 1), SCA2 (Spinocerebellar ataxia Type 2), SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease), SCA6 (Spinocerebellar ataxia Type 6), SCA7 (Spinocerebellar ataxia Type 7), SCA12 (Spinocerebellar ataxia Type 12), SCA17 (Spinocerebellar ataxia Type 17), FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor/ataxia syndrome), FRAXE (Fragile XE mental retardation), Baratela-Scott syndrome, FRDA (Friedreich's ataxia), DM1 (Myotonic dystrophy Type 1), DM2 (Myotonic dystrophy Type 2) SCA8 (Spinocerebellar ataxia Type 8), Fuchs endothelial corneal dystrophy, Desbuquois dysplasia, amyotrophic lateral sclerosis, frontotemporal dementia, GLS (glutaminase) disease, and SBMA/Kennedy disease. [0203] In some embodiments, the disease is Huntington’s disease. [0204] Also provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein, wherein the disease is Huntington’s disease. [0205] In some embodiments, the disease is myotonic dystrophy 1. [0206] Also provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein, wherein the disease is myotonic dystrophy 1. [0207] In some embodiments, the disease is selected from the group consisting of FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor/ataxia syndrome), FRAXE (Fragile XE mental retardation). [0208] Also provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein, wherein the disease is selected from the group consisting of FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor/ataxia syndrome), FRAXE (Fragile XE mental retardation). Routes of Administration [0209] The compounds of the disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action). [0210] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Enumerated Embodiments 1. A compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3-12 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted 8-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R¹ is independently selected from halogen and C_1-6alkyl; each R² is independently selected from halogen and C_1-6alkyl; each R^a is independently selected from the group consisting of halogen, C_1-6alkyl, C_{1- 6}haloalkyl, and -N(R^cR^d), or two R^a attached to the same carbon atom, together with carbon atom to which they are attached, combine to form a C_3-6cycloalkyl; each R^b is independently selected from the group consisting of halogen, -OH, C_1-6alkyl, C_{1- 6}haloalkyl, C_1-6 alkoxy, C_1-6haloalkoxy, wherein the C_1-6 alkoxy is optionally substituted with C_3-6cycloalkyl; each R^c is independently selected from H and C_1-6alkyl; each R^d is independently selected from H and C_1-6alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. 2. The compound of embodiment 1, wherein m and n are each 0. 3. The compound of embodiment 1 or 2, wherein Ring A is an optionally substituted 5-6 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4. The compound of any one of embodiments 1-3, wherein Ring A is selected from optionally substituted piperidinyl and optionally substituted pyrrolidinyl. 5. The compound of any one of embodiments 1-4, wherein each R^a is independently selected from C_1-6alkyl and -N(R^cR^d). 6. The compound of any one of embodiments 1-5, wherein each R^c is methyl and each R^d is H. 7. The compound of any one of embodiments 1-6, wherein each R^a is independently selected from methyl and -N(H)CH₃. 8. The compound of any one of embodiments 1-7, wherein p is 1 or 2. 9. The compound of any one of embodiments 1-8, wherein the portion of the compound represented

_{selected from the group consisting of}

,

10. The compound of embodiment 1, wherein the compound is a compound of formula (Ia),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3; and the rest of the variables are as defined in embodiment 1. 11. The compound of embodiment 10, wherein p is 0. 12. The compound of embodiment 10, wherein p is 1 or 2. 13. The compound of embodiment 10 or 12, wherein each R^a is methyl. 14. The compound of embodiment 1, wherein the compound is a compound of formula (Ib),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in embodiment 1. _{15. The compound of embodiment 14, wherein each Ra is -N(H)CH3. 16. The compound of embodiment 14 or 15, wherein p is 1. 17. The compound of embodiment 1, wherein the compound is a compound of formula} (Ic),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in embodiment 1. _{18. The compound of embodiment 17, wherein p is 0. 19. The compound of any one of embodiments 1-18, wherein Ring B is an optionally} substituted 9 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. _{20. The compound of any one of embodiments 1-19, wherein Ring B is selected from the} group consisting of optionally substituted indazolyl, optionally substituted imidazo[1,2- a]pyridyl, and optionally substituted 2,7a-dihyrdobenzo[d]oxazolyl. _{21. The compound of any one of embodiments 1-20, wherein each Rb is independently} selected from the group consisting of halogen, C_1-6alkyl, C_1-6haloalkyl, and C_1-6alkoxy. _{22. The compound of any one of embodiments 1-21, wherein each Rb is independently} selected from the group consisting of fluoro, methyl, methoxy, ethoxy, -CHF₂, and -CF₃. _{23. The compound of any one of embodiments 1-22, wherein q is 2 or 3.}

_{24. The compound of any one of embodiments 1-23, wherein the portion of the}

_{25. The compound of any one of embodiments 1-24, wherein the portion of the}

_{26. A pharmaceutical composition comprising a compound of any one of embodiments 1-} 25, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. _{27. A compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt} thereof, for use as a small molecule splicing modulator. _{28. A pharmaceutical composition comprising a compound of any one of embodiments 1-} 25 and 27, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. _{29. A method of treating a disorder related to a nucleotide repeat expansion n a subject in} need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-25 or a pharmaceutical composition of embodiment 26. _{30. The method of embodiment 29, wherein the nucleotide repeat expansion comprises a} nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CNN, ANN, TNN, and GNN, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C). _{31. The method of embodiment 29, wherein the nucleotide repeat expansion comprises a} nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CAG, CAG/CTG, GCG, GCN, CGG, CCG, CCCCGCCCCGCG, GCA, GGGGCC, CTG, GAA, ATTCT, TGGAA, GGCCTG, AAGGG, CCCTCT, ATTTT/ATTTC, and CCCTCT, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C). _{32. The method of embodiment 30 or 31, wherein the nucleotide repeat expansion} comprises a trinucleotide sequence repeated two or more times, wherein the trinucleotide sequence is selected from the group consisting of CAG, CTG, CGG, and GCN. _{33. A method of treating a disease in a subject in need thereof, the method comprising} administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-25 or a pharmaceutical composition of embodiment 26, wherein the disease is selected from the group consisting of Dentatorubropallidoluysian atrophy, Huntington's disease, spinal and bulbar muscular atrophy, SCA1 (Spinocerebellar ataxia Type 1), SCA2 (Spinocerebellar ataxia Type 2), SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease), SCA6 (Spinocerebellar ataxia Type 6), SCA7 (Spinocerebellar ataxia Type 7), SCA12 (Spinocerebellar ataxia Type 12), SCA17 (Spinocerebellar ataxia Type 17), FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor/ataxia syndrome), FRAXE (Fragile XE mental retardation), Baratela-Scott syndrome, FRDA (Friedreich's ataxia), DM1 (Myotonic dystrophy Type 1), DM2 (Myotonic dystrophy Type 2), SCA8 (Spinocerebellar ataxia Type 8), Fuchs endothelial corneal dystrophy, Desbuquois dysplasia, amyotrophic lateral sclerosis, frontotemporal dementia, GLS (glutaminase) disease, and SBMA/Kennedy disease. _{34. A method of treating a disease in a subject in need thereof, the method comprising} administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-25 or a pharmaceutical composition of embodiment 26, wherein the disease is Huntington’s disease. _{35. A method of treating a disease in a subject in need thereof, the method comprising} administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-25 or a pharmaceutical composition of embodiment 26, wherein the disease is Myotonic dystrophy 1. _{36. A method of treating a disease in a subject in need thereof, the method comprising} administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-25 or a pharmaceutical composition of embodiment 26, wherein the disease is selected from the group consisting of FRAXA (Fragile X syndrome), FXTAS (Fragile X- associated tremor/ataxia syndrome), and FRAXE (Fragile XE mental retardation). EXAMPLES [0211] For exemplary purpose, neutral compounds of formula (I), (Ia), (Ib), (Ic), and/or (Id) are may be synthesized and tested in the examples. It is understood that neutral compounds of formula (I), (Ia), (Ib), (Ic), and/or (Id) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt). [0212] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated; the chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using a Bruker or Varian instrument with 8, 16 or 32 scans. [0213] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as C182.1 x 30 mm, unless otherwise stated. Injection volumes were 0.7 – 8.0 µl and the flow rates were typically 0.8 or 1.2 ml/min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionisation. MS range was 100 - 1000 Da. Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01 – 0.04 %) such as trifluoroacetic acid or ammonium carbonate. Abbreviations: ACN acetonitrile (Ac)₂O acetic anhydride B_INAP ^{2,2′-bis(diphenylphosphino)-1,1′-binaphthyl} CDCl₃ chloroform-d Cs₂CO₃ caesium carbonate DCM dichloromethane DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMSO dimethylsulphoxide DMSO-d₆ hexadeuterodimethylsulphoxide ESI electrospray ionisation EA ethyl acetate FA formic acid h hour(s) ¹H NMR proton nuclear magnetic resonance spectroscopy H₂ hydrogen H₂O water HCl hydrochloric acid HDMS bis(trimethylsilyl)amine HOAc acetic acid HPLC high performance liquid chromatography IPA isopropyl alcohol K₂CO₃ potassium carbonate M molar MeOD-d₄ methanol-d₄ MeOH methanol MS mass spectrometry N₂ nitrogen NBS N-bromosuccinimide NH₃ ammonia Na₂CO₃ sodium carbonate Na₂SO₄ sodium sulfate NaOAc sodium acetate NMR nuclear magnetic resonance Pd/C palladium on carbon Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)₂ palladium (II) acetate PE petroleum ether PPTS pyridinium p-toluenesulfonate prep-HPLC preparative high performance liquid chromatography RT room temperature sat. saturated TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMSOTf trimethylsilyl trifluoromethanesulfonate wt weight Y Yield

Example 1 – Preparation of (S)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride (Compound 1)

Step 1: Preparation of 5-bromo-2, 3-difluorobenzaldehyde [0214] To a mixture of 2, 3-difluorobenzaldehyde (25 g, 176 mmol) in H₂SO₄ (250 mL) was added NBS (37.6 g, 211 mmol). The mixture was stirred at 60℃ for 16 h. The reaction was poured into ice-water (200 mL) and extracted with EA (300 mL x 3). The combined organic layer was washed with brine (200 mL), dried over Na₂SO₄ and evaporated in vacuo. The residue was purified by silica gel column chromatography (PE) to give title product (20.00 g, Y: 51.6 %) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (s, 1H), 8.23 – 8.01 (m, 1H), 7.88 – 7.69 (m, 1H). Step 2: Preparation of (E)-5-bromo-2,3-difluorobenzaldehyde oxime [0215] To a mixture of 5-bromo-2, 3-difluorobenzaldehyde (40 g, 181 mmol) in THF (400 mL) were added NH₂OH·HCl (15 g, 217 mmol) and K₂CO₃ (30 g, 217 mmol). The mixture was stirred at 40 ^oC for 16 h. The reaction was diluted with water (300 mL) and extracted with EA (400 mL x 3). The combined organic layer was washed with brine (400 mL), dried over Na₂SO₄ and evaporated in vacuo to give tittle product (30 g, Y: 70.5 %) as a white solid, which was used to next step without further purification. ESI-MS (M+H) ⁺: 236.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.23 – 8.15 (m, 1H), 7.88 – 7.76 (m, 1H), 7.71 – 7.63 (m, 1H). Step 3: Preparation of 5-bromo-7-fluoro-1H-indazole [0216] To a mixture of (E)-5-bromo-2, 3-difluorobenzaldehyde oxime (30 g, 128 mmol) in 1,4-dioxane (300 mL) was added N₂H₄ ^.H₂O (44.7 g, 894 mmol). The mixture was stirred at 145 ^oC for 16 h. The mixture was diluted with water (350 mL) and extracted with EA (450 mL x 3). The combined organic layer was washed with brine (300 mL), dried over Na₂SO₄ and evaporated in vacuo. The crude was purified by silica gel column chromatography (PE: EA= 5:1) to give title product (16.5 g, Y: 60.2 %) as a white solid. ESI-MS (M+H) ⁺: 215.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 – 8.15 (m, 1H), 7.88 (s, 1H), 7.45 (d, J = 10.4 Hz, 1H). Step 4: Preparation of 5-bromo-7-fluoro-2-methyl-2H-indazole [0217] To a mixture of 5-bromo-7-fluoro-1H-indazole (33 g, 154 mmol) in EA (330 mL) was added trimethyloxonium tetrafluoroborate (27.2 g, 185 mmol) and stirred at r.t for 5 h. The mixture was quenched with NaHCO₃ (200 mL) and extracted with EA (350 mL x 3). The combined organic layer was washed with brine (400 mL), dried over Na₂SO₄, filtered and concentrate in vacuo. The residue was purified by column chromatography (PE: EA= 5:1) to give title product (18 g, Y: 51.4 %) as a white solid. ESI-MS (M+H) ⁺: 229.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 – 8.36 (m, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.30 – 7.17 (m, 1H), 4.20 (s, 3H). Step 5: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine [0218] To a mixture of 5-bromo-7-fluoro-2-methyl-2H-indazole (10 g, 44 mmol) and diphenylmethanimine (7.93 g, 44 mmol) in 1.4-dioxane (200 mL) were added BINAP (5.46 g, 8 mmol), Pd(OAc)₂ (1 g, 4.4 mmol) and Cs₂CO₃ (28.6 g, 88 mmol). The mixture was stirred at 100 ℃ for 16 h. The reaction was diluted with water (300 mL), extracted with EA (500 mL x 3). The organic layer was washed with brine, dried over Na₂SO₄ and evaporated in vacuo. The crude was purified by silica gel column chromatography (PE: EA =3:1) to give title product (7 g, yield 65%) as a yellow solid. ESI-MS (M+H)⁺: 330.1¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J = 2.8 Hz, 1H), 7.69 – 7.64 (m, 2H), 7.56 – 7.52 (m, 1H), 7.50 – 7.44 (m, 2H), 7.34 – 7.29 (m, 3H), 7.21 – 7.16 (m, 2H), 6.68 (d, J = 1.3 Hz, 1H), 6.58 (dd, J = 12.7, 1.3 Hz, 1H), 4.10 (s, 3H). Step 6: Preparation of 7-fluoro-2-methyl-2H-indazol-5-amine hydrochloride [0219] A mixture of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (5 g, 15.2 mmol) in 3M HCl / EA (70 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (2.5 g, yield 82%) as a yellow solid. ESI-MS (M+H)⁺: 166.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.63 (s, 2H), 8.61 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.11 (dd, J = 11.7, 1.4 Hz, 1H), 4.22 (s, 3H). Step 7: Preparation of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine [0220] A solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (96 g, 627.45 mmol) in dimethylsulfide borane (600 mL, 2M in THF) was stirred at 60 ^oC for 16 h. The mixture was diluted with MeOH (300 mL) and concentrated in vacuo, the residue was purified by column gel chromatography (PE / EA=3 / 1) to give title product (16 g, 16.45 %) as a yellow solid. ESI-MS (M+H)⁺: 155.2. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 5.7 Hz, 1H), 6.42 (d, J = 5.8 Hz, 1H), 3.60 (t, J = 8.5 Hz, 2H), 3.05 (t, J = 8.5 Hz, 2H). Step 8: Preparation of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate [0221] To a solution of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (350 mg, 2.26 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (904 mg, 4.52 mmol) in a sealed tube was added DIEA (1.5 g, 11.3 mmol). The reaction mixture was stirred at 140 °C for 16 h. The mixture was concentrated in vacuo and the residue was purified by column gel chromatography (DCM / MeOH=10 / 1) and C18 (0.1% FA in H₂O / ACN) to give title product (200 mg, 27.86 %) as a yellow solid. ESI-MS (M+H)⁺: 319.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (d, J = 5.9 Hz, 1H), 6.05 (d, J = 6.0 Hz, 1H), 5.86 (s, 1H), 4.21 – 4.09 (m, 1H), 3.80 – 3.71 (m, 1H), 3.49 – 3.41 (m, 1H), 3.40 – 3.35 (m, 3H), 3.16 – 3.05 (m, 1H), 3.01 – 2.90 (m, 2H), 2.87 – 2.80 (m, 1H), 2.76 – 2.67 (m, 1H), 1.41 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H). Step 9: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate [0222] To a solution of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (180 mg, 0.57 mmol) and 7-fluoro-2-methyl-2H-indazol-5- amine (188 mg, 1.14 mmol) in DCM (10 mL) were added TEA (230 mg, 2.28 mmol) and triphosgene (271 mg, 0.91 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by C18 (0.1% FA in H₂O / ACN) to give title product (40 mg, 13.94 %) as a yellow solid. ESI-MS (M+H)⁺: 510.4. ¹H NMR (400 MHz, CDCl₃) δ 11.65 (s, 1H), 7.84 (d, J = 5.9 Hz, 1H), 7.78 (dd, J = 6.8, 1.9 Hz, 2H), 7.01 (d, J = 12.7 Hz, 1H), 6.27 (d, J = 6.0 Hz, 1H), 4.32 – 4.24 (m, 1H), 4.14 (s, 3H), 4.12 – 4.03 (m, 2H), 3.93 – 3.84 (m, 1H), 3.48 – 3.33 (m, 2H), 3.20 – 3.12 (m, 1H), 3.06 – 2.96 (m, 3H), 2.93 – 2.82 (m, 1H), 1.42 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H). Step 10: Preparation of (S)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride [0223] To a solution of tert-butyl (S)-4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 3 M HCl / EA (1 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered, washed with EA (5 mL) and lyophilized to give title product (25 mg, 71.43 %) as a yellow solid. ESI-MS (M+H) ⁺: 410.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 2H), 8.44 (s, 1H), 7.91 – 7.77 (m, 1H), 7.76 – 7.71 (m, 1H), 7.33 (d, J = 13.5 Hz, 1H), 7.01 – 6.68 (m, 1H), 4.38 – 4.20 (m, 2H), 4.18 (s, 3H), 4.17 – 4.11 (m, 1H), 3.61 – 3.21 (m, 7H), 3.16 – 3.08 (m, 1H), 1.32 (d, J = 6.1 Hz, 3H).

Example 2 – Preparation of (R) -N- (7-fluoro-2-methyl-2H-indazol-5-yl) -4- (3- (methylamino) pyrrolidin-1-yl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-1-carboxamide 2,2,2-trifluoroacetate (Compound 2)

Step 1: Preparation of phenyl (7-fluoro-2-methyl-2H-indazol-5-yl)carbamate [0224] To a solution of 7-fluoro-2-methyl-2H-indazol-5-amine (400 mg, 2.42 mmol) in DCM (10 mL) were added pyridine (573 mg, 7.26 mmol) and phenyl carbonochloridate (455 mg, 2.90 mmol) at 0 ^oC. The mixture was stirred at RT for 3 h. The reaction mixture was diluted with H₂O (15 mL), the precipitate was filtered, washed with water and dried in vacuo to give title product (500 mg, 72.46 %) as yellow solid. ESI-MS (M+H) ⁺: 286.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.68 (s, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.29 – 7.14 (m, 4H), 4.16 (s, 3H). Step 2: Preparation of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate [0225] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (600 mg, 3.88 mmol) in DIEA (3.2 mL) was added tert-butyl (R)-methyl(pyrrolidin-3-yl) carbamate (930 mg, 4.65 mmol). The resulting mixture was stirred at 140 ^oC for 24 h in a sealed tube. The mixture was allowed to cooling down to room temperature and concentrated in vacuo. The crude was purified by silica gel column (PE / EA=1:1 to DCM / MeOH=10:1) to give title product (562 mg, 45%) as a black oil. ESI-MS (M+H)⁺: 319.2. ¹H NMR (400 MHz, DMSO- d₆) δ 7.43 (d, J = 6.7 Hz, 1H), 6.01 (d, J = 6.8 Hz, 1H), 3.69 – 3.63 (m, 2H), 3.50 – 3.42 (m, 3H), 3.35 – 3.27 (m, 4H), 2.74 (s, 3H), 2.17 – 2.01 (m, 2H), 1.41 (s, 9H). Step 3: Preparation of tert-butyl (R)-(1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl) carbamoyl) - 2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate [0226] To a mixture of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate (500 mg, 1.57 mmol) in THF (5 mL) were added DMAP (20 mg, 0.16 mmol) and phenyl (7-fluoro-2-methyl-2H-indazol-5-yl) carbamate (493 mg, 1.73 mmol) at 0 ^oC. The resulting mixture was stirred at 80 ^oC for 16 h in a sealed tube. The mixture was allowed to cooling down to room temperature and concentrated in vacuo. The mixture was diluted with water (5 mL), extracted with EA (5 mL × 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE / EA=1:1) to give title product (388 mg, 48%) as a yellow solid. ESI- MS (M+H)⁺: 510.3. Step 4: Preparation of (R) -N- (7-fluoro-2-methyl-2H-indazol-5-yl) -4- (3-(methylamino) pyrrolidin-1-yl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-1-carboxamide 2,2,2- trifluoroacetate [0227] To a mixture of tert-butyl (R)-(1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl) carbamoyl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate (360 mg, 0.71 mmol) in EA (5 mL) was added 3M HCl / EA (5 mL). The mixture was stirred at RT for 2 h. The mixture was diluted with water (5 mL), extracted with EA (5 mL × 3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / ACN) to give title product (34.98 mg, yield: 12 %) as a white solid. ESI-MS (M+H)⁺: 410.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 2H), 8.40 (s, 1H), 7.81 (s, 1H), 7.71 (d, J = 1.3 Hz, 1H), 7.27 (dd, J = 13.2 Hz, 1H), 6.37 (s, 1H), 4.17 (s, 3H), 4.13 – 3.97 (m, 2H), 3.94 – 3.86 (m, 2H), 3.83 – 3.66 (m, 5H), 2.67 (s, 3H), 2.34 – 2.26 (m, 1H), 2.17 – 2.16 (m, 1H). Example 3 – Preparation of (S)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound

Step 1: Preparation of tert-butyl (S)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate [0228] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (300 mg, 1.94 mmol) in DIEA (1.6 mL) was added tert-butyl (S)-methyl(pyrrolidin-3-yl) carbamate (465 mg, 2.32 mmol). The resulting mixture was stirred at 140 ^o C for 16 h in a sealed tube. The mixture was allowed to cooling down to room temperature and concentrated in vacuo. The crude was purified by silica gel column (DCM / MeOH=10:1) to give title product (270 mg, 44%) as a yellow oil. ESI-MS (M+H)⁺: 319.2. Step 2: Preparation of tert-butyl (S)-(1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate [0229] To a mixture of tert-butyl (S)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate (200 mg, 0.63 mmol) in THF (5 mL) were added phenyl (7-fluoro-2-methyl-2H-indazol-5-yl)carbamate (197 mg, 0.69 mmol) and DMAP (8 mg, 0.06 mmol). The mixture was stirred at 80 ^oC for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=1:1) to give the title compound (40 mg, Y: 12.4%) as a yellow solid. ESI-MS: (M+H)⁺:510.2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 6.4 Hz, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.71 – 7.70 (m, 1H), 6.61 (d, J = 6.4 Hz, 1H), 4.16 (s, 3H), 4.07 – 3.96 (m, 1H), 3.96 – 3.87 (m, 2H), 3.84 – 3.72 (m, 2H), 3.70 – 3.62 (m, 4H), 2.96 (s, 3H), 2.06 – 2.04 (m, 2H), 1.42 (s, 9H). Step 3: Preparation of (S)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide [0230] To a solution of tert-butyl (S)-(1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl) carbamate (20 mg, 0.04 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtered and the residue was purified by prep-HPLC (0.03% NH₃.H₂O in water / ACN) to give title product (1.31 mg, Y: 8.2%) as a white solid. ESI-MS (M+H)⁺: 410.2. ¹H NMR (400 MHz, MeOD-d₄) δ 8.17 (d, J = 2.7 Hz, 1H), 7.79 (d, J = 6.1 Hz, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.17 (dd, J = 12.9, 1.5 Hz, 1H), 6.18 (d, J = 6.2 Hz, 1H), 4.20 (s, 3H), 3.99 (t, J = 8.6 Hz, 2H), 3.77 – 3.67 (m, 2H), 3.59 – 3.53 (m, 1H), 3.41 – 3.34 (m, 4H), 2.44 (s, 3H), 2.23 – 2.14 (m, 1H), 1.92 – 1.82 (m, 1H). Example 4 – Preparation of (R)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 4)

Step 1: Preparation of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate [0231] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (400 mg, 2.58 mmol) in DIEA (1.7 g, 12.90 mmol) was added tert-butyl (R)-2-methylpiperazine-1-carboxylate (1.0 g, 5.16 mmol). The mixture was stirred at 140 ^oC for 16 h in a sealed tube. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE / EA=3:1) to give the title compound (120 mg, 14.6 %) as a yellow oil. ESI-MS (M+H)⁺:319.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (d, J = 5.9 Hz, 1H), 6.05 (d, J = 6.0 Hz, 1H), 5.89 (s, 1H), 4.18 – 4.12 (m, 1H), 4.00 – 3.91 (m, 1H), 3.76 (d, J = 13.3 Hz, 1H), 3.56 (d, J = 12.3 Hz, 1H), 3.15 – 3.05 (m, 2H), 2.99 – 2.93 (m, 2H), 2.84 – 2.79 (m, 2H), 2.72 – 2.67 (m, 1H), 1.41 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 2: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate [0232] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) in THF (5 mL) were added TEA (159 mg, 1.57 mmol), triphosgene (112 mg, 0.38 mmol), 7-fluoro-2-methyl-2H-indazol-5-amine (52 mg, 0.31 mmol). The mixture was stirred at RT for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE / EA=2:1) to give the title compound (60 mg, Y: 37.4 %) as a yellow solid. ESI-MS (M+H)⁺:510.3. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.72 – 7.67 (m, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.18 (dd, J = 13.9, 1.5 Hz, 1H), 4.14 (s, 3H), 4.04 – 4.02 (m, 2H), 3.91 – 3.87 (m, 1H), 3.76 – 3.69 (m, 2H), 3.12 – 3.08 (m, 2H), 3.07 – 3.04 (m, 2H), 2.93 – 2.86 (m, 2H), 1.42 (s, 9H), 1.09 (d, J = 6.7 Hz, 3H). Step 3: Preparation of (R)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate [0233] To a solution of tert-butyl (R)-4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (5.21 mg, 14.6 %) as a white solid. ESI-MS (M+H)⁺:410.2. ¹H NMR (400 MHz, MeOD-d₄) δ 8.62 – 8.43 (m, 1H), 8.19 (d, J = 2.7 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.19 (dd, J = 12.8, 1.4 Hz, 1H), 6.55 (d, J = 6.1 Hz, 1H), 4.20 (s, 3H), 4.10 – 4.05 (m, 2H), 3.71 (d, J = 13.1 Hz, 2H), 3.28 – 3.22 (m, 2H), 3.17 – 3.12 (m, 3H), 3.10 – 3.07 (m, 1H), 2.82 – 2.76 (m, 1H), 1.28 (d, J = 6.5 Hz, 3H). Example 5 – Preparation of 4-(3,3-dimethylpiperazin-1-yl) -N-(7-fluoro-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate (Compoun

Step 1: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate [0234] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine (250 mg, 1.62 mmol) and tert-butyl 2,2-dimethylpiperazine-1-carboxylate (1.3 g, 6.49 mmol) in a sealed tube was stirred at 140 ℃ for 16 h. The mixture was concentrated in vacuo and purified by column C18 (0.1 % FA in water / ACN) to give title product (400 mg, 61 %) as a brown solid. ESI- MS (M+H)⁺: 333.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H), 7.47 (d, J = 6.1 Hz, 1H), 6.06 (d, J = 6.3 Hz, 1H), 3.65 (t, J = 5.5 Hz, 2H), 3.51 – 3.45 (m, 2H), 3.45 – 3.38 (m, 4H), 3.16 (t, J = 8.5 Hz, 2H), 1.42 (s, 9H), 1.35 (s, 6H). Step 2: Preparation of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl) carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate [0235] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (200 mg, 0.60 mmol) and 7-fluoro-2-methyl-2H-indazol-5- amine (199 mg, 1.20 mmol) in THF (4 mL) were added TEA (182 mg, 1.81 mmol) and triphosgene (356 mg, 1.20 mmol) at 0 ^oC. The reaction mixture was stirred at RT for 16 h. The mixture was diluted with water (4 mL), extracted with EA (4 mL × 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE / EA=1:1) to give title product (140 mg, 44%) as a yellow oil. ESI-MS (M+H)⁺: 524.4. Step 3: Preparation of 4-(3,3-dimethylpiperazin-1-yl) -N-(7-fluoro-2-methyl-2H-indazol-5-yl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide diformate [0236] To a mixture of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl) carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (120 mg, 0.23 mmol) in EA (2 mL) was added 4 M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL × 3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / ACN) to give title product (42.53 mg, yield: 43 %) as a purple-pink solid. ESI-MS (M+H)⁺: 424.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.22 (s, 2H), 7.94 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.26 (dd, J = 13.3, 1.6 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.16 (s, 3H), 3.98 (t, J = 8.6 Hz, 2H), 3.31 – 3.26 (m, 2H), 3.15 – 3.09 (m, 4H), 3.05 – 2.99 (m, 2H), 1.21 (s, 6H). Example 6 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 6)

Step 1: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate [0237] To a solution of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (5 g, 32.23 mmol) and tert-butyl piperazine-1-carboxylate (12 g, 64.46 mmol) was added DIEA (10 mL). The reaction mixture was stirred at 140 °C for 16 h in a sealed tube. The mixture was concentrated in vacuo and the residue was purified by column gel chromatography (DCM / MeOH=10 / 1) and C18 (0.1% FA in H₂O / ACN) to give title product (3 g, 30.61 %) as a yellow solid. ESI-MS (M+H)⁺: 305.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (d, J = 6.0 Hz, 1H), 6.10 (d, J = 6.1 Hz, 1H), 3.46 – 3.38 (m, 6H), 3.15 – 3.09 (m, 4H), 3.01 – 2.95 (m, 2H), 1.41 (s, 9H). Step 2: Preparation of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0238] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (300 mg, 0.99 mmol) and 7-fluoro-2-methyl-2H-indazol-5-amine (163 mg, 0.99 mmol) in THF (10 mL) were added TEA (300 mg, 2.97 mmol) and triphosgene (294 mg, 0.99 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column gel chromatography (PE / EA = 1 / 2) to give title product (120 mg, 24.54 %) as a yellow solid. ESI-MS (M+H)⁺: 496.3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.95 (d, J = 6.1 Hz, 1H), 7.77 – 7.66 (m, 1H), 7.26 (d, J = 13.4 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.16 (s, 3H), 3.98 (t, J = 8.6 Hz, 2H), 3.48 – 3.41 (m, 4H), 3.29 – 3.27 (m, 4H), 3.12 (t, J = 8.5 Hz, 2H), 1.43 (s, 9H). Step 3: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate [0239] To a solution of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (120 mg, 0.24 mmol) in EA (2 mL) was added 4 M HCl / EA (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.1 % FA in water / ACN) to give title product (53 mg, 49.72 %) as a yellow solid. ESI-MS (M+H)⁺: 396.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 8.35 (d, J = 2.7 Hz, 1H), 8.24 – 8.15 (m, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.74 – 7.65 (m, 1H), 7.26 (d, J = 13.0 Hz, 1H), 6.52 (d, J = 5.8 Hz, 1H), 4.16 (s, 3H), 3.97 (t, J = 8.5 Hz, 2H), 3.25 – 3.23 (m, 4H), 3.10 – 3.09 (m, 2H), 2.93 – 2.76 (m, 4H).

Example 7 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 7)

Compound 7 Step 1: Preparation of 5-bromo-4-fluoropyridin-2-amine [0240] To a solution of 4-fluoropyridin-2-amine (24 g, 0.21 mol) in ACN (300 mL) was added NBS (38.1 g, 0.21 mol), the mixture was stirred for 4 h at RT. The mixture was diluted with water (300 mL), extracted with EA (300 mL × 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuum. The crude was purified by silica gel column chromatography (PE: EA= 5: 1) to give title product (38 g, 92.93 %) as a white solid. ESI-MS (M+H) ⁺: 192.9. ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J = 9.6 Hz, 1H), 6.28 (d, J = 10.0 Hz, 1H), 4.79 (s, 2H). Step 2: Preparation of 6-bromo-7-fluoro-2-methylimidazo[1,2-a]pyridine [0241] To a solution of 5-bromo-4-fluoropyridin-2-amine (10 g, 52.36 mmol ) in IPA (120 mL) was added 1-bromopropan-2-one (8.8 mL, 104.71 mmol), the mixture was stirred at 85^oC for 16 h. The mixture was concentrated in vacuo, the residue was diluted with 2 M NaOH (100 mL) and stirred at RT overnight. The mixture was extracted with EA (150 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuum. The crude was purified by silica gel column chromatography (PE : EA= 4 : 1) to give title product (4.4 g, 36.69%) as an off-white solid. ESI-MS (M+H) ⁺: 231.0. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 6.5 Hz, 1H), 7.20 (s, 1H), 7.16 (d, J = 8.9 Hz, 1H), 2.35 (d, J = 0.6 Hz, 3H). Step 3: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine [0242] To a solution of 6-bromo-7-fluoro-2-methylimidazo[1,2-a]pyridine (4 g, 17.46 mmol), diphenylmethanimine (3.8 g, 20.96 mmol), Cs₂CO₃ (17 g, 52.39 mmol) and Pd(OAc)₂ (39.2 mg, 0.17 mmol) in 1,4-dioxane (50 mL) was added BINAP (217 mg, 0.35 mmol), the mixture was stirred at 100 ^oC for 16 h under N₂. The mixture was diluted with water (100 mL), extracted with EA (80 mL × 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuum. The crude was purified by silica gel column chromatography (PE : EA= 4 : 1) to give title product (2.7 g, 46.94 %) as a yellow solid. ESI-MS (M+H) ⁺: 330.2. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 7.2 Hz, 2H), 7.44 (s, 1H), 7.35 (t, J = 6.6 Hz, 3H), 7.22 (d, J = 20.2 Hz, 3H), 7.11 (s, 2H), 7.04 (s, 1H), 6.95 (d, J = 10.3 Hz, 1H), 2.29 (s, 3H). Step 4: Preparation of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride [0243] A solution of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (2.35 g, 7.13 mmol ) in 3M HCl / EA (24 mL) was stirred at RT for 2 h. The precipitate was filtered, washed with EA (30 mL) and dried to give the title compound (1.4 g, 97.32 %) as a white solid. ESI-MS (M+H) ⁺: 166.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (d, J = 7.3 Hz, 1H), 7.94 (s, 1H), 7.75 (d, J = 10.0 Hz, 1H), 5.81 (s, 2H), 2.40 (s, 3H). Step 5: Preparation of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0244] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.32 mmol) and 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (132 mg, 0.65 mmol) in THF (5 mL) was added TEA (332 mg, 3.29 mmol), then triphosgene (194 mg, 0.65 mmol) was added slowly at 0 ^oC. The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE : EA= 1: 2) to give the compound (100 mg, 61.42%) as a yellow solid. ESI-MS (M+H) ⁺: 496.2. ¹H NMR (400 MHz, CDCl₃) δ 9.09 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 5.9 Hz, 1H), 7.48 (dd, J = 12.1, 6.8 Hz, 1H), 7.12 (d, J = 11.1 Hz, 1H), 7.07 (t, J = 5.3 Hz, 1H), 6.30 (d, J = 6.0 Hz, 1H), 4.08 (t, J = 8.5 Hz, 2H), 3.51 – 3.47 (m, 4H), 3.20 – 3.14 (m, 4H), 3.05 (t, J = 8.4 Hz, 2H), 2.34 (s, 3H), 1.42 (s, 9H). Step 6: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate [0245] To a mixture of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (90 mg, 0.18 mmol) in EA (3 mL) was added 3 M HCl / EA (1.5 mL), the mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (33 mg, Y: 45.95 %) as a white solid. ESI-MS (M+H) ⁺: 396.1. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 9.19 (d, J = 7.4 Hz, 1H), 8.21 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.71 (s, 1H), 7.42 (d, J = 11.7 Hz, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.01 (t, J = 8.5 Hz, 2H), 3.41 – 3.38 (m, 4H), 3.16 – 3.11 (m, 2H), 3.07 – 3.01 (m, 4H), 2.29 (s, 3H). Example 8 – Preparation of N-(7-fluoro-2,6-dimethyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate (Compound 8)

Step 1: Preparation of 5-bromo-2,3-difluoro-4-methylbenzaldehyde [0246] To a solution of 2,3-difluoro-4-methylbenzaldehyde (25 g, 0.16 mol) in concentrated H₂SO₄ (300 mL) was added NBS (31.38 g, 0.18 mmol) . The mixture was stirred at 60^oC for 16 h. The mixture was poured into ice-water (500 mL) and extracted with EA (150 mLx3). The combined organic washed with brine (300 mL x3), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE) to give title product (24 g, 64.10%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 7.83 (dd, J = 5.8, 1.8 Hz, 1H), 2.37 (d, J = 2.8 Hz, 3H). Step 2: Preparation of (E)-5-bromo-2,3-difluoro-4-methylbenzaldehyde oxime [0247] To a mixture of 5-bromo-2,3-difluoro-4-methylbenzaldehyde (24 g, 0.10 mol), NH₂OH.HCl (8.58 g, 0.12 mol) in THF (300 mL) was added K₂CO₃ (16.56 g, 0.12 mol). The mixture was stirred at 40^oC for 16 h. The mixture was filtered and the filtrate was diluted with EA (300 mL), the combined organic layer was washed with brine (500 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give title product (20 g, 80.32%) as a yellow oil. ESI-MS (M+H) ⁺: 293.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 8.17 (s, 1H), 7.72 (dd, J = 6.0, 1.8 Hz, 1H), 2.32 (d, J = 2.6 Hz, 3H). Step 3: Preparation of 5-bromo-7-fluoro-6-methyl-1H-indazole [0248] To a mixture of (E)-5-bromo-2,3-difluoro-4-methylbenzaldehyde oxime (20 g, 0.08 mol) in 1.4-dioxane (200 mL) was added N₂H₄.H₂O (20.48 g, 0.64 mol). The mixture was stirred at 150 ^oC for 10 h. The mixture was diluted with H₂O (300 mL) and extracted with EA (300 mL x 3). The organic phase was washed with brine (300 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (15.1 g, 82.79%) as a white solid. ESI-MS (M+H) ⁺: 230.9. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (d, J = 3.4 Hz, 1H), 7.91 (s, 1H), 2.38 (d, J = 2.7 Hz, 3H). Step 4: Preparation of 5-bromo-7-fluoro-2,6-dimethyl-2H-indazole [0249] To a mixture of 5-bromo-7-fluoro-6-methyl-1H-indazole (15.1 g, 0.07 mol) in THF (200 mL) was added NaH (5.6 g, 0.14 mol) at 0 ^oC, the mixture was stirred at this temperature for 30 min. CH₃I (29.82 g, 0.21 mol) was added to the mixture and stirred at r.t for 4 h. The mixture was diluted with H₂O (100 mL) and extracted with EA (200 mL x 2). The organic phase was washed with brine (200 mLx3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (7.4 g, 47.04%) as a white solid. ESI- MS (M+H) ⁺:245.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J = 2.8 Hz, 1H), 7.88 (s, 1H), 4.18 (s, 3H), 2.34 (d, J = 3.0 Hz, 3H). Step 5: Preparation of N-(7-fluoro-2,6-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine [0250] To a mixture of 5-bromo-7-fluoro-2,6-dimethyl-2H-indazole (3 g, 12.3 mmol), diphenylmethanimine (2.69 g, 14.88 mmol) in 1,4-dioxane (50 mL) were added Pd₂(dba)₃ (1.12 g, 1.23 mmol), BINAP (1.53 g, 2.46 mmol) and Cs₂CO₃ (8.02 g, 24.6 mmol), the mixture was charged with Ar for three times and stirred at 115^oC for 16 h. The mixture was diluted with H₂O (50 mL) and extracted with EA (50 mL x 3). The organic phase was washed with brine (50 mLx3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 4/1) to afford title product (3.5 g, 82.96%) as a yellow solid. ESI-MS (M+H) ⁺:344.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.50 (dt, J = 13.3, 6.7 Hz, 4H), 7.34 – 7.25 (m, 3H), 7.15 (d, J = 6.9 Hz, 2H), 6.40 (s, 1H), 4.05 (s, 3H), 2.17 (s, 3H). Step 6: Preparation of 7-fluoro-2,6-dimethyl-2H-indazol-5-amine hydrochloride [0251] A mixture of N-(7-fluoro-2,6-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (3.5 g, 10.20 mmol) in 3M EA / HCl (50 mL) was stirred at r.t for 2 h. The precipitate was filtered to give title product (1.6 g, 87.63%) as a yellow solid. ESI-MS (M+H) ⁺: 180.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 2H), 8.55 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 4.20 (s, 3H), 2.36 (s, 3H). Step 7: Preparation of tert-butyl 4-(1-((7-fluoro-2,6-dimethyl-2H-indazol-5-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate [0252] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (100 mg, 0.33 mmol) and 7-fluoro-2,6-dimethyl-2H-indazol-5-amine (160 mg, 0.97 mmol) in THF (2 mL) were added TEA (98 mg, 0.97 mmol) and triphosgene (292 mg, 0.97 mmol) at 0^oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (EA) to give title product (40 mg, 24%) as a yellow solid. ESI-MS (M+H) ⁺: 510.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.32 (d, J = 2.9 Hz, 1H), 8.12 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.14 (s, 3H), 4.00 (t, J = 8.5 Hz, 2H), 3.47 – 3.42 (m, 4H), 3.29 – 3.26 (m, 4H), 3.14 (t, J = 8.7 Hz, 2H), 2.35 (s, 3H), 1.43 (s, 9H). Step 8: Preparation of N-(7-fluoro-2,6-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate [0253] To a mixture of tert-butyl 4-(1-((7-fluoro-2,6-dimethyl-2H-indazol-5-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / ACN) to give title product (8.16 mg, yield: 25 %) as a white solid. ESI-MS (M+H) ⁺: 410.5. ¹H NMR (400 MHz, DMSO-d₆) δ 11.68 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.14 (s, 3H), 3.99 (t, J = 8.4 Hz, 2H), 3.29 – 3.23 (m, 4H), 3.12 (t, J = 8.4 Hz, 2H), 2.91 – 2.81 (m, 4H), 2.35 (s, 3H). Example 9 – Preparation of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 9)

Step 1: Preparation of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine [0254] To a mixture of 5-bromo-7-methoxy-2-methyl-2H-indazole (5.5 g, 22.92 mmol) in 1,4-dioxane (60 mL) were added diphenylmethanimine (4.98 g, 27.50 mmol), BINAP (2.86 g, 4.58 mmol), Cs2CO3 (14.94 g, 45.84 mmol), Pd(OAc)2 (517.54 mg, 2.29 mmol), the mixture was stirred at 100 ^oC for 16 h under N₂. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE : EA = 4:1) to give the title compound (3.0 g, Y: 38.38 %) as a yellow oil. ESI-MS (M+H)⁺:342.2. Step 2: Preparation of 7-methoxy-2-methyl-2H-indazol-5-amine HCl salt [0255] A mixture of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (3.0 g, 8.80 mmol) in 4 M HCl / EA (40 mL) was stirred at RT for 16 h. The mixture was filtered and the residue was diluted with PE / EA (v:v=1:1, 20 mL) and stirred at RT for 2 h. The precipitate was filtered and dried to give the title compound (1.30 g, Y: 83.45 %) as a white oil. ESI-MS (M+H)⁺:178.3. ¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s, 2H), 8.38 (s, 1H), 7.90 (s, 1H), 7.17 (s, 1H), 4.12 (s, 3H), 3.92 (s, 3H). Step 3: Preparation of tert-butyl 4-(1-((7-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0256] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) in THF (5 mL) were added TEA (199 mg, 1.97 mmol), triphosgene (117 mg, 0.39 mmol), 7-methoxy-2-methyl-2H-indazol-5-amine HCl salt (70 mg, 0.39 mmol). The mixture was stirred at RT for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE / EA=2:1) to give the title compound (50 mg, Y: 29.9 %) as a yellow solid. ESI-MS (M+H)⁺:508.2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.00 – 6.99 (m, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.06 (s, 6H), 3.47 – 3.43 (m, 4H), 3.41 – 3.39 (m, 2H), 3.27 – 3.26 (m, 2H), 3.15 – 3.09 (m, 4H), 1.43 (s, 9H). Step 4: Preparation of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate [0257] To a solution of tert-butyl 4-(1-((7-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (3.49 mg, 9.8 %) as a white solid. ESI-MS (M+H)⁺:408.2. ¹H NMR (400 MHz, MeOD-d₄) δ 8.50 (s, 1H), 8.40 – 8.37 (m, 1H), 8.02 (d, J = 5.8 Hz, 1H), 7.99 (s, 1H), 6.97 (s, 1H), 6.56 (d, J = 6.0 Hz, 1H), 4.12 (s, 3H), 4.11 – 4.08 (m, 2H), 4.02 (s, 3H), 3.47 – 3.42 (m, 4H), 3.28 – 3.25 (m, 4H), 3.17 – 3.13 (m, 2H).

Example 10 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 10) NH

Compound 10 Step 1: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine [0258] To a solution of 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (3 g, 13.10 mmol), diphenylmethanimine (2.85 g, 15.72 mmol), Cs2CO3 (12.80 g, 39.29 mmol) and Pd(OAc)2 (29.40 mg, 0.13 mmol) in 1,4-dioxane (25 mL) was added BINAP (163 mg, 0.26 mmol), the mixture was stirred at 100 ^oC for 16 h under N₂. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE: EA= 4 : 1) to give title product (3.9 g, 90.40 %) as a yellow solid. ESI-MS (M+H) ⁺: 330.2. Step 2: Preparation of 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine [0259] A solution of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (3.4 g, 10.32 mmol ) in 3M HCl / EA (35 mL) was stirred at RT for 2 h. The mixture was diluted with sat. Na₂CO₃ (100 mL), extracted with EA (60 mL × 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuo. The residue was purified by silica gel column chromatography (PE : EA= 1 : 9) to give title product (1.2 g, 70.38%) as a grey solid. ESI-MS (M+H) ⁺: 166.1. ¹H NMR (400 MHz, CDCl₃) δ 7.28 (d, J = 1.5 Hz, 1H), 7.16 (d, J = 1.3 Hz, 1H), 6.42 (dd, J = 11.4, 1.7 Hz, 1H), 2.35 (s, 3H). Step 3: Preparation of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0260] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (60 mg, 0.19 mmol) and 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (130 mg, 0.78 mmol) in DCM (5 mL) were added TEA (119 mg, 1.18 mmol) and triphosgene (223 mg, 0.78 mmol) at 0 ^oC. The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE: EA= 1: 1) to give title product (65 mg, crude) as a white solid. ESI-MS (M+H) ⁺: 496.2. Step 4: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate [0261] To a mixture of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (42 mg, 0.08 mmol) in EA (3 mL) was added 3M HCl / EA (0.5 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (2.65 mg, Y: 7.91 %) as a white solid. ESI-MS (M+H) ⁺: 396.1. ¹H NMR (400 MHz, MeOD-d₄) δ 8.61 (s, 1H), 8.19 (s, 1H), 7.88 (d, J = 5.9 Hz, 1H), 7.54 (t, J = 6.8 Hz, 1H), 7.01 (d, J = 12.0 Hz, 1H), 6.45 (d, J = 6.0 Hz, 1H), 3.94 (t, J = 8.5 Hz, 2H), 3.48 – 3.38 (m, 4H), 3.30 – 3.24 (m, 4H), 3.00 (t, J = 8.4 Hz, 2H), 2.30 (s, 3H). Example 11 – Preparation of N-(8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl) -4- (piperazin-1-yl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide diformate (Compound 11)

Step 1: Preparation of 6-bromo-8-methoxy-2-methylimidazo[1,2-a] pyridine [0262] To a mixture of 5-bromo-3-methoxypyridin-2-amine (15 g, 13.89 mmol) in IPA (150 mL) were added 1-bromo-2,2-dimethoxypropane (21.64 g, 118.23 mmol) and PPTS (1847 mg, 7.39 mmol). The reaction solution was stirred at 95 ℃ for 5 h. The reaction was diluted with DCM (300 mL), washed with brine (300 mL x 3), the organic layer was concentrated in vacuo to give title product (12 g, yield: 67%) as a brown solid. ESI-MS (M+H) ⁺: 243.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (d, J = 7.0 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.55 (s, 1H), 4.09 (s, 3H), 2.43 (d, J = 20.5 Hz, 3H). Step 2: Preparation of N-(8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl)-1,1- diphenylmethanimine [0263] To a mixture of 6-bromo-8-methoxy-2-methylimidazo[1,2-a] pyridine (5 g, 20.75 mmol) and diphenylmethanimine (5.6 g, 31.12 mmol) in 1,4-dioxane (50 mL) were added BINAP (2.5 g, 4.15 mmol), Pd(OAc)₂ (467 mg, 2.08 mmol) and Cs₂CO₃ (20.3 g, 62.25 mmol). The reaction solution was stirred at 100 ℃ for 16 h under N2. The reaction was diluted with H₂O (50 mL), extracted with EA (50 mL x 3), the organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA=1:1) to give title product (4.7 g, yield: 66%) as a brown oil. ESI-MS (M+H)⁺: 342.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.71 – 7.66 (m, 2H), 7.57 – 7.53 (m, 2H), 7.50 – 7.44 (m, 3H), 7.39 – 7.35 (m, 3H), 7.26 – 7.21 (m, 2H), 6.11 (d, J = 1.5 Hz, 1H), 3.66 (s, 3H), 2.22 (s, 3H). Step 3: Preparation of 8-methoxy-2-methylimidazo[1,2-a] pyridin-6-amine hydrochloride [0264] To a mixture of N-(8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl)-1,1- diphenylmethanimine (4.2 g, 12.32 mmol) in EA (20 mL) was added 4M HCl / EA (40 mL). The reaction solution was stirred at RT for 2 h. The mixture was filtered, washed with EA (20 mL) and dried in vacuo. The residue was beated with PE: EA (1:1, 20 mL) to give title product (2 g, 83%) as a white solid. ESI-MS (M+H)⁺: 178.0. ¹H NMR (400 MHz, DMSO- d₆) δ 8.08 – 7.95 (m, 1H), 7.91 – 7.77 (m, 1H), 7.16 – 7.02 (m, 1H), 6.03 (s, 3H), 4.02 (s, 3H), 2.40 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate [0265] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (100 mg, 0.33 mmol) and 8-methoxy-2-methylimidazo[1,2-a] pyridin-6-amine hydrochloride (175 mg, 0.97 mmol) in THF (3 mL) were added TEA (98 mg, 0.97 mmol) and triphosgene (288 mg, 0.97 mmol) at 0 ^oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL × 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (EA) to give title product (67 mg, 40%) as a yellow solid. ESI-MS (M+H)⁺: 508.3. Step 5: Preparation of N-(8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl) -4-(piperazin-1- yl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide diformate [0266] To a mixture of tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL × 3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / ACN) to give title product (24.18 mg, yield: 75 %) as a white solid. ESI-MS (M+H)⁺: 408.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.58 (d, J = 1.1 Hz, 1H), 8.27 (s, 2H), 7.94 (d, J = 6.1 Hz, 1H), 7.65 (s, 1H), 6.62 – 6.47 (m, 2H), 4.00 – 3.96 (m, 2H), 3.94 (s, 3H), 3.33 – 3.26 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.98 – 2.83 (m, 4H), 2.28 (s, 3H). Example 12 – Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 12)

Step 1: Preparation of 5-bromo-2,7-dimethyl-2H-indazole [0267] To a mixture of 5-bromo-7-methyl-2H-indazole (9.00 g, 42.65 mmol) in EA (150 mL) was added trimethyloxonium tetrafluoroborate (9.47 g, 68.98 mmol). The mixture was stirred at r.t for 2 h. The mixture was diluted with water (300 mL), extracted with EA (200 mL×2), the organic layer washed with brine, dried with Na₂SO₄ and concentration in vacuo to give title product (9.5 g, 96 %) as a white solid. ESI-MS (M+H)⁺: 225.1. ¹ H NMR (400 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.76 – 7.74 (m, 1H), 7.12 – 7.10 (m, 1H), 4.17 (s, 3H), 2.49 – 2.48 (m, 3H). Step 2: Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine [0268] A mixture of 5-bromo-2,7-dimethyl-2H-indazole (5 g, 22.22 mmol) in 1,4-dioxane (50 mL) were added diphenylmethanimine (4.22 g, 23.33 mmol), BINAP (2.77 g, 4.44 mmol), Cs₂CO₃ (14.48 g, 44.44 mmol), Pd(OAc)₂ (499 mg, 2.22 mmol). The mixture was stirred at 115 °C for 16 h. The mixture was diluted with H₂O (50 mL) and extracted with EA (50 mL x 3). The organic phase washed with brine (100 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude product was purified by silica gel column (PE/EA=5:1) to afford title product (1.24 g, 17 %) as a white solid. ESI-MS (M+H)⁺ : 326.3. ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.67 – 7.63 (m, 2H), 7.54 – 7.44 (m, 3H), 7.33 – 7.27 (m, 3H), 7.17 – 7.13 (m, 2H), 6.60 – 6.54 (m, 2H), 4.06 (s, 3H), 2.35 (s, 3H). Step 3: Preparation of 2,7-dimethyl-2H-indazol-5-amine hydrochloride [0269] To a solution of N-(2,7-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (924 mg, 2.84 mmol) in 3M HCl / EA (10 mL) was stirred at r.t for 4 h. The precipitate was filtered to give title product (500 mg, 89 %) as a white solid. ESI-MS (M+H)⁺ : 162.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 2H), 8.42 (s, 1H), 7.58 (d, J = 1.3 Hz, 1H), 6.95 (dd, J = 1.9, 1.1 Hz, 1H), 4.19 (s, 3H), 2.53 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((2,7-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0270] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and 2,7-dimethyl-2H-indazol-5-amine (110 mg, 0.66 mmol) in THF (10 mL) were added triethylamine (0.25 mL, 1.65 mmol) and triphosgene (200 mg, 0.66 mmol) at 0 ^oC. The mixture was stirred at RT for 16 h. The precipitate was filtered and dried in vacuum to give title product (60 mg, yield: 37.03%) as a white solid. ESI-MS (M+H)⁺: 492.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.18 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 1.4 Hz, 1H), 6.97 (s, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 3.97 (t, J = 8.9 Hz, 2H), 3.44 (d, J = 4.9 Hz, 4H), 3.29 – 3.24 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.48 (s, 3H), 1.43 (s, 9H). Step 5: Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxamide [0271] A mixture of tert-butyl 4-(1-((2,7-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.12 mmol) in 3M HCl / EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% NH₃·H₂O in H₂O / ACN) to give title product (33.28 mg, yield: 70.92%) as a white solid. ESI-MS (M+H)⁺: 392.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.18 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.84 (s, 1H), 6.97 (s, 1H), 6.55 (d, J = 6.1 Hz, 1H), 4.13 (s, 3H), 3.99 (t, J = 8.5 Hz, 2H), 3.38 – 3.35 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 3.05 – 2.99 (m, 4H), 2.49 (s, 3H). Example 13 – Preparation of N-(7-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide 2,2,2- trifluoroacetate (Compound 13)

Step 1: Preparation of methyl 2-amino-5-bromo-3-methylbenzoate [0272] To a mixture of methyl 2-amino-3-methylbenzoate (5 g, 30.30 mmol) in DCM (40 mL) was added NBS (5.9 g, 33.34 mmol). The resulting mixture was stirred at RT for 16 h. The mixture was diluted with water (40 mL), extracted with DCM (40 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title product (7 g, crude) as a brown solid. ESI-MS (M+H) ⁺: 244.0. ¹H NMR (400 MHz, DMSO- d₆) δ 7.70 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 2.4, 0.7 Hz, 1H), 6.53 (s, 2H), 3.79 (s, 3H), 2.13 (s, 3H). Step 2: Preparation of methyl 5-bromo-1H-indazole-7-carboxylate [0273] To a mixture of methyl 2-amino-5-bromo-3-methylbenzoate (5 g, 20.57 mmol) and KOAc (2116 mg, 21.59 mmol) in CHCl₃ (50 mL) was added Ac₂O (4 mL). The resulting mixture was stirred at 0 ^o C for 1 h. Isopentylnitrite (6 mL, 45.25 mmol) and 18-crown-6 (977 mg, 3.70 mmol) were added to the mixture. The resulting mixture was stirred at RT for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to give title product (5 g, crude) as a white solid. ESI-MS (M+H+CH₃CN) ⁺: 297.9. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J = 1.8 Hz, 1H), 8.28 – 8.23 (m, 1H), 8.02 (d, J = 1.8 Hz, 1H), 3.98 (s, 3H). Step 3: Preparation of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate [0274] To a mixture of methyl 5-bromo-1H-indazole-7-carboxylate (10.5 g, 41.18 mmol) in EA (100 mL) was added trimethyloxonium tetrafluoroborate (9.14 g, 61.76 mmol). The resulting mixture was stirred at RT for 2 h. The mixture was diluted with water (100 mL), extracted with EA (100 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title product (9.43 g, 85%) as a yellow solid. ESI-MS (M+H) ⁺: 269.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.30 (d, J = 1.9 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 4.24 (s, 3H), 3.90 (s, 3H). Step 4: Preparation of (5-bromo-2-methyl-2H-indazol-7-yl) methanol [0275] To a mixture of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate (7 g, 26.02 mmol) in dry-THF (70 mL) was added LiAlH₄ (52 mL, 52.04 mmol, 1.0 M in THF). The resulting mixture was stirred at 0 ^o C for 2 h. The mixture was quenched by water (2 mL) dropwise at 0 ^o C. Then added 15% NaOH (2 mL) and water (6 mL). The mixture was diluted with THF (20 mL) and Na₂SO₄. The resulting mixture was stirred at RT for 0.15 h. The mixture was filtered and the filtrate cake was washed with EA (10 mL) and DCM/MeOH (20 mL, 10:1). The filtrate was concentrated in vacuo to give title product (6 g, 96%) as a white solid. ESI-MS (M+H) ⁺: 241.0. Step 5: Preparation of 5-bromo-2-methyl-2H-indazole-7-carbaldehyde [0276] To a mixture of (5-bromo-2-methyl-2H-indazol-7-yl) methanol (5 g, 20.75 mmol) in DCM (50 mL) was added Dess-Martin periodinane (10.5 g, 24.89 mmol). The resulting mixture was stirred at RT for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude was purified by silica gel column (PE/EA=1:1) to give title product (2 g, Y: 40.8 %) as a yellow solid. ESI-MS (M+H) ⁺:239.0. ¹H NMR (400 MHz, DMSO- d₆) δ 10.43 (d, J = 26.9 Hz, 1H), 8.59 (s, 1H), 8.38 (d, J = 1.7 Hz, 1H), 7.98 – 7.87 (m, 1H), 4.26 (s, 3H). Step 6: Preparation of 5-bromo-7-(difluoromethyl)-2-methyl-2H-indazole [0277] To a mixture of 5-bromo-2-methyl-2H-indazole-7-carbaldehyde (1.8 g, 7.56 mmol) in DCM (15 mL) was added DAST (2069 mg, 12.86 mmol) at 0 ^oC. The resulting mixture was stirred at RT under N₂ (balloon) for 16 h. The mixture was quenched by sat. NaHCO₃ (15 mL) at 0 ^o C, extracted with DCM (15 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE / EA=2:1) to give title product (1.43 g, Y: 72 %) as a white solid. ESI-MS (M+H) ⁺:241.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J = 4.4 Hz, 1H), 8.18 (s, 1H), 7.52 (dd, J = 30.9, 3.0 Hz, 1H), 7.32 (t, J = 54.7 Hz, 1H), 4.23 (s, 3H). Step 7: Preparation of N-(7-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine [0278] To a mixture of 5-bromo-7-(difluoromethyl)-2-methyl-2H-indazole (5 g, 19.16 mmol) and diphenylmethanimine (5.2 g, 28.75 mmol) in 1,4-dioxane (50 mL) were added BINAP (2387 mg, 3.83 mmol), Pd(OAc)₂ (431 mg, 1.92 mmol) and Cs₂CO₃ (18.68 g, 57.48 mmol). The reaction solution was stirred at 100 ℃ for 16 h. The reaction was diluted with H₂O (50 mL), extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE : EA = 5 :1) to give title product (4.3 g, yield: 62.3%) as a yellow solid. ESI-MS (M+H)⁺: 362.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H), 7.71 – 7.66 (m, 2H), 7.55 – 7.45 (m, 4H), 7.34 – 7.29 (m, 3H), 7.19 – 7.16 (m, 2H), 7.05 – 6.97 (m, 2H), 4.12 (s, 3H). Step 8: Preparation of 7-(difluoromethyl)-2-methyl-2H-indazol-5-amine hydrochloride [0279] To a mixture of N-(7-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine (4 g, 11.08 mmol) in EA (20 mL) was added 4M HCl / EA (40 mL). The reaction solution was stirred at RT for 2 h. The precipitate was filtered, washed with EA (20 mL) and dried in vacuo. The crude was diluted with PE : EA (1 : 1, 20 mL) and stirred at RT for 1 h. The precipitate was filtered and dried in vacuo to give title product (2 g, 77.5%) as a yellow solid. ESI-MS (M+H)⁺: 198.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 2H), 8.63 (s, 1H), 8.02 (s, 1H), 7.50 (s, 1H), 7.43 – 7.28 (m, 1H), 4.25 (s, 3H). Step 9: Preparation of tert-butyl 4-(1-((7-(difluoromethyl)-2-methyl-2H-indazol-5-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate [0280] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (80 mg, 0.26 mmol) and 7-(difluoromethyl)-2-methyl-2H-indazol-5-amine hydrochloride (156 mg, 0.79 mmol) in THF (2 mL) were added TEA (80 mg, 0.79 mmol) and triphosgene (193 mg, 0.65 mmol) at 0 ^oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title product (120 mg, 28%) as a brown solid. ESI-MS (M+H)⁺: 528.3. Step 10: Preparation of N-(7-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide 2,2,2-trifluoroacetate [0281] To a mixture of tert-butyl 4-(1-((7-(difluoromethyl)-2-methyl-2H-indazol-5-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (100 mg, 0.19 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / ACN) to give title product (11.50 mg, yield: 13 %) as a white solid. ESI-MS (M+H)⁺: 428.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 2H), 8.41 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.61 (s, 1H), 7.34 (t, J = 55.0 Hz, 1H), 6.67 (s, 1H), 4.19 (s, 3H), 4.12 – 4.03 (m, 2H), 3.63 – 3.49 (m, 4H), 3.27 – 3.22 (m, 4H), 3.22 – 3.15 (m, 2H). Example 14 – Preparation of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 14)

Step 1: Preparation of 5-bromo-2-methyl-7-(trifluoromethyl)-2H-indazole [0282] To a mixture of 5-bromo-7-(trifluoromethyl)-1H-indazole (10 g, 37.74 mmol) in EA (100 mL) was added trimethyloxonium tetrafluoroborate (27.9 g, 188.68 mmoL). The mixture was stirred at RT for 16 h. The mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (9 g, Y: 85.5 %). ESI-MS (M+H)⁺:279.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.33 (s, 1H), 7.72 (s, 1H), 4.28 (s, 3H). Step 2: Preparation of N-(2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl)-1,1- diphenylmethanimine [0283] To a mixture of 5-bromo-2-methyl-7-(trifluoromethyl)-2H-indazole (4.5 g, 16.13 mmol) in 1,4-dioxane (50 mL) were added diphenylmethanimine (4.4 g, 24.19 mmol), BINAP (2.0 g, 3.23 mmol), Cs₂CO₃ (10.5 g, 32.26 mmol), Pd(OAc)₂ (363 mg, 1.61 mmol), the mixture was charged with N₂ for three times and stirred at 120 ^oC for 16 h under N₂. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA = 4:1) to give the title compound (5 g, Y: 81.8 %) as a yellow oil. ESI-MS (M+H)⁺:380.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 7.71 (s, 1H), 7.70 – 7.69 (m, 1H), 7.56 – 7.53 (m, 1H), 7.50 – 7.46 (m, 2H), 7.33 – 7.30 (m, 3H), 7.21 (s, 1H), 7.20 – 7.17 (m, 2H), 7.10 (s, 1H), 4.14 (s, 3H). Step 3: Preparation of 2-methyl-7-(trifluoromethyl)-2H-indazol-5-amine HCl salt [0284] To a mixture of N-(2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl)-1,1- diphenylmethanimine (4 g, 10.55 mmol) in EA (40 mL) was added 4M HCl / EA (40 mL). The mixture was stirred at RT for 16 h. The mixture was filtered and the residue was diluted with PE / EA (v:v=1:1, 20 mL) and stirred at RT for 2 h. The precipitate was filtered and dried to give the title compound (2.1 g, Y: 92.5 %) as a white solid. ESI-MS (M+H)⁺:216.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (s, 2H), 8.68 (s, 1H), 8.09 (s, 1H), 7.67 (s, 1H), 4.27 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((2-methyl-7-(trifluoromethyl)-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0285] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (120 mg, 0.39 mmol) in THF (5 mL) were added TEA (239 mg, 2.37 mmol), triphosgene (141 mg, 0.47 mmol), 2-methyl-7-(trifluoromethyl)-2H-indazol-5-amine HCl salt (85 mg, 0.39 mmol). The mixture was stirred at RT for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA = 3:1) to give the title compound (100 mg, Y: 46.4 %) as a yellow solid. ESI-MS (M+H)⁺:546.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.83 (s, 1H), 6.54 (d, J = 6.3 Hz, 1H), 4.21 (s, 3H), 4.02 – 3.97 (m, 2H), 3.46 – 3.43 (m, 4H), 3.30 – 3.28 (m, 4H), 3.14 – 3.11 (m, 2H), 1.43 (s, 9H). Step 5: Preparation of N-(2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate [0286] To a solution of tert-butyl 4-(1-((2-methyl-7-(trifluoromethyl)-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.15 mmol) in EA (3 mL) was added 4M HCl / EA (3 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (3.52 mg, 4.9 %) as a white solid. ESI-MS (M+H)⁺: 446.2. ¹H NMR (400 MHz, MeOD-d₄) δ 8.50 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.76 (s, 1H), 6.58 (d, J = 6.1 Hz, 1H), 4.24 (s, 3H), 4.12 – 4.08 (m, 2H), 3.47 – 3.44 (m, 4H), 3.28 – 3.25 (m, 4H), 3.16 (t, J = 8.5 Hz, 2H). Example 15 – Preparation of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 15)

Step 1: Preparation of 5-bromo-2-fluoro-4-methoxybenzaldehyde [0287] To a solution of 2-fluoro-4-methoxybenzaldehyde (50 g, 324.7 mol) in MeOH (500 mL), Br2 (103.9 g, 649.4 mol) was added dropwise at 0 ^oC, the mixture was stirred for 16 h at RT. The mixture was diluted with sat. Na₂SO₃ (1000 mL) at 0 ^oC, and stirred for 1 hour. The precipitate was filtered, washed with water and dried under vacuum to give crude product (66 g, 87.2 %) as a white solid, which was used to next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 12.7 Hz, 1H), 3.98 (s, 3H). Step 2: Preparation of (E)-5-bromo-2-fluoro-4-methoxybenzaldehyde oxime [0288] To a solution of 5-bromo-2-fluoro-4-methoxybenzaldehyde (100 g, 429.2 mmol) in THF (1000 mL) was added NH₂OH·HCl (35.5 g, 515 mmol) and K₂CO₃ (71.1 g, 515 mmol). The mixture was stirred at 40 ℃ for 16 h. The mixture was concentrated in vacuo to give crude. The crude was diluted with water (1000 mL) and stirred at r.t for 30 min, the precipitate was filtered and dried under vacuum to give crude title product (98 g, Y: 92.4%) as a white solid which was used to next step without further purification. ESI-MS (M+H) ⁺: 248.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.54 (s, 1H), 8.14 – 8.08 (m, 1H), 7.89 – 7.82 (m, 1H), 7.18 – 7.08 (m, 1H), 3.91 (s, 3H). Step 3: Preparation of 5-bromo-6-methoxy-1H-indazole [0289] To a solution of (E)-5-bromo-2-fluoro-4-methoxybenzaldehyde oxime (50 g, 202.4 mmol) in 1,4-dioxane (500 mL) was added N₂H₄ ^.H₂O (75.8 g, 1516 mmol). The mixture was stirred at 145℃ for 24 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA= 4:1) to give title product (20 g, Y: 43.7 %) as a yellow solid. ESI-MS (M+H) ⁺: 228.9. ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (s, 1H), 7.94 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H). Step 4: Preparation of 5-bromo-6-methoxy-2-methyl-2H-indazole [0290] To a solution of 5-bromo-6-methoxy-1H-indazole (30 g, 132 mmol) in EA (900 mL) was added BF₄.OMe₃ (29.3 g, 198 mmol). The mixture was stirred for 2 h at RT. The mixture was concentrated in vacuo and diluted with water (400 mL), extracted with EA (400 mL x 3). The organic phase was washed with brine (300 mL), dried over Na₂SO₄ and concentrated to give title product (25 g, Y: 78.6%) as a yellow solid which was used to next step without further purification. ESI-MS (M+H)⁺: 241.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (s, 1H), 7.98 (s, 1H), 7.09 (s, 1H), 4.11 (s, 3H), 3.87 (s, 3H). Step 5: Preparation of methyl 5-bromo-2-methyl-2H-indazol-6-ol [0291] A mixture of 5-bromo-6-methoxy-2-methyl-2H-indazole (20 g, 83.3 mmol) in BBr₃ (1M, 400 mL, 400 mmol) was stirred at r.t for 16 h. The mixture was quenched with MeOH (300 mL) at 0 ^oC and concentrated in vacuo. The residue was diluted with sat.Na₂CO₃ (300 mL) and stirred for 16 h. The precipitate was filtered and dried under vacuum to afford title compound (16 g, 85.4% yield) as a yellow solid. ESI-MS (M+H) ⁺: 229.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.83 (s, 1H), 6.85 (s, 1H), 4.02 (s, 3H). Step 6: Preparation of 5-bromo-6-ethoxy-2-methyl-2H-indazole [0292] To a solution of 5-bromo-2-methyl-2H-indazol-6-ol (50 g, 221 mmol) in DMF (1000 mL) was added K₂CO₃ (91.5 g, 663 mmol), CH₃CH₂I (87.3 g, 552.5 mmol) was added at 0 ^oC, the mixture was stirred at r.t for 16 h. The mixture was diluted with water (3000 mL), the precipitate was filtered, washed with water and dried to afford title compound (47 g, 83.3% yield) as an off-white solid. ESI-MS (M+H)⁺:257.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.97 (s, 1H), 7.06 (s, 1H), 4.15 – 4.05 (m, 5H), 1.39 (t, J = 6.9 Hz, 3H). Step 7: Preparation of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine [0293] To a solution of 5-bromo-6-ethoxy-2-methyl-2H-indazole (3 g, 11.76 mmol), diphenylmethanimine (2.56 g, 14.11 mmol), Cs₂CO₃ (11.49 g, 35.28 mmol) and Pd(OAc)₂ (26.40 mg, 0.12 mmol) in 1,4-dioxane (50 mL) was added BINAP (146 mg, 0.23 mmol), the mixture was stirred at 100 ^oC for 16 h under N₂. The mixture was concentrate in vacuo, the residue was purified by silica gel column chromatography (PE : EA= 1 : 4) to give title product (2.2 g, 52.63 %) as a yellow solid. ESI-MS (M+H) ⁺: 356.3. ¹H NMR (400 MHz, CDCl₃) δ 7.74 – 7.68 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.15 – 7.06 (m, 5H), 6.74 (s, 1H), 6.68 (s, 1H), 3.99 (s, 3 H), 3.87 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H). Step 8: Preparation of 6-ethoxy-2-methyl-2H-indazol-5-amine [0294] A solution of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (2.0 g, 5.63 mmol ) in 3M HCl / EA (15 mL) was stirred at RT for 2 h. The mixture was diluted with sat. Na₂CO₃ (40 mL), extracted with EA (60 mL × 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuo. The crude was purified by silica gel column chromatography (PE: EA= 1: 8) to give title product (800 mg, 74.35%) as a yellow solid. ESI-MS (M+H) ⁺: 192.2. ¹H NMR (400 MHz, CDCl₃) δ 7.45 (s, 1H), 6.83 (s, 1H), 6.67 (s, 1H), 4.04 (q, J = 14.0, 7.0 Hz, 2H), 4.00 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H). Step 9: Preparation of tert-butyl 4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0295] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and 6-ethoxy-2-methyl-2H-indazol-5-amine (125 mg, 0.66 mmol) in THF (10 mL) were added TEA (199 mg, 1.97 mmol) and triphosgene (194 mg, 0.66 mmol) at 0^oC. The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE: EA= 1: 3) to give the compound (100 mg, 58.36%) as an off-white solid. ESI-MS (M+H) ⁺: 522.3. ¹H NMR (400 MHz, CDCl₃) δ 11.95 (s, 1H), 8.53 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.66 (s, 1H), 6.91 (s, 1H), 6.29 (d, J = 6.0 Hz, 1H), 4.14 – 4.07 (m, 7H), 3.52 – 3.47 (m, 4H), 3.17 – 3.12 (m, 4H), 3.05 – 2.99 (m, 2H), 1.56 – 1.54 (m, 3H), 1.42 (s, 9H). Step 10: Preparation of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate [0296] To a mixture of tert-butyl 4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (90 mg, 0.17 mmol) in EA (5 mL) was added 3M HCl / EA (1.5 mL), the mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / CN) to give title product (23 mg, Y: 31.63 %) as a white solid. ESI-MS (M+H) ⁺: 422.2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.87 (d, J = 5.8 Hz, 1H), 6.97 (s, 1H), 6.53 (d, J = 6.0 Hz, 1H), 4.16 – 4.11 (m, 2H), 4.05 (s, 3H), 4.02 – 3.97 (m, 2H), 3.34 – 3.23 (m, 4H), 3.10 (t, J = 8.2 Hz, 2H), 3.03 – 2.85 (m, 4H), 1.52 (t, J = 6.8 Hz, 3H). Example 16 – Preparation of N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 16)

Step 1: Preparation of N-(4-bromo-2-methoxyphenyl)acetamide [0297] To a mixture of 4-bromo-2-methoxyaniline (20 g, 99.00 mmol) in EA (200 mL) was added Ac₂O (15.14 g, 148.51 mmol) at 0 ^oC. The mixture was stirred at r.t for 3 h. The mixture was diluted with H₂O (200 mL) and extracted with EA (200 mL x 3). The organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=5:1) to give title product (23 g, 95.8%) as a white solid. ESI-MS (M+H) ⁺: 244.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.6, 2.1 Hz, 1H), 3.85 (s, 3H), 2.09 (s, 3H). Step 2: Preparation of 6-bromo-4-methoxy-2-methylbenzo[d]oxazole [0298] To a solution of N-(4-bromo-2-methoxyphenyl)acetamide (25 g, 102.88 mmol) in AcOH : DMF (180 mL : 22 mL) were added Pd(OAc)₂ (2.5 g, 0.1wt), K₂S₂O₈ (37.65 g, 154.32 mmol), TfOH (15.43 g, 102.88 mmol) at 0^oC. The mixture was stirred at 100 ^oC for 16 h. The mixture was diluted with H₂O (250 mL) and extracted with DCM (250 mL x 3). The organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=9:1) to give title product (2.5 g, 10%) as a white solid. ESI-MS (M+H) ⁺: 243.9. Step 3: Preparation of N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine [0299] A mixture of 6-bromo-4-methoxy-2-methylbenzo[d]oxazole (250 mg, 1.00 mmol), Benzenemethanimine (280 mg, 1.55 mmol), Pd(OAc)₂ (23 mg, 0.10 mmol) and BINAP (128.7 mg, 0.21 mmol) in 1,4-dioxane (5 mL) was purged with N₂ for three times at RT. Then the mixture was stirred at 100 ^oC for 16 hours. The mixture was cooled to RT, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=10:1) to provide title product (300 mg, yield: 88%) as a yellow solid. ESI-MS (M+H)⁺: 345.1. ¹H NMR (400 MHz, CDCl₃) δ 7.72 – 7.64 (m, 2H), 7.40 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 7.4 Hz, 2H), 7.19 (t, J = 6.8 Hz, 3H), 7.06 (dd, J = 7.8, 1.6 Hz, 2H), 6.36 (d, J = 1.5 Hz, 1H), 6.15 (d, J = 1.5 Hz, 1H), 3.72 (s, 3H), 2.45 (s, 3H). Step 4: Preparation of 4-methoxy-2-methylbenzo[d]oxazol-6-amine [0300] To a solution of N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine (280 mg, 0.82 mmol) in EA (1 mL) was added 4 M HCl / EA (3 mL) at 0 ^oC. Then the mixture was stirred at RT for 2 hours. The precipitate was filtered, washed with EA. Then adjusted pH to 8 with Na₂CO₃ aqueous, the precipitate was filtered and dried under vacuum to afford title product (124 mg, yield: 82%) as a white solid. ESI-MS (M+H)⁺: 179.1. Step 5: Preparation of tert-butyl 4-(1-((4-methoxy-2-methylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0301] To a solution of 4-methoxy-2-methylbenzo[d]oxazol-6-amine (53.4 mg, 0.30 mmol), tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.20 mmol) in THF (1.5 mL) were added TEA (0.12 mL, 0.60 mmol) and triphosgene (89 mg, 0.30 mmol) at 0 ^oC. Then the mixture was stirred at 60 ^oC for 16 hours. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to provide title product (80 mg, yield: 78%) as a white solid. ESI-MS (M+H)⁺: 509.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 7.95 (s, 1H), 7.62 (s, 1H), 6.95 (s, 1H), 6.55 (s, 1H), 3.97 (s, 3H), 3.47 – 3.41 (m, 4H), 3.31 – 3.26 (m, 6H), 3.12 (t, J = 8.2 Hz, 2H), 2.54 (s, 3H), 1.43 (s, 9H). Step 6: Preparation of N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide [0302] To a solution of ert-butyl 4-(1-((4-methoxy-2-methylbenzo[d]oxazol-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) were added HMDS (32.2 mg. 0.20 mmol), TMSOTf (44.4 mg, 0.20 mmol) at 0 ^oC. Then the mixture was stirred at RT for 2 hours. The mixture was adjusted pH to 8 with Na₂CO₃ aqueous, extracted with DCM. The organic phase was concentrated in vacuo. The crude was purified by pre-HPLC (0.03% NH₃·H₂O in water / ACN) to give title product (12.28 mg, Y: 30%) as a white solid. ESI-MS (M+H)⁺: 409.2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 1.2 Hz, 1H), 6.94 (s, 1H), 6.51 (d, J = 6.2 Hz, 1H), 4.03 – 3.92 (m, 5H), 3.24 – 3.17 (m, 4H), 3.10 (t, J = 8.5 Hz, 2H), 2.85 – 2.76 (m, 4H), 2.54 (s, 3H). Example 17 – Preparation of N-(2,4-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 17)

Step 3

Step 1: Preparation of 6-bromo-2,4-dimethylbenzo[d]oxazole [0303] To a mixture of N-(4-bromo-2-methylphenyl)acetamide (10 g, 44.05 mmol) in AcOH (160 mL) and DMF (20 mL) were added TfOH (6.6 g, 44.05 mmol), K₂S₂O₈ (17.8 g, 66.08 mmol) and Pd(OAc)₂ (987 mg, 4.41 mmol), the mixture was charged with N₂ for three times and stirred at 100 ℃ for 16 h under N₂. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography eluted with (EA/PE=1:1) to give the title compound (3 g, 30 %) as a yellow solid. ESI-MS (M+H) ⁺:226.1. Step 2: Preparation of N-(2,4-dimethylbenzo[d]oxazol-6-yl)-1,1-diphenylmethanimine [0304] To a mixture of 6-bromo-2,4-dimethylbenzo[d]oxazole (2 g, 8.85 mmol) and diphenylmethanimine (2.4 g, 13.27 mmol) in 1,4-dioxane (50 mL) were added BINAP (1.10 g, 1.77 mmol), Pd(OAc)₂ (199 mg, 0.88 mmol) and Cs₂CO₃ (8.6 g, 26.55 mmol). The reaction solution was stirred at 100℃ for 16 h. The reaction was diluted with H₂O (100 mL), extracted with EA (100 mLx3), the organic layer was washed with brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA=7 %) to give title product (2 g, yield: 69.32%) as a yellow solid. ESI-MS (M+H) ⁺: 327.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.68 – 7.64 (m, 2H), 7.55 – 7.51 (m, 1H), 7.50 – 7.44 (m, 2H), 7.34 – 7.29 (m, 3H), 7.19 – 7.15 (m, 2H), 6.72 (d, J = 1.3 Hz, 1H), 6.57 – 6.55 (m, 1H), 2.50 (s, 3H), 2.33 (s, 3H). Step 3: Preparation of 2,4-dimethylbenzo[d]oxazol-6-amine [0305] A mixture of N-(2,4-dimethylbenzo[d]oxazol-6-yl)-1,1-diphenylmethanimine (1.9 g, 5.83 mmol) in 3M HCl / EA (10 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was diluted with water (5 mL), adjusted pH to 7~8 by sat. Na₂CO₃, extracted with EA (20 mL×3). The organic layer was washed with brine (30 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 40 %) to give title product (1 g, yield: 98.8 %) as a white solid. ESI-MS (M+H) ⁺: 163.1. ¹H NMR (400 MHz, DMSO-d₆) δ 6.52 (d, J = 1.6 Hz, 1H), 6.37 (dd, J = 1.8, 0.8 Hz, 1H), 5.11 (s, 2H), 2.47 (s, 3H), 2.32 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((2,4-dimethylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0306] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.49 mmol) and 2,4-dimethylbenzo[d]oxazol-6-amine (240 mg, 1.48 mmol) in THF (2 mL) were added TEA (247.4 mg, 2.45 mmol) and triphosgene (439.5 mg, 1.48 mmol) at 0 ^oC. The reaction mixture was stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (100 mg, 41%) as a yellow solid. ESI-MS (M+H) ⁺: 493.3. Step 5: Preparation of N-(2,4-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide [0307] A mixture of tert-butyl 4-(1-((2,4-dimethylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) in 4 M HCl / EA (5 mL) was stirred at RT for 15 min. The precipitate was filtered and purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title product (1.89 mg, yield: 2.4 %) as a white solid. ESI-MS (M+H) ⁺: 393.2. ¹H NMR (400 MHz, MeOD-d₄) δ 7.94 (d, J = 6.0 Hz, 1H), 7.86 (s, 1H), 7.05 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.05 (t, J = 8.6 Hz, 2H), 3.28 – 3.25 (m, 4H), 3.12 (t, J = 8.5 Hz, 2H), 2.97 – 2.92 (m, 4H), 2.60 (s, 3H), 2.51 (s, 3H). Example 18 – Preparation of N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 18) (_Ac)2 ^O H_{OAc, RT, 3 h Step 1}

S_{tep 2} c)2 F

3M HCl/EA d^{ioxane, 100 o} C_{, 16 h}

RT, 2 h S_{tep 3 Step 4}

Step 1: Preparation of N-(4-bromo-2,6-difluorophenyl)acetamide [0308] To a solution of 4-bromo-2,6-difluoroaniline (25 g, 0.12 mol) in HOAc (250 mL) was added (Ac)₂O (74 mL, 0.78 mol). The mixture was stirred at RT for 3 h. The reaction mixture was poured into ice water, the precipitate was filtered, washed with ice water and dried in vacuo to give title product (29 g, yield: 96.67%) as a white solid. ESI-MS (M+H)⁺: 251.9. ¹H NMR (400 MHz, DMSO-d₆) δ 9.73 (s, 1H), 7.56 – 7.51 (m, 2H), 2.06 (s, 3H). Step 2: Preparation of 6-bromo-4-fluoro-2-methylbenzo[d]oxazole [0309] To a solution of N-(4-bromo-2,6-difluorophenyl)acetamide (29 g, 0.12 mol) in 1- methylpyrrolidin-2-one (300 mL) was added Cs₂CO₃ (97.8 g, 0.36 mol). The mixture was stirred at 150 ^oC for 2 h. The mixture was diluted with water (300 mL) and extracted with EA (300 mL × 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title product (5.4 g, yield: 19.49%) as a yellow solid. ESI-MS (M+H) ⁺: 231.9. ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (d, J = 1.2 Hz, 1H), 7.55 (dd, J = 9.7, 1.6 Hz, 1H), 2.63 (s, 3H). Step 3: Preparation of N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-1,1-diphenylmethanimine [0310] A mixture of 6-bromo-4-fluoro-2-methylbenzo[d]oxazole (5.3 g, 23.1 mmol), diphenylmethanimine (5.82 mL, 34.7 mmol), Cs₂CO₃ (22.5 g, 69.3 mmol), Pd(OAc)₂ (520 mg, 2.31 mmol) and BINAP (2.88 g, 4.62 mmol) in 1,4-dioxane (80 mL) was stirred at 100 ^oC for 16 h. The mixture was diluted with water (300 mL) and extracted with EA (300 mL × 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluted with EA: PE = 1:1) to give title product (5 g, yield: 65.79%) as a white solid. ESI-MS (M+H)⁺: 331.1. ¹H NMR (400 MHz, DMSO-d₆) δ 7.70 – 7.65 (m, 2H), 7.55 – 7.54 (m, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.35 – 7.30 (m, 3H), 7.23 – 7.18 (m, 2H), 6.87 (d, J = 1.6 Hz, 1H), 6.64 (dd, J = 11.3, 1.6 Hz, 1H), 2.54 (s, 3H). Step 4: Preparation of 4-fluoro-2-methylbenzo[d]oxazol-6-amine HCl salt [0311] To a mixture of N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-1,1-diphenylmethanimine (2 g, 6.06 mmol) in MeOH (20 mL) was added 3.0 M HCl / EA (4 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (1 g, yield: 99.41%) as a white solid. ESI-MS (M+H)⁺: 167.1. ¹H NMR (400 MHz, DMSO-d₆) δ 6.54 (d, J = 1.7 Hz, 1H), 6.37 (dd, J = 12.6, 1.7 Hz, 1H), 5.51 (s, 2H), 2.49 (s, 3H). Step 5: Preparation of tert-butyl 4-(1-((4-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate [0312] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and 4-fluoro-2-methylbenzo[d]oxazol-6-amine (110 mg, 0.66 mmol) in THF (10 mL) were added triethylamine (0.25 mL, 1.65 mmol) and triphosgene (200 mg, 0.66 mmol) at 0 ^oC. The mixture was stirred at RT for 16 h. The precipitate was filtered, washed with THF (5 mL) and dried in vacuo to give title product (70 mg, yield: 42.94%) as a white solid. ESI-MS (M+H)⁺: 497.2. Step 6: Preparation of N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide [0313] A mixture of tert-butyl 4-(1-((4-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in 3.0 M HCl / EA (3 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% NH₃·H₂O in H₂O / ACN) to give title product (15.70 mg, yield: 39.65%) as a white solid. ESI-MS (M+H)⁺: 397.2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 12.2, 1.6 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 3.97 (t, J = 8.5 Hz, 2H), 3.26 – 3.17 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.84 – 2.78 (m, 4H), 2.60 (s, 3H).

Example 19 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(pyrrolidin-3-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride (Compound 19)

Step 1: Preparation of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,5-dihydro- 1H-pyrrole-1-carboxylate [0314] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2 g, 12.94 mmol), tert- butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (5.76 g, 19.41 mmol), K₂CO₃ (5.35 g, 38.82 mmol) and Pd(dppf)Cl₂ (944.3 mg, 1.29 mmol) in 1,4-dioxane / H₂O (30 mL / 6 mL) was stirred at 110 ^oC for 16 h. The mixture was cooled to RT, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (DCM : MeOH = 20 : 1) to provide title product (3.0 g, yield: 81%) as a yellow solid. ESI-MS (M+H)⁺: 288.3. ¹H NMR (400 MHz, DMSO-d₆) δ 7.68 (s, 1H), 7.58 – 7.46 (m, 1H), 6.40 (s, 1H), 6.27 (d, J = 10.1 Hz, 1H), 4.38 (s, 2H), 4.22 (s, 2H), 3.48 (t, J = 8.4 Hz, 2H), 3.10 (t, J = 8.4 Hz, 2H), 1.44 (s, 9H). Step 2: Preparation of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine-1- carboxylate tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine-1- carboxylate [0315] To a solution tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,5-dihydro- 1H-pyrrole-1-carboxylate (500 mg, 1.74 mmol) in THF (10 mL) was added Pd/C (250 mg, 50 % wt). The obtained solution was charged with H₂ for three times and stirred at RT for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (450 mg, yield: 89%) as a brown solid. ESI-MS (M+H)⁺:290.2. Step 3: Preparation of tert-butyl 3-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine-1-carboxylate [0316] To a solution of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine- 1-carboxylate (400 mg, 1.38 mmol) and 7-fluoro-2-methyl-2H-indazol-5-amine (683 mg, 4.14 mmol) in THF (8 mL) were added TEA (697 mg, 6.90 mmol) and triphosgene (614 mg, 2.07 mmol) at 0 ^oC. Then the mixture was stirred at RT for 16 hours. The mixture was allowed to cool down to room temperature and concentrated. The residue was purified by silica gel column chromatography (DCM : MeOH = 40 : 1) to provide title product (200 mg, yield: 30%) as white solid. ESI-MS (M+H)⁺:481.2. Step 4: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(pyrrolidin-3-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride [0317] To a solution of tert-butyl 3-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine-1-carboxylate (40 mg, 0.08 mmol) in EA (1 mL) was added 4 M HCl / EA (3 mL) at 0 ^oC. Then the mixture was stirred at RT for 2 hours. The precipitate was filtered, washed with EA and lyophilized to give title product (18 mg, 30%) as a yellow solid. ESI-MS (M+H) ⁺:381.2. ¹H NMR (400 MHz, MeOD-d₄) δ 8.32 (d, J = 2.6 Hz, 1H), 8.04 (d, J = 6.6 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 6.6 Hz, 1H), 7.33 (dd, J = 12.8, 1.5 Hz, 1H), 4.47 (t, J = 8.2 Hz, 2H), 4.24 (s, 3H), 3.87 – 3.70 (m, 2H), 3.68 – 3.62 (m, 1H), 3.54 – 3.37 (m, 4H), 2.62 – 2.51 (m, 1H), 2.25 – 2.13 (m, 1H). Example 20 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 20)

Step 1: Preparation of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate [0318] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (500 mg, 3.22 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (1.36 g, 6.45 mmol) in a sealed tube was stirred at 140 ^oC for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (MeOH : DCM = 15 %) to give title product (1 g, yield: 94%) as a yellow solid. ESI-MS (M+H)⁺: 331.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (d, J = 6.4 Hz, 1H), 6.48 – 6.40 (m, 1H), 6.17 (d, J = 6.5 Hz, 1H), 3.54 – 3.52 (m, 3H), 3.26 – 3.22 (m, 3H), 3.07 (s, 2H), 3.03 – 3.00 (m, 2H), 1.41 (s, 9H), 0.94 – 0.91 (m, 2H), 0.85 – 0.80 (m, 2H). Step 2: Preparation of tert-butyl 7-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5] octane-4-carboxylate [0319] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.61 mmol) and 7-fluoro-2-methyl-2H-indazol- 5-amine (199.95 mg, 1.21 mmol) in THF (20 mL) were added TEA (245 mg, 2.42 mmol) and triphosgene (359.2 mg, 1.21mmol) at 0 ^oC. The reaction mixture was stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (200 mg, 63.35 %) as a yellow solid. ESI-MS (M+H)⁺: 522.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 1H), 8.37 – 8.29 (m, 2H), 7.61 – 7.60 (m, 1H), 7.16 – 7.13 (m, 1H), 4.16 (s, 3H), 4.14 (m, 1H), 3.96 (t, J = 8.5 Hz, 1H), 3.59 – 3.52 (m, 2H), 3.45 (m, 1H), 3.32 – 3.26 (m, 3H), 3.12 – 3.06 (m, 2H), 1.42 (s, 9H), 0.96 – 0.91 (m, 2H), 0.87 – 0.82 (m, 2H). Step 3: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan-7- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate [0320] A mixture of tert-butyl 7-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.38 mmol) in 3 M HCl / EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (7.12 mg, yield: 4.45 %) as a yellow solid. ESI-MS (M+H)⁺: 422.1. ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 13.3, 1.6 Hz, 1H), 6.49 (d, J = 6.2 Hz, 1H), 4.16 (s, 3H), 3.95 (t, J = 9.0 Hz, 2H), 3.26 – 3.22 (m, 2H), 3.10 (s, 2H), 3.09 – 3.04 (m, 2H), 2.88 – 2.84 (m, 2H), 0.54 – 0.46 (m, 4H). Example 21 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound

Step 1: Preparation of 6-bromo-8-fluoro-2-methylimidazo[1,2-a] pyridine [0321] A mixture of 5-bromo-3-fluoropyridin-2-amine (50 g, 263 mmol) and 1- bromopropan-2-one (89.5 g, 658 mmol) in EtOH (500 mL) was stirred at 90 ^oC for 16 h. The reaction was cooled to r.t, the precipitated solids were collected by filtration and washed with EtOH. The cake was dissolved in H₂O and basified to pH 10 with Na₂CO₃, the precipitated solids were collected by filtration, washed with H₂O and dried by vacuum to afford title product (40 g, Y: 67%) as a white solid. ESI-MS (M+H)⁺: 229.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (d, J = 1.4 Hz, 1H), 7.82 – 7.73 (m, 1H), 7.38 (dd, J = 10.7, 1.5 Hz, 1H), 2.35 (d, J = 0.6 Hz, 3H). Step 2: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-1,1- diphenylmethanimine [0322] A mixture of 6-bromo-8-fluoro-2-methylimidazo[1,2-a] pyridine (15 g, 65.8 mmol), diphenylmethanimine (12.5 g, 69.1 mmol), Pd(OAc)₂ (1.48 g, 6.58 mmol), BINAP (8.2 g, 13.2 mmol) and Cs₂CO₃ (42.8 g, 131.6 mmol) in 1,4-dioxane (150 mL) was purged with N₂ for three times at rt. Then the mixture was stirred at 115 ^oC for 16 h. The mixture was cooled to r.t and filtered and filter was concentrated under reduce pressure. The residue was purified by silica gel column (0~50% EA in PE) to provide title product (16 g, yield: 74%) as light brown solid. ESI-MS (M+H)⁺: 330.4. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (d, J = 1.2 Hz, 1H), 7.68 (d, J = 7.3 Hz, 2H), 7.62 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.43 – 7.35 (m, 3H), 7.24 – 7.21 (m, 2H), 6.65 – 6.63 (m, 1H), 2.27 (s, 3H). Step 3: Preparation of 8-fluoro-2-methylimidazo[1,2-a] pyridin-6-amine [0323] To a solution of N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-1,1- diphenylmethanimine (15 g, 45.6 mmol) in EA (100 mL) at 0 ^oC was added 3M HCl-EA (90 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered and dissolved in H₂O and basified to pH 10 with Na₂CO₃, the precipitated solids were collected by filtration, washed with H₂O and dried by vacuum to afford title product (7.2 g, yield: 96%) as yellow solid. ESI-MS (M+H)⁺: 166.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.85 (s, 1H), 7.38 (d, J = 12.3 Hz, 1H), 2.43 (s, 3H). Step 4: Preparation of 4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine [0324] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.94 mmol) and 1-methylpiperazine (580 mg, 5.81 mmol) in DIEA (1.3 g, 9.70 mmol) was stirred at 140 ℃ for 16 h in sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH= 10: 1) to give title product (200 mg, Y: 47 %) as a yellow solid. ESI-MS (M+H) ⁺:219.1. ¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (d, J = 5.9 Hz, 1H), 6.06 (d, J = 6.0 Hz, 1H), 5.86 (s, 1H), 3.47 – 3.36 (m, 2H), 3.14 – 3.08 (m, 4H), 2.93 (t, J = 8.4 Hz, 2H), 2.42 – 2.35 (m, 4H), 2.20 (s, 3H). Step 5: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide [0325] To a mixture of 4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.37 mmol) in THF (5 mL) were added 8-fluoro-2-methylimidazo[1,2-a]pyridin-6- amine (182 mg, 1.10 mmol), TEA (187 mg, 1.85 mmol) and triphosgene (220 mg, 0.74 mmol) at 0 ℃. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title product (42.42 mg, yield: 27 %) as a white solid. ESI-MS (M+H)⁺:410.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.82 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.83 (d, J = 2.8 Hz, 1H), 7.23 (dd, J = 12.5, 1.5 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 3.97 (t, J = 8.6 Hz, 2H), 3.30 – 3.27 (m, 4H), 3.12 (t, J = 8.5 Hz, 2H), 2.46 – 2.39 (m, 4H), 2.32 (d, J = 5.1 Hz, 3H), 2.22 (s, 3H). Example 22 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 22)

Step 1: Preparation of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate [0326] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.94 mmol) and tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (832 mg,3.88 mmol) was stirred at 140 ^oC for 16 h in a sealed tube. The mixture was purified by column chromatography on silica gel (eluted with DCM : MeOH = 10 : 1) to give title product (200 mg, yield: 31.06%) as a white solid. ESI-MS (M+H) ⁺: 333.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (d, J = 5.9 Hz, 1H), 6.08 (d, J = 6.0 Hz, 1H), 5.94(s, 1H), 3.86 – 3.76 (m, 4H), 3.41 – 3.36 (m, 4H), 3.02 – 2.96 (m, 1H), 2.82 – 2.76 (m, 1H), 1.39 (s, 9H), 1.16 (s, 3H), 1.15 (s, 3H). Step 2: Preparation of tert-butyl (2R,6S)-4-(1-((7-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate [0327] To a solution of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (160 mg, 0.48 mmol) and 7-fluoro-2-methyl-2H-indazol-5- amine (158 mg, 0.96 mmol) in THF (15 mL) were added triethylamine (0.33 mL, 2.40 mmol) and triphosgene (285 mg, 0.96 mmol) at 0 ^oC. The mixture was stirred at RT for 16 h. The precipitate was filtered, washed with THF (5 mL) and dried in vacuo to give title product (60 mg, yield: 23.90%) as a white solid. ESI-MS (M+H) ⁺: 524.4. Step 3: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide [0328] A mixture of tert-butyl (2R,6S)-4-(1-((7-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (40 mg, 0.08 mmol) in 3.0 M HCl / EA (3 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% NH₃·H₂O in H₂O / ACN) to give title product (1.05 mg, yield: 3.10%) as a white solid. ESI-MS (M+H)⁺: 424.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.19 (d, J = 2.6 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.20 (dd, J = 12.9, 1.5 Hz, 1H), 6.59 (d, J = 6.1 Hz, 1H), 4.21 (s, 3H), 4.14 – 4.05 (m, 2H), 3.83 (d, J = 11.9 Hz, 2H), 3.42 – 3.36 (m, 2H), 3.20 – 3.12 (m, 2H), 2.80 (dd, J = 13.1, 11.4 Hz, 2H), 1.34 (d, J = 6.5 Hz, 6H). Example 23 – Preparation of N-(6,8-dimethylimidazo[1,2-a] pyrazin-2-yl) -4-(piperazin- 1-yl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.

C^{ompound 23} Step 1: Preparation of tert-butyl 4-(1-((6,8-dimethylimidazo[1,2-a] pyrazin-2-yl) carbamoyl) - 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate. [0329] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (100 mg, 0.33 mmol) and 6,8-dimethylimidazo[1,2-a] pyrazin-2-amine (159 mg, 0.97 mmol) in THF (3 mL) were added TEA (98 mg, 0.97 mmol) and triphosgene (288 mg, 0.97 mmol) at 0^oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column (PE / EA=1:3) to give title product (120 mg, 74%) as a yellow oil. ESI-MS (M+H)⁺: 493.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (s, 1H), 7.94 (d, J = 6.1 Hz, 1H), 7.77 (s, 1H), 6.94 (s, 1H), 6.57 (d, J = 6.2 Hz, 1H), 3.48 – 3.43 (m, 4H), 3.18 – 3.16 (m, 6H), 2.71 – 2.70 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(6,8-dimethylimidazo[1,2-a] pyrazin-2-yl) -4-(piperazin-1-yl) -2,3- dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate. [0330] To a mixture of tert-butyl 4-(1-((6,8-dimethylimidazo[1,2-a] pyrazin-2-yl) carbamoyl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (100 mg, 0.21 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (14.42 mg, yield: 17 %) as a white solid. ESI-MS (M+H)⁺: 393.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (s, 1H), 8.26 (s, 1H), 7.94 (d, J = 6.1 Hz, 1H), 7.83 (s, 1H), 7.62 (s, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.01 (t, J = 8.3 Hz, 2H), 3.36 – 3.28 (m, 4H), 3.15 (t, J = 8.4 Hz, 2H), 3.01 – 2.88 (m, 4H), 2.70 (s, 3H), 2.39 (s, 3H). Example 24 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of 4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. [0331] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.94 mmol) and 1-methylpiperazine (580 mg, 5.81 mmol) in DIEA (1.3 g, 9.70 mmol) was stirred at 140 ℃ for 16 h in sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH= 10: 1) to give title product (200 mg, Y: 47 %) as a yellow solid. ESI-MS (M+H) ⁺:219.1.¹H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 5.9 Hz, 1H), 6.06 (d, J = 6.0 Hz, 1H), 5.86 (s, 1H), 3.47 – 3.36 (m, 2H), 3.14 – 3.08 (m, 4H), 2.93 (t, J = 8.4 Hz, 2H), 2.42 – 2.35 (m, 4H), 2.20 (s, 3H). Step 2: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(4-methylpiperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0332] To a mixture of 7-fluoro-2-methyl-2H-indazol-5-amine (182 mg, 1.10 mmol) in THF (5 mL) were added 4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.37 mmol), TEA (187 mg, 1.85 mmol) and triphosgene (220 mg, 0.74 mmol) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (20.11 mg, yield: 13 %) as a white solid. ESI-MS (M+H) ⁺:410.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.18 (s, 1H), 7.92 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.26 (dd, J = 13.3, 1.6 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.16 (s, 3H), 3.99 – 3.94 (m, 2H), 3.31 – 3.27 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.45 – 2.39 (m, 4H), 2.22 (s, 3H).

Example 25 – Preparation of N-(5,7-dimethylimidazo[1,2-c]pyrimidin-2-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of ethyl 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylate. [0333] To a solution of 2,6-dimethylpyrimidin-4-amine (10 g, 81.30 mmol) in EtOH (100 mL) was added ethyl 3-bromo-2-oxopropanoate (24 g, 121.95 mmol). The reaction mixture was stirred at 80 ^oC for 16 h. The mixture was concentrated in vacuo and diluted with aq. NaHCO₃ (50 mL), extracted with DCM (100 mL×2), the organic was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by column gel chromatography (PE/EA=1/1) to give title product (2 g, 11.24 %) as a yellow solid. ESI-MS (M+H) ⁺: 220.2. Step 2: Preparation of 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylic acid. [0334] To a solution of ethyl 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylate (2 g, 9.13 mmol) in EtOH (20 mL) was added 2 M NaOH (20 mL) at 0 °C. The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and diluted with H₂O (30 mL), extracted with EA (20 mL×2). The aqueous phase was adjust to PH =2~3, the precipitate was filtered to give title product (1.6 g, 91.95 %) as a yellow solid. ESI-MS (M+H) ⁺: 192.2. Step 3: Preparation of tert-butyl (5,7-dimethylimidazo[1,2-c]pyrimidin-2-yl)carbamate. [0335] To a solution of 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylic acid (1 g, 5.24 mmol) in DCM (20 mL) were added TEA (1.6 g, 15.72 mmol) and DPPA (1.6 g, 5.76 mmol). The mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo, the residue was diluted with t-BuOH (20 mL) and stirred at 85 ^oC for 16 h. The mixture was concentrated in vacuo and the residue was purified by column gel chromatography (PE/EA=1/1) to give title product (200 mg, 14.60 %) as a yellow solid. ESI-MS (M+H) ⁺: 263.1.¹H NMR (400 MHz, CDCl₃) δ 8.34 – 8.16 (m, 1H), 7.55 (s, 1H), 7.04 (s, 1H), 2.68 (s, 3H), 2.42 (s, 3H), 1.49 (s, 9H). Step 4: Preparation of 5,7-dimethylimidazo[1,2-c]pyrimidin-2-amine. [0336] To a solution of tert-butyl (5,7-dimethylimidazo[1,2-c]pyrimidin-2-yl)carbamate (200 mg, 0.76 mmol) in EA (2 mL) was added 4 M HCl / EA (2 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered, washed with EA (5 mL) and concentrated in vacuo. The crude was diluted with aq. Na₂CO_3, the precipitate was filtered to give title product (100 mg, 81.30 %) as a yellow solid. ESI-MS (M+H) ⁺: 163.3.¹H NMR (400 MHz, DMSO-d₆) δ 6.91 (s, 1H), 6.66 (s, 1H), 5.25 (s, 2H), 2.58 (s, 3H), 2.34 (s, 3H). Step 5: Preparation of tert-butyl 4-(1-((5,7-dimethylimidazo[1,2-c]pyrimidin-2- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0337] To a solution of 5,7-dimethylimidazo[1,2-c]pyrimidin-2-amine (80 mg, 0.31 mmol) and tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (94 mg, 0.31 mmol) in THF (5 mL) were added TEA (94 mg, 0.93 mmol) and triphosgene (92 mg, 0.31 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by column gel chromatography (PE/EA=0/1) to give title product (100 mg, 66.45 %) as a yellow solid. ESI-MS (M+H) ⁺: 493.2. Step 6: Preparation of N-(5,7-dimethylimidazo[1,2-c]pyrimidin-2-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0338] To a solution of tert-butyl 4-(1-((5,7-dimethylimidazo[1,2-c]pyrimidin-2- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) in EA (2 mL) was added 4 M HCl / EA (3 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered, washed with EA (5 mL) and lyophilized to give title product (74 mg, 85.06 %) as a yellow solid. ESI-MS (M+H) ⁺: 393.2.¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 2H), 8.01 – 7.92 (m, 1H), 7.80 (s, 1H), 7.30 (s, 1H), 6.85 – 6.58 (m, 1H), 4.20 – 4.01 (m, 2H), 3.72 – 3.43 (m, 4H), 3.28 – 3.16 (m, 6H), 2.80 (s, 3H), 2.46 (s, 3H). Example 26 – Preparation of N-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-(piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

C_{ompound 26} Step 1: Preparation of tert-butyl 4-(1-((4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0339] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) in THF (5 mL) were added 4,6-dimethylpyrazolo[1,5- a]pyrazin-2-amine (107 mg, 0.66 mmol), TEA (196 mg, 1.65 mmol) and triphosgene (196 mg, 0.66 mmol) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: EA=1:1) to give title product (80 mg, yield: 49 %) as a yellow solid. ESI-MS (M+H) ⁺:493.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.31 (s, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.98 (s, 1H), 6.56 (d, J = 6.2 Hz, 1H), 4.02 (t, J = 8.6 Hz, 2H), 3.47 – 3.42 (m, 4H), 3.30 – 3.27 (m, 4H), 3.15 (t, J = 8.5 Hz, 2H), 2.62 (s, 3H), 2.38 (s, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0340] To a mixture of tert-butyl 4-(1-((4,6-dimethylpyrazolo[1,5-a]pyrazin-2- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (70 mg, 0.14 mmol) in EA (5 mL) was added 4M HCl / EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and lyophilized to give title compound (31.71 mg, 52 %) as a white solid. ESI-MS (M+H)⁺:393.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 9.06 (s, 2H), 8.41 (s, 1H), 8.00 (s, 1H), 7.08 (s, 1H), 6.65 (s, 1H), 4.11 – 4.08 (m, 2H), 3.56 – 3.48 (m, 4H), 3.24 – 3.16 (m, 6H), 2.68 (s, 3H), 2.41 (s, 3H). Example 27 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(1- methylpyrrolidin-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

C^{ompound 27} Step 1: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(1-methylpyrrolidin-3-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0341] To a solution of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(pyrrolidin-3-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (60 mg, 0.16 mmol) in MeOH / THF (2 mL / 2 mL) were added (HCHO)_n (14 mg, 0.48 mmol) and AcOH (48 mg, 0.80 mmol). The mixture was stirred at r.t for 1h. Then NaBH₃CN (30 mg, 0.80 mmol) was added to the mixture and stirred at 50 ^oC for 16 h. The mixture was concentrated in vacuo, the residue was purified by silica gel column (DCM: MeOH = 20:1) to provide title product (20 mg, yield: 32%) as a white solid. ESI-MS (M+H)⁺:395.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.57 (s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 5.5 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.28 (dd, J = 13.3, 1.5 Hz, 1H), 6.98 (d, J = 5.6 Hz, 1H), 4.17 (s, 3H), 4.04 (t, J = 8.6 Hz, 2H), 3.10 (t, J = 8.6 Hz, 2H), 2.80 – 2.67 (m, 2H), 2.59 – 2.52 (m, 3H), 2.32 (s, 3H), 2.30 – 2.25 (m, 1H), 1.75 (dd, J = 13.2, 7.4 Hz, 1H). Example 28 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(1- methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(1-methylpiperidin-4-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0342] A mixture of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperidin-4-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide (100 mg, 0.25 mmol), (CH₂O)_n (68 mg, 0.76 mmol), TEA (76 mg, 0.76 mmol) and NaBHCN (45.6 mg, 0.76 mmol) in MeOH (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (35.59 mg, yield: 34.89%) as a pink solid. ESI-MS (M+H) ⁺: 409.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (s, 1H), 8.37 (d, J = 2.7 Hz, 1H), 8.21 (s, 1H), 8.10 (d, J = 5.5 Hz, 1H), 7.73 (d, J = 1.3 Hz, 1H), 7.28 (dd, J = 13.3, 1.3 Hz, 1H), 6.90 (d, J = 5.6 Hz, 1H), 4.17 (s, 3H), 4.05 (t, J = 8.6 Hz, 2H), 3.11 (t, J = 8.5 Hz, 2H), 2.97 (d, J = 11.2 Hz, 2H), 2.61 – 2.52 (m, 1H), 2.29 (s, 3H), 2.17 – 2.11 (m, 2H), 1.75 – 1.68 (m, 4H). Example 29 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperidin-4-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate. [0343] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2 g, 12.94 mmol), tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.9 g, 25.87 mmol), Pd(dppf)Cl₂ (948 mg, 1.29 mmol) and K₂CO₃ (5.35 mg,38.32 mmol) in 1,4-dioxane / H₂O (20 mL / 5 mL) was stirred at 100 ^oC for 16 h under N₂. The mixture was diluted with water (30 mL), extracted with EA (30 mL×3). The organic layer was washed with brine (30 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 71 %) to give title product (1.7 g, yield: 43.64 %) as a yellow solid. ESI-MS (M+H) ⁺: 302.2.¹H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 5.5 Hz, 1H), 6.36 (d, J = 5.6 Hz, 1H), 5.76 (br.s, 1H), 4.00 – 3.95 (m, 2H), 3.50 (t, J = 5.5 Hz, 2H), 3.41 (t, J = 8.4 Hz, 2H), 3.03 (t, J = 8.3 Hz, 2H), 2.37 (d, J = 1.5 Hz, 2H), 2.37 (d, J = 1.5 Hz, 2H), 1.43 (s, 9H). Step 2: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1- carboxylate. [0344] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.1 g, 3.32 mmol), Pd(OH)₂ (250 mg) and Pd/C (250 mg) in THF (50 mL) was stirred at RT for 2 h under H₂. The precipitate was filtered and the filtrate was dried in vacuo to give title product (1 g, yield: 99.41 %) as a white solid. ESI-MS (M+H) ⁺: 304.1.¹H NMR (400 MHz, DMSO- d₆) δ 7.62 (d, J = 5.5 Hz, 1H), 6.30 (d, J = 5.5 Hz, 1H), 6.21 (s, 1H), 4.05 (d, J = 11.3 Hz, 2H), 3.43 (t, J = 8.1 Hz, 2H), 2.96 (t, J = 8.4 Hz, 2H), 2.84 – 2.70 (m, 2H), 2.63 – 2.57 (m, 1H), 1.68 – 1.61 (m, 2H), 1.46 – 1.38 (m, 11H). Step 3: Preparation of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1-carboxylate. [0345] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1- carboxylate (437,6 mg, 1.44 mmol), phenyl (7-fluoro-2-methyl-2H-indazol-5-yl)carbamate (343 mg 1.20 mmol) and DMAP (14.6 mg, 0.12 mmol) in THF (10 mL) was stirred at 80 ^oC for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE= 100%) to give title product (400 mg, yield: 60.52 %) as a white solid. ESI-MS (M+H) ⁺: 495.2.¹H NMR (400 MHz, DMSO- d₆) δ 11.55 (s, 1H), 8.37 (s, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.74 (s, 1H), 7.28 (d, J = 13.1 Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H), 4.17 (s, 3H), 4.08 – 4.03 (m, 3H), 3.15 – 3.11 (m, 2H), 2.84 – 2.76 (m, 4H), 1.74 – 1.69 (m, 2H), 1.56 – 1.50 (m, 2H), 1.43 (s, 9H). Step 4: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperidin-4-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0346] A mixture of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1-carboxylate (350 mg, 0.71 mmol) in 3M HCl / EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered to give title product (200 mg, yield: 71.31 %) as a pink solid. ESI-MS (M+H) ⁺: 395.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H), 9.02 (s, 2H), 8.38 (d, J = 2.8 Hz, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.29 (dd, J = 13.3, 1.5 Hz, 1H), 6.85 (d, J = 5.6 Hz, 1H), 4.17 (s, 3H), 4.11 – 4.10 (m, 2H), 3.41 – 3.35 (m, 2H), 3.19 – 3.13 (m, 2H), 3.06 – 2.93 (m, 3H), 1.96 _{– 1.85 (m, 4H).} Example 30 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- (methylamino)azetidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0347] To a solution of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.94 mmol) and tert-butyl azetidin-3-yl(methyl)carbamate (541 mg, 2.91 mmol) was added DIEA (2 mL). The reaction mixture was stirred at 120 °C for 16 h in a sealed tube. The mixture was concentrated in vacuo and purified by column gel chromatography (PE/EA=1/2) to give title product (200 mg, 34.01 %) as a yellow solid. ESI-MS (M+H) ⁺: 305.1. Step 2: Preparation of tert-butyl (1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-yl)(methyl)carbamate. [0348] To a solution of tert-butyl (1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3- yl)(methyl)carbamate (200 mg, 0.66 mmol) and 7-fluoro-2-methyl-2H-indazol-5-amine (109 mg, 0.66 mmol) in THF (5 mL) were added TEA (200 mg, 1.98 mmol) and triphosgene (196 mg, 0.66 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column chromatography (PE/EA=0/1) to give title product (50 mg, 15.34 %) as a yellow solid. ESI-MS (M+H) ⁺: 496.4. Step 3: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3-(methylamino)azetidin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0349] To a solution of tert-butyl (1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-yl)(methyl)carbamate (50 mg, 0.10 mmol) in EA (2 mL) was added 4 M HCl / EA (0.5 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (2 mg, 4.49 %) as a yellow solid. ESI-MS (M+H) ⁺: 396.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.42 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 5.9 Hz, 1H), 7.68 (s, 1H), 7.18 (d, J = 13.6 Hz, 1H), 6.07 (d, J = 5.9 Hz, 1H), 4.39 (t, J = 7.9 Hz, 2H), 4.20 (s, 3H), 4.08 – 3.99 (m, 4H), 3.95 – 3.87 (m, 1H), 3.14 (t, J = 8.6 Hz, 2H), 2.57 (s, 3H). Example 31 – Preparation of 4-(piperazin-1-yl)-N-(quinolin-4-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxamide formate.

C_{ompound 31} Step 1: Preparation of tert-butyl 4-(1-(quinolin-4-ylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate. [0350] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and quinolin-4-amine (48 mg, 0.33 mmol) in THF (5 mL) were added TEA (100 mg, 0.99 mmol) and triphosgene (98 mg, 0.33 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column chromatography (PE/EA=1/2) to give title product (50 mg, 32.05 %) as a yellow solid. ESI-MS (M+H) ⁺: 475.4.¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (d, J = 5.1 Hz, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 6.1 Hz, 1H), 8.05 – 7.99 (m, 1H), 7.83 – 7.72 (m, 2H), 6.64 (d, J = 6.2 Hz, 1H), 4.09 – 4.04 (m, 2H), 3.49 – 3.44 (m, 4H), 3.37 – 3.35 (m, 4H), 3.20 – 3.19 (m, 2H), 1.43 (s, 9H). Step 2: Preparation of 4-(piperazin-1-yl)-N-(quinolin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine-1-carboxamide formate. [0351] To a solution of tert-butyl 4-(1-(quinolin-4-ylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.11 mmol) in EA (2 mL) was added 4 M HCl / EA (0.5 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (27 mg, 60.95 %) as a yellow solid. ESI-MS (M+H) ⁺: 375.2.¹H NMR (400 MHz, DMSO-d₆) δ 13.06 (s, 1H), 8.76 (d, J = 5.1 Hz, 1H), 8.33 (d, J = 5.1 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H), 8.21 (s, 1H), 8.14 (d, J = 6.1 Hz, 1H), 8.04 – 7.97 (m, 1H), 7.84 – 7.71 (m, 2H), 6.62 (d, J = 6.2 Hz, 1H), 4.06 (t, J = 8.5 Hz, 2H), 3.33 – 3.29 (m, 4H), 3.20 – 3.15 (m, 2H), 2.92 – 2.84 (m, 4H). Example 32 – Preparation of N-(1-methyl-1H-pyrrolo[2,3-b] pyridin-4-yl)-4-(piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.

C^{ompound 32} Step 1: Preparation of tert-butyl 4-(1-((1-methyl-1H-pyrrolo[2,3-b] pyridin-4-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate. [0352] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (100 mg, 0.33 mmol) and 1-methyl-1H-pyrrolo[2,3-b] pyridin-4-amine (60 mg, 0.39 mmol) in THF (2 mL) were added TEA (99 mg, 0.99 mmol) and triphosgene (116 mg, 0.39 mmol) at 0^oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 2: 1) to give title product (120 mg, 70%) as a yellow solid. ESI-MS (M+H) ⁺: 478.3. Step 2: Preparation of N-(1-methyl-1H-pyrrolo[2,3-b] pyridin-4-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate. [0353] To a mixture of tert-butyl 4-(1-((1-methyl-1H-pyrrolo[2,3-b] pyridin-4-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (100 mg, 0.21 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by Prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (12.75 mg, yield: 16 %) as a yellow solid. ESI-MS (M+H) ⁺: 378.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 8.31 (s, 1H), 8.18 – 8.06 (m, 2H), 7.86 (d, J = 4.5 Hz, 1H), 7.45 (s, 1H), 6.58 (s, 2H), 4.03 – 4.00 (m, 2H), 3.81 (s, 3H), 3.39 – 3.27 (m, 4H), 3.18 – 3.08 (m, 2H), 3.06 – 2.84 (m, 4H). Example 33 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 7-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5] octane-4- carboxylate. [0354] To a solution of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol) and 8-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (99 mg, 0.60 mmol) in THF (10 mL) were added TEA (153 mg, 1.51 mmol) and triphosgene (179 mg, 0.60 mmol) at 0^oC. The mixture was stirred at r.t for 3 h. The mixture was concentrated and purified by silica gel column chromatography (PE: EA= 1: 3) to give the compound (110 mg, 36.90%) as a yellow solid. ESI-MS (M+H) ⁺: 522.3.¹H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.24 (d, J = 12.6 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 3.99 – 3.94 (m, 2H), 3.59 – 3.54 (m, 4H), 3.18 – 3.16 (m, 2H), 3.11 – 3.07 (m, 2H), 2.32 (s, 3H), 1.42 (s, 9H), 0.96 – 0.92 (m, 2H), 0.86 – 0.83 (m, 2H). Step 2: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0355] To a mixture of tert-butyl 3-((1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidine-1-carboxylate (100 mg, 0.19 mmol) in EA (3 mL) was added 3M HCl / EA (1 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (43 mg, Y: 53.21%) as a white solid. ESI-MS (M+H) ⁺: 422.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 8.82 (s, 1H), 8.19 (s, 1H), 7.89 (d, J = 5.6 Hz, 1H), 7.83 (s, 1H), 7.23 (d, J = 12.3 Hz, 1H), 6.51 (d, J = 5.8 Hz, 1H), 4.00 – 3.93 (m, 2H), 3.28 – 3.22 (m, 2H), 3.15 – 3.04 (m, 4H), 2.92 – 2.84 (m, 2H), 2.33 (s, 3H), 0.51 (d, J = 8.4 Hz, 4H). Example 34 – Preparation of N-(6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of 5-bromo-6-(cyclopropylmethoxy)-2-methyl-2H-indazole. [0356] To a mixture of 5-bromo-2-methyl-2H-indazol-6-ol (3.0 g, 13.22 mmol) and (bromomethyl)cyclopropane (2.14 g, 15.86 mmol) in DMF (30 mL) was added K₂CO₃ (5.47 g, 39.66 mmol). The mixture was stirred at r.t for 16 h. The mixture was diluted with water (30 mL). The precipitate was filtered, washed with water and dried in vacuo to give title product (3.5 g, 80.76 %) as a yellow solid. ESI-MS (M+H)⁺: 283.1. Step 2: Preparation of N-(6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine. [0357] A mixture of 5-bromo-6-(cyclopropylmethoxy)-2-methyl-2H-indazole (3.5 g, 12.46 mmol), diphenylmethanimine (5.64 g, 31.15 mmol) and Cs₂CO₃ (8.12 g, 24.92 mmol) in 1,4- dioxane (40 mL) were added Pd(OAc)₂ (285.04 mg, 1.25 mmol) and BINAP (1.55 g, 2.49 mmol). The mixture was stirred at 100 ^oC for 16 h under N₂. The mixture was diluted with H₂O (40 mL) and extracted with EA (40 mL x 3). The organic phase was washed with brine (40 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (1.4 g, 29.45%) as a brown solid. ESI-MS (M+H)⁺:382.2. Step 3: Preparation of 6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-amine hydrochloride. [0358] A mixture of N-(6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine (1.4 g, 3.67 mmol) in 3M HCl/EA (15 mL) was stirred at rt for 2 h. The precipitate was filtered, washed with EA and dried in vacuo to give title product (800 mg, 86.16 %) as a brown solid. ESI-MS (M+H)⁺: 218.3.¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 2H), 8.38 (s, 1H), 7.91 (s, 1H), 7.13 (s, 1H), 4.12 (s, 3H), 3.99 (d, J = 6.7 Hz, 2H), 1.38 – 1.26 (m, 1H), 0.66 – 0.56 (m, 2H), 0.51 – 0.39 (m, 2H). Step 4: Preparation of tert-butyl 4-(1-((6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0359] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.44 mmol), 6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-amine hydrochloride (111.32 mg, 0.44 mmol) in THF (10 mL) were added TEA (133.32 mg, 1.32 mmol) and triphosgene (156.82 mg, 0.53 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (80 mg, 33.23%) as a white solid. ESI-MS (M+H) ⁺: 548.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 8.44 (s, 1H), 8.10 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 6.93 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.05 (s, 3H), 4.03 – 3.98 (m, 2H), 3.96 – 3.91 (m, 2H), 3.47 – 3.43 (m, 4H), 3.28 – 3.08 (m, 6H), 1.43 (s, 9H), 1.24 – 1.11 (m, 1H), 0.71 – 0.60 (m, 2H), 0.43 – 0.39 (m, 2H). Step 5: Preparation of N-(6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0360] To a mixture of tert-butyl 4-(1-((6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.15 mmol) in 3M HCl/EA (5 mL) was stirred at r.t for 2 h. The precipitate was filtered, washed with EA and dried in vacuo to give title product (54 mg, 74.38 %) as a white solid. ESI-MS (M+H)⁺: 448.3.¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 2H), 8.42 (s, 1H), 8.21 (s, 1H), 7.92 (d, J = 5.9 Hz, 1H), 6.97 (s, 1H), 6.61 (d, J = 5.2 Hz, 1H), 4.08 (s, 3H), 4.07 – 4.01 (m, 2H), 3.97 (d, J = 6.8 Hz, 2H), 3.58 – 3.48 (m, 4H), 3.22 – 3.14 (m, 6H), 1.43 – 1.34 (m, 1H), 0.66 – 0.61 (m, 2H), 0.45 – 0.40 (m, 2H). Example 35 – Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of 6-fluoro-2-methyl-5-nitro-2H-indazole. [0361] To a solution of 6-fluoro-5-nitro-1H-indazole (1.69 g, 9.34 mmol) in EA (50 mL) were added trimethyloxonium tetrafluoroborate (2.07 g, 14.01 mmol) at 0℃, The mixture was stirred at r.t for 5 h. The mixture was diluted with sat. NaHCO₃ (20 mL), extracted with EA (30 mL). The organic layer was washed with brine, dried and concentrated to afford the title product (1.2 g, 65%) as a yellow solid. ESI-MS (M+CAN+H)⁺ 237.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d, J = 7.6 Hz, 1H), 8.77 (s, 1H), 7.68 (d, J = 12.7 Hz, 1H), 4.23 (s, 3H). Step 2: Preparation of 6-fluoro-2-methyl-2H-indazol-5-amine. [0362] To a solution of 6-fluoro-2-methyl-5-nitro-2H-indazole (1.2 g, 6.15 mmol) in MeOH (30 mL) and DCM (30 mL) was added Pd / C (880 mg, 10% w.t). The mixture was charged with H₂ for three times and stirred at r.t for 16 h. The mixture was filtered and the filtrate concentration to afford title product (500 mg, Y=49%) as a gray solid. ESI-MS (M+H)⁺ 166.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (s, 1H), 7.19 (d, J = 12.3 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 4.87 (s, 2H), 4.03 (s, 3H). Step 3: Preparation of tert-butyl 4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0363] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) in THF (5 mL) were added 6-fluoro-2-methyl-2H-indazol- 5-amine (163 mg, 0.99 mmol) and TEA (167 mg, 1.65 mmol), triphosgene (196 mg, 0.66 mmol) at 0℃, The mixture was stirred at r.t for 16 h. After concentration, the residue was diluted with water (10 mL), extracted with DCM (10 mLx3). The organic layer washed with brine (10 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE=3:1) to give title product (70 mg, 42 %) as a yellow solid. ESI-MS (M+H)⁺ 496.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (d, J = 2.8 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 6.58 – 6.48 (m, 1H), 4.12 (s, 3H), 4.03 – 3.98 (m, 2H), 3.47 – 3.42 (m, 4H), 3.30 – 3.27 (m, 4H), 3.17 – 3.12 (m, 2H), 1.43 (s, 9H). Step 4: Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0364] To a solution of tert-butyl 4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (5 mL) was added 4M HCl / EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (4.17 mg, 10%) as a white solid. ESI-MS (M+H) ⁺:396.1. ¹H NMR (400 MHz, MeOD-d₄) δ 8.42 (d, J = 7.7 Hz, 2H), 8.15 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.31 (d, J = 11.8 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 4.17 (s, 3H), 4.12 (d, J = 8.8 Hz, 2H), 3.54 – 3.45 (m, 4H), 3.30 – 3.28 (m, 4H), 3.21 – 3.16 (m, 2H). Example 36 – Preparation of N-(5-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of 5-fluoro-2-methylbenzo[d]oxazol-6-amine. [0365] To a mixture of 5-fluoro-2-methyl-6-nitrobenzo[d]oxazole (1 g, 5.10 mmol) in THF (30 mL) and MeOH (10 mL) was added Raney-Nickel (5 mL), the mixture was stirred at room temperature for 3h under H_2. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (820 mg, 94.44%) as an amaranth solid. ESI-MS (M+H) ⁺: 167.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.31 (d, J = 11.0 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 5.25 (s, 2H), 3.33 (s, 3H). Step 2: Preparation of tert-butyl 4-(1-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0366] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.09 mmol) and 5-fluoro-2-methylbenzo[d]oxazol-6-amine (163 mg, 0.98 mmol) in THF (4mL) were added TEA (249 mg, 2.48 mmol) and triphosgene (292 mg, 0.98 mmol) at 0^oC. The mixture was stirred at r.t. for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EA= 1: 3) to give title compound (160 mg, 65.39 %) as a white solid. ESI-MS (M+H) ⁺: 497.2. Step 3: Preparation of N-(5-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0367] To a mixture of tert-butyl 4-(1-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (140 mg, 0.28 mmol) in DCM (5 mL) were added HMDS (136 mg, 0.84 mmol) and TMSOTf (187 mg, 0.184 mmol) at 0^oC, the mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with MeOH (5 mL), then filtered and lyophilized to give title product (55 mg, 49.21 %) as a white solid. ESI-MS (M+H) ⁺: 397.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1H), 9.78 (s, 2H), 8.50 (d, J = 6.5 Hz, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 10.8 Hz, 1H), 6.61 (d, J = 6.1 Hz, 1H), 4.03 (t, J = 8.5 Hz, 2H), 3.58 – 3.54 (m, 4H), 3.18 – 3.14 (m, 6H), 2.59 (s, 3H). Example 37 – Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of 6-bromo-2,7-dimethylimidazo[1,2-a]pyridine. [0368] To a solution of 5-bromo-4-methylpyridin-2-amine (10 g, 0.05 mol) in IPA(100 mL) was added 1-chloropropan-2-one (15 g, 0.16 mol), the mixture was stirred at 85 ℃ for 16 hours. The mixture was concentrated, the residue was diluted with 2M NaOH (30 mL) and stirred at room temperature for 1 h. The resulting mixture was extracted with EA (100 mL *2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE: EA= 2:1 to afford title product (9 g, yield: 74.8%) as a yellow solid. ESI-MS (M+H) ⁺: 224.9.¹H-NMR (400 MHz, MeOD-d₄) δ 8.97 (s, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 2.44 (s, 3H), 2.34 (s, 3H). Step 2: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1-diphenylmethanimine. [0369] A mixture of 6-bromo-2,7-dimethylimidazo[1,2-a]pyridine (5 g, 0.02 mol), diphenylmethanimine (6.03 g, 0.03 mol), BINAP(2.77 g, 0.004 mol), Cs₂CO₃ (14.49 g, 0.04 mol) and Pd(OAc)₂ (0.50 g, 0.002 mmol) in 1,4-dioxane (50 mL) was stirred for 16 hours at 100℃ under N₂ atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE: EA (1:1) to afford product (4 g, yield: 55.4%) as a dark yellow solid. ESI-MS (M+H) ⁺: 326.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.74 – 7.70 (m, 2H), 7.54 (d, J = 7.2 Hz, 2H), 7.48 (dd, J = 8.0, 6.7 Hz, 2H), 7.33 (dd, J = 11.8, 9.0 Hz, 4H), 7.21 (dd, J = 7.8, 1.6 Hz, 3H), 2.24 – 2.19 (m, 6H). Step 3: Preparation of 2,7-dimethylimidazo[1,2-a]pyridin-6-amine. [0370] A solution of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1-diphenylmethanimine (2 g, 0.01 mol) in 3M HCl / EA(20 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was purified by C18 column chromatography eluted with CH₃CN:H₂O (0.1% NH₃.H₂O=21%) to afford title product (0.9 g, yield: 90.8 %) as a dark yellow solid. ESI-MS (M+H) ⁺: 162.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (s, 1H), 7.36 (s, 1H), 7.06 (s, 1H), 4.55 (s, 2H), 2.22 (s, 3H), 2.16 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0371] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (189 mg, 0.62 mmol) in THF (1.5 mL) were added TEA (188.2 mg, 1.86 mmol) and Triphosgene (221 mg, 0.75 mmol) at 0℃, the mixture was stirred at room temperature for 1 hour.2,7-dimethylimidazo[1,2-a]pyridin-6-amine (100 mg, 0.62 mmol) was added to the mixture and stirred at room temperature for 15 h. The mixture was concentrated in vacuo, the residue was purified by C18 column chromatography eluted with CH₃CN:H₂O (0.1% NH₃.H₂O) = 60-95% to afford title product (60 mg, 20%) as a yellow solid. ESI-MS (M+H) ⁺: 492.3. Step 5: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0372] A solution of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in 3M HCl / EA(1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title product (21.29 mg, yield: 53.47 %) as a white solid. ESI-MS (M+H) ⁺: 392.2. ¹H NMR (400 MHz, MeOD-d₄) δ 8.97 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 6.48 (d, J = 6.1 Hz, 1H), 4.03 (t, J = 8.6 Hz, 2H), 3.28 – 3.24 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.97 – 2.91 (m, 4H), 2.44 (s, 3H), 2.34 (s, 3H). Example 38 – Preparation of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((7-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [0373] To a solution of 6-methoxy-2-methyl-2H-indazol-5-amine (209 mg, 1.18 mmol) and TEA (1.64 mL, 11.83 mmol) in THF (21 mL) was added triphosgene (350 mg, 1.18 mmol) at 0^oC, after 10 min, tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (300 mg, 0.98 mmol) was added at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (80 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (280 mg, crude) as a white solid. ESI-MS (M+H) ⁺: 508.2. Step 2: Preparation of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0374] To a mixture of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (260 mg, 0.51 mmol) in EA (2 mL) was added HCl/EA(5 mL, 4M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (195 mg, Y: 67.91 %) as a white solid. ESI-MS (M+H) ⁺: 407.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 8.81 (s, 2H), 8.39 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.01 (s, 1H), 6.59 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.02 (t, J = 8.6 Hz, 2H), 3.96 (s, 3H), 3.51 – 3.46 (m, 4H), 3.26 – 3.20 (m, 4H), 3.17 – 3.11 (m, 2H). Example 39 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 7-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0375] To a solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (120 mg, 0.72 mmol) and TEA (734 mg, 7.26 mmol) in THF (15 mL) was added triphosgene (215 mg, 0.72 mmol) at 0^oC, after 10 min, tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.60 mmol) was added at 0^oC to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (170 mg, 53.85 %) as a white solid. ESI-MS (M+H) ⁺:522.4. Step 2: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0376] To a mixture of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (170 mg, 0.34 mmol) in EA (3 mL) was added HCl/EA (8 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with DCM: MeOH (8 mL, 10:1), then filtered and lyophilized to give title product (110 mg, 76.08 %) as an off-white solid. ESI-MS (M+H) ⁺:422.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 10.01 (s, 2H), 9.64 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 9.9 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.67 (d, J = 5.4 Hz, 1H), 4.10 – 4.03 (m, 2H), 3.71 (s, 2H), 3.51 – 3.46 (m, 2H), 3.33 – 3.27 (m, 2H), 3.23 – 3.15 (m, 2H), 2.46 (s, 3H), 1.15 (t, J = 5.9 Hz, 2H), 0.94 – 0.90 (m, 2H). Example 40 – Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0377] To a mixture of 2-cyclopropylimidazo[1,2-a]pyridin-6-amine (259 mg, 1.57 mmol) and TEA (1.27 g, 12.58 mmol) in THF (40 mL) was added triphosgene (466.3 mg, 1.57 mmol) at 0^oC, the mixture was stirred at 0^oC for 30 min, tert-butyl (R)-4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (400 mg, 1.26 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (50 mL), stirred at rt for 1 h. The precipitate was filtered and triturated with MeOH to afford title product (400 mg, 62.37 %) as a white solid. ESI-MS (M+H) ⁺: 510.2. Step 2: Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0378] A mixture of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (400 mg, 0.78 mmol) in 4M HCl /EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (191.03 mg, yield: 59.88 %) as a white solid. ESI-MS (M+H) ⁺: 410.1.¹H NMR (400 MHz, D₂O) δ 8.91 (d, J = 6.1 Hz, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.71 – 7.66 (m, 2H), 6.74 (d, J = 7.1 Hz, 1H), 4.31 – 4.22 (m, 2H), 4.12 – 4.03 (m, 2H), 3.55 – 3.46 (m, 3H), 3.41 – 3.26 (m, 4H), 2.42 (s, 3H), 1.33 (d, J = 6.6 Hz, 3H). Example 41 – Preparation of N-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of 5-bromo-4-ethoxypyridin-2-amine. [0379] To a solution of 4-ethoxypyridin-2-amine (50 g, 0.07 mol) in DCM (500 mL) was added NBS (14 g, 0.08 mol) at 0℃, the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE: EA= 1:3) to afford title product (45 g, yield: 57.7 %) as a yellow solid. ESI-MS (M+H) ⁺: 218.9.¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (s, 1H), 6.10 (s, 1H), 6.01 (s, 2H), 4.05 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). Step 2: [0380] Preparation of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine. To a solution of 5-bromo-4-ethoxypyridin-2-amine (20 g, 0.09 mol) in IPA(100 mL) was added 1- chloropropan-2-one (26 g, 0.28 mol), the mixture was stirred at 80 ℃ for 16 hours. The mixture was concentrated, the residue was diluted in 2M NaOH (100 mL) and stirred at room temperature for 1 h. The resulting mixture was extracted with EA (200 mL *2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE: EA= 1:4) to afford title product (6 g, yield: 25.53%) as a dark yellow solid. ESI-MS (M+H)⁺: 257.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (s, 1H), 7.43 (s, 1H), 6.92 (s, 1H), 4.13 (q, J = 6.9 Hz, 2H), 2.26 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H). Step 3: Preparation of N-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0381] A mixture of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (5 g, 0.02 mol), diphenylmethanimine (5.32 g, 0.03 mol), BINAP (2.44 g, 0.004 mol), Cs₂CO₃ (12.78 g, 0.04 mol) and Pd(OAc)₂ (0.44 g, 0.002 mol) in 1.4-dioxane (50 mL) was stirred at 100℃ for 16 hours under N₂ atmosphere. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with PE: EA=3:1) to afford title product (4 g, yield: 57.5%) as a dark yellow solid. ESI-MS (M+H)⁺: 356.3.¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J = 18.7 Hz, 3H), 7.77 – 7.74 (m, 4H), 7.72 – 7.67 (m, 2H), 7.58 (t, J = 7.6 Hz, 4H), 4.19 – 4.06 (m, 2H), 2.27 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H). Step 4: Preparation of 7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-amine. [0382] A solution of N-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (2 g, 5.62 mmol) in 3M HCl / EA (20 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was purified by C18 column chromatography (eluted with 0.1% NH₃.H₂O in water / CH₃CN) to afford title product (0.5 g, yield: 46.5 %) as a yellow solid. ESI-MS (M+H) ⁺: 192.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.68 (s, 1H), 7.37 (s, 1H), 6.78 (s, 1H), 4.11 (q, J = 6.9 Hz, 2H), 2.23 (s, 3H), 1.40 (t, J = 6.9 Hz, 3H). Step 5: Preparation of tert-butyl 4-(1-((7-ethoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0383] To a solution oftert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (122 mg, 0.40 mmol) in THF (1.5 mL) were added TEA (122 mg, 0.21 mmol) and Triphosgene (144 mg, 0.48 mmol) at 0℃, the mixture was stirred at room temperature for 1 hour.7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-amine (100 mg, 0.52 mmol) was added to the mixture and stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was purified by C18 column chromatography (eluted with 0.1% NH₃.H₂O in water / CH₃CN) to afford title product (60 mg, yield: 21.97 %) as a yellow solid. ESI-MS (M+H)⁺: 522.3. Step 6: Preparation of N-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0384] A solution of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.14 mmol) in 3M HCl / EA (1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% FA in water / ACN) to give title product (17 mg, yield: 35.1%) as a white solid. ESI-MS (M+H) ⁺:422.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 9.15 (s, 1H), 8.25 (s, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.51 (s, 1H), 6.87 (s, 1H), 6.53 (d, J = 6.0 Hz, 1H), 4.17 (q, J = 6.8 Hz, 2H), 3.99 (t, J = 8.4 Hz, 2H), 3.24 (s, 4H), 3.14 – 3.09 (m, 2H), 2.86 (s, 4H), 2.24 (s, 3H), 1.51 (t, J = 6.9 Hz, 3H), 1.24 (s, 1H). Example 42 – Preparation of N-(2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of 5-bromo-4-(trifluoromethyl)pyridin-2-amine. [0385] To a mixture of 4-(trifluoromethyl)pyridin-2-amine (30.1 g, 185.8 mmol) in DCM (300 mL) was added NBS (36.38 g, 204.4 mmol) at 0℃. The reaction solution was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was diluted with (PE: EA=5:1) (200mL) and stirred at r.t for 2h. The precipitate was filtered and dried in vacuo to give title product (50 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 242.7.¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (s, 1H), 6.88 (s, 1H). Step 2: Preparation of 6-bromo-2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridine. [0386] To a mixture of 5-bromo-4-(trifluoromethyl)pyridin-2-amine (5 g, 20.75 mmol) in EtOH (50 mL) was added 1-chloropropan-2-one (3.82 g, 41.49 mmol). The reaction solution was stirred at 100℃ for 48 h. The reaction concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give title product (4 g, 68%) as a yellow solid. ESI-MS (M+H) ⁺: 280.8.¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 2.53 (s, 3H). Step 3: Preparation of N-(2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0387] To a mixture of 6-bromo-2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridine (5 g, 14.34 mmol) and diphenylmethanimine (2.59 g, 14.34 mmol) in 1,4-dioxane (40 mL) were added BINAP (1.78 g, 2.86 mmol), Pd(OAc)₂ (349 mg, 1.43 mmol) and Cs₂CO₃ (14 g, 43.1 mmol). The reaction solution was stirred at 100℃ for 16 h under N₂. The reaction was diluted with H₂O (60 mL), extracted with EA (60 mLx3), the organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA=3:1) to give title product (4 g, 73.4%) as a yellow solid. ESI-MS (M+H) ⁺: 380.3.¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (s, 1H), 7.82 (s, 1H), 7.73 – 7.67 (m, 2H), 7.61 – 7.55 (m, 2H), 7.51 (t, J = 7.4 Hz, 2H), 7.39 (d, J = 1.5 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.22 (dd, J = 7.9, 1.5 Hz, 2H), 2.28 (s, 3H). Step 4: Preparation of 2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine. [0388] A mixture of N-(2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (3.6 g, 9.47 mmol) in 4M HCl / EA (21 mL) was stirred at RT for 2 h. The precipitate was filtered, diluted with sat. Na₂CO₃ (20 mL) and stirred at r.t for 30 min. The precipitate was filtered and dried in vacuo to give title product (1.1 g, 55%) as a yellow solid. ESI-MS (M+H) ⁺: 216.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 4.83 (s, 2H), 2.31 (s, 3H). Step 5: Preparation of tert-butyl 4-(1-((2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0389] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and 72-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin- 6-amine (142 mg, 0.66 mmol) in THF (3 mL) were added TEA (100 mg, 0.99 mmol) and triphosgene (243 mg, 0.82 mmol) at 0 ^oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:3) to give title product (100 mg, 56.0%) as a white solid. ESI-MS (M+H) ⁺: 546.0. Step 6: Preparation of N-(2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0390] A mixture of tert-butyl 4-(1-((2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.15 mmol) in 4M HCL / EA (6 mL) was stirred at RT for 1 h. The mixture concentrated in vacuo and purified by Prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (34 mg, 52.1 %) as a white solid. ESI-MS (M+H) ⁺: 446.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 9.13 (s, 1H), 8.33 (s, 1H), 7.92 (d, J = 5.9 Hz, 2H), 7.82 (d, J = 6.1 Hz, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.01 – 3.95 (m, 2H), 3.26 – 3.20 (m, 4H), 3.16 – 3.10 (m, 2H), 2.87 – 2.79 (m, 4H), 2.38 (s, 3H). Example 43 – Preparation of N-(6-hydroxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine. [0391] To a solution of 5-bromo-6-methoxy-2-methyl-2H-indazole (3 g, 12.44 mmol), diphenylmethanimine (3.38 g, 18.67 mmol), Cs₂CO₃12.16 g, 37.33 mmol) and Pd(OAc)₂ (139.68 mg, 0.62 mmol) in 1,4-dioxane (50 mL) was added BIANP (774 mg, 1.24 mmol), the mixture was stirred at 100^oC for 16 h under N₂. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE: EA= 5: 1) to give title compound (2.45 g, 57.87 %) as a yellow solid. ESI-MS (M+H) ⁺: 342.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 1H), 7.65 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 6.8 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 7.26 (d, J = 6.7 Hz, 3H), 7.11 (d, J = 6.8 Hz, 2H), 6.82 (s, 1H), 6.62 (s, 1H), 3.99 (s, 3H), 3.70 (s, 3H). Step 2: Preparation of 6-methoxy-2-methyl-2H-indazol-5-amine HCl salt. [0392] A mixture of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (2,15 g, 8.30 mmol) in 3M HCl / EA (20 mL) was stirred at r.t for 2 h. The precipitate was filtered and washed with EA (30 mL) and dried to give the title compound (1.62 g, crude) as a white solid. ESI-MS (M+H) ⁺: 178.0.¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 2H), 8.36 (s, 1H), 7.85 (s, 1H), 7.18 (s, 1H), 4.12 (s, 3H), 3.93 (s, 3H). Step 3: Preparation of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0393] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (300 mg, 0.98 mmol) and 6-methoxy-2-methyl-2H-indazol-5-amine HCl salt (349 mg, 1.97 mmol) in THF (30 mL) was added TEA (498 mg, 4.93 mmol), then triphosgene (584 mg,1.97 mmol) was added slowly at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EA= 1: 1) to give the compound (230 mg, 45.98 %) as a yellow solid. ESI-MS (M+H) ⁺: 508.3 Step 4: Preparation of N-(6-hydroxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0394] To a mixture of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (140 mg, 0.27 mmol) in DCM (0.5 mL) was added 1 M BBr₃ (3 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (35 mg, Y: 32.24%) as a white solid. ESI-MS (M+H) ⁺: 394.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 10.19 (s, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.84 (d, J = 6.1 Hz, 1H), 6.84 (s, 1H), 6.49 (d, J = 6.1 Hz, 1H), 4.02 (s, 3H), 4.01 – 3.96 (m, 2H), 3.24 – 3.21 (m, 4H), 3.12 – 3.08 (m, 2H), 2.89 – 2.84 (m, 4H). Example 44 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide benzoate salt.

Step 1: Preparation of 5-bromo-4-fluoropyridin-2-amine. [0395] To a solution of 4-fluoropyridin-2-amine (50 g, 0.45 mol) in ACN (600 mL) was added NBS (79 g, 0.45 mol), the mixture was stirred at 15 ^oC for 16 h. The mixture was concentrated in vacuo and the residue was diluted with water (500 mL), extracted with EA (1000 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The residue was triturated with PE/EA (1200 mL, 10/1), stirred at r.t overnight. The precipitate was filtered and dried to give title product (76 g, Y: 89.21 %) as a white solid. ESI-MS (M+H) ⁺: 191.0.¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 9.5 Hz, 1H), 6.26 (d, J = 10.0 Hz, 1H), 4.69 (s, 2H). Step 2: Preparation of 6-bromo-7-fluoro-2-methylimidazo[1,2-a]pyridine. [0396] To a solution of 5-bromo-4-fluoropyridin-2-amine (110 g, 0.58 mol) and 1-bromo- 2,2-dimethoxypropane (127 g, 0.69 mol) in IPA (1000 mL) was added PPTS (15.9 g, 63.35 mmol), the mixture was stirred at 85^oC for 16 h. The reaction was concentrated in vacuo, the residue was diluted with water (1000 mL), adjusted pH to 11 by sat. NaOH, stirred at r.t for 1h. The precipitate was filtered and purified by column chromatography (EA) to give title product (93.3 g, 70.75 %) as a yellow solid. ESI-MS (M+H) ⁺: 231.0.¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 6.5 Hz, 1H), 7.20 (s, 1H), 7.16 (d, J = 8.9 Hz, 1H), 2.35 (d, J = 0.6 Hz, 3H). Step 3: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0397] To a solution of 6-bromo-7-fluoro-2-methylimidazo[1,2-a]pyridine (50 g, 0.22 mol), diphenylmethanimine (43.96 mL, 0.26 mol), Cs₂CO₃ (142 g, 0.43 mol) and Pd(OAc)₂ (4.90 g, 21.83 mmol) in 1,4-dioxane (500 mL) was added BIANP (27.19 g, 43.66 mmol), the mixture was stirred for at 100 ^oC for 16 h under N₂. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EA= 3: 1) to give title product (51.4 g, 71.49 %) as a yellow solid. ESI-MS (M+H) ⁺: 330.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (d, J = 7.7 Hz, 1H), 7.69 (dd, J = 5.2, 3.3 Hz, 2H), 7.63 – 7.57 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.45 (s, 1H), 7.40 – 7.35 (m, 3H), 7.23 – 7.19 (m, 3H), 2.23 (s, 3H). Step 4: Preparation of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride. [0398] To a solution of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (50 g, 151.80 mmol) in EA (20 mL) was added HCl in EA (400 mL, 4 M), the mixture was stirred at r.t for 16 h. The precipitate was filtered, triturated with DCM/MeOH (2 L, 10/1) and filtered to give the title compound (28.8 g, 94.09 %) as an off- white solid. ESI-MS (M+H) ⁺: 166.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 2H), 8.22 (d, J = 7.4 Hz, 1H), 7.96 (s, 1H), 7.74 (d, J = 10.0 Hz, 1H), 2.40 (s, 3H). Step 5: Preparation of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine. [0399] A solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (50 g, 119.19 mmol) in H₂O (800 mL) was adjusted to pH = 9 with solid Na₂CO₃, then the mixture was stirred for at r.t for 2 h. The mixture was extracted with EA (1000 mL×6). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuum to give title product (33 g, 80.57%) as a brown solid. ESI-MS (M+H) ⁺: 166.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.22 (d, J = 11.7 Hz, 1H), 4.93 (s, 2H), 2.28 (s, 3H). Step 6: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate. [0400] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (50 g, 32.34 mmol), tert-butyl 2,2-dimethylpiperazine-1-carboxylate (83.17 g, 38.81 mmol) in DIEA (50 mL) was stirred at 140 ^oC for 48 h. The mixture was diluted with water (200 mL), extracted with EA (200 mL×3). The organic layer was washed with brine (200 mL), dried with Na₂SO₄ and concentrated in vacuo. The residue was triturated with EA (1 L) and filtered to afford title product (85 g, 79.05 %) a white solid. ESI-MS (M+H) ⁺: 333.2.¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 6.0 Hz, 1H), 5.98 (d, J = 6.1 Hz, 1H), 4.22 (s, 1 H), 3.75 – 3.70 (m, 2H), 3.54 (t, J = 8.1 Hz, 2H), 3.49 – 3.45 (m, 2H), 3.33 (s, 2H), 3.17 (t, J = 8.2 Hz, 2H), 1.49 (s, 9H), 1.43 (s, 6H). Step 7: Preparation of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0401] To a solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (4.97 g, 30.08mmol) and TEA (41.8 mL,300.80 mmol) in THF (500 mL) was added triphosgene (8.93 g, 30.08 mmol) at 0^oC and stirred at for 30 min, tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (8 g, 24.06 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (1 L) and stirred at r.t for 2 h. The precipitate was filtered and triturated with MeOH (300 mL) to give the compound (8 g, 63.49 %) as a white solid. ESI-MS (M+H) ⁺: 524.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (d, J = 1.9 Hz, 1H), 9.19 (d, J = 7.4 Hz, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 11.6 Hz, 1H), 6.41 (d, J = 6.3 Hz, 1H), 4.00 – 3.93 (m, 2H), 3.73 – 3.67 (m, 2H), 3.60 – 3.55 (m, 2H), 3.17 (d, J = 5.2 Hz, 4H), 2.28 (s, 3H), 1.43 (s, 9H), 1.38 (s, 6H). Step 8: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0402] To a mixture of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (28 g, 53.47 mmol) in EA (30 mL) was added HCl/EA(350 mL, 4M). The mixture was stirred at r.t for 16 h. The precipitate was filtered and diluted with water (300 mL), then adjusted to pH 9 with saturated sodium carbonate aqueous solution. The mixture was stirred at r.t for 4 h. The precipitate was filtered, washed with water (1 L) and dried to give the title compound (17.5 g, 77.4 %) as a white solid. ESI-MS (M+H) ⁺: 424.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (d, J = 2.0 Hz, 1H), 9.19 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.72 (s, 1H), 7.42 (d, J = 11.6 Hz, 1H), 6.59 (d, J = 6.2 Hz, 1H), 4.05 – 3.98 (m, 2H), 3.42 – 3.38 (m, 2H), 3.25 – 3.21 (m, 2H), 3.20 – 3.11 (m, 4H), 2.29 (s, 3H), 1.30 (s, 6H). Step 9: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate salt. [0403] To a solution of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (35 g, 82.74 mmol) in EtOH (500 mL), DCM (500 mL) and MeOH (500 mL) was added benzoate (10.60 g, 86.87 mmol) at 50 ^oC, and the mixture was stirred at 50 ^oC for 16 h. The mixture was concentrated in vacuo, the residue was triturated with DCM (100 mL) and stirred at r.t for 2 h. The precipitate was filtered and dried to give title product (39 g, 85.5%) as an off-white solid. ESI-MS (M+H) ⁺: 424.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 9.19 (d, J = 7.4 Hz, 1H), 7.94 (t, J = 7.0 Hz, 3H), 7.72 (s, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 11.7 Hz, 1H), 6.60 (d, J = 6.1 Hz, 1H), 4.02 (t, J = 8.4 Hz, 2H), 3.43 (s, 2H), 3.26 (s, 2H), 3.18 (d, J = 8.0 Hz, 4H), 2.29 (s, 3H), 1.33 (s, 6H). Example 45 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-

Step 1: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0404] To a mixture of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (110 mg, 0.27 mmol), (HCHO)_n (75 mg, 0.83 mmol) and TEA (84 mg, 0.83 mmol) in MeOH (2 mL) was added NaBHCN (50 mg, 0.83mmol).The mixture was stirred at r.t for 2 h. The mixture was filtered and the filtrate was purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (10 mg, Y: 45.95 %) as an orange solid. ESI-MS (M+H) ⁺: 410.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.59 (d, J = 6.3 Hz, 1H), 7.98 (d, J = 5.9 Hz, 1H), 7.92 (s, 1H), 7.81 (d, J = 9.5 Hz, 1H), 6.65 (d, J = 5.9 Hz, 1H), 4.20 – 4.12 (m, 2H), 4.04 – 3.79 (m, 2H), 3.70 – 3.38 (m, 4H), 3.29 – 3.16 (m, 4H), 2.98 (s, 3H), 2.51 (s, 3H). Example 46 – Preparation of (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate. [0405] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (350 mg, 2.26 mmol) in DIEA (1.5 g, 11.30 mmol) was added tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (678 mg, 3.39 mmol). The reaction mixture was stirred at 140 ℃ for 16 h in a sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give title product (500 mg, yield: 69 %) as a yellow oil. ESI-MS (M+H) ⁺:319.4.¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (d, J = 6.0 Hz, 1H), 5.81 (d, J = 6.1 Hz, 1H), 5.76 (d, J = 5.8 Hz, 1H), 4.71 – 4.49 (m, 1H), 3.57 – 3.51 (m, 2H), 3.40 (d, J = 9.3 Hz, 4H), 3.22 – 3.18 (m, 2H), 2.74 (s, 3H), 2.05 – 1.96 (m, 2H), 1.41 (s, 9H). Step 2: Preparation of tert-butyl (R)-(1-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate. [0406] To a mixture of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate (100 mg, 0.31 mmol) in THF (5 mL) were added 8- fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (155 mg, 0.94 mmol), TEA (157 mg, 1.55 mmol) and triphosgene (184 mg, 0.62 mmol) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: EA=2:1) to give title product (80 mg, yield: 50 %) as a gray solid. ESI-MS (M+H) ⁺:510.6.¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.81 (t, J = 4.3 Hz, 1H), 7.81 (dd, J = 12.3, 4.4 Hz, 2H), 7.22 (dd, J = 12.6, 1.5 Hz, 1H), 6.23 (d, J = 6.2 Hz, 1H), 3.92 (dd, J = 16.3, 7.1 Hz, 2H), 3.71 – 3.64 (m, 2H), 3.55 – 3.34 (m, 5H), 2.76 (s, 3H), 2.32 (s, 3H), 2.11 – 2.01 (m, 2H), 1.42 (s, 9H). Step 3: Preparation of R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0407] To a mixture of tert-butyl (R)-(1-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (60 mg, 0.12 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo give title compound (14.37 mg, 29 %) as a white solid. ESI-MS (M+H) ⁺:410.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.12 (s, 1H), 8.09 (s, 1H), 8.04 (d, J = 12.0 Hz, 1H), 7.83 – 7.71 (m, 1H), 6.72 – 6.57 (m, 1H), 4.46 – 4.28 (m, 2H), 4.21 – 3.89 (m, 5H), 3.79 – 3.65 (m, 2H), 2.83 (s, 3H), 2.57 (s, 3H), 2.56 – 2.49 (m, 1H), 2.39 – 2.28 (m, 1H). Example 47 – Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate. [0408] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine(1 g, 6.45 mmol) and tert-butyl (S)-methyl(pyrrolidin-3-yl)carbamate (3 mL) was stirred at 140 ^oC for 16h in a sealed tube. The mixture was concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH = 10:1) to provide title product (1.9 g, yield: 91%) as a brown solid. ESI-MS (M+H) ⁺:319.3.¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (d, J = 7.1 Hz, 1H), 6.14 (d, J = 7.3 Hz, 1H), 3.80 – 3.71 (m, 2H), 3.65 – 3.50 (m, 5H), 3.44 – 3.32 (m, 2H), 2.75 (s, 3H), 2.14 – 1.97 (m, 2H), 1.42 (s, 9H). Step 2: Preparation of tert-butyl (S)-(1-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate. [0409] To a solution of tert-butyl (S)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate (100 mg, 0.31 mmol) in THF (5 mL) were added TEA (313 mg, 3.10 mmol) and triphosgene (276 mg, 0.93 mmol) at 0 ^oC. Then 8-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (93 mg, 0.47 mmol) was added to the reaction after stirring for 0.5 h. Then the mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:3) to provide title product (140 mg, yield: 89%) as a white solid. ESI-MS (M+H) ⁺:510.4. Step 3: Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0410] To a solution of tert-butyl (S)-(1-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (130 mg, 0.26 mmol) in EtOAc (2 mL) was added 4M HCl/EtOAc (6 mL) at 0 ^oC. Then the mixture was stirred at r.t for 2 hours. The reaction mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in H₂O / ACN) to give title compound (35 mg, yield: 33%) as a white solid. ESI-MS (M+H)⁺: 410.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.81 (s, 1H), 8.28 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.22 (d, J = 12.6 Hz, 1H), 6.19 (d, J = 6.0 Hz, 1H), 3.92 (t, J = 8.7 Hz, 2H), 3.70 – 3.64 (m, 2H), 3.62 – 3.60 (m, 1H), 3.55 – 3.62 (m,, 1H), 3.38 – 3.40 (m,, 2H), 3.27 – 3.24 (m,, 1H), 2.32 (s, 6H), 2.07 – 1.99 (m,, 1H), 1.82 – 1.78 (m, 1H). [0411] Example 48 – Preparation of N-(6-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-4- (piperazin-1-yl)-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridine-1-carboxamide formate.

S ₄ 6 h

l _{Step 7}

C^{ompound 48} Step 1: Preparation of methyl 5-bromo-2-methyl-2H-indazole-6-carboxylate. [0412] To a solution of methyl 5-bromo-2-methyl-2H-indazole-6-carboxylate (3 g, 11.81 mmol) in EA (30 mL) was added trimethyloxonium tetrafluoroborate (2.1 g, 14.17 mmol). The resulting mixture was stirred at RT for 2 h. The mixture was diluted with water (30 mL), extracted with EA (30 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title product (3 g, 93%) as a yellow solid. ESI-MS (M+H+CH₃CN) ⁺: 310.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 4.23 (s, 3H), 3.88 (s, 3H). Step 2: Preparation of (5-bromo-2-methyl-2H-indazol-6-yl) methanol. [0413] To a solution of methyl 5-bromo-2-methyl-2H-indazole-6-carboxylate (3 g, 11.19 mmol) in dry-THF (30 mL) was added LiAlH₄ (851 mg, 22.39 mmol) at 0^oC. The resulting mixture was stirred at 0 ^o C for 2 h. The mixture was quenched by water (0.85 mL) at 0 ^o C, followed by 15% NaOH (0.85 mL) and water (1.7 mL). The mixture was diluted with THF (5 mL) and Na₂ SO₄. The resulting mixture was stirred at RT for 0.5 h. The mixture was filtered and the filtrate was concentrated in vacuo to give title product (3 g, crude) as a white solid. ESI-MS (M+H) ⁺: 243.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J = 14.7 Hz, 1H), 7.97 (s, 1H), 7.69 (s, 1H), 4.55 (s, 2H), 4.16 (s, 3H). Step 3: Preparation of 5-bromo-2-methyl-2H-indazole-6-carbaldehyde. [0414] To a solution of (5-bromo-2-methyl-2H-indazol-6-yl) methanol (3 g, 12.50 mmol) in DCM (30 mL) was added Dess-martain (6.4 g, 15.00 mmol). The resulting mixture was stirred at RT for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude was purified by silica gel column (PE/EA=2:1) to give title product (2.3 g, Y: 68 %) as a yellow solid. ESI-MS (M+H) ⁺:238.9.¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.48 (d, J = 3.2 Hz, 1H), 8.21 (t, J = 11.8 Hz, 2H), 4.25 (s, 3H). Step 4: Preparation of 5-bromo-6-(difluoromethyl)-2-methyl-2H-indazole. [0415] To a solution of 5-bromo-2-methyl-2H-indazole-6-carbaldehyde (2 g, 8.40 mmol) in DCM (20 mL) was added DAST (2299 mg, 14.29 mmol) at 0 ^oC under N₂. The resulting mixture was stirred at RT for 16 h. The mixture was quenched by aq NaHCO₃ (15 mL) at 0 ^o C, extracted with DCM (20 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE/EA=2:1) to give title product (1.2 g, Y: 55 %) as a yellow solid. ESI-MS (M+H) ⁺:261.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J = 3.6 Hz, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.31 – 7.02 (m, 1H), 4.22 (d, J = 5.0 Hz, 3H). Step 5: Preparation of N-(6-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-1, 1- diphenylmethanimine. [0416] To a solution of 5-bromo-6-(difluoromethyl)-2-methyl-2H-indazole (1 g, 3.83 mol) and diphenylmethanimine (1040 mg, 5.75 mmol) in 1,4-dioxane (10 mL) were added BINAP (479 mg, 0.77 mmol), Pd(OAC)₂ (86 mg, 0.38 mmol) and Cs₂CO₃ (3734 mg, 11.49 mmol). The reaction solution was stirred at 100℃ for 16 h under N₂. The reaction was diluted with H₂O (10 mL), extracted with EA (10 mLx3), the organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by reserve silica gel column chromatography (PE: EA=2:1) to give title product (1.7 g, yield: 99%) as a yellow solid. ESI- MS (M+H) ⁺: 362.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.81 (s, 1H), 7.75 – 7.70 (m, 2H), 7.57 – 7.52 (m, 1H), 7.51 – 7.46 (m, 2H), 7.36 – 7.26 (m, 4H), 7.21 – 7.17 (m, 2H), 6.98 (t, J = 31.5 Hz, 1H), 4.09 (s, 3H). Step 6: Preparation of 6-(difluoromethyl)-2-methyl-2H-indazol-5-amine HCl salt. [0417] To a solution of N-(6-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine (1.5 g, 5.75 mmol) in EA (10 mL) was added 4M HCl / EA (10 mL). The reaction solution was stirred at RT for 2 h. The precipitate was filtered, washed with EA (20 mL), then diluted with EA (20 mL) and stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (1.068 g, y: 90%) as a yellow solid. ESI-MS (M+H) ⁺: 198.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.47 (t, J = 54.6 Hz, 1H), 4.24 (s, 3H). Step 7: Preparation of tert-butyl 4-(1-((6-(difluoromethyl)-2-methyl-2H-indazol-5-yl) carbamoyl)-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-4-yl) piperazine-1-carboxylate. [0418] To a solution of tert-butyl 4-(2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-4-yl) piperazine-1-carboxylate (100 mg, 0.33 mmol) and 6-(difluoromethyl)-2-methyl-2H-indazol- 5-amine HCl salt (95 mg, 0.39 mmol) in THF (2 mL) were added TEA (100 mg, 0.99 mmol) and triphosgene (116 mg, 0.39 mmol) at 0^oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na₂ SO₄ and concentrated in vacuo. The crude was purified by silica gel column (EA) to give title product (60 mg, 34%) as a yellow solid. ESI-MS (M+H) ⁺: 528.0. Step 8: Preparation of N-(6-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridine-1-carboxamide formate. [0419] To a solution of tert-butyl 4-(1-((6-(difluoromethyl)-2-methyl-2H-indazol-5-yl) carbamoyl)-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-4-yl) piperazine-1-carboxylate (60 mg, 0.11 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (14.89 mg, yield: 30 %) as a white solid. ESI-MS (M+H) ⁺: 428.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 7.92 – 7.78 (m, 2H), 7.13 (t, J = 54.8 Hz, 1H), 6.50 (d, J = 6.1 Hz, 1H), 4.19 (s, 3H), 4.01 – 3.96 (m, 2H), 3.28 – 3.21 (m, 4H), 3.15 – 3.08 (m, 2H), 2.85 (s, 4H). Example 49 – Preparation of N-(2,5-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of 2,5-dimethyl-6-nitrobenzo[d]oxazole. [0420] To a solution of 2,5-dimethylbenzo[d]oxazole (9.7 g, 0.066 mol) in H₂SO₄ (100 mL) was added HNO₃ (8.3 mL, 0.198 mol) at 0 ^oC. Then, the mixture was stirred at 0 ^oC for 3 h. The solution was slowly poured into ice-water. The precipitate was filtered, washed with water and dried in vacuo to give title product (10 g, yield: 79.36%) as a white solid. ESI-MS (M+H) ⁺: 192.9.¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 7.79 (s, 1H), 2.68 (s, 3H), 2.60 (s, 3H). Step 2: Preparation of 2,5-dimethylbenzo[d]oxazol-6-amine. [0421] A solution of 2,5-dimethyl-6-nitrobenzo[d]oxazole (10 g, 0.052 mol), NH₄HCO₃ (16.38 g, 0.26 mol) and 10% Pd/C (1 g) in MeOH (100 mL) was stirred at 80 ^oC for 0.5 h under H₂. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluted with EA:PE = 1:5 to give title product (2.4 g, yield: 28.49%) as a white solid. ESI-MS (M+H) ⁺: 163.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.18 (s, 1H), 6.78 (s, 1H), 5.00 (s, 2H), 2.47 (s, 3H), 2.11 (s, 3H). Step 3: Preparation of tert-butyl 4-(1-((2,5-dimethylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0422] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (200 mg, 0.66 mmol) and 2,5-dimethylbenzo[d]oxazol-6-amine (214 mg, 1.32 mmol) in THF (80 mL) were added TEA (458 μL, 3.30 mmol) and triphosgene (392 mg, 1.32 mmol, dissolved in THF (1 mL)) at 0 ^oC. Then, the mixture was stirred at RT for 16 h. The mixture was diluted with water (30 mL) and extracted with EA (30 mL x 3). The mixture was concentrated in vacuo and purified by column chromatography on silica gel eluted with DCM:MeOH = 50:1 to give title product (70 mg, yield: 21.56%) as a white solid. ESI-MS (M+H) ⁺: 493.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.39 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.50 (s, 1H), 6.54 (d, J = 6.1 Hz, 1H), 4.04 – 3.98 (m, 2H), 3.44 (s, 6H), 3.26 – 3.21 (m, 2H), 3.18 – 3.04 (m, 8H), 1.43 (s, 9H). Step 4: Preparation of N-(2,5-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0423] To a solution of tert-butyl 4-(1-((2,5-dimethylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.12 mmol) in DCM (5 mL) were added HMDS (51 μL, 0.24 mmol) and TMSOTf (42 μL, 0.24 mmol) at 0 ^oC. Then, the mixture was stirred at RT for 2 h. The mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title product (27.83 mg, 59.16%) as a white solid. ESI-MS (M+H) ⁺: 393.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 8.38 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.48 (s, 1H), 6.49 (d, J = 6.1 Hz, 1H), 3.98 (t, J = 8.5 Hz, 2H), 3.22 – 3.15 (m, 4H), 3.10 (t, J = 8.5 Hz, 2H), 2.84 – 2.72 (m, 4H), 2.55 (s, 3H), 2.42 (s, 3H). Example 50 – Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of N-(3-fluoro-2-methylphenyl)acetamide. [0424] To a solution of 3-fluoro-2-methylaniline (8 g, 64 mmol) in DCM (100 mL) was added Ac₂O (9.8 g, 96 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to provide title compound (10 g, crude) as a pink solid. ESI-MS (M+H) ⁺:168.1.¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 7.31 – 7.10 (m, 2H), 7.04 – 6.90 (m, 1H), 2.12 – 2.04 (m, 6H). Step 2: Preparation of N-(4-bromo-3-fluoro-2-methylphenyl)acetamide. [0425] To a mixture of N-(3-fluoro-2-methylphenyl)acetamide (11 g, 65.87 mmol) in AcOH (110 mL) was added Br₂ (31.6 g, 197.6 mmol). The mixture was stirred at RT for 2 h. The mixture was diluted with water (400 mL), the precipitate was filtered and washed with H₂O (50 mL), dried in vacuum to give title product (12 g, 74.5 %) as a yellow solid. ESI-MS (M+H) ⁺:246.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 7.47 (t, J = 8.3 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 2.14 (d, J = 2.3 Hz, 3H), 2.07 (s, 3H). Step 3: Preparation of 6-bromo-5-fluoro-2,4-dimethylbenzo[d]oxazole. [0426] To a suspension of N-(4-bromo-3-fluoro-2-methylphenyl)acetamide (13.4 g, 54.69 mmol) in DMF :HOAC(10 mL: 80 mL) were added K₂S₂O₈ (22.2 g, 82.04 mmol), TfOH (8.2 g, 54.69 mmol) and Pd(OAc)₂ (1.2 g, 5.47 mmol). The reaction mixture was stirred at 100 ^oC for 16 h. The mixture was concentrated in vacuo. The crude was purified by flash column chromatography (PE / EA = 0 % to 50 %) to provide title product (2.5 g, 18.8 %) as a yellow solid. ESI-MS (M+H) ⁺:244.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.97 (d, J = 5.5 Hz, 1H), 2.61 (s, 3H), 2.45 (d, J = 1.7 Hz, 3H). Step 4: Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine. [0427] To a mixture of 6-bromo-5-fluoro-2,4-dimethylbenzo[d]oxazole (3.2 g, 13.17 mmol), diphenylmethanimine (3.6 g, 19.75 m mol) in 1,4-dioxane (100 mL) were added Cs₂CO₃ (13 g, 39.51 mmol), BINAP (1.6 g, 2.63 mmol) and Pd(OAc)₂ (300 mg,1.32 mmol), the mixture was charged with N₂ for three times and stirred at 100 ^oC for 16 h. The reaction mixture was evaporated to give crude title compound. The crude was purified by silica gel column chromatography eluted with (EtOAc/PE=1:2) to give title compound (3 g, crude) as a brown solid. ESI-MS (M+H) ⁺:345.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.71 – 7.68 (m, 2H), 7.59 – 7.54 (m, 1H), 7.51 – 7.47 (m, 3H), 7.33 – 7.31 (m, 2H), 7.21 – 7.16 (m, 2H), 6.92 (d, J = 6.5 Hz, 1H), 2.52 (s, 3H), 2.29 (s, 3H). Step 5: Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine. [0428] To a solution of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine (3 g, 8.72 mmol) was added HCl in EA (30 mL, 4 M) at RT, the mixture was stirred for 1 h at RT. The mixture was concentrated in vacuo and the residue was diluted with water (10 mL), adjusted the PH≈ 8 with aq.NaHCO₃. Exacted with DCM (80 mL*3), the organic layer was washed with brine, dried over Na₂SO₄ and evaporated in vacuo. The residue was purified by silica gel column chromatography eluted with (EtOAc/PE=1:3) to give title compound (600 mg, 38.3 %) as a brown solid. ESI-MS (M+H) ⁺:181.1.¹H NMR (400 MHz, DMSO-d₆) δ 6.77 (d, J = 7.2 Hz, 1H), 5.17 (s, 2H), 2.49 (s, 3H), 2.33 (s, 3H). Step 6: Preparation of tert-butyl 4-(1-((5-fluoro-2,4-dimethylbenzo[d]oxazol-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0429] To a solution of 5-fluoro-2,4-dimethylbenzo[d]oxazol-6-amine (150 mg, 0.83 mmol) and tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (278 mg, 0.91 mmol) in THF (15 mL) was added TEA (421 mg, 4.18 mmol), triphosgene (271 mg, 0.91 mmol) was added slowly at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EA= 1: 2) to give the compound (230 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 511.2. Step 7: Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0430] To a mixture of tert-butyl 4-(1-((5-fluoro-2,4-dimethylbenzo[d]oxazol-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (200 mg, 0.39 mmol) in DCM (5 mL) were added HMDS (189 mg, 1.18 mmol) and TMSOTf (261 mg, 1.18 mmol) at 0^oC, the mixture was stirred at r.t for 2 h. The mixture was diluted with H₂O (50 mL), extracted with EA (30 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuum. The crude was purified by prep-HPLC (0.05 % NH₃.H₂O in water / ACN) to give title product (6 mg, Y: 3.73 %) as a white solid. ESI-MS (M+H) ⁺: 411.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (s, 1H), 8.35 (d, J = 6.2 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.04 – 3.95 (m, 2H), 3.22 (d, J = 4.8 Hz, 4H), 3.15 – 3.10 (m, 2H), 2.85 – 2.77 (m, 4H), 2.59 (s, 3H), 2.45 (s, 3H). Example 51 – Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide .

Step 1: Preparation of tert-butyl 7-(1-((5-fluoro-2,4-dimethylbenzo[d]oxazol-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0431] To a mixture of 5-fluoro-2,4-dimethylbenzo[d]oxazol-6-amine (163.6 mg, 0.91 mmol) and tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (150 mg, 0.45 mmol) in THF (10 mL) were added TEA (227.2 mg, 2.25 mmol) and triphosgene (267.3mg, 0.90 mmol) at 0^oC for 15 min. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo, the crude was purified by silica gel column chromatography (EA: PE= 100 %) to give title product (80 mg, yield: 16.4 %) as a yellow solid. ESI-MS (M+H) ⁺: 537.2. Step 2: Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0432] A mixture of tert-butyl 7-(1-((5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (70 mg, 0.13 mmol), HMDS (42 mg, 0.26mmol) and TMSOTf (58 mg, 0.26 mmol) in DCM (10 mL) was stirred at 0 ^oC for 2 h. The mixture was diluted with water (20 mL), extracted with DCM (20 mL×3). The organic layer was washed with brine (20 mL), dried with Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% NH₃·H₂O in H₂O / ACN) to give title product (1.2 mg, yield: 2.11 %) as a white solid. ESI-MS (M+H) ⁺: 437.2. ¹H NMR (400 MHz, CDCl₃) δ 12.16 (s, 1H), 8.40 (d, J = 6.3 Hz, 1H), 7.96 (d, J = 6.0 Hz, 1H), 6.34 (d, J = 6.0 Hz, 1H), 4.20 – 4.13 (m, 2H), 3.29 (d, J = 4.9 Hz, 2H), 3.20 – 3.13 (m, 2H), 3.13 – 3.10 (m, 2H), 3.09 – 3.04 (m, 2H), 2.62 (s, 3H), 2.52 (d, J = 1.6 Hz, 3H), 0.89 – 0.81 (m, 2H), 0.70 – 0.61 (m, 2H). Example 52 – Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 2,6-dimethyl-5-nitro-2H-indazole. [0433] To a solution of 6-methyl-5-nitro-1H-indazole (1 g, 0.01 mol) in EA (10 mL) was added Trimethyloxonium Tetrafluoroborate (1 g, 0.01 mol), the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (50 mL), extracted with EA (30 mL *2). The combined organic layer was washed with brine, dried over Na₂SO_4, filtered and concentrated in vacuo. The residue was purified by C18 column chromatography eluted with CH₃CN: H₂O (0.1% NH₃.H₂O) = 30-80 % to afford product (1 g, yield: 92.7%) as a yellow solid. ESI-MS (M+H) ⁺:192.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.60 (s, 1H), 7.61 (s, 1H), 4.21 (s, 3H), 2.56 (d, J = 0.8 Hz, 3H). Step 2: Preparation of 2,6-dimethyl-2H-indazol-5-amine. [0434] To a solution of 2,6-dimethyl-5-nitro-2H-indazole (3 g, 15.62 mmol) in MeOH (30 mL) were added Raney Nickel (300 mg,) and NH₃.H₂O (3 mL). The mixture was charged with H₂ for three times and stirred at r.t for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford title product (1.4 g, yield: 55 %) as a purple solid. ESI-MS (M+H) ⁺:162.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.81 (s, 1H), 7.20 (s, 1H), 6.65 (s, 1H), 4.54 (s, 2H), 4.01 (s, 3H), 2.18 (s, 3H). Step 3: Preparation of phenyl (2,6-dimethyl-2H-indazol-5-yl)carbamate. [0435] To a solution of 2,6-dimethyl-2H-indazol-5-amine (100 mg, 0.62 mmol) in DCM (5 mL) were added phenyl carbonochloridate (116 mg, 0.75 mmol) and pyridine (147 mg, 1.86 mmol) at 0℃. The mixture was stirred at r.t for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to give title product (100 mg, yield: 57 %) as a brown solid. ESI-MS (M+H) ⁺:282.2. Step 4: Preparation of tert-butyl 4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate formate. [0436] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (70 mg, 0.23 mmol) in THF (5 mL) were added phenyl (2,6-dimethyl-2H- indazol-5-yl)carbamate (65 mg, 0.23 mmol) and TEA (70 mg, 0.69 mmol). The reaction mixture was stirred at 70℃ for 16 h in a sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (30 mg, Y: 26 %) as a white solid. ESI-MS (M+H) ⁺:492.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.44 (s, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.10 (s, 3H), 4.00 (t, J = 8.6 Hz, 2H), 3.45 (s, 4H), 3.28 – 3.26 (m, 4H), 3.13 (t, J = 8.7 Hz, 2H), 2.44 (s, 3H), 1.43 (s, 9H). Step 5: Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0437] To a solution of tert-butyl 4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate formate (20 mg, 0.041 mmol) in EA (3 mL) was added 4M HCl / EA (3 mL). The mixture was stirred at r.t for 2 h. The reaction solution was concentrated in vacuo, the residue was diluted with TFA () (5 mL, 0.5 M), concentrated in vacuo and lyophilized to give title product (9.83 mg, 47%) as a white solid. ESI-MS (M+H) ⁺:392.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.55 – 8.51 (m, 1H), 7.83 (s, 1H), 7.78 (d, J = 6.4 Hz, 1H), 7.58 (s, 1H), 6.92 (s, 1H), 4.48 – 4.36 (m, 2H), 4.30 (s, 3H), 4.02 – 3.91 (m, 4H), 3.62 – 3.52 (m, 2H), 3.48 – 3.40 (m, 4H), 2.48 (s, 3H). Example 53 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-5-methyl-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of 4-chloro-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. [0438] To a solution of 4-chloro-5-methyl-1H-pyrrolo[2,3-b]pyridine (1 g, 6.02 mmol) in MeOH (20 mL) was added Raney-Ni (360 mg, 20% w.t). The mixture was stirred at 70 ^oC for 16 h under H₂. The mixture was cooled down to r.t. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 1:1) to provide title product (400 mg, yield: 40%) as a white solid. ESI-MS (M+H) ⁺:169.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (d, J = 0.5 Hz, 1H), 6.45 (s, 1H), 3.50 (t, J = 8.6 Hz, 2H), 2.99 (t, J = 8.5 Hz, 2H), 2.09 (s, 3H). Step 2: Preparation of tert-butyl 4-(5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate. [0439] A mixture of 4-chloro-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.79 mmol) and tert-butyl piperazine-1-carboxylate (997 mg, 5.36 mmol) was stirred at 140 ^oC for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH = 10:1) to provide title product (200 mg, yield: 35%) as a brown solid. ESI- MS (M+H) ⁺:319.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (s, 1H), 5.87 (s, 1H), 3.41 – 3.37 (m, 4H), 3.24 – 3.22 (m, 2H), 3.08 (t, J = 8.4 Hz, 2H), 2.97 – 2.94 (m, 4H), 2.01 (s, 3H), 1.42 (s, 9H). Step 3: Preparation of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-5- methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0440] To a solution of tert-butyl 4-(5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (150 mg, 0.47 mmol) in THF (10 mL) were added TEA (143 mg, 1.42 mmol) and triphosgene (56 mg, 0.19 mmol) at 0 ^oC. Then 6-ethoxy-2-methyl-2H- indazol-5-amine (117 mg, 0.71 mmol) was added to the reaction after stirring for 1h. Then the mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:1) to provide title product (70 mg, yield: 30%) as a white solid. ESI-MS (M+H) ⁺:510.4.¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.86 (d, J = 1.4 Hz, 1H), 7.84 (s, 1H), 7.83 (s, 1H), 4.32 (s, 3H), 3.53 – 3.51 (m, 4H), 3.49 – 3.45 (m, 4H), 3.43 – 3.41 (m, 2H), 3.36 – 3.33 (m, 2H), 2.20 (s, 3H), 1.49 (s, 9H). Step 4: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-5-methyl-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0441] To a solution of 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-5-methyl-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in EtOAc (1 mL) was added 4M HCl / EtOAc (3 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in H₂O / ACN), 0.5 M TFA (1 mL) was added and lyophilized to give title compound (22 mg, yield: 54%) as a white solid. ESI-MS (M+H)⁺:410.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 8.77 (s, 2H), 8.37 (d, J = 2.8 Hz, 1H), 7.93 (s, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 13.3, 1.6 Hz, 1H), 4.17 (s, 3H), 4.03 – 4.00 (m, 2H), 3.33 – 3.28 (m, 4H), 3.26 – 3.19 (m, 6H), 2.19 (s, 3H).

Example 54 – Preparation of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (4-fluoropyridin-2-yl)carbamate. [0442] To a solution of 4-fluoropyridin-2-amine (18 g, 160.71 mmol) and DMAP (1.98 g, 16.07 mmol) in DCM (200 mL) was added Boc₂O (42.04 g, 192.86 mmol), the mixture stirred at r.t for 2 h. The mixture was diluted with water (200 mL) and extracted with DCM (200 mLx3). The organic layer concentrated in vacuo. The crude was purified by reserve silica gel column chromatography (PE: DCM=2:1) to give title compound (30 g, y: 87.9) as a white solid. ESI-MS (M+H)⁺: 213.0.¹H NMR (400 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.27 (dd, J = 9.4, 5.7 Hz, 1H), 7.61 (dd, J = 12.3, 2.3 Hz, 1H), 6.95 (ddd, J = 8.2, 5.7, 2.4 Hz, 1H), 1.48 (s, 9H). Step 2: Preparation of tert-butyl (4-fluoro-3-methylpyridin-2-yl)carbamate. [0443] To a solution of tert-butyl (4-fluoropyridin-2-yl)carbamate (30.1 g, 141.31 mmol) in dry-THF (300 mL) was added N1,N1,N2,N2-tetramethylethane-1,2-diamine (40.98 g, 353.29 mmol) at -78℃ for 0.5 h, n-BuLi (169.6 mL, 423.94 mmol, 2.5 M) was added to the mixture and stirred at -78℃ for 0.5 h. MeI (60.2 g, 423.94 mmol) was added, the mixture stirred at - 78℃ for 0.5 h then warm to r.t and stirred at r.t for 2 h. The mixture was quenched with NH₄Cl (200 mL) and extracted with EA (200 mLx3). The organic layer concentrated in vacuo to give title compound (36 g, crude) as a yellow solid. ESI-MS (M+H)⁺: 227.0. Step 3: Preparation of 4-fluoro-3-methylpyridin-2-amine HCl salt. [0444] A mixture of tert-butyl (4-fluoro-3-methylpyridin-2-yl)carbamate (34 g, 149.78 mmol) in EA (100 mL) and 4M HCl / EA (140 mL) was stirred at RT for 2 h. The mixture concentrated in vacuo to give title product (21 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 126.9. Step 4: Preparation of 5-bromo-4-fluoro-3-methylpyridin-2-amine. [0445] To a mixture of 4-fluoro-3-methylpyridin-2-amine (19 g, 149.61 mmol) in DCM (300 mL) was added NBS (29.3 g, 164.57 mmol) at 0℃. The reaction solution was stirred at r.t for 2 h. The reaction concentrated in vacuo to give title product (40 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 204.9.¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J = 7.4 Hz, 1H), 2.11 (d, J = 1.9 Hz, 3H). Step 5: Preparation of 6-bromo-7-fluoro-2,8-dimethylimidazo[1,2-a]pyridine. [0446] To a mixture of 5-bromo-4-fluoro-3-methylpyridin-2-amine (14 g, 68.31 mmol) in IPA (140 mL) were added 1-bromo-2,2-dimethoxypropane (25 g, 136.61 mmol) and PPTS (1.71 g, 6.83 mmol). The reaction solution was stirred at 95℃ for 48 h. The reaction was concentrated in vacuo the residue was diluted with water (100 mL), adjusted pH to 11 by sat. NaOH, stirred at r.t for 1h. The precipitate was filtered and purified by column chromatography (EA) to give title product (5.5 g, yield: 33.1%) as a yellow solid. ESI-MS (M+H) ⁺: 244.9.¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (d, J = 6.1 Hz, 1H), 8.00 (s, 1H), 2.50 (s, 3H), 2.49 (s, 3H). Step 6: Preparation of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0447] To a mixture of 6-bromo-7-fluoro-2,8-dimethylimidazo[1,2-a]pyridine (5 g, 20.58 mmol) and diphenylmethanimine (4.1 g, 22.63 mmol) in 1,4-dioxane (100 mL) were added BINAP (2.58 g, 4.12 mmol), Pd₂(dba)₃ (1.88 g, 2.06 mmol) and Cs₂CO₃ (20.06 g, 61.73 mmol). The reaction solution was stirred at 100℃ for 16 h under N₂. The reaction was diluted with H₂O (100 mL), extracted with EA (100 mLx3), the organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA=2:1) to give title product (2.3 g, crude) as a yellow oil. ESI-MS (M+H) ⁺: 344.1. Step 7: Preparation of 7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-amine. [0448] A mixture of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (2.1 g, 6.10 mmol) in 4M HCl / EA (21 mL) was stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (700 mg, y: 45.2%) as a white solid. ESI-MS (M+H) ⁺: 180.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J = 7.3 Hz, 1H), 7.90 (d, J = 0.9 Hz, 1H), 2.44 (s, 3H), 2.42 (s, 3H). Step 8: Preparation of tert-butyl 4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0449] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (200 mg, 0.66 mmol) and 7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-amine (118 mg, 0.66 mmol) in THF (12 mL) were added TEA (200 mg, 1.98 mmol) and triphosgene (490 mg, 1.65 mmol) at 0^oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (10 mL), extracted with DCM (10 mL×3). The organic layer was washed with brine, dried with Na₂ SO₄ and concentrated in vacuo. The crude was purified by silica gel column (EA) to give title product (90 mg, 26.9%) as a yellow solid. ESI-MS (M+H) ⁺: 510.3. Step 9: Preparation of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0450] A mixture of tert-butyl 4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.16 mmol) in 4M HCl / EA (6 mL) was stirred at RT for 2 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.03 %TFA in water / CH₃CN) to give title product (43 mg, yield: 66.9 %) as a yellow solid. ESI-MS (M+H) ⁺: 410.1.¹H NMR (400 MHz, DMSO- d₆) δ 12.39 (d, J = 2.2 Hz, 1H), 9.51 (d, J = 6.3 Hz, 1H), 9.14 (s, 2H), 8.13 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 6.63 (d, J = 6.2 Hz, 1H), 4.06 – 4.01 (m, 2H), 3.55 – 3.48 (m, 4H), 3.28 – 3.21 (m, 4H), 3.20 – 3.13 (m, 2H), 2.49 (s, 3H), 2.46 (s, 3H).

Example 55 – Preparation of N-(1-methyl-1H-indol-3-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((1-methyl-1H-indol-3-yl)carbamoyl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0451] To a solution of 1-methyl-1H-indole-3-carboxylic acid (350 mg, 2.00 mmol) in toluene (5 mL) were added TEA (404 mg, 4.00 mmol) and DPPA (770 mg, 2.80 mmol). The mixture was stirred at RT for 1 h and 1 h at 90 ^oC. The tert-butyl 4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (304 mg, 1.00 mmol) was added to the solution and stirred at 110 ^oC for 4 h. The mixture was diluted with water (15 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluted with DCM:MeOH = 30:1) to give title product (80 mg, yield: 16.81%) as a white solid. ESI-MS (M+H) ⁺: 477.6.¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 7.57 – 7.54 (m, 2H), 7.42 (s, 1H), 7.20 – 7.17 (m, 2H), 7.08 – 7.05 (m, 2H), 4.06 – 3.96 (m, 2H), 3.76 (s, 3H), 3.47 – 3.44 (m, 4H), 3.30 – 3.27 (m, 4H), 3.20 – 3.09 (m, 2H), 1.44 (s, 9H). Step 2: Preparation of N-(1-methyl-1H-indol-3-yl)-4-(piperazin-1-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0452] A solution of tert-butyl 4-(1-((1-methyl-1H-indol-3-yl)carbamoyl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (70 mg, 0.15 mmol) in 3.0 M HCl / EA was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (9.44 mg, yield: 16.74%) as a white solid. ESI-MS (M+H) ⁺: 377.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 8.76 (s, 2H), 8.08 (s, 1H), 7.56 (d, J = 6.1 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.23 – 7.17 (m, 1H), 7.11 – 7.05 (m, 1H), 6.62 (s, 1H), 4.06 – 4.02 (m, 2H), 3.77 (s, 3H), 3.50 – 3.48 (m, 4H), 3.23 – 3.22 (m, 4H), 3.19 – 3.13 (m, 2H). Example 56 – Preparation of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-6-methyl-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of 6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide. [0453] To a solution of 6-methyl-1H-pyrrolo[2,3-b]pyridine (3 g, 22.70 mmol) in EtOAc (30 mL) was added m-CPBA (5877 mg, 34.05 mmol) at 0 ^oC. Then left the mixture warm to r.t and stirred for 16 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give the title compound (2.98 g, yield: 89%) as a pink solid. ESI-MS (M+H) ⁺:149.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.52 (d, J = 3.1 Hz, 1H), 2.51 (s, 3H). Step 2: Preparation of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine. [0454] To a solution of 6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (3 g, 20.27 mmol) in dry DMF (20 mL) was added MsCl (6.97 g, 60.81 mmol)) under N₂. The mixture was stirred at 75 ^oC for 16 h. After cooling down to r.t, the mixture was diluted with water (100 mL) and extracted EtOAc (50 mL*3). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=5:1) to give the title compound (1.85 g, yield: 55%) as a white solid. ESI-MS (M+H) ⁺: 169.0.¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 7.46 (t, J = 2.8 Hz, 1H), 7.08 (s, 1H), 6.46 – 6.35 (m, 1H), 2.50 (s, 3H). Step 3: Preparation of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. [0455] To a solution of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (1.8 g, 10.84 mmol) in MeOH (20 mL) was added Raney-Ni (360 mg, 20% w.t). The mixture was stirred at 70 ^oC for 24 h under H₂. The mixture was cooled down to r.t. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 3:1) to provide title product (500 mg, yield: 26%) as a brown solid. ESI-MS (M+H) ⁺:169.0.¹H NMR (400 MHz, DMSO-d₆) δ 6.63 (s, 1H), 6.33 (s, 1H), 3.57 – 3.45 (m, 2H), 2.95 (t, J = 8.5 Hz, 2H), 2.18 (s, 3H). Step 4: Preparation of tert-butyl 4-(6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate. [0456] A mixture of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.49 mmol) and tert-butyl piperazine-1-carboxylate (830 mg, 4.46 mmol) was stirred at 140 ^oC for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH = 10:1) to provide title product (240 mg, yield: 51%) as a brown solid. ESI- MS (M+H) ⁺:319.3. Step 5: Preparation of tert-butyl 4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-6- methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0457] To a solution of tert-butyl 4-(6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (200 mg, 0.63 mmol) in THF (10 mL) were added TEA (191 mg, 1.89 mmol) and triphosgene (75 mg, 0.25 mmol) at 0 ^oC. Then 6-ethoxy-2-methyl-2H- indazol-5-amine (180 mg, 0.95 mmol) was added to the reaction after stirring for 1h. Then the mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:1) to provide title product (100 mg, yield: 30%) as a white solid. ESI-MS (M+H) ⁺:536.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.38 (s, 1H), 8.11 (d, J = 4.1 Hz, 2H), 7.91 (s, 1H), 4.29 (q, J = 6.9 Hz, 2H), 4.10 – 4.06 (m, 4H), 4.06 (s, 3H), 3.98 (t, J = 8.5 Hz, 2H), 3.25 – 3.21 (m, 4H), 3.05 (t, J = 8.3 Hz, 2H), 2.42 (s, 3H), 1.42 (s, 9H), 1.38 – 1.36 (m, 3H). Step 6: Preparation of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-6-methyl-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0458] To a solution of 4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-6-methyl-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (90 mg, 0.17 mmol) in DCM (1.5 mL) was added TFA (1.5 mL). The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (31 mg, yield: 42%) as a white solid. ESI-MS (M+H)⁺:436.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 8.75 (s, 2H), 8.38 (s, 1H), 8.12 (s, 1H), 7.04 (s, 1H), 6.48 (s, 1H), 4.30 (q, J = 7.0 Hz, 2H), 4.06 (s, 3H), 4.04 – 3.99 (m, 2H), 3.50 – 3.40 (m, 4H), 3.22 – 3.21 (m, 4H), 3.06 (t, J = 8.4 Hz, 2H), 2.44 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H). Example 57 – Preparation of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of methyl 6-bromo-2-methylimidazo[1,2-a]pyridine-7-carboxylate. [0459] To a solution of methyl 2-amino-5-bromoisonicotinate (37 g, 0.16 mol) in EtOH (500 mL) was added 1-chloropropan-2-one (149 g, 1.609 mol). The mixture was stirred at 90 oC for 16 h. After cooling to RT, the mixture was concentrated under reduced pressure, then the precipitate was filtered, washed by EA. The residue was dissolved in NaOH (2 M, 150 mL) and stirred at RT for 2 h. Then extracted with EA (200 mLx3) and the organic layer was washed with saturated NaCl solution and concentrated in vacuo. The crude was purified by silica gel column (PE: EA=4:1~1:1) to give the title compound (18 g, 41.6 %) as a yellow solid. ESI-MS (M+H) +: 268.9.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 3.87 (s, 3H), 2.38 (s, 3H). Step 2: Preparation of (6-bromo-2-methylimidazo[1,2-a]pyridin-7-yl)methanol. [0460] To a stirred solution of methyl 6-bromo-2-methylimidazo[1,2-a]pyridine-7- carboxylate (19 g, 70.9 mmol) in EtOH (250 mL) was added NaBH₄ (8.3 g, 212.7 mmol) and the mixture was stirred at r.t for 4 h. After diluting with water (40 mL), the solid was collected by filtration and washed with water (20 mL*3) to give title product (14 g, 82.4 %) as a white solid. ESI-MS (M+H)⁺: 241.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 4.50 (s, 2H), 2.32 (s, 3H). Step 3: Preparation of 6-bromo-2-methylimidazo[1,2-a]pyridine-7-carbaldehyde. [0461] To a solution of (6-bromo-2-methylimidazo[1,2-a]pyridin-7-yl)methanol (14.5 g, 0.06 mol) in DCM (200 mL) was added MnO₂ (26.3 g, 0.302 mmol), the mixture was stirred at 45 ^oC for 16 h. Then the mixture was filtered through a celite pad, and the filtrate was concentrated to give the crude product (12 g, crude) as a white solid. ESI-MS (M+H)⁺: 238.9. ¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.98 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 2.41 (s, 3H). Step 4: Preparation of 6-bromo-7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine. [0462] To a solution of 6-bromo-2-methylimidazo[1,2-a]pyridine-7-carbaldehyde (12 g, 0.05 mol) in DCM (150 mL) was added Bast (27.7 g,0.126 mol). The mixture was stirred at r.t for 4 h. The mixture was adjusted to pH≈8 with aq.NaHCO₃.Then the solution was extracted with DCM (100 mLx3) and the organic layer was concentrated in vacuo. The crude was purified by silica gel column (PE: EA=2:1~1:1) to give the title compound (3.2 g, 24.4 %) as a brown solid. ESI-MS (M+H) +: 260.7.¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 7.78 (d, J = 5.0 Hz, 2H), 7.12 (t, J = 54.1 Hz, 1H), 2.37 (s, 3H). Step 5: Preparation of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0463] A mixture of 6-bromo-7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine (3.2 g, 12.31 mmol), diphenylmethanimine (3.3 g, 18.46 mmol), Pd(OAc)₂ (276 mg, 1.23 mmol), BINAP (1.5 g, 2.46 mmol) and Cs₂CO₃ (12 g, 36.92 mmol) in 1,4-dioxane (50 mL) was purged with N₂ for three times. Then the reaction mixture was stirred at 100 ^oC for 16 h. After cooling to r.t, the mixture was concentrated to dryness. The crude was purified by silica gel column (PE: EA=1:1) to give the title product (3.5 g, 76.4 %) as a brown solid. ESI-MS: [M+H] ⁺ 362.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.74 – 7.70 (m, 2H), 7.68 (s, 1H), 7.62 (s, 1H), 7.59 – 7.55 (m, 1H), 7.52 – 7.47 (m, 3H), 7.40 – 7.33 (m, 3H), 7.25 – 7.22 (m, 2H), 2.26 (s, 3H). Step 6: Preparation of 4-fluoro-2-methylbenzo[d]oxazol-6-amine. [0464] A mixture of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (3 g, 8.31 mmol) in HCl / EA (4 M, 30 mL) was stirred at r.t for 16 h. The mixture was adjusted to pH≈9 with aq.NaHCO₃. The mixture was extracted with EA (50 mL x 2). The combined organics was concentrated. The crude was purified by silica gel column (PE: EA=1:1~1:7) to give the title compound (1 g, 61.1%) as yellow solid. ESI-MS: [M+H] ⁺ 198.¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (s, 1H), 7.61 (s, 1H), 7.47 (s, 1H), 7.08 (t, J = 54.6 Hz, 1H), 4.77 (s, 2H), 2.28 (s, 3H). Step 7: Preparation of tert-butyl 4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0465] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (200 mg, 0.66 mmol) and 7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- amine (130 mg, 0.66 mmol) in THF (12 mL) were added TEA (199 mg, 1.98 mmol) and triphosgene (487 mg, 1.64 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (10 mL), extracted with EA (10 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 1: 4) to give title product (120 mg, 34.7%) as a white solid. ESI-MS (M+H) ⁺: 528.4. Step 8: Preparation of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0466] A mixture of ttert-butyl 4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.189 mmol) in 4M HCl / EA (10 mL) was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (80 mg, 98.8 %) as a white solid. ESI-MS (M+H) ⁺: 428.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (s, 1H), 9.62 (s, 1H), 9.12 (s, 2H), 8.26 (s, 1H), 8.16 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.38 (t, J = 53.5 Hz, 1H), 6.65 (d, J = 6.2 Hz, 1H), 4.11 – 4.00 (m, 2H), 3.58 – 3.48 (m, 4H), 3.28 – 3.13 (m, 6H), 2.50 (s, 3H). Example 58 – Preparation of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4- (4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 7-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0467] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.60 mmol) and 7-fluoro-2,8- dimethylimidazo[1,2-a]pyridin-6-amine (109 mg, 0.60 mmol) in THF (10 mL) were added TEA (182 mg, 1.80 mmol) and triphosgene (449 mg, 1.51 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na₂ SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 1: 5) to give title product (90 mg, 27.8%) as a white solid. ESI-MS (M+H) ⁺: 536.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (d, J = 2.2 Hz, 1H), 9.12 (d, J = 7.1 Hz, 1H), 7.94 (d, J = 6.1 Hz, 1H), 7.75 (s, 1H), 6.59 (d, J = 6.2 Hz, 1H), 3.67 – 3.57 (m, 2H), 3.37 – 3.30 (m, 4H), 3.21 – 3.13 (m, 4H), 2.44 (d, J = 1.8 Hz, 3H), 2.35 (s, 3H), 1.48 (s, 9H), 1.03 – 0.97 (m, 2H), 0.93 – 0.88 (m, 2H). Step 2: Preparation of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0468] A mixture of tert-butyl 7-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (90 mg, 0.17 mmol) in 4M HCl / EA (6 mL) was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (61 mg, 83.3 %) as a white solid. ESI-MS (M+H) ⁺: 436.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (d, J = 2.1 Hz, 1H), 9.54 (d, J = 6.3 Hz, 1H), 9.43 (s, 2H), 8.15 (d, J = 0.9 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.64 (d, J = 6.2 Hz, 1H), 4.05 – 4.01 (m, 2H), 3.64 – 3.55 (m, 2H), 3.48 – 3.42 (m, 2H), 3.40 – 3.32 (m, 2H), 3.22 – 3.12 (m, 2H), 2.49 (s, 3H), 2.47 (d, J = 0.8 Hz, 3H), 1.11 – 0.89 (m, 4H). Example 59 – Preparation of N-(4-hydroxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of N-(4-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine. [0469] To a solution of 5-bromo-4-methoxy-2-methyl-2H-indazole (3 g,12.45 mmol) in 1,4- dioxane (50 mL) were added diphenylmethanimine (2.4 g,13.07 mmol), Cs₂CO₃ (8.1 g, 24.90 mmol), Pd(OAc)₂ (280 mg, 1.25 mmol), BINAP (1.55 g,2.49 mmol). The mixture was stirred at 115 ℃ for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title product (2 g, yield: 46 %) as a yellow solid. ESI-MS (M+H) ⁺:342.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.70 – 7.64 (m, 2H), 7.53 (dd, J = 8.4, 6.2 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 7.30 – 7.23 (m, 3H), 7.18 – 7.10 (m, 2H), 7.03 (dd, J = 8.9, 0.6 Hz, 1H), 6.62 (d, J = 8.9 Hz, 1H), 4.06 (s, 3H), 3.83 (s, 3H). Step 2: Preparation of 4-methoxy-2-methyl-2H-indazol-5-amine. [0470] A solution of N-(4-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (1.8 g, 5.26 mmol) in 3M HCl / EA (20 mL) was stirred at r.t for 3 h. The mixture was concentrated in vacuo, the residue was dissolved in water (10 mL), adjusted pH=10 by sat. Na₂CO₃. Then extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give title product (450 mg, yield: 48 %) as a yellow solid. ESI-MS (M+H) ⁺:178.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.09 (dd, J = 8.9, 0.8 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 4.41 (s, 2H), 4.06 (s, 3H), 3.84 (s, 3H). Step 3: Preparation of tert-butyl 4-(1-((4-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0471] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (90 mg, 0.30 mmol) in THF (5 mL) were added 4-methoxy-2-methyl-2H- indazol-5-amine (158 mg, 0.90 mmol), TEA (152 mg, 1.50 mmol) and triphosgene (178 mg, 0.60 mmol) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE= 2:1) to give title product (60 mg, yield: 39 %) as a white solid. ESI-MS (M+H) ⁺:508.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.52 (s, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 6.60 – 6.43 (m, 1H), 4.14 (s, 3H), 4.05 (s, 3H), 4.01 – 3.98 (m, 2H), 3.47 – 3.42 (m, 4H), 3.29 – 3.25 (m, 4H), 3.15 – 3.09 (m, 2H), 1.43 (s, 9H). Step 4: Preparation of N-(4-hydroxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0472] A mixture of tert-butyl 4-(1-((4-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (20 mg, 0.039 mmol) in BBr₃ (3 mL, 1.0 M in DCM) was stirred at r.t for 3 h. The mixture was quenched with MeOH (3 mL) at 0^oC and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (9.2 mg, 59 %) as a white solid. ESI-MS (M+H) ⁺:394.1.¹H NMR (400 MHz, MeOD-d₄) δ 8.24 – 8.20 (m, 1H), 7.92 (s, 1H), 7.26 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.73 (s, 1H), 4.28 – 4.20 (m, 2H), 4.18 (s, 3H), 3.72 – 3.67 (m, 2H), 3.42 – 3.39 (m, 4H), 3.32 – 3.31 (m, 4H). Example 60 – Preparation of N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0473] To a mixture of 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (250 mg, 0.82 mmol) in toluene (5 mL) were added DPPA (623 mg, 2.30 mmol) and TEA (332 mg, 3.29 mmol). The mixture was stirred at r.t for 1 h and warmed up to 90^oC and stirred for 1 h. tert- butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (289 mg, 1.64 mmol) was added to the mixture and stirred at 110^oC for 4 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3), the organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 2) to get title product (200 mg, Y: 51.0%) as a white solid. ESI-MS (M+H)⁺:478.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H), 8.30 (d, J = 3.4 Hz, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 7.1 Hz, 1H), 7.70 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 4.01 (t, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.47 – 3.43 (m, 4H), 3.31 – 3.27 (m, 4H), 3.17 – 3.13 (m, 2H), 1.43 (s, 9H). Step 2: Preparation of N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0474] To a solution of tert-butyl 4-(1-((1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (200 mg, 0.42 mmol) in EA (4 mL) was added 4 M HCl/EA (5 mL). The mixture was stirred at rt for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title product (166 mg, Y: 80.7%) as a yellow solid. ESI-MS (M+H)⁺:378.1.¹H NMR (400 MHz, MeOD-d4) δ 8.33 (d, J = 4.1 Hz, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 6.8 Hz, 1H), 7.63 (s, 1H), 7.24 (dd, J = 7.9, 5.0 Hz, 1H), 6.82 (d, J = 7.0 Hz, 1H), 4.33 (t, J = 8.5 Hz, 2H), 3.90 (s, 3H), 3.87 – 3.78 (m, 4H), 3.47 – 3.39 (m, 6H). Example 61 – Preparation of 4-(piperazin-1-yl)-N-(6-(trifluoromethyl)-2H-indazol-5-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 4-bromo-2-methyl-5-(trifluoromethyl)aniline. [0475] A mixture of 2-methyl-5-(trifluoromethyl)aniline (33 g, 188.57 mmol) in ACN (400 mL) was added NBS (33.6 g, 188.57 mmol) at 0^oC. The mixture was stirred at r.t for 2 h. The mixture was diluted with water (1000 mL) and extracted with EA (1000 mL x 3). The organic phase was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=5:1) to afford title product (31.6 g, 65.5%) as a brown oil. ESI-MS (M+H)⁺: 295.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.35 (s, 1H), 7.05 (s, 1H), 5.50 (s, 2H), 2.10 (s, 3H). Step 2: Preparation of 5-bromo-6-(trifluoromethyl)-1H-indazole. [0476] To a solution of 4-bromo-2-methyl-5-(trifluoromethyl)aniline (30 g, 118.5 mmol) in water (300 mL) was added acetic acid (7.11 g, 118.5 mmol) and sodium nitrite (8.18 g, 118.5 mmol) at 0^oC. Then the mixture was stirred at r.t overnight. The mixture was diluted with water (300 mL), the precipitate was filtered to provide title product (29 g, yield: 92.6%) as a yellow solid. ESI-MS (M+H)⁺: 265.0. Step 3: Preparation of 5-bromo-2-methyl-6-(trifluoromethyl)-2H-indazole. [0477] To a solution of 5-bromo-6-(trifluoromethyl)-1H-indazole (6 g, 22.84 mmol) in THF (1.5 mL) was added trimethyloxonium tetrafluoroborate (4.35 g, 29.43 mmol). Then the mixture was stirred at r.t for 2 hours. The mixture was diluted with H₂O (70 mL) and extracted with EA (70 mL x 3). The organic phase was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=1:1) to afford title product (3.3 g, 52.3%) as yellow solid. ESI-MS (M+H)⁺: 279.1. Step 4: Preparation of N-(2-methyl-6-(trifluoromethyl)-2H-indazol-5-yl)-1,1- diphenylmethanimine. [0478] To a solution of 5-bromo-2-methyl-6-(trifluoromethyl)-2H-indazole (2 g, 7.17 mmol) in 1,4-dioxane (20 mL) were added diphenylmethanimine (1.95 g, 10.75 mmol), Cs₂CO₃ (7.01 g, 21.5 mmol), Pd(OAc)₂ (161 mg, 0.71 mmol) and BIANP (893 mg, 1.43 mmol). Then the mixture was stirred at 100^oC for 16 hours under N₂. The mixture was diluted with H₂O (50 mL) and extracted with EA (50 mL x 3). The organic phase was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=1:1) to afford title product (2.7 g, 99.2%) as yellow solid. ESI-MS (M+H)⁺: 380.2. Step 5: Preparation of 2-methyl-6-(trifluoromethyl)-2H-indazol-5-amine HCl salt. [0479] To a solution of N-(2-methyl-6-(trifluoromethyl)-2H-indazol-5-yl)-1,1- diphenylmethanimine (2.7 g, 7.12 mmol) in EA (50 mL) was added 3 M HCl / EA (50 mL) at 0^oC. Then the mixture was stirred at r.t for 2 hours. The precipitate was filtered and dried to provide title product (1.5 g, yield: 98.6%) as a yellow solid. ESI-MS (M+H)⁺: 216.2. Step 6: Preparation of N-(2-methyl-6-(trifluoromethyl)-2H-indazol-5-yl)-1,1- diphenylmethanimine. [0480] To a solution of 2-methyl-6-(trifluoromethyl)-2H-indazol-5-amine (200 mg, 0.93 mmol) in DCM (8 mL) were added py (221 mg, 10.75 mmol) and phenyl carbonochloridate (893 mg, 1.43 mmol) at 0^oC. Then the mixture was stirred at r.t for 1 hours. The mixture was diluted with H₂O (30 mL) and extracted with DCM (30 mL x 3). The mixture was filtered and concentrated to provide title product (300 mg, yield: 96.4%) as a yellow solid. ESI-MS (M+H)⁺: 336.1 Step 7: Preparation of tert-butyl 4-(1-((2-methyl-6-(trifluoromethyl)-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0481] To a solution of phenyl (2-methyl-6-(trifluoromethyl)-2H-indazol-5-yl)carbamate (300 mg, 1.39 mmol) in THF (8 mL) were added tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate (509 mg, 1.67 mmol) and TEA (423 mg, 4.17 mmol) at 0^oC. Then the mixture was stirred at r.t for 16 hours. The mixture was diluted with H₂O (30 mL) and extracted with EA (30 mL x 3). The organic phase was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (PE: EA=1:1) to afford title product (140 mg, 57.3%) as yellow solid. ESI-MS (M+H)⁺: 546.3. Step 8: Preparation of 4-(piperazin-1-yl)-N-(6-(trifluoromethyl)-2H-indazol-5-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0482] To a solution of tert-butyl 4-(1-((2-methyl-6-(trifluoromethyl)-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (140 mg, 0.26 mmol) in EA (2 mL) was added 4M HCl / EA(4 mL) at 0^oC. Then the mixture was stirred at r.t for 2 hours. The precipitate was filtered, washed with EtOAc and purified by prep-HPLC (0.05% TFA in water / CH₃CN) to afford title product (100.9 mg, yield: 88.5%) as an off-white solid. ESI-MS (M+H)⁺: 446.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.41 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.77 (d, J = 7.3 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.37 (t, J = 8.5 Hz, 2H), 4.30 (s, 3H), 4.01 – 3.91 (m, 4H), 3.56 (t, J = 8.5 Hz, 2H), 3.48 – 3.41 (m, 4H). Example 62 – Preparation of N-(4-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of N-(4-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0483] To a solution of tert-butyl 4-(1-((4-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (20 mg, 0.039 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (10.43 mg, 65%) as a colorless oil. ESI-MS (M+H) ⁺:408.1.¹H NMR (400 MHz, MeOD-d₄) δ 8.45 (s, 1H), 7.84 – 7.75 (m, 2H), 7.27 (d, J = 9.1 Hz, 1H), 6.73 (d, J = 6.0 Hz, 1H), 4.22 – 4.18 ( m, 5H), 4.14 (s, 3H), 3.72 – 3.70 (m, 4H), 3.44 – 3.36 (m, 4H), 3.29 – 3.25 (m, 2H). Example 63 – Preparation of N-(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-4-(piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. PMB

Step 1: Preparation of 2-chloro-N,N-bis(4-methoxybenzyl)-3-nitropyridin-4-amine. [0484] To a mixture of 2,4-dichloro-3-nitropyridine (9.3 g, 48.19 mmol) in DMF (62 mL) were added TEA (7.3 g, 72.29 mmol) and NH(PMB)₂ (12.4 g, 48.19 mmol) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mLx3). The combined organic layer was washed with brine (100 mL x3), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=10:1) to give title product (8.8 g, yield: 44 %) as a yellow oil. ESI-MS (M+H) ⁺:414.1.¹H NMR (400 MHz, MeOD-d₄) δ 8.01 (d, J = 6.1 Hz, 1H), 7.11 (d, J = 8.6 Hz, 4H), 7.03 (d, J = 6.1 Hz, 1H), 6.90 – 6.85 (m, 4H), 4.35 (s, 4H), 3.76 (s, 6H). Step 2: Preparation of N4,N4-bis(4-methoxybenzyl)-N2-methyl-3-nitropyridine-2,4-diamine. [0485] To a solution of 2-chloro-N,N-bis(4-methoxybenzyl)-3-nitropyridin-4-amine (8.8 g, 21.25 mmol) in EtOH (62 mL) were added methanamine (40% in H₂O) (11.53 g, 148.75 mmol). The reaction mixture was stirred at 80℃ for 16 h in a sealed tube. The reaction was concentrated to give title product (11 g, crude) as a yellow oil. ESI-MS (M+H) ⁺:409.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (s, 1H), 7.49 (d, J = 4.6 Hz, 1H), 7.13 (d, J = 8.6 Hz, 4H), 6.87 (d, J = 8.7 Hz, 4H), 6.35 (d, J = 6.0 Hz, 1H), 4.23 (s, 3 H), 3.72 (s, 4H), 2.34 (s, 6H). Step 3: Preparation of N4,N4-bis(4-methoxybenzyl)-N2-methylpyridine-2,3,4-triamine. [0486] To a mixture of N4,N4-bis(4-methoxybenzyl)-N2-methyl-3-nitropyridine-2,4-diamine (11 g, 26.89 mmol) in MeOH (150 mL) was added Pd /C (1.1 g, 10% w.t). The mixture was charged with H₂ for three times and stirred at r.t for 2 h. The mixture was filtered and the filtrate concentration to afford title product (7.2 g, Y=70%) as a yellow oil. ESI-MS (M+H)⁺ 379.3.¹H NMR (400 MHz, DMSO-d₆) δ 7.77 (s, 1H), 7.24 (d, J = 5.6 Hz, 1H), 7.17 (d, J = 8.6 Hz, 4H), 6.82 (d, J = 8.6 Hz, 4H), 6.22 (d, J = 5.7 Hz, 1H), 3.94 (s, 4H), 3.70 (s, 6H), 3.17 (s, 3H). Step 4: Preparation of N,N-bis(4-methoxybenzyl)-3-methyl-3H-imidazo[4,5-b]pyridin-7- amine. [0487] A mixture of N4,N4-bis(4-methoxybenzyl)-N2-methylpyridine-2,3,4-triamine (7.2 g, 18.99 mmol) in trimethoxymethane (100 mL) was stirred at 100℃ for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to give title product (6.5 g, yield: 87 %) as a white solid. ESI-MS (M+H) ⁺:389.6.¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 4H), 6.86 (d, J = 8.7 Hz, 4H), 6.29 (d, J = 5.8 Hz, 1H), 5.04 (s, 4H), 3.75 (s, 3H), 3.71 (s, 6H). Step 5: Preparation of 3-methyl-3H-imidazo[4,5-b]pyridin-7-amine. [0488] A mixture of N,N-bis(4-methoxybenzyl)-3-methyl-3H-imidazo[4,5-b]pyridin-7-amine (6.5 g, 16.70 mmol) in TFA (100 mL) was stirred at 70℃ for 3 h. The mixture was concentrated in vacuo, the residue was dissolved in water (30 mL), adjusted pH=10 by sat. Na₂CO₃. Then extracted with EA (50 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to give title product (1.3 g, 52%) as a green solid. ESI-MS (M+H) ⁺:149.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H), 7.89 (d, J = 5.4 Hz, 1H), 6.39 (dd, J = 17.0, 13.9 Hz, 3H), 3.78 (s, 3H). Step 6: Preparation of phenyl (3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)carbamate. [0489] To a solution of 3-methyl-3H-imidazo[4,5-b]pyridin-7-amine (150 mg, 1.01 mmol) in DCM (5 mL) were added phenyl carbonochloridate (190 mg, 1.22 mmol) and Pyridine (239 mg, 3.03 mmol) at 0℃. The mixture was stirred at r.t for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=2:1) to give title product (150 mg, yield: 55 %) as a white solid. ESI-MS (M+H) ⁺:270.0. Step 7: Preparation of tert-butyl 4-(1-((3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0490] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) in THF (5 mL) were added phenyl (3-methyl-3H- imidazo[4,5-b]pyridin-7-yl)carbamate (89 mg, 0.33 mmol) and TEA (100 mg, 0.99 mmol). The reaction mixture was stirred at 70℃ for 16 h in a sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (60 mg, yield: 37 %) as a white solid. ESI-MS (M+H) ⁺:479.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.74 (s, 1H), 8.32 (s, 1H), 8.23 (d, J = 5.5 Hz, 1H), 8.07 (d, J = 5.5 Hz, 1H), 7.98 (d, J = 6.1 Hz, 1H), 6.56 (d, J = 6.1 Hz, 1H), 4.08 – 4.01 (m, 2H), 3.83 (s, 3H), 3.48 – 3.42 (m, 4H), 3.31 – 3.27 (m, 4H), 3.20 – 3.14 (m, 2H), 1.43 (s, 9H). Step 8: Preparation of N-(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0491] To a solution of tert-butyl 4-(1-((3-methyl-3H-imidazo[4,5-b]pyridin-7- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (30 mg, 60%) as a white solid. ESI-MS (M+H) ⁺:379.0.¹H NMR (400 MHz, MeOD-d₄) δ 8.47 (s, 1H), 8.34 (d, J = 5.8 Hz, 1H), 8.16 (dd, J = 15.0, 6.0 Hz, 2H), 6.69 (d, J = 6.1 Hz, 1H), 4.21 (t, J = 8.5 Hz, 2H), 3.98 (s, 3H), 3.63 – 3.56 (m, 4H), 3.41 – 3.37 (m, 4H), 3.27 – 3.22 (m, 2H). Example 64 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(2,6- diazaspiro[3.3]heptan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 6-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate. [0492] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (587 mg, 3.79 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (500 mg, 2.53 mmol) in DIEA (3 mL) was stirred at 140^oC for 16 h in a sealed tube. The mixture was concentrated in vacuo and purified by silica gel column (DCM: MeOH = 15: 1) to give title product (250 mg, Y: 31.2%) as a yellow oil. ESI-MS (M+H) ⁺: 317.1. Step 2: Preparation of tert-butyl 6-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate. [0493] A mixture of tert-butyl 6-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (200 mg, 0.59 mmol) and phenyl (7-fluoro-2-methyl- 2H-indazol-5-yl)carbamate (340 mg, 1.19 mmol) in THF (10 mL) was added TEA (179 mg, 1.77 mmol). The mixture was stirred at 70^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 4) to give title product (120 mg, Y: 39.8%) as a white solid. ESI-MS (M+H) ⁺: 508.3.¹H NMR (400 MHz, CDCl₃) δ 11.68 (s, 1H), 7.74 (d, J = 5.9 Hz, 1H), 7.42 (s, 1H), 7.01 – 6.95 (m, 1H), 6.82 (s, 1H), 6.72 (d, J = 13.5 Hz, 1H), 4.13 – 4.12 (m, 4H), 4.04 (s, 3H), 3.66 – 3.60 (m, 4H), 3.53 – 3.46 (m, 2H), 3.06 – 2.95 (m, 2H), 1.36 (s, 9H). Step 3: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(2,6-diazaspiro[3.3]heptan- 2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0494] A mixture of ttert-butyl 6-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (110 mg, 0.22 mmol) in DCM (6 mL) and TFA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (46 mg, Y: 52.1%) as a white solid. ESI-MS (M+H) ⁺: 408.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 2H), 8.38 (s, 1H), 7.78 (s, 1H), 7.69 (d, J = 1.3 Hz, 1H), 7.25 (d, J = 13.3 Hz, 1H), 6.13 (s, 1H), 4.56 – 4.22 (m, 6H), 4.20 – 4.18 (m, 2H), 4.17 (s, 3H), 4.16 – 4.14 (m, 2H), 3.24 – 3.05 (m, 2H). Example 65 – Preparation of N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

[0495] To a solution of 5-fluoro-2-methylaniline (1 g, 8.00 mmol) in ACN (10 mL) was added NCS (1117 mg, 8.40 mmol). The resulting mixture was stirred at 80 ^o C for 2 h. The mixture was diluted with water (10 mL), extracted with EA (10 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE/EA=4:1) to give title product (900 mg, Y: 70 %) as a brown solid. ESI-MS (M+H) ⁺:160.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.03 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 11.9 Hz, 1H), 5.30 (s, 2H), 2.00 (s, 3H). Step 2: Preparation of 2-bromo-4-chloro-3-fluoro-6-methylaniline. [0496] To a solution of 4-chloro-5-fluoro-2-methylaniline (800 mg, 5.00 mmol) in ACN (10 mL) was added NBS (889 mg, 5.00 mmol). The resulting mixture was stirred at 0 ^o C for 2 h. The mixture was diluted with water (10 mL), extracted with EA (10 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE/EA=4:1) to give title product (1 g, Y: 83 %) as a white solid. ESI-MS (M+H) ⁺:239.9.¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (d, J = 8.2 Hz, 1H), 2.12 (s, 3H). Step 3: Preparation of 7-bromo-5-chloro-6-fluoro-1H-indazole. [0497] To a solution of 2-bromo-4-chloro-3-fluoro-6-methylaniline (1 g, 4.20 mmol) in AcOH (10 mL) was added NaNO₂ (290 mg, 4.20 mmol) in H₂O (3 mL). The resulting mixture was stirred at RT for 17 h. The mixture was pour into ice-water (10 mL), extracted with EA (10 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE/EA=2:1) to give title product (547 mg, Y: 52 %) as a brown solid. ESI-MS (M+H) ⁺:248.9. ¹H NMR (400 MHz, DMSO-d₆) δ 13.83 (s, 1H), 8.24 (s, 1H), 8.09 (d, J = 6.7 Hz, 1H). Step 4: Preparation of 7-bromo-5-chloro-6-fluoro-2-methyl-2H-indazole. [0498] To a solution of 7-bromo-5-chloro-6-fluoro-1H-indazole (447 mg, 1.80 mmol) in EA (5 mL) was added trimethyloxonium tetrafluoroborate (320 mg, 2.16 mmol). The resulting mixture was stirred at RT for 2 h. The mixture was diluted with water (5 mL), extracted with EA (5 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title product (500 mg, crude) as a brown solid. ESI-MS (M+H+41) ⁺: 264.9. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H), 4.21 (s, 3H). Step 5: Preparation of 5-chloro-6-fluoro-2,7-dimethyl-2H-indazole. [0499] To a solution of 7-bromo-5-chloro-6-fluoro-2-methyl-2H-indazole (450 mg, 1.17 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (432 mg, 3.42 mmol) in 1,4-dioxane / H₂O (10 mL, 5:1) were added Pd(dppf)Cl₂ (125 mg, 0.17 mmol) and K₂CO₃ (708 mg, 5.13 mmol). The resulting mixture was stirred at 80 ^o C under N₂ (balloon) for 16 h. The mixture was allowed to cooling down to room temperature and concentrated in vacuo. The mixture was diluted with water (10 mL), extracted with EA (10 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE/EA=1:1) to give title product (197 mg, Y: 84%) as a white solid. ESI- MS (M+H⁺):199.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.76 (d, J = 7.2 Hz, 1H), 4.11 (s, 3H), 2.39 (d, J = 2.2 Hz, 3H). Step 6: Preparation of N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine. [0500] To a solution of 5-chloro-6-fluoro-2,7-dimethyl-2H-indazole (880 mg, 4.44 mmol) and diphenylmethanimine (1207 mg, 6.67 mmol) in 1,4-dioxane (10 mL) were added BINAP (555 mg, 0.88 mmol), Pd(OAc)₂ (99 mg, 0.44 mmol) and Cs₂CO₃ (4329 mg, 13.32 mmol). The reaction solution was stirred at 120℃ for 16 h under N₂. The reaction was diluted with H₂O (10 mL), extracted with EA (10 mLx3), the organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by reserve silica gel column chromatography (PE: EA=2:1) to give title product (1.1 g, yield: 73%) as a green solid. ESI- MS (M+H) ⁺: 344.2. Step 7: Preparation of 6-fluoro-2,7-dimethyl-2H-indazol-5-amine HCl salt. [0501] To a solution of N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-1,1- diphenylmethanimine (1 g, 2.92 mmol) in EA (5 mL) was added 4M HCl/EA (10 mL). The reaction solution was stirred at RT for 2 h. The mixture was filtered, washed with EA (20 mL) and the filtrate cake was concentrated in vacuo and diluted with EA (20 mL). The reaction solution was stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (600 g, y: 97%) as a white solid. ESI-MS (M+H) ⁺: 180.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (s, 1H), 7.84 – 7.76 (m, 1H), 4.18 (s, 3H), 2.45 (d, J = 1.9 Hz, 3H). Step 8: Preparation of tert-butyl 7-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5-yl) carbamoyl) - 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate. [0502] To a solution of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-4,7- diazaspiro [2.5] octane-4-carboxylate (200 mg, 0.61 mmol) in THF (4 mL) were added TEA (185 mg, 1.83 mmol) and triphosgene (217 mg, 0.73 mmol) at 0^oC for 0.5 h.6-fluoro-2,7- dimethyl-2H-indazol-5-amine (131 mg, 0.73 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na₂ SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 0: 1) to give title product (60 mg, 18%) as a yellow solid. ESI-MS (M+H) ⁺: 536.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (d, J = 3.0 Hz, 1H), 8.28 (d, J = 6.2 Hz, 2H), 7.90 (d, J = 6.0 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 4.04 – 3.97 (m, 2H), 3.59 – 3.56 (m, 2H), 3.31 – 3.28 (m, 2H), 3.14 – 3.09 (m, 4H), 2.44 (d, J = 1.7 Hz, 3H), 1.43 (s, 9H), 0.97 – 0.92 (m, 2H), 0.89 – 0.83 (m, 3H). Step 9: Preparation of N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-4-(4,7-diazaspiro [2.5] octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0503] To a solution of tert-butyl 7-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (50 mg, 0.09 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (34.95 mg, yield: 71 %) as a white solid. ESI- MS (M+H) ⁺: 436.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.87 (s, 1H), 9.28 (s, 2H), 8.27 (s, 1H), 8.24 (d, J = 6.5 Hz, 1H), 7.95 (d, J = 6.1 Hz, 1H), 6.61 (d, J = 6.1 Hz, 1H), 4.13 (s, 3H), 4.03 (t, J = 8.5 Hz, 2H), 3.63 – 3.54 (m, 2H), 3.43 (s, 2H), 3.40 – 3.33 (m, 2H), 3.14 (t, J = 8.4 Hz, 2H), 2.43 (d, J = 1.8 Hz, 3H), 1.05 (t, J = 6.2 Hz, 2H), 0.95 (t, J = 6.4 Hz, 2H). Example 66 – Preparation of N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5-yl) carbamoyl) - 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate. [0504] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (200 mg, 0.66 mmol) in THF (4 mL) were added TEA (200 mg, 1.98 mmol) and triphosgene (235 mg, 0.79 mmol) at 0^oC for 0.5 h.6-fluoro-2,7-dimethyl-2H-indazol-5- amine (142 mg, 0.79 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA =0: 1) to give title product (93 mg, 27%) as a yellow solid. ESI-MS (M+H) ⁺: 510.0.¹H NMR (400 MHz, DMSO-d6) δ 11.99 (d, J = 3.0 Hz, 1H), 8.30 – 8.24 (m, 2H), 7.92 (d, J = 6.1 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 4.03 – 3.99 (m, 2H), 3.46 – 3.44 (m, 4H), 3.30 – 3.28 (m, 4H), 3.16 – 3.12 (m, 2H), 2.44 (d, J = 1.7 Hz, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0505] To a solution of tert-butyl 4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (80 mg, 0.16 mmol) in EA (1 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (25.03 mg, yield: 30 %) as a white solid. ESI-MS (M+H) ⁺: 410.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.69 (s, 1H), 9.04 (s, 2H), 8.28 (s, 1H), 8.21 (s, 1H), 7.94 (d, J = 6.1 Hz, 1H), 6.63 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 4.05 (t, J = 8.4 Hz, 2H), 3.53 (s, 4H), 3.24 (s, 4H), 3.17 (t, J = 8.3 Hz, 2H), 2.43 (d, J = 1.6 Hz, 3H). Example 67 – Preparation of N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 7-(1-((2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0506] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (369.6 mg, 1.12 mmol), 2-methylimidazo[1,2-a]pyridin- 6-amine (110 mg, 0.75 mmol), triphosgene (325.9 mg, 1.12 mmol) and TEA (339.3 mg, 3.36 mmol) in THF (20 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo, the crude was purified by silica gel column chromatography (MeOH: DCM= 15 %) to give title product (500 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 504.3. Step 2: Preparation of N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7-diazaspiro[2.5]octan-7- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0507] A mixture of tert-butyl 7-(1-((2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5] octane-4-carboxylate (100 mg, 0.20 mmol) in 3M HCl / EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (0.98 mg, yield: 1.17 %) as a white solid. ESI-MS (M+H) ⁺: 404.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.34 (d, J = 1.1 Hz, 1H), 8.02 (d, J = 6.2 Hz, 1H), 7.96 – 7.90 (m, 2H), 7.79 (d, J = 9.6 Hz, 1H), 6.66 (d, J = 6.2 Hz, 1H), 4.16 (t, J = 8.5 Hz, 2H), 3.71 – 3.65 (m, 2H), 3.54 – 3.49 (m, 4H), 3.22 (t, J = 8.5 Hz, 2H), 2.54 (s, 3H), 1.18 – 1.13 (m, 2H), 1.11 – 1.06 (m, 2H). Example 68 – Preparation of N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

C^{ompound 68} Step 1: Preparation of tert-butyl 7-(1-((2-methylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0508] To a solution of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.66 mmol) and 2-methylpyrazolo[1,5- a]pyridin-5-amine (132 mg, 0.90 mmol) in THF (10 mL) were added TEA (182 mg, 1.80 mmol) and a solution of triphosgene (71 mg, 0.24 mmol) in THF (1 mL) at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:1) to provide title product (50 mg, yield: 17%) as a white solid. ESI-MS (M+H)⁺: 504.4.¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 6.78 (dd, J = 7.5, 2.2 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 6.14 (s, 1H), 5.91 (s, 1H), 4.14 (dd, J = 11.3, 5.9 Hz, 2H), 3.71 – 3.67 (m, 2H), 3.30 – 3.23 (m, 2H), 3.09 – 3.00 (m, 4H), 2.44 (s, 3H), 1.48 (s, 9H), 1.08 (t, J = 6.4 Hz, 2H), 0.85 – 0.83 (m, 2H). Step 2: Preparation of N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(4,7-diazaspiro[2.5]octan- 7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0509] To a solution of tert-butyl 7-(1-((2-methylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (40 mg, 0.08 mmol) in DCM (0.5 mL) was added TFA (0.5 mL). The mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (14 mg, yield: 42%) as a white solid. ESI-MS (M+H)⁺:404.2.¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (s, 2H), 8.47 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 6.91 – 6.83 (m, 1H), 6.65 (d, J = 6.2 Hz, 1H), 6.23 (s, 1H), 4.03 (t, J = 7.8 Hz, 2H), 3.66 – 3.56 (m, 2H), 3.45 (s, 2H), 3.41 – 3.32 (m, 2H), 3.14 (t, J = 8.0 Hz, 2H), 2.34 (s, 3H), 1.05 (t, J = 6.0 Hz, 2H), 0.95 (t, J = 6.2 Hz, 2H). Example 69 – Preparation of N-(2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

step 1 ^100o _{C, 16h, N2} step 2

sep step 5

Step 1: Preparation of 6-bromo-2-ethyl-8-fluoroimidazo[1,2-a]pyridine. [0510] To a solution of 5-bromo-3-fluoropyridin-2-amine (10 g, 52.36 mmol) in EtOH (150 mL) were added 1-chlorobutan-2-one (5.58 g, 52.36 mmol) and NaI (1.57 g, 10.47 mmol). The mixture was stirred at 85^oC for 16 h in a sealed tube. The mixture was diluted with water (300 mL) and extracted with EA (120 mL x 3). The organic layer was washed with brine (100 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (C18, ACN/0.1% FA in H₂O=0 % to 40 %) to afford title product (1 g, 7.86 % yield) as a yellow solid. ESI-MS (M+H) ⁺:243.1.¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 1.2 Hz, 1H), 7.38 (d, J = 3.0 Hz, 1H), 6.98 (dd, J = 9.6, 1.5 Hz, 1H), 2.84 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H). Step 2: Preparation of N-(2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0511] To a solution of 6-bromo-2-ethyl-8-fluoroimidazo[1,2-a]pyridine (1 g, 4.11 mmol) in 1,4-dioxane (20 mL) were added diphenylmethanimine (890 mg, 4.94 mmol), Pd(OAc)₂ (90 mg, 0.41 mmol), BINAP (510 mg, 0.82 mmol) and Cs₂CO₃ (4.02 g, 12.30 mmol). The mixture was stirred at 100^oC for 16 h under N₂. The mixture was diluted with water (50 mL) and extracted with EA (35 mL x 3). The organic layer was washed with brine (40 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, EA/PE=0 % to 50 %) to afford title product (890 mg, 63.00 % yield) as a yellow solid. ESI- MS (M+H) ⁺:344.2.¹H NMR (400 MHz, CDCl₃) δ 7.75 – 7.71 (m, 2H), 7.53 – 7.48 (m, 1H), 7.44 – 7.40 (m, 3H), 7.37 – 7.31 (m, 3H), 7.24 (d, J = 3.0 Hz, 1H), 7.16 (dd, J = 7.7, 1.6 Hz, 2H), 6.38 (dd, J = 11.5, 1.5 Hz, 1H), 2.79 (q, J = 7.6 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H). Step 3: Preparation of 2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-amine hydrochloride. [0512] A mixture of N-(2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (400 mg, 1.16 mmol) in HCl / EA (8 mL, 4 M) was stirred at r.t for 2 h. The mixture was concentrated. The crude was beating with EA. The mixture was filtered and the filter cake was dried to get title product as a white solid (240 mg, 95.54% yield). ESI-MS (M+H) ⁺:180.3.¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H), 7.81 (s, 1H), 7.36 (d, J = 11.7 Hz, 1H), 2.78 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H). Step 4: Preparation of phenyl (2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate. [0513] To a solution of 2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-amine hydrochloride (240 mg, 1.34 mmol) in DCM (5 mL) were added phenyl carbonochloridate (252 mg, 1.61 mmol) and Pyridine (318 mg, 4.02 mmol) at 0^oC. The mixture was stirred at r.t for 1 h. The mixture was diluted with H₂O (25 mL) and extracted with DCM (15 mL x 3). The organic layer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated to afford title product (370 mg, 100 % yield) as a yellow solid. ESI-MS (M+H) ⁺:300.1. Step 5: Preparation of tert-butyl 7-(1-((2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0514] To a solution of phenyl (2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate (370 mg, 0.49 mmol) in THF (10 mL) were added tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (163 mg, 0.49 mmol) and DIEA (0.21 mL, 1.48 mmol), the mixture was stirred at 50^oC for 5 h. The mixture was diluted with H₂O (30 mL) and extracted with EA (20 mL x 3). The organic layer was washed with brine (30 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (EA/PE=0 % to 50 %) to afford title product (120 mg, 60.41 % yield) as a yellow solid. ESI-MS (M+H) ⁺:536.3. Step 6: Preparation of N-(2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0515] To a solution of tert-butyl 7-(1-((2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (100 mg, 0.19 mmol) in DCM (2 mL) was added TFA (1 mL), the mixture was stirred at r.t for 1 h. The mixture was concentrated and purified by prep-HPLC (0.05% TFA in H₂O / ACN) to get title product (41.97 mg, 51.62% yield) as a yellow solid. ESI-MS (M+H) ⁺:436.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.18 (d, J = 1.2 Hz, 1H), 8.08 – 8.06 (m, 1H), 8.02 (d, J = 6.2 Hz, 1H), 7.93 (dd, J = 11.6, 1.5 Hz, 1H), 6.65 (d, J = 6.2 Hz, 1H), 4.18 – 4.12 (m, 2H), 3.66 (d, J = 5.1 Hz, 2H), 3.52 – 3.49 (m, 2H), 3.48 (s, 2H), 3.20 (t, J = 8.5 Hz, 2H), 2.92 (q, J = 7.5 Hz, 2H), 1.41 (t, J = 7.6 Hz, 3H), 1.16 – 1.07 (m, 4H).

Example 70 – Preparation of N-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of 6-bromo-8-fluoroimidazo[1,2-a]pyridine. [0516] To a solution of 5-bromo-3-fluoropyridin-2-amine (5 g, 26.18 mmol) in EtOH (80 mL) was added 2-chloroacetaldehyde (3.06 g, 39.27 mmol). The mixture was stirred reflux at 100^oC for 16 h. The mixture was diluted with NaHCO₃ solution (150 mL) and extracted with EA (80 mL x 3). The organic layer was washed with brine (100 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO2, EA/PE=0 % to 50 %) to afford title product (4.5 g, 79.95 % yield) as a yellow solid. ESI-MS (M+H) ⁺:215.1.¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 1.0 Hz, 1H), 7.66 (d, J = 1.0 Hz, 1H), 7.63 (dd, J = 3.0, 1.1 Hz, 1H), 7.02 (dd, J = 9.5, 1.5 Hz, 1H). Step 2: Preparation of N-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-1,1-diphenylmethanimine. [0517] To a solution of 6-bromo-8-fluoroimidazo[1,2-a]pyridine (2.5 g, 11.63 mmol) in 1,4- dioxane (50 mL) were added diphenylmethanimine (2.53 g, 13.95 mmol), Pd(OAc)₂ (261 mg, 1.16 mmol), BINAP (1.45 g, 2.33 mmol) and Cs₂CO₃ (11.36 g, 34.88 mmol). The mixture was stirred at 100^oC for 16 h under N₂. The mixture was diluted with water (50 mL) and extracted with EA (30 mL x 3). The organic layer was washed with brine (40 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, EA/PE=0 % to 70 %) to afford title product (2.6 g, 70.91 % yield) as a yellow solid. ESI-MS (M+H) ⁺:316.2.¹H NMR (400 MHz, CDCl₃) δ 7.73 – 7.70 (m, 2H), 7.53 – 7.51 (m, 1H), 7.50 – 7.45 (m, 3H), 7.43 – 7.38 (m, 2H), 7.35 – 7.29 (m, 3H), 7.16 – 7.12 (m, 2H), 6.42 (dd, J = 11.4, 1.5 Hz, 1H). Step 3: Preparation of 8-fluoroimidazo[1,2-a]pyridin-6-amine hydrochloride. [0518] A mixture of N-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-1,1-diphenylmethanimine (400 mg, 1.27 mmol) in HCl / EA (8 mL, 4 M) was stirred at r.t for 2 h. The mixture was filtered and the filter cake was dried to get title product as a white solid (230 mg, 96.65% yield). ESI- MS (M+H) ⁺:152.2. Step 4: Preparation of phenyl (8-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate. [0519] To a solution of 8-fluoroimidazo[1,2-a]pyridin-6-amine hydrochloride (230 mg, 1.23 mmol) in DCM (6 mL) were added phenyl carbonochloridate (232 mg, 1.48 mmol) and Pyridine (292 mg, 3.69 mmol), the mixture was stirred at r.t for 1 h. The mixture was diluted with H₂O (40 mL) and extracted with DCM (20 mL x 3). The organic layer was washed with brine (30 mL), dried over Na₂SO₄ and concentrated to afford title product (440 mg, 100 % yield) as a yellow solid. ESI-MS (M+H) ⁺:272.1. Step 5: Preparation of tert-butyl 7-(1-((8-fluoroimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0520] To a solution of phenyl (8-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate (440 mg, 1.62 mmol) in THF (10 mL) were added tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 4,7-diazaspiro[2.5]octane-4-carboxylate (85 mg, 0.26 mmol) and DIEA (0.68 mL, 4.87 mmol), the mixture was stirred at 50^oC for 5 h. The mixture was diluted with H₂O (25 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (EA/PE=0 % to 50 %) to afford title product (100 mg, 12.15 % yield) as a yellow solid. ESI- MS (M+H) ⁺:508.1. Step 6: Preparation of N-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-(4,7-diazaspiro[2.5]octan-7- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0521] To a solution of tert-butyl 7-(1-((8-fluoroimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (50 mg, 0.099 mmol) in DCM (1 mL) was added TFA (0.5 mL), the mixture was stirred at r.t for 1 h. The mixture was concentrated and purified by prep-HPLC (0.05% TFA in H₂O / ACN) to get title product (16.54 mg, 40.78% yield) as a yellow solid. ESI-MS (M+H) ⁺:408.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.21 (s, 1H), 8.24 (t, J = 2.0 Hz, 1H), 8.03 (d, J = 6.2 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 12.7 Hz, 1H), 6.65 (d, J = 6.2 Hz, 1H), 4.17 – 4.11 (m, 2H), 3.68 – 3.64 (m, 2H), 3.52 – 3.50 (m, 2H), 3.48 (s, 2H), 3.20 (t, J = 8.4 Hz, 2H), 1.15 – 1.07 (m, 4H). Example 71 – Preparation of N-(4-fluoro-2-methyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of 5-bromo-4-fluoro-2-methyl-2H-indazole. [0522] To a mixture of 5-bromo-4-fluoro-1H-indazole (10 g, 46.51 mmol) in EA (200 mL) was added trimethyloxonium tetrafluoroborate (10 g, 69.76 mmol) at r.t. The mixture was stirring at the same temperature for 16 h. The mixture was quenched with sat. NaHCO₃ (150 mL) and extracted with EA (200 mL*2). The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound (9.7 g, 91.06%) as a yellow solid. ESI-MS (M+H) ⁺: 228.9.¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.44 – 7.28 (m, 2H), 4.22 (s, 3H). Step 2: Preparation of N-(4-fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine. [0523] To a solution of 5-bromo-4-fluoro-2-methyl-2H-indazole (4 g, 17.46 mmol), diphenylmethanimine (3.48 g, 19.21 mmol), Cs2CO3 (17.07 g, 52.39 mmol) and Pd(OAc)2 (196 mg, 0.87 mmol) in 1,4-dioxane (20 mL) was added BIANP (1.09 g, 1.75 mmol), the mixture was stirred at 100^oC for 16 h under N₂. The mixture was diluted with water (300 mL), extracted with EA (180 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuo. The mixture was purified by silica gel column chromatography (PE: EA= 2: 1) to give title product (6.2 g, crude) as a yellow solid ESI-MS (M+H) ⁺: 330.2. Step 3: Preparation of 4-fluoro-2-methyl-2H-indazol-5-amine HCl salt. [0524] To a solution of N-(4-fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (5.8 g, 17.61 mmol) in EA (50 mL) was added HCl in EA (50 mL, 3 M), the mixture was stirred at r.t for 5 h. The precipitate was filtered, the solid was triturated with EA (120 mL) and filtered to give the title compound (2.5 g, 85.96 %) as a pink solid. ESI-MS (M+H) ⁺: 166.1.¹H NMR (400 MHz, DMSO-d₆) δ 10.13 (s, 2H), 8.71 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.45 (dd, J = 8.9, 7.4 Hz, 1H), 6.65 (s, 2H), 4.22 (s, 3H). Step 4: Preparation of tert-butyl 7-(1-((4-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0525] To a solution of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (300 mg, 0.91 mmol) and 4-fluoro-2-methyl-2H-indazol- 5-amine (225 mg, 1.36 mmol) in THF (30 mL) was added TEA (459 mg, 4.54 mmol), triphosgene (404 mg, 1.36 mmol) was added slowly at 0^oC. The mixture was stirring at r.t for 16 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE: EA= 1: 3) to give the compound (180 mg, 38.01 %) as a yellow solid. ESI-MS (M+H) ⁺: 522.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 8.53 (d, J = 5.0 Hz, 1H), 7.97 (dd, J = 14.9, 7.4 Hz, 2H), 7.48 (d, J = 9.2 Hz, 1H), 6.59 (d, J = 6.1 Hz, 1H), 4.25 (s, 3H), 4.08 – 4.01 (m, 2H), 3.66 – 3.59 (m, 2H), 3.37 – 3.34 (m, 2H), 3.23 – 3.14 (m, 4H), 1.49 (s, 9H), 1.01 – 1.00 (m, 2H), 0.91 (t, J = 6.9 Hz, 2H). Step 5: Preparation of N-(4-fluoro-2-methyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan-7- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0526] To a mixture of tert-butyl 7-(1-((4-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (160 mg, 0.31 mmol) in EA (5 mL) was added 3M HCl/EA (3 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (90 mg, Y: 69.61 %) as a white solid. ESI-MS (M+H) ⁺: 422.2.¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 2H), 8.50 (s, 1H), 7.91 (d, J = 5.8 Hz, 1H), 7.78 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H), 6.67 (s, 1H), 4.18 (s, 3H), 4.11 – 4.02 (m, 2H), 3.69 – 3.60 (m, 2H), 3.54 – 3.45 (m, 2H), 3.42 – 3.33 (m, 2H), 3.23 – 3.13 (m, 2H), 1.06 – 1.05 (m, 2H), 0.96 – 0.94 (m, 2H). Example 72 – Preparation of N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of phenyl (2-methylpyrazolo[1,5-a]pyridin-5-yl)carbamate. [0527] To a solution of 2-methylpyrazolo[1,5-a]pyridin-5-amine (200 mg, 1.36 mmol) in DCM (5 mL) were added pyridine (322 mg, 4.08 mmol) and phenyl carbonochloridate (255 mg, 1.63 mmol) at 0 ^oC. The mixture was stirred at r.t for 2 h. The mixture was diluted with water and extracted with DCM (5 mL*3). The organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give title compound (260 mg, yield: 72%) as a brown solid. ESI-MS (M+H) ⁺: 268.1.¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.49 (d, J = 7.5 Hz, 1H), 7.35 – 7.31 (m, 2H), 7.28 – 7.24 (m, 2H), 7.18 – 7.13 (m, 1H), 6.86 (dd, J = 7.5, 2.3 Hz, 1H), 6.76 – 6.74 (m, 1H), 6.24 (s, 1H), 2.33 (s, 3H). Step 2: Preparation of tert-butyl 4-(1-((2-methylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0528] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.49 mmol ), phenyl (2-methylpyrazolo[1,5-a]pyridin-5-yl)carbamate (158 mg, 0.59 mmol) and TEA (148 mg, 1.47 mmol) in THF (5 mL) was stirred at 70 ^oC for 16h. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE: EA=1:1) to give the title compound (100 mg, yield: 43%) as a white solid. ESI-MS (M+H) ⁺:478.0.¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 6.2 Hz, 1H), 6.78 (dd, J = 7.5, 2.2 Hz, 1H), 6.43 (d, J = 5.8 Hz, 1H), 6.37 (d, J = 6.1 Hz, 1H), 6.14 (s, 1H), 4.21 (t, J = 8.4 Hz, 2H), 4.19 – 4.13 (m, 2H), 3.26 – 3.21 (m, 4H), 3.20 – 3.13 (m, 4H), 2.44 (s, 3H), 1.49 (s, 9H). Step 3: Preparation of N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0529] To a solution of tert-butyl 4-(1-((2-methylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.17 mmol) in DCM (0.5 mL) was added TFA (0.5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (38 mg, yield: 59%) as a white solid. ESI-MS (M+H)⁺:378.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 2H), 8.47 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 7.4, 2.2 Hz, 1H), 6.64 (d, J = 5.8 Hz, 1H), 6.23 (s, 1H), 4.06 – 4.01 (m, 2H), 3.56 – 3.46 (m, 4H), 3.27 – 3.20 (m, 4H), 3.15 (t, J = 8.2 Hz, 2H), 2.33 (s, 3H). Example 73 – Preparation of N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0530] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (410.4 mg, 1.35 mmol), phenyl (2-methylimidazo[1,2-a]pyridin-6-yl)carbamate (300 mg, 1.12 mmol) and DMAP (13.6 mg, 0.11 mmol) in THF (10 mL) was stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (MeOH: DCM= 4 %) to give title product (210 mg, 35.98%) as a white solid. ESI-MS (M+H) ⁺: 478.3.¹H NMR (400 MHz, CDCl₃) δ 11.70 (s, 1H), 8.97 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.45 (d, J = 9.5 Hz, 1H), 7.30 (s, 1H), 7.02 (dd, J = 9.5, 1.9 Hz, 1H), 6.37 (d, J = 6.1 Hz, 1H), 4.18 – 4.13 (m, 2H), 3.58 – 3.55 (m, 4H), 3.26 – 3.22 (m, 4H), 3.10 (t, J = 8.6 Hz, 2H), 2.44 (s, 3H), 1.49 (s, 9H). Step 2: Preparation of N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0531] A mixture of tert-butyl 4-(1-((2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (150 mg, 0.31 mmol) in 3M HCl / EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep- HPLC (0.1% TFA in H₂O / ACN) to give title product (77.60 mg, yield: 66.39 %) as a white solid. ESI-MS (M+H) ⁺: 378.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 9.39 (s, 1H), 8.96 (s, 2H), 8.17 (s, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.94 – 7.86 (m, 2H), 6.66 (d, J = 6.2 Hz, 1H), 4.05 (t, J = 8.5 Hz, 2H), 3.57 – 3.49 (m, 4H), 3.28 – 3.16 (m, 6H), 2.48 (s, 3H). Example 74 – Preparation of (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate. [0532] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (1 g, 6.45 mmol) and tert-butyl (R)-2-methylpiperazine-1-carboxylate (2.58 g, 12.90 mmol) in DIEA (2 mL) was stirred at 140^oC for 24 h in a sealed tube. The mixture was concentrated in vacuo and purified by silica gel column (DCM: MeOH = 20: 1) to give title product (600 Mg, Y: 29.2%) as a white solid. ESI-MS (M+H) ⁺: 319.1. Step 2: Preparation of tert-butyl (R)-4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0533] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (500 mg, 1.57 mmol) and 8-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (260 mg, 1.57 mmol) in THF (15 mL) were added TEA (475 mg, 4.70 mmol) and triphosgene (933 mg, 3.14 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (15 mL), extracted with DCM (15 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 1: 5) to give title product (300 mg, Y: 37.5%) as a yellow solid. ESI-MS (M+H) ⁺: 510.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 6.1 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 12.5, 1.6 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.25 – 4.11 (m, 1H), 4.03 – 3.94 (m, 2H), 3.83 – 3.74 (m, 1H), 3.68 – 3.55 (m, 2H), 3.20 – 3.05 (m, 4H), 2.98 – 2.89 (m, 1H), 2.33 (s, 3H), 1.42 (s, 9H), 1.18 (d, J = 6.7 Hz, 3H). Step 3: Preparation of (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0534] A mixture of tert-butyl (R)-4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (250 mg, 0.49 mmol) in 4M HCl / EA (10 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (55 mg, Y: 27.4 %) as a white solid. ESI-MS (M+H) ⁺: 410.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.13 (s, 2H), 8.81 (s, 1H), 8.12 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.82 (d, J = 12.5 Hz, 1H), 6.68 (d, J = 6.2 Hz, 1H), 4.05 – 4.01 (m, 2H), 3.85 – 3.78 (m, 2H), 3.43 – 3.34 (m, 2H), 3.25 – 3.10 (m, 4H), 3.04 – 2.95 (m, 1H), 2.44 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 75 – Preparation of (R)-4-(3,4-dimethylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (R)-4-(3,4-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0535] A mixture of (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (150 mg, 0.37 mmol), AcOH (109.8 mg, 1.83 mmol) and (CHO)n (54.9 mg, 1.83 mmoL) in MeOH (6 mL) was stirred at 50℃ for 1 h. NaBH₃CN (69 mg, 1.1 mmol) was added to the mixture and stirred at 50℃ for 16 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (22 mg, Y: 14.2 %) as a white solid. ESI-MS (M+H) ⁺: 424.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 9.87 (s, 1H), 9.14 (s, 1H), 8.13 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 7.84 (d, J = 12.1 Hz, 1H), 6.69 (d, J = 6.1 Hz, 1H), 4.08 – 4.01 (m, 2H), 3.96 – 3.89 (m, 2H), 3.35 – 3.32 (m, 1H), 3.27 – 3.15 (m, 5H), 3.06 – 2.98 (m, 1H), 2.88 (s, 3H), 2.44 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H). Example 76 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

C^{ompound 76} Step 1: Preparation of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0536] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (180 mg, 0.60 mmol) in THF (10 mL) were added 8- fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (269 mg, 1.80 mmol), TEA (273 mg, 3.00 mmol) and triphosgene (320 mg, 1.20 mmol) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=4:1) to give title product (140 mg, yield: 44 %) as a white solid. ESI-MS (M+H) ⁺:524.3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 7.90 – 7.78 (m, 2H), 7.24 (dd, J = 12.5, 1.6 Hz, 1H), 6.43 (d, J = 6.3 Hz, 1H), 4.00 – 3.91 (m, 2H), 3.74 – 3.68 (m, 2H), 3.61 – 3.50 (m, 4H), 3.31 – 3.28 (m, 2H), 2.33 (s, 3H), 1.44 (s, 9H), 1.38 (s, 6H). Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0537] To a mixture of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (130 mg, 0.25 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure to give title compound (110 mg, 95 %) as a white solid.40 mg of HCl of product was diluted in TFA (0.2 M in H₂O) (5 mL). Concentration under reduced pressure to give title product (31.66 mg, 67 %) as a white solid. ESI-MS (M+H) ⁺:424.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.15 (s, 1H), 8.10 (s, 1H), 8.06 (d, J = 11.8 Hz, 1H), 7.90 (s, 1H), 6.95 (s, 1H), 4.50 – 4.26 (m, 2H), 4.06 – 3.83 (m, 2H), 3.81 – 3.65 (m, 2H), 3.58 – 3.45 (m, 4H), 2.58 (s, 3H), 1.51 (s, 6H). Example 77 – Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [0538] To a solution of tert-butyl (S)-4-(2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-4-yl)-2- methylpiperazine-1-carboxylate (300 mg, 0.94 mmol) and phenyl (8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)carbamate (296 mg, 1.03 mmol) in THF (3 mL) was added TEA (285 mg, 2.82 mmol). The reaction mixture was stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 0: 1) to give title product (348 mg, 70%) as a white solid. ESI-MS (M+H) ⁺: 510.3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.82 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.25 (d, J = 11.6 Hz, 1H), 7.88 – 7.79 (m, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.23 – 4.14 (m, 1H), 4.03 – 3.95 (m, 2H), 3.82 – 3.75 (m, 1H), 3.68 – 3.53 (m, 2H), 3.23 – 3.06 (m, 4H), 2.97 – 2.88 (m, 1H), 1.43 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H). Step 2: Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0539] To a solution of tert-butyl (S)-4-(1-((8-fluoro-2-methylimidazo [1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (330 mg, 0.65 mmol) in EA (5 mL) was added 4M HCl / EA (5 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtrated and dried in vacuo to give title product (300 mg, crude). The compound (50 mg) was purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (31.96 mg, yield: 50 %) as a white solid. ESI-MS (M+H) ⁺: 410.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.17 (d, J = 1.2 Hz, 1H), 8.03 (d, J = 6.2 Hz, 2H), 7.93 (dd, J = 11.6, 1.5 Hz, 1H), 6.68 (d, J = 6.2 Hz, 1H), 4.19 – 4.12 (m, 2H), 3.92 – 3.85 (m, 2H), 3.55 – 3.46 (m, 2H), 3.30 – 3.28 (m, 2H), 3.27 – 3.23 (m, 2H), 3.15 – 3.01 (m, 1H), 2.55 (d, J = 0.9 Hz, 3H), 1.41 (d, J = 6.6 Hz, 3H). [0540] [0541] Example 78 - (S)-4-(3,4-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

[0543] Step 1: Preparation of (S)-4-(3,4-dimethylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. To a solution of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (60 mg, 0.15 mmol) and (CH₂O)_n (39 mg, 0.44 mmol) in MeOH (2 mL) was added HOAC (45 mg, 0.75 mmol) at RT for 1 h. NaBH₃CN (28 mg, 0.45 mmol) was added to the mixture and stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (29.95 mg, yield: 37 %) as a white solid. ESI-MS (M+H) ⁺: 424.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.20 (s, 1H), 9.18 (s, 1H), 8.18 (s, 1H), 7.95 (dd, J = 15.9, 9.1 Hz, 2H), 6.70 (d, J = 6.1 Hz, 1H), 4.08 – 4.01 (m, 2H), 3.98 – 3.91 (m, 1H), 3.84 – 3.63 (m, 1H), 3.62 – 3.53 (m, 1H), 3.43 – 3.28 (m, 2H), 3.27 – 3.17 (m, 3H), 3.10 – 2.99 (m, 1H), 2.92 – 2.81 (m, 3H), 2.45 (d, J = 5.6 Hz, 3H), 1.34 (d, J = 6.3 Hz, 3H). Example 79 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [0544] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (400 mg, 1.2 mmol) and TEA (370 mg, 3.6 mmol) in THF (12 mL) was added triphosgene (713 mg, 2.4 mmol) at 0^oC, the mixture was stirred at RT for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (199 mg, 1.2 mmol) was added. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (12 mL), extracted with EA (12 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 1: 4) to give title product (170 mg, Y: 27.0%) as a green solid. ESI-MS (M+H) ⁺: 524.2. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0545] A mixture of tert-butyl (2R,6S)-4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (150 mg, 0.29 mmol) in 4M HCl / EA (6 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (36 mg, Y: 29.7 %) as a white solid. ESI-MS (M+H) ⁺: 424.1. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.37 (d, J = 9.1 Hz, 1H), 9.17 (s, 1H), 8.73 (d, J = 10.3 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.91 (d, J = 12.0 Hz, 1H), 6.71 (d, J = 6.3 Hz, 1H), 3.90 – 3.85 (m, 4H), 3.44 – 3.35 (m, 2H), 3.25 – 3.17 (m, 2H), 2.98 – 2.89 (m, 2H), 2.46 (s, 3H), 1.27 (d, J = 6.5 Hz, 6H). Example 80 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methyl-4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

⁰ Step 1: Preparation of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0546] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.61 mmol), phenyl (8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)carbamate (207.27 mg, 0.73 mmol), TEA (184.8 mg, 1.83 mmol) in THF (10 mL) was stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 71 %) to give title product (120 mg, 37.76 %) as a white solid. ESI-MS (M+H) ⁺: 522.3.¹H NMR (400 MHz, CDCl₃) δ 11.75 (s, 1H), 8.77 (d, J = 1.5 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 11.3, 1.6 Hz, 1H), 6.33 (d, J = 6.1 Hz, 1H), 4.13 (t, J = 8.0 Hz, 2H), 3.71 – 3.68 (m, 2H), 3.29 – 3.25 (m, 2H), 3.08 – 3.04 (m, 4H), 2.45 (s, 3H), 1.49 (s, 9H), 1.10 – 1.07 (m, 2H), 0.85 – 0.82 (m, 2H). Step 2: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0547] A mixture of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (110 mg, 0.21 mmol) in 3M HCl / EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (120 mg, crude) as a white solid. ESI-MS (M+H) ⁺: 422.1.¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 2H), 9.21 (s, 1H), 8.27 (s, 1H), 8.15 (d, J = 10.0 Hz, 1H), 7.92 (d, J = 5.8 Hz, 1H), 6.73 (s, 1H), 4.20 – 4.07 (m, 2H), 3.80 – 3.69 (m, 2H), 3.61 – 3.50 (m, 2H), 3.31 – 3.21 (m, 4H), 2.49 (s, 3H), 1.17 – 1.15 (m, 2H), 0.93 – 0.90 (m, 2H). Step 3: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0548] A mixture of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide HCl salt (120 mg, 0.28 mmol), (CH₂O)_n (77 mg, 0.85 mmol), TEA (86 mg, 0.85 mmol) and NaBH₃CN (51.3 mg, 0.85 mmol) in MeOH (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, the crude was diluted with water (20 mL), extracted with EA (20 mL×3). The organic layer was washed with brine (20 mL), dried with Na₂SO₄ and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (48.94 mg, yield: 39.47 %) as a colorless oil. ESI-MS (M+H) ⁺: 436.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, 1H), 9.21 (s, 1H), 8.22 (s, 1H), 7.99 (dd, J = 13.5, 9.1 Hz, 2H), 6.69 (d, J = 6.3 Hz, 1H), 4.05 (t, J = 8.4 Hz, 2H), 3.74 (s, 3H), 3.50 (s, 3H), 3.19 (t, J = 8.4 Hz, 2H), 2.97 (s, 3H), 2.47 (s, 3H), 1.25 (s, 2H), 0.98 (s, 2H). Example 81 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- ((3R,5S)-3,4,5-trimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-((3R,5S)-3,4,5- trimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0549] A mixture of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide TFA salt (80 mg, 0.19 mmol), AcOH (56.6 mg, 0.94 mmol) and (CHO)n (28.3 mg, 0.94 mmoL) in MeOH (6 mL) was stirred at 50℃ for 1 h. NaBH₃CN (35.9 mg, 0.57 mmol) was added. The mixture was stirred at 50℃ for 16 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (31 mg, Y: 37.5 %) as a yellow solid. ESI-MS (M+H) ⁺: 438.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 9.84 (s, 1H), 9.14 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.84 (d, J = 12.1 Hz, 1H), 6.71 (d, J = 6.2 Hz, 1H), 4.06 – 4.00 (m, 2H), 3.99 – 3.91 (m, 2H), 3.47 – 3.35 (m, 2H), 3.25 – 3.17 (m, 2H), 3.15 – 3.03 (m, 2H), 2.88 (s, 3H), 2.44 (s, 3H), 1.37 (d, J = 6.3 Hz, 6H). Example 82 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3,3,5,5- tetramethyl-2-oxopiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3,3,5,5- tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0550] To a solution of 1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,3,5,5- tetramethylpiperazin-2-one (50 mg, 0.19 mmol) in THF (10 mL) were added phenyl (7- fluoro-2-methyl-2H-indazol-5-yl)carbamate (66 mg,0.23 mmol), DMAP (70 mg, 0.58 mmol). Then the reaction mixture was stirred at 70 ^oC for 16 h. After cooling to rt, the mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.05% TFA in H2O / MeCN) to give the title compound (20 mg, 17.9 %) as a yellow solid. ESI-MS: [M+H]⁺: 466.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.23 (dd, J = 11.9, 4.0 Hz, 2H), 7.74 (s, 1H), 7.23 (dd, J = 12.7, 1.3 Hz, 1H), 6.93 (d, J = 5.8 Hz, 1H), 4.21 (s, 3H), 4.16 (t, J = 8.6 Hz, 2H), 4.00 (s, 2H), 3.05 (t, J = 8.5 Hz, 2H), 1.78 (s, 6H), 1.63 (s, 6H). Example 83 – Preparation of N-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 7-(1-((6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0551] A mixture of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (150 mg, 0.68 mmol), TEA (183 mg, 1.82 mmol) and DPPA (248 mg, 0.90 mmol) in Tol (4 mL) was stirred at RT for 1 h, heated to 80^oC and stirred for 1h, tert-butyl 7-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (150 mg, 0.45 mmol) was added. The mixture was stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 4) to give title product (100 mg, Y: 39.2%) as a yellow solid. ESI-MS (M+H) ⁺: 548.2. Step 2: Preparation of N-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0552] A mixture of tert-butyl 7-(1-((6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (80 mg, 0.15 mmol) in 4M HCl / EA (4 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (53 mg, Y: 81.0 %) as a pink solid. ESI-MS (M+H) ⁺: 448.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 9.24 (s, 2H), 8.28 (s, 1H), 8.24 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 6.61 (d, J = 6.1 Hz, 1H), 6.16 (s, 1H), 4.15 – 4.09 (m, 2H), 4.04 – 3.98 (m, 4H), 3.59 – 3.52 (m, 2H), 3.39 – 3.32 (m, 2H), 3.16 – 3.07 (m, 2H), 2.30 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H), 1.10 – 0.90 (m, 4H). Example 84 – Preparation of N-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0553] A mixture of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (163mg, 0.74 mmol), TEA (199 mg, 1.97 mmol) and DPPA (270.5 mg, 0.98 mmol) in Tol (4 mL) was stirred at RT for 1 h, heated to 80^oC and stirred for 1h, tert-butyl 4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (150 mg, 0.49 mmol) was added. The mixture was stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 4) to give title product (100 mg, Y: 39.0%) as a yellow solid. ESI-MS (M+H) ⁺: 522.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.86 (d, J = 6.0 Hz, 1H), 6.55 (d, J = 6.1 Hz, 1H), 6.16 (s, 1H), 4.15 – 4.08 (m, 2H), 4.04 – 3.94 (m, 2H), 3.48 – 3.42 (m, 4H), 3.30 – 3.24 (m, 4H), 3.17 – 3.08 (m, 2H), 2.31 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0554] A mixture of tert-butyl 4-(1-((6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.15 mmol) in 4M HCl / EA (6 mL) was stirred at RT for 1 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (53 mg, Y: 82.0 %) as a pink solid. ESI-MS (M+H) ⁺: 422.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 8.80 (s, 2H), 8.28 (s, 1H), 8.25 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 6.62 (d, J = 6.1 Hz, 1H), 6.16 (s, 1H), 4.16 – 4.09 (m, 2H), 4.06 – 3.98 (m, 2H), 3.53 – 3.43 (m, 4H), 3.28 – 3.19 (m, 4H), 3.18 – 3.08 (m, 2H), 2.30 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H). Example 85 – Preparation of N-(2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0555] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (200 mg, 0.66 mmol) and 2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-amine (177 mg, 0.99 mmol) in THF (10 mL) were added TEA (300 mg, 2.97 mmol) and a solution of triphosgene (196 mg, 0.66 mmol) in THF (1 mL) at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:1) to provide title product (180 mg, yield: 54%) as a white solid. ESI-MS (M+H)⁺:510.3.¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.85 (d, J = 3.1 Hz, 1H), 7.27 – 7.24 (m, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.01 – 3.95 (m, 2H), 3.46 – 3.42 (m, 4H), 3.30 – 3.26 (m, 4H), 3.13 (t, J = 8.6 Hz, 2H), 2.73 – 2.68 (m, 2H), 1.43 (s, 9H), 1.27 – 1.24 (m, 3H). Step 2: Preparation of N-(2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0556] To a solution of tert-butyl 4-(1-((2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (150 mg, 0.29 mmol) in DCM (1.5 mL) was added TFA (1.5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (75 mg, yield: 63%) as a white solid. ESI-MS (M+H)⁺:410.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.84 (s, 2H), 8.14 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 7.78 (s, 1H), 6.66 (d, J = 6.2 Hz, 1H), 4.06 – 4.01 (m, 2H), 3.54 – 3.48 (m, 4H), 3.26 – 3.21 (m, 4H), 3.17 (t, J = 8.5 Hz, 2H), 2.79 (q, J = 7.7 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H). Example 86 – Preparation of N-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((8-fluoroimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0557] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (200 mg, 0.66 mmol) and 8-fluoroimidazo[1,2-a]pyridin-6-amine (157 mg, 0.99 mmol) in THF (10 mL) were added TEA (300 mg, 2.97 mmol) and a solution of triphosgene (196 mg, 0.66 mmol) in THF (1 mL) at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:3) to provide title product (150 mg, yield: 47%) as a white solid. ESI-MS (M+H)⁺: 482.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 8.13 – 8.10 (m, 1H), 7.94 (d, J = 6.1 Hz, 1H), 7.39 (d, J = 0.9 Hz, 2H), 7.31 (dd, J = 12.5, 1.6 Hz, 1H), 6.56 (d, J = 6.2 Hz, 1H), 3.99 (t, J = 8.5 Hz, 2H), 3.47 – 3.43 (m, 4H), 3.31 – 3.28 (m, 4H), 3.18 – 3.16 (m, 2H), 1.43 (s, 9H). Step 2: Preparation of N-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0558] To a solution of tert-butyl 4-(1-((8-fluoroimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (120 mg, 0.25 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (75 mg, yield: 79%) as a white solid. ESI-MS (M+H)⁺:382.1.¹H NMR (400 MHz, DMSO-d₆) δ 9.25 – 9.17 (m, 1H), 8.88 (s, 2H), 8.37 (s, 1H), 7.97 (d, J = 6.0 Hz, 2H), 7.81 (d, J = 11.9 Hz, 1H), 6.67 (d, J = 6.2 Hz, 1H), 4.05 (t, J = 8.4 Hz, 2H), 3.59 – 3.47 (m, 4H), 3.27 – 3.21 (m, 4H), 3.21 – 3.14 (m, 2H). Example 87 – Preparation of N-(4-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((4-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0559] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (120 mg, 0.40 mmol) and 4-fluoro-2-methyl-2H-indazol-5-amine (130 mg, 0.79 mmol) in THF (15 mL) were added TEA (199 mg, 1.97 mmol), then triphosgene (173 mg, 0.59 mmol) was added slowly at 0^oC, the mixture was stirred at r.t for 16 h. The mixture was concentrated and purified by silica gel column chromatography (PE: EA= 1: 4) to give the compound (60 mg, 30.71%) as a yellow solid. ESI-MS (M+H) ⁺: 496.2.¹H NMR (400 MHz, CDCl₃) δ 11.63 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.27 (s, 1H), 6.36 (s, 1H), 4.36 – 4.11 (m, 5H), 3.66 – 3.52 (m, 4H), 3.33 – 3.18 (m, 4H), 3.16 – 3.06 (m, 2H), 1.49 (s, 9H). Step 2: Preparation of N-(4-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0560] To a mixture of tert-butyl 4-(1-((4-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (55 mg, 0.11 mmol) in EA (3 mL) was added 3M HCl/EA (2 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (36 mg, Y: 63.67 %) as an off-white solid. ESI-MS (M+H) ⁺: 396.3.¹H NMR (400 MHz, DMSO- d₆) δ 9.59 (s, 2H), 8.54 (s, 1H), 7.84 (s, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.00 – 6.57 (m, 1H), 4.19 (s, 3H), 4.18 – 4.01 (m, 2H), 3.73 – 3.53 (m, 4H), 3.45 – 3.26 (m, 2H), 3.24 – 3.08 (m, 4H). Example 88 – Preparation of (S)-4-(4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)-N- (8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine- 1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (S)-4-(4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a] pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0561] To a solution of (S)-N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide (50 mg, 0.12 mmol) and (bromomethyl)cyclopropane (20 mg, 0.15 mmol) in DMF (1 mL) was added K₂CO₃ (40 mg, 0.36 mmol). The reaction mixture was stirred at 70 ^oC for 16 h. The mixture was diluted with water (10 mL), extracted with EA (4 mL×3). The organic layer was concentrated in vacuo and purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (30.74 mg, yield: 43 %) as a white solid. ESI-MS (M+H) ⁺: 464.6.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 9.60 (s, 1H), 9.13 (s, 1H), 8.12 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.80 (s, 1H), 6.69 (d, J = 6.3 Hz, 1H), 4.06 – 4.02 (m, 2H), 3.98 – 3.90 (m, 2H), 3.78 – 3.73 (m, 1H), 3.49 – 3.41 (m, 1H), 3.36 – 3.18 (m, 5H), 3.13 – 3.06 (m, 2H), 2.43 (s, 3H), 1.35 (d, J = 6.2 Hz, 3H), 1.12 – 1.04 (m, 1H), 0.74 – 0.64 (m, 2H), 0.47 – 0.35 (m, 2H). Example 89 – Preparation of (S)-4-(4-ethyl-3-methylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (S)-4-(4-ethyl-3-methylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0562] A mixture of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (40 mg, 0.09 mmol), acetaldehyde (11 mg, 0.25 mmol), NaBH₃CN (15.7 mg, 0.25 mmol) and TEA (48.5 mg, 0.48 mmol) in MeOH (3 mL) was stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (43.17 mg, yield: 80.69%) as a colorless oil. ESI-MS (M+H) ⁺: 438.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.18 (d, J = 1.2 Hz, 1H), 8.05 – 8.01 (m, 2H), 7.96 (dd, J = 11.5, 1.5 Hz, 1H), 6.71 (d, J = 6.3 Hz, 1H), 4.18 (t, J = 8.5 Hz, 2H), 4.08 – 3.83 (m, 2H), 3.77 – 3.49 (m, 3H), 3.35 – 3.32 (m, 2H), 3.29 – 3.20 (m, 4H), 2.56 (d, J = 0.9 Hz, 3H), 1.48 (d, J = 6.6 Hz, 3H), 1.39 (t, J = 7.3 Hz, 3H). Example 90 – Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- (2-methoxyethyl)-3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4-(2- methoxyethyl)-3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate. [0563] To a solution of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (40 mg, 0.10 mmol) and 1-bromo-2-methoxyethane (27 mg, 0.20 mmol) in DMF(1 mL) was added K₂CO₃ (40 mg, 0.29 mmol), the mixture was stirred at 70^oC for 16 h. The mixture was purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (6 mg, Y: 13.14 %) as a yellow solid. ESI-MS (M+H) ⁺: 468.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.15 (s, 1H), 8.02 (d, J = 5.5 Hz, 2H), 7.93 (d, J = 11.6 Hz, 1H), 6.69 (d, J = 6.2 Hz, 1H), 4.20 – 4.13 (m, 2H), 3.90 – 3.56 (m, 8H), 3.44 (s, 3H), 3.30 – 3.17 (m, 5H), 2.55 (s, 3H), 1.49 (d, J = 6.5 Hz, 3H). Example 91 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3,3,4- trimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3,3,4- trimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0564] To a solution of 4-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (60 mg, 0.14 mmol) in MeOH (5 mL) were added (CH₂O)n (13 mg, 0.42 mmol),CH₃COOH (42 mg, 0.70 mmol). The mixture was stirred at r.t for 1 h, NaBH₃CN (27 mg, 0.42 mmol) was added to the mixture and stirred at 50 ^oC for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep- HPLC (0.1% TFA in H₂O / ACN) to give title product (30.90 mg, yield: 42 %) as a colorless oil. ESI-MS (M+H) ⁺:438.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.18 (d, J = 1.2 Hz, 1H), 8.04 (dd, J = 5.6, 4.5 Hz, 2H), 7.96 (dd, J = 11.5, 1.5 Hz, 1H), 6.71 (d, J = 6.2 Hz, 1H), 4.18 (t, J = 8.5 Hz, 2H), 4.07 – 3.69 (m, 2H), 3.55 – 3.48 (m, 2H), 3.34 – 3.32 (m, 2H), 3.29 – 3.25 (m, 2H), 2.90 (s, 3H), 2.56 (d, J = 0.9 Hz, 3H), 1.50 (s, 6H).

Example 92 – Preparation of 6-cyclopropyl-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin- 6-yl)-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide TFA salt.

Step 1: Preparation of tert-butyl (2-(4-bromo-2,6-dichloropyridin-3-yl)ethyl)carbamate. [0565] To a solution of LDA (13 mL, 26.54 mmol) in THF (20 mL) was added 4-bromo-2,6- dichloropyridine (5.0 g, 22.12 mmol) at -78 ^oC under N₂. Then the mixture was stirred at -78 ^oC for 1 h under N₂. Then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5.9 g, 26.54 mmol) was added to the above mixture at -78 ^oC, the mixture was stirred at -78 ^oC for 3 h. Then the mixture was quenched with NH₄Cl solution (100 mL), and extracted with EtOAc (100 mL x 3). The organic extract was dried over Na₂SO₄, and the solvent was removed to afford the crude product. The crude product was purified by column flash chromatography (EA/PE=0%~30%) to afford the title product (3.2 g, 39.10 % yield) as a yellow solid. ESI- MS (M+H) ⁺: 314.9. Step 2: Preparation of tert-butyl 4-bromo-6-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate. [0566] To a solution of tert-butyl (2-(4-bromo-2,6-dichloropyridin-3-yl)ethyl)carbamate (3.2 g, 8.65 mmol) in THF (60 mL) was added NaH (1.4 g, 34.60 mmol) at 0 ^oC. Then the mixture was stirred at 50 ^oC for 2 h under N₂. Then the mixture was quenched with NH₄Cl solution (100 mL), and extracted with EtOAc (100 mL x 3). The organic extract was dried over Na₂SO₄, and the solvent was removed to afford the crude product. The crude product was purified by column flash chromatography (EA/PE=0%~20%) to afford the title product (1.8 g, 63.10 % yield) as a white solid. ESI-MS (M+H) ⁺: 335.0. Step 3: Preparation of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6-chloro-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [0567] To a solution of tert-butyl 4-bromo-6-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine- 1-carboxylate (1.8 g, 5.40 mmol) in 1,4-dioxane (20 mL) were added Cs₂CO₃ (3.5 g, 10.80 mmol), Xantphos (636 mg, 1.10 mmol) and Pd₂(dba)₃ (458 mg, 0.50 mmol) at rt under N₂. Then the mixture was stirred at 110 ^oC for 4 h under N₂. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3). The organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluted with PE in EA from 0% to 50%) to afford the title product (1.1 g, 43.12 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 473.6. Step 4: tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6-cyclopropyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxylate. [0568] To a solution of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6-cyclopropyl- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.1 g, 2.33 mmol) in toluene (10 mL) were added cyclopropylboronic acid (240 mg, 2.80 mmol), Pd(OAc)₂ (26 mg, 0.11 mmol), Cy₃P (61 mg, 0.22 mmol) and H₂O (0.5 mL) at rt under N₂. Then the mixture was stirred at 110 ^oC for 16 h under N₂. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3). The organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluted with PE in EA from 0% to 50%) to afford the title product (850 mg, 76.50 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 479.3. Step 5: benzyl 4-(6-cyclopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [0569] A mixture of tert-butyl (S)-4-(8-cyano-2-(5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)quinoxalin-6-yl)-2-methylpiperazine-1-carboxylate (850.0 mg, 0.28 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at 25 ℃ for 16 h under N₂. PH of the mixture was adjusted to neutral by NaHCO₃, and extracted with EtOAc (50 mL x 3). The organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title product (420 mg, 62.50 % yield) as a yellow solid, which was used to the next step without further purification. ESI-MS (M+H) ⁺: 379.3. Step 6: benzyl 4-(6-cyclopropyl-1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0570] To a solution of benzyl 4-(6-cyclopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (210.0 mg, 0.56 mmol) and triethylamine (280 mg, 0.28 mmol) in THF (10 mL) was added triphosgene (246 mg, 0.83 mmol) at 0 ^oC under N₂. The mixture was stirred for 1 h at 0 ^oC. Then 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (137 mg, 0.83 mmol) in THF (6 mL) was dropwised to the above reaction mixture, and stirred for 12 h at 70 ^oC. The reaction mixture was diluted with water (10 mL), extracted with EA (50 mL x 3). The organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluted with PE in EA from 0% to 50%) to afford the title product (128 mg, 40.30 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 544.5. Step 7: 6-cyclopropyl-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide TFA salt. [0571] A mixture of benzyl 4-(6-cyclopropyl-1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (30 mg, 0.05 mmol) in HBr (0.5 mL) and DCM (5 mL) was stirred at 25 ℃ for 2 h under N₂. The mixture was concentrated and purified by pre-HPLC (0.1 % TFA in water / CH₃CN) to afford the title product (5.5 mg, 18.17 % yield) as a white solid. ESI-MS (M+H) ⁺: 436.3.¹H NMR (400 MHz, CD₃OD) δ 9.09 (s, 1H), 8.00 (s, 1H), 7.47 (d, J = 11.2 Hz, 1H), 6.58 (s, 1H), 4.10 (t, J = 8.4 Hz, 2H), 3.61 – 3.49 (m, 4H), 3.43 – 3.35 (m, 5H), 3.13 (t, J = 8.4 Hz, 2H), 2.53 (s, 3H), 2.26 – 2.04 (m, 1H), 1.21 – 1.08 (m, 2H), 1.03 (dd, J = 7.2, 3.6 Hz, 2H).

Example 93 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl- 4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [0572] A mixture of tert-butyl 4-(5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (100 mg, 0.31 mmol ), phenyl (8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)carbamate (94 mg, 0.93 mmol) and TEA (94 mg, 0.93 mmol) in THF (5 mL) was stirred at 70 ^oC for 16 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE: EA=1:1) to give the title compound (40 mg, yield: 25%) as a white solid. ESI-MS (M+H) ⁺: 510.2.¹H NMR (400 MHz, CDCl₃) δ 11.59 (s, 1H), 8.78 (d, J = 1.5 Hz, 1H), 7.83 (s, 1H), 7.36 (d, J = 2.8 Hz, 1H), 6.81 (dd, J = 11.3, 1.6 Hz, 1H), 4.19 – 4.09 (m, 2H), 3.58 – 3.53 (m, 4H), 3.21 (t, J = 8.6 Hz, 2H), 3.12 – 3.05 (m, 4H), 2.45 (s, 3H), 2.21 (s, 3H), 1.49 (s, 9H). Step 2: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0573] To a solution of 4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-6-methyl-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (90 mg, 0.17 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (9.5 mg, yield: 29%) as a white solid. ESI-MS (M+H)⁺:410.0.¹H NMR (400 MHz, MeOD-d₄) δ 9.19 (d, J = 1.2 Hz, 1H), 8.04 (s, 1H), 7.96 (dd, J = 10.9, 1.9 Hz, 2H), 4.17 – 4.11 (m, 2H), 3.45 – 3.41 (m, 4H), 3.40 – 3.33 (m, 6H), 2.55 (s, 3H), 2.28 (s, 3H). Example 94 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1-carboxylate. [0574] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1- carboxylate (203 mg, 0.67 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (80 mg, 0.45 mmol), triphosgene (199 mg, 0.67 mmol) and TEA (136.3 mg, 1.35 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 100 %) to give title product (80 mg, 35.98) as a white solid. ESI-MS (M+H) ⁺: 495.0.¹H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.84 (s, 1H), 8.08 (d, J = 5.6 Hz, 1H), 7.85 (s, 1H), 7.27 (d, J = 12.5 Hz, 1H), 6.93 (d, J = 5.6 Hz, 1H), 4.11 – 4.03 (m, 4H), 3.14 (t, J = 8.5 Hz, 2H), 2.86 – 2.72 (m, 3H), 2.33 (s, 3H), 1.74 – 1.68 (m, 2H), 1.58 – 1.50 (m, 2H), 1.42 (s, 9H). Step 2: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0575] A mixture of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1-carboxylate (80 mg, 0.16 mmol) in TFA / DCM (0.5 mL / 5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (80.55 mg, yield: 82.23 %) as a white solid. ESI-MS (M+H) ⁺: 395.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H), 9.21 (s, 1H), 8.76 – 8.58 (m, 1H), 8.54 – 8.36 (m, 1H), 8.15 (d, J = 5.7 Hz, 2H), 7.94 (d, J = 11.7 Hz, 1H), 6.89 (d, J = 5.6 Hz, 1H), 4.12 – 4.08 (m, 2H), 3.41 (d, J = 11.7 Hz, 2H), 3.17 (t, J = 8.5 Hz, 2H), 3.08 – 2.92 (m, 3H), 2.45 (s, 3H), 1.93 – 1.80 (m, 4H). Example 101 – Preparation of (S)-N-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate (Compound 101).

Step 1: Preparation of tert-butyl (S)-2-methyl-4-(1-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0576] A mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (120 mg, 0.38 mol), 7-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-amine (67 mg, 0.45 mmol), triphosgene (133.65 mg, 0.45 mmol) and TEA (380.7 mg, 3.77 mmol) in THF (20 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at rt for 1h, the precipitate was filtered to afford title product (80 mg, 42.97 %) as a white solid. ESI-MS (M+H) ⁺: 493.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 9.50 (s, 1H), 8.35 (s, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.76 (s, 1H), 6.54 (d, J = 6.1 Hz, 1H), 4.21 – 4.16 (m, 1H), 4.02 (t, J = 8.6 Hz, 2H), 3.81 – 3.76 (m, 1H), 3.63 (dd, J = 27.5, 12.6 Hz, 2H), 3.21 – 3.13 (m, 3H), 3.11 – 3.06 (m, 1H), 2.99 – 2.92 (m, 1H), 2.52 (s, 3H), 1.43 (s, 9H), 1.18 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. A mixture of tert-butyl (S)-2-methyl-4-(1-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.16 mmol) in 4M HCl / EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (38.62 mg, yield: 61.57 %) as a yellow oil. ESI-MS (M+H) ⁺: 393.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 9.49 (s, 1H), 9.03 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 7.79 (s, 1H), 6.66 (d, J = 6.2 Hz, 1H), 4.06 – 4.05 (m, 2H), 3.82 (d, J = 12.6 Hz, 2H), 3.41 – 3.36 (m, 2H), 3.24 – 3.16 (m, 4H), 3.03 – 2.97 (m, 1H), 2.53 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 125 – Preparation of (S)-N-(1-methyl-1H-benzo[d]imidazol-4-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 1

( c)2 s_{tep 1 step 2}

Step 1: Preparation of N-(1-methyl-1H-benzo[d]imidazol-4-yl)-1,1-diphenylmethanimine. [0577] To a mixture of 4-bromo-1-methyl-1H-benzo[d]imidazole (2.5 g, 11.90 mmol), diphenylmethanimine (4.31 g, 23.81 mmol) and BINAP (1.48 g, 2.38 mmol) in 1,4-dioxane (30 mL) were added Cs₂CO₃ (7.76 g, 23.81 mmol) and Pd(OAc)₂ (268.94 mg, 1.19 mmol). The mixture was stirred at 110 ^oC for 16 h under N₂. The mixture was diluted with H₂O (30 mL) and extracted with EA (30 mL x 3). The organic phase was washed with brine (30 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (1.2 g, 32.42%) as a brown solid. ESI-MS (M+H) ⁺: 312.4. Step 2: Preparation of 1-methyl-1H-benzo[d]imidazol-4-amine hydrochloride. [0578] A mixture of N-(1-methyl-1H-benzo[d]imidazol-4-yl)-1,1-diphenylmethanimine (1.2 g, 3.86 mmol) in 4M HCl/EA (20 mL) was stirred at r.t for 5 h. The reaction was diluted with EA (20 mL), the precipitate was filtered and triturate with EA (20 mL) to give title product (600 mg, 84.94%) as a white solid. ESI-MS (M+H) ⁺: 147.6. Step 3: Preparation of tert-butyl (S)-2-methyl-4-(1-((1-methyl-1H-benzo[d]imidazol-4- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0579] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mmol), 1-methyl-1H-benzo[d]imidazol-4- amine hydrochloride (86.32 mg, 0.47 mmol) in THF (10 mL) were added TEA (142.41 mg, 1.41 mmol) and triphosgene (278.24 mg, 0.94 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (10 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (80 mg, 34.67%) as a white solid. ESI-MS (M+H) ⁺: 492.3. Step 4: Preparation of (S)-N-(1-methyl-1H-benzo[d]imidazol-4-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. To a mixture of tert-butyl (S)-2-methyl-4-(1-((1-methyl-1H-benzo[d]imidazol-4- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.16 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (15.31 mg, 21.85%) as a white solid. ESI-MS (M+H) ⁺:392.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.08 – 8.03 (m, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.22 – 7.16 (m, 2H), 6.53 (d, J = 6.1 Hz, 1H), 4.05 – 4.00 (m, 2H), 3.84 (s, 3H), 3.66 – 3.64 (m, 2H), 3.17 – 3.11 (m, 2H), 3.02 – 2.83 (m, 4H), 2.61 – 2.54 (m, 1H), 1.07 (d, J = 6.3 Hz, 3H).

Example 145 – Preparation of (S)-N-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 145).

Step 1: Preparation of tert-butyl (S)-2-methyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0580] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mmol), 2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-amine hydrochloride (86.48 mg, 0.47 mmol) in THF (5 mL) were added TEA (142.92 mg, 1.42 mmol) and triphosgene (278.24 mg, 0.94 mmol) (in THF (1 mL ) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=4:1) to give title product (80 mg, 34.60 %) as a white solid. ESI-MS (M+H) ⁺:493.3. Step 2: Preparation of (S)-N-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0581] A mixture of tert-butyl (S)-2-methyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.16 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (6.57 mg, 9.38%) as a white solid. ESI-MS (M+H) ⁺:393.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 9.25 (d, J = 1.3 Hz, 1H), 8.25 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.68 (d, J = 9.4 Hz, 1H), 7.59 (dd, J = 9.5, 2.0 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.01 – 3.96 (m, 2H), 3.64 – 3.61 (m, 2H), 3.17 – 3.12 (m, 2H), 3.00 – 2.96 (m, 1H), 2.88 – 2.55 (m, 4H), 2.44 (s, 3H), 1.05 (d, J = 6.3 Hz, 3H). Example 170 – Preparation of (S)-N-(2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 170).

Step 1: Preparation of tert-butyl (S)-2-methyl-4-(1-((2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0582] To a solution of 2-methyl-2H-indazol-5-amine (83 mg, 0.56 mmol) and TEA (572 mg, 5.65 mmol) in THF (12 mL) was added triphosgene (167 mg, 0.56 mmol) at 0^oC, after 10 min, tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (150 mg, 0.47 mmol) was added at 0 ^oC to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (40 mL). The precipitate was filtered and triturated with MeOH (7 mL) to give the compound (200 mg, 86.36 %) as a white solid. ESI-MS (M+H) ⁺:492.2. Step 2: Preparation of (S)-N-(2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0583] To a mixture of tert-butyl (S)-2-methyl-4-(1-((2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (180 mg, 0.37 mmol) in EA (4 mL) was added HCl/EA (5 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (42 mg, Y: 29.30 %) as a yellow solid. ESI-MS (M+H) ⁺:392.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.74 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.22 (dd, J = 9.1, 1.5 Hz, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.14 (s, 3H), 3.97 (t, J = 8.5 Hz, 2H), 3.69 – 3.60 (m, 2H), 3.14 – 2.96 (m, 5H), 2.91 (t, J = 10.7 Hz, 1H), 2.77 – 2.67 (m, 1H), 1.14 (d, J = 6.2 Hz, 3H). Example 176 – Preparation of N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4- (4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate (Compound 176).

Step 1: Preparation of tert-butyl 7-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0584] A mixture of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (90 mg, 0.43 mmol), TEA (132 mg, 1.30 mmol) and DPPA (239 mg, 0.87 mmol) in Tol (4 mL) was stirred at RT for 1 h, heated to 80 ^oC and stirred for 1h, tert-butyl 7-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (144 mg, 0.43 mmol) was added. The mixture was stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 2) to give title product (100 mg, Y: 42.0%) as a pink solid. ESI-MS (M+H) ⁺: 534.2. Step 2: Preparation of N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0585] A mixture of tert-butyl 7-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (80 mg, 0.15 mmol) in 4M HCl / EA (8 mL) was stirred at RT for 2 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (82 mg, Y: 99.9 %) as a pink solid. ESI-MS (M+H) ⁺: 434.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 9.32 (s, 2H), 8.30 (s, 1H), 8.23 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 6.60 (d, J = 6.1 Hz, 1H), 6.17 (s, 1H), 4.06 – 3.98 (m, 2H), 3.96 (s, 3H), 3.56 (d, J = 5.3 Hz, 2H), 3.41 (s, 2H), 3.39 – 3.32 (m, 2H), 3.12 (t, J = 8.5 Hz, 2H), 2.31 (s, 3H), 1.05 (t, J = 6.2 Hz, 2H), 0.95 (t, J = 6.3 Hz, 2H). Example 177 – Preparation of N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-4- (4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 177).

Step 1: Preparation of tert-butyl 7-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0586] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (80 mg, 0.24 mmol), 6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-amine (62 mg, 0.29 mmol), and TEA (293 mg, 2.89 mmol) in THF (8 mL) was added triphosgene (86 mg, 0.29 mmol), the mixture was stirred at 0 ^oC for 15 min and stirred at RT for 16 h. The mixture was diluted with water, stirred at rt for 1 h. The precipitate was filtered to afford title product (50 mg, 37.5 %) as a yellow solid. ESI-MS (M+H) ⁺: 535.2. Step 2: Preparation of N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0587] A mixture of tert-butyl 7-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (40 mg, 0.07 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (3.35 mg, yield: 11.06 %) as a white solid. ESI-MS (M+H) ⁺: 435.0.¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.64 (s, 1H), 8.20 (s, 1H), 7.88 (dd, J = 11.8, 3.4 Hz, 2H), 6.49 (d, J = 6.2 Hz, 1H), 4.04 (s, 3H), 3.99 – 3.95 (m, 2H), 3.26 – 3.23 (m, 2H), 3.09 (d, J = 12.1 Hz, 4H), 2.88 – 2.84 (m, 2H), 2.31 (s, 3H), 0.50 (d, J = 11.1 Hz, 4H). Example 178 – Preparation of N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate (Compiund 178).

Step 1: Preparation of tert-butyl 4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0588] A mixture of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (90 mg, 0.43 mmol), TEA (132 mg, 1.30 mmol) and DPPA (239 mg, 0.87 mmol) in Tol (4 mL) was stirred at RT for 1 h, heated to 70^oC and stirred for 1h, tert-butyl 4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (133 mg, 0.43 mmol) was added. The mixture was stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 4) to give title product (100 mg, Y: 45.3%) as a yellow solid. ESI-MS (M+H) ⁺: 508.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.96 (d, J = 5.9 Hz, 1H), 6.55 (d, J = 6.1 Hz, 1H), 6.17 (s, 1H), 4.03 – 3.98 (m, 2H), 3.96 (s, 3H), 3.48 – 3.42 (m, 4H), 3.31 – 3.27 (m, 4H), 3.17 – 3.10 (m, 2H), 2.31 (s, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0589] A mixture of tert-butyl 4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.16 mmol) in 4M HCl / EA (8 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (80 mg, Y: 97.3 %) as a pink solid. ESI-MS (M+H) ⁺: 408.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 8.88 (s, 2H), 8.31 (s, 1H), 8.23 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 6.61 (d, J = 6.1 Hz, 1H), 6.17 (s, 1H), 4.07 – 3.99 (m, 2H), 3.96 (s, 3H), 3.55 – 3.46 (m, 4H), 3.28 – 3.19 (m, 4H), 3.17 – 3.08 (m, 2H), 2.31 (s, 3H). Example 179 – Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-6-methyl-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate (Compound 179).

Step 1: Preparation of tert-butyl 4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-6- methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0590] To a mixture of tert-butyl 4-(6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (70 mg, 0.22 mmol) and TEA (66.5 mg, 0.66 mmol) in THF (10 mL) was added triphosgene (131 mg, 0.44 mmol) at 0^oC, the mixture was stirred at RT for 1 h.6-fluoro-2-methyl-2H-indazol-5-amine (36 mg, 0.22 mmol) was added. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 2) to give title product (50 mg, Y: 43.7%) as a white solid. ESI-MS (M+H) ⁺: 510.2. Step 2: Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-6-methyl-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0591] A mixture of tert-butyl 4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-6- methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (40 mg, 0.08 mmol) in 4M HCl / EA (6 mL) was stirred at RT for 2 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (33 mg, Y: 80.3 %) as a white solid. ESI-MS (M+H) ⁺: 410.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.31 (s, 1H), 8.79 (s, 2H), 8.48 (d, J = 7.8 Hz, 1H), 8.30 (s, 1H), 7.48 (d, J = 12.3 Hz, 1H), 6.50 (s, 1H), 4.12 (s, 3H), 4.05 – 3.98 (m, 2H), 3.54 – 3.41 (m, 4H), 3.28 – 3.17 (m, 4H), 3.14 – 3.05 (m, 2H), 2.40 (s, 3H). Example 180 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(2-oxa-5,8- diazaspiro[3.5]nonan-8-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 8-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate. [0592] To a solution of tert-butyl 8-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8- diazaspiro[3.5]nonane-5-carboxylate (120 mg, 0.35 mmol) in THF (10 mL) were added TEA (106 mg, 1.05 mmol) and phenyl (7-fluoro-2-methyl-2H-indazol-5-yl)carbamate (119 mg, 0.42 mmol). The reaction mixture was stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo and purified by (PE/EA=0/1) to give title product (40 mg, 21.48 %) as a yellow solid. ESI-MS (M+H) ⁺: 538.2. Step 2: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(2-oxa-5,8- diazaspiro[3.5]nonan-8-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0593] To a solution of tert-butyl 8-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate (40 mg, 0.07 mmol) in DCM (5 mL) was added ZnBr₂ (158 mg, 0.70 mmol). The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (2.93 mg, 7.35 %) as a yellow solid. ESI-MS (M+H) ⁺: 438.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 9.69 (s, 2H), 8.37 (d, J = 2.7 Hz, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.74 (s, 1H), 7.26 (d, J = 13.0 Hz, 1H), 6.69 (d, J = 5.9 Hz, 1H), 4.68 (d, J = 7.5 Hz, 2H), 4.54 (d, J = 7.6 Hz, 2H), 4.17 (s, 3H), 4.07 – 4.02 (m, 2H), 3.74 – 3.71 (m, 2H), 3.38 – 3.36 (m, 2H), 3.31 – 3.28 (m, 2H), 3.23 – 3.18 (m, 2H). Example 181 – Preparation of N-(6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of ethyl 2-bromo-5-fluoroisonicotinate. [0594] To a mixture of 2-bromo-5-fluoroisonicotinic acid (25 g, 113.66 mmol) in EtOH (500 mL) was added H₂SO₄ (46 g, 469.00 mmol). The mixture was stirred at 80 ^o C for 16 h. After the reaction in complete, cool to r.t and distill under reaction pressure to remove the solvent. The residue was dissolved in DCM (100 mL), followed by saturated aqueous sodium bicarbonate solution, wash with saturated bine, combine the organic phases, dry with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give title product (26 g, 92%) as a white solid. ESI-MS (M+H) ⁺: 248.1.¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 5.2 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). Step 2: Preparation of ethyl 5-fluoro-2-(prop-1-yn-1-yl)isonicotinate. [0595] A solution of ethyl 2-bromo-5-fluoroisonicotinate (26 g, 104.84 mmol), trimethyl(prop-1-yn-1-yl)silane (41.2 g, 366.94 mmol), Pd(PPh₃)₄ (12 g, 10.48 mmol), CuI (6 g, 31.45 mmol) , TBAF (27 g, 94.36 mmol ) and TEA (31.8 g, 314.52 mmol) in toluene (500 mL) was stirred at r.t for 5 h. The mixture was diluted with water (500 mL) and extracted with EA (500 mL× 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuo. The crude was purified by silica gel column chromatography (PE/EA= 3:1) to afford title product (15 g, Y: 68 %) as a yellow solid. ESI-MS (M+H) ⁺: 208.1. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 5.7 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.09 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). [0596] Step 3 and 4: Preparation of ethyl 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5- carboxylate. [0597] To a mixture of ethyl 5-fluoro-2-(prop-1-yn-1-yl)isonicotinate (11 g, 52.88 mmol) in trichloromethane (500 mL) was added and O-(mesitylsulfonyl) hydroxylamine (32 g, 237.98 mmol) in 0^oC. The mixture was stirred at r.t for 16 h. The reaction mixture was concentrated in vacuo, the residue was diluted with DMF (500 mL), K₂CO₃ (14.6 g, 105.76 mmol) was added and stirred at r.t for 5 h. The mixture was concentration in vacuo. The crude was diluted with water (500 mL) and extracted with EA (500 mL ×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuo. The crude was purified by silica gel column chromatography (PE/EA= 5:1) to give title product (3.5 g, Y: 29 %) as a yellow solid. ESI-MS (M+H) ⁺: 223.1.¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J = 5.8 Hz, 1H), 8.11 (d, J = 7.1 Hz, 1H), 6.50 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.42 (dd, J = 9.1, 5.2 Hz, 3H). Step 5: Preparation of 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid. [0598] To a mixture of ethyl 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5-carboxylate (500 mg, 2.25 mmol) in THF (5 mL) and water (70 mL) was added LiOH (108 mg, 4.50 mmol). The mixture was stirred at r.t for 2 h. The mixture was concentrated to remove THF. The aqueous phase was adjusted PH=5 by 1 M HCl. The precipitate was filtered and dried to give title product (200 mg, 45%) as a white solid. ESI-MS (M+H) ⁺: 195.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d, J = 6.3 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 6.66 (s, 1H), 2.41 (s, 3H). Step 6: Preparation of tert-butyl 7-(1-((6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0599] To a solution of 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (130 mg, 0.60 mmol) in toluene (10 mL) were added TEA (121 mg, 1.20 mmol), DPPA (248 mg, 0.90 mmol). The mixture was stirred at r.t for 1 h and 70 ^o C for 1 h. Then tert-butyl 7-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (100 mg, yield: 63 %) as a white solid. ESI-MS (M+H) ⁺:522.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (d, J = 6.3 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 6.30 (s, 1H), 4.02 – 3.96 (m, 2H), 3.60 – 3.54 (m, 2H), 3.31 – 3.25 (m, 2H), 3.16 – 3.09 (m, 4H), 2.33 (s, 3H), 1.42 (s, 9H), 0.97 – 0.92 (m, 2H), 0.87 – 0.84 (m, 2H). Step 7: Preparation of N-(6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. To a solution of tert-butyl 7-(1-((6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (80 mg, 0.15 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). [0600] The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (56.3 mg, 70%) as a colorless oil. ESI-MS (M+H) ⁺:422.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 9.30 – 9.10 (m, 2H), 8.92 (d, J = 6.3 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 6.1 Hz, 1H), 6.62 (d, J = 6.2 Hz, 1H), 6.31 (s, 1H), 4.03 (t, J = 8.5 Hz, 2H), 3.58 (s, 2H), 3.43 (s, 2H), 3.39 – 3.30 (m, 2H), 3.14 (t, J = 8.5 Hz, 2H), 2.33 (s, 3H), 1.07 – 0.99 (m, 2H), 0.95 (t, J = 6.4 Hz, 2H). Example 182 – Preparation of N-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine. [0601] A mixture of 6-chloro-4-methylpyridazin-3-amine (7 g, 48.76 mmol), 1- chloropropan-2-one (9022 mg, 97.51 mmol) and TEA (14774 mg, 146.28 mmol) in EtOH (80 mL) was stirred at 150 ^oC for 1h in a sealed tube. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=3:1) to provide title product (5 g, yield: 57%) as a white solid. ESI- MS (M+H)⁺: 182.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.25 (s, 1H), 2.59 (s, 3H), 2.43 (s, 3H). Step 2: Preparation of methyl 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylate. [0602] A mixture of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine (500 mg, 2.75 mmol), Pd(OAc)₂ (63 mg, 0.28 mmol), Xantphos (329 mg, 0.55 mmol) in TEA (5 mL) and MeOH (5 mL) was stirred at 70 ^oC for 16h under CO. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to provide title product (380 mg, yield: 67%) as a white solid. ESI-MS (M+H)⁺:206.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.57 (d, J = 0.9 Hz, 1H), 3.93 (s, 3H), 2.60 (d, J = 0.7 Hz, 3H), 2.43 (s, 3H). Step 3: Preparation of 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid. [0603] To a solution of methyl 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylate (350 mg, 1.70 mmol) in THF/MeOH/H₂O (5 mL /1 mL /1 mL) was added LiOH (204 mg, 8.50 mmol). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was diluted with water (5 mL), extracted with EA (10 mL). The aqueous phase was adjusted pH to 5 by 1N HCl. The precipitate was filtered, washed with water (5 mL) and lyophilized to give title product (250 mg, 76%) as a white solid. ESI-MS (M+H)⁺ :192.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.42 (s, 1H), 2.49 (s, 3H), 2.37 (s, 3H). Step 4: Preparation of tert-butyl 7-(1-((2,8-dimethylimidazo[1,2-b]pyridazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate 2,2,2-trifluoroacetate. [0604] To a solution of 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid (150 mg, 0.79 mmol) in Toluene (5 mL) were added TEA (239 mg, 2.37 mmol) and DPPA (543 mg, 1.98 mmol). The mixture was stirred at 30 ^oC for 1h. Then the mixture was stirred at 90 ^oC for another 1h. Tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (260 mg, 0.79 mmol) was added to the mixture and stirred at 90 ^oC for 16h. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:4) to provide title product (100 mg, yield: 24%) as a brown solid. ESI-MS (M+H)⁺: 519.2. Step 5: Preparation of N-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0605] To a solution of tert-butyl tert-butyl 7-(1-((2,8-dimethylimidazo[1,2-b]pyridazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (90 mg, 0.17 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep- HPLC (0.05% NH₄HCO₃ in H₂O / ACN) and concentrated in vacuo and dissolved with 0.5M TFA. The solution was concentrated in vacuo to give (12.63 mg, yield: 18%) as a brown solid. ESI-MS (M+H)⁺: 419.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 9.34 (s, 2H), 8.28 (s, 1H), 8.19 (s, 1H), 8.02 (d, J = 6.0 Hz, 1H), 6.66 (d, J = 6.2 Hz, 1H), 4.03 (t, J = 8.4 Hz, 2H), 3.63 – 3.57 (m, 2H), 3.44 (s, 2H), 3.39 – 3.32 (m, 2H), 3.15 (t, J = 8.4 Hz, 2H), 2.62 (s, 3H), 2.47 (s, 3H), 1.06 (t, J = 6.1 Hz, 2H), 0.94 (t, J = 6.2 Hz, 2H). Example 183 – Preparation of N-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of 2-cyclopropyl-6-nitroimidazo[1,2-a]pyridine. [0606] A mixture of 5-nitropyridin-2-amine (9 g, 65.43 mmol), 2-bromo-1-cyclopropylethan- 1-one (16 g, 98.15 mmol) and PPTS (1.64 g, 6.54 mmol) in IPA (100 mL) was stirred at 80 ^oC for 16 h. The precipitate was filtered and dried to give title product (10 g, 75.4%) as a yellow solid. ESI-MS (M+H) ⁺: 204.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J = 9.1 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J = 9.5 Hz, 1H), 2.28 (s, 1H), 1.17 (d, J = 6.3 Hz, 2H), 0.99 (s, 2H). Step 2: Preparation of 2-cyclopropylimidazo[1,2-a]pyridin-6-amine. [0607] A mixture of 2-cyclopropyl-6-nitroimidazo[1,2-a]pyridine (2.0 g, 9.85 mmol) and Pd/C (200 mg) in EA / EtOH (20 mL / 4mL) was stirred at RT for 16 h under H₂. The mixture was filtered and the filtrate was concentrated in vacuo to give title product (1.70 g, crude) as a black solid. ESI-MS (M+H) ⁺: 174.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.97 (s, 1H), 7.87 (s, 1H), 7.59 (d, J = 9.5 Hz, 1H), 7.43 – 7.37 (m, 1H), 5.74 (s, 2H), 2.16 – 2.07 (m, 1H), 1.13 – 1.07 (m, 2H), 0.93 – 0.87 (m, 2H). Step 3: Preparation of tert-butyl 7-(1-((2-cyclopropylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0608] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (343.3 mg, 1.04 mmol), 2-cyclopropylimidazo[1,2- a]pyridin-6-amine (150 mg, 0.87 mmol), triphosgene (310 mg, 1.04 mmol) and TEA (439.3 mg, 4.35 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE= 50 %) to give title product (40 mg, 7.25%) as a white solid. ESI-MS (M+H) ⁺: 530.2.¹H NMR (400 MHz, CDCl₃) δ 11.70 (s, 1H), 8.94 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.42 (d, J = 9.5 Hz, 1H), 7.31 (s, 1H), 7.03 – 6.98 (m, 1H), 6.32 (d, J = 6.1 Hz, 1H), 4.16 – 4.12 (m, 2H), 3.70 – 3.67 (m, 2H), 3.28 – 3.24 (m, 2H), 3.08 – 3.03 (m, 4H), 2.03 – 2.00 (m, 1H), 1.55 (s, 9H), 1.27 – 1.25 (m, 2H), 1.09 – 1.07 (m, 2H), 0.94 – 0.93 (m, 2H), 0.84 – 0.82 (m, 2H). Step 4: Preparation of N-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0609] A mixture of tert-butyl 7-(1-((2-cyclopropylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (30 mg, 0.06 mmol) in TFA / DCM (1 mL / 1 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (28.49 mg, yield: 86.66 %) as a colorless oil. ESI-MS (M+H) ⁺: 430.0.¹H NMR (400 MHz, MeOD-d₄) δ 9.31 – 9.28 (m, 1H), 8.02 – 7.89 (m, 3H), 7.78 – 7.71 (m, 1H), 6.77 – 6.65 (m, 1H), 4.25 – 4.14 (m, 2H), 3.79 – 3.67 (m, 2H), 3.52 (d, J = 6.0 Hz, 4H), 3.29 – 3.21 (m, 2H), 2.20 – 2.11 (m, 1H), 1.25 – 1.19 (m, 2H), 1.19 – 1.13 (m, 2H), 1.11 – 1.05 (m, 2H), 1.00 – 0.95 (m, 2H). Example 184 – Preparation of N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)-4-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate. H_{N Ph}

Step 1: Preparation of 2-chloro-3-(difluoromethyl)pyridine. [0610] A mixture of 2-chloronicotinaldehyde (12 g, 84.8 mmol), DAST (38 g, 237.45 mmol) in DCM (100 mL) was stirred at RT for 4 h. The mixture was diluted with water (100 mL), extracted with DCM (100 mL×3). The organic layer was washed with brine (100 mL), dried with Na₂SO₄ and concentrated in vacuo to give title product (12 g, crude) as a yellow liquid. ESI-MS (M+H) ⁺: 164.2.¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J = 4.8 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.39 (dd, J = 7.7, 4.8 Hz, 1H), 6.93 (t, J = 54.5 Hz, 1H). Step 2: Preparation of N-(3-(difluoromethyl)pyridin-2-yl)-1,1-diphenylmethanimine. [0611] A mixture of 2-chloro-3-(difluoromethyl)pyridine (12 g, 73.71 mmol), diphenylmethanimine (19.8 g,109.76 mmol), Pd(OAc)₂ (1.64 g, 7.32 mmol) BINAP (9.1 g, 14.63 mmol) and Cs₂CO₃ (71 g, 219.51 mmol) in 1,4-dioxnae (200 mL) was stirred at 100 ^oC for 16 h under N₂. The mixture was diluted with water (200 mL), extracted with EA (200 mL×3). The organic layer was washed with brine (200 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 6 %) to give title product (18 g, yield: 79.87 %) as a yellow liquid. ESI-MS (M+H) ⁺: 309.1.¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J = 3.7 Hz, 1H), 7.89 – 7.74 (m, 3H), 7.55 – 7.39 (m, 3H), 7.31 – 7.16 (m, 5H), 6.99 (dd, J = 10.3, 5.4 Hz, 1H), 6.86 (t, J = 45.1 Hz, 1H). Step 3: Preparation of 3-(difluoromethyl)pyridin-2-amine. [0612] A mixture of N-(3-(difluoromethyl)pyridin-2-yl)-1,1-diphenylmethanimine (17 g, 55.19 mmol) in HCl / EA (18 mL / 50 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was diluted with water (20 mL), adjusted pH to 7~8 by Na₂CO₃, extracted with EA (100 mL×3). The organic layer was washed with brine (100 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 30 %) to give title product (5.7 g, yield: 71.23 %) as a white solid. ESI-MS (M+H) ⁺: 145.2.¹H NMR (400 MHz, CDCl₃) δ 8.22 – 8.13 (m, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.75 – 6.40 (m, 2H), 4.98 (s, 2H). Step 4: Preparation of 5-bromo-3-(difluoromethyl)pyridin-2-amine. [0613] A mixture of 3-(difluoromethyl)pyridin-2-amine ( 5.5 g, 38.19 mmol) and NBS ( 8.16g, 45.83 mmol) in ACN (50 mL) was stirred at 0 ^oC for 1 h. The mixture was concentrated in vacu, the residue was diluted with water (100 mL), extracted with EA (100 mL×3). The organic layer was washed with brine (100 mL), dried with Na₂SO₄ and concentrated in vacuo to give title product (8.7 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 222.9.¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.63 (s, 1H), 6.53 (t, J = 55.0 Hz, 1H), 4.93 (s, 2H). Step 5: Preparation of 6-bromo-8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine. [0614] A mixture of 5-bromo-3-(difluoromethyl)pyridin-2-amine (6.9 g, 31.09 mmol), 1- bromo-1,1-dimethoxyethane (17.07 g, 93.28 mmol) and PPTS (1.56 g, 6.22 mmol) in IPA (50 mL) was stirred at 80 ^oC for 16 h. The precipitate was filtered and dried to give title product (7 g, 84.4 %) as a white solid. ESI-MS (M+H) ⁺: 262.8.¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.59 – 7.28 (m, 1H), 2.51 (d, J = 2.0 Hz, 3H). Step 6: Preparation of N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0615] A mixture of 6-bromo-8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine (6 g, 23.8 mmol), diphenylmethanimine (5.01 g,27.69 mmol), Pd(OAc)₂ (535 mg, 2.38 mmol), BINAP (2.96 g, 4.76 mmol) and Cs₂CO₃ (23 g, 71.4 mmol) in 1,4-dioxnae (100 mL) was stirred at 100 ^oC for 16 h under N₂. The mixture was concentrated in vacuo. The residue was diluted with water (100 mL), extracted with DCM (100 mL×3). The organic layer was washed with brine (100 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 32 %) to give title product (7 g, yield: 81.47 %) as a yellow oil. ESI-MS (M+H) ⁺: 362.1. Step 7: Preparation of 8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-amine HCl salt. [0616] A mixture of N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (7 g, 19.39 mmol) in 3M HCl / EA (100 mL) was stirred at RT for 16 h. The precipitate was filtered and dried to give title product (3 g, 78.53 %) as a white solid. ESI-MS (M+H) ⁺: 198.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 8.07 (d, J = 0.8 Hz, 1H), 7.69 – 7.40 (m, 2H), 5.88 (s, 2H), 2.45 (s, 3H). Step 8: Preparation of tert-butyl 7-(1-((8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0617] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (368.5 mg, 1.02 mmol), 8-(difluoromethyl)-2- methylimidazo[1,2-a]pyridin-6-amine (200 mg, 1.02 mmol), triphosgene (333.2 mg, 1.12 mmol) and TEA (515.1 mg, 5.10 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 80 %) to give title product (200 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 554.2. Step 9: Preparation of N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0618] A mixture of tert-butyl 7-(1-((8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (200 mg, 0.36 mmol) in TFA / DCM (1 mL / 2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (86.94 mg, yield: 42.55 %) as a white solid. ESI-MS (M+H) ⁺: 453.9.¹H NMR (400 MHz, MeOD-d₄) δ 9.42 (s, 1H), 8.23 (d, J = 1.2 Hz, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.98 (d, J = 6.5 Hz, 1H), 7.25 (t, J = 53.9 Hz, 1H), 6.74 (d, J = 6.5 Hz, 1H), 4.23 (t, J = 8.5 Hz, 2H), 3.84 – 3.73 (m, 2H), 3.59 (s, 2H), 3.54 – 3.50 (m, 2H), 3.30 – 3.27 (m, 2H), 2.57 (d, J = 0.8 Hz, 3H), 1.20 – 1.14 (m, 2H), 1.13 – 1.07 (m, 2H). [0619] (s, 3H). Example 185 – Preparation of N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0620] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.31 mmol) in THF (5 mL) were added TEA (137 mg, 1.36 mmol), triphosgene (162 mg, 0.54 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.8-methoxy-2- methylimidazo[1,2-a]pyrazin-6-amine (92 mg, 0.54 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (100 mg, Y: 43.9 %) as a yellow solid. ESI-MS (M+H) ⁺:509.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H), 8.65 (s, 1H), 7.94 (d, J = 6.1 Hz, 1H), 7.87 (s, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.05 (s, 3H), 4.00 (t, J = 8.6 Hz, 2H), 3.47 – 3.43 (m, 4H), 3.31 – 3.27 (m, 4H), 3.14 (t, J = 8.5 Hz, 2H), 2.32 (s, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0621] To a solution of tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) in EA (3 mL) was added 4M HCl / EA (3 mL) at r.t. The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (83.43 mg, 81.2 %) as a white solid. ESI-MS (M+H)⁺:409.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.92 – 8.80 (m, 3H), 8.10 (s, 1H), 7.99 (d, J = 6.1 Hz, 1H), 6.64 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 4.04 (t, J = 8.5 Hz, 2H), 3.53 – 3.48 (m, 4H), 3.26 – 3.20 (m, 4H), 3.16 (t, J = 8.4 Hz, 2H), 2.40 (s, 3H). Example 186 – Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- isopropyl-3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4-isopropyl-3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0622] To a mixture of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (40 mg, 0.10 mmol), propan-2-one (56 mg, 0.98 mmol) and TEA (29 mg, 0.29 mmol) in MeOH (4 mL) was added NaBH₃CN (29.71 mg, 0.49 mmol). The mixture was stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (12 mg, Y: 27.20 %) as a yellow solid. ESI-MS (M+H) ⁺: 452.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.14 (s, 1H), 8.06 (s, 1H), 7.99 (dd, J = 11.5, 1.2 Hz, 1H), 7.94 (d, J = 6.7 Hz, 1H), 6.82 (d, J = 6.7 Hz, 1H), 4.28 (t, J = 8.5 Hz, 2H), 4.24 – 3.96 (m, 3H), 3.75 – 3.43 (m, 4H), 3.43 – 3.32 (m, 3H), 2.56 (s, 3H), 1.46 (dd, J = 10.3, 6.6 Hz, 6H), 1.34

Example 187 – Preparation of N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)-4-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 5-bromo-3-(trifluoromethyl)pyridin-2-amine. [0623] To a mixture of 3-(trifluoromethyl)pyridin-2-amine (10.0 g, 61.73 mmol) in ACN (100 mL) was added NBS (11.0 g, 61.73 mmol) at 0^oC. The mixture was stirred at r.t for 2 h. The mixture was diluted with sodium sulfite solution (100 mL) and extracted with EA (100 mL*3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 4: 1) to get title product (8.0 g, Y: 53.8%) as a yellow solid. ESI-MS (M+H)⁺:241.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 6.71 (s, 2H). Step 2: Preparation of 6-bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine. [0624] To a mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (8.0 g, 33.20 mmol) in IPA (30 mL) were added 1-bromo-2,2-dimethoxypropane (9.7 g, 53.11 mmol) and PPTS (833 mg, 3.32 mmol). The mixture was stirred at 95^oC for 5 h. The mixture was concentrated in vacuo, the residue was diluted with sat. NaOH (100 mL) and extracted with EA (100 mL*3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 5: 1) to get title product (8.2 g, Y: 88.5%) as a white solid. ESI-MS (M+H)⁺:278.9.¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (d, J = 0.9 Hz, 1H), 7.84 (s, 1H), 7.76 (s, 1H), 2.39 (d, J = 0.7 Hz, 3H). Step 3: Preparation of N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0625] To a mixture of 6-bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (7.7 g, 27.60 mmol) in 1,4-dioxane (100 mL) were added diphenylmethanimine (7.5 g, 41.40 mmol), BINAP (3.4 g, 5.52 mmol), Pd(OAc)₂ (621 mg, 2.76 mmol) and Cs₂CO₃ (18.0 g, 55.20 mmol). The mixture was stirred at 80^oC for 16 h under N₂. The mixture was diluted with water (100 mL) and extracted with EA (100 mL*3), the organic layer was washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 1) to get title product (6.0 g, Y: 57.4%) as a yellow solid. ESI-MS (M+H)⁺:380.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (s, 1H), 7.71 – 7.67 (m, 3H), 7.62 – 7.32 (m, 7H), 7.20 – 7.16 (m, 2H), 2.29 (s, 3H). Step 4: Preparation of 2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine hydrochloride. [0626] To a mixture of N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (5.5 g, 14.51 mmol) in EA (60 mL) was added 4 M HCl/EA (60 mL). The mixture was stirred at r.t for 2 h. The mixture was filtered and the residue was diluted with EA (30 mL). The mixture was stirred at r.t for 2 h and the precipitate was filtered to get title product (3.1 g, Y: 84.8%) as a white solid. ESI-MS (M+H)⁺:216.2. Step 5: Preparation of tert-butyl 7-(1-((2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0627] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol) in THF (5 mL) were added TEA (92 mg, 0.91 mmol), triphosgene (108 mg, 0.36 mmol) at 0^oC. The mixture was stirred at r.t for 1 h. Then 2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine hydrochloride (78 mg, 0.36 mmol)was adde to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (100 mg, Y: 57.7 %) as a yellow solid. ESI-MS (M+H) ⁺:572.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 9.16 (s, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.89 (s, 1H), 7.72 (s, 1H), 6.55 (d, J = 6.0 Hz, 1H), 3.98 (t, J = 8.5 Hz, 2H), 3.58 – 3.56 (m, 2H), 3.31 – 3.29 (m, 2H), 3.15 – 3.10 (m, 4H), 2.47 (s, 3H), 1.43 (s, 9H), 0.97 – 0.94 (m, 2H), 0.87 – 0.85 (m, 2H). Step 6: Preparation of N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0628] To a solution of tert-butyl 7-(1-((2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (80 mg, 0.14 mmol) in EA (5 mL) was added 4M HCl / EA (5 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (39.3 mg, 48.0 %) as a white solid. ESI- MS (M+H)⁺:472.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (s, 1H), 9.42 – 9.17 (m, 3H), 8.08 – 7.96 (m, 3H), 6.67 (d, J = 5.1 Hz, 1H), 4.04 (t, J = 7.7 Hz, 2H), 3.65 – 3.57 (m, 2H), 3.49 – 3.43 (m, 2H), 3.40 – 3.34 (m, 2H), 3.17 (t, J = 7.4 Hz, 2H), 2.42 (s, 3H), 1.09 – 1.03 (m, 2H), 0.95 (t, J = 6.4 Hz, 2H). Example 188 – Preparation of N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0629] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.49 mmol) in THF (5 mL) were added TEA (499 mg, 4.93 mmol), triphosgene (175 mg, 0.59 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.2-methyl-8- (trifluoromethyl)imidazo[1,2-a]pyridin-6-amine (127 mg, 0.59 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (100 mg, Y: 37.2 %) as a yellow solid. ESI-MS (M+H) ⁺:546.1. Step 2: Preparation of N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0630] To a solution of tert-butyl 4-(1-((2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.18 mmol) in EA (3 mL) was added 4M HCl / EA (3 mL) at r.t. The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (80.83 mg, 78.8 %) as a white solid. ESI-MS (M+H)⁺:446.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.68 (s, 1H), 9.37 (s, 1H), 8.98 (s, 2H), 8.14 (s, 2H), 7.97 (d, J = 6.3 Hz, 1H), 6.70 (d, J = 6.2 Hz, 1H), 4.08 (t, J = 8.2 Hz, 2H), 3.60 – 3.53 (m, 4H), 3.26 – 3.19 (m, 6H), 2.45 (s, 3H). Example 189 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-6-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide FA salt.

Step 1: Preparation of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6-(pyridin-2-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [0631] To a solution of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6-chloro-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (500 mg, 1.06 mmol) and 2- (tributylstannyl)pyridine (507 mg, 1.40 mmol) in 1,4-dioxane (10 mL) were added LiCl (280 mg, 6.36 mmol) and Pd(PPh₃)₂Cl₂ (80 mg, 0.11 mmol) at rt. Then the mixture was stirred at 100 ℃ for 16 h under N₂. The reaction was diluted with EA (20 mL) and washed with water (20 mLx3) and brine (20 mL). The organic extract was dried over Na₂SO₄, and the solvent was removed to afford the crude product. The crude product was purified by silica gel chromatography (eluted with MeOH in DCM from 0% to 8 %) to afford title product (230 mg, 42.2 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 516.2. Step 2: Preparation of benzyl 4-(6-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate. [0632] A mixture of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6-(pyridin-2-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (230 mg, 0.45 mmol) in TFA (2 mL) and DCM (10 mL) was stirred at 25 ℃ for 2 h under N₂. The mixture was concentrated and beated with ACN to afford the title product (100 mg, 54 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 416.2. Step 3: Preparation of benzyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-6-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [0633] To a solution of benzyl 4-(6-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (100 mg, 0.24 mmol) in THF (10 mL) were added TEA (122 mg, 1.20 mmol) and TBC (86 mg, 0.29 mmol ) at 0 ℃ for 1 h under N₂. Then the mixture was added 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine(60 mg, 0.36 mmol) and stirred at 70 ℃ for 16 h under N₂. The reaction was diluted with EA (20 mL) and washed with water (20 mLx3) and brine (20 mL). The organic extract was dried over Na₂SO₄, and the solvent was removed to afford the crude product. The crude product was purified by silica gel chromatography (eluted with EA in PE from 0% to 100 %) to afford title product (44 mg, 30 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 607.2. Step 4: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)-6- (pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide FA salt. [0634] A mixture of benzyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 6-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (44 mg, 0.07 mmol) in HBr (0.5 mL) and DCM (2 mL) was stirred at 25 ℃ for 0.5 h under N₂. The crude product was purified by prep-HPLC (0.05% FA in H₂O / ACN) to afford title product (5.96 mg, 17.5 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 473.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.71 (d, J = 1.4 Hz, 1H), 8.67 – 8.63 (m, 1H), 8.43 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.99 – 7.94 (m, 1H), 7.60 (d, J = 2.6 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.44 (s, 1H), 7.03 – 6.97 (m, 1H), 4.10 (t, J = 8.4 Hz, 2H), 3.61 – 3.54 (m, 4H), 3.35 – 3.32 (m, 4H), 3.20 – 3.12 (m, 2H), 2.40 (s, 3H). Example 190 – Preparation of (S)-4-(3,4-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (S)-4-(3,4-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0635] To a solution of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (40 mg, 0.097 mmol) and (CH₂O)_n (26 mg, 0.29 mmol) in MeOH / THF (1 mL, 1:1) was added HOAC (29 mg, 0.29 mmol), the mixture was stirred at RT for 1 h. Then NaBH₃CN (18 mg, 0.29 mmol) was added to the mixture and stirred at 50 ^oC for 16 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (15.68 mg, yield: 30 %) as a yellow solid. ESI-MS (M+H) ⁺: 424.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 9.84 (s, 1H), 9.66 (d, J = 6.6 Hz, 1H), 8.15 (s, 1H), 8.06 (d, J = 10.1 Hz, 1H), 7.98 (d, J = 6.1 Hz, 1H), 6.69 (d, J = 6.1 Hz, 1H), 4.06 (t, J = 8.6 Hz, 2H), 3.98 – 3.90 (m, 2H), 3.59 – 3.53 (m, 1H), 3.39 – 3.33 (m, 1H), 3.23 – 3.19 (m, 2H), 3.07 – 2.95 (m, 1H), 2.90 – 2.87 (m, 2H), 2.45 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H). Example 191 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methyl-4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0636] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.60 mmol), 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine hydrochloride (141.9 mg, 0.66 mmol), triphosgene (216.8 mg, 0.73 mmol) and TEA (333.3 mg, 3.3 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (MeOH: DCM= 7 %) to give title product (80 mg, yield: 23.26 %) as a yellow solid. ESI-MS (M+H) ⁺: 521.9.¹H NMR (400 MHz, DMSO- d₆) δ 11.97 (s, 1H), 9.19 (d, J = 7.4 Hz, 1H), 7.88 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.42 (d, J = 11.6 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.01 – 3.96 (m, 2H), 3.57 – 3.55 (m, 2H), 3.30 – 3.28 (m, 2H), 3.15 – 3.11 (m, 4H), 2.28 (s, 3H), 1.42 (s, 9H), 0.96 – 0.93 (m, 2H), 0.87 – 0.84 (m, 2H). Step 2: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide HCl salt. [0637] A mixture of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (70 mg, 0.13 mmol) in 3M HCl / EA (1 mL) was stirred at RT for 2 h. The precipitate was filtered to give title product (50 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 422.1.¹H NMR (400 MHz, DMSO- d₆) δ 12.44 (s, 1H), 9.94 (s, 2H), 9.70 – 9.65 (m, 1H), 8.17 (s, 1H), 8.07 (d, J = 10.0 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.65 (d, J = 6.4 Hz, 1H), 4.06 – 4.03 (m, 2H), 3.65 – 3.64 (m, 2H), 3.48 – 3.46 (m, 2H), 3.31 – 3.29 (m, 2H), 3.19 – 3.16 (m, 2H), 2.46 (s, 3H), 1.15 – 1.12 (m, 2H), 0.93 – 0.90 (m, 2H). Step 3: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0638] A mixture of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (50 mg, 0.12 mmol), (CH₂O)_n (32 mg, 0.36 mmol), NaBH₃CN (21.6 mg, 0.36 mmol) and TEA (36.36 mg, 0.36 mmol) in MeOH (1 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (34.28 mg, yield: 46.40 %) as a yellow oil. ESI-MS (M+H) ⁺: 436.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 10.32 (s, 1H), 9.68 (d, J = 6.6 Hz, 1H), 8.17 (s, 1H), 8.09 (d, J = 10.0 Hz, 1H), 7.99 (d, J = 6.1 Hz, 1H), 6.66 (d, J = 6.2 Hz, 1H), 4.05 (t, J = 8.5 Hz, 2H), 3.84 – 3.68 (m, 3H), 3.59 – 3.41 (m, 2H), 3.19 (t, J = 8.5 Hz, 3H), 2.96 (s, 3H), 2.45 (d, J = 0.8 Hz, 3H), 1.30 – 1.17 (m, 2H), 0.97 – 0.95 (m, 2H). Example 192 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- ((3R,5S)-3,4,5-trimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-

Step 1: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-((3R,5S)-3,4,5- trimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0639] A mixture of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (40 mg, 0.09 mmol), ACOH (16.2 mg, 0.27 mmol) and (CHO)n (13.5 mg, 0.45 mmoL) in MeOH (3 mL) was stirred at 50℃ for 1 h. NaBH₃CN (11.3 mg, 0.18 mmol) was added. The mixture was stirred at 50℃ for 16 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (46.36 mg, Y: 88.9 %) as a yellow solid. ESI-MS (M+H) ⁺: 438.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 9.82 (s, 1H), 9.66 (d, J = 6.6 Hz, 1H), 8.15 (s, 1H), 8.08 (d, J = 10.0 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.69 (d, J = 6.2 Hz, 1H), 4.08 – 4.02 (m, 2H), 3.99 – 3.93 (m, 2H), 3.43 – 3.37 (m, 2H), 3.23 (t, J = 8.3 Hz, 2H), 3.16 – 3.06 (m, 2H), 2.88 (s, 3H), 2.45 (s, 3H), 1.37 (d, J = 6.3 Hz, 6H). Example 193 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [0640] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (1 g, 6.05 mmol) and tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (4.1 g, 19.35 mmol) in DIEA (3 mL) was stirred at 140^oCfor 48 h in a sealed tube. The mixture was concentrated in vacuo and purified by silica gel column (DCM : MeOH = 20 : 1) to give title product (1 g, Y:46.6%) as a yellow solid. ESI-MS (M+H) ⁺: 333.5. Step 2: Preparation of tert-butyl (2R,6S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [0641] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (200 mg, 0.60 mmol) and 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine hydrochloride (99.7 mg, 0.60 mmol) in THF (10 mL) were added TEA (181 mg, 1.8 mmol) and triphosgene (365 mg, 1.20 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo, the residue was purified by silica gel column (PE: EA = 1: 4) to give title product (100 mg, Y: 31.8%) as a white solid. ESI-MS (M+H) ⁺: 524.2. Step 3: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0642] A mixture of tert-butyl (2R,6S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (30 mg, 0.06 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (27.37 mg, Y:88.7 %) as a yellow solid. ESI-MS (M+H) ⁺: 424.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.44 (s, 1H), 9.66 (d, J = 6.5 Hz, 1H), 9.27 (s, 1H), 8.67 (s, 1H), 8.16 (s, 1H), 8.08 (d, J = 10.0 Hz, 1H), 7.97 (d, J = 6.0 Hz, 1H), 6.70 (d, J = 6.1 Hz, 1H), 4.08 – 4.01 (m, 2H), 3.95 – 3.85 (m, 3H), 3.27 – 3.18 (m, 3H), 2.92 (t, J = 12.6 Hz, 2H), 2.45 (s, 3H), 1.27 (d, J = 6.3 Hz, 6H). Example 194 – Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-(1-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate. [0643] To a tert-butyl (S)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3- yl)(methyl)carbamate (150 mg, 0.47 mmol), 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (142 mg, 0.71 mmol) and TEA (142 mg, 1.41 mmol) in THF (10 mL) was added a solution of triphosgene (211 mg, 0.71 mmol) in THF (1 mL) dropwise to the mixture at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:4) to provide title product (120 mg, yield: 50%) as a green solid. ESI-MS (M+H)⁺:509.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 1H), 9.20 (d, J = 7.4 Hz, 1H), 7.79 – 7.77 (m, 1H), 7.71 (s, 1H), 7.41 (d, J = 11.7 Hz, 1H), 6.24 (d, J = 6.2 Hz, 1H), 3.97 – 3.91 (m, 2H), 3.70 – 3.66 (m, 2H), 3.56 – 3.41 (m, 7H), 2.77 (s, 3H), 2.23 (s, 3H), 1.43 (s, 9H). Step 2: Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0644] To a solution of tert-butyl (S)-(1-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (100 mg, 0.20 mmol) in DCM (1.5 mL) was added TFA (1.5 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (67 mg, yield: 82%) as a white solid. ESI-MS (M+H)⁺: 409.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (s, 1H), 9.66 (d, J = 6.4 Hz, 1H), 8.86 (s, 2H), 8.16 (s, 1H), 8.08 (d, J = 10.1 Hz, 1H), 7.84 (d, J = 6.1 Hz, 1H), 6.30 (d, J = 6.3 Hz, 1H), 4.02 (t, J = 8.7 Hz, 2H), 3.90 – 3.83 (m, 2H), 3.79 – 3.73 (m, 1H), 3.72 – 3.67 (m, 1H), 3.65 – 3.58 (m, 1H), 3.46 – 3.36 (m, 2H), 2.67 (t, J = 5.1 Hz, 3H), 2.45 (s, 3H), 2.34 – 2.27 (m, 1H), 2.18 – 2.09 (m, 1H).

Example 195 – Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-(1-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate. [0645] To a mixture of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate (100 mg, 0.31 mmol) in THF (10 mL) were added 7- fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (76 mg, 0.38 mmol), TEA (784.3 mg, 7.75 mmol) and triphosgene (110 mg, 0.38 mmol) (in THF (0.5 mL )) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (70 mg, yield: 44 %) as a brown solid. ESI-MS (M+H) ⁺:510.2.¹H NMR (400 MHz, CDCl₃) δ 12.32 (s, 1H), 9.17 (d, J = 7.1 Hz, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.25 (s, 1H), 6.09 (d, J = 6.1 Hz, 1H), 4.09 (dd, J = 15.5, 7.2 Hz, 2H), 3.71 (dd, J = 15.8, 6.6 Hz, 2H), 3.59 – 3.32 (m, 7H), 2.83 (s, 3H), 2.41 (s, 3H), 1.49 (s, 9H). Step 2: Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0646] To a mixture of tert-butyl (R)-(1-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (70 mg, 0.10 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (29.15 mg, 39%) as a colorless oil. ESI-MS (M+H) ⁺:410.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.45 (s, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.80 (d, J = 3.8 Hz, 1H), 6.42 (d, J = 6.5 Hz, 1H), 4.18 (t, J = 8.5 Hz, 2H), 3.97 (dd, J = 18.4, 8.0 Hz, 2H), 3.87 (dd, J = 16.6, 9.2 Hz, 2H), 3.77 (d, J = 5.4 Hz, 1H), 3.61 – 3.51 (m, 2H), 2.82 (s, 3H), 2.52 (s, 3H), 2.48 (dd, J = 14.1, 7.0 Hz, 1H), 2.28 (dd, J = 13.4, 5.7 Hz, 1H). Example 196 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

C^{ompound 196} Step 1: Preparation of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1-carboxylate. [0647] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1- carboxylate (100 mg, 0.33 mmol), 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (71 mg, 0.33 mmol), triphosgene (147 mg, 0.50 mmol) and TEA (166.6 mg, 1.65 mmol) in THF (5 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 100 %) to give title product (50 mg, 30.67 %) as a yellow solid. ESI-MS (M+H) ⁺: 495.2. Step 2: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0648] A mixture of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1-carboxylate (40 mg, 0.08 mmol) in TFA / DCM (0.5 mL / 0.5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (19.04 mg, yield: 60.40 %) as a white solid. ESI-MS (M+H) ⁺: 395.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 9.69 (d, J = 6.7 Hz, 1H), 8.72 – 8.37 (m, 2H), 8.16 (d, J = 5.2 Hz, 2H), 8.09 (d, J = 9.7 Hz, 1H), 6.90 (d, J = 5.6 Hz, 1H), 4.12 (t, J = 8.9 Hz, 2H), 3.41 (d, J = 11.3 Hz, 2H), 3.19 (t, J = 8.4 Hz, 2H), 3.08 – 3.01 (m, 2H), 2.99 – 2.94 (m, 1H), 2.45 (s, 3H), 1.91 – 1.80 (m, 4H). Example 197 – Preparation of (S)-4-(4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)-N- (7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

C^{ompound 197} Step 1: Preparation of (S)-4-(4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0649] To a solution of (S)-N-(7-fluoro-2-methylimidazo [1,2-a]pyridin-6-yl)-4- (3- methylpiperazin-1-yl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide TFA (40 mg, 0.08 mmol, 0.2 mL) and cyclopropanecarbaldehyde (16 mg, 0.24 mmol) in MeOH / THF (2 mL, 1:1) was added TEA (48 mg, 0.48 mmol) at RT for 1 h. Then NaBH₃CN (16 mg, 0.24 mmol) was added to the mixture and stirred at 50 ^oC for 16 h. The mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (23.91 mg, yield: 52 %) as a yellow solid. ESI-MS (M+H) ⁺: 464.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 9.67 (d, J = 6.8 Hz, 1H), 9.55 (s, 1H), 8.16 (s, 1H), 8.08 (d, J = 10.1 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H), 6.70 (d, J = 5.9 Hz, 1H), 4.09 – 4.04 (m, 2H), 3.97 – 3.93 (m, 2H), 3.49 – 3.43 (m, 2H), 3.30 – 3.18 (m, 5H), 3.14 – 3.04 (m, 2H), 2.45 (s, 3H), 1.35 (d, J = 6.3 Hz, 3H), 1.13 – 1.05 (m, 1H), 0.74 – 0.63 (m, 2H), 0.49 – 0.34 (m, 2H).

Example 198 – Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0650] To a solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (124 mg, 0.75 mmol) and TEA (190 mg, 1.88 mmol) in THF (15 mL) was added triphosgene (223 mg, 0.75 mmol) at 0^oC, after 10 min, tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (200 mg, 0.63 mmol) was added at 0^oC to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (170 mg, 53.11 %) as a white solid. ESI-MS (M+H) ⁺:510.2 Step 2: Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0651] To a mixture of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (170 mg, 0.33 mmol) in EA (3 mL) was added HCl/EA (8 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with DCM:MeOH (8 mL, 10:1), then filtered and lyophilized to give title product (125 mg, 91.51 %) as an off-white solid. ESI-MS (M+H) ⁺:410.2.¹H NMR (400 MHz, D₂O) δ 8.90 (d, J = 6.4 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J = 9.0 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 4.27 (t, J = 8.5 Hz, 2H), 4.09 (t, J = 11.6 Hz, 2H), 3.55 – 3.47 (m, 3H), 3.42 – 3.36 (m, 2H), 3.32 – 3.24 (m, 2H), 1.33 (d, J = 6.6 Hz, 3H). Example 199 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(2- oxopiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide TFA salt.

Step 1: Preparation of tert-butyl (2-(4-bromo-2-chloropyridin-3-yl)ethyl)carbamate. [0652] To a solution of 4-bromo-2-chloropyridine (7 g, 36.38 mmol) in THF (500 mL) was added LDA (2 M, 21.8 mL, 43.66 mmol) at -78 °C and the mixture was stirred at -78 °C for 1 h. Tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.7 g, 43.66 mmol) was added at -78 °C and the mixture was stirred at -78 °C for 2 h. The mixture was quenched with aqueous NH4Cl (400 mL) and extracted with EA (200 mL × 3) and the combined organic was washed with brine (500 mL) and dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column flash chromatography (EA/PE = 1/5) to afford the product (5.5 g, 45.8% yield) as a white solid. ESI-MS (M+H) ⁺: 335.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 5.2 Hz, 1H), 7.03 – 6.91 (m, 1H), 3.25 – 3.16 (m, 2H), 3.06 – 3.00 (m, 2H), 1.35 (s, 9H). Step 2: Preparation of tert-butyl 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate. [0653] To a solution of tert-butyl (2-(4-bromo-2-chloropyridin-3-yl)ethyl)carbamate (5.5 g, 16.42 mmol) in THF (100 mL) was added NaH (2.6 g, 65.67 mmol) and the reaction was stirred at 50 °C for 1 h. The mixture was quenched with ice water (250 mL) and extracted with EA (100 mL × 3) and the combined organic was washed with brine (300 mL) and dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column flash chromatography (EA/PE = 1/5) to afford the product (2.3 g, 46.9% yield) as a white solid. ESI-MS (M+H) ⁺: 299.0.¹HNMR (400 MHz, DMSO-d₆) δ 7.93 (d, J = 5.6 Hz, 1H), 7.13 (d, J = 5.6 Hz, 1H), 4.03 – 3.88 (m, 2H), 3.03 – 2.90 (m, 2H), 1.49 (s, 9H). Step 3: Preparation of tert-butyl 4-(4-((benzyloxy)carbonyl)-2-oxopiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [0654] To a solution of tert-butyl 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate (500 mg, 1.67 mmol) in 1,4-dioxane (20 mL) were added benzyl 3- oxopiperazine-1-carboxylate (392 mg, 1.67 mmol), Pd₂(dba)₃ (153 mg, 0.17 mmol), Xantphos (193 mg, 0.17 mmol) and K₃PO₄ (1.06 g, 5.01 mmol) and the reaction was stirred at 100 °C for 16 h. The mixture was concentrated to dryness and the crude product was purified by column flash chromatography (EA = 97%) to afford the product (370 mg, 48.8% yield) as a light-yellow solid. ESI-MS (M+H) ⁺: 453.2.¹HNMR (400 MHz, DMSO-d₆) δ 8.10 (d, J = 5.6 Hz, 1H), 7.41 – 7.33 (m, 5H), 6.90 (d, J = 5.6 Hz, 1H), 5.14 (s, 2H), 4.16 (s, 2H), 3.94 – 3.87 (m, 2H), 3.73 (s, 4H), 2.90 – 2.80 (m, 2H), 1.49 (s, 9H). Step 4: Preparation of benzyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3- oxopiperazine-1-carboxylate. [0655] To a solution of tert-butyl 4-(4-((benzyloxy)carbonyl)-2-oxopiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (370 mg, 0.82 mmol) in DCM (10 mL) was added TFA (3 mL) and the reaction was stirred at rt for 2 h. The mixture was poured into aqueous NH₄HCO₃ (30 mL), extracted with DCM (15 mL × 3) and the combined organic was washed with brine (50 mL) and dried over Na₂SO₄. The crude product was used next step without purification. ESI-MS (M+H) ⁺: 353.1.¹HNMR (400 MHz, DMSO-d₆) δ 7.69 (d, J = 5.6 Hz, 1H), 7.42 – 7.32 (m, 5H), 6.49 (s, 1H), 6.36 (d, J = 5.6 Hz, 1H), 5.13 (s, 2H), 4.14 (s, 2H), 3.77 – 3.66 (m, 4H), 3.49 – 3.39 (m, 2H), 2.89 – 2.75 (m, 2H). Step 5: Preparation of 4-nitrophenyl 4-(4-((benzyloxy)carbonyl)-2-oxopiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [0656] To a solution of benzyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3- oxopiperazine-1-carboxylate (381 mg, 1.08 mmol) in THF (20 mL) was added TEA (327 mg, 3.24 mmol), then 4-nitrophenyl carbonochloridate (261 mg, 1.29 mmol) was added at 0 °C and the reaction was stirred at rt for 16 h. The mixture was poured into water (100 mL), extracted with EA (25 mL × 3) and the combined organic was washed with brine (100 mL) and dried over Na₂SO₄. The crude product was purified by column flash chromatography (EA/PE = 1/1) to afford the product (300 mg, 53.7% yield) as a white solid. ESI-MS (M+H) ⁺: 518.2.¹HNMR (400 MHz, DMSO-d₆) δ 8.40 – 8.28 (m, 2H), 8.21 (d, J = 5.6 Hz, 1H), 7.60 – 7.51 (m, 2H), 7.44 – 7.30 (m, 5H), 7.05 (d, J = 5.6 Hz, 1H), 5.15 (s, 2H), 4.28 – 4.12 (m, 4H), 3.78 (s, 4H), 3.08 – 2.93 (m, 2H). Step 6: Preparation of benzyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxopiperazine-1-carboxylate. [0657] To a solution of 4-nitrophenyl 4-(4-((benzyloxy)carbonyl)-2-oxopiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (223 mg, 0.43 mmol) in DMF (20 mL) were added 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (92 mg, 0.56 mmol), HOBT (87 mg, 0.64 mmol) and Et₃N (217 mg, 2.15 mmol) and the reaction was stirred at rt for 16 h. The mixture was poured into water (200 mL), extracted with EA (35 mL × 3) and the combined organic was washed with brine (500 mL) and dried over Na₂SO₄. The crude product was purified by column flash chromatography (DCM/MeOH = 10/1) to afford the product (115 mg, 49% yield) as a red solid. ESI-MS (M+H) ⁺: 544.2. Step 7: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(2-oxopiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide TFA salt. [0658] To a solution of benzyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxopiperazine-1-carboxylate (80 mg, 0.15 mmol) in DCM (4 mL) was added HBr/HOAc (2 mL) and the reaction was stirred at rt for 1 h. The mixture was poured into aqueous NH₄HCO₃ (30 mL), extracted with DCM (10 mL × 3) and the combined organic was washed with brine (50 mL) and dried over Na₂SO₄. The crude product was purified by Prep-HPLC (0.1% TFA in H₂O and ACN) to afford the product (1.15 mg, 2% yield) as a white solid. ESI-MS (M+H) ⁺: 410.2.¹HNMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.59 (s, 1H), 9.30 (s, 1H), 8.25 (d, J = 5.5 Hz, 1H), 8.09 (s, 1H), 8.02 – 7.91 (m, 1H), 7.05 (d, J = 5.8 Hz, 1H), 4.16 – 4.11 (m, 2H), 3.96 (s, 2H), 3.90 – 3.87 (m, 2H), 3.58 – 3.56 (m, 2H), 3.04 – 2.99 (m, 2H), 2.43 (s, 3H). Example 200 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (3,3,5,5-tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3,3,5,5- tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0659] To a solution of 4-(3,3,5,5-tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine (100 mg, 0.38 mmol) and 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (95 mg, 0.58 mmol) in THF (10 mL) were added TEA (2 mL) and a solution of triphosgene (171 mg, 0.58 mmol) in THF (1 mL) dropwise to the mixture at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to provide title product (42 mg, yield: 25%) as a white solid. ESI-MS (M+H)⁺: 451.9.¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (d, J = 6.3 Hz, 1H), 8.11 (s, 1H), 8.04 – 7.94 (m, 2H), 6.71 (d, J = 6.1 Hz, 1H), 4.07 (t, J = 8.3 Hz, 2H), 3.34 (s, 4H), 3.26 (t, J = 8.7 Hz, 2H), 2.45 (s, 3H), 1.44 (s, 12H). Example 201 – Preparation of N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0660] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol), 8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- amine (90.8 mg, 0.39 mmol), triphosgene (115.8 mg, 0.39 mmol) and TEA (166 mg, 1.65 mmol) in THF (5 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. the mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 97.5 %) to give title product (28 mg, 16.06%) as a yellow solid. ESI-MS (M+H) ⁺: 528.1. Step 2: Preparation of N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0661] A mixture of tert-butyl 4-(1-((8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (28 mg, 0.03 mmol) in TFA / DCM (1 mL / 1 mL) was stirred at RT for 2 h. the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (20.80 mg, yield: 97.42 %) as a colorless oil. ESI-MS (M+H) ⁺: 428.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 9.43 (s, 1H), 8.87 (s, 2H), 8.20 (s, 1H), 8.12 (s, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.44 (t, J = 53.8 Hz, 1H), 6.67 (d, J = 6.2 Hz, 1H), 4.07 – 4.03 (m, 2H), 3.54 – 3.50 (m, 4H), 3.25 – 3.16 (m, 6H), 2.48 (s, 3H). Example 202 – Preparation of N-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((2-cyclopropylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0662] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol), 2-cyclopropylimidazo[1,2-a]pyridin-6-amine (67 mg, 0.39 mmol), triphosgene (115.8 mg, 0.39 mmol) and TEA (166 mg, 1.65 mmol) in THF (5 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. the mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 100 %) to give title product (40 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 504.1. Step 2: Preparation of N-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0663] A mixture of tert-butyl 4-(1-((2-cyclopropylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (30 mg, 0.06 mmol) in TFA / DCM (1 mL / 1 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (4.92 mg, yield: 20.29 %) as a yellow oil. ESI-MS (M+H) ⁺: 404.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.28 (s, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.94 – 7.91 (m, 2H), 7.76 (d, J = 9.6 Hz, 1H), 6.73 (d, J = 6.4 Hz, 1H), 4.21 (t, J = 8.5 Hz, 2H), 3.69 – 3.64 (m, 4H), 3.41 – 3.38 (m, 4H), 3.30 – 3.27 (m, 2H), 2.18 – 2.12 (m, 1H), 1.24 – 1.19 (m, 2H), 1.00 – 0.96 (m, 2H). Example 203 – Preparation of N-(4-cyano-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((4-cyano-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0664] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and 5-amino-2-methyl-2H-indazole-4-carbonitrile (56.7 mg, 0.33 mmol) in THF (8 mL) were added TEA (100 mg, 0.99 mmol) and triphosgene (196 mg, 0.66 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was diluted with water (10 mL), extracted with DCM (10 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 1: 5) to give title product (90 mg, Y: 54.5%) as a yellow solid. ESI-MS (M+H) ⁺: 503.2. Step 2: Preparation of N-(4-cyano-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0665] A mixture of tert-butyl 4-(1-((4-cyano-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (70 mg, 0.14 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (46.31 mg, Y: 82.6%) as a white solid. ESI-MS (M+H) ⁺: 403.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H), 8.88 (s, 2H), 8.51 (s, 1H), 8.24 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 9.6 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 6.65 (d, J = 6.1 Hz, 1H), 4.20 (s, 3H), 4.10 – 4.00 (m, 2H), 3.54 – 3.51 (m, 4H), 3.28 – 3.21 (m, 4H), 3.21 – 3.14 (m, 2H). Example 204 – Preparation of N-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((2,8-dimethylimidazo[1,2-b]pyridazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0666] To a solution of 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid (40 mg, 0.21 mmol) in Toluene (5 mL) were added TEA (64 mg, 0.63 mmol) and DPPA (144 mg, 0.53 mmol). The mixture was stirred at 30 ^oC for 1h. Then the mixture was stirred at 90 ^oC for another 1h. tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (64 mg, 0.21 mmol) was added to the mixture and stirred at 90 ^oC for 16h. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:5) to provide title product (40 mg, yield: 39%) as a white solid. ESI-MS (M+H)⁺: 493.2. Step 2: Preparation of N-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide2,2,2-trifluoroacetate. [0667] To a solution of tert-butyl 4-(1-((2,8-dimethylimidazo[1,2-b]pyridazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (70 mg, 0.15 mmol) in DCM (1.5 mL) was added TFA (1.5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC(0.05% NH₄HCO₃ in H₂O / ACN) and concentrated in vacuo and dissolved with 0.5M TFA. The solution was concentrated in vacuo to give title compound (1.57 mg, yield: 0.03%) as a white solid. ESI-MS (M+H)⁺: 393.1.¹H NMR (400 MHz, MeOD-d₄) δ 8.53 (d, J = 1.1 Hz, 1H), 8.05 – 8.01 (m, 2H), 6.67 (d, J = 6.1 Hz, 1H), 4.18 – 4.12 (m, 2H), 3.59 – 3.55 (m, 4H), 3.40 – 3.37 (m, 4H), 3.22 (t, J = 8.5 Hz, 2H), 2.69 (d, J = 1.0 Hz, 3H), 2.58 (d, J = 0.7 Hz, 3H). Example 205 – Preparation of N-(7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of 4-cyclopropylpyridin-2-amine. [0668] To a mixture of 4-bromopyridin-2-amine (12 g, 0.070 mol), cyclopropylboronic acid (7.20 g, 0.084 mol) in 1,4-dioxane (120 mL) and H₂O (10 mL) were added K₂CO₃ (19.32 g, 0.14 mmol) and Pd(dppf)Cl₂ (2.88 g, 7.0 mmol). The mixture was stirred at 90 ^oC for 12 h under N₂. The mixture was diluted with H₂O (100 mL) and extracted with EA (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (9.0 g, 85.29%) as a white solid. ESI- MS (M+H) ⁺: 135.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (d, J = 5.3 Hz, 1H), 6.20 (d, J = 13.2 Hz, 1H), 6.16 (d, J = 3.3 Hz, 1H), 5.68 (s, 2H), 1.79 – 1.64 (m, 1H), 1.00 – 0.88 (m, 2H), 0.70 – 0.59 (m, 2H). Step 2: Preparation of 5-bromo-4-cyclopropylpyridin-2-amine. [0669] To a mixture of 4-cyclopropylpyridin-2-amine (8.0 g, 0.060 mol) in CAN (80 mL) was added NBS (10.63 g, 0.060 mmol). The mixture was stirred at r.t for 2 h. The mixture was diluted with H₂O (80 mL) and extracted with EA (80 mL x 3). The organic phase was washed with brine (80 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (4.50 g, 35.38%) as a yellow solid. ESI-MS (M+H) ⁺:213.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, J = 6.0 Hz, 1H), 6.03 (s, 1H), 5.93 (s, 2H), 2.02 – 1.93 (m, 1H), 1.04 – 0.97 (m, 2H), 0.66 – 0.60 (m, 2H). Step 3: Preparation of 6-bromo-7-cyclopropyl-2-methylimidazo[1,2-a]pyridine. [0670] A mixture of 5-bromo-4-cyclopropylpyridin-2-amine (5.0 g, 0.024 mol), 1- chloropropan-2-one (2.65 g, 0.029 mmol) in IPA (50 mL) was stirred at 100 ^oC for 16 h. The mixture was concentrated in vacuo, the residue was adjusted pH~9 by 2M NaOH (100 mL) and stirred at r.t for 1h. Then extracted with EA (30 mLx2). The organics were washed with water (30 mL) and brine (30 mL), concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (5.0 g, 83.33%) as a yellow solid. ESI-MS (M+H) ⁺: 253.0. Step 4: Preparation of N-(7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0671] To a mixture of 6-bromo-7-cyclopropyl-2-methylimidazo[1,2-a]pyridine (5.0 g, 0.02 mol), diphenylmethanimine (5.43 g, 0.03 mol) and BINAP (2.49 g, 4.0 mol) in 1,4-dioxane (50 mL) were added Cs₂CO₃ (13.04 g, 0.04 mol) and Pd(OAc)₂ (0.45 mg, 2.0 mmol). The mixture was stirred at 120 ^oC for 16 h under N₂. The mixture was diluted with H₂O (50 mL) and extracted with EA (50 mL x 3). The organic phase was washed with brine (50 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (3.0 g, 42.74%) as a white solid. ESI-MS (M+H) ⁺: 354.0. Step 5: Preparation of 7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride. [0672] A mixture of N-(7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (3.0 g, 0.19 mmol) in 3M HCl/EA (30 mL) was stirred at rt for 3 h. The precipitate was filtered and dried in vacuo to give title product (1.0 g, Y: 28.2%) as a yellow solid. ESI-MS (M+H⁺): 188.2. Step 6: Preparation of tert-butyl 7-(1-((7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0673] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.61 mmol) and 7-cyclopropyl-2- methylimidazo[1,2-a]pyridin-6-amine hydrochloride (125.29 mg, 0.67 mmol) in THF (10 mL) were added TEA (184.83 mg, 1.83 mmol) and triphosgene (437.68 mg, 1.53 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with water (5 mL), the precipitate was filtered and dried in vacuo to give crude title product (100 mg, Y: 30.19 %) as a yellow solid. ESI-MS (M+H)⁺: 544.1. Step 7: Preparation of N-(7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0674] A mixture of tert-butyl 7-(1-((7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (100 mg,0.18 mmol) in 3M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (16 mg, 13.12%) as a brown oil. ESI-MS (M+H) ⁺: 444.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.22 (s, 1H), 8.45 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.57 (s, 1H), 7.23 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.08 (t, J = 8.6 Hz, 2H), 3.40 – 3.37 (m, 2H), 3.21 (s, 2H), 3.15 – 3.09 (m, 4H), 2.40 (s, 3H), 2.12 – 2.04 (m, 1H), 1.24 – 1.17 (m, 2H), 0.85 – 0.80 (m, 2H), 0.78 – 0.71 (m, 4H). Example 206 – Preparation of N-(4-cyano-2-methyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

C^{ompound 206} Step 1: Preparation of 5-((diphenylmethylene)amino)-2-methyl-2H-indazole-4-carbonitrile. [0675] To a mixture of 5-bromo-2-methyl-2H-indazole-4-carbonitrile (1 g, 4.26 mmol), diphenylmethanimine (1.54 g, 8.51 mmol) and BINAP (530.80 mg, 0.85 mmol) in 1,4- dioxane (10 mL) were added Cs₂CO₃ (2.78 g, 8.52 mmol) and Pd(OAc)₂ (97.18 mg, 0.43 mmol). The mixture was stirred at 100 ^oC for 16 h under N₂. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (10 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (1.0 g, 69.95%) as a brown solid. ESI-MS (M+H) ⁺: 337.2. Step 2: Preparation of 5-amino-2-methyl-2H-indazole-4-carbonitrile hydrochloride. [0676] A mixture of 5-((diphenylmethylene)amino)-2-methyl-2H-indazole-4-carbonitrile (1.0 g, 2.98 mmol) in 4M HCl/EA (10 mL) was stirred at r.t for 2 h. The precipitate was filtrated and concentrated in vacuo to give title product (500 mg, 80.67%) as a yellow solid. ESI-MS (M+H) ⁺: 173.2. Step 3: Preparation of tert-butyl 7-(1-((4-cyano-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0677] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (150 mg, 0.45 mmol) and 5-amino-2-methyl-2H- indazole-4-carbonitrile HCl salt (78 mg, 0.45 mmol) in THF (10 mL) were added TEA (137.4 mg, 1.36 mmol) and triphosgene (267 mg, 0.90 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was diluted with water (10 mL), extracted with DCM (10 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 1: 5) to give title product (80 mg, Y: 33.3%) as a yellow solid. ESI-MS (M+H) ⁺: 529.2. Step 4: Preparation of N-(4-cyano-2-methyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan-7- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0678] A mixture of tert-butyl 7-(1-((4-cyano-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (60 mg, 0.11 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (25.07 mg, Y: 51.3%) as a white solid. ESI-MS (M+H) ⁺: 429.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.80 (s, 1H), 9.22 (s, 2H), 8.50 (s, 1H), 8.26 (d, J = 9.5 Hz, 1H), 7.97 (d, J = 9.5 Hz, 1H), 7.91 (d, J = 6.0 Hz, 1H), 6.64 (d, J = 6.1 Hz, 1H), 4.20 (s, 3H), 4.07 – 3.99 (m, 2H), 3.62 – 3.57 (m, 2H), 3.46 – 3.42 (m, 4H), 3.21 – 3.10 (m, 2H), 1.09 – 1.00 (m, 2H), 1.00 – 0.93 (m, 2H). Example 207 – Preparation of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 7-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0679] To a mixture of 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine hydrochloride (150 mg, 0.73 mmol) in THF (20 mL) were added TEA (1.2 g, 12.20 mmol), triphosgene (217 mg, 0.73 mmol) and stirred at 0℃ for 5 min, then tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.61 mmol) was added slowly at 0℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (100 mg, yield: 31 %) as a white solid. ESI-MS (M+H) ⁺:519.0.¹H NMR (400 MHz, CDCl₃) δ 12.02 (s, 1H), 8.85 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.39 (s, 1H), 6.33 (d, J = 6.1 Hz, 1H), 4.17 – 4.11 (m, 2H), 3.75 – 3.66 (m, 2H), 3.30 – 3.23 (m, 2H), 3.11 – 3.00 (m, 4H), 2.84 (s, 3H), 2.49 (s, 3H), 1.48 (s, 9H), 1.08 (t, J = 6.2 Hz, 2H), 0.84 (t, J = 6.3 Hz, 2H). [0680] Step 2: Preparation of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0681] To a mixture of tert-butyl 7-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.19 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered, washed with EA (5 mL) and dried in vacuo to give title product (36.32 mg, 42 %) as a white solid. ESI-MS (M+H) ⁺:419.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (s, 1H), 9.80 (s, 2H), 9.21 (s, 1H), 8.28 (s, 1H), 8.01 (d, J = 6.1 Hz, 1H), 6.65 (d, J = 6.1 Hz, 1H), 4.06 – 4.02 (m, 2H), 3.64 – 3.60 (m, 2H), 3.47 – 3.42 (m, 2H), 3.33 – 3.28 (m, 2H), 3.18 – 3.11 (m, 2H), 2.80 (s, 3H), 2.52 (s, 3H), 1.12 (t, J = 6.1 Hz, 2H), 0.92 (t, J = 6.3 Hz, 2H).

Example 208 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(2- oxa-5,8-diazaspiro[3.5]nonan-8-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (2-(4-bromo-2-fluoropyridin-3-yl)ethyl)carbamate. [0682] To a solution of 4-bromo-2-fluoropyridine (12 g, 68.18 mmol) in THF (100 mL) was added LDA (51 mL, 102.27 mmol) at -78°C. The mixture was stirred at -78°C for 1 h. Then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (22.8 g, 102.27 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with aqueous NH4Cl and extracted with EtOAc (200 mL x3). The organics were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title compound (20 g, 91.95 % yield) a yellow solid. ESI-MS (M+H-56) ⁺: 264.9.¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 5.3 Hz, 1H), 7.06 – 6.97 (m, 1H), 3.24 – 3.19 (m, 2H), 2.93 (t, J = 6.6 Hz, 2H), 1.39 (s, 9H). Step 2: Preparation of 2-(4-bromo-2-fluoropyridin-3-yl)ethan-1-amine hydrochloride. [0683] To a solution of tert-butyl (2-(4-bromo-2-fluoropyridin-3-yl)ethyl)carbamate (20 g, 62.70 mmol) in EtOAc (20 mL) was added 4 M HCl / EA (200 mL). The mixture was stirred at RT for 5 h. The precipitate was filtered, washed with EA (50 mL) and concentrated in vacuo to give title product (15 g, 93.75 %) as a white solid. ESI-MS (M+H) ⁺: 220.9.¹H NMR (400 MHz, DMSO-d₆) δ 8.37 – 8.15 (m, 3H), 8.06 (d, J = 5.3 Hz, 1H), 7.69 (d, J = 5.4 Hz, 1H), 3.12 – 3.04 (m, 2H), 3.01 – 2.92 (m, 2H). Step 3: Preparation of 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. [0684] To a solution of 2-(4-bromo-2-fluoropyridin-3-yl)ethan-1-amine hydrochloride (1 g, 4.57 mmol) in DMF (10 mL) was added K₂CO₃ (1.9 g, 13.71 mmol). The mixture was stirred at 70 ^oC for 16 h. The reaction mixture was diluted with H₂O (20 mL), extracted with EA (20 mL×2). The organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to give title product (850 mg, 93.54 % yield) as a white solid. ESI-MS (M+H) ⁺: 201.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J = 5.5 Hz, 1H), 7.23 (d, J = 5.6 Hz, 1H), 3.98 (t, J = 8.5 Hz, 2H), 3.00 (t, J = 8.5 Hz, 2H). Step 4: Preparation of 1-(4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethan-1-one. [0685] To a solution of 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (850 mg, 4.27 mmol) in DCM (10 mL) were added TEA (1.3 g, 12.81 mmol) and acetyl chloride (436 mg, 5.55 mmol) at 0 ^oC. The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (10 mL), extracted with DCM (20 mL×2). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by column gel chromatography (PE/EA=1/1) to give title product (570 mg, 55.37 %) as a yellow solid. ESI-MS (M+H) ⁺: 243.0. Step 5: Preparation of tert-butyl 8-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate. [0686] To a solution of 1-(4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethan-1-one (500 mg, 2.07 mmol) in 1,4-dioxane (10 mL) were added tert-butyl 2-oxa-5,8- diazaspiro[3.5]nonane-5-carboxylate (616 mg, 2.70 mmol), Cs₂CO₃ (2 g, 6.21 mml), BINAP (124 mg, 0.41 mml) and Pd(OAc)₂ (22 mg, 0.21 mml). The mixture was stirred at 100 ^oC for 16 h. The mixture was concentrated in vacuo to give title product (800 mg, crude) as a yellow solid. ESI-MS (M+H⁺): 389.0. Step 6: Preparation of tert-butyl 8-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8- diazaspiro[3.5]nonane-5-carboxylate. [0687] To a solution of tert-butyl 8-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate (800 mg, 2.06 mmol) in MeOH (10 mL) and H₂O (2 mL) was added K₂CO₃ (1.4 g, 10.30 mmol). The mixture was stirred at 60 ^oC for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude was purified by (PE: EA=0:1) to give title product (600 mg, 84.10 %) as a yellow solid. ESI-MS (M+H) ⁺: 347.2.¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 5.9 Hz, 1H), 6.14 (d, J = 6.0 Hz, 1H), 4.83 (d, J = 6.7 Hz, 2H), 4.40 (d, J = 6.8 Hz, 2H), 3.59 (t, J = 8.1 Hz, 2H), 3.50 (s, 2H), 3.39 – 3.33 (m, 2H), 3.12 (t, J = 8.2 Hz, 2H), 3.05 – 2.99 (m, 2H), 1.47 (s, 9H). Step 7: Preparation of tert-butyl 8-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8-diazaspiro[3.5]nonane- 5-carboxylate. [0688] To a solution of tert-butyl 8-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8- diazaspiro[3.5]nonane-5-carboxylate (100 mg, 0.29 mmol) in THF (10 mL) were added TEA (146 mg, 1.45 mmol), triphosgene (84 mg, 0.29 mmol) and 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (73 mg, 0.44 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by (PE/EA=1/3) to give title product (40 mg, 25.78 %) as a yellow solid. ESI-MS (M+H) ⁺: 538.1. Step 8: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(2-oxa-5,8- diazaspiro[3.5]nonan-8-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0689] To a solution of tert-butyl 8-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8-diazaspiro[3.5]nonane- 5-carboxylate (40 mg, 0.07 mmol) in DCM (5 mL) was added ZnBr₂ (168 mg, 0.70 mmol). The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (5.57 mg, 13.59 %) as a yellow solid. ESI-MS (M+H⁺): 438.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.64 (d, J = 6.5 Hz, 1H), 8.06 (d, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J = 9.6 Hz, 1H), 6.72 (d, J = 6.0 Hz, 1H), 4.78 (d, J = 8.0 Hz, 2H), 4.67 (d, J = 8.0 Hz, 2H), 4.25 – 4.10 (m, 2H), 3.79 (s, 2H), 3.49 – 3.44 (m, 2H), 3.44 – 3.39 (m, 2H), 3.29 – 3.23 (m, 2H), 2.51 (s, 3H). Example 209 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3,3,5,5- tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of 1-(2,4-dimethoxybenzyl)-3,3,5,5-tetramethylpiperazin-2-one. [0690] AcOH (0.260 mL, 4.54 mmol) was added to 2-methylpropane-1,2-diamine (0.595 mL, 5.67 mmol) and 2,4-dimethoxybenzaldehyde(943 mg, 5.67 mmol) in MeOH (20 mL) at r.t. under nitrogen. The resulting slurry turns yellow rapidly. The reaction mixture was stirred at r.t. for 1 h. The reaction mixture was then diluted with MeOH (20 mL), NaBH₄ (429 mg, 11.34 mmol) was added slowly, and the reaction mixture was stirred at r.t. for 1 h. The solvent was removed under reduced pressure, and the white residue was treated with H₂O (20 mL) and extracted with CH₂Cl₂ (30 mL *2). The solvent removed under reduced pressure to give a mixture of intermediate. The crude yellow oil obtained was purified by flash silica chromatography, elution gradient 0-10% NH₃·H₂O in MeOH in CH₂Cl₂. Pure fractions were evaporated to dryness to afford the product as a mixture of intermediate (1 g, crude) as a colorless oil.50% aq. NaOH (1.908 mL, 36.14 mmol) was added slowly to 1,1,1-trichloro-2- methylpropan-2-ol (2.70 g, 14.46 mmol), intermediate (2.36 g, 7.23 mmol), and N-benzyl- N,N-triethylammonium chloride (0.165 g, 0.72 mmol) in CH₂Cl₂ (70 mL) cooled to 0 °C. The resulting mixture was stirred at 0 °C and left to warm to r.t. over 20 h. The reaction mixture was treated with H₂O (50 mL) until any solid had dissolved. The organic layer was separated and the aqueous layer was extracted with CH₂Cl₂ (2 × 50 mL).The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give a pale yellow oil. The crude product was purified by flash silica chromatography, elution gradient 50-100% EtOAc in PE to afford production (1 g, 25%) as a yellow oil ¹ H NMR (400 MHz, CDCl₃) δ 7.20 (d, J = 7.9 Hz, 1H), 6.48 – 6.42 (m, 2H), 4.58 (s, 2H), 3.80 (d, J = 4.5 Hz, 6H), 3.09 (s, 2H), 1.39 (s, 6H), 1.09 (s, 6H). Step 2: Preparation of 3,3,5,5-tetramethylpiperazin-2-one 4-methylbenzenesulfonate. [0691] 1-(2,4-dimethoxybenzyl)-3,3,5,5-tetramethylpiperazin-2-one (2 g, 6.536 mmol) was dissolved in toluene (25 mL) at r.t. p-TsOH (2.5 g, 14.379 mmol) was then added, and the resulting solution was stirred at 120 °C for 16 h. The reaction was quenched with MeOH. The purple residue was triturated with DCM and filtered to give title product (p-TsOH salt, 1 g, 46.7 %) as a white powder.¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 2H), 8.36 (s, 1H), 7.48 (d, J = 8.1 Hz, 3H), 7.12 (d, J = 7.8 Hz, 3H), 3.28 (d, J = 3.2 Hz, 2H), 2.29 (s, 4H), 1.51 (s, 6H), 1.39 (s, 6H). Step 3: Preparation of 1-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,3,5,5- tetramethylpiperazin-2-one. [0692] A mixture of 3,3,5,5-tetramethylpiperazin-2-one 4-methylbenzenesulfonate (945 mg, 2.88 mmol), 1-(4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethan-1-one (830 mg, 3.46 mmol), Pd2(dba)₃(264 mg, 0.29 mmol), xantphos (334 mg, 0.58 mmol) and Cs₂CO₃ (3.4 g, 10.38 mmol) in 1,4-dioxane (30 mL) at room temperature was purged with N₂ for three times. Then the reaction mixture was stirred at 95 ^oC for 16 h. After cooling to rt, the mixture was concentrated in vacuo. The crude was purified by silica gel column (PE: EA=1:5) to give the title product (300 mg, 33 %) as a brown solid. ESI-MS: [M+H] ⁺: 317.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (d, J = 5.6 Hz, 1H), 6.91 (d, J = 5.6 Hz, 1H), 3.96 (t, J = 8.5 Hz, 2H), 3.57 (s, 2H), 2.86 (t, J = 8.5 Hz, 2H), 2.56 (s, 3H), 1.31 (s, 6H), 1.18 (s, 6H). Step 4: Preparation of 1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,3,5,5- tetramethylpiperazin-2-one. [0693] To a solution of 1-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,3,5,5- tetramethylpiperazin-2-one (1 g, 3.16 mmol) in MeOH:H₂O (22 mL:4 mL) was added KOH (532 mg, 9.49 mmol). The mixture was stirred at 45 ^oC for 16 h. The mixture was collected by filtered, washed with water (5 mL*3) and dryness in vacuo to give the title compound (400 mg, 46 %) as a brown solid. ESI-MS (M+H) ⁺: 275.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.68 (d, J = 5.7 Hz, 1H), 6.27 (d, J = 5.7 Hz, 1H), 3.44 (t, J = 8.5 Hz, 2H), 3.17 (s, 2H), 2.79 (t, J = 8.5 Hz, 2H), 1.28 (s, 6H), 1.15 (s, 6H). Step 5: Preparation of 4-(3,3,5,5-tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine. [0694] To a mixture of 1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,3,5,5- tetramethylpiperazin-2-one (400 mg, 1.46 mmol) in THF (5.8 mL) was added LiAlH₄ (5.8 mL, 5.84 mmol, 1 M in THF). Then the reaction mixture was stirred at 70 ^oC for 1 h. After cooling to rt, the mixture was concentrated in vacuo. The crude was purified by C18 flash (0.1 % NH₃·H₂O in water / MeCN) to give the product (140 mg, 36.9 %) as a brown solid. ESI-MS: [M+H] ⁺: 261.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (d, J = 5.9 Hz, 1H), 6.05 (d, J = 6.0 Hz, 1H), 3.38 (t, J = 8.4 Hz, 2H), 2.96 (t, J = 8.3 Hz, 2H), 2.80 (s, 4H), 1.11 (s, 12H). Step 6: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3,3,5,5- tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0695] To a solution of 4-(3,3,5,5-tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine (50 mg, 0.19 mmol) in THF (10 mL) were added phenyl (7-fluoro-2-methyl-2H- indazol-5-yl)carbamate (66 mg, 6.23 mmol), DMAP (70 mg, 0.58 mmol). Then the reaction mixture was stirred at 70 ^oC for 16 h. After cooling to rt, the mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.05% TFA in H₂O / MeCN) to give the title compound (30 mg, 27.6 %) as yellow solid. ESI-MS: [M+H]⁺: 452.0.¹H NMR (400 MHz, DMSO-d₆)δ 8.57 (s, 2H), 8.38 (d, J = 2.5 Hz, 1H), 8.00 (d, J = 5.7 Hz, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.33 – 7.23 (m, 1H), 6.76 – 6.63 (m, 1H), 4.18 (s, 3H), 4.09 – 4.01 (m, 2H), 3.39 – 3.32 (m, 4H), 3.26 – 3.20 (m, 2H), 1.44 (s, 12H). Example 210 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (3,3,5,5-tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

[0696] Step 1: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3,3,5,5- tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0697] To a solution of 4-(3,3,5,5-tetramethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine (40 mg, 0.15 mmol) in THF (3 mL) were added TEA (47 mg, 0.46 mmol), DMAP (4 mg, 0.03 mmol) and phenyl (8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamate (53 mg, 0.18 mmol). The reaction mixture was stirred at 70 °C for 16 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (33 mg, 47.57 %) as a yellow solid. ESI-MS (M+H) ⁺: 452.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 9.11 (s, 1H), 8.55 (s, 2H), 8.10 (s, 1H), 8.00 (d, J = 6.1 Hz, 1H), 7.77 (s, 1H), 6.70 (d, J = 6.1 Hz, 1H), 4.06 – 4.01 (m, 2H), 3.39 – 3.29 (m, 4H), 3.24 (t, J = 8.9 Hz, 2H), 2.43 (s, 3H), 1.44 (s, 12H).

Example 211 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2- methyl-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (1-(4-bromo-2-fluoropyridin-3-yl)propan-2-yl)carbamate. [0698] To a solution of 4-bromo-2-fluoropyridine (446 mg, 2.53 mmol) in THF (5 mL) was added LDA (1.6 mL, 13.17 mmol, 2.0 M in THF) at -78°C. The mixture was stirred at -78°C for 2 h. Then tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (500 mg, 2.11 mmol) was added to the reaction and stirred at r.t for 16 h. The reaction mixture was quenched with sat. NH₄Cl (10 mL) and extracted with EtOAc (10 mL x3). The organics were washed with brine, dried with Na₂SO₄ and concentrated in vacuo, the residue was recrystallized by PE/EA=2:1 to give title compound (500 mg, crude) a yellow solid. ESI-MS (M+H) ⁺: 414.9. Step 2: Preparation of 1-(4-bromo-2-fluoropyridin-3-yl)propan-2-amine. [0699] To a solution of tert-butyl (1-(4-bromo-2-fluoropyridin-3-yl)propan-2-yl)carbamate (400 mg, 0.99 mmol) in DCM (2 mL) and TFA (2 mL). The mixture was stirred at RT for 2 h. The mixture was diluted with H₂O (3 mL), extracted with DCM (5 mL*3), the aqueous was concentrated in vacuo to give title compound (120 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 234.9. Step 3: Preparation of 4-bromo-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. [0700] To a solution of 1-(4-bromo-2-fluoropyridin-3-yl)propan-2-amine (100 mg, 20.43 mmol) in DMF (2 mL) was added DIEA (130 mg, 1.29 mmol). The mixture was stirred at 80^oC for 6 h. The mixture was diluted with H₂O (10 mL), extracted with EA (6 mL*3), organic layer concentrated in vacuo to give title compound (100 mg, crude) as a brown solid. ESI-MS (M+H) ⁺: 214.8. Step 4: Preparation of tert-butyl 4-(2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate. [0701] A mixture of 4-bromo-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.47 mmol) and tert-butyl piperazine-1-carboxylate (263 mg, 1.41 mmol) in DIEA (1 mL) was stirred at 140^oC for 16h in a sealed tube. The mixture was concentrated in vacuo and purified by silica gel column (100%EA) to give title product (80 mg, Y: 53.4%) as a yellow solid. ESI-MS (M+H) ⁺: 319.5.¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J = 6.4 Hz, 1H), 6.09 (d, J = 6.5 Hz, 1H), 3.58 – 3.50 (m, 4H), 3.46 – 3.42 (m, 4H), 2.70 – 2.60 (m, 1H), 2.37 – 2.35 (m, 2H), 1.46 (s, 9H), 1.31 (d, J = 6.2 Hz, 3H). Step 5: Preparation of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [0702] To a mixture of tert-butyl 4-(2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (60 mg, 0.19 mmol) 8-fluoro-2-methylimidazo[1,2-a]pyridin-6- amine (47 mg, 0.28 mmol) and TEA (57 mg, 0.56 mmol) in THF (6 mL) was added triphosgene (113 mg, 0.38 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by prep-TCL (100% EA) to give title product (25 mg, Y: 26.0%) as a white solid. ESI-MS (M+H) ⁺: 510.2. Step 6: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methyl-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0703] A mixture of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (20 mg, 0.04 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (15 mg, Y: 93.2%) as a white solid. ESI-MS (M+H) ⁺: 410.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 9.19 (s, 1H), 8.94 (s, 2H), 8.15 (s, 1H), 8.00 (d, J = 6.1 Hz, 1H), 7.87 (d, J = 12.2 Hz, 1H), 6.68 (d, J = 6.2 Hz, 1H), 4.72 – 4.60 (m, 1H), 3.53 – 3.48 (m, 4H), 3.44 – 3.41 (m, 1H), 3.28 – 3.20 (m, 4H), 2.76 – 2.69 (m, 1H), 2.45 (s, 3H), 1.32 (d, J = 6.2 Hz, 3H). Example 212 – Preparation of (R)-4-(3-aminopyrrolidin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 3 ^{Compound 212} Step 1: Preparation of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)carbamate. [0704] To a solution of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (500 mg, 3.23 mmol) and tert-butyl (R)-pyrrolidin-3-ylcarbamate (720 mg, 3.87 mmol) in DIEA (1250 mg, 9.19 mmol) was stirred at 140 ^oC for 16 h in a sealed tube. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1, DCM: MeOH=10: 1) to give title product (484 mg, 49%) as a yellow solid. ESI-MS (M+H) ⁺: 305.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.45 – 7.36 (m, 2H), 6.12 (d, J = 7.4 Hz, 1H), 4.14 – 4.04 (m, 2H), 3.82 – 3.70 (m, 2H), 3.67 – 3.55 (m, 4H), 3.19 – 3.15 (m, 1H), 2.10 – 2.00 (m, 1H), 1.91 – 1.82 (m, 1H), 1.39 (s, 9H). Step 2: Preparation of tert-butyl (R)-(1-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)carbamate. [0705] To a solution of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)carbamate (400 mg, 1.32 mmol) and 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (261 mg, 1.58 mmol) in THF (10 mL) were added TEA (2 mL) and triphosgene (469 mg, 1.58 mmol) at 0 ^oC . The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1, DCM: MeOH= 10: 1) to give title product (240 mg, 36%) as a yellow solid. ESI-MS (M+H) ⁺: 496.2. Step 3: Preparation of (R)-4-(3-aminopyrrolidin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0706] To a solution of tert-butyl (R)-(1-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)carbamate (235 mg, 0.47 mmol) in EA ( 2 mL) was added 4M HCl / EA (5 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtrated and dried in vacuo to give 220 mg crude product as HCl salt. The compound (40 mg) was purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (15.94 mg, yield: 35 %) as a white solid. ESI-MS (M+H) ⁺: 396.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (d, J = 6.0 Hz, 1H), 7.94 (s, 1H), 7.82 (d, J = 9.3 Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 6.48 (d, J = 6.8 Hz, 1H), 4.29 – 4.21 (m, 2H), 4.10 – 4.01 (m, 2H), 3.99 – 3.91 (m, 1H), 3.89 – 3.78 (m, 2H), 3.67 – 3.57 (m, 2H), 2.53 (s, 3H), 2.50 – 2.42 (m, 1H), 2.28 – 2.18 (m, 1H). Example 213 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(2- oxa-5,8-diazaspiro[3.5]nonan-8-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

C^{ompound 213} Step 1: Preparation of tert-butyl 8-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8-diazaspiro[3.5]nonane- 5-carboxylate. [0707] To a solution of tert-butyl 8-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8- diazaspiro[3.5]nonane-5-carboxylate (100 mg, 0.29 mmol) and 8-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (57 mg, 0.35 mmol) in THF (2 mL) were added TEA (0.5 mL) and triphosgene (104 mg, 0.35 mmol) at 0 ^oC . The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1) to give title product (60 mg, 38.7%) as a yellow solid. ESI-MS (M+H) ⁺: 537.9.¹H NMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H), 8.84 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 12.2 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 4.71 – 4.70 (m, 2H), 4.29 (d, J = 6.6 Hz, 2H), 4.04 – 3.99 (m, 2H), 3.59 (s, 2H), 3.40 – 3.35 (m, 2H), 3.28 – 3.15 (m, 2H), 3.15 – 3.10 (m, 2H), 2.33 (s, 3H), 1.42 (s, 9H). Step 2: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(2-oxa-5,8- diazaspiro[3.5]nonan-8-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0708] To a solution of tert-butyl 8-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxa-5,8-diazaspiro[3.5]nonane- 5-carboxylate (50 mg, 0.09 mmol) in DCM/MeOH (1 mL, 1: 1) was added ZnBr₂ (104 mg, 0.46 mmol). The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (9.77 mg, yield: 25 %) as a white solid. ESI-MS (M+H) ⁺: 438.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.18 (s, 1H), 8.09 – 8.03 (m, 2H), 7.97 (dd, J = 11.5, 1.3 Hz, 1H), 6.77 (d, J = 6.2 Hz, 1H), 4.80 (d, J = 8.0 Hz, 2H), 4.67 (d, J = 8.0 Hz, 2H), 4.24 – 4.16 (m, 2H), 3.85 (d, J = 5.3 Hz, 2H), 3.56 – 3.50 (m, 2H), 3.46 – 3.41 (m, 2H), 3.35 – 3.32 (m, 2H), 2.56 (s, 3H).

Example 214 – Preparation of N-(6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0709] To a solution of 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (153 mg, 0.79 mmol) in toluene (10 mL) were added TEA (162 mg, 1.60 mmol), DPPA (330 mg, 1.20 mmol). The mixture was stirred at r.t for 1 h and 70 ^o C for 1 h. Then tert-butyl 4-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (120 mg, 0.40 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The precipitate was filtered, washed with toluene (5 mL) and dried in vacuo to give title product (90 mg, yield: 45 %) as a white solid. ESI-MS (M+H) ⁺:496.2.¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J = 7.9 Hz, 1H), 8.30 (d, J = 5.7 Hz, 1H), 7.94 (d, J = 5.9 Hz, 1H), 6.37 (d, J = 6.1 Hz, 1H), 6.18 (s, 1H), 4.22 – 4.12 (m, 2H), 3.61 – 3.54 (m, 4H), 3.27 – 3.19 (m, 4H), 3.09 – 3.06 (m, 2H), 2.43 (s, 3H), 1.49 (s, 9H). Step 2: Preparation of N-(6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0710] To a solution of tert-butyl 4-(1-((6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (43.06 mg, 83%) as a white solid. ESI-MS (M+H) ⁺:396.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (s, 1H), 8.93 (d, J = 6.3 Hz, 1H), 8.78 (s, 2H), 8.27 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 6.31 (s, 1H), 4.04 (t, J = 8.5 Hz, 2H), 3.49 (d, J = 5.0 Hz, 4H), 3.26 – 3.20 (m, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.33 (s, 3H). Example 215 – Preparation of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Boc ^{H Compound 215} Step 1: Preparation of tert-butyl 4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0711] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) in THF (10 mL) were added 2,8-dimethylimidazo[1,2- a]pyrazin-6-amine hydrochloride (131 mg, 0.66 mmol), TEA (834.9 mg, 8.25 mmol) and triphosgene (157 mg, 0.53 mmol) (in THF (0.5 mL )) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:2) to give title product (50 mg, yield: 30 %) as a white solid. ESI-MS (M+H) ⁺:493.2.¹H NMR (400 MHz, CDCl₃) δ 12.00 (s, 1H), 8.86 (s, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.39 (s, 1H), 6.38 (d, J = 6.1 Hz, 1H), 4.16 (t, J = 8.5 Hz, 2H), 3.59 – 3.53 (m, 4H), 3.24 (d, J = 4.7 Hz, 4H), 3.11 (t, J = 8.6 Hz, 2H), 2.84 (s, 3H), 2.49 (s, 3H), 1.49 (s, 9H). [0712] Step 2: Preparation of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0713] To a mixture of tert-butyl 4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was diluted in 0.2 M TFA (5 mL) and concentration under reduced pressure to give title product (48.85 mg, 96%) as a white solid. ESI-MS (M+H) ⁺:393.2.¹H NMR (400 MHz, DMSO-d₆₊D₂O) δ 9.15 (s, 1H), 8.21 (d, J = 0.8 Hz, 1H), 8.00 (d, J = 6.2 Hz, 1H), 6.70 (d, J = 6.4 Hz, 1H), 4.13 – 4.10 (m, 2H), 3.62 – 3.54 (m, 4H), 3.29 – 3.19 (m, 6H), 2.80 (s, 3H), 2.54 (s, 3H). Example 216 – Preparation of N-(7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

H ^{Compound 216} Step 1: Preparation of tert-butyl 4-(1-((7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0714] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (120 mg, 0.39 mmol), 7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (86.97 g, 0.39 mmol) in THF (10 mL) were added TEA (393.90 mg, 3.90 mmol) and triphosgene (289.56 mg, 0.98 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (60 mg, 29.76%) as a white solid. ESI-MS (M+H) ⁺: 518.1. Step 2: Preparation of N-(7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0715] A mixture of tert-butyl 4-(1-((7-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h . The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in water / CH₃CN) to give title product (20.34 mg, 43.60%) as a white solid. ESI-MS (M+H) ⁺:418.2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (s, 1H), 9.61 (s, 1H), 8.88 (s, 2H), 8.12 (s, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.54 (s, 1H), 6.64 (d, J = 6.2 Hz, 1H), 4.10 – 4.04 (m, 2H), 3.52 – 3.49 (m, 4H), 3.26 – 3.21 (m, 4H), 3.20 – 3.16 (m, 2H), 2.44 (s, 3H), 2.17 – 2.09 (m, 1H), 1.29 – 1.22 (m, 2H), 0.94 – 0.88 (m, 2H). Example 217 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6- methyl-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [0716] To a solution of tert-butyl 4-(6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (70 mg, 0.22 mmol) and 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (55 mg, 0.33 mmol) in THF (10 mL) were added TEA (2 mL) and a solution of triphosgene (98 mg, 0.33 mmol) in THF (1 mL) dropwise to the mixture at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:4) to provide title product (98 mg, crude) as a green solid. ESI-MS (M+H)⁺:509.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (s, 1H), 9.25 (d, J = 6.6 Hz, 1H), 7.18 (s, 1H), 7.15 (s, 1H), 6.43 (s, 1H), 3.99 (t, J = 8.5 Hz, 2H), 3.46 – 3.41 (m, 4H), 3.29 – 3.25 (m, 4H), 3.10 (t, J = 8.5 Hz, 2H), 2.37 (s, 3H), 2.28 (s, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methyl-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0717] To a solution tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (110 mg, 0.22 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (53 mg, yield: 46 %) as a white solid. ESI-MS (M+H)⁺: 409.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.79 (d, J = 2.2 Hz, 1H), 9.67 (d, J = 6.6 Hz, 1H), 8.92 (s, 2H), 8.15 (s, 1H), 8.07 (d, J = 10.2 Hz, 1H), 6.55 (s, 1H), 4.07 – 4.01 (m, 2H), 3.53 – 3.46 (m, 4H), 3.27 – 3.18 (m, 4H), 3.14 (t, J = 8.4 Hz, 2H), 2.44 (s, 3H), 2.41 (s, 3H). Example 218 – Preparation of (S)-4-(4-ethyl-3-methylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (S)-4-(4-ethyl-3-methylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0718] A mixture of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (40 mg, 0.09 mmol), acetaldehyde (11 mg, 0.25 mmol), NaBH₃CN (15.7 mg, 0.25 mmol) and TEA (48.5 mg, 0.48 mmol) in MeOH (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (27.19 mg, yield: 63.99 %) as a colorless oil. ESI-MS (M+H) ⁺: 438.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 9.90 – 9.71 (m, 1H), 9.68 (d, J = 6.7 Hz, 1H), 8.17 (s, 1H), 8.09 (d, J = 10.1 Hz, 1H), 7.99 (d, J = 6.1 Hz, 1H), 6.70 – 6.65 (m, 1H), 4.06 (t, J = 8.4 Hz, 2H), 3.96 – 3.91 (m, 1H), 3.86 – 3.75 (m, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.49 – 3.37 (m, 2H), 3.28 – 3.14 (m, 5H), 3.11 – 3.04 (m, 1H), 2.45 (d, J = 0.8 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.24 (t, J = 6.6 Hz, 3H).

Example 219 – Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- (2-methoxyethyl)-3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4-(2- methoxyethyl)-3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate. [0719] To a mixture of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (40 mg, 0.10 mmol) and propan-2-one (27.16 mg, 0.19 mmol) in ACN (3 mL) was added K₂CO₃ (40.5 mg, 0.29 mmol).The mixture was stirred at 70 ^oC for 16 h. The mixture was filtered and the filtrate was purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (15 mg, Y: 32.84 %) as a yellow solid. ESI-MS (M+H) ⁺: 468.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.63 (d, J = 6.4 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J = 9.7 Hz, 1H), 6.65 (d, J = 6.1 Hz, 1H), 4.16 (t, J = 8.5 Hz, 2H), 4.03 – 3.51 (m, 8H), 3.44 (s, 3H), 3.39 – 3.32 (m, 2H), 3.29 – 3.20 (m, 3H), 2.51 (s, 3H), 1.49 (d, J = 6.5 Hz, 3H).

Example 220 – Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- isopropyl-3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4-isopropyl-3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0720] To a mixture of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (40 mg, 0.10 mmol), propan-2-one (56 mg, 0.98 mmol) and TEA (29 mg, 0.29 mmol) in MeOH (4 mL) was added NaBH₃CN (29.71 mg, 0.49 mmol). The mixture was stirred at 70 ^oC for 48 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (23 mg, Y: 52.14 %) as a yellow solid. ESI-MS (M+H) ⁺: 452.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 9.85 (s, 1H), 9.67 – 9.63 (m, 1H), 8.15 (s, 1H), 8.07 (d, J = 10.0 Hz, 1H), 7.98 (d, J = 6.0 Hz, 1H), 6.67 (d, J = 6.0 Hz, 1H), 4.06 (t, J = 8.4 Hz, 2H), 3.96 – 3.91 (m, 2H), 3.48 – 3.44 (m, 2H), 3.35 – 3.27 (m, 2H), 3.25 – 3.20 (m, 2H), 3.17 – 3.08 (m, 2H), 2.45 (s, 3H), 1.35 (d, J = 6.6 Hz, 6H), 1.19 (d, J = 6.4 Hz, 3H).

Example 221 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3,3,4- trimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3,3,4- trimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0721] To a solution of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (60 mg, 0.14 mmol) in MeOH (5 mL) were added (CH₂O)n (13 mg, 0.42 mmol), CH₃COOH (42 mg, 0.70 mmol). The mixture was stirred at r.t for 1 h, NaBH₃CN (27 mg, 0.42 mmol) was added to the mixture and stirred at 50 ^oC for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep- HPLC (0.1% TFA in H2O / ACN) to give title product (8 mg, yield: 10 %) as a yellow solid. ESI-MS (M+H) ⁺:438.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.63 (d, J = 6.4 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J = 9.7 Hz, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.16 (t, J = 8.5 Hz, 2H), 3.97 – 3.68 (m, 2H), 3.52 – 3.46 (m, 2H), 3.30 – 3.18 (m, 4H), 2.89 (s, 3H), 2.51 (d, J = 0.7 Hz, 3H), 1.51 (s, 6H).

Example 222 – Preparation of (R)-4-(3,4-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0722] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) in THF (5 mL) were added TEA (143 mg, 1.42 mmol), triphosgene (168 mg, 0.57 mmol) at 0^oC. The mixture was stirred at r.t for 1 h. The mixture was added 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (114 mg, 0.57 mmol). The mixture was stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (100 mg, Y: 41.6 %) as a yellow solid. ESI-MS (M+H) ⁺:510.2. Step 2: Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0723] To a solution of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (90 mg, 0.18 mmol) in EA (3 mL) was added 4M HCl / EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered to give title compound (70 mg, 88.9 %) as a brown solid. ESI-MS (M+H)⁺:410.2. Step 3: Preparation of (R)-4-(3,4-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0724] To a mixture of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride (50 mg, 0.12 mmol) in MeOH (2 mL) were added (CH₂O)n (18 mg, 0.61 mmol) and AcOH (22 mg, 0.37 mmol). The mixture was stirred at r.t for 1 h. Then NaBH₃CN (38 mg, 0.61 mmol) was added to the mixture and stirred at 50^oC for 16 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.03% FA in water/ ACN) to give title product (5.2 mg, Y: 14.5%) as a yellow solid. ESI-MS (M+H)⁺:424.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.61 (d, J = 6.4 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.80 (d, J = 9.7 Hz, 1H), 6.65 (d, J = 6.1 Hz, 1H), 4.16 (t, J = 8.5 Hz, 2H), 3.97 – 3.91 (m, 1H), 3.67 – 3.59 (m, 1H), 3.49 – 3.41 (m, 1H), 3.32 (s, 2H), 3.27 – 3.22 (m, 2H), 3.15 – 3.03 (m, 1H), 2.99 (s, 3H), 2.51 (s, 3H), 1.47 (d, J = 6.5 Hz, 3H). Example 223 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2,8- dimethylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [0725] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (200 mg, 0.6 mmol) and TEA (181 mg, 1.8 mmol) in THF (8 mL) was added triphosgene (356 mg, 1.2 mmol) at 0^oC, the mixture was stirred at RT for 1 h .7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-amine (0.8 mg, 0.6 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 5) to give title product (60 mg, Y: 18.6%) as a yellow solid. ESI-MS (M+H) ⁺: 538.2. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2,8- dimethylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0726] A mixture of tert-butyl (2R,6S)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (51 mg, Y: 99.4%) as a yellow solid. ESI-MS (M+H) ⁺: 438.1. ¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 9.54 (d, J = 6.3 Hz, 1H), 9.30 (d, J = 8.7 Hz, 1H), 8.67 (d, J = 9.6 Hz, 1H), 8.16 (d, J = 1.0 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.70 (d, J = 6.2 Hz, 1H), 4.08 – 4.01 (m, 2H), 3.94 – 3.86 (m, 2H), 3.40 – 3.35 (m, 2H), 3.25 – 3.18 (m, 2H), 2.97 – 2.87 (m, 2H), 2.52 (d, J = 1.7 Hz, 3H), 2.47 (s, 3H), 1.27 (d, J = 6.5 Hz, 6H). Example 224 – Preparation of (S)-N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)- 4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0727] To a solution of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (80 mg, 0.25 mmol) and 7-fluoro-2,8-dimethylimidazo[1,2- a]pyridin-6-amine (68 mg, 0.38 mmol) in THF (2 mL) were added TEA (1 mL) and triphosgene (89 mg, 0.30 mmol) at 0 ^oC . The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1) to give title product (40 mg, 31%) as a white solid. ESI-MS (M+H) ⁺: 524.1. Step 2: Preparation of (S)-N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0728] To a solution of tert-butyl (S)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate(35 mg, 0.07 mmol) in DCM (2 mL) was added TFA (2 mL), the mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (31.65 mg, yield: 86 %) as a white solid. ESI- MS (M+H) ⁺: 424.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.47 (d, J = 6.2 Hz, 1H), 8.00 (d, J = 6.1 Hz, 1H), 7.91 (d, J = 1.0 Hz, 1H), 6.67 (d, J = 6.1 Hz, 1H), 4.20 – 4.11 (m, 2H), 3.90 – 3.82 (m, 2H), 3.56 – 3.47 (m, 2H), 3.30 – 3.21 (m, 4H), 3.09 – 3.00 (m, 1H), 2.57 – 2.52 (m, 6H), 1.41 (d, J = 6.6 Hz, 3H). Example 225 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2,8- dimethylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0729] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) and tert-butyl 4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (122 mg, 0.68 mmol) in THF (5 mL) were added TEA (227 mg, 2.25 mmol) and triphosgene (134 mg, 0.45 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column gel chromatography (PE/EA=1/3) to give title product (80 mg, 32.98 %) as a yellow solid. ESI-MS (M+H) ⁺: 538.2. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2,8-dimethylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0730] To a solution of tert-butyl 4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (80 mg, 0.15 mmol) in EA (2 mL) was added 4 M HCl/EA (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (38 mg, 58.37 %) as a yellow solid. ESI-MS (M+H) ⁺: 438.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.48 (d, J = 6.0 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.91 (s, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.16 (t, J = 8.5 Hz, 2H), 3.59 – 3.51 (m, 2H), 3.46 – 3.40 (m, 2H), 3.36 (s, 2H), 3.25 (t, J = 8.5 Hz, 2H), 2.57 – 2.54 (m, 3H), 2.53 (s, 3H), 1.51 (s, 6H). Example 248 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6- oxa-2,9-diazaspiro [4.5]decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide.

Step 1: Preparation of tert-butyl 2-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6- oxa-2,9-diazaspiro [4.5] decane-9-carboxylate. [0731] A mixture of 1-(4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-1-yl) ethan-1- one (410 mg, 1.7 mmol), tert-butyl 6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (411 mg, 1.7 mmol), Pd₂(dba)₃ (155 mg, 0.17 mmol), BINAP (212 mg, 0.34 mmol) and Cs₂CO₃ (1664 mg, 5.1 mmol) in 1,4-dioxane (8 mL) was stirred for 3 hours at 100°C under nitrogen atmosphere. The resulting mixture was diluted with H₂O (50 mL). The resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by C18 column chromatography eluted with (0.05% FA in water / ACN) to afford tert-butyl 2-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (600 mg, 87%) as a yellow solid. ESI-MS (M+1) ⁺: 403.2. Step 2: Preparation of tert-butyl 2-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9- diazaspiro [4.5] decane-9-carboxylate. [0732] A mixture of tert-butyl 2-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6- oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (550 mg, 1.37 mmol) and NaOH (109 mg, 2.73 mmol) in EtOH (11 mL) was stirred for 2 hours at 70°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by C18 column chromatography eluted with (0.05% FA in water / ACN) to afford tert-butyl 2-(2,3-dihydro- 1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (450 mg, 83%) as a yellow solid. ESI-MS (M+1) ⁺: 361.3.¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (d, J = 6.1 Hz, 1H), 5.81 (d, J = 6.2 Hz, 1H), 3.65 – 3.61 (m, 2H), 3.50 (dd, J = 14.5, 6.0 Hz, 4H), 3.40 – 3.32 (m, 6H), 3.23 – 3.17 (m, 2H), 2.04 (dt, J = 12.7, 6.4 Hz, 1H), 1.94 – 1.86 (m, 1H), 1.39 (s, 9H). Step 3: Preparation of tert-butyl 2-(1-((8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9- carboxylate. [0733] To a solution of tert-butyl 2-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9- diazaspiro [4.5] decane-9-carboxylate (350 mg, 1 mmol) in THF (7 mL) were added DIEA (627 mg, 5 mmol), triphosgene (281 mg, 1 mmol) and 8-fluoro-2-methylimidazo[1,2-a] pyridin-6-amine (292 mg, 1.5 mmol) at 0°C. The reaction mixture was stirred at RT for 16 h. The resulting mixture was diluted with H₂O (20 mL). The resulting mixture was extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by C18 column chromatography eluted with (0.05% FA in water / ACN) to afford tert-butyl 2-(1-((8- fluoro-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (190 mg, 35%) as a yellow solid. ESI-MS (M+1) ⁺: 552.3. Step 4: Preparation of N-(2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9-diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide. To a mixture of tert-butyl 2-(1-((8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (40 mg, 0.075 mmol) in DCM (1 mL) was added HCl/dioxane (1 mL, 6 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by C18 column chromatography eluted with (0.05% NH4HCO3 in water / ACN) to afford N-(2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9- diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide (10 mg, 30%) as a yellow solid. ESI-MS (M+1) ⁺: 452.2.¹H NMR (400 MHz, CD₃OD) δ 8.69 (d, J = 1.5 Hz, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.10 (dd, J = 12.0, 1.6 Hz, 1H), 6.16 (d, J = 6.2 Hz, 1H), 3.98 (dt, J = 10.1, 7.0 Hz, 2H), 3.76 – 3.60 (m, 5H), 3.53 (d, J = 10.7 Hz, 1H), 3.42 – 3.33 (m, 2H), 2.85 (dt, J = 9.7, 8.7 Hz, 4H), 2.39 (s, 3H), 2.27 – 2.19 (m, 1H), 1.92 (dt, J = 13.1, 8.7 Hz, 1H). Example 257 – Preparation of (S)-4-(3-butylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a] pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-2-butyl-4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate. [0734] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine (106 mg, 0.689 mmol) in DIEA (0.1 mL) was added tert-butyl (S)-2-butylpiperazine-1-carboxylate (200 mg, 0.826 mmol) and the mixture was stirred at 140 ℃ for 16 hours. After cooled, the mixture was diluted with H₂O (30 mL) and extracted with DCM (30 mL x 2). The organic layers were washed with brine (30 mL), dried over Na₂SO₄, concentrated in vacuo. The crude was purified by silica gel chromatography eluted with (PE: EtOAc=3:1) to give the title compound (150 mg, yield: 60 %) as a yellow solid. ESI-MS (M+H) ⁺: 361.4.¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 6.1 Hz, 1H), 6.08 (d, J = 6.1 Hz, 1H), 4.19 – 4.12 (m, 1H), 4.05 – 3.97 (m, 1H), 3.61 – 3.55 (m, 2H), 3.48 – 3.40 (m, 2H), 3.15 – 3.03 (m, 3H), 2.96 – 2.92 (m, 1H), 2.85 – 2.80 (m, 1H), 1.48 (s, 9H), 1.35 – 1.24 (m, 6H), 0.90 (t, J = 7.2 Hz, 3H). Step 2: Preparation of tert-butyl (S)-2-butyl-4-(1-((8-fluoro-2-methylimidazo[1,2-a] pyridin- 6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate. [0735] To a mixture of tert-butyl (S)-2-butyl-4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (100 mg, 0.278 mmol) and TEA (140 mg, 1.39 mmol) in THF (5 mL) was added triphosgene (99 mg, 0.333 mmol) and 8-fluoro-2-methylimidazo[1,2-a] pyridin-6-amine (50 mg, 0.306 mmol) at 0 ℃ under N₂ atmosphere. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and purified by pre-HPLC (0.1% FA in water/CH₃CN) to obtain the title product (50 mg, yield: 22 %) as a yellow solid. ESI-MS (M+H) ⁺: 552.7.¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.82 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.83 (d, J = 2.7 Hz, 1H), 7.24 (dd, J = 12.5, 1.5 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 4.12 – 4.04 (m, 1H), 4.01 – 3.97 (m, 2H), 3.65 – 3.59 (m, 2H), 3.18 – 2.85 (m, 6H), 2.33 (s, 3H), 1.79 – 1.68 (m, 1H), 1.58 – 1.50 (m, 1H), 1.42 (s, 9H), 1.34 – 1.22 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H). Step 3: Preparation of (S)-4-(3-butylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide hydrochloride. A mixture of tert-butyl (S)-2-butyl-4-(1-((8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (40 mg, 0.073 mmol) in HCl/dioxane (3 mL, 4M) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and purified by pre-HPLC (0.05% HCl in water/CH₃CN) to obtain title product (5 mg, yield: 14 %) as a yellow solid. ESI-MS (M+H) ⁺: 452.5.¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.77 – 9.46 (m, 2H), 9.32 – 9.14 (m, 1H), 8.24 (s, 1H), 8.11 – 7.92 (m, 2H), 6.79 – 6.62 (m, 1H), 4.14 – 4.04 (m, 2H), 3.95 – 3.84 (m, 3H), 3.35 – 3.29 (m, 2H), 3.25 – 3.20 (m, 2H), 3.15 – 3.07 (m, 2H), 2.48 (s, 3H), 1.74 – 1.61 (m, 2H), 1.44 – 1.30 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H). Example 267 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 3-(1-((8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-3,8-diazabicyclo [3.2.1] octane-8- carboxylate. [0736] To a mixture of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-3,8- diazabicyclo [3.2.1] octane-8-carboxylate (100 mg, 0.303 mmol) and TEA (153 mg, 1.515 mmol) in THF (3 mL) was added triphosgene (108 mg, 0.364 mmol) and 8-fluoro-2- methylimidazo[1,2-a] pyridin-6-amine (55 mg, 0.333 mmol) at 0⁰C under N₂ atmosphere. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was purified by pre-HPLC (0.1% FA in water/CH₃CN) to obtain title product (40 mg, yield: 25 %) as a yellow solid. ESI-MS (M+H) ⁺: 522.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.82 (d, J = 1.5 Hz, 1H), 8.29 (s, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.83 (d, J = 2.7 Hz, 1H), 7.26 – 7.22 (m, 1H), 6.51 (d, J = 6.2 Hz, 1H), 4.21 (s, 2H), 3.97 (t, J = 8.5 Hz, 2H), 3.54 (d, J = 11.2 Hz, 2H), 3.19 (t, J = 8.6 Hz, 2H), 3.01 (d, J = 11.5 Hz, 2H), 2.32 (s, 3H), 1.88 – 1.78 (m, 4H), 1.43 (s, 9H). Step 2: Preparation of 4-(3,8-diazabicyclo [3.2.1] octan-3-yl)-N-(8-fluoro-2- methylimidazo[1,2-a] pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide hydrochloride. A mixture of tert-butyl 3-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.077 mmol) in HCl/dioxane (3 mL, 4M) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was purified by pre-HPLC (0.05% HCl in water/CH₃CN) to obtain title product (12 mg, yield: 37 %) as a yellow solid. ESI-MS (M+H) ⁺: 422.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.89 (s, 1H), 9.63 (s, 1H), 9.23 (s, 1H), 8.27 (s, 1H), 8.15 (d, J = 10.9 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H), 6.68 (s, 1H), 4.11 (s, 4H), 3.76 (s, 2H), 3.52 (s, 2H), 3.29 (s, 2H), 2.49 (s, 3H), 2.05 – 1.98 (m, 2H), 1.93 (d, J = 8.0 Hz, 2H). Example 273 – Preparation of (R)-4-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(7-fluoro- 2-methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (R)-4-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0737] To a solution of (R)-4-(3-aminopyrrolidin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (50 mg, 0.13 mmol) and (1-ethoxycyclopropoxy) trimethylsilane (44 mg, 0.25 mmol) in MeOH / THF (2 mL, 1:1) was added TEA (67 mg, 0.65 mmol) at RT for 1 h. Then NaBH₃CN (25 mg, 0.39 mmol) was added to the mixture and stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / CH3CN) to give title product (22.79 mg, yield: 40 %) as a white solid. ESI-MS (M+H) ⁺:436.0.¹H NMR (400 MHz, MeOD-d₄) δ 9.59 (s, 1H), 7.92 (s, 1H), 7.87 – 7.74 (m, 2H), 6.34 (d, J = 6.2 Hz, 1H), 4.18 – 4.07 (m, 3H), 4.04 – 3.95 (m, 1H), 3.91 – 3.79 (m, 2H), 3.79 – 3.68 (m, 1H), 3.50 – 3.46 (m, 2H), 2.93 – 2.86 (m, 1H), 2.55 – 2.48 (m, 4H), 2.35 – 2.23 (m, 1H), 1.03 – 0.92 (m, 4H).

Example 274 – Preparation of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of 3-cyclopropylpyridin-2-amine. [0738] To a solution of 3-bromopyridin-2-amine (10 g, 58.14 mmol) in toluene (100 mL) and H₂O (10 mL) were added cyclopropylboronic acid (6.5 g, 75.58 mmol). Pcy3 (1.63 g, 5.81 mmol), K₃PO₄ (42 g, 200.00 mmol) and Pd(OAc)₂ (650 mg, 2.91 mmol). The mixture was stirred at 90 ℃ for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine (200 mL x 3), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to give title product (6.4 g, yield: 82 %) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 7.98 – 7.90 (m, 1H), 7.25 (d, J = 7.3 Hz, 1H), 6.60 (dd, J = 7.3, 5.1 Hz, 1H), 4.72 (s, 2H), 1.68 – 1.57 (m, 1H), 0.96 – 0.89 (m, 2H), 0.62 – 0.56 (m, 2H). Step 2: Preparation of 5-bromo-3-cyclopropylpyridin-2-amine. [0739] To a mixture of 3-cyclopropylpyridin-2-amine (6.2 g, 46.27 mmol) in ACN (100 mL) were added NBS (8.65 g, 48.58 mmol). The reaction mixture was stirred at r.t for 30 min and concentrated in vacuo. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=5:1) to give title product (8 g, yield: 81 %) as a yellow solid. ESI- MS (M+H) ⁺:214.9.¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J = 2.2 Hz, 1H), 7.37 – 7.31 (m, 1H), 4.77 (s, 2H), 1.61 (tt, J = 8.3, 5.4 Hz, 1H), 0.97 – 0.92 (m, 2H), 0.63 – 0.58 (m, 2H). Step 3: Preparation of 6-bromo-8-cyclopropyl-2-methylimidazo[1,2-a]pyridine. [0740] To a solution of 5-bromo-3-cyclopropylpyridin-2-amine (6.1 g, 28.78 mmol) in IPA (100 mL) were added 1-bromo-2,2-dimethoxypropane (7.9 g, 43.17 mmol) and PPTS (722 mg, 2.88 mmol). The mixture was stirred at 90 ℃ for 16 h. The reaction mixture was concentrated in vacuo, the residue was diluted with sat. NaOH (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=3:1) to give title product (5 g, yield: 69 %) as a yellow oil. ESI-MS (M+H) ⁺:252.9.¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H), 7.29 (s, 1H), 6.63 (s, 1H), 2.62 – 2.55 (m, 1H), 2.47 (s, 3H), 1.18 – 1.12 (m, 2H), 0.86 (dd, J = 5.9, 4.0 Hz, 2H). Step 4: Preparation of N-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0741] To a solution of 6-bromo-8-cyclopropyl-2-methylimidazo[1,2-a]pyridine (4.3 g, 17.13 mmol) in 1,4-dioxane (100 mL) were added diphenylmethanimine (3.3 g, 17.98 mmol), Pd(OAc)₂ (385 mg, 1.71 mmol), BINAP (2.1 g, 3.43 mmol) and Cs₂CO₃ (11.2 g, 34.26 mmol). The mixture was stirred at 115 ℃ for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to give title product (6 g, yield: 99 %) as a yellow solid. ESI-MS (M+H) ⁺:352.3. Step 5: Preparation of 8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride. [0742] To a solution of N-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (6 g, 17.05 mmol) in EA (60 mL) was added 4M HCl/EA (60 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered, washed with EA (60 mL) and dried in vacuo to give title product (2.9 g, 75%) as a white solid. ESI-MS (M+H) ⁺:188.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (s, 1H), 7.91 (s, 1H), 7.02 (s, 1H), 5.13 (s, 2H), 2.46 (s, 3H), 2.36 – 2.34 (m, 1H), 1.18 – 1.11 (m, 2H), 0.85 – 0.77 (m, 2H). Step 6: Preparation of tert-butyl 7-(1-((8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0743] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol) in THF (20 mL) were added TEA (759 mg, 7.50 mmol) and triphosgene (143 mg, 0.48 mmol) (in THF (1 mL )) at 0 ℃. The reaction mixture was stirred at r.t for 1 h. Then 8-cyclopropyl-2-methylimidazo[1,2- a]pyridin-6-amine hydrochloride (136 mg, 0.61 mmol) was added to the reaction solution and stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (50 mg, yield: 30 %) as a yellow solid. ESI-MS (M+H) ⁺:544.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (s, 1H), 8.75 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.66 (s, 1H), 6.65 (d, J = 1.7 Hz, 1H), 6.55 – 6.48 (m, 1H), 3.96 (t, J = 8.6 Hz, 2H), 3.56 (s, 2H), 3.30 – 3.26 (m, 2H), 3.14 – 3.06 (m, 4H), 2.35 – 2.32 (m, 3H), 1.42 (s, 9H), 1.04 – 0.99 (m, 4H), 0.96 – 0.92 (m, 2H), 0.86 – 0.84 (m, 2H). Step 7: Preparation of N-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0744] To a mixture of tert-butyl 7-(1-((8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (40 mg, 0.74 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (35.78 mg, 86%) as a white solid. ESI-MS (M+H) ⁺:444.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.16 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 6.2 Hz, 1H), 7.94 (s, 1H), 7.49 (s, 1H), 6.67 (d, J = 6.3 Hz, 1H), 4.16 (t, J = 8.7 Hz, 2H), 3.71 – 3.64 (m, 2H), 3.54 – 3.49 (m, 4H), 3.22 (t, J = 8.2 Hz, 2H), 2.57 (s, 3H), 2.27 – 2.16 (m, 1H), 1.28 – 1.22 (m, 2H), 1.15 (t, J = 6.8 Hz, 2H), 1.09 (t, J = 6.8 Hz, 2H), 0.99 (q, J = 4.8 Hz, 2H). Example 275 – Preparation of N-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0745] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.49 mmol) in THF (20 mL) were added TEA (1.24 g, 12.25 mmol) and triphosgene (232 mg, 0.78 mmol) (in THF (1 mL )) at 0 ℃. The reaction mixture was stirred at r.t for 1 h. Then 8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (221 mg, 0.99 mmol) was added to the reaction solution and stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (50 mg, yield: 19 %) as a yellow solid. ESI-MS (M+H) ⁺:518.3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (s, 1H), 8.86 (s, 1H), 7.95 (d, J = 6.2 Hz, 1H), 7.77 (s, 1H), 6.88 – 6.73 (m, 1H), 6.55 (d, J = 6.3 Hz, 1H), 4.00 – 3.96 (m, 2H), 3.45 – 3.43 (m, 4H), 3.29 – 3.27 (m, 4H), 3.14 – 3.12 (m, 2H), 2.36 – 2.33 (m, 4H), 1.43 (s, 9H), 1.27 – 1.22 (m, 4H). [0746] Step 2: Preparation of N-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0747] To a mixture of tert-butyl 4-(1-((8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (40 mg, 0.77 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (26.16 mg, 63%) as a white solid. ESI-MS (M+H) ⁺:418.4.¹H NMR (400 MHz, MeOD-d4) δ 9.15 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 6.6 Hz, 1H), 7.94 (s, 1H), 7.51 (s, 1H), 6.70 (d, J = 6.0 Hz, 1H), 4.20 – 4.15 (m, 2H), 3.65 – 3.60 (m, 4H), 3.41 – 3.38 (m, 4H), 3.27 – 3.19 (m, 2H), 2.57 (s, 3H), 2.27 – 2.17 (m, 1H), 1.24 (dd, J = 8.4, 2.0 Hz, 2H), 0.99 (dd, J = 8.0, 3.3 Hz, 2H). Example 276 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6- methyl-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [0748] To a solution of tert-butyl 4-(6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (50 mg, 0.16 mmol) and 8-fluoro-2-methylimidazo [1,2- a]pyridin-6-amine (31 mg, 0.19 mmol) in THF (2 mL) were added TEA (1 mL) and triphosgene (56 mg, 0.19 mmol) at 0 ^oC . The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1) to give title product (89 mg, 79%) as a green solid. ESI-MS (M+H) ⁺: 510.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s, 1H), 8.83 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 2.6 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 6.63 (dd, J = 13.1, 1.7 Hz, 1H), 4.01 – 3.95 (m, 2H), 3.45 – 3.43 (m, 4H), 3.28 – 3.25 (m, 4H), 3.13 – 3.06 (m, 2H), 2.44 (s, 3H), 2.26 (s, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methyl-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0749] To a solution of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (70 mg, 0.14 mmol) in EA ( 2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (56.85 mg, yield: 76 %) as a white solid. ESI-MS (M+H) ⁺: 410.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.19 (d, J = 1.1 Hz, 1H), 9.05 (s, 2H), 8.19 (s, 1H), 7.83 (d, J = 11.7 Hz, 1H), 6.52 (s, 1H), 4.06 – 3.96 (m, 2H), 3.54 – 3.46 (m, 4H), 3.27 – 3.19 (m, 4H), 3.15 – 3.06 (m, 2H), 2.48 (s, 3H), 2.46 (s, 3H). Example 277 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (2,2,6,6-tetramethylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate. [0750] To a solution of 2,2,6,6-tetramethylpiperidin-4-one (4 g, 25.81 mmol) in THF (100 mL) was added NaHDMS (51 mL, 51.61 mmol) at -78 ^oC. The reaction was stirred for 15 mins, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl) methanesulfonamide (1.4 g, 38.71 mmol) was added to the mixture slowly and warmed to rt before quenched by sat NaHCO₃ (100 mL). The solution was extracted with EA (200 mL), dried over Na₂SO₄, concentrated and purified by SGC (EA/PE=1%) to give the product as a yellow oil (2 g, 27% yield). ESI-MS (M+H) ⁺: 288.0.¹H NMR (400 MHz, CDCl₃) δ 5.73 (s, 1H), 2.21 (s, 2H), 1.33 – 1.23 (m, 12H) Step 2: Preparation of tert-butyl 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [0751] To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (3.9 g, 11.27 mmol) in dixoane/H₂O (50 mL/10 mL) were added 2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (4.9 g, 16.91 mmol), K₂CO₃ (2.3 g, 16.91 mmol) and Pd(pddf)Cl₂ (823 mg, 1.13 mmol). The reaction was stirred for 5 h at 100 ^oC under Ar. The mixture was diluted with water (200 mL), extracted with EA (400 mL). The organic layer was dried over Na₂SO₄, concentrated and purified by SGC (DCM/MEOH=10/1) to give product (1 g, 24% yield) as a black oil. ESI-MS (M+H) ⁺: 358.1 [0752] ¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J = 5.6 Hz, 1H), 6.65 (d, J = 5.6 Hz, 1H), 5.72 (s, 1H), 3.98 (t, J = 8.5 Hz, 2H), 3.06 (t, J = 8.5 Hz, 2H), 2.41 (s, 2H), 1.56 (s, 9H), 1.49-1.47 (m, 12H). Step 3: Preparation of tert-butyl 4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxylate. [0753] To a solution of tert-butyl 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxylate (800 mg, 2.24 mmol) in MeOH (20 mL) was added Pd/C (800 mg, 10% w.t). The reaction was stirred at 25 ^oC for 5 h under H₂.The mixture was filtered and the filtrate was concentrated to give product (400 mg, 50% yield) as a yellow oil. ESI-MS (M+H) ⁺: 360.2.¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J = 5.6 Hz, 1H), 6.73 (d, J = 5.2 Hz, 1H), 4.07 – 3.94 (m, 2H), 3.10 – 2.92 (m, 3H), 1.58 – 1.46 (m, 21H). Step 4: Preparation of 4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine. [0754] To a solution of tert-butyl 4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxylate (500 mg, 1.39 mmol) in DCM (5 mL) was added TFA (5 mL) and the reaction was stirred at rt for 16 h . The reaction was concentrated, basified by sat. Na₂CO₃ solution (20 mL), extracted with DCM (20 mLx3) and concentrated to give product (250 mg, 69% yield) as a yellow solid. ESI-MS (M+H) ⁺: 260.2.¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 5.6 Hz, 1H), 6.41 (d, J = 5.6 Hz, 1H), 4.48 (s, 1H), 3.68 – 3.54 (m, 2H), 3.13 – 2.92 (m, 2H), 1.41 – 1.23 (m, 12H). Step 5: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(2,2,6,6- tetramethylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0755] To a solution of 4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine (80 mg, 30.88 mmol) in THF (5.0 mL) were added phenyl (7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)carbamate (88 mg, 30.88 mmol ) and TEA (94 mg, 92.64 mmol). The reaction was stirred at 70 ^oC for 16 h. The mixture was concentrated and slurry in MeOH (2 mL) to give a white solid. The white solid was added to a mixture of CH₃CN (10 mL) and TFA (0.5% in water, 25 mL). The mixture was concentrated in vacuo at 40 ^oC and lyophilized to give product (45.6 mg, 26% yield) as a white powder. ESI-MS (M+H) ⁺: 451.3. ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 9.68 (d, J = 6.0 Hz, 1H), 8.77 (d, J = 10.0 Hz, 1H), 8.17 (s, 2H), 8.09 (d, J = 10.0 Hz, 1H), 7.89 (d, J = 11.6 Hz, 1H), 6.96 (d, J = 5.2 Hz, 1H), 4.13 (t, J = 8.3 Hz, 2H), 3.32 – 3.15 (m, 3H), 2.45 (s, 3H), 1.88 – 1.64 (m, 4H), 1.46-1.44 (m, 12H).

Example 278 – Preparation of 5-cyano-4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of 1-benzyl 4-(tert-butyl) 2,2-dimethylpiperazine-1,4-dicarboxylate [0756] To a solution of tert-butyl 3,3-dimethylpiperazine-1-carboxylate (9.5 g, 44.39 mmol) in THF (200 mL) and H₂O (20 mL) were added NaHCO₃ (11.2 g, 133.18 mmol) and CbzCl (9.1 g, 53.27 mmol) and the mixture was stirred at 30 °C for 3 h. The mixture was poured into water (500 mL), extracted with EA (150 mL × 3) and the combined organic was washed with brine (500 mL) and dried over Na2SO4. The crude product was purified by column flash chromatography (EA/PE = 1/5) to afford the product (7 g, 45.4% yield) as colorless oil.¹H NMR (400 MHz, CDCl₃) δ 7.40 – 7.28 (m, 5H), 5.12 (s, 2H), 3.73 – 3.67 (m, 2H), 3.49 – 3.36 (m, 4H), 1.46 (s, 9H), 1.40 (s, 6H). Step 2: Preparation of benzyl 2,2-dimethylpiperazine-1-carboxylate. [0757] To a solution of 1-benzyl 4-(tert-butyl) 2,2-dimethylpiperazine-1,4-dicarboxylate (2.3 g, 6.61 mmol) in DCM (15 mL) was added TFA (5 mL) and the reaction was stirred at rt for 16 h. The mixture was poured into aqueous NH₄HCO₃ (150 mL), extracted with DCM (50 mL × 3) and the combined organic was washed with brine (200 mL) and dried over Na₂SO₄. The crude product was used next step without purification. ESI-MS (M+H) ⁺: 249.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.45 – 7.30 (m, 5H), 5.04 (s, 2H), 3.48 – 3.38 (m, 2H), 2.88 – 2.80 (m, 2H), 2.67 (s, 2H), 1.34 (s, 6H). Step 3: Preparation of tert-butyl 4-(4-((benzyloxy)carbonyl)-3,3-dimethylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [0758] To a solution of benzyl 2,2-dimethylpiperazine-1-carboxylate (1.5 g, 6.054 mmol) in 1,4-Dioxane (80 mL) were added tert-butyl 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine- 1-carboxylate (1.81 g, 6.05 mmol), Pd2(dba)3 (554 mg, 0.61 mmol), Xantphos (706 mg, 1.22 mmol) and K₃PO₄ (3.85 g, 0.61 mmol) and the reaction was stirred at 100 °C for 16 h. The mixture was concentrated to dryness and the crude product was purified by column flash chromatography (EA = 95%) to afford the product (640 mg, 23% yield) as a white solid. ESI- MS (M+H) ⁺: 467.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.78 (d, J = 5.9 Hz, 1H), 7.39 – 7.32 (m, 5H), 6.34 (d, J = 6.0 Hz, 1H), 5.08 (s, 2H), 3.85 – 3.78 (m, 2H), 3.76 – 3.71 (m, 2H), 3.48 – 3.43 (m, 2H), 3.39 (s, 2H), 3.17 – 3.08 (m, 2H), 1.46 (s, 9H), 1.38 (s, 6H). Step 4: Preparation of tert-butyl 4-(4-((benzyloxy)carbonyl)-3,3-dimethylpiperazin-1-yl)-5- bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate [0759] To a solution of tert-butyl 4-(4-((benzyloxy)carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (640 mg, 1.37 mmol) in DCM (20 mL) were added NBS (220 mg, 1.23 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 h. The mixture was quenched with water (100 mL), extracted with DCM (40 mL × 3) and the combined organic was washed with brine (150 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column flash chromatography (EA/PE = 1/1) to afford the product (700 mg, 93.7% yield) as a white solid. ESI-MS (M+H) ⁺: 543.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.41 – 7.29 (m, 5H), 5.07 (s, 2H), 3.94 – 3.84 (m, 2H), 3.69 – 3.60 (m, 2H), 3.27 – 3.17 (m, 4H), 3.12 (s, 2H), 1.47 (s, 9H), 1.42 (s, 6H). Step 5: Preparation of benzyl 4-(5-cyano-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate. [0760] To a solution of tert-butyl 4-(4-((benzyloxy)carbonyl)-3,3-dimethylpiperazin-1-yl)-5- bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (650 mg, 1.19 mmol) in DMA (5 mL) were added Pd₂(dba)₃ (56 mg, 0.06 mmol), DPPF (69 mg, 0.12 mmol), Zn(CN)₂ (139 mg, 1.19 mmol) and Zn (4 mg, 0.60 mmol). The reaction mixture was stirred at 140 °C for 2 h under N₂. The mixture was concentrated in vacuo and purified by column gel chromatography (PE/EA=2/1) to give title product (250 mg, 42.74 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 392.3. Step 6: Preparation of benzyl 4-(5-cyano-1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0761] To a solution of benzyl 4-(5-cyano-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (250 mg, 0.64 mmol) and 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (158 mg, 0.96 mmol) in THF (10 mL) were added TEA (323 mg, 3.20 mmol) and triphosgene (247 mg, 0.83 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column chromatography (DCM/MeOH=20/1) to give title product (55 mg, 14.78 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 583.3. Step 7: Preparation of 5-cyano-4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0762] To a solution of benzyl 4-(5-cyano-1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (55 mg, 0.09 mmol) in DCM (3 mL) was added HBr in AcOH (0.5 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (4.0 mg, 8.57 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 449.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.17 (d, J = 7.2 Hz, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 7.55 (s, 1H), 7.26 (d, J = 10.8 Hz, 1H), 4.15 (t, J = 8.8 Hz, 2H), 3.64 (d, J = 5.2 Hz, 2H), 3.47 (s, 2H), 3.44 – 3.39 (m, 2H), 3.32 (d, J = 3.6 Hz, 2H), 2.36 (s, 3H), 1.48 (s, 6H). Example 279 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-6-fluoro-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide trifluoroacetate.

Step 1: Preparation of tert-butyl (2-(2,6-difluoro-4-iodopyridin-3-yl)ethyl)carbamate. [0763] To a solution of 2,6-difluoro-4-iodopyridine (10 g, 41.49 mmol) in dry THF (200 mL) was added LDA (25 mL, 50.00 mmol, 2.0 M in THF) at -78 ^oC in Ar. The reaction was stirred for 60 min. A solution of tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (11.1 g, 49.79 mmol) in THF (200 mL) was added dropwise to the mixture and stirred for 2 h. The mixture was quenched by sat NH₄Cl (200 mL) at -78 °C. The solution was extracted with EA (300 mL), dried over Na₂SO₄, concentrated and purified by SGC (EA/PE=1) to give product (6 g, 37.60 % yield) as a white solid. ESI-MS (M+H-t-Bu) ⁺: 328.8.¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J = 3.2 Hz, 1H), 4.62 (s, 1H), 3.46 – 3.30 (m, 2H), 3.03 – 2.85 (m, 2H), 1.41 (s, 9H). Step 2: Preparation of tert-butyl 6-fluoro-4-iodo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate. [0764] To a solution of tert-butyl (2-(2,6-difluoro-4-iodopyridin-3-yl)ethyl)carbamate (4 g, 10.42 mmol) in THF (100 mL) was added NaH (833 mg, 20.84 mmol) at RT. The mixture was stirred at RT for 1 h. The reaction was quenched by sat NH₄Cl (100 mL) and extracted with EA (200 mL), dried over Na₂SO₄, concentrated in vacuo and purified by SGC (PE/EA=1/1) to give product (1.6 g, 42.1% yield) as a white solid. ESI-MS (M+H) ⁺: 364.9. ¹H NMR (400 MHz, CDCl₃) δ 6.83 (d, J = 2.4 Hz, 1H), 4.17 – 3.91 (m, 2H), 3.08 – 2.83 (m, 2H), 1.56 (s, 9H). Step 3: Preparation of tert-butyl 4-(4-((benzyloxy)carbonyl)-3,3-dimethylpiperazin-1-yl)-6- fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [0765] To a solution of tert-butyl 6-fluoro-4-iodo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate (900 mg, 2.47 mmol) in 1,4-Dioxane (10 mL) were added Pd₂(dba)₃ (238 mg, 0.25 mmol), Xantphos (289 mg, 0.50 mmol) and Cs₂CO₃ (1.6 g, 4.94 mmol). The reaction mixture was stirred at 100 °C for 16 h under N₂. The mixture was concentrated in vacuo and purified by column gel chromatography (PE/EA=2/1) to give title product (220 mg, 18.38 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 485.3. Step 4: Preparation of benzyl 4-(6-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate. [0766] To a solution of tert-butyl 4-(4-((benzyloxy)carbonyl)-3,3-dimethylpiperazin-1-yl)-6- fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (220 mg, 0.45 mmol) in DCM (5 mL) was added TFA (4 mL). The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column chromatography (DCM/MeOH=20/1) to give title product (110 mg, 63.22 % yield) as a yellow oil. ESI-MS (M+H) ⁺: 385.2. Step 5: Preparation of benzyl 4-(6-fluoro-1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0767] To a solution of benzyl 4-(6-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (110 mg, 0.29 mmol) and 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (71 mg, 0.43 mmol) in THF (10 mL) were added TEA (146 mg, 1.45 mmol) and triphosgene (112 mg, 0.38 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column chromatography (DCM/MeOH=20/1) to give title product (65 mg, 39.20 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 576.3. Step 6: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-6-fluoro-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide trifluoroacetate. [0768] To a solution of benzyl 4-(6-fluoro-1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (65 mg, 0.11 mmol) in DCM (3 mL) was added HBr in AcOH (0.5 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (2.7 mg, 4.31 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 442.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.62 (d, J = 6.4 Hz, 1H), 7.93 (s, 1H), 7.81 (d, J = 9.6 Hz, 1H), 6.30 (d, J = 1.2 Hz, 1H), 4.24 – 4.14 (m, 2H), 3.65 – 3.56 (m, 2H), 3.45 – 3.40 (m, 4H), 3.22 (t, J = 8.4 Hz, 2H), 2.51 (s, 3H), 1.49 (s, 6H). Example 280 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)azetidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

^p Step 1: Preparation of tert-butyl (1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3- yl)(methyl)carbamate. [0769] To a solution of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.94 mmol) and tert-butyl azetidin-3-yl(methyl)carbamate (541 mg, 2.91 mmol) was added DIEA (2 mL) in a sealed tube. The reaction mixture was stirred at 120 °C for 16 h. The mixture was concentrated in vacuo and purified by column gel chromatography (PE/EA=1/2) to give title product (150 mg, 25.51 %) as a yellow solid. ESI-MS (M+H) ⁺: 305.0. Step 2: Preparation of tert-butyl (1-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-yl)(methyl)carbamate. [0770] To a solution of tert-butyl (1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3- yl)(methyl)carbamate (150 mg, 0.49 mmol) and 7-fluoro-2-methylimidazo[1,2-a]pyridin-6- amine (165 mg, 0.74 mmol) in THF (5 mL) were added TEA (247 mg, 2.45 mmol) and triphosgene (146 mg, 0.49 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by (PE/EA=0/1) to give title product (50 mg, 20.49 %) as a yellow solid. ESI-MS (M+H) ⁺: 496.3. Step 3: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)azetidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0771] To a solution of tert-butyl (1-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-yl)(methyl)carbamate (50 mg, 0.10 mmol) in EA (2 mL) was added 4 M HCl/EA (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (1.56 mg, 3.91 %) as a yellow solid. ESI-MS (M+H) ⁺: 396.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.57 (d, J = 6.4 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J = 6.1 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 6.18 (d, J = 6.0 Hz, 1H), 4.59 – 4.47 (m, 2H), 4.32 – 4.23 (m, 2H), 4.22 – 4.10 (m, 3H), 3.27 – 3.20 (m, 2H), 2.77 (s, 3H), 2.51 (s, 3H).

Example 281 – Preparation of 6-fluoro-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (2-(2,6-difluoro-4-iodopyridin-3-yl)ethyl)carbamate. [0772] To a solution of 2,6-difluoro-4-iodopyridine (10 g, 41.49 mmol) in dry THF (200 mL) was added LDA (25 mL, 50.00 mmol, 2.0 M in THF) at -78 ^oC in Ar. The reaction was stirred for 60 min. A solution of tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (11.1 g, 49.79 mmol) in THF (200 mL) was added dropwise to the mixture and stirred for 2 h. The mixture was quenched by sat NH₄Cl (200 mL) at -78 °C. The solution was extracted with EA (300 mL), dried over Na₂SO₄, concentrated and purified by SGC (EA/PE=1) to give product (6 g, 37.60 % yield) as a white solid. ESI-MS (M+H-t-Bu) ⁺: 328.8.¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J = 3.2 Hz, 1H), 4.62 (s, 1H), 3.46 – 3.30 (m, 2H), 3.03 – 2.85 (m, 2H), 1.41 (s, 9H). Step 2: Preparation of tert-butyl 6-fluoro-4-iodo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate. [0773] To a solution of tert-butyl (2-(2,6-difluoro-4-iodopyridin-3-yl)ethyl)carbamate (4 g, 10.42 mmol) in THF (100 mL) was added NaH (833 mg, 20.84 mmol) at RT. The mixture was stirred at RT for 1 h. The reaction was quenched by sat NH₄Cl (100 mL) and extracted with EA (200 mL), dried over Na₂SO₄, concentrated in vacuo and purified by SGC (PE/EA=1/1) to give product (1.6 g, 42.1% yield) as a white solid. ESI-MS (M+H) ⁺: 364.9. ¹H NMR (400 MHz, CDCl₃) δ 6.83 (d, J = 2.4 Hz, 1H), 4.17 – 3.91 (m, 2H), 3.08 – 2.83 (m, 2H), 1.56 (s, 9H). Step 3: Preparation of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6-fluoro-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [0774] To a solution of tert-butyl 6-fluoro-4-iodo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate (800 mg, 2.20 mmol) in 1,4-dioxane (20 mL) were added benzyl piperazine-1- carboxylate (580 mg, 2.64 mmol)，Xantphos (127 mg, 0.22 mmol), Pd₂(dba)₃ (201 mg， 0.22 mmol), Cs₂CO₃ (59 mg, 2.64 mmol) at rt. The mixture was stirred at 100 ℃ for 16 h under Ar. The reaction was diluted with water (30 mL), extracted with EA (100 mL). The organic layer was washed with sat. NaCl (50 mL), dried over Na₂SO₄, concentrated and purified by SGC (PE/EA=1) to give product (400 mg, 39% yield) a yellow oil. ESI-MS (M+H) ⁺: 457.1.¹H NMR (400 MHz, CDCl₃) δ 7.43 – 7.31 (m, 6H), 4.05 – 3.92 (m, 2H), 3.68 – 3.60 (m, 4H), 3.22 – 3.11 (m, 4H), 2.99 – 2.92 (m, 2H), 1.55 (s, 9H). Step 4: Preparation of benzyl 4-(6-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate. [0775] To a solution of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6-fluoro-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (400 mg, 0.88 mmol) in DCM (4 mL) was added TFA (4 mL). The reaction was stirred at rt for 16 h and concentrated, basified by sat. Na₂CO₃ solution, extracted with DCM (20 mL*3) and concentrated to give product (250 mg, 79% yield) as a yellow solid. ESI-MS (M+H) ⁺: 357.0 Step 5: Preparation of benzyl 4-(6-fluoro-1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0776] To a solution of benzyl 4-(6-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (100 mg, 0.28 mmol) in THF (5 mL) at 0 ℃ were added Et₃N (113 mg, 1.12 mmol) and TBC (83 mg，0.28 mmol) under Ar. A solution of 7-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (69 mg, 0.42 mmol) in THF (5 mL) was added to the mixture and stirred for 30 min at 0 ℃. The reaction was stirred at 70 ℃ for 16 h and quenched by water (20 mL)，extracted with EA (30 mL),dried over Na₂SO₄ and concentrated in vacuo. The residue was beated with EA/PE (1/1, 5 mL) to give title product (20 mg, 13% yield) a white solid. ESI-MS (M+H) ⁺: 548.2 Step 6: Preparation of 6-fluoro-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0777] To a solution of benzyl 4-(6-fluoro-1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (20 mg, 0.036 mmol) in DCM (1 mL) was added HBr (0.5 mL, 33% in HOAc). The mixture was stirred for 30 mins. The reaction was concentrated. The residue was diluted with DCM (20 mL) and sat NaHCO₃ (10 mL). The organic layer was concentrated and purified by prep- HPLC (0.1 % TFA in H₂O / ACN) to give title product (1.04 mg, 5% yield) as a white solid. ESI-MS (M+H) ⁺: 414.1.¹H NMR (400 MHz, MeOD-d₄) δ 11.52 (s, 1H), 9.61 (d, J = 6.8 Hz, 1H), 7.92 (s, 1H), 7.79 (d, J = 9.6 Hz, 1H), 6.29 (d, J = 1.3 Hz, 1H), 4.30 – 4.10 (m, 2H), 3.66 – 3.56 (m, 4H), 3.42 – 3.34 (m, 4H), 3.20 (t, J = 8.4 Hz, 2H), 2.51 (s, 3H). Example 282 – Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methyl-4- (2,2,2-trifluoroethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0778] A mixture of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (50 mg, 0.12 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (85.3 mg, 0.37 mmol), K₂CO₃ (50.7 mg, 0.37 mmol) in ACN (1 mL) was stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (2.19 mg, yield: 3.65 %) as a yellow oil. ESI-MS (M+H) ⁺: 491.8.¹H NMR (400 MHz, MeOD-d₄) δ 9.50 (s, 1H), 7.93 (s, 1H), 7.86 (d, J = 6.3 Hz, 1H), 7.80 (d, J = 9.5 Hz, 1H), 6.63 (d, J = 6.3 Hz, 1H), 4.17 (t, J = 8.5 Hz, 2H), 3.64 (d, J = 11.6 Hz, 2H), 3.41 – 3.33 (m, 2H), 3.15 – 3.06 (m, 3H), 3.02 – 2.96 (m, 1H), 2.91 – 2.70 (m, 3H), 2.52 (d, J = 0.9 Hz, 3H), 1.17 (d, J = 6.2 Hz, 3H). Example 283 – Preparation of (R)-N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)- 4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0779] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) and 7-fluoro-2,8-dimethylimidazo[1,2- a]pyridin-6-amine (169 mg, 0.94 mmol) in THF (10 mL) were added TEA (142 mg, 1.41 mmol) and triphosgene (279 mg, 0.94 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (10 mL), extracted with EA (10 mL×3). The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to give crude. The crude was purified by silica gel column (PE: EA = 1: 5) to give title product (120 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 524.2. Step 2: Preparation of (R)-N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0780] A mixture of tert-butyl (R)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.19 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (21 mg, Y: 26.0%) as a white solid. ESI-MS (M+H) ⁺: 424.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 9.55 (d, J = 6.2 Hz, 1H), 9.16 (s, 1H), 8.83 (s, 1H), 8.16 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 6.68 (d, J = 6.2 Hz, 1H), 4.09 – 4.02 (m, 2H), 3.85 – 3.80 (m, 2H), 3.41 – 3.37 (m, 2H), 3.24 – 3.14 (m, 4H), 3.06 – 2.96 (m, 1H), 2.51 (s, 3H), 2.48 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H). Example 284 – Preparation of (S)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of (S)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0781] A mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.32 mmol) and 2-methylimidazo[1,2-a]pyridin-6- amine (46 mg, 0.32 mmol) in THF (8 mL) were added TEA (96 mg, 0.94 mmol) and triphosgene (182 mg, 0.63 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 6) to give title product (70 mg, Y: 45.5%) as a yellow solid. ESI-MS (M+H) ⁺: 492.2. Step 2: Preparation of (S)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0782] A mixture of (S)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (60 mg, 0.12 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (50.05 mg, Y: 73.9%) as a white solid. ESI-MS (M+H) ⁺: 392.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 1H), 9.40 (s, 1H), 9.18 (s, 1H), 8.86 (s, 1H), 8.16 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 7.93 – 7.87 (m, 2H), 6.68 (d, J = 6.2 Hz, 1H), 4.04 (t, J = 8.6 Hz, 2H), 3.86 – 3.76 (m, 2H), 3.47 – 3.33 (m, 2H), 3.27 – 3.09 (m, 4H), 3.06 – 2.93 (m, 1H), 2.48 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 285 – Preparation of (R)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of (R)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0783] To a solution of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) and 2-methylimidazo[1,2-a]pyridin-6- amine (69 mg, 0.47 mmol) in THF (5 mL) were added TEA (1 mL) and triphosgene (110 mg, 0.37 mmol) at 0 ^oC . The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1) to give title product (53 mg, 34 %) as a white solid. ESI-MS (M+H) ⁺: 492.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H), 9.00 (s, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.76 (s, 1H), 7.46 (d, J = 9.5 Hz, 1H), 7.20 (dd, J = 9.5, 2.1 Hz, 1H), 6.59 (d, J = 6.2 Hz, 1H), 4.31 – 4.20 (m, 1H), 4.06 (t, J = 8.6 Hz, 2H), 3.88 – 3.81 (m, 1H), 3.74 – 3.62 (m, 2H), 3.27 – 3.09 (m, 4H), 3.04 – 2.94 (m, 1H), 2.37 (s, 3H), 1.48 (s, 9H), 1.25 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (R)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0784] To a solution of (R)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (40 mg, 0.08 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (65.32 mg, yield: 90 %) as a white solid. ESI-MS (M+H) ⁺: 392.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 9.39 (s, 1H), 9.10 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 7.94 – 7.84 (m, 2H), 6.69 (d, J = 6.2 Hz, 1H), 4.05 (t, J = 8.5 Hz, 2H), 3.88 – 3.77 (m, 2H), 3.43 – 3.34 (m, 2H), 3.25 – 3.11 (m, 4H), 3.07 – 2.96 (m, 1H), 2.48 (d, J = 0.8 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 286 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 2,2-dimethyl-4-(1-((2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0785] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 2-methylimidazo[1,2-a]pyridin-6- amine (80 mg, 0.54 mmol), triphosgene (160 mg, 0.54 mmol) and TEA (227 mg, 2.25 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (MeOH: DCM= 10 %) to give title product (50 mg, 22 %) as a yellow solid. ESI-MS (M+H) ⁺: 506.3.¹H NMR (400 MHz, CDCl₃) δ 11.86 (s, 1H), 8.97 (s, 1H), 7.84 (d, J = 6.1 Hz, 1H), 7.44 (d, J = 9.4 Hz, 1H), 7.30 (s, 1H), 7.02 (d, J = 9.6 Hz, 1H), 6.22 (d, J = 6.2 Hz, 1H), 4.14 (t, J = 8.4 Hz, 2H), 3.81 – 3.77 (m, 2H), 3.57 (t, J = 5.5 Hz, 2H), 3.45 (s, 2H), 3.23 (t, J = 8.7 Hz, 2H), 2.44 (s, 3H), 1.50 (s, 9H), 1.45 (s, 6H). Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0786] A mixture of tert-butyl 2,2-dimethyl-4-(1-((2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (40 mg, 0.08 mmol) in TFA / DCM (0.5 mL / 0.5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (22.7 mg, yield: 70.06 %) as a yellow oil. ESI-MS (M+H) ⁺: 405.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 1H), 9.39 (s, 1H), 8.90 (s, 2H), 8.16 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.91 – 7.86 (m, 2H), 6.67 (d, J = 6.1 Hz, 1H), 4.06 – 4.03 (m, 2H), 3.51 – 3.47 (m, 2H), 3.34 – 3.29 (m, 4H), 3.23 – 3.18 (m, 2H), 2.48 (s, 3H), 1.37 (s, 6H). Example 287 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-ethoxy-2- methyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation oftert-butyl (2R,6S)-4-(1-((6-ethoxy-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [0787] To a solution of 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (100 mg, 0.45 mmol) in Toluene (10 mL) were added TEA (136 mg, 1.35 mmol) and DPPA (313 mg, 1.14 mmol). The mixture was stirred at 20 ^oC for 1h. Then the mixture was stirred at 60 ^oC for another 1h. Tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (149 mg, 0.45 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:4) to provide title product (90 mg, yield: 36%) as a white solid. ESI-MS (M+H)⁺: 549.9. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0788] To a solution of tert-butyl (2R,6S)-4-(1-((6-ethoxy-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (80 mg, 0.15 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep- HPLC (0.05% TFA in H₂O / ACN) to give title compound (41 mg, yield: 62%) as a white solid. ESI-MS (M+H)⁺: 449.9.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.36 (s, 1H), 8.19 (s, 1H), 7.91 (d, J = 6.2 Hz, 1H), 7.01 (s, 1H), 6.67 (d, J = 6.3 Hz, 1H), 4.15 (q, J = 6.9 Hz, 2H), 4.10 – 4.04 (m, 5H), 3.95 – 3.95 (m, 2H), 3.89 (d, J = 12.9 Hz, 2H), 3.43 – 3.35 (m, 2H), 3.20 (t, J = 8.4 Hz, 2H), 2.98 – 2.88 (m, 2H), 1.52 (t, J = 6.8 Hz, 3H), 1.28 (d, J = 6.5 Hz, 6H). Example 288 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate.

Step 1: Preparation of tert-butyl 7-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0789] To a solution of 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (240 mg, 1.09 mmol) in toluene (20 mL) were added TEA (370 mg, 3.64 mmol), DPPA (751 mg, 2.73 mmol). The mixture was stirred at r.t for 1 h and 40 min at 70 ^o C. Then tert-butyl 7-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (300 mg, 0.91 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mLx3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (150 mg, yield: 30 %) as a white solid. ESI-MS (M+H) ⁺:548.0. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methyl-2H-indazol-5- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate. [0790] To a solution of tert-butyl 7-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (150 mg, 0.27 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% NH₃.H₂O in H₂O/ ACN) to give title product (50 mg, 41%) as a white solid. To a solution of crude product (50 mg, 0.11 mmol) in DCM (5 mL) and MeOH (1 mL) was added benzoate (14 mg, 0.11 mmol). The mixture was stirred at 50 ^o C for 2 h. Concentration under reduced pressure to give title product (46.29 mg, 29%) as a white solid. ESI-MS (M+H) ⁺: 448.3.¹H NMR (400 MHz, MeOD-d₄) δ 8.44 (s, 1H), 8.01 – 7.99 (m, 2H), 7.98 – 7.94 (m, 2H), 7.54 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 6.94 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.23 – 4.16 (m, 2H), 4.13 – 4.07 (m, 5H), 3.37 – 3.34 (m, 2H), 3.19 (s, 2H), 3.14 – 3.09 (m, 4H), 1.61 (t, J = 6.9 Hz, 3H), 0.75 (d, J = 7.3 Hz, 4H). Example 289 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((6-methoxy-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [0791] To a solution of 6-methoxy-2-methyl-2H-indazol-5-amine hydrochloride (141 mg, 0.66 mmol) and TEA (0.92 mL, 37.60 mmol) in THF (20 mL) was added triphosgene (1.12 mg, 6.62 mmol), the mixture was stirred at 0^oC for 15 min, then tert-butyl (2R,6S)-4-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (200 mg, 0.60 mmol) was added slowly at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (60 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (200 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 536.3. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0792] To a mixture of tert-butyl (2R,6S)-4-(1-((6-methoxy-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (200 mg, 0.37 mmol) in EA (1 mL) was added HCl/EA(6 mL, 4 M). The mixture was stirred at r.t for 2 h. The mixture was concentrated and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (75 mg, Y: 36.54 %) as an off-white solid. ESI-MS (M+H) ⁺:436.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 9.22 (d, J = 8.3 Hz, 1H), 8.58 (d, J = 9.8 Hz, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.02 (s, 1H), 6.63 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 4.02 (t, J = 8.5 Hz, 2H), 3.97 (s, 3H), 3.87 (d, J = 13.5 Hz, 2H), 3.47 – 3.32 (m, 2H), 3.22 – 3.14 (m, 2H), 2.95 – 2.84 (m, 2H), 1.27 (d, J = 6.5 Hz, 6H). Example 290 – Preparation of (S)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [0793] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (120 mg, 0.38 mmol) in THF (5 mL) were added TEA (114 mg, 1.13 mmol), triphosgene (134 mg, 0.45 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.6-methoxy-2-methyl-2H-indazol-5-amine (80 mg, 0.45 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (80 mg, Y: 40.7 %) as a yellow solid. ESI-MS (M+H) ⁺:522.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.01 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.21 – 4.16 (m, 1H), 4.07 (s, 3H), 4.03 – 3.98 (m, 3H), 3.97 (s, 3H), 3.81 – 3.77 (m, 1H), 3.66 – 3.61 (m, 1H), 3.59 – 3.54 (m, 1H), 3.18 – 3.13 (m, 2H), 3.07 – 3.02 (m, 1H), 2.95 – 2.89 (m, 1H), 1.43 (s, 9H), 1.20 (d, J = 6.6 Hz, 3H). Step 2: Preparation of (S)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0794] To a solution of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (70 mg, 0.13 mmol) in EA (3 mL) was added 4M HCl / EA (3 mL) at r.t. The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (47.66 mg, 58.0 %) as a white solid. ESI-MS (M+H)⁺:422.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, 1H), 9.03 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.01 (s, 1H), 6.61 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.02 (t, J = 8.8 Hz, 2H), 3.97 (s, 3H), 3.79 (d, J = 12.0 Hz, 2H), 3.41 – 3.35 (m, 2H), 3.15 (t, J = 8.6 Hz, 4H), 2.97 (dd, J = 13.7, 10.4 Hz, 1H), 1.27 (d, J = 6.5 Hz, 3H). Example 291 – Preparation of (R)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [0795] To a solution of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) and 6-methoxy-2-methyl-2H-indazol- 5-amine (84 mg, 0.47 mmol) in THF (5 mL) were added TEA (1 mL) and triphosgene (110 mg, 0.37 mmol) at 0 ^oC . The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1) to give title product (45 mg, 27%) as a white solid. ESI-MS (M+H) ⁺: 522.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 7.95 (d, J = 5.9 Hz, 1H), 7.00 (s, 1H), 6.50 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.03 – 3.98 (m, 2H), 3.96 (s, 3H), 3.80 (t, J = 13.4 Hz, 2H), 3.65 – 3.53 (m, 2H), 3.18 – 3.01 (m, 4H), 2.96 – 2.87 (m, 1H), 1.42 (s, 9H), 1.27 (d, J = 6.4 Hz, 3H). Step 2: Preparation of (R)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0796] To a solution of tert-butyl (R)-4-(1-((6-methoxy-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (30.04 mg, yield: 69 %) as a white solid. ESI- MS (M+H) ⁺: 422.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 9.10 (s, 1H), 8.78 (s, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.02 (s, 1H), 6.62 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 4.03 (t, J = 8.6 Hz, 2H), 3.97 (s, 3H), 3.86 – 3.72 (m, 2H), 3.45 – 3.32 (m, 2H), 3.24 – 3.09 (m, 4H), 3.04 – 2.93 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H). Example 292 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl- 2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [0797] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 6-methoxy-2-methyl-2H-indazol-5- amine (96 mg, 0.54 mmol), triphosgene (160 mg, 0.54 mmol) and TEA (227 mg, 2.25 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (MeOH: DCM= 10 %) to give title product (60 mg, 24.92 %) as a yellow solid. ESI-MS (M+H) ⁺: 536.2. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl-2H-indazol-5- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0798] A mixture of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (50 mg, 0.09 mmol) in TFA / DCM (0.5 mL / 0.5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (34.88 mg, yield: 89.09 %) as a yellow oil. ESI-MS (M+H) ⁺: 436.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.90 (s, 2H), 8.39 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.01 (s, 1H), 6.61 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.05 – 4.00 (m, 2H), 3.96 (s, 3H), 3.48 – 3.43 (m, 2H), 3.33 – 3.27 (m, 4H), 3.16 (t, J = 8.5 Hz, 2H), 1.38 (s, 6H). Example 293 – Preparation of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate.

Step 1: Preparation of tert-butyl 7-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0799] To a solution of 6-methoxy-2-methyl-2H-indazol-5-amine (644 mg, 3.64 mmol) in THF (100 mL) were added TEA (3672 mg, 36.36 mmol) and triphosgene (1081 mg, 3.64 mmol). The mixture was stirred for 30 min. Tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (1 g, 3.03 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:3) to provide title product (600 mg, yield: 37%) as a white solid. ESI-MS (M+H)⁺:534.4. Step 2: Preparation of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan- 7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0800] To a solution of tert-butyl 7-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (550 mg, 1.03 mmol) in EtOAc (4 mL) was added 4M HCl/EtOAc (12 mL) at 0 ^oC. The mixture was stirred at r.t for 2h. The precipitate was filtered, washed with EtOAc (5 mL). The solid was triturated with EtOAc (10 mL) and diluted with H₂O (5 mL), adjusted pH to 8 by Na₂HCO₃ aqueous solution. The precipitate was filtered, washed with water and concentrated in vacuo to give title product (480 mg, yield: 98%) as a white solid. ESI-MS (M+H)⁺: 434.2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.00 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.01 – 3.96 (m, 2H), 3.96 (s, 3H), 3.37 (s, 2H), 3.21 (s, 2H), 3.11 – 3.03 (m, 4H), 0.71 (d, J = 11.4 Hz, 4H). Step 3: Preparation of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan- 7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate. [0801] To a solution of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (480 mg, 1.11 mmol) in DCM (20 mL) and MeOH (5 mL) was added Benzoate (142 mg, 1.16 mmol). The mixture was stirred at 50 ^oC for 6 h. The mixture was concentrated in vacuo, and triturated with MTBE (10 mL). The precipitate was filtered and washed with MTBE (2 mL) and concentrated in vacuo to give title product (500 mg, yield: 81%) as a white solid. ESI-MS (M+H) ⁺: 434.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 7.98 – 7.92 (m, 3H), 7.66 – 7.59 (m, 1H), 7.50 (dd, J = 10.5, 4.7 Hz, 2H), 7.00 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.01 – 3.94 (m, 5H), 3.39 – 3.34 (m, 3H), 3.22 (s, 2H), 3.11 – 3.04 (m, 4H), 0.71 (d, J = 15.5 Hz, 4H). Example 294 – Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [0802] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) in THF (20 mL) were added TEA (759 mg, 7.50 mmol) and triphosgene (107 mg, 0.36 mmol) (in THF (1 mL )) in 0 ℃. The reaction mixture was stirred at r.t for 1 h. Then 2,6-dimethyl-2H-indazol-5-amine (58 mg, 0.36 mmol) was added to the reaction solution and stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (50 mg, yield: 32 %) as a white solid. ESI-MS (M+H) ⁺:520.3.¹H NMR (400 MHz, DMSO- d₆) δ 11.72 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.82 (d, J = 6.3 Hz, 1H), 7.43 (s, 1H), 6.39 (d, J = 6.4 Hz, 1H), 4.10 (s, 3H), 4.00 – 3.94 (m, 2H), 3.70 (s, 2H), 3.57 (s, 2H), 3.53 (s, 2H), 3.30 – 3.25 (m, 2H), 1.43 (s, 9H), 1.38 (s, 6H). Step 2: Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3,3-dimethylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0803] To a mixture of tert-butyl 4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (40 mg, 0.077 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (28.11 mg, 68%) as a white solid. ESI-MS (M+H) ⁺:420.1.¹H NMR (400 MHz, MeOD-d₄) δ 8.14 (s, 1H), 7.88 (d, J = 6.1 Hz, 2H), 7.47 (s, 1H), 6.76 (s, 1H), 4.32 – 4.24 (m, 2H), 4.19 (s, 3H), 3.77 – 3.64 (m, 2H), 3.61 – 3.50 (m, 2H), 3.47 – 3.44 (m, 2H), 3.42 – 3.34 (m, 2H), 2.45 (s, 3H), 1.50 (s, 6H).

Example 295 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-5-fluoro-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (2-(4-chloro-2,5-difluoropyridin-3-yl)ethyl)carbamate. [0804] To a solution of 4-chloro-2,5-difluoropyridine (5.0 g, 33.33 mmol) in THF (50 mL) was added LDA (25 mL, 50.00 mmol) dropwise at -75 ℃. After 1 h, tert-butyl 1,2,3- oxathiazolidine-3-carboxylate 2,2-dioxide (8.17 g, 36.66 mmol) in THF (80 mL) was added dropwise at -75 ℃, the reaction was stirred at rt for 16 h. The mixture was quenched with NH₄Cl aq. (200 mL), extracted with EA (100 mL *3), and the organic phase was concentrated, purified by silica gel chromatography (PE: EA=1:1) to give the title compound (4.8 g, 49% yield) as a yellow solid. ESI-MS (M+H) ⁺: 237.0.¹H NMR (400 MHz, DMSO- d₆) δ 8.30 (s, 1H), 6.95 (t, J = 6.0 Hz, 1H), 3.21 – 3.16 (m, 2H), 2.87 (t, J = 6.4 Hz, 2H), 1.31 (s, 9H). Step 2: Preparation of tert-butyl 4-chloro-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate. [0805] To a solution of tert-butyl (2-(4-chloro-2,5-difluoropyridin-3-yl)ethyl)carbamate (2.8 g, 9.59 mmol) in THF (150 mL) was added NaH (60%, 460 mg, 11.51 mmol) at 0 ℃, the reaction was stirred at rt for 16 h. The reaction was concentrated in vacuo, diluted with EA (150 mL), washed with H₂O (200 mL), the EA phase was concentrated and purified by silica gel chromatography by (PE: EA = 1:1) to give the title compound (1.1 g, 44% yield) as a white solid. ESI-MS (M+H) ⁺: 217.0.¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 4.09 (t, J = 8.8 Hz, 2H), 3.09 (t, J = 8.8 Hz, 2H), 1.56 (s, 9H). Step 3: Preparation of tert-butyl 4-(4-((benzyloxy)carbonyl)-3,3-dimethylpiperazin-1-yl)-5- fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [0806] A solution of tert-butyl 4-chloro-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate (800 mg, 2.94 mmol), benzyl 2,2-dimethylpiperazine-1-carboxylate (1.4 g, 5.88 mmol), Cs₂CO₃ (1.9 g, 5.88 mmol), xantphos (341 mg, 0.59 mmol), and Pd₂(dba)₃ (265 mg, 0.29 mmol) in1,4-dioxane (30 mL) was stirred at 110 ℃ under Ar for 16 h. The mixture was diluted with EA (200 mL), washed with H₂O (200 mL *2) and brine (100 mL). The EA phase was concentrated in vacuo, purified by silica gel chromatography (PE: EA = 1:1 ~ 0:1) to give the title compound (1.0 g, 71% yield) as a yellow solid. ESI-MS (M+H) ⁺: 485.2.¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J = 5.2 Hz, 1H), 7.40 – 7.30 (m, 5H), 5.13 (s, 2H), 4.00 – 3.96 (m, 2H), 3.78 – 3.73 (m, 2H), 3.47 – 3.42 (m, 2H), 3.25 (d, J = 1.2 Hz, 2H), 3.06 (t, J = 8.8 Hz, 2H), 1.54 (s, 9H), 1.47 (s, 6H). Step 4: Preparation of benzyl 4-(5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate TFA salt. [0807] A solution of tert-butyl 4-(4-((benzyloxy)carbonyl)-3,3-dimethylpiperazin-1-yl)-5- fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.0 g, 2.06 mmol) and TFA (3 mL) in DCM (9 mL) was stirred at 30 ℃ for 16 h. The mixture was concentrated in vacuo to give the title compound (750 mg, 94% yield) as a yellow solid. ESI-MS (M+H) ⁺: 385.2. Step 5: Preparation of benzyl 4-(5-fluoro-1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0808] A solution of benzyl 4-(5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate TFA salt (50 mg, 0.10 mmol), 7-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (50 mg, 0.26 mmol) and TEA (1 mL) was stirred at rt, then triphosgene (77 mg, 0.26 mmol) in THF (1 mL) was added to the mixture and stirred at r.t for 16 h. The mixture was concentrated in vacuo, diluted with EA (100 mL), washed with H₂O (100 mL) and brine (50 mL), and the EA phase was concentrated in vacuo, purified by silica gel chromatography (DCM: MeOH = 10:1) to give the title compound (20 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 576.2. Step 6: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-5-fluoro-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0809] To a solution of benzyl 4-(5-fluoro-1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (10 mg) in DCM (5 ml) was added HBr/AcOH (0.1 mL), and the reaction was stirred at rt for 30 min. The reaction was concentrated in vacuo, and purified by reverse flash (0.1% TFA in H₂O / ACN) to give the title compound (1.46 mg, 9% yield) as a yellow solid. ESI-MS (M+H) ⁺: 442.2.¹H NMR (400 MHz, CD₃OD) δ 9.60 (d, J = 6.4 Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J = 9.8 Hz, 1H), 4.19 (t, J = 8.8 Hz, 2H), 3.62 – 3.56 (m, 2H), 3.44 – 3.38 (m, 4H), 3.33 – 3.30 (m, 2H), 2.50 (s, 3H), 1.50 (s, 6H). Example 296 – Preparation of (S)-N-(6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0810] To a solution of 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (100 mg, 0.52 mmol) in Toluene (10 mL) were added TEA (158 mg, 1.56 mmol) and DPPA (378 mg, 1.30 mmol). The mixture was stirred at 20 ^oC for 1h. Then the mixture was stirred at 60 ^oC for another 1h. tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (164 mg, 0.52 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The precipitate was filtered to provide title product (370 mg, crude) as a white solid. ESI-MS (M+H)⁺: 509.8.¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J = 7.9 Hz, 1H), 8.30 (d, J = 5.6 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H), 6.36 (d, J = 6.0 Hz, 1H), 6.18 (s, 1H), 4.35 (s, 1H), 4.21 – 4.13 (m, 2H), 3.96 (d, J = 13.8 Hz, 1H), 3.57 – 3.40 (m, 3H), 3.23 (td, J = 13.2, 2.9 Hz, 1H), 3.15 – 3.11 (m, 2H), 2.96 (td, J = 11.9, 3.4 Hz, 1H), 2.43 (s, 3H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0811] To a solution of tert-butyl (S)-4-(1-((6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (350 mg, 0.69 mmol) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% NH₃HCO₃ in H₂O / ACN) to give title compound. The residue was diluted with 0.5 M TFA in water and concentrated in vacuo to give title compound (49 mg, yield: 17%) as a green solid. ESI-MS (M+H)⁺: 409.8.¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (s, 1H), 8.99 (s, 1H), 8.93 (d, J = 6.3 Hz, 1H), 8.68 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 6.1 Hz, 1H), 6.65 (d, J = 6.2 Hz, 1H), 6.31 (s, 1H), 4.05 – 4.02 (m, 2H), 3.81 (d, J = 13.0 Hz, 2H), 3.38 (d, J = 9.3 Hz, 2H), 3.23 – 3.11 (m, 4H), 3.02 – 2.94 (m, 1H), 2.33 (s, 3H), 1.26 (d, J = 6.5 Hz, 3H). Example 297 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-fluoro-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0812] To a solution of 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (100 mg, 0.52 mmol) in Toluene (10 mL) were added TEA (158 mg, 1.56 mmol) and DPPA (378 mg, 1.30 mmol). The mixture was stirred at 20 ^oC for 1h. Then the mixture was stirred at 60 ^oC for another 1h. Tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (165 mg, 0.52 mmol) was added to the mixture. The reaction mixture was stirred at 90 ^oC for 16 h. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:3) to provide title product (300 mg, crude) as a white solid. ESI- MS (M+H)⁺: 524.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (s, 1H), 8.91 (d, J = 6.5 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 6.43 (d, J = 6.3 Hz, 1H), 6.31 (s, 1H), 4.00 – 3.94 (m, 2H), 3.73 – 3.68 (m, 2H), 3.60 – 3.56 (m, 2H), 3.55 (s, 2H), 3.32 – 3.29 (m, 2H), 2.33 (s, 3H), 1.44 (s, 9H), 1.38 (s, 6H). Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-fluoro-2-methylpyrazolo[1,5- a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0813] To a solution of tert-butyl 4-(1-((6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (280 mg, 0.54 mmol) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep- HPLC (0.05% TFA in H₂O / ACN) to give title compound (49 mg, yield: 17%) as a white solid. ESI-MS (M+H)⁺: 423.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (d, J = 2.2 Hz, 1H), 9.05 – 8.85 (m, 3H), 8.26 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 6.0 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 6.31 (s, 1H), 4.03 (t, J = 8.5 Hz, 2H), 3.47 (s, 2H), 3.31 – 3.30 (m, 4H), 3.18 (t, J = 8.4 Hz, 2H), 2.33 (s, 3H), 1.37 (s, 6H).

Example 298 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide benzoate.

Step 1: Preparation of phenyl (2-methylimidazo[1,2-a]pyridin-6-yl)carbamate. [0814] To a mixture of 2-methylimidazo[1,2-a]pyridin-6-amine (19 g, 129.25 mmol) and pyridine (30.63 g, 387.75 mmol) in DCM (500 mL) was added phenyl carbonochloridate (30.36 g, 193.88 mmol) at 0 ^oC, the mixture was stirred for 30 min. The mixture was diluted with water (500 mL), extracted with DCM (500 mL×3). The organic layer was washed with brine (500 mL), dried with Na₂SO₄ and concentrated in vacuo to give title product (30 g, yield: 86.93 %) as a yellow solid. ESI-MS (M+H) ⁺: 268.1.¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 7.47 – 7.39 (m, 4H), 7.31 (s, 1H), 7.26 – 7.23 (m, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 9.0 Hz, 1H), 2.44 (s, 3H). Step 2: Preparation of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((2-methylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0815] A mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (20 g, 60.24 mol), phenyl (2-methylimidazo[1,2-a]pyridin- 6-yl)carbamate (24.1 g, 90.36 mmol), and TEA (18.25 g, 180.72 mmol) in THF (200 mL) was stirred at 70 ^oC for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered and diluted with MeOH, stirred at RT for 1 h. The precipitate was filtered and dried to afford title product (25 g, yield: 82.18 %) as a yellow solid. ESI-MS (M+H) ⁺: 506.3.¹H NMR (400 MHz, CDCl₃) δ 11.70 (s, 1H), 8.97 (d, J = 1.4 Hz, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 9.5 Hz, 1H), 7.30 (s, 1H), 7.02 (dd, J = 9.5, 2.0 Hz, 1H), 6.40 (d, J = 6.1 Hz, 1H), 4.30 – 4.23 (m, 2H), 4.20 – 4.13 (m, 2H), 3.45 (d, J = 12.2 Hz, 2H), 3.15 (t, J = 8.6 Hz, 2H), 3.02 (dd, J = 12.1, 4.3 Hz, 2H), 2.45 (s, 3H), 1.50 (s, 9H), 1.37 (d, J = 6.8 Hz, 6H). Step 3: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0816] A mixture of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (25 g, 49.50 mmol) in 4M HCl /EA (200 mL) was stirred at RT for 2 h. The precipitate was filtered and diluted with water (50 mL), adjusted pH to 8~9 by 1N Na₂CO₃. The precipitate was filtered, washed with water (100 mL*3) and dried in vacuo to give title product (19 g, yield: 94.77 %) as a yellow solid. ESI-MS (M+H) ⁺: 406.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 8.94 (d, J = 1.3 Hz, 1H), 7.89 (d, J = 6.1 Hz, 1H), 7.69 (s, 1H), 7.40 (d, J = 9.5 Hz, 1H), 7.14 (dd, J = 9.5, 2.0 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 3.97 (t, J = 8.6 Hz, 2H), 3.62 (d, J = 11.8 Hz, 2H), 3.13 (t, J = 8.6 Hz, 2H), 2.85 (s, 2H), 2.43 (t, J = 11.0 Hz, 2H), 2.30 (s, 3H), 1.02 (d, J = 6.2 Hz, 6H). Step 4: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate. [0817] A mixture of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (19 g, 46.91 mmol) and benzoic acid (6.009 g, 49.26 mmol) in MeOH (200 mL) was stirred at 50 ^oC for 16 h. The mixture was concentrated in vacuo. The mixture was diluted with MTBE, stirred at r.t for 1 h. The precipitate was filtered and dried to afford title product (21.3 g, yield: 86.2 %) as a yellow solid ESI-MS (M+H) ⁺: 406.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 8.94 (d, J = 1.3 Hz, 1H), 7.94 (dd, J = 5.1, 3.3 Hz, 2H), 7.89 (d, J = 6.1 Hz, 1H), 7.69 (s, 1H), 7.63 – 7.53 (m, 1H), 7.47 (dd, J = 10.5, 4.6 Hz, 2H), 7.40 (d, J = 9.5 Hz, 1H), 7.13 (dd, J = 9.5, 2.0 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 3.97 (t, J = 8.6 Hz, 2H), 3.63 (d, J = 11.1 Hz, 2H), 3.12 (t, J = 8.5 Hz, 2H), 2.97 – 2.78 (m, 2H), 2.46 – 2.43 (m, 2H), 2.31 (s, 3H), 1.05 (d, J = 6.3 Hz, 6H). Example 299 – Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate. [0818] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) in THF (10 mL) were added TEA (759 mg, 7.50 mmol) and triphosgene (107 mg, 0.36 mmol) (in THF (1 mL )) in 0 ℃. The reaction mixture was stirred at r.t for 1 h. Then 2,6-dimethyl-2H-indazol-5-amine (58 mg, 0.36 mmol) was added to the reaction solution and stirred at r.t for16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (50 mg, yield: 32 %) as a white solid. ESI-MS (M+H) ⁺:519.8.¹H NMR (400 MHz, DMSO- d₆) δ 11.57 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 7.94 (d, J = 6.2 Hz, 1H), 7.44 (s, 1H), 6.55 (d, J = 5.9 Hz, 1H), 4.10 – 4.08 (m, 5H), 4.01 (t, J = 4.3 Hz, 2H), 3.58 (d, J = 12.4 Hz, 2H), 3.18 (t, J = 8.9 Hz, 2H), 2.99 (d, J = 8.4 Hz, 2H), 2.44 (s, 3H), 1.43 (s, 9H), 1.26 (d, J = 6.8 Hz, 6H). Step 2: Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-((3R,5S)-3,5-dimethylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0819] To a mixture of tert-butyl (2R,6S)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (40 mg, 0.077 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep- HPLC (0.1% TFA in H₂O / ACN) to give title product (22.82 mg, 55%) as a white solid. ESI- MS (M+H) ⁺:419.9.¹H NMR (400 MHz, MeOD-d₄) δ 8.15 (s, 1H), 7.86 (d, J = 6.3 Hz, 2H), 7.47 (s, 1H), 6.79 (s, 1H), 4.27 (d, J = 8.2 Hz, 2H), 4.19 (s, 3H), 4.10 (s, 2H), 3.57 – 3.51 (m, 2H), 3.39 (s, 2H), 3.08 (s, 2H), 2.44 (s, 3H), 1.41 (d, J = 6.6 Hz, 6H). Example 300 – Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 7-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0820] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.61 mmol), 2,6-dimethyl-2H-indazol-5-amine (149.9 mg, 0.91 mmol), triphosgene (270 mg, 0.91 mmol) and TEA (616.1 mg, 6.1 mmol) in THF (40 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 100 %) to give title product (60 mg, crude) as a yellow solid. ESI- MS (M+H) ⁺: 517.8. [0821] Step 2 Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan- 7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0822] A mixture of tert-butyl 7-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (40 mg, 0.08 mmol) in TFA / DCM (2 mL / 2 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (3.42 mg, yield: 6.7 %) as a yellow solid. ESI-MS (M+H) ⁺: 417.9.¹H NMR (400 MHz, MeOD-d₄) δ 8.15 (s, 1H), 7.86 (d, J = 5.7 Hz, 2H), 7.47 (s, 1H), 6.74 (s, 1H), 4.30 – 4.24 (m, 2H), 4.19 (s, 3H), 3.84 (s, 2H), 3.70 – 3.63 (m, 2H), 3.55 – 3.52 (m, 2H), 3.40 – 3.35 (m, 2H), 2.45 (s, 3H), 1.19 – 1.15 (m, 2H), 1.12 – 1.09 (m, 2H). Example 301 – Preparation of 4-(3-(aminomethyl)azetidin-1-yl)-N-(7-fluoro-2-methyl- 2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl ((1-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)azetidin-3-yl)methyl)carbamate. [0823] To a solution of 1-(4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethan-1-one (500 mg, 2.08 mmol) and tert-butyl (azetidin-3-ylmethyl)carbamate (774 mg, 4.16 mmol) in 1,4- dioxane (10 mL) were added BINAP (260 mg, 0.42 mmol),Cs₂CO₃(2028 mg, 6.24 mmol) and Pd(OAc)₂( 47 mg, 0.21 mmol). The reaction mixture was stirred at 100^oC for 16 h. The mixture was concentrated in vacuo and diluted with water (10 mL), extracted with EA (10 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title product (700 mg, crude) as a yellow oil. ESI-MS (M+H) ⁺: 347.3. Step 2: Preparation of tert-butyl ((1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3- yl)methyl)carbamate. [0824] To a solution of tert-butyl ((1-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)azetidin-3-yl)methyl)carbamate (500mg, 1.44 mmol) in MeOH / H₂O (10 mL, 5:1) was added K₂CO₃ (994 mg, 7.20 mmol). The reaction mixture was stirred at 60^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 0: 1, DCM: MeOH= 10: 1) to give title product (479 mg, 79%) as a yellow solid. ESI-MS (M+H) ⁺: 305.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (d, J = 5.8 Hz, 1H), 5.58 (d, J = 5.9 Hz, 1H), 3.97 – 3.93 (m, 2H), 3.65 – 3.61 (m, 2H), 3.23 – 3.13 (m, 4H), 2.93 – 2.88 (m, 2H), 2.71 – 2.65 (m, 1H), 1.38 (s, 9H). Step 3: Preparation of tert-butyl ((1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-yl)methyl)carbamate. [0825] To a solution of tert-butyl ((1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3- yl)methyl)carbamate (150 mg, 0.49 mmol) and phenyl (7-fluoro-2-methyl-2H-indazol-5- yl)carbamate (211 mg, 0.73 mmol) in THF (5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at 70^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 0: 1) to give title product (193 mg, 79%) as a yellow solid. ESI- MS (M+H) ⁺: 496.3. Step 4: Preparation of 4-(3-(aminomethyl)azetidin-1-yl)-N-(7-fluoro-2-methyl-2H-indazol-5- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0826] To a solution of tert-butyl ((1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-yl)methyl)carbamate (180 mg, 0.36 mmol) in EA (2 mL) was added 4M HCl / EA (5 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtrated and dried in vacuo to give title product (93 mg, crude) as a white solid. The compound (50 mg) was purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (16.92 mg, yield: 27 %) as a yellow solid. ESI-MS (M+H) ⁺: 396.1.¹H NMR (400 MHz, MeOD-d₄) δ 8.23 (d, J = 2.6 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.25 (dd, J = 13.0, 1.1 Hz, 1H), 6.10 (d, J = 7.1 Hz, 1H), 4.60 – 4.34 (m, 2H), 4.24 – 4.19 (m, 5H), 3.37 – 3.32 (m, 2H), 3.32 – 3.28 (m, 2H), 3.26 – 3.19 (m, 2H), 3.17 – 3.08 (m, 1H).

Example 302 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3- methyl-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of 4-chloro-3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. [0827] To a solution of 4-chloro-3-methyl-3H-pyrrolo[2,3-b]pyridine (1 g, 6.0 mmol) and Raney-Ni (500 mg, 50 %) in MeOH (20 mL) was stirred at 60 ^oC for 16 h under H₂. The mixture was filtered and the filtrate concentrated in vacuo to give title product (120 mg, 11.9%) as a white solid. ESI-MS (M+H) ⁺: 169.1. Step 2: Preparation of tert-butyl 4-(3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate. [0828] To a solution of 4-chloro-3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.18 mmol) and tert-butyl piperazine-1-carboxylate (442 mg, 2.37 mmol) in DIEA (0.5 mL) was stirred at 140 ^oC for 16 h in a sealed tube. The mixture was concentrated in vacuo and diluted with water (5 mL), extracted with EA (5 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 0: 1) to give title product (206 mg, 54%) as a yellow oil. ESI-MS (M+H) ⁺: 319.1. [0829] ¹H NMR (400 MHz, DMSO-d₆) δ 7.57 (d, J = 5.9 Hz, 1H), 6.09 (d, J = 5.9 Hz, 1H), 5.97 (s, 1H), 3.63 – 3.56 (m, 2H), 3.50 – 3.39 (m, 4H), 3.20 – 3.13 (m, 2H), 3.01 – 2.95 (m, 1H), 2.94 – 2.85 (m, 2H), 1.42 (s, 9H), 1.17 (d, J = 6.6 Hz, 3H). Step 3: Preparation of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [0830] To a solution of tert-butyl 4-(3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (100 mg, 0.31 mmol) and 8-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (78 mg, 0.47 mmol) in in THF (5 mL) were added TEA (0.5 mL) and triphosgene (140 mg, 0.47 mmol) at 0 ^oC . The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1) to give title product (80 mg, crude) as a green solid. ESI-MS (M+H) ⁺: 510.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.31 (dd, J = 12.5, 1.6 Hz, 1H), 6.65 (d, J = 6.1 Hz, 1H), 4.20 – 4.12 (m, 1H), 3.77 – 3.65 (m, 2H), 3.61 – 3.53 (m, 2H), 3.52 – 3.41 (m, 4H), 3.20 – 3.12 (m, 2H), 2.39 (s, 3H), 1.49 (s, 9H), 1.27 (d, J = 6.7 Hz, 3H). Step 4: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0831] To a solution of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (70 mg, 0.14 mmol) in EA (1 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (86.63 mg, yield: 99 %) as a yellow solid. ESI-MS (M+H) ⁺: 410.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 9.15 (s, 1H), 8.88 (s, 2H), 8.14 (s, 1H), 8.02 (d, J = 6.1 Hz, 1H), 7.85 (s, 1H), 6.70 (d, J = 6.2 Hz, 1H), 4.17 – 4.11 (m, 1H), 3.72 – 3.64 (m, 2H), 3.60 – 3.52 (m, 2H), 3.38 – 3.31 (m, 2H), 3.30 – 3.16 (m, 4H), 2.44 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H).

Example 303 – Preparation of 4-(2,2-dimethylpiperidin-4-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-1(2H)-carboxylate. [0832] To a solution of tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (3 g, 13.22 mmol) in dry THF (30 mL) was added LiHMDS (15.87 mL, 15.87 mmol, 1.0 M) dropwise at - 70 ^oC. The mixture was stirred at this temperature for 30 min.1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (6.15 g, 17.19 mmol) in dry THF (20 mL) was added to the mixture and stirred at RT for 24 h. The mixture was diluted with aq. NH₄Cl (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA/PE=1:100) to give title product (3 g, 63.24 %) as a yellow oil. ESI-MS (M+H-Boc+ACN) ⁺: 301.2.¹H NMR (400 MHz, CDCl₃-d) δ 5.82 – 5.69 (m, 1H), 4.11 – 4.02 (m, 2H), 2.45 – 2.34 (m, 2H), 1.49 (s, 6H), 1.46 (s, 9H). Step 2: Preparation of tert-butyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3,6-dihydropyridine-1(2H)-carboxylate. [0833] To a solution of tert-butyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-1(2H)-carboxylate (3 g, 8.34 mmol) in 1,4-dioxane (30 mL) were added B₂pin₂ (5.3 g, 20.88 mmol), Pd(dppf)Cl₂ (677 mg, 0.83 mmol) and KOAc (2.9 g, 29.22 mmol). The mixture was charged with N₂ for three times and stirred at 100 ^oC for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mLx3).The organic layer was washed with bine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA/PE=1:10) to give title product (1.2 g, 42.61 %) as a yellow oil. ESI-MS (M+H) ⁺:338.2. Step 3: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6,6-dimethyl- 3,6-dihydropyridine-1(2H)-carboxylate. [0834] To a solution of tert-butyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g, 3.56 mmol) in 1,4-dioxane (20 mL) and H₂O (4 mL) were added 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (708 mg, 3.56 mmol), K₂CO₃ (1.5 g, 10.68 mmol) and Pd(dppf)Cl₂ (294 mg, 0.36 mmol). The mixture was charged with N₂ for three times and stirred at 90 ^oC for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (20 mLx3). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA/PE=1:3) to give title product (400 mg, 34.19 %) as a yellow solid. ESI-MS (M+H) ⁺: 330.2. Step 4: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperidine-1-carboxylate. [0835] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6,6- dimethyl-3,6-dihydropyridine-1(2H)-carboxylate (350 mg, 1.06 mmol) in MeOH (10 mL) was added Pd(OH)₂ (70 mg). The mixture was charged with H₂ for three times and stirred at 50 °C for 16 h. The mixture was filtered and concentrated in vacuo to give title product (250 mg, 71.02 %) as a yellow solid. ESI-MS (M+H) ⁺: 332.3. Step 5: Preparation of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperidine-1- carboxylate. [0836] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperidine-1-carboxylate (250 mg, 0.75 mmol) and 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (124 mg, 0.75 mmol) in THF (5 mL), were added TEA (379 mg, 3.75 mmol) and triphosgene (223 mg, 0.75 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by (PE/EA=1/3) to give title product (120 mg, 30.46 %) as a yellow solid. ESI-MS (M+H) ⁺: 523.3. Step 6: Preparation of 4-(2,2-dimethylpiperidin-4-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0837] To a solution of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperidine-1- carboxylate (120 mg, 0.23 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep- HPLC (0.03 % TFA in water / CH₃CN) to give title product (24 mg, 24.74 %) as a yellow solid. ESI-MS (M+H) ⁺: 423.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (d, J = 2.4 Hz, 1H), 9.69 (d, J = 6.6 Hz, 1H), 8.87 – 8.75 (m, 1H), 8.66 – 8.51 (m, 1H), 8.16 (d, J = 4.8 Hz, 2H), 8.10 (d, J = 10.1 Hz, 1H), 6.92 (d, J = 5.6 Hz, 1H), 4.16 – 4.10 (m, 2H), 3.33 – 3.24 (m, 2H), 3.23 – 3.18 (m, 2H), 3.16 – 3.07 (m, 1H), 2.45 (s, 3H), 1.91 – 1.69 (m, 4H), 1.45 – 1.33 (m, 6H). Example 304 – Preparation of (S)-4-(4-cyclopropyl-3-methylpiperazin-1-yl)-N-(7-fluoro- 2-methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of(S)-4-(4-cyclopropyl-3-methylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0838] To a solution of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (60 mg, 0.15 mmol) and (1-ethoxycyclopropoxy) trimethylsilane (51 mg, 0.29 mmol) in MeOH / THF (2 mL, 1:1) was added TEA (26 mg, 0.75 mmol) at RT for 1 h. Then NaBH₃CN (25 mg, 0.39 mmol) was added to the mixture and stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (20.71 mg, yield: 29 %) as a white solid. ESI-MS (M+H) ⁺:450.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.55 (d, J = 6.4 Hz, 1H), 7.96 – 7.88 (m, 2H), 7.81 (d, J = 9.6 Hz, 1H), 6.64 (d, J = 6.1 Hz, 1H), 4.18 – 4.09 (m, 2H), 3.99 – 3.79 (m, 2H), 3.77 – 3.68 (m, 2H), 3.53 – 3.40 (m, 2H), 3.27 – 3.22 (m, 3H), 2.94 – 2.83 (m, 1H), 2.51 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H), 1.26 – 1.09 (m, 2H), 1.08 – 0.94 (m, 2H). Example 305 – Preparation of N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide TFA salt.

Step 1: Preparation of 6-bromo-2,7-dimethylimidazo[1,2-a]pyrimidine. [0839] To a solution of 5-bromo-4-methylpyrimidin-2-amine (15 g, 79.77 mmol) in IPA (500 mL) and DMF (100 mL) was added 1-chloropropan-2-one (74 g, 797.74 mmol) and the mixture was stirred at 100 °C for 16 h. The mixture was concentrated to dryness and purified by column flash chromatography (DCM/MeOH = 20/1) to afford the product (5.0 g, 27.8% yield) as a yellow solid. ESI-MS (M+H) ⁺: 226.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 7.54 (s, 1H), 2.60 (s, 3H), 2.34 (s, 3H). Step 2: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-1,1- diphenylmethanimine. [0840] To a solution of 6-bromo-2,7-dimethylimidazo[1,2-a]pyrimidine (1.1 g, 4.87 mmol) in 1,4-dioxane (30 mL) were added diphenylmethanimine (1.1 g, 6.32 mmol), Pd(OAc)₂ (109 mg, 0.49 mmol), Cs₂CO₃ (3.2 mg, 9.74 mmol) and BINAP (606 mg, 0.97 mmol) and the reaction was stirred at 115 °C for 16 h. The mixture was concentrated to dryness and purified by column flash chromatography (DCM/MeOH = 10/1) to afford the product (520 mg, 32.5% yield) as a yellow solid. ESI-MS (M+H)⁺: 327.2. Step 3: Preparation of 2,7-dimethylimidazo[1,2-a]pyrimidin-6-amine. [0841] To a solution of N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-1,1- diphenylmethanimine (2.6 g, 7.97 mmol) in EA (15 mL) was added HCl/1,4-Dioxane (20 mL) and the reaction was stirred at rt for 16 h. The mixture was concentrated to dryness and purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / CH₃CN) to afford the product (250 mg, 19.2% yield). ESI-MS (M+H) ⁺: 162.9. Step 4: Preparation of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0842] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) and 2,7-dimethylimidazo[1,2- a]pyrimidin-6-amine (49 mg, 0.60 mmol) in THF (15 mL) was added TEA (151.5 mg, 1.50 mmol) at 0 °C, then TBC (267 mg, 0.90 mmol) was added at 0 °C and the mixture was stirred at rt for 16 h. The mixture was poured into water (30 mL), extracted with EA (20 mL × 3) and the combined organic was washed with brine (50 mL) and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column flash chromatography (DCM/MeOH = 20/1) to afford the product (44 mg, 28% yield) as a yellow solid. ESI-MS (M+H) ⁺: 521.3. Step 5: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide TFA salt. [0843] To a solution of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (30 mg, 0.06 mmol) in DCM (4 mL) was added TFA (4 mL) and the reaction was stirred at 30 °C for 1 h. The mixture was concentrated to dryness purified by Prep-HPLC (0.05% TFA in H2O / ACN) to afford the product (11.39 mg, 47.4% yield) as a grey solid. ESI-MS (M+H) ⁺: 421.3.¹H NMR (400 MHz, D₂O) δ 9.24 (s, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.44 (s, 1H), 6.45 (s, 1H), 3.88 – 3.87 (m, 2H), 3.45 (s, 2H), 3.30 (d, J = 24.7 Hz, 4H), 3.01 – 2.99 (m, 2H), 2.56 (s, 3H), 2.30 (s, 3H), 1.38 (s, 6H). [0844] Example 306 – Preparation of (S)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [0845] To a mixture of 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (125 mg, 0.57 mmol) in toluene (5 mL) were added DPPA (291 mg, 1.06 mmol) and TEA (152 mg, 1.51 mmol). The mixture was stirred at r.t for 1 h and warmed up to 90^oC and stirred for 1 h. The mixture was added tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (120 mg, 0.38 mmol) and stirred at 110^oC for 4 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3), the organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 2) to get title product (60 mg, Y: 29.7%) as a white solid. ESI-MS (M+H)⁺:536.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.94 (d, J = 5.8 Hz, 1H), 7.03 (s, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.28 (t, J = 6.6 Hz, 1H), 4.21 – 4.18 (m, 2H), 4.11 (s, 3H), 4.06 (t, J = 8.6 Hz, 2H), 3.87 – 3.82 (m, 1H), 3.68 – 3.59 (m, 2H), 3.24 – 3.17 (m, 3H), 3.12 – 3.08 (m, 1H), 3.00 – 2.95 (m, 1H), 1.58 (t, J = 6.9 Hz, 3H), 1.49 (s, 9H), 1.25 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0846] To a solution of tert-butyl (S)-4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.09 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.03% TFA in water / ACN) to give title product (43.5 mg, Y: 84.8%) as a yellow solid. ESI-MS (M+H)⁺:436.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 8.86 – 8.67 (m, 2H), 8.43 (s, 1H), 8.12 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 6.99 (s, 1H), 6.62 (d, J = 6.1 Hz, 1H), 4.14 (q, J = 6.9 Hz, 2H), 4.06 (s, 3H), 4.05 – 4.00 (m, 2H), 3.80 – 3.74 (m, 2H), 3.42 – 3.34 (m, 2H), 3.19 – 3.11 (m, 4H), 3.00 – 2.93 (m, 1H), 1.52 (t, J = 6.9 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 307 – Preparation of (S)-N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate.

Step 1: Preparation of 5-bromo-2,6-dimethyl-2H-indazole. [0847] To a solution of 6- 5-bromo-6-methyl-1H-indazole (10 g, 47.39 mmol) in EA (200 mL) was added Trimethyloxonium Tetrafluoroborate (8.4 g, 56.87 mmol) at 0℃. The mixture was stirred at r.t for 5 h. The precipitate was filtered, washed with EA (100 mL) and dried in vacuo to give title product (14 g, crude) as a yellow solid. ESI-MS (M+H) ⁺:227.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 4.14 (s, 3H), 2.42 (s, 3H). Step 2: Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine. [0848] To a solution of 5-bromo-2,6-dimethyl-2H-indazole (11 g, 49.11 mmol) in 1,4- dioxane (200 mL) were added diphenylmethanimine (11 g, 58.03 mmol), Pd(OAc)₂ (1.1 g, 4.91 mmol), BINAP (6.1 g, 9.82 mmol), Cs₂CO₃ (32 g, 98.22 mmol). The mixture was stirred at 115 ℃ for 5 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to give title product (11 g, yield: 69 %) as a yellow solid. ESI- MS (M+H) ⁺:326.2.¹H NMR (400 MHz, CDCl₃) δ 7.81 – 7.78 (m, 2H), 7.53 (s, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.43 – 7.40 (m, 3H), 7.23 – 7.20 (m, 3H), 7.11 (dd, J = 6.6, 2.9 Hz, 2H), 6.48 (s, 1H), 4.07 (s, 3H), 2.34 (s, 3H). Step 3: Preparation of 2,6-dimethyl-2H-indazol-5-amine. [0849] To a solution of N-(2,6-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (10.5 g, 32.21 mmol) in EA (50 mL) was added 4M HCl/EA (50 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered, washed with EA (100 mL) and dried in vacuo to give title product (HCl salt) (5.5 g, 86%) as a white solid. To a solution 2,6-dimethyl-2H-indazol- 5-amine hydrochloride (3 g, 15.15 mmol) in H₂O (20 mL) was added NaHCO₃ to pH=9. The precipitate was filtered, washed with H₂O (5 mL) and dried in vacuo to give title product (2.2 g, 89%) as a yellow solid. ESI-MS (M+H) ⁺: 162.2.¹H NMR (400 MHz, CDCl₃) δ 7.58 (s, 1H), 7.41 (s, 1H), 6.77 (s, 1H), 4.12 (s, 3H), 3.56 (s, 2H), 2.31 (s, 3H). Step 4: Preparation of tert-butyl (S)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [0850] To a mixture of 2,6-dimethyl-2H-indazol-5-amine (733 mg, 4.53 mmol), TEA (3.82 g, 37.70 mmol) in THF (50 mL) were added triphosgene (1.3 g, 4.53 mmol) and stirred at 0℃ for 5 min, then tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (1.2 g, 3.77 mmol) was added slowly at 0℃. The reaction mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (100 mL) and stirred at r.t for 20 min. The precipitate was filtered, washed with water (20 mL) and dried to give title product (1.7 g, yield: 82 %) as a white solid. ESI-MS (M+H) ⁺:506.0.¹H NMR (400 MHz, CDCl₃) δ 11.56 (s, 1H), 8.39 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.77 (s, 1H), 7.48 (s, 1H), 6.34 (d, J = 6.0 Hz, 1H), 4.34 – 4.33 (m, 1H), 4.23 – 4.16 (m, 5H), 3.97 (d, J = 13.4 Hz, 1H), 3.52 (d, J = 12.4 Hz, 1H), 3.43 (d, J = 12.4 Hz, 1H), 3.23 – 3.21 (m, 1H), 3.14 – 3.04 (m, 3H), 2.95 – 2.94 (m, 1H), 2.52 (s, 3H), 1.49 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H). Step 5: Preparation of (S)-N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0851] To a mixture of tert-butyl (S)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (1.7 g, 3.36 mmol) in EA (20 mL) was added 4M HCl/EA (20 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo. The residue was diluted with H₂O (10 mL), adjusted pH=9 with sodium carbonate solution and stirred at r.t for 2 h. The mixture was filtered through a Celite pad and collect solid to give title product (1 g, 73 %) as a white solid. The crude product (S)-N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide (200 mg, 0.49 mmol) was purified by prep-HPLC (0.1% NH₃.H₂O in EtOH / Hexane) to give title product (117.69 mg, 59%) as a white solid. ESI-MS (M+H) ⁺:406.2.¹H NMR (400 Hz, DMSO-d₆) δ 11.63 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.87 (d, J = 6.1 Hz, 1H), 7.43 (s, 1H), 6.49 (d, J = 6.1 Hz, 1H), 4.10 (s, 3H), 3.98 (t, J = 8.6 Hz, 2H), 3.57 (d, J = 11.4 Hz, 2H), 3.12 (t, J = 8.5 Hz, 2H), 2.91 (d, J = 10.4 Hz, 1H), 2.83 – 2.72 (m, 3H), 2.43 (d, J = 6.6 Hz, 4H), 1.00 (d, J = 6.3 Hz, 3H). Step 6: Preparation of (S)-N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate. [0852] To a mixture of (S)-N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (800 mg, 1.97 mmol) in DCM (20 mL) and MeOH (2 mL) was added benzoate (240 mg, 1.97 mmol). The mixture was stirred at 50℃ for 2 h. The mixture was concentrated under reduced pressure, triturated with MTBE and lyophilized to give title product (957 mg, 92%) as a white solid. ESI-MS (M+H) ⁺:406.3. ¹H NMR (400 MHz, MeOD-d₄) δ 8.21 (s, 1H), 8.05 (s, 1H), 7.98 – 7.93 (m, 3H), 7.47 (d, J = 7.3 Hz, 1H), 7.43 – 7.37 (m, 3H), 6.58 – 6.51 (m, 1H), 4.16 (s, 3H), 4.12 – 4.06 (m, 2H), 3.72 (d, J = 13.7 Hz, 2H), 3.32 (d, J = 6.8 Hz, 1H), 3.29 – 3.25 (m, 1H), 3.19 – 3.07 (m, 4H), 2.86 – 2.78 (m, 1H), 2.48 (s, 3H), 1.30 (d, J = 6.5 Hz, 3H). Example 308 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

[0853] Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((6-methoxy-2-methylpyrazolo[1,5- a]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. A mixture of 6-methoxy-2-methylpyrazolo[1,5- a]pyridine-5-carboxylic acid (100 mg, 0.48 mmol), TEA (146 mg, 1.45 mmol) and DPPA (267 mg, 0.97 mmol) in Tol (3 mL) was stirred at RT for 1 h, then stirred at 70 ^oC for 1h, tert- butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (161 mg, 0.48 mmol) was added. The mixture was stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 5) to give title product (180 mg, Y: 69.5%) as a white solid. ESI-MS (M+H) ⁺: 536.3. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0854] A mixture of tert-butyl (2R,6S)-4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (160 mg, 0.30 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at RT for 1 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (25.78 mg, Y: 19.8 %) as a white solid. ESI-MS (M+H) ⁺: 436.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 9.26 (d, J = 8.4 Hz, 1H), 8.63 (d, J = 9.9 Hz, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 6.65 (d, J = 6.1 Hz, 1H), 6.17 (s, 1H), 4.05 – 3.99 (m, 2H), 3.97 (s, 3H), 3.89 – 3.86 (m, 2H), 3.46 – 3.32 (m, 2H), 3.24 – 3.14 (m, 2H), 2.96 – 2.83 (m, 2H), 2.31 (s, 3H), 1.27 (d, J = 6.5 Hz, 6H). Example 309 – Preparation of (S)-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)- 4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0855] A mixture of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (100 mg, 0.48 mmol), TEA (146 mg, 1.45 mmol) and DPPA (267 mg, 0.97 mmol) in Tol (3 mL) was stirred at RT for 1 h, then stirred at 70 ^oC for 1h. tert-butyl (S)-4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (154 mg, 0.48 mmol) was added to the mixture and stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 4) to give title product (120 mg, Y: 47.6%) as a white solid. ESI-MS (M+H) ⁺: 522.4. Step 2: Preparation of (S)-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0856] A mixture of tert-butyl (S)-4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.1 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (44.14 mg, Y: 85.97%) as a white solid. ESI-MS (M+H) ⁺: 422.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 9.15 (s, 1H), 8.81 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 6.17 (s, 1H), 4.02 (t, J = 8.7 Hz, 2H), 3.96 (s, 3H), 3.80 (s, 2H), 3.44 – 3.32 (m, 2H), 3.24 – 3.08 (m, 4H), 3.04 – 2.92 (m, 1H), 2.31 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H). Example 310 – Preparation of (R)-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)- 4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0857] A mixture of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (100 mg, 0.48 mmol), TEA (146 mg, 1.45 mmol) and DPPA (267 mg, 0.97 mmol) in Tol (3 mL) was stirred at RT for 1 h, then stirred at 70 ^oC for 1h. tert-butyl (R)-4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (154 mg, 0.48 mmol) was added to the mixture and stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 5) to give title product (180 mg, Y: 71.4%) as a white solid. ESI-MS (M+H) ⁺: 522.2. Step 2: Preparation of (R)-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0858] A mixture of tert-butyl (R)-4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (160 mg, 0.1 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at RT for 1 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (63.99 mg, Y: 49.5%) as a white solid. ESI-MS (M+H) ⁺: 422.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 9.11 (s, 1H), 8.78 (s, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 6.17 (s, 1H), 4.02 (t, J = 8.7 Hz, 2H), 3.97 (s, 3H), 3.79 (d, J = 11.8 Hz, 2H), 3.42 – 3.33 (m, 2H), 3.23 – 3.10 (m, 4H), 3.04 – 2.94 (m, 1H), 2.31 (s, 3H), 1.34 – 1.22 (m, 3H). Example 311 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate

Step 1: Preparation of tert-butyl 4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0859] A mixture of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (100 mg, 0.48 mmol), TEA (146 mg, 1.45 mmol) and DPPA (267 mg, 0.97 mmol) in Tol (3 mL) was stirred at RT for 1 h, then stirred at 70 ^oC for 1h. tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (160.9 mg, 0.48 mmol) was added to the mixture and stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 5) to give title product (120 mg, Y: 46.3%) as a white solid. ESI-MS (M+H) ⁺: 536.3. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methylpyrazolo[1,5- a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0860] A mixture of tert-butyl 4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (100 mg, 0.19 mmol) in 4MHCl/EA (4 mL) was stirred at RT for 2 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (95 mg, Y: 93.1%) as a white solid. ESI-MS (M+H) ⁺: 436.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.24 (s, 1H), 9.09 (s, 2H), 8.28 (d, J = 12.4 Hz, 1H), 8.23 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 6.62 (d, J = 6.1 Hz, 1H), 6.17 (s, 1H), 4.03 – 3.99 (m, 2H), 3.96 (s, 3H), 3.51 – 3.42 (m, 2H), 3.34 – 3.24 (m, 4H), 3.19 – 3.10 (m, 2H), 2.31 (s, 3H), 1.38 (s, 6H). Example 312 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methoxy-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

s_{tep 1 step 2}

Step 1: Preparation of 7-methoxy-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride. [0861] To a solution of 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (8 g, 33.20 mmol) in 1,4-dioxane (200 mL) were added diphenylmethanimine (3.3 g, 17.98 mmol), Pd(OAc)₂ (747 mg, 3.23 mmol), BINAP (4.14 g, 6.64 mmol), Cs₂CO₃ (21.6 g, 66.40 mmol). The mixture was stirred at 115 ℃ for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH=20:1) to give title product (7 g, yield: 61 %) as a yellow solid. ESI-MS (M+H) ⁺:342.3.¹H NMR (400 MHz, DMSO-d₆) δ 7.72 – 7.62 (m, 3H), 7.56 = 7.3 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.39 – 7.30 (m, 3H), 7.23 (s, 1H), 7.14 (dd, J = 7.4, 1.8 Hz, 2H), 6.70 (s, 1H), 3.70 (s, 3H), 2.18 (s, 3H). Step 2: Preparation of 8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride. [0862] To a solution of N-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (7 g, 20.53 mmol) in EA (50 mL) was added 4M HCl/EA (50 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered, washed with EA (50 mL) and dried in vacuo to give title product (3 g, 68%) as a white solid. ESI-MS (M+H) ⁺:178.2.¹H NMR (400 MHz, DMSO-d₆) δ 13.92 (s, 1H), 8.00 (s, 1H), 7.77 (s, 1H), 7.09 (s, 1H), 4.01 (s, 3H), 2.37 (d, J = 0.7 Hz, 3H). Step 3: Preparation of tert-butyl 4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0863] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) in THF (20 mL) were added 7- methoxy-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (144 mg, 0.68 mmol), TEA (911 mg, 9.00 mmol) and triphosgene (160 mg, 0.54 mmol) (in THF (1 mL )) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH=20:1) to give title product (80 mg, yield: 33 %) as a brown solid. ESI-MS (M+H) ⁺:536.2.¹H NMR (400 MHz, DMSO DMSO-d₆) δ 12.15 (s, 1H), 9.12 (s, 1H), 6.90 (s, 1H), 6.41 (d, J = 6.3 Hz, 1H), 5.96 (d, J = 5.9 Hz, 1H), 5.77 (d, J = 4.9 Hz, 1H), 3.98 (s, 3H), 3.70 (d, J = 5.9 Hz, 2H), 3.63 (d, J = 5.2 Hz, 2H), 3.58 (d, J = 5.6 Hz, 2H), 3.53 (s, 2H), 3.39 (d, J = 6.3 Hz, 2H), 2.25 (s, 3H), 1.43 (s, 9H), 1.36 (s, 6H). Step 4: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methoxy-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0864] To a mixture of tert-butyl 4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (70 mg, 0.13 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (45.37 mg, 63%) as a white solid. ESI-MS (M+H) ⁺:436.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.46 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.73 (s, 1H), 7.24 (s, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.22 (s, 3H), 4.18 – 4.13 (m, 2H), 3.53 (d, J = 5.9 Hz, 2H), 3.44 (d, J = 5.8 Hz, 2H), 3.35 (s, 2H), 3.26 – 3.22 (m, 2H), 2.47 (d, J = 1.0 Hz, 3H), 1.51 (s, 6H). Example 313 – Preparation of (R)-N-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0865] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 7-methoxy-2-methylimidazo[1,2- a]pyridin-6-amine (80 mg, 0.37 mmol), triphosgene (112 mg, 0.37 mmol) and TEA (158.6 mg, 1.57 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. the mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (MeOH: DCM=3 %) to give title product (40 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 521.8.¹H NMR (400 MHz, CDCl₃) δ 12.34 (s, 1H), 9.30 (s, 1H), 7.92 (d, J = 5.8 Hz, 1H), 7.36 – 7.32 (m, 2H), 7.13 (s, 1H), 6.38 (d, J = 6.1 Hz, 1H), 4.39 – 4.31 (m, 3H), 4.16 – 4.13 (m, 2H), 4.12 (s, 3H), 3.98 – 3.94 (m, 2H), 3.80 – 3.75 (m, 2H), 3.59 – 3.53 (m, 2H), 2.50 (s, 3H), 1.49 (s, 9H), 1.32 – 1.30 (m, 3H). Step 2: Preparation of (R)-N-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0866] A mixture of tert-butyl (R)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (30 mg, 0.06 mmol) in TFA / DCM (2 mL / 2 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (25.79 mg, yield: 80.34 %) as a white solid. ESI-MS (M+H) ⁺: 422.0.¹H NMR (400 MHz, MeOD-d₄) δ 9.47 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.73 (s, 1H), 7.24 (s, 1H), 6.65 (d, J = 6.1 Hz, 1H), 4.22 (s, 3H), 4.17 – 4.11 (m, 2H), 3.84 (d, J = 13.1 Hz, 2H), 3.52 – 3.50 (m, 2H), 3.29 – 3.18 (m, 4H), 3.03 – 3.01 (m, 1H), 2.47 (d, J = 1.0 Hz, 3H), 1.41 (d, J = 6.6 Hz, 3H). Example 314 – Preparation of ethyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate dihydrochloride.

Step 1: Preparation of ethyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate dihydrochloride. [0867] A mixture of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (3 g, 7.09 mmol) and TEA (2.3 g, 21.28 mmol) in THF (30 mL) was added ethyl carbonochloridate (2.3 g, 21.28 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.1% HCl in water / CH₃CN) to give title product (1.5 g, Y: 42.6 %) as a white solid. ESI-MS (M+H) ⁺: 496.2.¹H NMR (400 MHz, DMSO-d₆) δ 14.63 (s, 1H), 12.66 (s, 1H), 9.63 (s, 1H), 8.17 (s, 1H), 8.06 (d, J = 9.8 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 6.50 (s, 1H), 4.09 – 3.97 (m, 4H), 3.82 – 3.72 (m, 2H), 3.70 – 3.51 (m, 4H), 3.39 (s, 2H), 2.46 (s, 3H), 1.40 (s, 6H), 1.21 (t, J = 7.1 Hz, 3H). Example 315 – Preparation of (R)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [0868] To a solution of 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (100 mg, 0.45 mmol) in Toluene (10 mL) were added TEA (138 mg, 1.37 mmol) and DPPA (313 mg, 1.14 mmol). The mixture was stirred at 20 ^oC for 1h. Then the mixture was stirred at 60 ^oC for another 1h. Tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (145 mg, 0.45 mmol) was added to the mixture and stirred at 90 ^oC for 16h. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:4) to provide title product (110 mg, yield: 46%) as a white solid. ESI-MS (M+H)⁺: 536.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 6.97 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.20 – 4.11 (m, 3H), 4.05 (s, 3H), 4.00 (t, J = 8.6 Hz, 2H), 3.79 (d, J = 13.3 Hz, 1H), 3.62 (d, J = 11.8 Hz, 1H), 3.55 (d, J = 12.8 Hz, 1H), 3.13 (dd, J = 18.0, 8.6 Hz, 3H), 3.03 (dd, J = 12.8, 3.6 Hz, 1H), 2.91 (td, J = 11.7, 3.3 Hz, 1H), 1.52 (t, J = 6.9 Hz, 3H), 1.42 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (R)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0869] To a solution of tert-butyl (R)-4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.19 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (93 mg, yield: 89%) as a white solid. ESI-MS (M+H)⁺: 435.9.¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1H), 9.08 (s, 1H), 8.74 (s, 1H), 8.43 (s, 1H), 8.13 (s, 1H), 7.91 (d, J = 5.9 Hz, 1H), 6.99 (s, 1H), 6.62 (d, J = 6.0 Hz, 1H), 4.17 – 4.00 (m, 7H), 3.77 (d, J = 11.6 Hz, 2H), 3.39 (s, 2H), 3.15 (t, J = 8.5 Hz, 4H), 3.02 – 2.93 (m, 1H), 1.52 (t, J = 6.8 Hz, 3H), 1.27 (d, J = 6.4 Hz, 3H). [0870] Example 316 – Preparation of (R)-N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [0871] To a solution of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) and 2,6-dimethyl-2H-indazol-5-amine (101 mg, 0.63 mmol) in THF (10 mL) were added TEA (1 mL) and a solution of triphosgene (187 mg, 0.63 mmol) in THF (1 mL) dropwise to the mixture at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:4) to provide title product (80 mg, yield: 51%) as a pink solid. ESI-MS (M+H)⁺: 505.8.¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 7.93 (d, J = 5.6 Hz, 1H), 7.46 (s, 1H), 6.67 (s, 1H), 4.09 (d, J = 16.4 Hz, 5H), 3.84 (d, J = 8.0 Hz, 2H), 3.38 (d, J = 12.4 Hz, 2H), 3.16 (dd, J = 24.5, 12.0 Hz, 4H), 3.04 (t, J = 12.8 Hz, 1H), 2.42 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H). Step 2: Preparation of (R)-N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0872] To a solution of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (70 mg, 0.14 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (64 mg, yield: 88%) as a white solid. ESI-MS (M+H)⁺: 406.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 7.93 (d, J = 5.6 Hz, 1H), 7.46 (s, 1H), 6.67 (s, 1H), 4.09 (d, J = 16.4 Hz, 5H), 3.84 (d, J = 8.0 Hz, 2H), 3.38 (d, J = 12.4 Hz, 2H), 3.16 (dd, J = 24.5, 12.0 Hz, 4H), 3.04 (t, J = 12.8 Hz, 1H), 2.42 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H). Example 317 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

s_{tep 1 step 2}

Step 1: Preparation of 5-bromo-4-methoxypyridin-2-amine. [0873] To a mixture of 4-methoxypyridin-2-amine (5 g, 40.32 mmol) in ACN (100 mL) was NBS (7.2 g, 40.32 mmol) in portions at 0 ^o C. The mixture was stirred at r.t for 1 h. The solvent was evaporated and DCM was added. The solution was washed with satudium bicarbonate, dried, and concentrated to give title product (8 g, 96%) as a grey solid. ESI-MS (M+H) ⁺: 205.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (d, J = 2.7 Hz, 1H), 6.12 (s, 1H), 6.07 (s, 2H), 3.80 (s, 3H). Step 2: Preparation of 1,2-diamino-5-bromo-4-methoxypyridin-1-ium 2,4,6- trimethylbenzenesulfonate. [0874] To a solution of 5-bromo-4-methoxypyridin-2-amine (4.5 g, 22.28 mmol) in trichloromethane (200 mL) was added and O-(mesitylsulfonyl) hydroxylamine (10 g, 44.55 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The precipitate was filtered, washed with CHCl₃ (50 mL) and dried in vacuo to give tilte product (7.5 g, 80%) as a white solid. ESI-MS (M+H) ⁺: 223.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.25 (s, 1H), 6.74 (s, 2H), 6.54 (d, J = 5.4 Hz, 3H), 3.95 (s, 3H), 2.50 (s, 6H), 2.17 (s, 3H). Step 3: Preparation of 6-bromo-7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine. [0875] To a mixture of 1,2-diamino-5-bromo-4-methoxypyridin-1-ium 2,4,6- trimethylbenzenesulfonate (7.5 g, 17.94 mmol) in Ac₂O (50 mL) was added O- (mesitylsulfonyl)hydroxylamine (694 mg, 4.04 mmol). The mixture was stirred at 100 ^oC for 16 h. The reaction was quenched with H₂O (100 mL). The resulting mixture was adjusted to PH=9 with NaOH aqueous solution (1 M), and extracted with DCM (80 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na₂SO₄, filtrated, and concentrated in vacuo. The residue was diluted with EA (10 mL) and PE (10 mL) and stirred at r.t for 1 h. The precipitate was filtered, washed with PE: EA (5 mL) and dried in vacuo to give title product (3 g, 68%) as a white solid. ESI-MS (M+H) ⁺: 244.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 7.25 (s, 1H), 3.97 (s, 3H), 2.41 (s, 3H). Step 4: Preparation of N-(7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0876] To a solution of 6-bromo-7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (2.8 g, 11.57 mmol) in 1,4-dioxane (70 mL) were added diphenylmethanimine (2.3 g, 12.15 mmol), Pd(OAc)₂ (260 mg, 1.16 mmol), BINAP (1.45 g, 2.31 mmol), Cs₂CO₃ (7.5 g, 23.14 mmol). The mixture was stirred at 115 ℃ for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to give title product (3 g, yield: 75 %) as a yellow solid. ESI-MS (M+H) ⁺:343.1.¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 7.6 Hz, 2H), 7.67 (s, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.27 (d, J = 6.8 Hz, 3H), 7.16 – 7.11 (m, 2H), 6.76 (s, 1H), 3.80 (s, 3H), 2.47 (s, 3H). Step 5: Preparation of 7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine hydrochloride. [0877] To a solution of N-(7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine (2.5 g, 7.31 mmol) in EA (10 mL) was added 4M HCl/EA (10 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered, washed with EA (20 mL) and dried in vacuo to give title product (1.4 g, 89%) as a white solid. ESI-MS (M+H) ⁺: 179.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H), 7.36 (s, 1H), 4.14 (s, 3H), 2.63 (s, 3H). Step 6: Preparation of tert-butyl 4-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0878] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) in THF (20 mL) were added 7- methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine hydrochloride (97 mg, 0.45 mmol), TEA (759 mg, 7.50 mmol) and triphosgene (107 mg, 0.36 mmol) (in THF (1 mL )) at 0 ℃.The mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give title product (80 mg, yield: 49 %) as a white solid. ESI-MS (M+H) ⁺:536.8.¹H NMR (400 MHz, CDCl₃) δ 12.24 (s, 1H), 9.55 (s, 1H), 7.87 (s, 1H), 7.85 (d, J = 6.1 Hz, 1H), 6.22 (d, J = 6.1 Hz, 1H), 4.15 (d, J = 8.4 Hz, 2H), 4.05 (s, 3H), 3.81 – 3.77 (m, 2H), 3.58 – 3.54 (m, 2H), 3.45 (s, 2H), 3.30 – 3.23 (m, 2H), 2.53 (s, 3H), 1.50 (s, 9H), 1.45 (s, 6H). Step 7: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0879] To a solution of tert-butyl 4-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (60 mg, 0.11 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (41.82 mg, 69%) as a white solid. ESI-MS (M+H) ⁺:436.9.¹H NMR (400 MHz, MeOD-d₄) δ 9.56 (s, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.24 (s, 1H), 6.63 (d, J = 6.1 Hz, 1H), 4.20 (s, 3H), 4.17 – 4.10 (m, 2H), 3.55 – 3.50 (m, 2H), 3.45 – 3.41 (m, 2H), 3.34 (s, 2H), 3.22 (t, J = 8.5 Hz, 2H), 2.55 (s, 3H), 1.51 (s, 6H). Example 318 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

C^{ompound 318} Step 1: Preparation of N'-(5-bromopyridin-2-yl)-N,N-dimethylacetimidamide. [0880] To a mixture of 5-bromopyridin-2-amine (11 g, 64.33 mmol) in MeOH (110 mL) were added 1,1-dimethoxy-N,N-dimethylethan-1-amine (25.67 g, 192.99 mmol). The mixture was heated to reflux at 80°C for 16 h. The mixture was concentrated in vacuo. The mixture was diluted with H₂O (110 mL) and extracted with EA (110 mL x 3). The organic phase was washed with brine (110 mLx3), dried over anhydrous Na2SO4 and concentrated in vacuum to afford the title compound (14 g, crude) as a red oil. ESI-MS (M+H) ⁺:242.0 Step 2: Preparation of 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine. [0881] To a solution of N'-(5-bromopyridin-2-yl)-N,N-dimethylacetimidamide (14 g, 105.26 mmol) and pyridine (24.95 g, 315.78 mmol) in MeOH (140 mL) was added (aminooxy)sulfonic acid (23.58 g, 210.52 mmol) at 0 ^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo. The cake was dissolved in H₂O and basified to pH 10 with Na₂CO_3. The mixture was diluted with H₂O (150 mL) and extracted with EA (150 mL x 3). The organic phase was washed with brine (150 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (7.1 g, 32.05%) as a yellow solid. ESI-MS (M+H) ⁺:212.0¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 7.55 (s, 2H), 2.59 (s, 3H). Step 3: Preparation of N-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0882] To a mixture of 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (7.1 g, 33.65 mmol), diphenylmethanimine (9.19 g, 50.48 mmol) and BINAP (4.19 g, 6.73 mol) in 1,4-dioxane (70 mL) were added Cs₂CO₃ (21.94 g, 67.30 mmol) and Pd(OAc)₂ (758.25 mg, 3.37 mmol). The mixture was stirred at 115 ^oC for 16 h under N₂. The mixture was diluted with H₂O (70 mL) and extracted with EA (70 mL x 3). The organic phase was washed with brine (70 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (7.0 g, 66.69%) as a white solid. ESI-MS (M+H) ⁺:313.1. Step 4: Preparation of 2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine hydrochloride. [0883] A mixture of N-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine (7.0 g, 22.44 mmol) in 3M HCl/EA (70 mL) was stirred at rt for 2 h. The reaction was diluted with EA (30 mL), the precipitate was filtrated and dried in vacuo to give title product (2.0 g, 60.20%) as a yellow solid. ESI-MS (M+H⁺): 149.5. Step 5: Preparation of tert-butyl 2,2-dimethyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0884] To a mixture of t tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) and 2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-amine hydrochloride (83.13 mg,0.45 mmol) in THF (10 mL) were added TEA (136.35 mg, 1.35 mmol) and triphosgene (266.40 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (100 mg, 43.92 %) as a yellow solid. ESI-MS (M+H)⁺: 507.3. Step 6: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0885] A mixture of tert-butyl 2,2-dimethyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) in 3M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in water / CH₃CN) to give title product (24.61 mg, 23.66%) as a yellow oil. ESI-MS (M+H⁺): 407.3.¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 9.17 (s, 2H), 7.94 (d, J = 6.2 Hz, 1H), 7.72 (d, J = 9.4 Hz, 1H), 7.66 (dd, J = 9.5, 1.8 Hz, 1H), 6.69 (d, J = 6.2 Hz, 1H), 4.08 (t, J = 8.3 Hz, 2H), 3.58 – 3.50 (m, 2H), 3.42 – 3.36 (m, 2H), 3.34 – 3.28 (m, 2H), 3.26 – 3.19 (m, 2H), 2.46 (s, 3H), 1.38 (s, 6H). Example 319 – Preparation of (S)-N-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0886] To a solution of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) and 7-methoxy-2-methylimidazo[1,2- a]pyridin-6-amine (84 mg, 0.47 mmol) in THF (10 mL) were added TEA (1 mL) and a solution of triphosgene (140 mg, 0.47 mmol) in THF (1 mL) dropwise to the mixture at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:3) to provide title product (100 mg, yield: 62%) as a pink solid. ESI-MS (M+H)⁺: 521.8. Step 2: Preparation of (S)-N-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0887] To a solution of tert-butyl (S)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (34 mg, yield: 53%) as a white solid. ESI-MS (M+H)⁺: 422.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 9.52 (s, 1H), 9.09 (s, 1H), 8.77 (s, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.99 (s, 1H), 7.29 (s, 1H), 6.67 (d, J = 6.2 Hz, 1H), 4.18 (s, 3H), 4.03 (t, J = 8.7 Hz, 2H), 3.81 (d, J = 11.5 Hz, 2H), 3.40 (s, 2H), 3.23 – 3.14 (m, 4H), 3.04 – 2.95 (m, 1H), 2.41 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 320 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [0888] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) in THF (5 mL) were added TEA (137 mg, 1.36 mmol), triphosgene (161 mg, 0.54 mmol) at 0^oC. The mixture was stirred at r.t for 1 h. Then 7-methoxy-2-methylimidazo[1,2-a]pyridin-6-amine (96 mg, 0.54 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:4) to give the title compound (60 mg, Y: 24.8 %) as a yellow solid. ESI-MS (M+H) ⁺:536.3. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0889] To a solution of tert-butyl (2R,6S)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (50 mg, 0.09 mmol) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.03% TFA in water / ACN) to give title product (26.5 mg, Y: 65.2%) as a yellow solid. ESI-MS (M+H)⁺:436.3.¹H NMR (400 MHz, DMSO-d₆) δ 13.90 (s, 1H), 12.44 (s, 1H), 9.53 (s, 1H), 9.29 – 9.22 (m, 1H), 8.67 – 8.58 (m, 1H), 8.03 (d, J = 6.0 Hz, 1H), 8.00 (s, 1H), 7.31 (s, 1H), 6.68 (d, J = 6.2 Hz, 1H), 4.19 (s, 3H), 4.03 (t, J = 8.5 Hz, 2H), 3.91 – 3.86 (m, 2H), 3.43 – 3.36 (m, 2H), 3.21 (t, J = 8.5 Hz, 2H), 2.94 – 2.87 (m, 2H), 2.41 (d, J = 0.9 Hz, 3H), 1.27 (d, J = 6.5 Hz, 6H). Example 321 – Preparation of methyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate 2,2,2-trifluoroacetate.

Step 1: Preparation of methyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate 2,2,2-trifluoroacetate. [0890] To a solution of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (100 mg, 0.24 mmol) in THF (5 mL) were added TEA (0.5 mL) and methyl carbonochloridate (1128 mg, 12 mmol) at 0 ^oC for 5 h. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (32.5 mg, yield: 28 %) as a white solid. ESI-MS (M+H) ⁺:482.3.¹H NMR (400 MHz, MeOD- d₄) δ 9.29 (d, J = 6.1 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 7.0 Hz, 1H), 6.66 (d, J = 7.0 Hz, 1H), 4.32 – 4.23 (m, 2H), 3.93 – 3.87 (m, 2H), 3.84 – 3.78 (m, 2H), 3.78 – 3.74 (m, 2H), 3.70 (s, 3H), 3.61 – 3.52 (m, 2H), 2.53 (s, 3H), 1.49 (s, 6H). Example 322 – Preparation of (S)-N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0891] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 2,7-dimethylimidazo[1,2-a]pyrimidin- 6-amine (51 mg, 0.31 mmol) and TEA (1 mL) in THF (8 mL) was added triphosgene (184 mg, 0.62 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (MeOH: DCM= 1: 10) to give title product (100 mg, Y: 62.5%) as a yellow solid. ESI-MS (M+H) ⁺: 506.9. Step 2: Preparation of (S)-N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0892] A mixture of tert-butyl (S)-4-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.16 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (47.89 mg, Y: 74.6%) as a white solid. ESI-MS (M+H) ⁺: 407.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (s, 1H), 9.89 (s, 1H), 9.37 (s, 1H), 9.04 (s, 1H), 8.10 (dd, J = 8.9, 3.5 Hz, 2H), 6.77 (d, J = 6.2 Hz, 1H), 4.15 – 4.10 (m, 2H), 3.93 – 3.88 (m, 2H), 3.48 – 3.43 (m, 2H), 3.34 – 3.21 (m, 4H), 3.14 – 3.07 (m, 1H), 2.86 (s, 3H), 2.54 (s, 3H), 1.36 (d, J = 6.5 Hz, 3H). Example 323 – Preparation of (R)-N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0893] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 2,7-dimethylimidazo[1,2-a]pyrimidin- 6-amine (51 mg, 0.31 mmol) and TEA (1 mL) in THF (8 mL) was added triphosgene (184 mg, 0.62 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (MeOH: DCM= 1:10) to give title product (100 mg, Y: 62.5%) as a yellow solid. ESI-MS (M+H) ⁺: 506.9. Step 2: Preparation of (R)-N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0894] A mixture of tert-butyl (R)-4-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (70 mg, 0.14 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (64 mg, Y: 89.0%) as a yellow solid. ESI-MS (M+H) ⁺: 407.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 9.83 (s, 1H), 9.29 (s, 1H), 8.96 (s, 1H), 8.09 – 7.97 (m, 2H), 6.70 (d, J = 6.2 Hz, 1H), 4.09 – 4.02 (m, 2H), 3.88 – 3.80 (m, 2H), 3.44 – 3.34 (m, 2H), 3.27 – 3.09 (m, 4H), 3.07 – 2.97 (m, 1H), 2.79 (s, 3H), 2.47 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H). Example 324 – Preparation of N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 7-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0895] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol), 2,7-dimethylimidazo[1,2- a]pyrimidin-6-amine (51 mg, 0.30 mmol) and TEA (1 mL) in THF (8 mL) was added triphosgene (184 mg, 0.60 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (MeOH: DCM= 1: 10) to give title product (60 mg, Y: 38.5%) as a yellow solid. ESI-MS (M+H) ⁺: 519.2. Step 2: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0896] A mixture of tert-butyl 7-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (55.62 mg, Y: 89.7%) as a white solid. ESI-MS (M+H) ⁺: 419.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 9.89 (s, 1H), 9.50 (s, 2H), 8.09 (dd, J = 9.3, 3.5 Hz, 2H), 6.74 (d, J = 6.2 Hz, 1H), 4.14 – 4.07 (m, 2H), 3.54 – 3.50 (m, 3H), 3.46 – 3.38 (m, 3H), 3.28 – 3.21 (m, 2H), 2.86 (s, 3H), 2.54 (s, 3H), 1.13 (t, J = 6.1 Hz, 2H), 1.01 (t, J = 6.3 Hz, 2H). Example 325 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methoxy-2- methylimidazo[1,2-a] pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1- carboxamide.

, , s_{tep 1 step 2} C^s ₂ ^CO _{3, Pd(OAc)2} HCl/EA BINAP, 1,4-dioxane rt, 2 h

100 C, 16 h step 4

step 3

Step 1: Preparation of 5-bromo-4-methoxypyrimidin-2-amine. [0897] A mixture of 4-methoxypyrimidin-2-amine (50.5 g, 404 mmol) and NBS (71.84 g,403.5 mmol) in CHCI₃ (500 mL) was stirred at RT for 6 h. The mixture was diluted with sat-Na₂SO₃ (400 mL), extracted with EA (400 mL×3), organic layer was concentrated in vacuo to give title compound (80.8 g, Y: 98%) as a yellow solid. ESI-MS (M+H) ⁺: 205.9. Step 2: Preparation of 6-bromo-7-methoxy-2-methylimidazo[1,2-a] pyrimidine. [0898] A mixture of 5-bromo-4-methoxypyrimidin-2-amine (15 g, 73.52 mmol) and 1- chloropropan-2-one (13.6 g, 146.99 mmol) in EtOH (150 mL) was stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and the residue was diluted with 1M NaOH (100 mL), extracted with EA (200 mL *2), the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 1: 3) to give title compound (4.2 g, Y: 23.4%) as a white solid. ESI-MS (M+H) ⁺: 242.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 7.43 (d, J = 0.9 Hz, 1H), 4.04 (s, 3H), 2.33 (d, J = 0.7 Hz, 3H). Step 3: Preparation of N-(7-methoxy-2-methylimidazo[1,2-a] pyrimidin-6-yl)-1,1- diphenylmethanimine. [0899] A mixture of 6-bromo-7-methoxy-2-methylimidazo[1,2-a] pyrimidine (500 mg, 2.06 mmol), diphenylmethanimine (411 mg, 2.27 mmol) BINAP (257 mg, 0.41 mmol) Pd(OAc)₂ (22 mg, 0.21 mmol) and Cs₂CO₃ (2.02 g, 6.2 mmol) in 1,4-dioxane (100 ml) was stirred at 120℃ for 16 h. The mixture was diluted with water (100 mL), extracted with EA (100 mL×3), the organic layer was concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 1: 3) to give title compound (658 mg, Y: 93%) as a brown solid. ESI-MS (M+H)⁺: 343.1. Step 4: Preparation of 7-methoxy-2-methylimidazo[1,2-a] pyrimidin-6-amine. [0900] A mixture of N-(7-methoxy-2-methylimidazo[1,2-a] pyrimidin-6-yl)-1,1- diphenylmethanimine (658 mg, 1.92 mmol) in 4M HCI/EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and diluted with aq Na₂CO₃ (20 mL), the mixture was stirred at rt for 30 min. Then extracted with EA (20 mL *2), the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give title compound (210 mg, Y:46%) as a yellow solid. ESI-MS (M+H) ⁺: 179.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.68 (d, J = 0.9 Hz, 1H), 4.10 (s, 3H), 2.35 (d, J = 0.8 Hz, 3H). Step 5: Preparation of tert-butyl 4-(1-((7-methoxy-2-methylimidazo[1,2-a] pyrimidin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0901] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (240 mg, 2 mmol) and 7-methoxy-2-methylimidazo[1,2-a] pyrimidin-6-amine (223.8 mg, 0.67mmol), TEA (204 mg,2 mmol) in THF (10 mL) was added triphosgent (400.4 mg, 1.3 mmol) at 0^oC, the mixture stirred at rt for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 4) to give title compound (156 mg, Y: 65%) as a white solid. ESI-MS (M+H) ⁺: 537.2^. Step 6: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methoxy-2-methylimidazo[1,2-a] pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide. [0902] A mixture of tert-butyl 4-(1-((7-methoxy-2-methylimidazo[1,2-a] pyrimidin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (136 mg, 0.25 mmol) in 4M HCI/EA (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / ACN) to give title product (17.06 mg, 15%) as a yellow solid. ESI-MS (M+H)⁺: 437.2¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 1H), 9.33 (s, 1H), 7.92 (d, J = 6.1 Hz, 1H), 7.47 (d, J = 0.9 Hz, 1H), 6.51 (d, J = 6.2 Hz, 1H), 5.95 (s, 1H), 4.07 (s, 3H), 3.98 (t, J = 8.5 Hz, 2H), 3.16 (d, J = 5.9 Hz, 2H), 3.11 (d, J = 8.7 Hz, 2H), 2.99 (s, 2H), 2.87 – 2.81 (m, 2H), 2.24 (s, 3H), 1.08 (s, 6H). Example 326 – Preparation of N-(2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

seae u e step 2 step 1

Step 1: Preparation of 2,7-dimethyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine. [0903] To a mixture of 2-chloro-4-methyl-5-nitropyridine (6 g, 34.88 mmol) and 5-methyl- 1,3,4-thiadiazol-2-amine (4.0 g, 34.88 mmol) in Tol (60 mL) was added DIEA (9.07 g, 69.76 mmol). The mixture was stirred at RT for 2 h in a sealed tube. The mixture was diluted with H₂O (100 mL) and extracted with EA (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (4 g, 59.72%) as a white solid. ESI-MS (M+H) ⁺: 193.1. Step 2: Preparation of 2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine. [0904] To a solution of 2,7-dimethyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine (4 g, 20.83 mmol) in MeOH (40 mL) was added Raney-Ni (1 g, 25%w.t). The mixture was stirred at RT for 16 h under H₂. The mixture was filtered and filtrate was concentrated in vacuo to give title compound (1.0 g, 29.62%) as a brown oil. ESI-MS (M+H)⁺:163.2. Step 3: Preparation of tert-butyl 4-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0905] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 2,7-dimethyl-[1,2,4]triazolo[1,5- a]pyridin-6-amine (73.19 mg, 0.45 mmol) in THF (10 mL) were added TEA (136.35 mg, 1.35 mmol) and triphosgene (266.40 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (50 mg, 21.37%) as a yellow solid. ESI-MS (M+H) ⁺: 521.3. Step 4: Preparation of N-(2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0906] A mixture of tert-butyl 4-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (50 mg, 0.1 mmol) in 3M HCl/EA (5 mL) was stirred at rt for 2h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in water / CH₃CN) to give title product (3.15 mg, 5.90%) as a yellow solid. ESI-MS (M+H) ⁺:421.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.52 (s, 1H), 8.00 (d, J = 5.9 Hz, 1H), 7.62 (s, 1H), 6.65 (d, J = 6.1 Hz, 1H), 4.20 – 4.13 (m, 2H), 3.59 – 3.53 (m, 2H), 3.45 – 3.42 (m, 2H), 3.38 – 3.36 (m, 2H), 3.27 – 3.23 (m, 2H), 2.62 (s, 3H), 2.55 (s, 3H), 1.51 (s, 6H).

Example 327 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 1,2-diamino-5-bromo-4-fluoropyridin-1-ium 2,4,6- trimethylbenzenesulfonate. [0907] To a solution of 5-bromo-4-fluoropyridin-2-amine (3 g, 15.71 mmol) in CHCl₃ (200 mL) was added O-(mesitylsulfonyl)hydroxylamine (8442 mg, 39.27 mmol) at 0 ^oC. The mixture was stirred at r.t for 2h. The precipitate was filtered, washed with with CHCl₃ (10 mL) to give title compound (5.3 g, yield: 83%) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ 8.60 (d, J = 6.7 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 6.75 (s, 2H), 2.50 (s, 6H), 2.17 (s, 3H). Step 2: Preparation of 6-bromo-7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine. [0908] To a solution of 1,2-diamino-5-bromo-4-fluoropyridin-1-ium 2,4,6- trimethylbenzenesulfonate (5 g, 12.32 mmol) in AcOH (50 mL) was added TsOH (424 mg, 2.46 mmol). The mixture was stirred at 100 ^oC for 16 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA= 3: 1) to give title compound (1.6 g, yield: 56%) as a white solid. ESI-MS (M+H)⁺: 230.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (d, J = 6.5 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 2.46 (s, 3H). Step 3: Preparation of N-(7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0909] A mixture of 6-bromo-7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (1 g, 4.35 mmol), Benzenemethanimine (1180 mg, 6.52 mmol), Pd(OAc)₂ (99 mg, 0.44 mmol) and BINAP (542 mg, 0.87 mmol) in 1,4-dioxane (20 mL) was purged with N₂ for three times at r.t. Then the mixture was stirred at 100 ^oC for 16 hours. The mixture was cooled to r.t, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:1) to provide title product (1.2 g, yield: 84%) as a yellow solid. ESI-MS (M+H)⁺: 331.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J = 7.2 Hz, 1H), 7.75 – 7.71 (m, 2H), 7.59 (dd, J = 11.7, 8.8 Hz, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.41 – 7.36 (m, 3H), 7.26 (dd, J = 7.3, 2.1 Hz, 2H), 2.37 (s, 3H). Step 4: Preparation of 4-methoxy-2-methylbenzo[d]oxazol-6-amine HCl salt. [0910] To a solution of N-(7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine (1 g, 3.03 mmol) in EtOAc (5 mL) was added 4M HCl/EtOAc (15 mL) at 0 ^oC. Then the mixture was stirred at r.t for 2 hours. The precipitate was filtered, washed with EtOAc to afford title product (630 mg, crude) as a white solid. ESI-MS (M+H)⁺: 167.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J = 7.1 Hz, 1H), 7.90 (d, J = 10.0 Hz, 1H), 6.29 (s, 3H), 2.53 (s, 3H). Step 5: Preparation of tert-butyl 4-(1-((7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0911] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) and 7-fluoro-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine (60 mg, 0.36 mmol) in THF (10 mL) were added TEA (1 mL) and a solution of triphosgene (134 mg, 0.45 mmol) in THF (1 mL) dropwise at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=4:1) to provide title product (100 mg, yield: 64%) as a white solid. ESI-MS (M+H)⁺: 525.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 9.45 (d, J = 6.8 Hz, 1H), 7.83 (d, J = 6.1 Hz, 1H), 7.79 (d, J = 10.9 Hz, 1H), 6.43 (d, J = 6.2 Hz, 1H), 4.01 – 3.95 (m, 2H), 3.74 – 3.69 (m, 2H), 3.60 – 3.56 (m, 2H), 3.55 (s, 2H), 3.31 (s, 2H), 2.44 (s, 3H), 1.44 (s, 9H), 1.38 (s, 6H). Step 6: Preparation of 4- dimethylpiperazin-1-yl)-N-(7-fluoro-2-methyl-

[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0912] To a solution of tert-butyl 4-(1-((7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (80 mg, 0.15 mmol) in EA (2 mL) was added 4M HCL/EtOAc (6 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (40 mg, yield: 63%) as a white solid. ESI-MS (M+H)⁺: 424.9.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 9.41 (s, 1H), 7.95 (s, 1H), 7.77 (d, J = 10.1 Hz, 1H), 6.65 (d, J = 4.3 Hz, 1H), 4.06 (t, J = 8.6 Hz, 2H), 3.50 (s, 2H), 3.33 (s, 2H), 3.29 (s, 2H), 3.20 (t, J = 8.1 Hz, 2H), 2.45 (s, 3H), 1.38 (s, 6H). Example 328 – Preparation of isopropyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate.

Step 1: Preparation of isopropyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [0913] To a solution of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (130 mg, 0.31 mmol) in THF (5 mL) were added TEA (0.5 mL) and isopropyl carbonochloridate (1891 mg, 15.5 mmol) at 0 ^oC for 5 h. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product. The mixture was diluted with H₂O (1 mL) and aq. Na₂CO₃ (1 mL) at RT for 0.5 h and extracted with DCM (1 mL×3). The organic layer was concentrated in vacuo to give title product (17.13 mg, 11 %) as a white solid. ESI-MS (M+H) ⁺:510.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 9.19 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 11.6 Hz, 1H), 6.41 (d, J = 6.2 Hz, 1H), 4.84 – 4.73 (m, 1H), 4.03 – 3.93 (m, 2H), 3.77 – 3.69 (m, 2H), 3.63 – 3.53 (m, 4H), 3.31 – 3.26 (m, 2H), 2.28 (s, 3H), 1.39 (s, 6H), 1.21 (d, J = 6.2 Hz, 6H). [0914] Example 329 – Preparation of 1-(isobutyryloxy)ethyl 4-(1-((7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,2-dimethylpiperazine-1-carboxylate.

Step 1: Preparation of pentyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [0915] To a mixture of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (150 mg, 0.35 mmol) in DMF (10 mL) were added TEA (107 mg, 1.06 mmol), 1-(((4- nitrophenoxy)carbonyl)oxy)ethyl isobutyrate (316 mg, 1.06 mmol). The reaction mixture was stirred at r.t for 16 h. Concentration under reduced pressure, the residue was purified by prep- HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title compound (66.43 mg, 32 %) as a white solid. ESI-MS (M+H) ⁺:582.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.15 (d, J = 7.1 Hz, 1H), 7.83 (d, J = 6.2 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 11.0 Hz, 1H), 6.78 (d, J = 5.4 Hz, 1H), 6.39 (d, J = 6.2 Hz, 1H), 4.09 – 4.03 (m, 2H), 3.87 – 3.81 (m, 2H), 3.64 – 3.59 (m, 2H), 3.57 (s, 2H), 3.35 – 3.33 (m, 2H), 2.60 – 2.50 (m, 1H), 2.36 (s, 3H), 1.50 (d, J = 5.4 Hz, 3H), 1.47 (d, J = 5.5 Hz, 6H), 1.16 (d, J = 2.7 Hz, 3H), 1.14 (d, J = 2.7 Hz, 3H). Example 330 – Preparation of pentyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate.

Step 1: Preparation of pentyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [0916] To a mixture of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (50 mg, 0.12 mmol) in THF (5 mL) were added TEA (304 mg, 3.00 mmol), pentyl carbonochloridate (217 mg, 1.44 mmol) (in THF (1 mL)) in 0℃. The reaction mixture was stirred at r.t for 16 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title compound (5.9 mg, 9 %) as a white solid. ESI-MS (M+H) ⁺:538.3.¹H NMR (400 MHz, MeOD-d₄) δ 9.15 (d, J = 7.1 Hz, 1H), 7.83 (d, J = 6.1 Hz, 1H), 7.52 (s, 1H), 7.22 (d, J = 11.0 Hz, 1H), 6.39 (d, J = 6.2 Hz, 1H), 4.12 – 4.03 (m, 4H), 3.87 – 3.82 (m, 2H), 3.63 – 3.58 (m, 2H), 3.56 (s, 2H), 2.36 (s, 3H), 1.71 – 1.64 (m, 2H), 1.47 (s, 6H), 1.41 – 1.36 (m, 4H), 1.31 (d, J = 18.2 Hz, 2H), 0.94 (t, J = 7.1 Hz, 3H). Example 331 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. [0917] A mixture of4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2 g, 12.94 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3293 mg, 15.53 mmol) was stirred at 140 ^oC for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH = 5:1) to provide title product (730 mg, yield: 17%) as a white solid. ESI-MS (M+H) ⁺:331.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (d, J = 5.9 Hz, 1H), 6.02 (d, J = 6.0 Hz, 1H), 4.17 (s, 2H), 3.37 (d, J = 8.0 Hz, 4H), 2.99 (t, J = 8.4 Hz, 2H), 2.86 (d, J = 11.3 Hz, 2H), 1.79 (d, J = 10.9 Hz, 4H), 1.42 (s, 9H). Step 2: Preparation of tert-butyl (S)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0918] To a solution of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.45 mmol) and 7-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (90 mg, 0.55 mmol) in THF (10 mL) were added TEA (2 mL) and a solution of triphosgene (202 mg, 0.18 mmol) in THF (1 mL) dropwise at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:3) to provide title product (100 mg, yield: 43%) as a brown solid. ESI-MS (M+H)⁺: 522.2. Step 3: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0919] To a solution of tert-butyl 3-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (40 mg, 0.08 mmol) in EtOAc (0.5 mL) was added 4M HCl/EtOAc (1.5 mL) at room temperature. The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (26 mg, yield: 77%) as a white solid. ESI-MS (M+H)⁺:421.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.46 (s, 1H), 9.68 (d, J = 6.6 Hz, 1H), 9.07 (d, J = 17.0 Hz, 2H), 8.17 (s, 1H), 8.09 (d, J = 10.0 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.59 (d, J = 6.2 Hz, 1H), 4.14 (s, 2H), 4.05 (t, J = 8.5 Hz, 2H), 3.70 (d, J = 12.0 Hz, 2H), 3.29 (d, J = 12.4 Hz, 2H), 3.23 (t, J = 8.5 Hz, 2H), 2.45 (d, J = 0.9 Hz, 3H), 1.97 (s, 4H). Example 332 – Preparation of 4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,9- diazabicyclo[3.3.1]nonane-9-carboxylate. [0920] To a solution of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (573 mg, 3.72 mmol) and tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (840 mg, 3.72 mmol) in DIEA (998 mg, 7.74 mmol) was stirred at 140 ^oC for 16 h in a sealed tube. The mixture was concentrated in vacuo and diluted with H₂O (5 mL), extracted DCM (5mL*3). The organic layer was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1, DCM: MeOH= 10: 1) to give title product (130 mg, 12%) as a white solid. ESI-MS (M+H) ⁺: 345.3. Step 2: Preparation of tert-butyl 3-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9- carboxylate. [0921] To a solution of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,9- diazabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.29 mmol) and 7-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (72 mg, 0.43 mmol) in THF (5 mL) were added TEA (0.5 mL) and triphosgene (103 mg, 0.35 mmol) at 0 ^oC . The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA =0: 1) to give title product (90 mg, 58%) as a white solid. ESI-MS (M+H) ⁺: 536.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (d, J = 2.1 Hz, 1H), 9.20 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.73 (d, J = 4.2 Hz, 1H), 7.42 (d, J = 11.6 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.16 – 4.08 (m, 2H), 4.05 – 3.99 (m, 2H), 3.87 – 3.74 (m, 2H), 3.26 – 3.21 (m, 2H), 3.16 – 3.11 (m, 2H), 2.29 (s, 3H), 1.84 – 1.71 (m, 4H), 1.67 – 1.60 (m, 1H), 1.44 (s, 9H), 1.40 – 1.34 (m, 1H). Step 3: Preparation of 4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0922] To a solution of tert-butyl 3-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9- carboxylate (80 mg, 0.15 mmol) in EA (1 mL) was added 4M HCl / EA (3 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (21.52 mg, yield: 32 %) as a white solid. ESI-MS (M+H) ⁺: 436.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (d, J = 1.9 Hz, 1H), 9.19 (d, J = 7.4 Hz, 1H), 8.27 (s, 1H), 7.88 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.42 (d, J = 11.6 Hz, 1H), 6.51 (d, J = 6.2 Hz, 1H), 4.03 – 3.98 (m, 2H), 3.78 – 3.75 (m, 2H), 3.30 – 3.21 (m, 6H), 2.29 (s, 3H), 2.25 – 2.14 (m, 1H), 1.94 – 1.76 (m, 4H), 1.57 – 1.46 (m, 1H). Example 333 – Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- isopropylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- isopropylpiperazine-1-carboxylate. [0923] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.90 mmol) and tert-butyl (R)-2-isopropylpiperazine-1-carboxylate (888.31 mg, 3.90 mmol) in DIEA (5 mL) was stirred at 145 ^oC for 36 h in a sealed tube. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (10 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (300 mg, 22.23%) as a yellow solid. ESI-MS (M+H) ⁺: 347.3. Step 2: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-isopropylpiperazine-1- carboxylate. [0924] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- isopropylpiperazine-1-carboxylate (300 mg, 0.87 mmol), 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine hydrochloride (174.28 mg, 0.87 mmol) in THF (10 mL) were added TEA (263.61 mg, 2.61 mmol) and triphosgene (515.04 mg, 1.74 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (70 mg, 14.98%) as a yellow solid. ESI-MS (M+H) ⁺: 538.2. Step 3: Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- isopropylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0925] A mixture of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-isopropylpiperazine-1- carboxylate (70 mg, 0.13 mmol) in 3M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (3.79 mg, 6.04%) as a yellow solid. ESI-MS (M+H) ⁺:437.9.¹H NMR (400 MHz, MeOD-d₄) δ 9.18 (d, J = 7.1 Hz, 1H), 8.41 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.54 (s, 1H), 7.24 (d, J = 11.0 Hz, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.14 – 4.04 (m, 2H), 3.92 – 3.77 (m, 2H), 3.47 – 3.41 (m, 1H), 3.27 – 3.21 (m, 1H), 3.19 – 3.08 (m, 4H), 2.98 – 2.88 (m, 1H), 2.36 (s, 3H), 2.01 – 1.89 (m, 1H), 1.12 (dd, J = 9.4, 6.9 Hz, 6H). [0926] Example 334 – Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- isopropylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- isopropylpiperazine-1-carboxylate. [0927] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (400 mg, 2.58 mmol) in DIEA (998 mg, 7.74 mmol) was added tert-butyl (S)-2-isopropylpiperazine-1-carboxylate (647 mg, 2.84 mmol). The reaction mixture was stirred at 140℃ for 16 h in a sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mLx3). The combined organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=2:1) to give title product (500 mg, yield: 56 %) as a brown solid. ESI-MS (M+H) ⁺:347.2. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 6.2 Hz, 1H), 6.08 (d, J = 6.2 Hz, 1H), 4.05 – 4.04 (m, 1H), 3.75 (dd, J = 7.8, 5.4 Hz, 1H), 3.62 (dd, J = 16.6, 8.3 Hz, 3H), 3.48 (d, J = 10.4 Hz, 1H), 3.11 – 2.99 (m, 3H), 2.92 – 2.85 (m, 2H), 2.29 – 2.18 (m, 1H), 1.48 (s, 9H), 0.99 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). Step 2: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-isopropylpiperazine-1- carboxylate. [0928] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- isopropylpiperazine-1-carboxylate (100 mg, 0.29 mmol) in THF (20 mL) were added 7- fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (88 mg, 0.43 mmol), TEA (734 mg, 7.25 mmol) and triphosgene (103 mg, 0.35 mmol) (in THF ( 1 mL)) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (80 mg, yield: 51 %) as a white solid. ESI-MS (M+H) ⁺:537.9.¹H NMR (400 MHz, CDCl₃) δ 12.11 (d, J = 2.1 Hz, 1H), 9.16 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.25 (s, 1H), 7.18 (d, J = 11.1 Hz, 1H), 6.37 (d, J = 6.1 Hz, 1H), 4.16 (td, J = 8.6, 2.4 Hz, 2H), 3.66 (d, J = 12.6 Hz, 1H), 3.17 – 3.11 (m, 2H), 3.07 (d, J = 6.7 Hz, 2H), 3.01 – 2.79 (m, 4H), 2.41 (s, 3H), 2.26 – 2.21 (m, 1H), 1.48 (s, 9H), 1.01 – 0.99 (m, 3H), 0.89 – 0.86 (m, 3H). Step 3: Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- isopropylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0929] To a mixture of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-isopropylpiperazine-1- carboxylate (60 mg, 0.11 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title compound (14.94 mg, 24 %) as a white solid. ESI-MS (M+H) ⁺:437.9.¹H NMR (400 MHz, MeOD-d₄) δ 9.63 (d, J = 6.5 Hz, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.79 (d, J = 9.7 Hz, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.22 – 4.11 (m, 2H), 4.00 – 3.85 (m, 2H), 3.52 – 3.47 (m, 1H), 3.35 – 3.33 (m, 1H), 3.27 – 3.16 (m, 4H), 3.08 – 2.95 (m, 1H), 2.51 (d, J = 0.8 Hz, 3H), 2.04 – 1.93 (m, 1H), 1.14 (dd, J = 8.7, 6.9 Hz, 6H). Example 335 – Preparation of (S)-4-(3-ethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- ethylpiperazine-1-carboxylate. [0930] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (400 mg, 2.58 mmol) in DIEA (998 mg, 7.74 mmol) was added tert-butyl (S)-2-ethylpiperazine-1-carboxylate (607 mg, 2.84 mmol). The reaction mixture was stirred at 140℃ for 16 h in a sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mLx3). The combined organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=2:1) to give title product (600 mg, yield: 70 %) as a brown solid. ESI-MS (M+H) ⁺:333.0. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 6.6 Hz, 1H), 6.04 (d, J = 6.7 Hz, 1H), 3.68 (t, J = 8.5 Hz, 2H), 3.56 (t, J = 11.4 Hz, 2H), 3.14 – 3.07 (m, 4H), 2.98 (dt, J = 11.9, 5.9 Hz, 1H), 2.88 (d, J = 8.4 Hz, 1H), 1.82 (dt, J = 15.1, 7.6 Hz, 1H), 1.59 (dt, J = 13.8, 7.8 Hz, 1H), 1.48 (s, 9H), 0.91 (t, J = 7.4 Hz, 3H). Step 2: Preparation of tert-butyl (S)-2-ethyl-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0931] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- ethylpiperazine-1-carboxylate (120 mg, 0.36 mmol) in THF (20 mL) were added 7-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine hydrochloride (110 mg, 0.54 mmol), TEA (728 mg, 7.20 mmol) and triphosgene (128 mg, 0.43F mmol) (in THF ( 1 mL)) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=2:1) to give title product (60 mg, yield: 31 %) as a brown solid. ESI-MS (M+H) ⁺:523.8.¹H NMR (400 MHz, CDCl₃) δ 12.11 (d, J = 2.1 Hz, 1H), 9.16 (d, J = 7.1 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.25 (s, 1H), 7.19 (d, J = 11.1 Hz, 1H), 6.36 (d, J = 6.1 Hz, 1H), 4.15 (d, J = 8.4 Hz, 2H), 4.05 – 4.04 (m, 1H), 3.51 (d, J = 12.2 Hz, 3H), 3.18 – 3.10 (m, 3H), 3.05 (dd, J = 12.6, 3.7 Hz, 1H), 2.97 – 2.91 (m, 1H), 2.41 (s, 3H), 1.63 – 1.61 (m, 2H), 1.49 (s, 9H), 0.93 (t, J = 7.4 Hz, 3H). Step 3: Preparation of ((S)-4-(3-ethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. To a mixture of tert-butyl (S)-2-ethyl-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (40 mg, 0.076 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep- HPLC (0.1% FA in H₂O / ACN) to give title compound (7.85 mg, 22 %) as a white solid. ESI-MS (M+H) ⁺:424.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.16 (d, J = 7.0 Hz, 1H), 8.43 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 11.0 Hz, 1H), 6.56 (d, J = 6.0 Hz, 1H), 4.16 – 4.03 (m, 2H), 3.88 – 3.74 (m, 2H), 3.47 – 3.41 (m, 1H), 3.28 – 3.11 (m, 5H), 2.97 – 2.87 (m, 1H), 2.36 (s, 3H), 1.80 – 1.66 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H). Example 338 – Preparation of N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-((3R,5S)- 3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [0932] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (100 mg, 0.3 mmol) and TEA (1mL) in THF (8 mL) was added triphosgene (178 mg, 0.6 mmol) at 0^oC, the mixture was stirred at RT for 1 h.2,7- dimethylimidazo[1,2-a]pyrimidin-6-amine (49 mg, 0.3 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (MeOH: DCM = 1: 10) to give title product (80 mg, Y: 51.3.0%) as a yellow solid. ESI-MS (M+H) ⁺: 520.9. Step 2: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyrimidin-6-yl)-4-((3R,5S)-3,5- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0933] A mixture of tert-butyl (2R,6S)-4-(1-((2,7-dimethylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (60 mg, 0.12 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (48.35 mg, Y: 99.8 %) as a white solid. ESI-MS (M+H) ⁺: 421.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (s, 1H), 9.83 (s, 1H), 9.22 (s, 1H), 8.61 (d, J = 10.3 Hz, 1H), 8.03 (dd, J = 10.5, 3.6 Hz, 2H), 6.72 (d, J = 6.2 Hz, 1H), 4.08 – 4.02 (m, 2H), 3.94 – 3.87 (m, 2H), 3.46 – 3.34 (m, 2H), 3.29 – 3.18 (m, 2H), 2.98 – 2.86 (m, 2H), 2.79 (s, 3H), 2.47 (d, J = 0.9 Hz, 3H), 1.27 (d, J = 6.5 Hz, 6H). [0934]

Example 339 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy-2- methylimidazo[1,2-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide diformate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyrimidin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [0935] To a solution of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (50 mg, 0.15 mmol) and 7-methoxy-2-methylimidazo[1,2- a]pyrimidin-6-amine (27 mg, 0.15 mmol) in THF (5 mL) were added TEA (0.5 mL) and a solution of triphosgene (67 mg, 0.23 mmol) in THF (0.5 mL) dropwise at 0 ^oC. The mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH = 40: 1) to provide title product (90 mg, crude) as a yellow solid. ESI-MS (M+H)⁺:536.9.¹H NMR (400 MHz, CDCl₃) δ 12.05 (s, 1H), 9.26 (s, 1H), 7.96 (d, J = 6.1 Hz, 1H), 7.03 (s, 1H), 6.41 (d, J = 6.0 Hz, 1H), 4.29 – 4.24 (m, 4H), 4.18 (s, 3H), 4.15 (d, J = 8.7 Hz, 2H), 3.45 (d, J = 12.3 Hz, 2H), 3.03 (d, J = 7.9 Hz, 2H), 2.39 (s, 3H), 1.44 (s, 9H), 1.36 (d, J = 3.7 Hz, 6H). Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy-2- methylimidazo[1,2-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate. [0936] To a solution of tert-butyl (2R,6S)-4-(1-((7-methoxy-2-methylimidazo[1,2- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in H₂O / ACN) to give title compound (11.74 mg, yield: 18%) as a white solid. ESI-MS (M+H)⁺: 436.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 9.32 (s, 1H), 8.20 (s, 2H), 7.92 (d, J = 6.1 Hz, 1H), 7.46 (s, 1H), 6.54 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 3.97 (d, J = 8.9 Hz, 2H), 3.65 (d, J = 11.5 Hz, 2H), 3.15 (t, J = 8.5 Hz, 2H), 2.92 (s, 2H), 2.46 (s, 2H), 2.24 (s, 3H), 1.06 (d, J = 6.3 Hz, 6H). Example 340 – Preparation of N-(7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6-yl)-4- (4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 7-(1-((7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0937] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (40 mg, 0.13 mmol), 7-methoxy-2-methylimidazo[1,2- a]pyrimidin-6-amine (22.4 mg, 0.13 mmol) and TEA (252 mg, 2.5 mmol) in THF (6 mL) was added triphosgene (74 mg, 0.25 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA= 1: 4) to give title product (50 mg, Y: 78.0%) as a yellow solid. ESI-MS (M+H) ⁺: 535.4. Step 2: Preparation of N-(7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0938] A mixture of tert-butyl 7-(1-((7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (40 mg, 0.07 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (13 mg, Y: 40.07%) as a yellow solid. ESI-MS (M+H) ⁺: 435.1. ¹H NMR (400 MHz, DMSO-d₆) δ 12.46 (s, 1H), 9.67 (s, 1H), 9.30 (s, 2H), 8.05 (d, J = 6.0 Hz, 1H), 7.87 (d, J = 1.1 Hz, 1H), 6.65 (d, J = 6.2 Hz, 1H), 4.24 (s, 3H), 4.03 (t, J = 8.5 Hz, 2H), 3.61 – 3.58 (m, 2H), 3.39 – 3.27 (m, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.39 (d, J = 1.0 Hz, 3H), 1.10 – 0.89 (m, 4H). Example 341 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2,6- dimethylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

n Step 1 rt, 16 h RT,16h S_{tep 2 Step 3}

Step 1: Preparation of 3-methylpyridin-4-amine. [0939] A mixture of 3-methyl-4-nitropyridine (11 g, 79.14 mol) in MeOH (220 mL) was added Pd/C (2.2 g, 20%), the mixture was stirred at 50 ^oC for 16 h under H₂. The mixture was filtered and the filtrate was concentrated in vacuo to give title product (9.8 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 109.0. Step 2: Preparation of tert-butyl (3-methylpyridin-4-yl)carbamate. [0940] A mixture of 3-methylpyridin-4-amine (18 g, 166.67 mol), (Boc)₂O (39.9 g, 183.33 mmol), DMAP (4.01 g, 33.33 mmol) and TEA (50.5 g, 500.01 mmol) in THF (500 mL) was stirred at RT for 16 h. The mixture was concentrated in vacuo. The mixture was diluted with water (100 mL), extracted with DCM (100 mL×3). The organic layer was washed with brine (100 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 70 %) to give title product (33 g, yield: 95.19 %) as an orange solid. ESI-MS (M+H) ⁺: 209.3.¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J = 5.6 Hz, 1H), 8.29 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 2.21 (s, 3H), 1.54 (s, 9H). Step 3: Preparation of 1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-ium 2,4- dinitrophenolate. [0941] A mixture of tert-butyl (3-methylpyridin-4-yl)carbamate(32 g, 0.154 mol), O-(2,4- dinitrophenyl)hydroxylamine (30.6 g, 0.154 mol) was stirred at 40 ^oC for 5 h. Then the mixture was stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (56 g, crude) as a yellow solid. ESI-MS (M+CH₃CN) ⁺: 224.1. Step 4: Preparation of ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5- a]pyridine-3-carboxylate. [0942] A mixture of 1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-ium 2,4- dinitrophenolate (17 g, 105.65 mol), ethyl but-2-ynoate (13 g, 116.21 mol), K₂CO₃ (21 g, 158.4 mol) in DMF (20 mL) was stirred at RT for 16 h. The mixture was diluted with water (100 mL), extracted with DCM (100 mL×3). The organic layer was washed with brine (100 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 100 %) to give title product (11 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 334.1. Step 5: Preparation of 2,6-dimethylpyrazolo[1,5-a]pyridin-5-amine. [0943] A mixture of ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5- a]pyridine-3-carboxylate(1.7 g, 5.10 mol) in HBr (25 mL) was stirred at 100 ^oC for 16 h. The mixture was diluted with water (200 mL), adjusted pH to 7~8 by Na₂CO₃, the precipitate was filtered and dried to give title product (660 mg, 79.88 %) as a yellow solid. ESI-MS (M+H) ⁺: 162.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 6.37 (s, 1H), 5.75 (s, 1H), 5.30 (s, 2H), 2.22 (s, 3H), 2.05 (d, J = 0.5 Hz, 3H). Step 6: Preparation of tert-butyl (2R,6S)-4-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [0944] A mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mol), 2,6-dimethylpyrazolo[1,5-a]pyridin-5- amine (57.96 mg, 0.36 mmol), triphosgene (107 mg, 0.36 mmol) and TEA (364 mg, 3.61 mmol) in THF (5 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL) and the precipitate was filtered to afford title product (70 mg, crude) as a white solid. ESI-MS (M+H) ⁺: 520.2. Step 7: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2,6-dimethylpyrazolo[1,5- a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0945] A mixture of tert-butyl (2R,6S)-4-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (70 mg, 0.13 mmol) in 3M HCl / EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (5.36 mg, yield: 9.8 %) as an off-white solid. ESI-MS (M+H) ⁺: 420.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.88 (d, J = 6.1 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 6.16 (s, 1H), 3.99 (t, J = 8.5 Hz, 2H), 3.63 (d, J = 12.1 Hz, 2H), 3.17 – 3.13 (m, 2H), 2.88 – 2.81 (m, 2H), 2.45 – 2.40 (m, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 1.02 (d, J = 6.2 Hz, 6H). Example 342 – Preparation of (S)-N-(2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

C^{ompound 342} Step 1: Preparation of tert-butyl (S)-4-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0946] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) in THF (5 mL) were added TEA (143 mg, 1.42 mmol), triphosgene (168 mg, 0.57 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.2,6-dimethylpyrazolo[1,5-a]pyridin-5-amine hydrochloride (112 mg, 0.57 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (60 mg, Y: 25.2 %) as a yellow solid. ESI-MS (M+H) ⁺:506.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 7.93 (d, J = 5.9 Hz, 1H), 6.54 (d, J = 5.9 Hz, 1H), 6.17 (s, 1H), 3.82 – 3.75 (m, 2H), 3.69 – 3.64 (m, 2H), 3.63 – 3.57 (m, 2H), 3.11 – 3.06 (m, 2H), 2.99 – 2.91 (m, 3H), 2.35 (s, 3H), 2.32 (s, 3H), 1.43 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H). Step 2: Preparation of (S)-N-(2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [0947] To a solution of tert-butyl (S)-4-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t for 2 h and concentrated in vacuo.The crude was purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (30.88 mg, 60.1 %) as a white solid. ESI-MS (M+H)⁺:406.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 9.15 – 9.05 (m, 1H), 8.82 – 8.71 (m, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 7.96 (d, J = 5.8 Hz, 1H), 6.63 (d, J = 6.0 Hz, 1H), 6.17 (s, 1H), 4.02 (t, J = 8.5 Hz, 2H), 3.80 (d, J = 12.0 Hz, 2H), 3.38 (d, J = 9.7 Hz, 2H), 3.20 – 3.13 (m, 4H), 3.02 – 2.95 (m, 1H), 2.33 (d, J = 9.1 Hz, 6H), 1.27 (d, J = 6.4 Hz, 3H). Example 343 – Preparation of (R)-N-(2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

C^{ompound 343} Step 1: Preparation of tert-butyl (R)-4-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0948] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) in THF (20 mL) were added TEA (314 mg, 3.10 mmol) and triphosgene (111 mg, 0.37 mmol) (in THF (1 mL )) in 0 ℃. The reaction mixture was stirred at r.t for 1 h. Then 2,6-dimethylpyrazolo[1,5-a]pyridin-5-amine (73 mg, 0.37 mmol) was added to the reaction solution and stirred at r.t for16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=2:1) to give title product (70 mg, yield: 44 %) as a white solid. ESI-MS (M+H) ⁺:506.2.¹H NMR (400 MHz, CDCl₃) δ 11.83 (s, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 6.35 (d, J = 6.1 Hz, 1H), 6.11 (s, 1H), 4.35 – 4.34 (m, 1H), 4.22 – 4.15 (m, 2H), 3.97 (d, J = 12.9 Hz, 1H), 3.53 (d, J = 12.3 Hz, 1H), 3.44 (d, J = 12.2 Hz, 1H), 3.28 – 3.21 (m, 1H), 3.11 (dd, J = 18.5, 9.6 Hz, 3H), 2.97 (dd, J = 11.9, 3.6 Hz, 1H), 2.43 (s, 3H), 2.38 (s, 3H), 1.56 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (R)-N-(2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0949] To a mixture of tert-butyl (R)-4-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.098 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (26.27 mg, 48%) as a white solid. ESI-MS (M+H) ⁺:406.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.89 (d, J = 6.1 Hz, 1H), 6.57 – 6.51 (m, 1H), 6.16 (s, 1H), 4.01 – 3.97 (m, 2H), 3.63 – 3.60 (m, 2H), 3.16 – 3.11 (m, 2H), 3.01 – 2.97 (m, 1H), 2.94 – 2.74 (m, 4H), 2.34 (s, 3H), 2.31 (s, 3H), 1.05 (d, J = 6.3 Hz, 3H). Example 344 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2,6- dimethylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

C^{ompound 344} Step 1: Preparation of tert-butyl 4-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [0950] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (120 mg, 0.36 mmol), 2,6-dimethylpyrazolo[1,5-a]pyridin- 5-amine hydrochloride (71.20 mg, 0.36 mmol) in THF (10 mL) were added TEA (109.08 mg, 1.08 mmol) and triphosgene (213.12 mg, 0.72 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (60 mg, 32.11%) as a white solid. ESI-MS (M+H) ⁺: 520.3. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2,6-dimethylpyrazolo[1,5-a]pyridin- 5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0951] A mixture of tert-butyl 4-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (60 mg, 0.12 mmol) in 3M HCl/EA (5 mL) was stirred at rt for 2h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (5.41 mg, 9.70%) as a white solid. ESI-MS (M+H) ⁺:420.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.52 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 6.57 (d, J = 6.1 Hz, 1H), 6.17 (s, 1H), 4.14 – 4.08 (m, 2H), 3.42 – 3.39 (m, 2H), 3.23 – 3.22 (m, 2H), 3.22 – 3.11 (m, 4H), 2.40 (s, 3H), 2.38 (s, 3H), 1.41 (s, 6H). Example 345 – Preparation of N-(2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

C^{ompound 345} Step 1: Preparation of tert-butyl 7-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [0952] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mol), 2,6-dimethylpyrazolo[1,5-a]pyridin- 5-amine (58 mg, 0.36 mmol), triphosgene (107 mg, 0.36 mmol) and TEA (364 mg, 3.61 mmol) in THF (5 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O and the precipitate was filtered to afford title product (100 mg, crude) as a white solid. ESI-MS (M+H) ⁺: 518.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.90 (d, J = 6.1 Hz, 1H), 6.53 (d, J = 6.1 Hz, 1H), 6.16 (s, 1H), 3.98 (t, J = 8.5 Hz, 2H), 3.58 – 3.55 (m, 2H), 3.30 – 3.28 (m, 2H), 3.13 – 3.09 (m, 4H), 2.34 (s, 3H), 2.31 (s, 3H), 1.42 (s, 9H), 0.95 – 0.93 (m, 2H), 0.86 – 0.84 (m, 2H). Step 2: Preparation of N-(2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0953] A mixture of tert-butyl 7-(1-((2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.19 mmol) in 3M HCl /EA (3 mL) was stirred at RT for 2 h. [0954] The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (37.15 mg, yield: 46.89 %) as a pink-white solid. ESI-MS (M+H) ⁺: 418.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 6.50 (d, J = 6.2 Hz, 1H), 6.16 (s, 1H), 4.00 – 3.95 (m, 2H), 3.26 – 3.24 (m, 2H), 3.12 – 3.06 (m, 4H), 2.88 – 2.85 (m, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 0.50 (d, J = 12.4 Hz, 4H). Example 346 – Preparation of 4-(8-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-fluoro- 2-methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of 4-(8-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0955] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (50 mg, 0.12 mmol) in MeOH (10 mL) were added MeCHO (27 mg, 0.60 mmol), CH₃COOH (43 mg, 0.72 mmol). The mixture was stirred at r.t for 1 h, NaBH₃CN (23 mg, 0.36 mmol) was added to the mixture and stirred at r.t for 16 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (11.41 mg, yield: 19 %) as a white solid. ESI-MS (M+H) ⁺:449.9.¹H NMR (400 MHz, MeOD-d₄) δ 9.19 (d, J = 7.1 Hz, 1H), 8.40 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.56 (s, 1H), 7.26 (d, J = 10.9 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 4.14 – 4.02 (m, 4H), 3.76 (d, J = 11.9 Hz, 2H), 3.39 – 3.35 (m, 2H), 3.26 – 3.21 (m, 2H), 3.17 – 3.10 (m, 2H), 2.37 (s, 3H), 2.30 – 2.20 (m, 2H), 2.20 – 2.09 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H). Example 347 – Preparation of 4-(8-(cyclopropylmethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 4-(8-(cyclopropylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7- fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate. [0956] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (50 mg, 0.12 mmol) in MeOH/THF (2 mL/2 mL) were added cyclopropanecarbaldehyde (103 mg, 0.59 mmol) and HOAc (33 mg, 0.36 mmol). The mixture was stirred at r.t for 1h. NaBH₃CN (37 mg, 0.59 mmol) was added to the mixture and stirred at 50 ^oC for 16h. The mixture was purified by prep-TLC (DCM: MeOH = 20: 1) and prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (1.20 mg, yield: 2%) as a white solid. ESI-MS (M+H)⁺: 476.1.¹H NMR (400 MHz, MeOD-d₄) δ 9.62 (d, J = 6.5 Hz, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.91 (s, 1H), 7.77 (d, J = 9.8 Hz, 1H), 6.60 (d, J = 6.1 Hz, 1H), 4.30 (s, 2H), 4.20 – 4.11 (m, 2H), 3.84 (d, J = 12.3 Hz, 2H), 3.48 – 3.43 (m, 2H), 3.26 (s, 2H), 3.06 (d, J = 6.8 Hz, 2H), 2.51 (s, 3H), 2.27 (s, 2H), 2.20 (d, J = 9.6 Hz, 2H), 1.17 – 1.15 (m, 1H), 0.81 (q, J = 6.0 Hz, 2H), 0.50 (t, J = 5.3 Hz, 2H). Example 348 – Preparation of (R)-4-(3-ethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide TFA salt.

Step 1: Preparation of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- ethylpiperazine-1-carboxylate. [0957] To a mixture of tert-butyl (R)-2-ethylpiperazine-1-carboxylate (900 mg, 4.21 mmol) in DIEA (1 mL) was added 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (543 mg, 3.50 mmol). The mixture was stirred at 140^oC for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA = 100:0 to 0:100, DCM: MeOH = 100: 0 to 95: 5) to give the title compound (600 mg, Y: 51.6 %) as a white solid. ESI-MS (M+H) ⁺:333.2. Step 2: Preparation of tert-butyl (R)-2-ethyl-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [0958] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- ethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) in THF (5 mL) were added TEA (136 mg, 1.35 mmol), triphosgene (161 mg, 0.54 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (89 mg, 0.54 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (60 mg, Y: 24.9 %) as a white solid. ESI-MS (M+H) ⁺: 524.3. Step 3: Preparation of (R)-4-(3-ethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide TFA salt. [0959] To a solution of tert-butyl (R)-2-ethyl-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t for 2 h and concentrated in vacuo. The crude was purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (25.19 mg, 56.2 %) as a white solid. ESI-MS (M+H)⁺:424.1.¹H NMR (400 MHz, CDCl₃) δ 9.30 (d, J = 7.2 Hz, 1H), 8.99 (s, 2H), 7.96 (d, J = 6.0 Hz, 1H), 7.82 (s, 1H), 7.57 (d, J = 11.3 Hz, 1H), 6.65 (d, J = 6.2 Hz, 1H), 4.03 (t, J = 8.5 Hz, 2H), 3.83 (t, J = 11.5 Hz, 2H), 3.39 – 3.35 (m, 2H), 3.20 – 3.12 (m, 4H), 2.97 (dd, J = 13.7, 10.6 Hz, 1H), 2.32 (s, 3H), 1.69 – 1.58 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H). Example 349 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-b] pyridazin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 2,2-dimethyl-4-(1-((2-methylimidazo[1,2-b] pyridazin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate. [0960] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 2-methylimidazo[1,2-b] pyridazin-6- amine (89 mg, 0.61 mmol) and TEA (1 mL) in THF (10 mL) was added triphosgene (179 mg, 0.60 mmol) at 0^oC and the mixture was stirred at RT for 16h. The mixture was concentrated in vacuo and diluted with water (10 mL), extracted with EA (10 mL×3). The organic layer washed with brine, dried with Na₂ SO₄ and concentrated in vacuo to give crude. The crude was purified by silica gel column (PE: EA = 1: 3) to give title product (70 mg, Y: 46.0%) as a yellow solid. ESI-MS (M+H) ⁺: 507.2. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-b] pyridazine -6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate. [0961] A mixture of tert-butyl 2,2-dimethyl-4-(1-((2-methylimidazo[1,2-b] pyridazin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (70 mg, 0.13 mmol) in 4M HCI/EA (2 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % FA in water / CH₃CN) to give title product (14.24 mg, 23%) as a yellow solid. ESI-MS (M+H) ⁺: 407.2.¹H NMR (400 MHz, DMSO-d₆) δ12.42 (s, 1H), 8.26 (s, 1H), 8.04 – 7.96 (m, 2H), 7.96 – 7.94 (m, 1H), 7.91 (s, 1H), 6.55 (d, J = 6.2 Hz, 1H), 4.00 (t, J = 8.0 Hz, 2H), 3.29 – 3.19 (m, 2H), 3.13 (t, J = 8.5 Hz 2H), 3.08 (s, 2H), 2.98 – 2.89 (m, 2H), 2.35 (s, 3H), 1.15 (s, 6H). [0962] Example 350 – Preparation of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)-4-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide diformate.

Step 1: Preparation of 2-chloro-4-(difluoromethyl)pyridine. [0963] To a solution of 2-chloroisonicotinaldehyde (25 g, 177.30 mmol) in DCM (250 mL) was added DAST (71.37 g, 443.26 mmol) drop-wise over 15 minutes below 5 °C. Then the solution was stirred allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was gradually added to saturated sodium hydrogen carbonate solution (100 mL) and ice (250 mL), making sure that the pH of the solution was >7 at all times. After 30 minutes the mixture was diluted with DCM (200mL) and water (200 mL) and the organic phase separated. The aqueous phase was further extracted with DCM (2 x 200mL). The organic phase was washed with brine (10 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/10) to afford title product (20 g, 68.93%) as a yellow solid. ESI-MS (M+H) ⁺: 164.0. Step 2: Preparation of N- (difluoromethyl)pyridin-2-yl)-1,1-diphenylmethanimine.

[0964] To a mixture of 2-chloro-4-(difluoromethyl)pyridine (20 g, 122.70 mmol), diphenylmethanimine (34.50 g, 184.05 mmol) and BINAP (15.29 g, 24.54 mmol) in 1,4- dioxane (200 mL) were added Cs₂CO₃ (80.00 g, 245.40 mmol) and Pd(OAc)₂ (2.77 mg, 12.27 mmol). The mixture was stirred at 115 ^oC for 16 h under N₂. The mixture was diluted with H₂O (200 mL) and extracted with EA (200 mL x 3). The organic phase was washed with brine (200 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (25 g, 66.59%) as a brown solid. ESI-MS (M+H) ⁺:309.1. Step 3: Preparation of 4-(difluoromethyl)pyridin-2-amine hydrochloride. [0965] A mixture of N-(4-(difluoromethyl)pyridin-2-yl)-1,1-diphenylmethanimine (25 g, 81.17 mmol) in 4M HCl/EA (250 mL) was stirred at 85 ^oC for 2 h. The reaction was diluted with EA (250 mL), the precipitate was filtrated and dried in vacuo to give title product (6.0 g, 41.06%) as a yellow solid. ESI-MS (M+H⁺): 145.5. Step 4: Preparation of 5-bromo-4-(difluoromethyl)pyridin-2-amine. [0966] To a mixture of 4-(difluoromethyl)pyridin-2-amine hydrochloride (6 g, 33.33 mmol) in THF (60 mL) were added NBS (5.34 g, 30.00 mmol). The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (60 mL) and extracted with EA (60 mL x 3). The organic phase was washed with brine (60 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (3.0 g, 44.83%) as a yellow solid. ESI-MS (M+H) ⁺: 224.9. Step 5: Preparation of 6-bromo-7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine. [0967] To a mixture of 5-bromo-4-(difluoromethyl)pyridin-2-amine (3.0 g, 17.94 mmol) in IPA (30 mL) were added 1-bromo-2,2-dimethoxypropane (3.57 g, 19.73 mmol) and PPTS (10.63 g, 21.53 mmol). The mixture was stirred at 85^oC for 16 h. The mixture was diluted with sat.Na₂CO₃ (30 mL) and extracted with EA (30 mL*3), the organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 5: 1) to get title product (2.0 g, Y: 42.70%) as a white solid. ESI-MS (M+H) ⁺: 262.9.¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 7.82 – 7.75 (m, 2H), 7.12 (t, J = 54.1 Hz, 1H), 2.38 (s, 3H). Step 6: Preparation of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine. [0968] To a mixture of 6-bromo-7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine (2.0 g, 7.66 mmol), diphenylmethanimine (2.09 g, 11.49 mmol) and BINAP (954.44 mg, 1.53 mmol) in 1,4-dioxane (20 mL) were added Cs₂CO₃ (4.99 g, 15.32 mmol) and Pd(OAc)₂ (173.12 mg, 0.77 mmol). The mixture was stirred at 115 ^oC for 16 h under N₂. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (1.2 g, 43.34%) as a brown solid. ESI-MS (M+H) ⁺:362.2. Step 7: Preparation of 7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride. [0969] A mixture of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (1.2 g, 3.32 mmol) in 4M HCl/EA (20 mL) was stirred at rt for 2 h. The reaction was diluted with EA (20 mL), the precipitate was filtrated and dried in vacuo to give title product (700 mg, 90.49%) as a yellow solid. ESI-MS (M+H⁺): 198.5. Step 8: Preparation of tert-butyl 7-(1-((7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0970] To a mixture of 7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (150 mg, 0.64 mmol), tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (253.44 mg, 0.77 mmol) in THF (10 mL) were added TEA (233.31 mg, 2.31 mmol) and triphosgene (457.38 mg, 1.54 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (80 mg, 22.60%) as a white solid. ESI-MS (M+H) ⁺: 554.5. Step 9: Preparation of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate. [0971] A mixture of tert-butyl 7-(1-((7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (80 mg,0.14 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (20.60 mg, 26.70%) as a white solid. ESI-MS (M+H) ⁺:454.3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 9.09 (s, 1H), 8.16 (s, 2H), 7.85 – 7.80 (m, 2H), 7.70 (s, 1H), 7.13 (t, J = 54.3 Hz, 1H), 6.49 (d, J = 6.2 Hz, 1H), 3.99 – 3.95 (m, 2H), 3.28 – 3.25 (m, 2H), 3.13 – 3.07 (m, 4H), 2.91 – 2.87 (m, 2H), 2.35 (s, 3H), 0.57 – 0.50 (m, 4H). Example 351 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide.

C^{ompound 351} Step 1: Preparation of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)(methyl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine- 1-carboxylate. [0972] To a solution of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate ( 200 mg, 0.38 mmol) in dry-THF (5 mL) was added NaH (46 mg, 1.91 mmol) at 0^o C and stirred for 1 h. Then CH₃I (264 mg, 1.91 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with water (2 mL), concentrated in vacuo and purified by prep-TLC (DCM: MeOH= 10: 1) to give compound (200 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 538.2. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0973] To a solution of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)(methyl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine- 1-carboxylate (180 mg, 0.34 mmol) in EA (2 mL) was added 4M HCl / EA (5 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % NH₃·H₂O in water / CH₃CN) to give title product (12.67 mg, yield: 9 %) as a white solid. ESI-MS (M+H) ⁺: 438.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 5.9 Hz, 1H), 7.53 (s, 1H), 7.25 (d, J = 11.3 Hz, 1H), 6.23 (d, J = 6.0 Hz, 1H), 3.78 – 3.71 (m, 2H), 3.23 (s, 3H), 2.96 – 2.85 (m, 4H), 2.81 – 2.74 (m, 4H), 2.24 (s, 3H), 1.03 (s, 6H). Example 352 – Preparation of (S)-N-(7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6-yl)- 4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

C^{ompound 352} Step 1: Preparation of tert-butyl (S)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0974] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (50 mg, 0.16 mmol), 7-methoxy-2-methylimidazo[1,2- a]pyrimidin-6-amine (28 mg, 0.16 mmol) and TEA (330 mg, 3.2 mmol) in THF (1 mL) was added triphosgene (92 mg, 0.31 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA= 1: 4) to give title product (50 mg, Y: 61.1%) as a yellow solid. ESI-MS (M+H) ⁺: 523.4. Step 2: Preparation of (S)-N-(7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0975] A mixture of tert-butyl (S)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (29 mg, Y: 89.8%) as a yellow solid. ESI-MS (M+H) ⁺: 423.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s, 1H), 9.68 (s, 1H), 9.15 (s, 1H), 8.84 (s, 1H), 8.05 (d, J = 6.1 Hz, 1H), 7.88 (d, J = 1.0 Hz, 1H), 6.68 (d, J = 6.2 Hz, 1H), 4.25 (s, 3H), 4.04 (t, J = 8.6 Hz, 2H), 3.84 – 3.79 (m, 2H), 3.41 – 3.35 (m, 2H), 3.24 – 3.09 (m, 4H), 3.06 – 2.95 (m, 1H), 2.40 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H). Example 353 – Preparation of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [0976] A mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mol), 7-(difluoromethyl)-2- methylimidazo[1,2-a]pyridin-6-amine (84 mg, 0.36 mmol), triphosgene (107 mg, 0.36 mmol) and TEA (365 mg, 3.61 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The residue was diluted with H₂O and the precipitate was filtered to afford title product (80 mg, crude) as a white solid. ESI-MS (M+H) ⁺: 556.2. Step 2: Preparation of N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4- ((3R,5S)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [0977] A mixture of tert-butyl (2R,6S)-4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (70 mg, 0.13 mmol) in 3M HCl /EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered to give title product (11.99 mg, yield: 20.27 %) as a yellow solid. ESI-MS (M+H) ⁺: 456.1.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 9.48 (s, 1H), 8.14 (d, J = 12.9 Hz, 2H), 7.94 (d, J = 6.1 Hz, 1H), 7.46 – 7.15 (m, 1H), 6.70 (d, J = 5.8 Hz, 1H), 4.10 – 4.06 (m, 2H), 3.92 – 3.88 (m, 2H), 3.42 – 3.36 (m, 2H), 3.27 – 3.21 (m, 2H), 2.95 (t, J = 12.8 Hz, 2H), 2.52 (s, 3H), 1.30 (d, J = 6.4 Hz, 6H). Example 354 – Preparation of (R)-N-(7-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0978] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mol), 7-(difluoromethyl)-2- methylimidazo[1,2-a]pyridin-6-amine (88 mg, 0.38 mmol), triphosgene (112 mg, 0.38 mmol) and TEA (381 mg, 3.77 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O and the precipitate was filtered to afford title product (100 mg, crude) as a white solid. ESI-MS (M+H) ⁺: 541.8.¹H NMR (400 MHz, CDCl₃) δ 11.92 (s, 1H), 8.99 (s, 1H), 7.91 (d, J = 5.9 Hz, 1H), 7.70 (s, 1H), 7.37 (s, 1H), 6.89 – 6.77 (m, 1H), 6.36 (d, J = 6.1 Hz, 1H), 4.18 – 4.14 (m, 2H), 4.00 – 3.95 (m, 2H), 3.46 – 3.40 (m, 2H), 3.25 – 3.20 (m, 2H), 3.15 – 3.11 (m, 3H), 2.46 (s, 3H), 1.49 (s, 9H), 1.31 – 1.29 (m, 3H). Step 2: Preparation of (R)-N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0979] A mixture of tert-butyl (R)-4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (80 mg, 0.15 mmol) in 3M HCl /EA (2 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (14.29 mg, yield: 21.60 %) as a yellow solid. ESI-MS (M+H) ⁺: 442.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 9.09 (s, 1H), 8.26 (s, 1H), 7.86 – 7.81 (m, 2H), 7.70 (s, 1H), 7.13 (t, J = 54.3 Hz, 1H), 6.52 (d, J = 6.1 Hz, 1H), 3.98 (t, J = 8.6 Hz, 2H), 3.61 (d, J = 12.1 Hz, 2H), 3.14 (t, J = 8.5 Hz, 2H), 2.98 (d, J = 11.2 Hz, 1H), 2.90 – 2.76 (m, 3H), 2.58 – 2.52 (m, 1H), 2.35 (s, 3H), 1.04 (d, J = 6.3 Hz, 3H). Example 355 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(8- methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

C^{ompound 355} Step 1: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0980] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (50 mg, 0.12 mmol) in MeOH (5 mL) were added (HCOH)_n (10.7 mg, 0.36 mmol) and HOAc (23 mg, 0.60 mmol). The mixture was stirred at r.t for 1h. NaBH3CN (23 mg, 0.36 mmol) was added to the mixture and stirred at 50 ^oC for 16 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in H₂O / ACN) to give title compound (6.51 mg, yield: 12%) as a white solid. ESI-MS (M+H)⁺: 436.2. H NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 11.23 (s, 1H), 9.68 (d, J = 6.4 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J = 10.0 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.60 (d, J = 6.0 Hz, 1H), 4.04 (s, 4H), 3.75 (d, J = 13.2 Hz, 4H), 3.27 – 3.21 (m, 2H), 2.73 (d, J = 4.8 Hz, 3H), 2.45 (s, 3H), 2.19 (s, 2H), 1.98 (d, J = 8.5 Hz, 2H).

Example 356 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy-2- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [0981] A mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 7-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine (116 mg, 0.54 mmol), triphosgene (161 mg, 0.54 mmol) and TEA (547 mg, 5.42 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O and the precipitate was filtered to afford title product (100 mg, crude) as a white solid. ESI-MS (M+H) ⁺: 537.2. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy-2- methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0982] A mixture of tert-butyl (2R,6S)-4-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in 4M HCl /EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% NH₃·H₂O in H₂O / ACN) to give title product (18.32 mg, yield: 28.01 %) as a yellow solid. ESI-MS (M+H) ⁺: 437.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.31 (s, 1H), 9.36 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.19 (s, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.07 (s, 3H), 3.99 (t, J = 8.6 Hz, 2H), 3.60 (d, J = 11.8 Hz, 2H), 3.14 (t, J = 8.5 Hz, 2H), 2.82 – 2.76 (m, 2H), 2.39 – 2.37 (m, 4H), 2.25 – 2.24 (m, 1H), 1.00 (d, J = 6.2 Hz, 6H). Example 357 – Preparation of (S)-N-(7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of tert-butyl (S)-4-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0983] To a solution of 7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (150 mg, 0.45 mmol) in THF (10 mL) were added TEA (381 mg, 3.77 mmol) and triphosgene (113 mg, 0.38 mmol). Then tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) was added to the mixture and stirred at r.t for 16h. The mixture was diluted with H₂O (20 mL), and the precipitate was filtered to provide title product (60 mg, yield: 37%) as a white solid. ESI-MS (M+H)⁺:522.8. Step 2: Preparation of (S)-N-(7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [0984] To a solution of tert-butyl (S)-4-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (50 mg, 0.10 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at r.t for 2h. The mixture was concentrated in vacuo, the residue was purified by prep- HPLC (0.05% NH₃.H₂O in H₂O / ACN) to give title compound (9.69 mg, yield: 23%) as a white solid. ESI-MS (M+H)⁺: 423.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 9.35 (s, 1H), 7.98 (s, 1H), 7.18 (s, 1H), 6.60 (s, 1H), 4.07 (s, 3H), 4.01 – 4.00 (m, 2H), 3.73 – 3.71 (m, 2H), 3.17 – 3.15 (m, 5H), 2.97 – 2.95 (m, 2H), 2.38 (s, 3H), 1.23 – 1.21 (m, 3H). Example 358 – Preparation of (R)-N-(7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0985] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) in THF (5 mL) were added TEA (143 mg, 1.42 mmol), triphosgene (168 mg, 0.57 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (101 mg, 0.57 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (70 mg, Y: 28.4 %) as a yellow solid. ESI-MS (M+H) ⁺:523.5. Step 2: Preparation of (R)-N-(7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0986] To a solution of tert-butyl (R)-4-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t for 2 h and concentrated in vacuo. The crude was purified by prep- HPLC (0.03% TFA in water / ACN) to give title compound (37.94 mg, 73.9 %) as a white solid. ESI-MS (M+H)⁺: 423.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 9.39 (s, 1H), 9.16 – 9.06 (m, 1H), 8.83 – 8.71 (m, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.26 (s, 1H), 6.64 (d, J = 6.1 Hz, 1H), 4.10 (s, 3H), 4.03 (t, J = 8.6 Hz, 2H), 3.80 (d, J = 11.8 Hz, 2H), 3.42 – 3.35 (m, 2H), 3.20 – 3.12 (m, 4H), 2.99 (dd, J = 13.7, 10.4 Hz, 1H), 2.42 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 359 – Preparation of N-(7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)-4-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

C^{ompound 359} Step 1: Preparation of tert-butyl 7-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [0987] To a solution of 7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine hydrochloride (97.44 mg, 0.45 mmol) and TEA (0.63 mL,4.54 mmol) in THF (10 mL) was added triphosgene (134 mg, 0.45 mmol) at 0^oC, then tert-butyl 7-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol) was added slowly at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EA= 1: 5) to give the compound (110 mg, crude) as an off-white solid. ESI-MS (M+H) ⁺: 535.2. Step 2: Preparation of N-(7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0988] To a mixture of tert-butyl 7-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (100 mg, 0.19 mmol) in EA (2 mL) was added HCl / EA (3 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (15 mg, Y: 18.46 %) as a yellow solid. ESI- MS (M+H) ⁺: 435.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (s, 1H), 9.36 (s, 1H), 8.15 (s, 2H), 7.93 (d, J = 6.0 Hz, 1H), 7.19 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 4.00 – 3.96 (m, 2H), 3.29 – 3.27 (m, 2H), 3.15 – 3.13 (m, 2H), 3.11 – 3.07 (m, 2H), 2.94 – 2.89 (m, 2H), 2.38 (s, 3H), 0.56 (d, J = 3.9 Hz, 4H). [0989] Example 360 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate formate.

Compound 360 Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [0990] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (111 mg, 0.34 mmol) and TEA (507 mg, 5.03 mmol) in THF (8 mL) was added triphosgene (100 mg, 0.34 mmol) at 0^oC, the mixture was stirred at RT for 1 h.6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (60 mg, 0.34 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (EA) to give title product (70 mg, Y: 39.2%) as a yellow solid. ESI-MS (M+H) ⁺: 537.3. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0991] A mixture of tert-butyl (2R,6S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (60 mg, 0.11 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (29 mg, Y: 59.4 %) as a white solid. ESI-MS (M+H) ⁺: 437.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.18 (s, 1H), 8.67 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.10 – 4.02 (m, 6H), 3.98 (t, J = 8.5 Hz, 2H), 3.65 – 3.64 (m, 2H), 3.13 (t, J = 8.5 Hz, 2H), 2.93 – 2.83 (m, 2H), 2.49 – 2.38 (m, 2H), 1.04 (d, J = 6.3 Hz, 6H). Example 361 – Preparation of (S)-N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin- 5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [0992] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (107 mg, 0.34 mmol), 6-methoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-amine (60 mg, 0.34 mmol) and TEA (507 mg, 5.03 mmol) in THF (8 mL) was added triphosgene (100 mg, 0.34 mmol) at 0^oC, the mixture was stirred at RT for 16 h . The mixture was concentrated in vacuo and purified by silica gel column (EA) to give title product (70 mg, Y: 40.0%) as a white solid. ESI-MS (M+H) ⁺: 523.2.¹H NMR (400 MHz, DMSO-d₆)δ 12.15 (s, 1H), 8.67 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 6.92 (s, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.05 – 4.04 (m, 2H), 3.97 (s, 3H), 3.93 – 3.92 (m, 2H), 3.71 – 3.53 (m, 2H), 3.22 – 3.01 (m, 4H), 2.98 – 2.86 (m, 1H), 1.42 (s, 9H), 1.21 – 1.16 (m, 3H). Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [0993] A mixture of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (60 mg, 0.11 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (24 mg, Y: 49.5 %) as a yellow solid. ESI-MS (M+H) ⁺: 423.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 8.67 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 4.01 – 3.96 (m, 2H), 3.65 – 3.58 (m, 2H), 3.12 (t, J = 8.5 Hz, 2H), 3.04 – 2.97 (m, 1H), 2.93 – 2.79 (m, 3H), 2.61 – 2.53 (m, 1H), 1.07 (d, J = 6.3 Hz, 3H). Example 362 – Preparation of (R)-N-(6-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [0994] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (74 mg, 0.23 mmol) in THF (5 mL) were added TEA (71 mg, 0.70 mmol), triphosgene (83 mg, 0.28 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (50 mg, 0.28 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:2) to give the title compound (30 mg, Y: 25.5 %) as a yellow solid. ESI-MS (M+H) ⁺:523.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 7.93 (d, J = 5.9 Hz, 1H), 6.54 (d, J = 5.9 Hz, 1H), 6.17 (s, 1H), 3.82 – 3.75 (m, 2H), 3.69 – 3.64 (m, 2H), 3.63 – 3.57 (m, 2H), 3.11 – 3.06 (m, 2H), 2.99 – 2.91 (m, 3H), 2.35 (s, 3H), 2.32 (s, 3H), 1.43 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H). Step 2: Preparation of (R)-N-(6-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [0995] To a solution of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t for 2 h and concentrated in vacuo.The crude was purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (10.1 mg, 32.6 %) as a white solid. ESI-MS (M+H)⁺:423.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 9.00 (s, 1H), 8.74 – 8.62 (m, 2H), 8.15 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 4.05 (s, 3H), 4.03 – 4.01 (m, 2H), 3.79 (d, J = 12.3 Hz, 2H), 3.41 – 3.35 (m, 2H), 3.19 – 3.12 (m, 4H), 2.97 (dd, J = 13.7, 10.5 Hz, 1H), 1.27 (d, J = 6.4 Hz, 3H).

Example 363 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl- 2H-pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine. [0996] To a mixture of 6-chloro-2H-pyrazolo[3,4-b]pyridine (23.0 g, 149.35 mmol) in EA (250 mL) was added trimethyloxonium tetrafluoroborate (26.5 g, 179.22 mmol). The mixture was stirred at r.t for 16 h. The mixture was diluted with Saturated sodium bicarbonate aqueous solution (200 mL) and extracted with EA (200 mL*3), the organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to get title product (17.0 g, Y: 67.8%) as a brown solid. ESI-MS (M+H)⁺: 168.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.27 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 4.20 (s, 3H). Step 2: Preparation of 6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine. [0997] To a mixture of 6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine (16 g, 95.24 mmol) in MeOH (200 mL) was added NaOMe (6.2 g, 114.29 mmol). The mixture was stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo and diluted with water (300 mL) and extracted with EA (200 mL*3), the organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to get title product (14.4 g, Y: 92.8%) as a yellow solid. ESI-MS (M+H)⁺: 164.2. Step 3: Preparation of 5-bromo-6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine. [0998] To a mixture of 6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine (13.4 g, 82.21 mmol) in ACN (200 mL) was added NBS (17.6 g, 98.65 mmol). The mixture was stirred at 55 ^oC for 16 h. The mixture was diluted with water (200 mL) and extracted with EA (200 mL*3). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=10:1) to give the title compound (14.0 g, Y: 70.4 %) as a yellow solid. ESI-MS (M+H) ⁺:244.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.26 (s, 1H), 4.12 (s, 3H), 3.99 (s, 3H). Step 4: Preparation of N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,1- diphenylmethanimine. [0999] To a mixture of 5-bromo-6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine (14.0 g, 57.85 mmol) in 1,4-dioxane (200 mL) were added diphenylmethanimine (15.7 g, 86.78 mmol), BINAP (7.2 g, 11.57 mmol), Pd(OAc)₂ (1.3 g, 5.79 mmol) and Cs₂CO₃ (37.7 g, 115.70 mmol). The mixture was stirred at 110^oC for 16 h under N₂. The mixture was diluted with water (200 mL) and extracted with EA (200 mL*3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 1) to get title product (1.0 g, Y: 5.1%) as a yellow solid. ESI-MS (M+H)⁺:343.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.39 – 7.36 (m, 4H), 7.33 – 7.32 (m, 1H), 7.32 – 7.31 (m, 2H), 7.30 – 7.29 (m, 1H), 7.28 – 7.25 (m, 2H), 4.36 (s, 3H), 3.33 (s, 3H). Step 5: Preparation of 6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine HCl salt. [01000] To a mixture of N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,1- diphenylmethanimine (900 mg, 2.63 mmol) in EA (10 mL) was added 4 M HCl/EA (10 mL). The mixture was stirred at r.t for 2 h. The mixture was filtered and the residue was diluted with EA (10 mL). The mixture was stirred at r.t for 2 h and the precipitate was filtered to get title product (400 mg, Y: 85.4%) as a yellow solid. ESI-MS (M+H)⁺:179.5. Step 6: Preparation of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01001] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (78 mg, 0.23 mmol) in THF (3 mL) were added TEA (71 mg, 0.70 mmol), triphosgene (83 mg, 0.28 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (50 mg, 0.28 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:2) to give the title compound (30 mg, Y: 23.8 %) as a yellow solid. ESI-MS (M+H) ⁺:537.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 9.36 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.19 (s, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.07 – 4.07 (m, 2H), 4.01 (t, J = 8.5 Hz, 2H), 3.91 (s, 6H), 3.65 – 3.56 (m, 2H), 3.18 – 3.14 (m, 2H), 2.97 – 2.86 (m, 2H), 2.31 (s, 6H), 1.42 (s, 9H). Step 7: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01002] To a solution of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (30 mg, 0.06 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (12 mg, 31.7 %) as a white solid. ESI-MS (M+H)⁺:437.3. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 8.91 (s, 2H), 8.67 (s, 1H), 8.15 (s, 1H), 8.02 (d, J = 6.0 Hz, 1H), 6.62 (d, J = 6.1 Hz, 1H), 4.07 (s, 3H), 4.05 (s, 3H), 4.03 – 4.00 (m, 2H), 3.47 – 3.44 (m, 2H), 3.32 – 3.28 (m, 4H), 3.16 (t, J = 8.6 Hz, 2H), 1.38 (s, 6H).

Example 364 – Preparation of N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)- 4-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate.

Step 1: Preparation of phenyl (6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamate. [01003] To a mixture of 6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (10.2 g, 57.00 mmol) and pyridine (13.5 g, 170.95 mmol) in DCM (200 mL) was added phenyl carbonochloridate (13.42 g, 85.47 mmol) at 0^oC. The mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo and diluted with 1M NaOH (100 mL), the precipitate was filtered and dried in vacuo to give title product (18.9 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 299.2. Step 2: Preparation of tert-butyl 7-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [01004] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (11 g, 33.33 mmol), phenyl (6-methoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)carbamate (11 g, 47.00 mmol) and TEA (10.1 g, 100.00 mmol) in THF (200 mL) was stirred at 70 ^oC for 16 h. The mixture was diluted with H₂O (200 mL), extracted with DCM (200 mL x3), organic layer concentrated in vacuo and diluted with (MeOH:EA=3:1, 300mL), stirred at r.t for 1h, the precipitae was filtered and dried in vacuo to give title product (17 g, Y:98.3%) as a white solid. ESI-MS (M+H) ⁺: 535.4. Step 3: Preparation of N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01005] A mixture of tert-butyl 7-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (14 g, 26.17 mmol) in EA (100 mL) was added 4M HCl/EA (100 mL). The reaction mixture was stirred at r.t for 0.5 h. The mixture was diluted with 2M NaOH (200 mL), the precipitate was filtered, washed with water (100 mL *3) and dried to give title product (10 g, Y:87.9 %) as a white solid. ESI-MS (M+H) ⁺: 435.2. Step 4: Preparation of N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate. [01006] A mixture of N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (20 g, 45.98 mmol) and benzoate (5.61 g, 45.98 mmol) in DCM / MeOH (200 mL / 200 mL) was stirred at 50 ^oC for 16 h. The mixture was concentrated in vacuo, the residue was triturated with MTBE (200 mL) and lyophilized to give title product (22 g, Y: 85.9 %) as a white solid. ESI-MS (M+H) ⁺: 435.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.18 (s, 1H), 8.66 (s, 1H), 8.14 (s, 1H), 7.94 (t, J = 6.8 Hz, 3H), 7.62 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 6.49 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 3.97 (t, J = 8.5 Hz, 2H), 3.25 – 3.23 (m, 2H), 3.11 – 3.04 (m, 4H), 2.91 – 2.84 (m, 2H), 0.55 – 0.47 (m, 4H).

Example 365 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methyltetrazolo[1,5- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

t 4

Step 1: Preparation of 5-bromo-2-hydrazinyl-4-methylpyridine. [01007] To a mixture of 5-bromo-2-chloro-4-methylpyridine (20.0 g, 97.09mmol) in EtOH (200 mL) was added N₂H₄.H₂O (34.0 g, 679.61 mmol). The mixture was stirred at 120^oC for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water (200 mL) and extracted with EA (200 mLx3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 10: 1 to 1: 5) to get title product (18 g, Y: 91.8%) as a yellow solid. ESI-MS (M+H)⁺:204.4.¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (s, 1H), 7.53 (s, 1H), 6.71 (s, 1H), 4.13 (s, 2H), 2.23 (s, 3H). Step 2: Preparation of 6-bromo-7-methyltetrazolo[1,5-a]pyridine. [01008] A solution of NaNO₂ (7.4 g, 106.93 mmol) in H₂O (10 mL) was added to a mixture of 5-bromo-2-hydrazineyl-4-methylpyridine (18.0 g, 99.01 mmol) in AcOH (200 mL) at 0^oC. The mixture was stirred at 0^oC for 3 h. The mixture was diluted with sodium carbonate solution (100 mL) and stirred at r.t for 2 h. The mixture was extracted with EA (100 mL*3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 1) to get title product (14 g, Y: 73.87%) as a yellow solid. ESI-MS (M+H)⁺:213.4.¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.23 (s, 1H), 2.52 (s, 3H). Step 3: Preparation of N-(7-methyltetrazolo[1,5-a]pyridin-6-yl)-1,1-diphenylmethanimine. [01009] To a mixture of 6-bromo-7-methyltetrazolo[1,5-a]pyridine (13.8 g, 65.00 mmol) in 1,4-dioxane (150 mL) were added diphenylmethanimine (17.6 g, 97.51 mmol), BINAP (8.1 g, 13.00 mmol), Pd(OAc)₂ (1.5 g, 6.50 mmol) and Cs₂CO₃ (43.4 g, 130.01 mmol). The mixture was stirred at 90^oC for 16 h under N₂. The mixture was diluted with water (200 mL) and extracted with EA (200 mL*3), the organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 1) to get title product (3.0 g, Y: 14.8 %) as a yellow solid. ESI-MS (M+H)⁺: 314.4.¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.03 (s, 1H), 7.78 – 7.75 (m, 2H), 7.64 – 7.60 (m, 1H), 7.56 – 7.51 (m, 2H), 7.37 – 7.30 (m, 5H), 2.39 (s, 3H). Step 4: Preparation of 7-methyltetrazolo[1,5-a]pyridin-6-amine HCl salt. [01010] To a mixture of N-(7-methyltetrazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine (3.0 g, 9.58 mmol) in EA (30 mL) was added 4 M HCl/EA (30 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered and diluted with EA (10 mL). The mixture was stirred at r.t for 2 h and filtered to get title product (1.4 g, Y: 98.0%) as a yellow solid. ESI-MS (M+H)⁺: 150.2. Step 5: Preparation of tert-butyl 2,2-dimethyl-4-(1-((7-methyltetrazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01011] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) in THF (5 mL) were added TEA (137 mg, 1.36 mmol), triphosgene (161 mg, 0.54 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.7-methyltetrazolo[1,5-a]pyridin-6-amine (101 mg, 0.54 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (60 mg, Y: 26.1 %) as a yellow solid. ESI-MS (M+H) ⁺: 508.3. Step 6: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methyltetrazolo[1,5-a]pyridin-6- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01012] To a solution of tert-butyl 2,2-dimethyl-4-(1-((7-methyltetrazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (5.7 mg, 11.1 %) as a white solid. ESI- MS (M+H)⁺:408.3.¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 6.61 (d, J = 6.2 Hz, 1H), 4.05 (t, J = 8.5 Hz, 2H), 3.47 (s, 2H), 3.30 (s, 4H), 3.17 (t, J = 8.4 Hz, 2H), 2.59 (s, 3H), 1.38 (s, 6H). Example 366 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine. [01013] To a mixture of 3-methyl-1H-1,2,4-triazol-5-amine (4.0 g, 40.82 mmol) in AcOH (40 mL) was added 2- bromomalonaldehyde (6.8 g, 44.90 mmol). The mixture was stirred at 60^oC for 16 h under N₂. The mixture was concentrated in vacuo. The residue was dissolved in EA (50 mL) and filtered. The filtrate was diluted with NaHCO₃ (100 mL), and the aqueous layer was extracted with EA (100 mLx3). The combined organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM: MeOH= 100: 0 to DCM: MeOH= 98:2) to get title product (7.0 g, Y: 80.5%) as a white solid. ESI-MS (M+H)⁺: 215.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.73 (d, J = 2.3 Hz, 1H), 8.87 (d, J = 2.3 Hz, 1H), 2.48 (s, 3H). Step 2: Preparation of N-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-1,1- diphenylmethanimine. [01014] To a mixture of 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine (5.3 g, 24.88 mmol) in 1,4-dioxane (50 mL) were added diphenylmethanimine (6.8 g, 37.32 mmol), BINAP (3.1 g, 4.98 mmol), Pd(OAc)₂ (560 mg, 2.49 mmol) and Cs₂CO₃ (16.2 g, 49.77 mmol). The mixture was stirred at 115 ^oC for 16 h under N₂. The mixture was diluted with water (100 mL) and extracted with EA (100 mL*3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 3) to get title product (1.0 g, Y: 12.8%) as a yellow solid. ESI-MS (M+H)⁺: 314.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d, J = 2.6 Hz, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.76 – 7.73 (m, 2H), 7.63 – 7.59 (m, 1H), 7.55 – 7.51 (m, 2H), 7.41 – 7.38 (m, 3H), 7.31 – 7.28 (m, 2H), 2.43 (s, 3H). Step 3: Preparation of 2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine HCl salt. [01015] To a mixture of N-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-1,1- diphenylmethanimine (900 mg, 2.88 mmol) in EA (10 mL) was added 4 M HCl/EA (10 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered and diluted with EA (10 mL). The mixture was stirred at r.t for 2 h and filtered to get title product (300 mg, Y: 70.0%) as a white solid. ESI-MS (M+H)⁺: 150.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J = 0.9 Hz, 1H), 7.48 (s, 1H), 5.63 – 5.48 (m, 2H), 4.09 (s, 3H), 2.42 (d, J = 0.7 Hz, 3H). Step 4: Preparation of tert-butyl 2,2-dimethyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [01016] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) in THF (5 mL) were added TEA (137 mg, 1.36 mmol), triphosgene (161 mg, 0.54 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-amine hydrochloride (101 mg, 0.54 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (DCM/MeOH=10:1) to give the title compound (50 mg, Y: 21.8 %) as a yellow solid. ESI-MS (M+H) ⁺: 508.3. Step 5: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01017] To a solution of tert-butyl 2,2-dimethyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (14 mg, 27.3 %) as a white solid. ESI-MS (M+H)⁺: 408.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 9.52 (d, J = 2.6 Hz, 1H), 9.00 (s, 2H), 8.91 (d, J = 2.6 Hz, 1H), 7.98 (d, J = 6.1 Hz, 1H), 6.67 (d, J = 6.1 Hz, 1H), 4.05 (t, J = 8.5 Hz, 2H), 3.52 – 3.47 (m, 2H), 3.35 – 3.29 (m, 4H), 3.21 (t, J = 8.4 Hz, 2H), 2.49 (s, 3H), 1.37 (s, 6H). Example 367 – Preparation of (S)-N-(2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

C^{ompound 367} Step 1: Preparation of tert-butyl 4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01018] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) in THF (5 mL) were added TEA (137 mg, 1.36 mmol), triphosgene (161 mg, 0.54 mmol) at 0^oC. The mixture was stirred at r.t for 1 h.7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-amine (107 mg, 0.54 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:2) to give the title compound (60 mg, Y: 23.9 %) as a yellow solid. ESI-MS (M+H) ⁺:556.3. Step 2: Preparation of (S)-N-(2,6-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01019] To a solution of tert-butyl 4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t for 2 h and concentrated in vacuo. The crude was purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (18.08 mg, 35.1 %) as a white solid. ESI-MS (M+H)⁺: 456.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 9.59 (s, 1H), 9.06 (s, 2H), 8.24 (s, 1H), 8.12 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.36 (t, J = 53.6 Hz, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.05 (t, J = 8.4 Hz, 2H), 3.52 – 3.47 (m, 2H), 3.33 (s, 2H), 3.32 – 3.27 (m, 2H), 3.21 (t, J = 8.3 Hz, 2H), 2.50 (s, 3H), 1.37 (s, 6H). Example 368 – Preparation of (R)-4-(3-cyclopropylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 2-cyclopropyl-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate. [01020] A mixture of tert-butyl 2-cyclopropylpiperazine-1-carboxylate (954 mg, 4.18 mmol), 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (708.3 mg, 4.6 mmol) in a sealed tube was stirred at 140 ^oC for 16 h. the mixture was diluted with water (20 mL), extracted with EA (20 mL×3). The organic layer was washed with brine (20 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (MeOH: DCM= 6 %) to give title product (1 g, yield: 69.54 %) as a yellow solid. ESI-MS (M+H) ⁺: 345.1.¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 5.9 Hz, 1H), 6.12 (d, J = 6.0 Hz, 1H), 4.05 (d, J = 13.0 Hz, 1H), 3.64 – 3.55 (m, 3H), 3.52 – 3.47 (m, 1H), 3.40 – 3.30 (m, 2H), 3.12 – 3.07 (m, 2H), 2.92 – 2.85 (m, 2H), 1.47 (s, 9H), 0.61 – 0.49 (m, 4H), 0.32 – 0.27 (m, 1H). Step 2: Preparation of tert-butyl (R)-2-cyclopropyl-4-(1-((7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [01021] A mixture of tert-butyl 2-cyclopropyl-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate (400 mg, 1.16 mol), 7-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (239 mg, 1.45 mmol), triphosgene (417 mg, 1.45 mmol) and TEA (1.47 g, 14.53 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O and the precipitate was filtered and triturated with MeOD afford racemic product (280 mg, 45%) as a white solid. Then purified by SFC n- Hexane / IPA(0.2 % DEA) to give title product (170 mg) as a yellow solid and tert-butyl (S)- 2-cyclopropyl-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (110 mg) as a yellow solid. ESI-MS (M+H) ⁺: 536.4. Step 3: Preparation of (R)-4-(3-cyclopropylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01022] A mixture of tert-butyl (R)-2-cyclopropyl-4-(1-((7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (170 mg, 0.32 mmol) in 3M HCl /EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (99.38 mg, yield: 41.38 %) as a white solid. ESI-MS (M+H) ⁺: 436.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 9.85 (s, 1H), 9.60 (d, J = 43.7 Hz, 2H), 8.17 (s, 1H), 8.07 (d, J = 9.9 Hz, 1H), 7.95 (d, J = 6.0 Hz, 1H), 6.68 (d, J = 5.9 Hz, 1H), 4.06 (s, 2H), 3.86 – 3.77 (m, 2H), 3.42 – 3.29 (m, 3H), 3.24 – 3.15 (m, 2H), 3.08 – 2.98 (m, 1H), 2.68 – 2.58 (m, 1H), 2.46 (s, 3H), 1.14 – 1.06 (m, 1H), 0.62 (d, J = 7.1 Hz, 3H), 0.53 – 0.46 (m, 1H). Example 369 – Preparation of (S)-4-(3-cyclopropylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of (S)-4-(3-cyclopropylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01023] A mixture of tert-butyl (S)-2-cyclopropyl-4-(1-((7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (110 mg, 0.21 mmol) in 3M HCl /EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (75.2 mg, yield: 77.50 %) as a white solid. ESI-MS (M+H) ⁺: 436.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (s, 1H), 9.94 (s, 1H), 9.62 (d, J = 12.3 Hz, 2H), 8.17 (s, 1H), 8.06 (d, J = 9.9 Hz, 1H), 7.94 (d, J = 6.1 Hz, 1H), 6.68 (d, J = 5.6 Hz, 1H), 4.10 – 4.00 (m, 2H), 3.89 – 3.78 (m, 2H), 3.45 – 3.30 (m, 3H), 3.25 – 3.14 (m, 2H), 3.08 – 2.98 (m, 1H), 2.66 – 2.57 (m, 1H), 2.46 (s, 3H), 1.15 – 1.07 (m, 1H), 0.66 – 0.58 (m, 3H), 0.53 – 0.45 (m, 1H).

Example 370 – Preparation of (S)-4-(3-methylpiperazin-1-yl)-N-(6-methyl pyrazolo[1,5- a]pyrazin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate.

Step 1: Preparation of ethyl 6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate. [01024] To a mixture of ethyl 4-chloro-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (1.5 g, 6.28 mmol) in DMF (20 mL) was added HCOONa (640 mg, 9.41 mmol), Pd(PPh₃)₄ (363 mg, 0.31 mmol). The mixture was stirred at 120 ^o C for 4 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL× 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuo. The crude was purified by silica gel column chromatography (PE/EA= 3:1) to afford title product (1 g, Y: 77 %) as a yellow solid. ESI-MS (M+H) ⁺: 206.1.¹H NMR (400 MHz, CDCl₃) δ 9.07 (d, J = 1.3 Hz, 1H), 8.26 (d, J = 1.0 Hz, 1H), 7.30 (d, J = 0.8 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 2.57 (d, J = 0.8 Hz, 3H), 1.46 (t, J = 7.1 Hz, 3H). Step 2: Preparation of 6-methylpyrazolo[1,5-a]pyrazine-2-carboxylic acid. [01025] To a mixture of ethyl 6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (1 g, 4.88 mmol) in THF (10 mL) and water (10 mL) was added LiOH (234 mg, 9.76 mmol). The mixture was stirred at r.t for 2 h. Vacuum concentration of reaction liquild to remove THF. The aqueous phase was added 1 M HCl to PH=5. The precipitate was filtered and dried to give title product (200 mg, 23%) as a white solid. ESI-MS (M+H) ⁺: 178.1.¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.68 (s, 1H), 7.33 (s, 1H), 2.48 (s, 3H). Step 3: Preparation of tert-butyl (S)-2-methyl-4-(1-((6-methylpyrazolo[1,5-a]pyrazin-2- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01026] To a solution of 6-methylpyrazolo[1,5-a]pyrazine-2-carboxylic acid (56 mg, 0.31 mmol) in toluene (10 mL) were added TEA (125 mg, 1.24 mmol), DPPA (256 mg, 0.93 mmol). The mixture was stirred at r.t for 1 h and 1 h at 70 ^oC. Then tert-butyl (S)-4-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methyl piperazine-1-carboxylate (100 mg, 0.31 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:4) to give title product (80 mg, yield: 52 %) as a white solid. ESI-MS (M+H) ⁺:493.3.¹H NMR (400 MHz, CDCl₃) δ 12.41 (s, 1H), 8.84 (d, J = 1.2 Hz, 1H), 8.07 (s, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.12 (s, 1H), 6.36 (d, J = 6.1 Hz, 1H), 4.35 – 4.34 (m, 1H), 4.19 – 4.18 (m, 2H), 3.96 (d, J = 13.5 Hz, 1H), 3.52 (d, J = 12.2 Hz, 1H), 3.43 (d, J = 12.1 Hz, 1H), 3.27 – 3.19 (m, 1H), 3.16 – 3.05 (m, 3H), 2.95 – 2.94 (m, 1H), 2.51 (s, 3H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H). Step 4: Preparation of (S)-4-(3-methylpiperazin-1-yl)-N-(6-methylpyrazolo[1,5-a]pyrazin-2- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate. [01027] To a solution of tert-butyl (S)-2-methyl-4-(1-((6-methylpyrazolo[1,5- a]pyrazin-2-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (60 mg, 0.12 mmol) in EA (5 mL) was added 4M HCl / EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (42.29 mg, 81%) as a white solid. ESI-MS (M+H) ⁺:392.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 8.97 (d, J = 1.2 Hz, 1H), 8.47 (s, 1H), 8.19 (s, 2H), 7.94 (d, J = 6.1 Hz, 1H), 7.00 (s, 1H), 6.55 (d, J = 6.2 Hz, 1H), 4.01 (t, J = 8.6 Hz, 2H), 3.65 – 3.61 (m, 2H), 3.14 (t, J = 8.5 Hz, 2H), 3.03 – 2.98 (m, 1H), 2.90 – 2.79 (m, 3H), 2.61 – 2.55 (m, 1H), 2.43 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H). Example 371 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl 3-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. [01028] To a solution of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (100 mg, 0.49 mmol) in Toluene (10 mL) were added TEA (147.09 mg, 1.46 mmol) and DPPA (269.50 mg, 0.98 mmol). The mixture was stirred at rt for 1h. Then the mixture was stirred at 60 ^oC for another 1h. tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (161.70 mg, 0.49 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:3) to provide title product (40 mg, crude) as a white solid. ESI-MS (M+H)⁺: 534.3. Step 2: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01029] A solution of tert-butyl 3-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (40 mg, 0.08 mmol) in 4M HCl/EA (5 mL) stirred at rt for 2 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (3.0 mg, 7.81 %) as a white solid. ESI-MS (M+H⁺): 433.9.¹H NMR (400 MHz, MeOD-d₄) δ 8.50 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.96 (d, J = 5.9 Hz, 1H), 6.50 (d, J = 6.0 Hz, 1H), 6.13 (s, 1H), 4.10 – 4.08 (m, 2H), 4.07 – 4.02 (m, 2H), 3.98 (s, 3H), 3.69 – 3.64 (m, 2H), 3.28 – 3.24 (m, 2H), 3.18 – 3.13 (m, 2H), 2.37 (s, 3H), 2.15 – 2.09 (m, 4H). Example 372 – Preparation of 4-(4-(2,2-difluoroacetyl)-3,3-dimethylpiperazin-1-yl)-N- (7-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine- 1-carboxamide.

Step 1: Preparation of 4-(4-(2,2-difluoroacetyl)-3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a] pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide. [01030] A mixture of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a] pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide (200 mg, 0.47 mmol) and DMAP (144 mg,1.18 mmol) in DAF (10 mL) was stirred at 80 ^oC for 16 h. The reaction mixture was diluted with H₂O (20 mL) and extracted with DCM (20 mL*3). The organic layer was washed bine and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE: EA = 2:1) to give title compound (42.08 mg, Y: 17.0%) as a yellow solid. ESI-MS (M+H) ⁺: 502.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 9.52 – 9.08 (m, 1H), 8.26 – 7.73 (m, 2H), 7.44 (d, J = 25.0 Hz, 1H), 6.67 (t, J = 52.9 Hz, 1H), 6.40 (s, 1H), 3.97 (s, 2H), 3.80 (s, 2H), 3.63 – 3.62 (m, 4H), 3.32 – 3.30 (m, 2 H), 2.30 (s, 3H), 1.46 (s, 6H).

Example 373 – Preparation of 4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of methyl 5-methoxy-2-(prop-1-yn-1-yl)isonicotinate. [01031] To a solution of methyl 2-bromo-5-methoxyisonicotinate (13 g, 52.84 mmol), trimethyl(prop-1-yn-1-yl)silane (21 g, 184.96 mmol) in toluene (500 mL) were added Pd(PPh₃)₄ (6 g, 5.28 mmol), CuI (3 g, 15.86 mmol), TEA (31.8 g, 314.52 mmol), TBAF (14 g, 52.84 mmol), The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo. The mixture was diluted with water (300 mL) and extracted with EA (300 mL× 3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuo. The crude was purified by silica gel column chromatography (PE/EA= 4:1) to afford title product (9.5 g, Y: 87 %) as a yellow solid. ESI-MS (M+H) ⁺: 206.1. Step 2 and step 3: Preparation of methyl 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5- carboxylate. [01032] To a mixture of methyl 5-methoxy-2-(prop-1-yn-1-yl)isonicotinate (9.5 g, 46.12 mmol) in trichloromethane (300 mL) was added and O-(mesitylsulfonyl) hydroxylamine (30 g, 138.34 mmol) in 0^oC. The mixture was stirred at r.t for 16 h. The reaction mixture was concentrated in vacuo, the residue was diluted with DMF (300 mL), K₂CO₃ (11.4 g, 83.01 mmol) was added and stirred at r.t for 5 h. The crude was diluted with water (300 mL) and extracted with EA (300 mL ×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA= 3:1) to give title product (2.5 g, Y: 24 %) as a yellow solid. ESI-MS (M+H) ⁺: 221.1.¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.95 (s, 1H), 6.38 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.47 (s, 3H). Step 4: Preparation of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid. [01033] To a mixture of methyl 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5- carboxylate (500 mg, 2.26 mmol) in THF (5 mL) and water (5 mL) was added LiOH (109 mg, 4.50 mmol). The mixture was stirred at r.t for 2 h. The mixture was concentrated to remove most of THF. The aqueous phase was adjusted PH=5 with 1 M HCl. The mixture was filtered through a Celite pad and collect solid to give title product (200 mg, 42%) as a yellow solid. ESI-MS (M+H) ⁺: 207.5.¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 1H), 7.90 (s, 1H), 6.51 (s, 1H), 3.87 (s, 3H), 2.43 (s, 3H). Step 5: Preparation of tert-butyl 3-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9- carboxylate. [01034] To a solution of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (60 mg, 0.29 mmol) in toluene (20 mL) were added TEA (117 mg, 1.16 mmol), DPPA (239 mg, 0.87 mmol). The mixture was stirred at r.t for 1 h and 40 min at 70 ^o C. Then tert- butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9- carboxylate (100 mg, 0.29 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=2:1) to give title product (50 mg, yield: 31 %) as a white solid. ESI-MS (M+H) ⁺:548.3.¹H NMR (400 MHz, CDCl₃) δ 12.16 (s, 1H), 8.29 (s, 1H), 7.89 (s, 1H), 7.85 (d, J = 5.5 Hz, 1H), 6.25 (d, J = 6.1 Hz, 1H), 6.04 (s, 1H), 4.10 (dd, J = 17.5, 8.9 Hz, 4H), 3.88 (s, 3H), 3.58 – 3.52 (m, 2H), 3.18 – 3.10 (m, 4H), 2.35 (s, 3H), 1.88 – 1.81 (m, 2H), 1.76 – 1.64 (m, 4H), 1.43 (s, 9H). Step 6: Preparation of 4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. To a solution of tert-butyl 3-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9- carboxylate (40 mg, 0.072 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). [01035] The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (9 mg, 26%) as a white solid. ESI-MS (M+H) ⁺:448.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.51 (s, 1H), 8.27 (s, 1H), 8.05 – 7.99 (m, 2H), 6.55 (d, J = 6.0 Hz, 1H), 6.16 (s, 1H), 4.15 – 4.09 (m, 2H), 4.01 (s, 3H), 3.94 (d, J = 13.0 Hz, 2H), 3.64 (s, 2H), 3.44 (d, J = 11.8 Hz, 2H), 3.28 – 3.23 (m, 2H), 2.61 – 2.48 (m, 1H), 2.38 (s, 3H), 2.13 (d, J = 7.6 Hz, 4H), 1.69 (d, J = 13.5 Hz, 1H). Example 374 – Preparation of (R)-N-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide

Step 1: Preparation of tert-butyl (R)-2-methyl-4-(1-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01036] To a solution of 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (67 mg, 0.45 mmol) and TEA (0.63 mL, 4.52 mmol) in THF (8 mL) was added triphosgene (134 mg, 0.45 mmol) at 0^oC, after 10 min, tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (120 mg, 0.38 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (30 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (90 mg, 48.48 %) as a white solid. ESI- MS (M+H) ⁺: 493.2. Step 2: Preparation of (R)-N-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01037] To a mixture of tert-butyl (R)-2-methyl-4-(1-((7-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (80 mg, 0.16 mmol) in EA (1 mL) was added HCl/EA(3 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with MeOH (8 mL), then filtered and lyophilized to give title product (70 mg, 89.41 %) as an off-white solid. ESI-MS (M+H) ⁺: 393.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 9.52 (s, 3H), 8.50 (s, 1H), 7.96 – 7.95 (m, 1H), 7.82 (s, 1H), 6.70 – 6.69 (m, 1H), 4.12 – 4.07 (m, 3H), 3.43 – 3.29 (m, 4H), 3.27 – 3.18 (m, 2H), 3.16 – 3.06 (m, 2H), 2.53 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H). Example 375 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((7-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [01038] To a solution of 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (58.83 mg, 0.40 mmol) and TEA (0.55 mL, 3.97 mmol) in THF (8 mL) was added triphosgene (117 mg, 0.40 mmol) at 0^oC, after 10 min, tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2,6-dimethylpiperazine-1-carboxylate (120 mg, 0.36 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (30 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (70 mg, 38.28 %) as a white solid. ESI-MS (M+H) ⁺: 507.2. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01039] To a mixture of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((7-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (60 mg, 0.12 mmol) in EA (1mL) was added HCl/EA(3 mL, 4M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with MeOH (8 mL), then filtered and lyophilized to give title product (50 mg, 82.09 %) as an off- white solid. ESI-MS (M+H) ⁺: 407.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 9.52 (s, 2H), 9.06 (s, 1H), 8.46 – 8.45 (m, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 6.70 – 6.69 (m, 1H), 4.13 – 4.02 (m, 2H), 3.93 – 3.87 (m, 2H), 3.38 – 3.31 (m, 2H), 3.29 – 3.17 (m, 2H), 3.08 – 2.96 (m, 2H), 2.53 (s, 3H), 1.31 (d, J = 6.5 Hz, 6H). Example 376 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 2,2-dimethyl-4-(1-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01040] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (120 mg, 0.36 mol), 7-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-amine (64.2 mg, 0.43 mmol), triphosgene (127.7 mg, 0.43 mmol) and TEA (438.3 mg, 4.34 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at rt for 1h. The precipitate was filtered to afford title product (80 mg, 43.83 %) as a white solid. ESI-MS (M+H) ⁺: 507.2.¹H NMR (400 MHz, CDCl₃) δ 12.05 (s, 1H), 9.64 (s, 1H), 8.24 (s, 1H), 7.82 (d, J = 6.1 Hz, 1H), 7.53 (s, 1H), 6.23 (d, J = 6.1 Hz, 1H), 4.20 – 4.13 (m, 2H), 3.82 – 3.79 (m, 2H), 3.60 – 3.56 (m, 2H), 3.47 (s, 2H), 3.31 – 3.25 (m, 2H), 2.56 (s, 3H), 1.51 (s, 9H), 1.46 (s, 6H). Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01041] A mixture of tert-butyl 2,2-dimethyl-4-(1-((7-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (80 mg, 0.16 mmol) in 4M HCl /EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (72.56 mg, yield: 87.21 %) as a yellow solid. ESI-MS (M+H) ⁺: 407.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 9.49 (s, 1H), 8.94 (s, 2H), 8.41 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.79 (s, 1H), 6.66 (d, J = 6.2 Hz, 1H), 4.05 (d, J = 8.8 Hz, 2H), 3.52 – 3.48 (m, 2H), 3.34 – 3.30 (m, 4H), 3.23 – 3.19 (m, 2H), 2.53 (s, 3H), 1.37 (s, 6H). Example 377 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 3-(1-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. [01042] A mixture of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.36 mol), 7-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-amine (64.58 mg, 0.44 mmol), triphosgene (129.5 mg, 0.44 mmol) and TEA (367.3 mg, 3.64 mmol) in THF (20 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O, stirred at rt for 1h. The precipitate was filtered to afford title product (100 mg, 55.11 %) as a white solid. ESI-MS (M+H) ⁺: 505.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 9.49 (s, 1H), 8.34 (s, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.75 (s, 1H), 6.51 (d, J = 6.2 Hz, 1H), 4.21 (s, 2H), 4.00 (t, J = 8.5 Hz, 2H), 3.56 (d, J = 11.2 Hz, 2H), 3.20 (t, J = 8.6 Hz, 2H), 3.02 (d, J = 11.1 Hz, 2H), 1.87 – 1.77 (m, 4H), 1.43 (s, 9H). Step 2: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01043] A mixture of tert-butyl 3-(1-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (100 mg, 0.20 mmol) in 4M HCl / EA (1 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (62.04 mg, yield: 70.66 %) as a white solid. ESI-MS (M+H) ⁺: 404.9. [01044] ¹H NMR (400 MHz, MeOD-d₄) δ 9.29 (s, 1H), 9.10 (s, 1H), 8.02 (s, 1H), 7.86 – 7.84 (m, 1H), 6.91 – 6.90 (m, 1H), 4.45 – 4.35 (m, 2H), 4.25 (s, 2H), 4.20 – 4.06 (m, 2H), 3.69 – 3.54 (m, 4H), 2.67 (s, 3H), 2.20 – 2.14 (m, 4H). Example 378 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Compound 378 Step 1: Preparation of tert-butyl 3-(1-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. [01045] To a mixture of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.30 mmol), 2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-amine hydrochloride (99.00 mg, 0.30 mmol) and TEA (90.90 mg, 0.90 mmol) in THF (5 mL) was added triphosgene (177.60 mg, 0.60 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/1 to 1/100) to afford title product (50 mg, 33.07%) as a white solid. ESI-MS (M+H) ⁺: 505.3. Step 2: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01046] A mixture of tert-butyl 3-(1-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (50 mg, 0.10 mmol) in 4M HCl/EA (5 mL) was stirred at rt for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (9.84 mg, 21.87%) as a white solid. ESI-MS (M+H) ⁺:405.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 9.26 (s, 1H), 8.26 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.68 (d, J = 9.4 Hz, 1H), 7.59 (dd, J = 9.4, 2.0 Hz, 1H), 6.47 (d, J = 6.2 Hz, 1H), 4.00 – 3.96 (m, 2H), 3.60 – 3.59 (m, 2H), 3.51 – 3.49 (m, 2H), 3.20 – 3.16 (m, 2H), 3.08 – 3.03 (m, 2H), 2.44 (s, 3H), 1.79 – 1.72 (m, 4H). Example 379 – Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (hydroxymethyl)piperazine-1-carboxylate. [01047] To a solution of tert-butyl (S)-2-(hydroxymethyl)piperazine-1-carboxylate (839 mg, 3.88 mmol) in DIEA (6 mL) was added 4-chloro-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine (500 mg, 3.23 mmol). The reaction mixture was stirred at 140°C for 16 h in a seal tube. The mixture was diluted with water (20 mL) and extracted with DCM: MeOH =10:1 (30 mL×3), the combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and filtrate was concentrated in vacuo, the crude was purified by silica gel column chromatography (DCM: MeOH =20:1) to give title compound (470 mg, yield: 39 %) as a yellow solid. ESI-MS (M+H)⁺: 335.2. Step 2: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1- carboxylate. [01048] To a solution of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-(hydroxymethyl)piperazine-1-carboxylate (200 mg, 0.598 mmol) in THF (13 mL) were added 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (148 mg, 0.897 mmol), TEA (1.3 mL) and triphosgene (266 mg, 0.897 mmol). The mixture was stirred at r.t for 16 h. The reaction mixure was diluted with water (10 mL) and extracted with DCM: MeOH =10:1 (10 mL×3), the combined organic layers was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and filtrate was concentrated in vacuo, the crude was purified by silica gel column chromatography (DCM: MeOH =10:1) to give title compound (90 mg, yield: 26 %) as a yellow solid. ESI-MS (M+H)⁺: 526.2. Step 3: Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01049] To a solution of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1- carboxylate (70 mg, 0.133 mmol) in CH₂Cl₂ (2 mL) was added TFA (1.0 mL). The mixture was stirred at r.t for 1 h. The mixture was concentrated, the crude was purified by Prep-HPLC (0.1% HCl in H₂O/MeCN) to give title product (11.74 mg, yield:19 %) as a white solid. ESI- MS (M+H)⁺: 426.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.44 (s, 1H), 9.68 (d, J = 8.0 Hz, 1H), 9.47 (s, 1H), 9.21 (s, 1H), 8.17 (s, 1H), 8.07 (d, J = 12.0 Hz, 1H), 7.97 (d, J = 4.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.08 – 4.03 (m, 2H), 3.71 – 3.68 (m, 4H), 3.32 – 3.30 (m, 3H), 3.23 – 3.18 (m, 4H), 2.45 (s, 3H).

Example 380 – Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (hydroxymethyl)piperazine-1-carboxylate. [01050] To a solution of tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate (839 mg, 3.88 mmol) in DIEA (6 mL) was added 4-chloro-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine (500 mg, 3.23 mmol). The reaction mixture was stirred at 140°C for 16 h in a seal tube. The mixture was diluted with water (20 mL) and extracted with DCM: MeOH =10:1 (30 mL×3), the combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and filtrate was concentrated in vacuo, the crude was purified by silica gel column chromatography (DCM: MeOH =20:1) to give title compound (550 mg, yield:46 %) as a yellow solid. ESI-MS (M+H)⁺: 335.1. Step 2: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1- carboxylate. [01051] To a solution of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-(hydroxymethyl)piperazine-1-carboxylate (200 mg, 0.598 mmol) in THF (13 mL) were added 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (148 mg, 0.897 mmol), TEA (1.3 mL) and triphosgene (266 mg, 0.897 mmol). The mixture was stirred at r.t for 16 h. The reaction mixure was diluted with water (10 mL) and extracted with DCM: MeOH =10:1 (10 mL×3), the combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and filtrate was concentrated in vacuo, the crude was purified by silica gel column chromatography (DCM: MeOH =10:1) to give title compound (100 mg, yield: 28 %) as a yellow solid. ESI-MS (M+H)⁺: 526.2. Step 3: Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01052] To a solution of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1- carboxylate (80 mg, 0.152 mmol) in CH₂Cl₂ (2 mL) was added TFA (1 mL). The mixture was stirred at r.t for 1 h. The mixture was concentrated, the crude was purified by Prep-HPLC (0.1% HCl in H₂O / MeCN) to give title product (25.13 mg, yield: 35%) as a white solid. ESI-MS (M+H)⁺: 426.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 9.67 (d, J = 4.0 Hz, 1H), 9.54 (s, 1H), 9.29 (s, 1H), 8.17 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.06 – 4.03 (m, 2H), 3.86 – 3.84 (m, 2H), 3.71 – 3.69 (m, 2H), 3.32 – 3.29 (m, 3H), 3.21 – 3.19 (m, 4H), 2.45 (s, 3H). Example 381 – Preparation of (S)-N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin- 6-yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01053] To a solution of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 7-(difluoromethyl)-2- methylimidazo[1,2-a]pyridin-6-amine (73.28 mg, 0.37 mmol) in THF (10 mL) were added TEA (93.93 mg, 0.93 mmol) and triphosgene (184.14 mg, 0.62 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (80 mg, 47.70%) as a white solid. ESI-MS (M+H) ⁺: 542.3. Step 2: Preparation of (S)-N-(7-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01054] A mixture of tert-butyl (S)-4-(1-((7-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (80 mg,0.15 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (27.42 mg, 38.30%) as a white solid. ESI-MS (M+H) ⁺:441.9. ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 9.09 (s, 1H), 8.19 (s, 1H), 7.87 – 7.79 (m, 2H), 7.71 (s, 1H), 7.13 (t, J = 54.4 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.01 – 3.96 (m, 2H), 3.63 – 3.59 (m, 2H), 3.16 – 3.12 (m, 2H), 3.02 – 2.97 (m, 1H), 2.92 – 2.63 (m, 4H), 2.35 (s, 3H), 1.05 (d, J = 6.2 Hz, 3H).

Example 382 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4-(2- hydroxy-2-methylpropyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide.

Step 1: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4-(2-hydroxy-2- methylpropyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01055] To a mixture of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride (90 mg, 0.21 mmol) in EtOH (3 mL) were added 2,2-dimethyloxirane (75 mg, 1.04 mmol), K₂CO₃ (87 mg, 0.63 mmol), the mixture was stirred at 120 ℃ for 40 min on M.W. The reaction mixture was diluted with water (5 mL) and extracted with EA (5 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title product (3.41 mg, 6 %) as a white solid. ESI-MS (M+H) ⁺: 468.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1H), 9.20 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 6.2 Hz, 1H), 7.71 (s, 1H), 7.42 (d, J = 11.6 Hz, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.14 (s, 1H), 4.04 – 3.97 (m, 2H), 3.29 – 3.27 (m, 4H), 3.14 (t, J = 8.7 Hz, 2H), 2.65 – 2.61 (m, 4H), 2.28 (s, 3H), 2.24 (s, 2H), 1.11 (s, 6H). Example 383 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of methyl 2-bromo-5-methoxyisonicotinate. [01056] To a mixture of 2-bromo-5-fluoroisonicotinic acid (30 g, 40.32 mmol) in MeOH (200 mL) was added MeONa-MeOH (5.4 mol/mL) (76 mL, 409.08 mmol). The mixture was added at for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in MeOH (100 mL), SOCl₂ (48 g, 409.08 mmol) was added dropwise to the mixture and stirred at r.t for 16 h. After concentration the residue was diluted with EA (300 mL), washed with H2O and brine, dried with Na₂SO₄ and concentrated in vacuo. The crude product was purified by silica gel column (PE: EA= 5:1) to give title product (30 g, 89%) as a white solid. ESI-MS (M+H) ⁺: 246.3. Step 2: Preparation of N-(7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine. [01057] To a solution of methyl 2-bromo-5-methoxyisonicotinate (5 g, 20.24 mmol) in 1,4-dioxane (100 mL) were added diphenylmethanimine (7.3 g, 40.48 mmol), Pd(OAc)₂ (455 mg, 2.02 mmol), BINAP (2.5 g, 4.05 mmol), Cs₂CO₃ (13 g, 40.48 mmol). The mixture was stirred at 115 ℃ for 5 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=3:1) to give title product (7 g, yield: 99 %) as a yellow oil. ESI-MS (M+H) ⁺:347.2.¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.71 (d, J = 7.3 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 7.1 Hz, 3H), 7.07 (dd, J = 7.6, 1.5 Hz, 2H), 6.89 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H). Step 3: Preparation of methyl 2-amino-5-methoxyisonicotinate. [01058] To a solution of methyl 2-((diphenylmethylene)amino)-5- methoxyisonicotinate (6.5 g, 18.73 mmol) in EA (30 mL) was added 4M HCl/EA (30 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo. The reaction mixture was diluted with water (30 mL) and washed with EA (30 mL x 2). The aqueous phase was adjust pH=9 with sat. NaHCO₃, then extracted with EA (30 mL x 3). The organic layer was washed with brine, dried over Na₂SO₄ and concentration in vacuo to give title product (2.8 g, 81 %) as a yellow solid. ESI-MS (M+H) ⁺: 183.5.¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 6.84 (s, 1H), 4.32 (s, 2H), 3.89 (d, J = 9.6 Hz, 6H). Step 4: Preparation of 1,2-diamino-5-methoxy-4-(methoxycarbonyl)pyridin-1-ium 2,4,6- trimethylbenzenesulfonate. [01059] To a solution of methyl 2-amino-5-methoxyisonicotinate (2 g, 10.93 mmol) in trichloromethane (30 mL) was added O-(mesitylsulfonyl) hydroxylamine (4.7 g, 21.85 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo to give title product (6 g, crude) as a yellow oil. ESI-MS (M+H) ⁺: 198.1. Step 5: Preparation of methyl 6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7- carboxylate. [01060] To a mixture of 1,2-diamino-5-methoxy-4-(methoxycarbonyl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (6 g, 15.11 mmol) in Ac₂O (30 mL) was added O- (mesitylsulfonyl)hydroxylamine (580 mg, 3.40 mmol). The mixture was stirred at 100 ^oC for 16 h. The reaction was quenched with H₂O (50 mL). The resulting mixture was adjusted to PH=9 with NaOH aqueous solution (1M), and extracted with DCM (80 mL×3). The combined organic layers were washed with brine (80 mL×3), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: EA=3:1) to give title product (2.3 g, yield: 67 %) as a yellow solid. ESI-MS (M+H) ⁺: 222.1. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 8.01 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 2.60 (s, 3H). Step 6: Preparation of 6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid. [01061] To a mixture of methyl 6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7- carboxylate (500 mg, 2.26 mmol) in THF (5 mL) and water (5 mL) was added LiOH (110 mg, 4.53 mmol). The mixture was stirred at r.t for 2 h. The mixture was concentrated to remove most of THF. The aqueous phase was adjusted pH=5 with 1 M HCl. The mixture was filtered through a Celite pad and collect solid to give title product (130 mg, 27%) as a white solid. ESI-MS (M+H) ⁺: 208.4.¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 7.86 (s, 1H), 3.87 (s, 3H), 2.46 (s, 3H). Step 7: Preparation of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01062] To a solution of 6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7- carboxylic acid (75 mg, 0.36 mmol) in toluene (20 mL) were added TEA (145 mg, 1.44 mmol), DPPA (300 mg, 1.08 mmol). The mixture was stirred at r.t for 1 h and 40 min at 70 ^o C. Then tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (120 mg, 0.36 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (120 mg, yield: 60 %) as a white solid. ESI-MS (M+H) ⁺:537.1.¹H NMR (400 MHz, CDCl₃) δ 12.43 (s, 1H), 8.60 (s, 1H), 8.00 (s, 1H), 7.94 (d, J = 5.9 Hz, 1H), 6.41 (d, J = 6.1 Hz, 1H), 4.29 – 4.26 (m, 2H), 4.21 (d, J = 8.2 Hz, 2H), 4.00 (s, 3H), 3.49 (s, 3H), 3.44 (d, J = 6.5 Hz, 2H), 3.15 (d, J = 8.4 Hz, 2H), 3.04 – 2.99 (m, 2H), 1.50 (s, 9H), 1.37 (d, J = 6.8 Hz, 6H). Step 8: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01063] To a solution of tert-butyl (2R,6S)-4-(1-((6-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.23 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (32.52 mg, 29%) as a white solid. ESI-MS (M+H) ⁺: 437.1.¹H NMR (400 MHz, MeOD-d₄) δ 8.39 (s, 2H), 8.22 (s, 1H), 7.92 (d, J = 5.9 Hz, 1H), 6.51 (d, J = 6.0 Hz, 1H), 4.10 – 4.01 (m, 5H), 3.81 (d, J = 12.7 Hz, 2H), 3.47 – 3.38 (m, 2H), 3.12 (t, J = 8.4 Hz, 2H), 2.83 (dd, J = 13.3, 11.5 Hz, 2H), 2.43 (s, 3H), 1.37 (d, J = 6.5 Hz, 6H).

Example 384 – Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6- methoxy-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 2-fluoro-4-iodo-6-methoxypyridine. [01064] To a solution of 2,6-difluoro-4-iodopyridine (8.6 g, 35.68 mmol) in THF (100 mL) was added MeONa (7.93 mL, 42.82 mmol, 5.4 M in MeOH). The mixture was stirred at rt for 16 h. The reaction mixture was diluted with H₂O (100 mL) and extracted with DCM (100 mL x3). The organics were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title compound (9 g, Y: 99.3%) a yellow oil. ESI-MS (M+H) ⁺: 253.9.¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (t, J = 0.9 Hz, 1H), 7.19 (dd, J = 2.6, 0.9 Hz, 1H), 3.82 (s, 3H). Step 2: Preparation of tert-butyl (2-(2-fluoro-4-iodo-6-methoxypyridin-3-yl)ethyl)carbamate. [01065] To a solution of 2-fluoro-4-iodo-6-methoxypyridine (8 g, 31.50 mmol) in THF (80 mL) was added LDA (23.62 mL, 47.24 mmol, 2.0 M in THF) at -78°C. The mixture was stirred at -78°C for 1.5 h. Then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.13 g, 40.94 mmol) was added and the reaction mixture was stirred at r.t for 16 h. The reaction mixture was quenched with sat. NH₄Cl (100 mL) and extracted with DCM (100 mL x3). The organics were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title compound (10.5 g, Y: 84.0%) a yellow solid. Step 3: Preparation of 2-(2-fluoro-4-iodo-6-methoxypyridin-3-yl)ethan-1-amine HCl salt. [01066] To a solution of tert-butyl (2-(2-fluoro-4-iodo-6-methoxypyridin-3- yl)ethyl)carbamate (10.5 g, 26.45 mmol) in 4M HCl/EA (50 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title compound (8 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 296.9. Step 4: Preparation of 4-iodo-6-methoxy-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine [01067] To a solution of 2-(2-fluoro-4-iodo-6-methoxypyridin-3-yl)ethan-1-amine (8 g, 26.94 mmol) in ACN (80 mL) was added DIEA (20.85 g, 161.62 mmol). The mixture was stirred at 100^oC for 48 h. The mixture was diluted with H₂O (200 mL), extracted with DCM (200 mL*3), organic layer was concentrated in vacuo to give title compound (5.6 g, Y: 75.1%) as a yellow solid. ESI-MS (M+H) ⁺: 277.0. Step 5: Preparation of 1-(4-iodo-6-methoxy-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1- yl)ethan-1-one. [01068] To a mixture of 4-iodo-6-methoxy-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (5.6 g, 20.22 mmol) and TEA (6.13 g, 60.66 mmol) in DCM (80 mL) was added acetyl chloride (3.15 g, 40.43 mmol) at 0^oC, the mixture was stirred at 0^oC for 4 h. The mixture was diluted with H₂O (80 mL), extracted with DCM (100 mL*3), organic layer was concentrated in vacuo to give title product (5.5 g, Y: 85.3%) as a yellow solid. ESI-MS (M+H) ⁺: 318.9.¹H NMR (400 MHz, DMSO-d₆) δ 6.90 (s, 1H), 4.03 (t, J = 8.7 Hz, 2H), 3.88 (s, 3H), 2.91 (t, J = 8.7 Hz, 2H), 2.61 (s, 3H). Step 6: Preparation of tert-butyl (S)-4-(1-acetyl-6-methoxy-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [01069] A mixture of 1-(4-iodo-6-methoxy-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1- yl)ethan-1-one (5 g, 15.72 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (4.72 g, 23.58 mmol), BINAP (1.96 g, 3.14 mmol), Cs₂CO₃ (15.33 g, 47.17 mmol) and Pd₂(dba)₃ (1.44 g, 1.57 mmol) in 1,4-dioxane (50 mL) was stirred at 100^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 3: 1) to give title product (4 g, Y: 65.3%) as a yellow oil. ESI-MS (M+Na) ⁺: 413.1.¹H NMR (400 MHz, DMSO-d₆)δ 5.85 (s, 1H), 4.23 – 4.12 (m, 1H), 3.97 – 3.87 (m, 2H), 3.78 (s, 3H), 3.78 – 3.72 (m, 1H), 3.45 (t, J = 13.0 Hz, 2H), 3.20 – 3.07 (m, 1H), 3.03 – 2.85 (m, 3H), 2.82 – 2.70 (m, 1H), 2.54 (s, 3H), 1.42 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 7: Preparation of tert-butyl (S)-4-(6-methoxy-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2-methylpiperazine-1-carboxylate. [01070] A mixture of tert-butyl (S)-4-(1-acetyl-6-methoxy-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (2.5 g, 6.41 mmol) and KOH (1.795g, 32.05 mmol) in THF/MeOH/H₂O (10 /10 / 5mL) was stirred at 50 ^oC for 16 h. The mixture was diluted with H₂O (30 mL), extracted with DCM (30 mL*3), organic layer concentrated in vacuo to give title product (2 g, Y: 89.7%) as a yellow solid. ESI-MS (M+H) ⁺: 349.1.¹H NMR (400 MHz, DMSO-d₆) δ 5.88 (s, 1H), 4.18 – 4.08 (m, 1H), 3.80 – 3.72 (m, 2H), 3.68 (s, 3H), 3.43 – 3.39 (m, 2H), 3.13 – 2.75 (m, 5H), 2.72 – 2.61 (m, 1H), 1.42 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 8: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-6-methoxy-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01071] To a mixture of tert-butyl (S)-4-(6-methoxy-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (150 mg, 0.43 mmol), 7-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (107 mg, 0.64 mmol) and TEA (641 mg, 6.40 mmol) in THF (12 mL) was added triphosgene (255 mg, 0.86 mmol) at 0^oC, the mixture was stirred at RT for 16 h . The mixture was concentrated in vacuo and purified by silica gel column (100%EA) to give title product (120 mg, Y: 51.7%) as a yellow solid. ESI-MS (M+H) ⁺: 539.8. Step 9: Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methoxy-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01072] A mixture of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-6-methoxy-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (100 mg, 0.20 mmol) in 4M HCl / EA (4 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (68 mg, Y: 83.4 %) as a white solid. ESI-MS (M+H) ⁺: 440.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (d, J = 2.0 Hz, 1H), 9.64 (d, J = 6.8 Hz, 1H), 9.20 (s, 1H), 8.85 (s, 1H), 8.10 (s, 1H), 7.99 (d, J = 10.5 Hz, 1H), 6.02 (s, 1H), 4.06 (t, J = 8.7 Hz, 2H), 3.92 (s, 3H), 3.76 (d, J = 11.2 Hz, 2H), 3.40 – 3.32 (m, 2H), 3.17 – 3.06 (m, 4H), 3.00 – 2.90 (m, 1H), 2.42 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 385 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-methoxy-2- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Compound 385 Step 1: Preparation of tert-butyl 3-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. [01073] To a solution of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.31 mmol) , 7-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine hydrochloride (79.18 mg, 0.37 mmol) in THF (10 mL) were added TEA (93.93 mg, 0.93 mmol) and triphosgene (184.14 mg, 0.62 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (80 mg, 49.94%) as a white solid. ESI-MS (M+H) ⁺:535.4. Step 2: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01074] A mixture of tert-butyl 3-(1-((7-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (80 mg,0.15 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep- HPLC (0.05% FA in water / CH₃CN) to give title product (11.84 mg, 16.44%) as a white solid. ESI-MS (M+H) ⁺:435.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.34 (s, 1H), 9.36 (s, 1H), 8.27 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.18 (s, 1H), 6.45 (d, J = 6.2 Hz, 1H), 4.07 (s, 3H), 4.00 – 3.95 (m, 2H), 3.57 – 3.56 (m, 2H), 3.48 – 3.47 (m, 2H), 3.20 – 3.16 (m, 2H), 3.07 – 3.01 (m, 2H), 2.38 (s, 3H), 1.81 – 1.67 (m, 4H). Example 386 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(2,8- dimethylimidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 3-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [01075] To a mixture of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.36 mmol) in THF (20 mL) were added 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine hydrochloride (86 mg, 0.44 mmol), TEA (728 mg, 7.20 mmol) and triphosgene (130 mg, 0.44 mmol) (in THF ( 1 mL)) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE= 3:1) to give title product (70 mg, yield: 37 %) as a white solid. ESI-MS (M+H) ⁺:519.2.¹H NMR (400 MHz, CDCl₃) δ 12.07 (s, 1H), 8.86 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.39 (s, 1H), 6.32 (d, J = 6.1 Hz, 1H), 4.33 – 4.32 (m, 2H), 4.19 – 4.11 (m, 2H), 3.41 (d, J = 9.5 Hz, 2H), 3.19 – 3.03 (m, 4H), 2.84 (s, 3H), 2.49 (s, 3H), 2.01 – 1.95 (m, 2H), 1.87 (d, J = 7.3 Hz, 2H), 1.49 (s, 9H). Step 2: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(2,8-dimethylimidazo[1,2- a]pyrazin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01076] To a mixture of tert-butyl 3-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (50 mg, 0.096 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure to give title compound (37.95 mg, 85 %) as a white solid. ESI-MS (M+H) ⁺:419.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (s, 1H), 9.59 (s, 1H), 9.46 (s, 1H), 9.23 (s, 1H), 8.31 (s, 1H), 7.99 (d, J = 6.1 Hz, 1H), 6.59 (d, J = 6.3 Hz, 1H), 4.11 (s, 2H), 4.04 (s, 2H), 3.68 (d, J = 12.2 Hz, 2H), 3.40 (d, J = 12.3 Hz, 2H), 3.21 (t, J = 8.6 Hz, 2H), 2.82 (s, 3H), 2.54 (s, 3H), 1.97 (dd, J = 19.6, 9.4 Hz, 4H). Example 387 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2-methyl- [1,2,4] triazolo[1,5-a] pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1- carboxamide formate.

C^{ompound 387} Step 1: Preparation of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((2-methyl- [1,2,4] triazolo[1,5-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1- carboxylate. [01077] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2,6-dimethylpiperazine-1-carboxylate (200 mg, 0.6 mmol), 2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine (224 mg, 1.5 mmol) and TEA (204 mg, 2 mmol) in THF (10 mL) was added triphosgene (400 mg, 1.3 mmol) at 0^oC and the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column (PE: EA = 1: 4) to give title compound (96 mg, Y: 28.9%) as a yellow solid. ESI- MS (M+H) ⁺: 507.2 Step 2: 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2-methyl- [1,2,4] triazolo[1,5-a] pyridin- 6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate. [01078] A mixture of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((2-methyl- [1,2,4] triazolo[1,5-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (80 mg, 0.16 mmol) in 4M HCI/EA (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (16.18 mg, 26.1%) as a white solid. ESI-MS (M+H) ⁺: 407.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 9.25 (d, J = 1.3 Hz, 1H), 8.21 (s, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.68 (d, J = 9.3 Hz, 1H), 7.59 (dd, J = 9.5, 2.0 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 3.99 – 3.98 (m, 2H), 3.64 – 3.62 (m, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.90 – 2.81 (m, 2H), 2.44 (s, 3H), 1.03 (d, J = 6.3 Hz, 6H). Example 388 – Preparation of (R)-N-(2-methyl- [1,2,4] triazolo[1,5-a] pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 2,2-dimethyl-4-(1-((2-methyl-2H-indazol-5-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate. [01079] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (200 mg, 1.3 mmol), 2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-amine (215 mg, 0.67 mmol) and TEA (204 mg, 2 mmol) in THF (10 mL) was added triphosgene (400 mg, 1.3 mmol) at 0 ^oC and the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column (PE: EA = 5:1) to give title compound (107 mg, Y: 15.6%) as a white solid. ESI-MS (M+H) ⁺: 493.2 Step 2: (R)-N-(2-methyl- [1,2,4] triazolo[1,5-a] pyridin-6-yl)-4-(3-methylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate. [01080] A mixture of tert-butyl (R)-2-methyl-4-(1-((2-methyl- [1,2,4] triazolo[1,5-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1- carboxylate (92 mg, 0.18 mmol) in 4M HCI/EA (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (31.18 mg, 42%) as a white solid. ESI-MS (M+H) ⁺: 393.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 9.25 (d, J = 1.3 Hz, 1H), 8.23 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.72 – 7.63 (m, 1H), 7.59 (dd, J = 9.5, 2.0 Hz, 1H), 6.55 (d, J = 6.2 Hz, 1H), 3.99 – 3.98 (m, 2H), 3.62 (d, J = 12.1 Hz, 2H), 3.13 (t, J = 8.5 Hz, 2H), 3.00 (d, J = 11.6 Hz, 1H), 2.90 – 2.82 (m, 2H), 2.60 – 2.53 (m, 2H), 2.44 (s, 3H), 1.05 (d, J = 6.3 Hz, 3H). Example 389 – Preparation of (S)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate.

Step 1: Preparation of phenyl (6-fluoro-2-methyl-2H-indazol-5-yl)carbamate. [01081] To a mixture of 6-fluoro-2-methyl-2H-indazol-5-amine (2.5 g, 15.15 mmol) and pyridine (3.59 g, 45.45 mmol) in DCM (100 mL) was added phenyl carbonochloridate (3.54 g, 22.73 mmol), the mixture was stirred at 0 ^oC for 1 h. The mixture was diluted with water (100 mL), extracted with DCM (100 mL×3). The organic layer was washed with brine (500 mL), dried with Na₂SO₄ and concentrated in vacuo to give title product (5 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 286.0. Step 2: Preparation of tert-butyl (S)-4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [01082] A mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (3.7 g, 11.69 mol), phenyl (6-fluoro-2-methyl-2H-indazol-5- yl)carbamate (5 g, 17.54 mmol), and TEA (3.54 g, 35.07 mmol) in THF (100 mL) was stirred at 70 ^oC for 16 h. The mixture was diluted with water, stirred at rt for 1 h. The precipitate was filtered and diluted with MeOH, stirred at RT for 1 h to afford title product (5 g, 87.7%) as a yellow solid. ESI-MS (M+H) ⁺: 510.2.¹H NMR (400 MHz, CDCl₃) δ 12.06 (d, J = 2.8 Hz, 1H), 8.54 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.81 (s, 1H), 7.34 (d, J = 11.8 Hz, 1H), 6.35 (d, J = 6.0 Hz, 1H), 4.34 (s, 1H), 4.23 – 4.16 (m, 5H), 3.96 (d, J = 13.3 Hz, 1H), 3.49 (d, J = 5.3 Hz, 1H), 3.42 (d, J = 12.4 Hz, 1H), 3.27 – 3.19 (m, 1H), 3.14 – 3.05 (m, 3H), 2.99 – 2.90 (m, 1H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H). Step 3: Preparation of (S)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01083] A mixture of tert-butyl (S)-4-(1-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (7 g, 13.75 mmol) in 4M HCl /EA (100 mL) was stirred at RT for 2 h. The precipitate was filtered and diluted with water (50 mL), adjusted pH to 7~8 by 1N Na₂CO₃. The precipitate was filtered, washed with water (100 mL*2) and dried in vacuo to give title product (4.5 g, yield: 80.02 %) as a pink solid. ESI-MS (M+H) ⁺: 410.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (d, J = 2.8 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 7.88 (d, J = 6.1 Hz, 1H), 7.44 (d, J = 12.2 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.12 (s, 3H), 4.00 (t, J = 8.5 Hz, 2H), 3.61 (d, J = 11.8 Hz, 2H), 3.13 (t, J = 8.6 Hz, 2H), 3.00 (d, J = 11.0 Hz, 1H), 2.91 – 2.77 (m, 3H), 2.59 – 2.52 (m, 1H), 1.05 (d, J = 6.3 Hz, 3H). Step 4: Preparation of (S)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate. [01084] A mixture of (S)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (4.49 g, 10.98 mmol) and benzoic acid (1.406 g, 11.53 mmol) in MeOH / DCM (200 mL /10 mL) was stirred at 50 ^oC for 16 h. The mixture was concentrated in vacuo to removed most of DCM (1/2 V). The precipitate was filtered and dried to afford title product (4.28 g, yield: 73.40 %) as a pink solid ESI-MS (M+H) ⁺: 410.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (d, J = 2.7 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 7.95 – 7.92 (m, 2H), 7.87 (d, J = 6.1 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.44 (d, J = 12.2 Hz, 1H), 6.51 (d, J = 6.2 Hz, 1H), 4.12 (s, 3H), 3.99 (t, J = 8.6 Hz, 2H), 3.60 (d, J = 11.7 Hz, 3H), 3.13 (s, 2H), 2.96 (d, J = 11.1 Hz, 1H), 2.86 – 2.77 (m, 3H), 1.03 (d, J = 6.3 Hz, 3H). Example 390 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-fluoro-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [01085] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (200 mg, 0.60 mmol), 6-fluoro-2-methyl-2H-indazol-5- amine (145 mg, 0.90 mmol), triphosgene (268 mg, 0.90 mmol) and TEA (730 mg, 7.23 mmol) in THF (20 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at rt for 1 h. The precipitate was filtered and triturated with MeOH (5 mL) to afford title product (200 mg, 62%) as a yellow solid. ESI-MS (M+H) ⁺: 524.0. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-fluoro-2-methyl-2H-indazol-5- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01086] A mixture of tert-butyl 4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (200 mg, 0.38 mmol) in 4M HCl / EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (39.87 mg, yield: 24.80 %) as a white solid. ESI-MS (M+H) ⁺: 424.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (d, J = 2.7 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 12.2 Hz, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.12 (s, 3H), 4.01 (t, J = 8.5 Hz, 2H), 3.27 – 3.23 (m, 2H), 3.13 (t, J = 8.6 Hz, 2H), 3.09 (s, 2H), 3.00 – 2.96 (m, 2H), 1.18 (s, 6H). Example 391 – Preparation of 4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-N-(7-fluoro- 2-methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Compound 391 Step 1: Preparation of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-9-carboxylate. [01087] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (163 mg, 1.05 mmol), tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (200 mg, 0.88 mmol) in DIEA (1 mL) was stirred at 140^oC for 24 h in a sealed tube. The mixture was concentrated in vacuo and purified by silica gel column (DCM:MeOH=20:1) to give title product (130 mg, Y: 42.7%) as a yellow solid. ESI-MS (M+H) ⁺: 347.1. Step 2: Preparation of tert-butyl 7-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-9-carboxylate. [01088] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3- oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.29 mmol), 7-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (71.8 mg, 0.43 mmol) and TEA (431 mg, 4.30 mmol) in THF (6 mL) was added triphosgene (128 mg, 0.43 mmol) at 0^oC, the mixture was stirred at RT for 16 h . The mixture was concentrated in vacuo and purified by silica gel column (100%EA) to give title product (50 mg, Y: 32.3%) as a yellow solid. ESI-MS (M+H) ⁺: 538.2. Step 3: Preparation of 4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01089] A mixture of tert-butyl 7-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-9-carboxylate (40 mg, 0.07 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % TFA in water / CH₃CN) to give title product (16 mg, Y: 49.1 %) as a yellow solid. ESI-MS (M+H) ⁺: 338.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (s, 1H), 9.68 (s, 1H), 9.67 (d, J = 6.6 Hz, 1H), 8.16 (s, 1H), 8.08 (d, J = 10.0 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 6.59 (d, J = 6.3 Hz, 1H), 4.18 – 4.13 (m, 4H), 4.01 – 3.96 (m, 4H), 3.65 – 3.55 (m, 4H), 3.26 (t, J = 8.5 Hz, 2H), 2.45 (s, 3H). Example 392 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-fluoro- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Compound 392 Step 1: Preparation of (E)-N'-(5-bromo-4-fluoropyridin-2-yl)-N,N-dimethylformimidamide. [01090] To a mixture of 5-bromo-4-fluoropyridin-2-amine (50 g, 263.2 mmol) and DMF-DMA (43.8 g, 368.4 mmol) in DMF (300 mL) was stirred at 80℃ for 4 h. The mixture diluted with H₂O (1000 mL) and the precipitate was filtered, washed with water and dried in vacuo to give title product (30 g, Y: 46.4%) as a yellow solid. ESI-MS (M+H) ⁺: 246.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.34 (d, J = 10.5 Hz, 1H), 6.77 (d, J = 11.0 Hz, 1H), 3.10 (s, 3H), 2.99 (s, 3H). Step 2: Preparation of (E)-N'-(5-bromo-4-fluoropyridin-2-yl)-N-hydroxyformimidamide. [01091] To a mixture of (E)-N'-(5-bromo-4-fluoropyridin-2-yl)-N,N- dimethylformimidamide (28 g, 113.82 mmol) and NH₂-OH.HCl(15.7 g, 227.64 mmol) in MeOH (300 mL) was stirred at 80℃ for 1h. The reaction was concentrated in vacuo to give title product (30 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 235.9. Step 3: Preparation of 6-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine. [01092] To a mixture of (E)-N'-(5-bromo-4-fluoropyridin-2-yl)-N- hydroxyformimidamide (25 g, 106.84 mmol) in THF (300 mL) was added TFAA (44.87 g, 213.86 mmol) at 0℃. The reaction solution was stirred at rt for 16 h. The reaction was concentrated in vacuo and purified by silica gel column chromatography (PE: EA=3:1) to give title product (14 g, Y: 60.6%) as a yellow solid. ESI-MS (M+H) ⁺: 217.9.¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (d, J = 6.4 Hz, 1H), 8.55 (s, 1H), 8.01 (d, J = 8.9 Hz, 1H). Step 4: Preparation of N-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine. [01093] A mixture of 6-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine (9 g, 41.67 mmol), diphenylmethanimine (9.1 g, 49.99 mmol), BINAP (5.2 g, 8.35 mmol), Pd(OAc)₂(1.02 g, 4.18 mmol) and Cs₂CO₃ (40.63 g, 125.01 mmol) in dioxane (100 mL) was stirred at 110℃ for 16 h under N₂. The reaction concentrated in vacuo to and purified by silica gel chromatography (PE: EA=2:1) to give title product (3 g, Y: 22.7%) as a yellow solid. ESI-MS (M+H) ⁺: 317.0. Step 5: Preparation of 7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-amine HCl salt. [01094] A mixture of N-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine (2.5 g, 7.89 mmol) in 4 M HCl/EA (25 mL) was stirred at RT for 16h. The mixture diluted with EA (100 mL), the precipitate was filtered to give title product (700 mg, y: 58.0%) as a yellow solid. ESI-MS (M+H) ⁺: 153.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 1H), 8.53 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 10.1 Hz, 1H) Step 6: Preparation of tert-butyl 3-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. [01095] To a mixture of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.45 mmol), 7-fluoro-[1,2,4]triazolo[1,5- a]pyridin-6-amine (69.3 mg, 0.45 mmol) and TEA (687 mg, 6.80 mmol) in THF (12 mL) was added triphosgene (202 mg, 0.68 mmol) at 0^oC, the mixture was stirred at RT for 16 h . The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:10) to give title product (140 mg, Y: 60.7%) as a yellow solid. ESI-MS (M+H) ⁺: 509.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (d, J = 2.4 Hz, 1H), 9.56 (d, J = 6.8 Hz, 1H), 8.44 (s, 1H), 7.96 (d, J = 10.8 Hz, 1H), 7.89 (d, J = 6.1 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.22 (s, 2H), 4.02 (t, J = 8.6 Hz, 2H), 3.57 (d, J = 10.8 Hz, 2H), 3.22 (t, J = 8.6 Hz, 2H), 3.03 (d, J = 11.1 Hz, 2H), 1.90 – 1.76 (m, 4H), 1.43 (s, 9H). Step 7: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-fluoro-[1,2,4]triazolo[1,5- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01096] A mixture of tert-butyl 3-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylatee (120 mg, 0.24 mmol) in 4M HCl / EA (6 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (49 mg, Y: 51.0 %) as a white solid. ESI-MS (M+H) ⁺: 409.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (d, J = 2.3 Hz, 1H), 9.56 (d, J = 6.8 Hz, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 7.95 (d, J = 10.9 Hz, 1H), 7.86 (d, J = 6.1 Hz, 1H), 6.46 (d, J = 6.2 Hz, 1H), 4.04 – 3.96 (m, 2H), 3.58 – 3.53 (m, 2H), 3.50 (d, J = 11.7 Hz, 2H), 3.20 (t, J = 8.5 Hz, 2H), 3.04 (d, J = 10.3 Hz, 2H), 1.78 – 1.63 (m, 4H).

Example 393 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01097] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 7-fluoro-[1,2,4]triazolo[1,5- a]pyridin-6-amine (68 mg, 0.45 mmol) and TEA (687 mg, 6.80 mmol) in THF (12 mL) was added triphosgene (200.68 mg, 0.68 mmol) at 0^oC, the mixture was stirred at RT for 16 h . The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:6) to give title product (90 mg, Y: 39.2%) as a yellow solid. ESI-MS (M+H) ⁺: 511.3. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01098] A mixture of tert-butyl (2R,6S)-4-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (70 mg, 0.14 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (29 mg, Y: 51.8 %) as a white solid. ESI-MS (M+H) ⁺: 411.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (d, J = 2.2 Hz, 1H), 9.56 (d, J = 6.8 Hz, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 7.95 (d, J = 10.9 Hz, 1H), 7.87 (d, J = 6.1 Hz, 1H), 6.55 (d, J = 6.2 Hz, 1H), 4.04 – 3.97 (m, 2H), 3.64 (d, J = 10.8 Hz, 2H), 3.16 (d, J = 8.5 Hz, 2H), 2.88 – 2.78 (m, 2H), 2.42 (d, J = 10.8 Hz, 2H), 1.02 (d, J = 6.3 Hz, 6H). Example 394 – Preparation of (R)-N-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of methyl (E)-2-(((dimethylamino)methylene)amino)-5- methoxyisonicotinate. [01099] To a mixture of methyl 2-amino-5-methoxyisonicotinate (4.5 g, 24.59 mmol) in MeOH (100 mL) was DMF-DMA (4.4 g, 36.89 mmol). The mixture was added at 75^oC for 3 h. The reaction mixture was diluted with water (100 mL) and extrated with EA (100 mLx3). The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to give title product (5 g, 85%) as a yellow solid. ESI-MS (M+H) ⁺: 238.2.¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 8.05 (s, 1H), 7.28 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.08 (s, 6H). Step 2: Preparation of methyl 6-methoxy-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate. [01100] To a solution of methyl (E)-2-(((dimethylamino)methylene)amino)-5- methoxyisonicotinate (6 g, 25.32 mmol) in MeOH (60 mL) was added Pyridine (6 mL) (aminooxy)sulfonic acid (4.3 g, 37.97 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was filtered through a Celite pad and collect solid to give title product (1 g, 18%) as a white solid. ESI-MS (M+H) ⁺: 208.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 3.91 (s, 3H), 3.88 (s, 3H). Step 3: Preparation of 6-methoxy-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid. [01101] To a mixture of methyl (E)-2-(((dimethylamino)methylene)amino)-5- methoxyisonicotinate (500 mg, 2.04 mmol) in THF (5 mL) and water (5 mL) was added LiOH (115 mg, 4.81 mmol). The mixture was stirred at r.t for 2 h. The mixture was concentrated to remove most of THF. The aqueous phase was adjusted pH=5 with 1 M HCl. The mixture was filtered through a Celite pad and collect solid to give title product (400 mg, 85%) as a white solid. ESI-MS (M+H) ⁺: 194.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.51 (s, 1H), 8.03 (s, 1H), 3.90 (s, 3H). Step 4: Preparation of tert-butyl (R)-4-(1-((6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01102] To a solution of 6-methoxy-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (92 mg, 0.47 mmol) in toluene (20 mL) were added TEA (90 mg, 1.88 mmol), DPPA (390 mg, 1.41 mmol). The mixture was stirred at r.t for 1 h and 40 min at 70 ^o C. Then tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (80 mg, yield: 33 %) as a white solid. ESI-MS (M+H) ⁺:509.3.¹H NMR (400 MHz, CDCl₃) δ 12.48 (s, 1H), 8.72 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.93 (d, J = 6.0 Hz, 1H), 6.37 (d, J = 6.0 Hz, 1H), 4.35 – 4.34 (m, 1H), 4.23 – 4.16 (m, 2H), 4.03 (s, 3H), 3.97 (d, J = 13.4 Hz, 1H), 3.53 (d, J = 11.3 Hz, 1H), 3.44 (d, J = 12.6 Hz, 1H), 3.28 – 3.20 (m, 1H), 3.16 – 3.07 (m, 3H), 2.97 – 2.96 (m, 1H), 1.49 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H). Step 5: Preparation of (R)-N-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01103] To a solution of tert-butyl (R)-4-(1-((6-methoxy-[1,2,4]triazolo[1,5-a]pyridin- 7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (60 mg, 0.12 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (40.17 mg, 64%) as a white solid. ESI-MS (M+H) ⁺:409.1.¹H NMR (400 MHz, MeOD-d₄) δ 8.50 (s, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.91 (d, J = 5.9 Hz, 1H), 6.47 (d, J = 6.0 Hz, 1H), 4.13 – 4.05 (m, 5H), 3.76 (d, J = 13.5 Hz, 2H), 3.48 (dd, J = 9.3, 5.5 Hz, 2H), 3.27 (d, J = 9.6 Hz, 1H), 3.21 – 3.09 (m, 3H), 2.96 (dd, J = 13.7, 10.4 Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H). Example 395 – Preparation of (R)-N-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. NH

Step 1: Preparation of 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine. [01104] A mixture of 5-bromo-2H-pyrazolo[3,4-b]pyridine (25.2 g, 127.27 mmol), trimethyloxonium tetrafluoroborate (20.72 g, 140 mmol) in EA (250 mL) was stirred at RT for 2 h. the mixture was diluted with water (200 mL), extracted with EA (200 mL×3). The organic layer was washed with brine (200 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 63 %) to give title product (5.7 g, yield: 21.22 %) as a yellow solid. ESI-MS (M+H) ⁺: 214.0.¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.90 (s, 1H), 4.25 (s, 3H). Step 2: Preparation of N-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,1- diphenylmethanimine. [01105] A mixture of 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (5.1 g, 24.28 mmol), diphenylmethanimine (5.3 g, 29.14 mmol), Pd₂(dba)₃ (2.22 g, 2.43 mmol), BINAP (3 g, 4.80 mmol) and Cs₂CO₃ (15.8 g, 48.56 mmol) in 1,4-dioxnae (100 mL) was stirred at 100 ^oC for 16 h under N₂. The mixture was concentrated in vacuo. The residue was diluted with water (100 mL), extracted with DCM (100 mL×3). The organic layer was washed with brine (100 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 78 %) to give title product (1.5 g, yield: 19.8 %) as a yellow solid. ESI-MS (M+H) ⁺: 313.1.¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J = 2.5 Hz, 1H), 7.79 – 7.75 (m, 2H), 7.70 (s, 1H), 7.51 – 7.47 (m, 1H), 7.45 – 7.41 (m, 2H), 7.27 – 7.24 (m, 4H), 7.16 – 7.12 (m, 2H), 4.17 (s, 3H). Step 3: Preparation of 2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine hydrochloride. [01106] A mixture of N-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,1- diphenylmethanimine (1.5 g, 4.81 mmol) in 4M HCl / EA (20 mL) was stirred at RT for 16 h. The precipitate was filtered and triturated with EA to afford title product (200 mg, 32.32 %) as a white solid. ESI-MS (M+H) ⁺: 149.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (d, J = 2.5 Hz, 1H), 8.56 (s, 1H), 8.31 (d, J = 1.7 Hz, 1H), 4.24 (s, 3H). Step 4: Preparation of tert-butyl (R)-2-methyl-4-(1-((2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01107] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mol), 2-methyl-2H-pyrazolo[3,4-b]pyridin-5- amine hydrochloride (56 mg, 0.38 mmol), triphosgene (113 mg, 0.38 mmol) and TEA (301 mg, 3.77 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at rt for 1h, the precipitate was filtered to afford title product (90 mg, 58.14 %) as a white solid. ESI-MS (M+H) ⁺: 493.3. Step 5: Preparation of (R)-N-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01108] A mixture of tert-butyl (R)-2-methyl-4-(1-((2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (80 mg, 0.16 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 2 h. [01109] The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (51.9 mg, yield: 82.75 %) as a white soild. ESI-MS (M+H) ⁺: 393.2.¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 2H), 8.71 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.86 (s, 1H), 6.84 – 6.82 (m, 1H), 4.20 (s, 3H), 4.06 – 3.95 (m, 2H), 3.74 – 3.04 (m, 9H), 1.32 (d, J = 6.2 Hz, 3H). Example 396 – Preparation of (R)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Boc Step 1: Preparation of tert-butyl (R)-4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [01110] To a solution of 6-fluoro-2-methyl-2H-indazol-5-amine (93 mg, 0.48 mmol) in THF (5 mL) were added tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.45 mmol) and TEA (476 mg, 4.6mmol), triphosgene (168 mg, 0.56 mmol) at 0℃, The mixture was stirred at r.t for 16 h. After concentration, the residue was diluted with water (10 mL), extracted with DCM (10 mLx3). The organic layer washed with brine (10 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE=3:1) to give title product (107 mg, 45 %) as a white solid. ESI-MS (M+H) ⁺:510.3. [01111] Step 2: Preparation of (R)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. To a solution of tert-butyl (R)-4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.25 mmol) in EA (6 mL) was added 3M HCl / EA (6 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (7.74 mg, 8%) as a white solid. ESI-MS (M+H) ⁺:410.0. ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.87 (d, J = 6.2 Hz, 1H), 7.44 (d, J = 12.1 Hz, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.11 (s, 3H), 3.99 (t, J = 8.3 Hz, 2H), 3.61 – 3.57 (m, 2H), 3.15 – 3.11 (m, 2H), 2.96 – 2.92 (m, 1H), 2.87 – 2.75 (m, 4H), 1.02 (d, J = 6.0 Hz, 3H). Example 397 – Preparation of (R)-N-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

C^{ompound 397} Step 1: Preparation of tert-butyl (R)-4-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01112] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (146 mg, 0.46 mmol), 7-fluoro-[1,2,4]triazolo[1,5- a]pyridin-6-amine (70 mg, 0.46 mmol) and TEA (693 mg, 6.86 mmol) in THF (12 mL) was added triphosgene (203 mg, 0.69 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:6) to give title product (80 mg, Y: 35.2%) as a yellow solid. ESI-MS (M+H) ⁺: 497.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.34 (s, 1H), 9.57 (d, J = 6.7 Hz, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 7.67 (s, 1H), 6.56 (d, J = 6.2 Hz, 1H), 4.22 – 4.14 (m, 1H), 4.04 (t, J = 8.5 Hz, 2H), 3.86 – 3.74 (m, 2H), 3.71 – 3.57 (m, 3H), 3.22 – 3.16 (m, 2H), 3.00 – 2.93 (m, 1H), 1.43 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H). Step 2: Preparation of (R)-N-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01113] A mixture of tert-butyl (R)-4-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (60 mg, 0.12 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (28 mg, Y: 59.6 %) as a white solid. ESI-MS (M+H) ⁺: 397.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.37 (d, J = 2.1 Hz, 1H), 9.55 (d, J = 6.7 Hz, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 7.95 (d, J = 10.9 Hz, 1H), 7.88 (d, J = 6.1 Hz, 1H), 6.55 (d, J = 6.2 Hz, 1H), 4.01 (t, J = 8.5 Hz, 2H), 3.62 (d, J = 11.9 Hz, 2H), 3.16 (t, J = 8.5 Hz, 2H), 2.98 – 2.75 (m, 4H), 2.60 – 2.53 (m, 1H), 1.04 (d, J = 6.3 Hz, 3H). Example 398 – Preparation of (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01114] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) in THF (10 mL) were added 2,8- dimethylimidazo[1,2-a]pyrazin-6-amine hydrochloride (74 mg, 0.37 mmol), TEA (627 mg, 6.20 mmol) and triphosgene (110 mg, 0.37 mmol) (in THF ( 1 mL)) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (50 mL) and stirred at r.t for 20 min. The mixture was filtered through a Celite pad and collect solid to give title product (50 mg, yield: 31 %) as a white solid. ESI-MS (M+H) ⁺:507.4.¹H NMR (400 MHz, CDCl₃) δ 12.01 (s, 1H), 8.86 (s, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.39 (s, 1H), 6.37 (d, J = 6.0 Hz, 1H), 4.35 – 4.34 (m, 1H), 4.20 – 4.12 (m, 2H), 3.96 (d, J = 13.5 Hz, 1H), 3.53 – 3.52 (m, 1H), 3.43 (d, J = 12.5 Hz, 1H), 3.15 – 3.12 (m, 4H), 2.95 (dd, J = 11.8, 8.4 Hz, 1H), 2.84 (s, 3H), 2.49 (s, 3H), 1.49 (s, 9H), 1.31 – 1.30 (m, 3H). Step 2: Preparation of (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01115] To a mixture of tert-butyl (R)-4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.079 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title compound (21.83 mg, 61 %) as a white solid. ESI-MS (M+H) ⁺:407.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.87 (s, 1H), 8.47 (s, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.73 (s, 1H), 6.60 (d, J = 6.1 Hz, 1H), 4.15 – 4.06 (m, 2H), 3.78 (d, J = 13.3 Hz, 2H), 3.44 – 3.37 (m, 2H), 3.17 (t, J = 8.7 Hz, 4H), 2.91 (dd, J = 13.5, 10.4 Hz, 1H), 2.75 (s, 3H), 2.45 (s, 3H), 1.35 (d, J = 6.6 Hz, 3H). Example 399 – Preparation of (S)-N-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-4-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01116] A mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mol), 7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- amine (86 mg, 0.57 mmol), triphosgene (169.3 mg, 0.57 mmol) and TEA (571.6 mg, 5.66 mmol) in THF (15 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at rt for 1h, the precipitate was filtered to afford title product (35 mg, 14.98 %) as a white solid. ESI-MS (M+H) ⁺: 497.3.¹H NMR (400 MHz, CDCl₃) δ 12.38 (s, 1H), 9.75 (d, J = 6.7 Hz, 1H), 8.26 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 10.1 Hz, 1H), 6.38 (d, J = 6.1 Hz, 1H), 4.35 – 4.34 (m, 1H), 4.22 – 4.16 (m, 2H), 3.97 (d, J = 13.3 Hz, 1H), 3.55 (d, J = 11.6 Hz, 1H), 3.45 (d, J = 12.4 Hz, 1H), 3.29 – 3.21 (m, 1H), 3.17 – 3.09 (m, 3H), 3.01 – 2.93 (m, 1H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01117] A mixture of tert-butyl (S)-4-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (35 mg, 0.07 mmol) in 4M HCl /EA (1 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (22.17 mg, yield: 73.31 %) as a white solid. ESI-MS (M+H) ⁺: 397.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.47 (s, 1H), 8.89 (s, 1H), 7.96 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 4.42 (t, J = 8.3 Hz, 2H), 4.24 (t, J = 12.7 Hz, 2H), 3.63 – 3.53 (m, 5H), 3.43 – 3.35 (m, 2H), 1.44 (d, J = 6.5 Hz, 3H). Example 400 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methyl-2H-indazol-5- yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 2,2-dimethyl-4-(1-((2-methyl-2H-indazol-5-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate. [01118] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 2-methyl-2H-indazol-5-amine (132.8 mg, 0.95 mmol) and TEA (136.8 mg,1.35 mmol) in THF (20 mL) was added triphosgene (268.3 mg, 0.9 mmol) at 0^oC and the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 9) to give title compound (96 mg, Y: 42.0%) as a yellow solid. ESI-MS (M+H) ⁺: 506.2 Step 2: 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-2,3-dihydro-1H- pyrrolo[2,3-b] pyridine-1-carboxamide formate. [01119] A mixture of tert-butyl 2,2-dimethyl-4-(1-((2-methyl-2H-indazol-5-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (70 mg, 0.14 mmol) in 4M HCI/EA (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH3CN) to give title product (30.8 mg, Y：53.6%) as a brown solid. ESI-MS (M+H) ⁺: 406.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.74 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.55 (d, J = 9.1 Hz, 1H), 7.22 (dd, J = 9.2, 2.0 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 3.99 (t, J = 8.6 Hz, 2H), 3.30 – 3.22 (m, 2H), 3.14 – 3.06 (m, 4H), 3.01 – 2.95 (m, 2H), 1.19 (s, 6H). Example 401 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 4-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01120] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mol), 7-fluoro-[1,2,4]triazolo[1,5-a]pyridin- 6-amine (80 mg, 0.54 mmol), triphosgene (160 mg, 0.54 mmol) and TEA (545 mg, 5.4 mmol) in THF (15 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at rt for 1h, the precipitate was filtered to afford title product (50 mg, 21.78 %) as a white solid. ESI-MS (M+H) ⁺: 511.3. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-[1,2,4]triazolo[1,5- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01121] A mixture of tert-butyl 4-(1-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (40 mg, 0.08 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (24.60 mg, yield: 74.78 %) as a yellow solid. ESI-MS (M+H) ⁺: 411.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.39 (s, 1H), 8.74 (s, 1H), 7.88 – 7.81 (m, 2H), 6.93 – 6.92 (m, 1H), 4.43 – 4.35 (m, 2H), 3.97 – 3.87 (m, 2H), 3.79 – 3.69 (m, 2H), 3.60 – 3.52 (m, 2H), 3.49 – 3.46 (m, 2H), 1.51 (s, 6H). Example 402 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-b] pyridazin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate. D_IBAL-H N Cl DCM, -78 ^oC O Br

_{2 h} step 3

s_{tep 4 step 5} 100 C, 16 h step 6

Compound 402 Step 1: Preparation of 5-bromo-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile. [01122] A mixture of 6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (50 g, 372.74 mmol) and NBS (72.97 g, 408.47 mmol) in DCE (500 mL) was stirred at 90^oC for 16 h. The mixture was diluted with water (300 mL), extracted with DCM (400 mL×3), organic layer was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 3) to give title compound (45 g, Y:57.0%) as a yellow solid. ESI-MS (M+H) ⁺: 215.0. Step 2: Preparation of 5-bromo-2-chloro-6-methylnicotinonitrile. [01123] A mixture of 5-bromo-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (45 g, 213 mmol) in POCl₃ (450 mL) was stirred at 80^oC for 16h. The mixture was concentrated in vacuo and diluted with ice-water (1 L), extracted with DCM (500 mL×3), organic layer was concentrated in vacuo to give title compound (27 g, Y:57.0%) as a yellow solid. ESI-MS (M+H) ⁺: 236.9. Step 3: Preparation of 5-bromo-2-chloro-6-methylnicotinaldehyde. [01124] A mixture of 5-bromo-2-chloro-6-methylnicotinonitrile (20 g, 87.3mmol) and DIBAL-H (86 ml,175.6 mmol) in DCM (500 mL) was stirred at -78^oC for 2h. The mixture was concentrated in vacuo and diluted with water (300 mL), extracted with DCM (300 mL*3), organic layer was concentrated in vacuo to give title compound (5 g, Y:26%) as a white solid. ESI-MS (M+H) ⁺: 235.5. Step 4: Preparation of 5-bromo-6-methyl-2H-pyrazolo[3,4-b] pyridine. [01125] A mixture of 5-bromo-2-chloro-6-methylnicotinaldehyde (4 g, 17 mmol) and NH₂-NH₂ (20 ml) in 1.4-dioxane (50 mL) was stirred at 145^oC for 16h. The mixture diluted with water (50 mL), extracted with DCM (50 mL×3), organic layer and concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 1: 3) to give title compound (2.2 g, Y: 61%) as a white solid. ESI-MS (M+H) ⁺: 213.9¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.12 (s, 1H), 2.74 (s, 3H). Step 5: Preparation of 5-bromo-2,6-dimethyl-2H-pyrazolo[3,4-b] pyridine. [01126] A mixture of 5-bromo-6-methyl-2H-pyrazolo[3,4-b] pyridine (2.2 g,10.3 mmol) and trimethyloxonium tetrafluoroborate (1.53 g,10.3 mmol) in EA (30 mL) was stirred at rt for 2h. The mixture diluted with water (30 mL), extracted with EA (20 mL×3), the organic layer was concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 1: 3) to give title compound (1.5 g, Y: 65%) as a white solid. ESI-MS (M+H) ⁺: 228.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.40 (s, 1H), 4.23 (s, 3H), 2.56 (s, 3H). Step 6: Preparation of N-(2,6-dimethyl-2H-pyrazolo[3,4-b] pyridin-5-yl)-1,1- diphenylmethanimine. [01127] A mixture of 5-bromo-2,6-dimethyl-2H-pyrazolo[3,4-b] pyridine (1 g,4.4 mmol) diphenylmethanimine (4 g,23.7 mmol) BINAP (0.55 g,0.88 mmol) Pd (OAc)₂ (0.047 g, 23.7 mmol) and Cs₂CO₃ (4.3 g, 13.2 mmol) in 1,4-dioxane (50 ml) was stirred at 110℃ for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo, the residue was purified by column chromatography (PE/EA=2:1) to give title product (1.3 g, Y: 90%) as a yellow solid. ESI-MS (M+H)⁺: 327.1¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (s, 1H), 7.78 – 7.71 (m, 2H), 7.61 – 7.45 (m, 3H), 7.35 – 7.26 (m, 3H), 7.22 – 7.15 (m, 2H), 7.00 (s, 1H), 4.05 (s, 3H), 2.46 (s, 3H). Step 7: Preparation of 2,6-dimethyl-2H-pyrazolo[3,4-b] pyridin-5-amine hydrochloride. [01128] A mixture of N-(2,6-dimethyl-2H-pyrazolo[3,4-b] pyridin-5-yl)-1,1- diphenylmethanimine (1 g, 4.4 mmol) in HCI/EA (15 mL) was stirred at rt for 2 h. After concentration, the residue was dissolved in H₂O and basified to pH 10 with Na₂CO₃, extracted with EA (20 mL×3), the organic layer was concentrated in vacuo. The residue was purified by column chromatography (PE/EA=2:1) to give title product 745 mg, Y: 87%) as a yellow solid. ESI-MS (M+H)⁺: 163.1 Step 8: Preparation of tert-butyl 4-(1-((2,6-dimethyl-2H-pyrazolo[3,4-b] pyridin-5-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01129] A mixture of 2,6-dimethyl-2H-pyrazolo[3,4-b] pyridin-5-amine hydrochloride (100 mg, 0.74 mmol), tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (204.9 mg, 0.61 mmol) and TEA (1 mL) in THF (20 ml) was added triphosgene (366.6 mg, 1.23 mmol) at 0^oC and the mixture was stirred at RT for 16h. The mixture was concentrated in vacuo and purified by silica gel chromatography (PE: EA = 1: 10) to give title compound (85 mg, Y: 26.7%) as a yellow solid. ESI-MS (M+H)⁺: 521.2 Step 9: Preparation of N-(2,6-dimethyl-2H-pyrazolo[3,4-b] pyridin-5-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide. [01130] A mixture of tert-butyl 4-(1-((2,6-dimethyl-2H-pyrazolo[3,4-b] pyridin-5-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (85 mg, 0.167 mmol) in 4M HCI/EA (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 % FA in water / ACN) to give title product (35.65 mg, Y：51.9%) as a white solid. ESI-MS (M+H)⁺: 421.2¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.68 (s, 1H), 8.02 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.08 – 3.93 (m, 5H), 3.18 (s, 2H), 3.12 (t, J = 8.5 Hz, 2H), 3.01 (s, 2H), 2.87 (s, 2H), 2.68 (s, 3H), 1.10 (s, 6H). Example 403 – Preparation of (R)-N-(6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 7-yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01131] To a solution of 6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7- carboxylic acid (78 mg, 0.37 mmol) in toluene (20 mL) were added TEA (149 mg, 1.48 mmol), DPPA (305 mg, 1.11 mmol). The mixture was stirred at r.t for 1 h and 40 min at 70 ^o C. Then tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (120 mg, 0.36 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (70 mg, yield: 36 %) as a white solid. ESI-MS (M+H) ⁺:523.3. Step 2: Preparation of (R)-N-(6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01132] To a solution of tert-butyl (R)-4-(1-((6-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (50 mg, 0.096 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (31.40 mg, 71%) as a white solid. ESI-MS (M+H) ⁺: 423.3.¹H NMR (400 MHz, MeOD-d₄) δ 8.44 (s, 2H), 8.27 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 4.12 – 4.05 (m, 5H), 3.80 – 3.73 (m, 2H), 3.44 – 3.37 (m, 2H), 3.25 – 3.12 (m, 4H), 2.97 – 2.85 (m, 1H), 2.44 (s, 3H), 1.35 (d, J = 6.5 Hz, 3H).

Example 404 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(2,7-dimethyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of 2,7-dimethyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine. [01133] To a mixture of 2-chloro-4-methyl-5-nitropyridine (25 g, 145.35 mmol) and 5- methyl-1,3,4-thiadiazol-2-amine (25.07g, 218.03 mmol) in Tol (250 mL) was added DIEA (29.36 mg, 290.70 mmol). The mixture was stirred at 140 ^oC for 72 h in sealed tube. The mixture was diluted with EA (250 mL) and water (250 mL) and the organic phase separated. The aqueous phase was further extracted with DCM (2 x 250mL). The organic phase was washed with brine (250 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (3.6 g, 12.93%) as a yellow solid. ESI-MS (M+H) ⁺: 193.5.¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 1H), 7.86 (s, 1H), 2.70 (s, 3H), 2.58 (s, 3H). Step 2: Preparation of 2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine. [01134] To a mixture of 2,7-dimethyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine (3.6 g, 18.75 mmol) and Raney-Ni (20 mL) in MeOH (40 mL). The mixture was stirred at rt for 16 h under H₂. The mixture was filtered, washed with MeOH and the filtrate was concentrated in vacuo to give title product (2.5 g, 82.30 %) as a black solid. ESI-MS (M+H)⁺:163.5. Step 3: Preparation of tert-butyl 3-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. [01135] To a mixture of 2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (150 mg, 0.93 mmol), tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (305.56 mg, 0.93 mmol) in THF (10 mL) were added TEA (281.79 mg, 2.79 mmol) and triphosgene (550.56 mg, 1.86 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (80 mg, 16.61%) as a white solid. ESI-MS (M+H) ⁺: 519.3. Step 4: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(2,7-dimethyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01136] A mixture of tert-butyl 3-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (80 mg, 0.15 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (10 mg, 13.47%) as a white solid. ESI-MS (M+H) ⁺:419.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 9.38 (s, 1H), 8.22 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.60 (s, 1H), 6.45 (d, J = 6.2 Hz, 1H), 4.01 – 3.96 (m, 2H), 3.57 – 3.53 (m, 2H), 3.51 – 3.47 (m, 2H), 3.21 – 3.17 (m, 2H), 3.05 – 3.00 (m, 2H), 2.49 (s, 3H), 2.42 (s, 3H), 1.76 – 1.68 (m, 4H).

Example 405 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(6-fluoro-2- methyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

C_{ompound 405} Step 1: Preparation of tert-butyl 3-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [01137] To a solution of 6-fluoro-2-methyl-2H-indazol-5-amine hydrochloride (109 mg, 0.54 mmol) and TEA (551 mg, 5.45 mmol) in THF (15 mL) was added triphosgene (161 mg, 0.54 mmol) at 0^oC, after 10 min, tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.45 mmol) was added to the mixture at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (40 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (80 mg, 33.79 %) as a white solid. ESI-MS (M+H) ⁺:522.2. Step 2: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(6-fluoro-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01138] To a mixture of tert-butyl 3-(1-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (70 mg, 0.13 mmol) in EA (1 mL) was added HCl/EA (4 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (40 mg, Y: 70.72 %) as a white solid. ESI-MS (M+H) ⁺:422.2¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (d, J = 2.6 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 12.2 Hz, 1H), 6.48 (d, J = 6.1 Hz, 1H), 4.12 (s, 3H), 4.02 – 3.98 (m, 2H), 3.86 – 3.82 (m, 2H), 3.59 – 3.54 (m, 2H), 3.20 – 3.10 (m, 4H), 1.86 (s, 4H). Example 406 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-fluoro-2- methyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01139] A mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (2 g, 6.02 mmol), 6-fluoro-2-methyl-2H-indazol-5- amine (1.99 g, 12.05 mmol), triphosgene (3.58 g, 12.05 mmol) and TEA (7.29 g, 72.24 mmol) in THF (200 mL) was stirred at 0 ^oC for 15 min. Then The mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at rt for 1 h. The precipitate was filtered. The crude was diluted with MeOH, stirred at rt for 1 h. The precipitate was filtered to afford title product (1.3 g, 41.29 %) as a white solid. ESI-MS (M+H) ⁺: 524.3.¹H NMR (400 MHz, CDCl₃) δ 12.05 (d, J = 2.7 Hz, 1H), 8.54 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.82 (s, 1H), 7.34 (d, J = 11.8 Hz, 1H), 6.39 (d, J = 6.0 Hz, 1H), 4.30 – 4.25 (m, 2H), 4.22 – 4.16 (m, 5H), 3.44 (d, J = 12.2 Hz, 2H), 3.15 (t, J = 8.6 Hz, 2H), 3.00 (dd, J = 12.1, 4.2 Hz, 2H), 1.50 (s, 9H), 1.37 (d, J = 6.8 Hz, 6H). Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-fluoro-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01140] A mixture of tert-butyl (2R,6S)-4-(1-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (1.3 g, 2.48 mmol) in 4M HCl / EA (20 mL) was stirred at RT for 2 h. The precipitate was filtered diluted with water (20 mL), adjusted pH to 7~8 by 1N Na₂CO₃, the precipitate was filtered and dried to give title product (932.17 g, 88.86 %) as a pink solid. ESI-MS (M+H) ⁺:424.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (d, J = 2.7 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 7.85 (d, J = 6.1 Hz, 1H), 7.44 (d, J = 12.2 Hz, 1H), 6.50 (d, J = 6.2 Hz, 1H), 4.11 (s, 3H), 3.99 (t, J = 8.5 Hz, 2H), 3.60 (d, J = 11.6 Hz, 2H), 3.13 (t, J = 8.5 Hz, 2H), 2.84 – 2.76 (m, 2H), 2.38 (t, J = 11.3 Hz, 2H), 1.00 (d, J = 6.2 Hz, 6H). Example 407 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of (E)-N'-(5-bromo-4-methoxypyridin-2-yl)-N,N- dimethylformimidamide. [01141] To a mixture of 5-bromo-4-methoxypyridin-2-amine (50.0 g, 246.31 mmol) in MeOH (500 mL) was added DMF-DMA (38.1 g, 320.20 mmol). The mixture was stirred at 75^oC for 3 h. The mixture was concentrated in vacuo and the residue was diluted with water (500 mL) and the precipitate was filtered and concentrated in vacuo to get title product (50.0 g, Y: 78.8%) as a brown solid. ESI-MS (M+H)⁺:260.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.05 (s, 1H), 6.41 (s, 1H), 3.96 (s, 3H), 3.32 (s, 6H). Step 2: Preparation of 6-bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine. [01142] To a mixture of (E)-N'-(5-bromo-4-methoxypyridin-2-yl)-N,N- dimethylformimidamide (50 g, 193.80 mmol) in MeOH: pyridine (v: v= 10: 1, 550 mL) was added (aminooxy)sulfonic acid (32.8 g, 290.70 mmol). The mixture was stirred at r.t for 16 h. The mixture was quenched with NaHCO₃ (aq) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to get title product (12 g, Y: 27.2%) as a brown solid. ESI-MS (M+H)⁺:228.0. Step 3: Preparation of N-(7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine. [01143] To a mixture of 6-bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine (12.0 g, 52.63 mmol) in 1,4-dioxane (150 mL) were added diphenylmethanimine (14.3 g, 78.95 mmol), BINAP (6.6 g, 10.53 mmol), Pd₂(dba)₃ (2.4 g, 2.63 mmol) and Cs₂CO₃ (34.3 g, 105.26 mmol). The mixture was stirred at 100^oC for 16 h under nitrogen atmosphere. The mixture was diluted with water (200 mL) and extracted with EA (200 mL*3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 1) to get title product (2.0 g, Y: 11.6%) as a brown solid. ESI-MS (M+H)⁺:329.4.¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J = 7.6 Hz, 1H), 8.71 (s, 1H), 8.69 (s, 1H), 7.96 (d, J = 6.1 Hz, 2H), 7.87 (d, J = 5.8 Hz, 2H), 7.15 (dd, J = 7.4, 2.2 Hz, 2H), 6.56 (d, J = 6.2 Hz, 2H), 6.51 (d, J = 5.9 Hz, 2H), 3.60 (s, 3H). Step 4: Preparation of 7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-amine HCl salt. [01144] To a mixture of N-(7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine (2.0 g, 6.10 mmol) in EA (20 mL) was added 4 M HCl/EA (20 mL). The mixture was stirred at r.t for 2 h. The mixture was filtered and the residue was diluted with EA (10 mL). The mixture was stirred at r.t for 2 h and filtered to get title product (700 mg, Y: 70.0%) as a white solid. ESI-MS (M+H)⁺:165.1. Step 5: Preparation of tert-butyl (2R,6S)-4-(1-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01145] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) in THF (5 mL) were added TEA (91 mg, 0.90 mmol), triphosgene (107 mg, 0.36 mmol) at 0^oC. The mixture was stirred at r.t for 1 h. The mixture was added 7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-amine (59 mg, 0.36 mmol). The mixture was stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and the precipitate was filtered and concentrated in vacuo to get title product (60 mg, Y: 38.2 %) as a brown solid. ESI-MS (M+H) ⁺:523.4.¹H NMR (400 MHz, DMSO-d₆) δ 8.03 – 8.00 (m, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.33 – 7.30 (m, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.10 (s, 3H), 4.04 – 3.93 (m, 2H), 3.62 – 3.58 (m, 2H), 3.44 – 3.38 (m, 2H), 3.22 – 3.18 (m, 1H), 3.09 – 2.98 (m, 2H), 2.89 – 2.85 (m, 1H), 1.43 (s, 9H), 1.29 – 1.25 (m, 6H). Step 6: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01146] To a solution of tert-butyl (2R,6S)-4-(1-((7-methoxy-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (9 mg, 20.4 %) as a white solid. ESI-MS (M+H)⁺:423.2. ¹H NMR (400 MHz, MeOD-d₄) δ 9.37 (s, 1H), 8.49 (s, 1H), 8.13 (s, 1H), 7.77 (d, J = 5.8 Hz, 1H), 7.00 (s, 1H), 6.35 (d, J = 5.9 Hz, 1H), 4.09 (s, 3H), 4.01 (t, J = 8.4 Hz, 2H), 3.74 (d, J = 12.7 Hz, 2H), 3.43 – 3.37 (m, 2H), 3.05 (t, J = 8.4 Hz, 2H), 2.83 – 2.76 (m, 2H), 1.36 (d, J = 6.4 Hz, 6H).

Example 408 – Preparation of (R)-N-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of N-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1,1- diphenylmethanimine. [01147] To a mixture of 7-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (800 mg, 3.77 mmol) in 1,4-dioxane (10 mL) were added diphenylmethanimine (1.0 g, 5.66 mmol), BINAP (235 mg, 0.38 mmol), Pd₂(dba)₃ (173 mg, 0.19 mmol) and Cs₂CO₃ (2.5 g, 7.55 mmol). The mixture was stirred at 100^oC for 16 h under N₂. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3), the organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 1) to get title product (600 mg, Y: 51.0%) as a brown solid. ESI-MS (M+H)⁺:313.4.¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (dd, J = 7.2, 0.5 Hz, 1H), 7.70 (d, J = 7.3 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.37 – 7.32 (m, 3H), 7.28 – 7.24 (m, 2H), 6.85 (d, J = 1.6 Hz, 1H), 6.64 (dd, J = 7.2, 2.1 Hz, 1H), 2.35 (s, 3H). Step 2: Preparation of 2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine HCl salt. [01148] To a mixture of N-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1,1- diphenylmethanimine (600 mg, 1.92 mmol) in EA (5 mL) was added 4 M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered and the residue was diluted with EA (5 mL). The mixture was stirred at r.t for 2 h and filtered to get title product (250 mg, Y: 87.8%) as a white solid. ESI-MS (M+H)⁺:149.5. Step 3: Preparation of tert-butyl (R)-2-methyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01149] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) in THF (5 mL) were added TEA (114 mg, 1.13 mmol), triphosgene (112 mg, 0.31 mmol) at 0^oC. The mixture was stirred at r.t for 1 h. The mixture was added 2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine HCl salt (59 mg, 0.31 mmol). The mixture was stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:2) to give the title compound (80 mg, Y: 52.5 %) as a yellow solid. ESI-MS (M+H) ⁺:493.4.¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (s, 1H), 7.84 (s, 1H), 7.77 (d, J = 6.2 Hz, 1H), 7.70 (s, 1H), 6.40 (d, J = 6.3 Hz, 1H), 3.98 – 3.94 (m, 2H), 3.72 – 3.69 (m, 2H), 3.59 – 3.56 (m, 2H), 3.55 – 3.53 (m, 2H), 3.30 – 3.28 (m, 3H), 2.35 (s, 3H), 1.43 (s, 9H), 1.38 (d, J = 6.3 Hz, 3H). Step 4: Preparation of (R)-N-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01150] To a solution of tert-butyl (R)-2-methyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5- a]pyridin-7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (70 mg, 0.14 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (28.2 mg, 45.3 %) as a yellow solid. ESI-MS (M+H)⁺:393.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 8.70 (d, J = 7.3 Hz, 1H), 8.24 (s, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.94 (d, J = 6.1 Hz, 1H), 7.14 (dd, J = 7.4, 2.2 Hz, 1H), 6.56 (d, J = 6.2 Hz, 1H), 4.00 – 3.97 (m, 2H), 3.66 – 3.62 (m, 2H), 3.14 (t, J = 8.5 Hz, 2H), 3.04 – 2.99 (m, 1H), 2.95 – 2.87 (m, 2H), 2.86 – 2.80 (m, 1H), 2.63 – 2.57 (m, 1H), 2.41 (s, 3H), 1.07 (d, J = 6.3 Hz, 3H).

Example 409 – Preparation of (R)-N-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of 5-nitro-2H-benzo[d][1,2,3]triazole. [01151] To a mixture of 4-nitrobenzene-1,2-diamine (5.0 g, 32.68 mmol) in H₂O (100 mL) were added NaNO₂ (11.30 g, 163.4 mmol) and HOAc (30 mL) at 0 °C. The reaction mixture was stirred at rt for 1 h. The mixture was diluted with water (100 mL) and extracted with EA (300 mL*3). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuum to give the title compound (4.2 g, crude) as a yellow solid. ESI-MS (M+H) ⁺:165.0. Step 2: Preparation of 2-methyl-5-nitro-2H-benzo[d][1,2,3]triazole. [01152] To a solution of 5-nitro-2H-benzo[d][1,2,3]triazole (4.20 g, 25.60 mmol) in EtOH (50 mL) were added EtONa (3.18 g, 46.80 mmol) and MeI (7.27 g, 51.20 mmol). The mixture was reacted at 80˚C under N₂ for 16 h. LCMS showed the reaction was completed. The reaction mixture was quenched by water (60 mL). The mixture was extracted with Ethyl acetate (300 ml x 3). The organic phase was washed with brine (60 mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuum. The crude was purified by silica gel column chromatography (PE/EA=10:1) to give the title compound (1.10 g, Y: 24 %) as a yellow solid. ESI-MS (M+H) ⁺:179.0. Step 3: Preparation of 2-methyl-2H-benzo[d][1,2,3]triazol-5-amine. [01153] To a solution of 2-methyl-5-nitro-2H-benzo[d][1,2,3]triazole (1.0 g, 5.62 mmol) in EtOH (10 mL) were added Fe (1.57 g, 28.10 mmol), NH₄Cl (1.21 g, 22.48 mmol) and H₂O (2.0 mL), the reaction was stirred at 80 °C for 16 h. The mixture was filtered to remove solid residue. The filtrate was concentrated under reduced pressure and extracted with EA (100 mL). The organic phase was separated, dried over anhydrous Na₂SO₄, filtered, and evaporated. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (700 mg, Y: 84 %) as a yellow solid. ESI-MS (M+H) ⁺:149.1. Step 4: tert-butyl (R)-2-methyl-4-(1-((2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01154] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) in THF (5 mL) were added 2- methyl-2H-benzo[d][1,2,3]triazol-5-amine (55 mg, 0.37 mmol), TEA (156 mg, 1.55 mmol) and Triphosgene (92 mg, 0.31 mmol), the reaction was stirred at rt for 16 h. The reaction mixture was quenched by water (10 mL). The mixture was filtered to give title product (100 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺:493.3. Step 5: Preparation of (R)-N-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01155] To a solution of tert-butyl (R)-2-methyl-4-(1-((2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (45 mg, 0.09 mmol) in DCM (2.0 mL) was added TFA (0.60 mL) at rt. The reaction mixture was stirred at rt for 2 h. The precipitate was filtered and purified by prep-HPLC (10 mmol/L NH₄HCO₃ in water / ACN) to give title compound (14.37 mg, Y: 40 %) as a white solid. ESI-MS (M+H)⁺:393.4.¹H NMR (400 MHz, DMSO- d₆) δ 12.13 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.36 (dd, J = 9.2, 2.0 Hz, 1H), 6.52 (d, J = 6.4 Hz, 1H), 4.44 (s, 3H), 4.04 – 3.94 (m, 2H), 3.61 – 3.53 (m, 2H), 3.16 – 3.08 (m, 2H), 2.94 – 2.88 (m, 1H), 2.83 – 2.70 (m, 3H), 2.48 – 2.42 (m, 2H), 1.00 (d, J = 6.4 Hz, 3H).

Example 410 – Preparation of (R)-N-(2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-2-methyl-4-(1-((2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01156] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (120 mg, 0.37 mmol), 2-methyl-2H-indazol-5-amine (66 mg, 0.45 mmol) in THF (20 mL) were added TEA (748 mg, 7.40 mmol) and triphosgene (132 mg, 0.45 mmol) (in THF ( 1 mL)) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The mixture was diluted with H2O (50 mL) and stirred at r.t for 20 min. The precipitate was filtered, washed with water (20 mL) and dried to give title product (70 mg, yield: 39 %) as a white solid. ESI-MS (M+H) ⁺:492.3. Step 2: Preparation of (R)-N-(2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01157] To a mixture of tert-butyl (R)-2-methyl-4-(1-((2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O/ ACN) to give title compound (28.29 mg, 65 %) as a white solid. ESI-MS (M+H) ⁺:392.1.¹H NMR (400 MHz, MeOD-d4) δ 8.40 (s, 1H), 8.10 (s, 1H), 8.01 (dd, J = 11.3, 3.7 Hz, 2H), 7.56 (d, J = 9.2 Hz, 1H), 7.29 (dd, J = 9.2, 2.0 Hz, 1H), 6.59 (d, J = 6.1 Hz, 1H), 4.18 (s, 3H), 4.14 – 4.06 (m, 2H), 3.84 – 3.74 (m, 2H), 3.49 – 3.42 (m, 2H), 3.28 – 3.12 (m, 4H), 3.01 – 2.91 (m, 1H), 1.37 (d, J = 6.6 Hz, 3H). Example 411 – Preparation of (R)-N-(7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01158] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol), 7-methoxy-[1,2,4]triazolo[1,5- a]pyridin-6-amine (78 mg, 0.47 mmol) and TEA (712 mg, 7.05 mmol) in THF (12 mL) was added triphosgene (209 mg, 0.71 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:4) to give title product (90 mg, Y: 37.7%) as a yellow solid. ESI-MS (M+H) ⁺: 509.3. Step 2: Preparation of (R)-N-(7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01159] A mixture of tert-butyl (R)-4-(1-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (70 mg, 0.14 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03 %TFA in water / CH₃CN) to give title product (46 mg, Y: 82.1 %) as a yellow solid. ESI-MS (M+H) ⁺: 409.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 9.47 (s, 1H), 9.21 – 9.90 (m, 2H), 8.29 (s, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.36 (s, 1H), 6.64 (d, J = 6.1 Hz, 1H), 4.11 (s, 3H), 4.06 – 4.01 (m, 2H), 3.82 – 3.75 (m, 2H), 3.43 – 3.34 (m, 2H), 3.24 – 3.13 (m, 4H), 3.02 – 2.94 (m, 1H), 1.27 (d, J = 6.5 Hz, 3H). Example 412 – Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-methoxy- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Compound 412 Step 1: Preparation of tert-butyl 3-(1-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. [01160] To a mixture of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.30 mmol), 7-methoxy- [1,2,4]triazolo[1,5-a]pyridin-6-amine (74 mg, 0.45 mmol) in THF (20 mL) were added TEA (303 mg, 3.0 mmol) and triphosgene (132 mg, 0.45 mmol) (in THF ( 1 mL)) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (50 mL) and stirred at r.t for 20 min. The precipitate was filtered, washed with water (20 mL) and dried to give title product (98 mg, yield: 62 %) as a white solid. ESI-MS (M+H) ⁺:521.2. Step 2: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(7-methoxy- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01161] To a mixture of tert-butyl 3-(1-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (98 mg, 0.19 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title compound (60 mg, 69 %) as a white solid.

δ 12.41 (s, 1H), 9.47 (s, 1H), 8.25 (d, J = 3.2 Hz, 2H), 7.92 (d, J = 6.1 Hz, 1H), 7.34 (s, 1H), 6.46 (d, J = 6.2 Hz, 1H), 4.09 (s, 3H), 4.03 – 3.95 (m, 2H), 3.59 – 3.55 (m, 2H), 3.52 – 3.48 (m, 2H), 3.21 – 3.16 (m, 2H), 3.06 – 3.01 (m, 2H), 1.78 – 1.69 (m, 4H). Example 413 – Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 7-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [01163] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.61 mmol), 6-fluoro-2-methyl-2H-indazol-5- amine (145 mg, 0.73 mmol), triphosgene (208 mg, 0.73 mmol) and TEA (737 mg, 7.27 mmol) in THF (20 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at r.t for 1 h. The precipitate was filtered to afford title product (90 mg, 57.3%) as a white solid. ESI-MS (M+H) ⁺: 522.3.¹H NMR (400 MHz, CDCl₃) δ 12.06 (d, J = 2.9 Hz, 1H), 8.53 (d, J = 7.7 Hz, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.81 (s, 1H), 7.34 (d, J = 11.8 Hz, 1H), 6.31 (d, J = 6.0 Hz, 1H), 4.17 (s, 3H), 3.78 – 3.67 (m, 4H), 3.27 – 3.24 (m, 2H), 3.08 – 3.04 (m, 4H), 1.48 (s, 9H), 1.08 (t, J = 6.3 Hz, 2H), 0.86 – 0.83 (m, 2H). Step 2: Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan-7- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01164] A mixture of tert-butyl 7-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (80 mg, 0.15 mmol) in 4M HCl /EA (2 mL) was stirred at RT for 2 h. [01165] The precipitate was filtered and dried in vacuo to give title product (58.33 mg, yield: 85.09 %) as a white soild. ESI-MS (M+H) ⁺: 422.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.42 (s, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.41 (d, J = 10.7 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 4.39 (t, J = 8.4 Hz, 2H), 4.25 (s, 3H), 4.06 – 4.02 (m, 2H), 3.85 (s, 2H), 3.57 – 3.50 (m, 4H), 1.23 – 1.19 (m, 2H), 1.16 – 1.12 (m, 2H). Example 414 – Preparation of (R)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- (hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate. [01166] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (hydroxymethyl)piperazine-1-carboxylate (80 mg, 0.24 mmol), 6-fluoro-2-methyl-2H- indazol-5-amine (72.2 mg, 0.36 mmol), triphosgene (106.9 mg, 0.36 mmol) and TEA (362.6 mg, 3.59 mmol) in THF (8 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at r.t for 1 h. The precipitate was filtered to afford title product (90 mg, 56.6%) as a white solid. ESI-MS (M+H) ⁺: 526.3. Step 2: Preparation of (R)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- (hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01167] A mixture of tert-butyl (R)-4-(1-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1- carboxylate (80 mg, 0.15 mmol) in 4M HCl /EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (17.53 mg, yield: 24.78 %) as a white soild. ESI-MS (M+H) ⁺: 426.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (d, J = 2.7 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 7.88 (d, J = 6.1 Hz, 1H), 7.44 (d, J = 12.2 Hz, 1H), 6.50 (d, J = 6.2 Hz, 1H), 4.12 (s, 3H), 3.99 (t, J = 8.8 Hz, 2H), 3.71 – 3.69 (m, 1H), 3.61 (s, 1H), 3.38 – 3.37 (m, 2H), 3.15 – 3.11 (m, 2H), 2.98 (d, J = 11.5 Hz, 1H), 2.92 – 2.86 (m, 1H), 2.81 – 2.76 (m, 2H), 2.64 – 2.58 (m, 1H). Example 415 – Preparation of (R)-N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3- (hydroxymethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

C^{ompound 415} Step 1: Preparation of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate. [01168] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (hydroxymethyl)piperazine-1-carboxylate (80 mg, 0.24 mmol), 2,6-dimethyl-2H-indazol-5- amine (70.78 mg, 0.36 mmol), triphosgene (107 mg, 0.36 mmol) and TEA (362.6 mg, 3.59 mmol) in THF (8 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at r.t for 1 h. The precipitate was filtered to afford title product (130 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 522.3. Step 2: Preparation of (R)-N-(2,6-dimethyl-2H-indazol-5-yl)-4-(3-(hydroxymethyl)piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01169] A mixture of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (120 mg, 0.23 mmol) in 4M HCl /EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (12.43 mg, yield: 10.1 %) as a yellow solid. ESI-MS (M+H) ⁺: 422.2.¹H NMR ¹H NMR (400 MHz, DMSO-d₆) δ 11.51 (s, 1H), 9.14 (s, 1H), 8.76 (s, 1H), 8.20 (s, 2H), 7.94 (d, J = 5.3 Hz, 1H), 7.45 (s, 1H), 6.63 (s, 1H), 4.11 (s, 3H), 4.08 – 4.01 (m, 2H), 3.90 – 3.78 (m, 2H), 3.73 – 3.68 (m, 1H), 3.65 – 3.60 (m, 1H), 3.38 – 3.30 (m, 2H), 3.23 – 3.07 (m, 5H), 2.43 (s, 3H). Example 416 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

C^{ompound 416} Step 1: Preparation of tert-butyl 4-(1-((6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01170] To a solution of 6-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7- carboxylic acid (75 mg, 0.36 mmol) in toluene (10 mL) were added TEA (146 mg, 1.44 mmol), DPPA (297 mg, 1.08 mmol). The mixture was stirred at r.t for 1 h and 40 min at 70 ^o C. The tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (120 mg, 0.36 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The precipitate was filtered, washed with toluene (5 mL) and dried to give title product (70 mg, yield: 36 %) as a white solid. ESI-MS (M+H) ⁺:537.4.¹H NMR (400 MHz, CDCl₃) δ 12.57 (s, 1H), 8.59 (s, 1H), 7.99 (s, 1H), 7.85 (d, J = 6.0 Hz, 1H), 6.23 (d, J = 6.2 Hz, 1H), 4.18 – 4.13 (m, 2H), 3.99 (s, 3H), 3.81 – 3.77 (m, 2H), 3.58 – 3.54 (m, 2H), 3.45 (s, 2H), 3.30 – 3.23 (m, 2H), 2.53 (s, 3H), 1.50 (s, 9H), 1.45 (s, 6H). Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01171] To a solution of tert-butyl 4-(1-((6-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (50 mg, 0.093 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O/ ACN) to give title product (26.12 mg, 58%) as a white solid. ESI-MS (M+H) ⁺: 437.3.¹H NMR (400 MHz, MeOD-d₄) δ 8.44 (s, 2H), 8.27 (s, 1H), 7.98 (d, J = 5.9 Hz, 1H), 6.56 (d, J = 6.0 Hz, 1H), 4.13 – 4.03 (m, 5H), 3.48 – 3.42 (m, 2H), 3.38 – 3.34 (m, 2H), 3.26 (s, 2H), 3.20 – 3.13 (m, 2H), 2.44 (s, 3H), 1.46 (s, 6H). Example 417 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6- (piperazin-1-yl)-1,5-naphthyridine-2-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 4-bromo-5-methoxy-2-nitroaniline. [01172] To a solution of 5-methoxy-2-nitroaniline (15 g, 89.29 mmol) in ACN (200 mL) was added NBS (16 g, 89.29 mmol). The mixture was stirred at 70 ^oC for 16 h under N₂, the reaction was concentrated and purified by SGC (PE/EA=0-100%) to give product (16 g, yield: 72.73 %) as yellow solid. ESI-MS (M+H) ⁺ : 246.9. Step 2: Preparation of 4-bromo-5-methoxybenzene-1,2-diamine. [01173] To a solution of 4-bromo-5-methoxy-2-nitroaniline (15 g, 60.75 mmol) in EtOH (300 mL) and H₂O (60 mL) were added NH₄Cl (24 g, 455.70 mmol) and Fe (34.5 g, 60.75 mmol). The mixture was stirred at 90 ^oC for 4 h under N₂, the reaction was concentrated and purified by SGC (PE/EA=0-100%) to give product (5.1 g, yield: 38.72 %) as yellow solid. ESI-MS (M+H) ⁺: 217.1. Step 3: Preparation of 5-bromo-6-methoxy-2H-benzo[d][1,2,3]triazole. [01174] To a solution of 4-bromo-5-methoxybenzene-1,2-diamine (4 g, 17.56 mmol) in AcOH (4 mL) and H₂O (16 mL) was added NaNO₂ (6 g, 87.85 mmol). The mixture was stirred at r.t for 1 h under N₂, the reaction was concentrated and purified by SGC (PE/EA=0- 100%) to give product (3.1 g, yield: 73.81 %) as yellow solid. ESI-MS (M+H) ⁺: 228.0. Step 4: Preparation of 5-bromo-6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazole. [01175] To a solution of 5-bromo-6-methoxy-2H-benzo[d][1,2,3]triazole (3 g, 13.17 mmol) in Toluene (30 mL) was added DMF-DMA (2.4 g, 19.77 mmol). The mixture was stirred at 100 ^oC for 2 h under N₂, the reaction was concentrated and purified by SGC (PE/EA=0-100%) to give product (850 mg, yield: 33.07 %) as yellow solid. ESI-MS (M+H) ⁺: 244.1. Step 5: Preparation of N-(6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine. [01176] To a solution of 5-bromo-6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazole (1 g, 4.10 mmol) in 1,4-Dioxane (50 mL) was added diphenylmethanimine (8 g, 4.90 mmol) and Pd₂(dba)₃ (400 mg, 0.40 mmol), Xantphos (480 mg, 0.80 mmol) and Cs₂CO₃ (4 g, 12.30 mmol). The mixture was stirred at 110 ^oC for 5 h under N₂, the reaction was concentrated and purified by SGC (PE/EA=0-100%) to give product (510 mg, yield: 36.17 %) as yellow solid. ESI-MS (M+H) ⁺: 343.1. Step 6: Preparation of 6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine. [01177] To a solution of N-(6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine (500 mg, 1.45 mmol) in MeOH (20 mL) was added NH₂OHHCl (515 mg, 7.25 mmol) and NaOAc (72 mg, 4.35 mmol). The mixture was stirred at rt for 3 h under N₂, the reaction was concentrated and purified by SGC (DCM/MeOH=0-100%) to give product (115 mg, yield: 44.23 %) as yellow solid. ESI-MS (M+H) ⁺: 179.2. Step 7: Preparation of tert-butyl (R)-4-(1-((6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01178] To a solution of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.32 mmol) and Et₃N in THF (10 mL) was added TBC (126 mg, 0.42 mmol) at 0 ^oC. The mixture was stirred at 0 ^oC for 1 h under N₂, and tert- butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (86 mg, 0.48 mmol) was added to the above mixture and stirred at r.t for 16 h. The reaction was concentrated and purified by SGC (DCM/MeOH=0-100%) to give product (80 mg, yield: 48.78 %) as yellow solid. ESI-MS (M+H) ⁺: 523.4. Step 8: Preparation of (R)-N-(6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01179] To a solution of tert-butyl (R)-4-(1-((6-methoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (75 mg, 0.14 mmol) in EA (2 mL) was added 3M HCl / EA (2 mL). The mixture was stirred at r.t for 2 h under N₂. The residue was purified by prep- HPLC (0.1 % TFA in water / CH₃CN) to give title product (24.23 mg, yield: 14.26 %) as a yellow solid. ESI-MS (M+H) ⁺: 423.2.¹H NMR (400 MHz, CD₃OD-d₄) δ 8.55 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.19 (s, 1H), 6.61 (d, J = 6.0 Hz, 1H), 4.39 (s, 3H), 4.14 (t, J = 8.4 Hz, 2H), 4.05 (s, 3H), 3.93 – 3.78 (m, 2H), 3.56 – 3.42 (m, 2H), 3.27 (t, J = 9.2 Hz, 2H), 3.19 (t, J = 8.4 Hz, 2H), 3.04 (dd, J = 13.6, 10.4 Hz, 1H), 1.39 (d, J = 6.8 Hz, 3H). Example 418 – Preparation of (R)-N-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of 6-bromo-2-methylimidazo[1,2-a]pyrimidine. [01180] To a mixture of 5-bromopyrimidin-2-amine (15 g, 86.71 mmol) in IPA (150 mL) were added 1-bromo-2,2-dimethoxypropane (17.26 g, 95.38 mmol) and PPTS (51.40 g, 104.05 mmol). The mixture was stirred at 85^oC for 16 h. The mixture was concentrated in vacuo, the residue was diluted in water (200 mL), adjusted pH to 11 by sat. Na₂CO₃, the precipitate was filtered and dried to get title product (9 g, Y: 49.43%) as a white solid. ESI- MS (M+H) ⁺:214.4. Step 2: Preparation of N-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-1,1-diphenylmethanimine. [01181] To a mixture of 6-bromo-2-methylimidazo[1,2-a]pyrimidine (9.0 g, 42.65 mmol), diphenylmethanimine (11.64 g, 63.98 mmol) and BINAP (5.31 g, 8.53 mmol) in 1,4- dioxane (100 mL) were added Cs₂CO₃ (27.81 g, 85.3 mmol) and Pd(OAc)₂ (965.02 mg, 4.27 mmol). The mixture was stirred at 115 ^oC for 16 h under N₂. The mixture was diluted with H₂O (100 mL) and extracted with EA (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (6 g, 45.09%) as a brown solid. ESI-MS (M+H) ⁺:313.3. Step 3: Preparation of 2-methylimidazo[1,2-a]pyrimidin-6-amine hydrochloride. [01182] A mixture of N-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-1,1- diphenylmethanimine (6 g, 19.23 mmol) in 4M HCl/EA (60 mL) was stirred at rt for 2 h. The reaction was diluted with EA (60 mLx2), the precipitate was filtrated and dired in vacuo to give title product (3.5 g, 98.91%) as a brown solid. ESI-MS (M+H⁺): 149.3. Step 4: Preparation of tert-butyl (R)-2-methyl-4-(1-((2-methylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01183] To a mixture of 2-methylimidazo[1,2-a]pyrimidin-6-amine hydrochloride (150 mg, 0.82 mmol), (267.12 mg, 0.84 mmol) in THF (10 mL) were added TEA (248.46 mg, 2.46 mmol) and triphosgene (487.08 mg, 1.64 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (60 mg, 14.87%) as a brown solid. ESI-MS (M+H) ⁺: 493.3. Step 5: Preparation of (R)-N-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01184] A mixture of tert-butyl (R)-2-methyl-4-(1-((2-methylimidazo[1,2-a]pyrimidin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg,0.12 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (26 mg, 55.27%) as a yellow solid. ESI-MS (M+H) ⁺:393.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1H), 9.28 (d, J = 2.7 Hz, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.29 (s, 2H), 7.91 (d, J = 6.1 Hz, 1H), 7.69 (s, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.01 – 3.95 (m, 2H), 3.64 – 3.57 (m, 2H), 3.14 (t, J = 8.6 Hz, 2H), 2.99 – 2.78 (m, 3H), 2.59 – 2.51 (m, 2H), 2.34 (s, 3H), 1.04 (d, J = 6.2 Hz, 3H). Example 419 – Preparation of (S)-N-(6-methylimidazo[1,2-a]pyrazin-2-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

s_{tep 1 step 2}

Step 1: Preparation of 6-methylimidazo[1,2-a]pyrazine-2-carbonyl chloride. [01185] To a solution of 6-methylimidazo[1,2-a]pyrazine-2-carboxylic acid (900 mg, 5.08 mmol) in SOCl₂ (15 mL) was stirred at 80 ℃ for 16 h.The mixture was concentrated in vacuo to use for the next step. Step 2: Preparation of 6-methylimidazo[1,2-a]pyrazine-2-carbonyl azide. [01186] To a solution of 6-methylimidazo[1,2-a]pyrazine-2-carbonyl chloride (900 mg crude, 4.61 mmol) in acetone:H₂O (20 mL:2 mL) was added NaN₃ (450 mg, 6.92 mmol), the reaction was stirred at rt for 16 h. The mixture was diluted with EA (150 mL), washed with H₂O (100 mL×2) and brine (100 mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo，the crude was purified by silica gel column chromatography (DCM: MeOH = 10: 1) to give the title compound (400 mg, yield: 42 %) as a brown solid. ESI-MS (M+H) ⁺: 203.2. Step 3: Preparation of tert-butyl (S)-2-methyl-4-(1-((6-methylimidazo[1,2-a]pyrazin-2- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01187] To a solution of 6-methylimidazo[1,2-a]pyrazine-2-carbonyl azide (200 mg, 0.99 mmol) and tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (314 mg, 0.99 mmol) in toluene (10 mL) was stirred at 100 ℃ for 16 h. The mixture was concentrated in vacuo and the crude was purified by silica gel column chromatography (DCM: MeOH = 10: 1) to give the title compound (110 mg, yield: 22 %) as a white solid. ESI-MS (M+H) ⁺: 493.2. Step 4: Preparation of (S)-N-(6-methylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01188] To a solution of tert-butyl (S)-2-methyl-4-(1-((6-methylimidazo[1,2-a]pyrazin- 2-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (90 mg,0.18 mmol) in DCM (5 mL) was added TFA (1.5 mL) , the mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo and the crude purified by perp-HPLC (0.1 % TFA in water / CH₃CN) to give the title compound (38 mg, 53% yield) as a white solid. ESI-MS (M+H) ⁺: 393.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 9.17 (s, 1H), 8.88 (s, 1H), 8.82 (s, 1H), 8.51 (s, 1H), 8.20 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 6.67 (d, J = 6.0 Hz, 1H), 4.05 (t, J = 8.0 Hz, 2H), 3.82 (d, J = 12.8 Hz, 2H), 3.39 (d, J = 10.4 Hz, 2H), 3.26 – 3.11 (m, 4H), 3.06 – 2.97 (m, 1H), 2.43 (s, 3H), 1.27 (d, J = 6.4 Hz, 4H).

Example 420 – Preparation of (R)-N-(6-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of methyl 2-bromo-5-fluoroisonicotinate. [01189] To a solution 2-bromo-5-fluoroisonicotinic acid (40 g, 181.82 mmol) in MeOH (300 mL) was added H₂SO₄ (71.27 g, 727.27 mmol) at 0 ^oC. The mixture was stirred at 70 ^oC for 16 hours. The mixture was concentrated in vacuo and diluted with water, adjusted pH to 8 by Na₂CO₃ aqueous solution. The precipitate was filtered, washed with H₂O (20 mL) to give title compound (54 g, crude) as a white solid. ESI-MS (M+H)⁺: 235.9.¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 5.2 Hz, 1H), 3.91 (s, 3H). Step 2: Preparation of methyl 2-((diphenylmethylene)amino)-5-fluoroisonicotinate. [01190] A mixture of methyl 2-bromo-5-fluoroisonicotinate (48 g, 206 mmol), Benzenemethanimine (55.93 g, 309 mmol), Pd₂(dba)₃ (18.87 g, 20.6 mmol) and BINAP (25.67 g, 41.2 mmol) in 1,4-dioxane (600 mL) was purged with N₂ for three times at r.t. Then the mixture was stirred at 100 ^oC for 16 hours. The mixture was cooled to r.t, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=20:1) to provide title product (38 g, yield: 55%) as a white solid. ESI-MS (M+H)⁺: 335.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 7.3 Hz, 2H), 7.59 (d, J = 7.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.39 – 7.31 (m, 3H), 7.18 – 7.13 (m, 2H), 7.12 (d, J = 5.1 Hz, 1H), 3.84 (s, 3H). Step 3: Preparation of methyl 2-amino-5-fluoroisonicotinate HCl salt. [01191] To a solution of methyl 2-((diphenylmethylene)amino)-5-fluoroisonicotinate (38 g, 113.77 mmol) in EtOAc (30 mL) was added 4M HCl/EtOAc (300 mL) at 0 ^oC. Then the mixture was stirred at r.t for 2 hours. The precipitate was filtered, washed with EtOAc, dried under vacuum to afford title product (20 g, yield: 85%) as a white solid. ESI-MS (M+H)⁺: 171.1.¹H NMR (400 MHz, DMSO-d₆) 8.21 (d, J = 3.8 Hz, 1H), 7.20 (d, J = 5.3 Hz, 1H), 3.89 (s, 3H). Step 4: Preparation of 1,2-diamino-5-fluoro-4-(methoxycarbonyl)pyridin-1-ium 2,4,6- trimethylbenzenesulfonate. [01192] To a solution of methyl 2-amino-5-fluoroisonicotinate HCl salt (5 g, 29.41 mmol) in CHCl₃ (200 mL) was added O-(mesitylsulfonyl)hydroxylamine (15.8 g, 73.53 mmol) at 0 ^oC. The mixture was stirred at r.t for 2h. The precipitate was filtered, washed with with CHCl₃ (10 mL) to give title compound (5 g, crude) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J = 5.2 Hz, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 9H). Step 5: Preparation of methyl 6-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate. [01193] To a solution of 1,2-diamino-5-fluoro-4-(methoxycarbonyl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (4.5 g, 11.69 mmol) in AcOH (30 mL) was added TsOH (402 mg, 2.34 mmol). The mixture was stirred at 100 ^oC for 16 hours. The mixture was concentrated in vacuo and the residue was adjusted pH to7 by NaHCO₃ aqueous solution. The mixture was extracted with DCM (20 mL*3). The organic layer was concentrated in vacuo. The residue was purified by silica gel column (PE: EA= 1: 1) to give title compound (200 mg, yield: 8%) as a white solid. ESI-MS (M+H)⁺: 210.1.¹H NMR (400 MHz, DMSO- d₆) δ 9.38 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 6.7 Hz, 1H), 3.93 (s, 3H), 2.52 (s, 3H). Step 6: Preparation of 6-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid. [01194] To a solution of methyl 6-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7- carboxylate (150 mg, 0.71 mmol) in THF/MeOH/H₂O (5 mL /1 mL /1 mL) was added LiOH (86 mg, 3.57 mmol). The mixture was stirred at r.t for 2 h. The reaction mixture was concentrated in vacuo, the residue was diluted with water (15 mL), adjusted pH = 5 with 2M HCl. The precipitate was filtered, and washed with H₂O (5 mL), dried in vacuo to give title product (130 mg, yield: 94%) as a white solid. ESI-MS (M+H)⁺ : 196.2.¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (d, J = 5.4 Hz, 1H), 8.14 (d, J = 6.8 Hz, 1H), 2.51 (s, 3H). Step 7: Preparation of tert-butyl (R)-4-(1-((6-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01195] To a solution of 6-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (100 mg, 0.31 mmol) in Toluene (10 mL) were added TEA (94 mg, 0.93 mmol) and DPPA (129 mg, 0.47 mmol). The mixture was stirred at 30 ^oC for 1h. Then the mixture was stirred at 60 ^oC for another 1h. Tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was allowed to cool down to room temperature. The precipitate was filtered and triturated with MeOH (5 mL) to provide title product (100 mg, yield: 63%) as a white solid. ESI-MS (M+H)⁺: 511.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (d, J = 2.5 Hz, 1H), 9.24 (d, J = 5.7 Hz, 1H), 8.37 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 6.0 Hz, 1H), 6.55 (d, J = 6.1 Hz, 1H), 4.18 (s, 1H), 4.04 (t, J = 8.7 Hz, 2H), 3.78 (d, J = 13.8 Hz, 1H), 3.64 (dd, J = 28.4, 12.7 Hz, 2H), 3.22 – 3.16 (m, 3H), 3.10 (d, J = 9.2 Hz, 1H), 3.01 – 2.91 (m, 1H), 2.41 (s, 3H), 1.42 (s, 9H), 1.18 (d, J = 6.6 Hz, 3H). Step 8: Preparation of (R)-N-(6-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01196] To a tert-butyl (R)-4-(1-((6-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (90 mg, 0.18 mmol) in EtOAc (2 mL) was added 4M HCl/EtOAc (6 mL). The mixture was stirred at r.t for 2h. The precipitate was filtered, and washed with EtOAc (5 mL) and lyophilized to give title compound (63 mg, yield: 85%) as a white solid. ESI-MS (M+H)⁺: 411.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (s, 1H), 9.69 (d, J = 10.1 Hz, 1H), 9.55 (d, J = 10.8 Hz, 1H), 9.49 (d, J = 5.5 Hz, 1H), 8.48 (d, J = 6.9 Hz, 1H), 7.95 (d, J = 6.1 Hz, 1H), 6.68 (d, J = 6.2 Hz, 1H), 4.06 (t, J = 8.3 Hz, 2H), 3.83 (d, J = 12.1 Hz, 2H), 3.34 (t, J = 11.5 Hz, 3H), 3.21 (t, J = 8.4 Hz, 2H), 3.10 (dd, J = 23.3, 10.1 Hz, 2H), 2.52 (s, 3H), 1.31 (d, J = 6.5 Hz, 3H). Example 421 – Preparation of (S)-3-(5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)-7-(3-methylpiperazin-1-yl)quinoxaline-5-carbonitrile TFA salt.

Step 1: Preparation of 4-bromo-5-fluoro-2-nitroaniline. [01197] To a mixture of 5-fluoro-2-nitroaniline (10.0 g, 64.10 mmol) in AcOH (50 mL) was added NBS (11.4 g, 64.10 mmol) under N₂ at 25℃, then the reaction was stirred at 110℃ for 1.5 h. The reaction was diluted with EA (100 mL) and washed with water (100 mLx3) and brine (100 mL). The organic extract was dried over Na₂SO₄, and the solvent was removed to afford the crude product. The crude product was purified by column flash chromatography (EA/PE=0%~5%) to afford the title product (10.0 g, 66.6 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 235.0¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J = 7.4 Hz, 1H), 7.71 (s, 2H), 6.93 (d, J = 11.0 Hz, 1H). Step 2: Preparation of 4-bromo-5-fluorobenzene-1,2-diamine. [01198] To a solution of 4-bromo-5-fluoro-2-nitroaniline (5.0 g, 21.3 mmol) in EtOH (150 mL) and H₂O (30 mL) were added NH₄Cl (8.6 g, 160.7 mmol) and Fe (6.0 g, 107.4 mmol). The mixture was stirred at 80℃ for 1 h under N₂. The mixture was filtered over celite, washed with EA. The reaction was diluted with EA (100 mL) and washed with water (100 mLx3) and brine (100 mL). The organic extract was dried over Na₂SO₄, and the solvent was removed to afford the crude product. The crude product was purified by column flash chromatography (EA/PE=0%~50%) to afford the title product (2.0 g, 46.5 % yield) as a gray solid. ESI-MS (M+H) ⁺:206.0.¹H NMR (400 MHz, DMSO-d₆) δ 6.65 (d, J = 7.2 Hz, 1H), 6.43 (d, J = 10.8 Hz, 1H), 4.92 (s, 2H), 4.55 (s, 2H). Step 3: Preparation of 5-bromo-6-fluoro-2H-benzo[d][1,2,3]triazole. [01199] To a mixture of 4-bromo-5-fluorobenzene-1,2-diamine (1.0 g, 4.90 mmol) in AcOH (2 mL) and H₂O (10 mL) was slowly added NaNO₂ (1.7 g, 24.30 mmol) under N₂ at 25 ℃, then stirred at 25 ℃ for 1 h. The reaction was diluted with EA (50 mLx2) and washed with water (50 mLx3) and brine (50 mL). The organic extract was dried over Na₂SO₄, and the solvent was removed to afford the crude product. The crude product was purified by column flash chromatography (EA/PE=0%~100%) to give the title product (1 g, 95 % yield) as a white solid. ESI-MS (M+H) ⁺: 216.0 Step 4: Preparation of 5-bromo-6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazole. [01200] To a mixture of 5-bromo-6-fluoro-2H-benzo[d][1,2,3]triazole (500 mg, 2.32 mmol) in toluene (10 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (1 mL) under N₂ at rt. Then the mixture was stirred at 120 ℃ for 1 h under N₂. The mixture was filtered over celite and washed with EtOAc (20 mL). The reaction mixture was added water (10 mL), extracted with EtOAc (10 mL x 3). The organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to 10%) to afford the title product (218 mg, 41 % yield) as a white solid. ESI-MS (M+H) ⁺: 230.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J = 6.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 4.50 (s, 3H). Step 5: Preparation of N-(6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine. [01201] To a mixture of 5-bromo-6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazole (218 mg, 0.95 mmol) and diphenylmethanimine (206 mg, 1.14 mmol) in 1,4-dioxane (20 mL) were added Cs₂CO₃ (926.3 mg, 2.84 mmol), Xantphos (110 mg, 0.19 mmol) and Pd₂(dba)₃ (87 mg, 0.01 mmol) under N₂ at rt. Then the mixture was stirred at 110 ℃ for 5 h under N₂. The mixture was filtered over celite and washed with EtOAc. The reaction mixture was added water (20 mL), extracted with EtOAc (20 mL x 3). The organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to 50%) to afford the title product (281 mg, 89.7 % yield) as a yellow oil. ESI-MS (M+H) ⁺: 331.0 Step 6: Preparation of 6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine. [01202] To a mixture of N-(6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine (281 mg, 0.85 mmol) in MeOH (10 mL) was added H₂N-OH HCl (294 mg, 4.26 mmol) and CH₃COONa (209.5 mg, 2.55 mmol) under N₂ at rt. Then the mixture was stirred at 25 ℃ for 1 h under N₂. The mixture was filtered over celite and washed with EtOAc (20 mL). The reaction mixture was added water (10 mL), extracted with EtOAc (10 mL *3). The organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to 20%) to afford the title product (120 mg, 85.1 % yield) as a white solid. ESI-MS (M+H) ⁺: 167.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (d, J = 11.2 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.48 (s, 2H), 4.32 (s, 3H). Step 7: Preparation of tert-butyl (R)-4-(1-((6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01203] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) in THF (10 mL) were added triphosgene (121.2 mg, 0.41 mmol) and TEA (100 mg, 0.99 mmol) under N₂ at 0 ℃ for 1 h, then added 6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine (78.3 mg, 0.47 mmol) under N₂ at 0 ℃. Then the mixture was stirred at 70 ℃ for 16 h under N₂. The mixture was filtered over celite and washed with EtOAc. (20 mL) The reaction mixture was added water (10 mL), extracted with EtOAc (10 mL *3). The organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with MeOH in DCM from (0% to 10%) to afford the title product (120 mg, 75 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 511.2 Step 8: Preparation of (R)-N-(6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide TFA salt. [01204] A mixture of tert-butyl (R)-4-(1-((6-fluoro-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (120 mg, 0.24 mmol) in TFA (2 mL) and DCM (10 mL) was stirred at 25 ℃ for 2 h under N₂. The mixture was concentrated and purified by prep-HPLC (0.1%TFA in H₂O / ACN) to afford the title product (21.42 mg, 22.3 % yield) as a white solid. ESI-MS (M+H) ⁺: 411.2.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.64 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.86 (d, J = 11.2 Hz, 1H), 6.65 (d, J = 6.2 Hz, 1H), 4.44 (s, 3H), 4.06 (t, J = 8.0 Hz, 2H), 3.81 (d, J = 12.4 Hz, 2H), 3.44 – 3.33 (m, 2H), 3.25 – 3.10 (m, 4H), 3.05 – 2.95 (m, 1H), 1.28 (d, J = 6.4 Hz, 3H). Example 422 – Preparation of (R)-N-(2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of 4-bromo-5-methyl-2-nitroaniline. [01205] To a solution of 5-methyl-2-nitroaniline (10 g, 65.72 mmol) in CH₃CN (30 mL) was added NBS (11.7 g, 65.72 mmol) in portions under 0 ℃ under stirring. The mixture was stirred at room temperature for 1 h. The mixture was filtered to give the title product (15.3 g, yield: 100%) as an orange solid. ESI-MS (M+H) ⁺: 233.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.48 (s, 2H), 6.98 (s, 1H), 2.27 (s, 3H). Step 2: Preparation of 4-bromo-5-methylbenzene-1,2-diamine. [01206] To a solution of 4-bromo-5-methyl-2-nitroaniline (15.3 g, 66.23 mmol) in EtOH (100 mL) and H₂O (20 mL) were added NH₄Cl (26.6 g, 496.75 mmol) and Fe (37.1 g, 662.34 mmol). The mixture was stirred at 80 ℃ for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=90%:10%) to give title product (8.1 g, yield: 87%) as a yellow solid. ESI-MS (M+H) ⁺: 202.8.¹H NMR (400 MHz, DMSO-d₆) δ 6.66 (s, 1H), 6.43 (s, 1H), 4.51 (s, 4H), 2.08 (s, 3H). Step 3: Preparation of 5-bromo-6-methyl-2H-benzo[d][1,2,3]triazole. [01207] To a solution of 4-bromo-5-methylbenzene-1,2-diamine (7 g, 34.81 mmol) in H₂O (20 mL) and AcOH (12 mL) was added NaNO₂ (12.2 g, 174.04 mmol). The mixture was stirred at room temperature for 1 h. The pH of mixture was adjusted to ~8 by ammonium hydroxide. The mixture was then diluted with H₂O (100 mL) and extracted with EA (150 mL*3). The organic layer was collected and washed by brine (200 mL), dried over Na₂SO₄, filtered and concentrated to give crude product (2.9 g, yield:39%) as brown solid. ESI-MS (M+H) ⁺: 212.1. Step 4: Preparation of 5-bromo-2,6-dimethyl-2H-benzo[d][1,2,3]triazole. [01208] To a solution of 5-bromo-6-methyl-2H-benzo[d][1,2,3]triazole (2.5 g, 11.79 mmol) in toluene (20 mL) was added DMF-DMA (2 mL). The mixture was stirred at 120 ℃ for 1 h. The mixture was diluted with H₂O (20 mL), and extracted with EA (30 mL*3). The organic layer was collected and washed by brine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=80%:20%) to give the title product (553 mg, yield: 21%) as a yellow solid. ESI-MS (M+H) ⁺: 228.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.93 (s, 1H), 4.47 (s, 3H), 2.49 (s, 3H). Step 5: Preparation of N-(2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine. [01209] To a solution of 5-bromo-2,6-dimethyl-2H-benzo[d][1,2,3]triazole (450 mg, 1.99 mmol) in 1,4-dioxane (30 mL) were added diphenylmethanimine (433 mg, 2.39 mmol), Cs₂CO₃ (1945 mg, 5.97 mmol), XantPhos (231 mg, 0.40 mmol) and Pd₂(dba)₃ (183 mg, 0.20 mmol). The mixture was stirred at 110 ℃ for 5 h. The mixture was diluted with H₂O (30 mL), extracted with EA (50 mL*3). The organic layer was collected and washed by brine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=80%:20%) and triturated with DCM:MeOH=10%:90% to give title product (326 mg, yield: 50%) as a yellow solid. ESI-MS (M+H) ⁺: 327.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.75 – 7.71 (m, 2H), 7.62 (s, 1H), 7.58 – 7.46 (m, 3H), 7.28 (t, J = 7.5 Hz, 3H), 7.20 (dd, J = 7.6, 1.6 Hz, 2H), 6.78 (s, 1H), 4.33 (s, 3H), 2.30 (s, 3H). Step 6: Preparation of 2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-amine. [01210] To a solution of N-(2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine (200 mg, 0.61 mmol) in MeOH (10 mL) was added hydroxylamine hydrochloride (212 mg, 3.07 mmol), CH₃COONa (151 mg, 1.84 mmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=0%:100%) to give title product (126 mg, yield: 50%) as yellow solid. ESI-MS (M+H) ⁺: 163.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (s, 1H), 6.77 (s, 1H), 5.12 (s, 2H), 4.29 (s, 3H), 2.21 (d, J = 0.5 Hz, 3H). Step 7: Preparation of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01211] To a solution of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) in THF (30 mL) was added TEA (318 mg, 3.14 mmol), triphosgene (113 mg, 0.38 mmol), and 2,6-dimethyl-2H- benzo[d][1,2,3]triazol-5-amine (62 mg, 0.38 mmol) under 0 ℃ under stirring. The mixture was stirred at 70 ℃ overnight. The mixture diluted with H₂O (30 mL) and the precipitate was filtered to give title product (30 mg, yield: 19%) as yellow solid. ESI-MS (M+H) ⁺: 507.5.¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1H), 8.58 (s, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.75 (s, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.42 (s, 3H), 4.18 – 4.17 (m, 1H), 4.03 (t, J = 8.5 Hz, 2H), 3.78 (d, J = 13.3 Hz, 1H), 3.62 (dd, J = 26.1, 12.1 Hz, 2H), 3.16 – 3.14 (m, 2H), 3.07 (dd, J = 12.8, 3.7 Hz, 1H), 2.94 (dd, J = 11.9, 8.6 Hz, 1H), 2.52 (s, 3H), 1.43 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 8: Preparation of (R)-N-(2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01212] To a solution of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-benzo[d][1,2,3]triazol- 5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (30 mg, 0.06 mmol) in MeOH (4 mL) was added HCl (4M in dioxane, 2 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated and purified by Prep-HPLC (0.05% NH₃.H₂O in water / CH₃CN) to give title product (2.25 mg, yield: 9%) as a yellow solid. ESI-MS (M+H) ⁺: 407.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 8.58 (s, 1H), 7.89 (d, J = 6.1 Hz, 1H), 7.75 (s, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.41 (s, 3H), 4.01 (t, J = 8.6 Hz, 2H), 3.59 (d, J = 12.0 Hz, 2H), 3.14 (t, J = 8.5 Hz, 2H), 2.92 (d, J = 10.9 Hz, 1H), 2.78 (dd, J = 18.5, 11.5 Hz, 3H), 2.52 (s, 3H), 2.46 – 2.45 (m, 1H), 1.01 (d, J = 6.3 Hz, 3H). Example 423 – Preparation of N-(2-methyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan- 7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

C^{ompound 423} Step 1: Preparation of tert-butyl 7-(1-((2-methyl-2H-indazol-5-yl)carbamoyl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [01213] A mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol), 2-methyl-2H-indazol-5-amine (53 mg, 0.36 mmol), triphosgene (107 mg, 0.36 mmol) and TEA (365 mg, 3.62 mmol) in THF (10 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at r.t for 1 h. The precipitate was filtered to afford title product (100 mg, 65.7%). ESI-MS (M+H) ⁺: 504.4.¹H NMR (400 MHz, CDCl₃) δ 11.69 (s, 1H), 8.15 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.80 (s, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.26 – 7.22 (m, 1H), 6.30 (d, J = 6.0 Hz, 1H), 4.15 (d, J = 8.9 Hz, 2H), 3.71 – 3.67 (m, 2H), 3.27 – 3.23 (m, 2H), 3.07 – 3.02 (m, 4H), 1.49 (s, 9H), 1.10 – 1.06 (m, 2H), 0.86 – 0.82 (m, 2H). Step 2: Preparation of N-(2-methyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan-7-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01214] A mixture of tert-butyl 7-(1-((2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (90 mg, 0.18 mmol) in 4M HCl /EA (10mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (29.66 mg, yield: 37.53 %) as a yellow solid. ESI-MS (M+H) ⁺: 404.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.52 (s, 1H), 8.11 – 8.09 (m, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.72 – 7.66 (m, 2H), 6.91 (d, J = 7.4 Hz, 1H), 4.44 – 4.37 (m, 2H), 4.31 (s, 3H), 4.07 – 4.02 (m, 2H), 3.85 (s, 2H), 3.57 – 3.48 (m, 4H), 1.23 – 1.18 (m, 2H), 1.17 – 1.12 (m, 2H). [01215] [01216] Example 424 – Preparation of (R)-4-(3-(hydroxymethyl)piperazin-1-yl)-N-(6-methoxy-2- methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide.

Step 1: Preparation of tert-butyl (R)-2-(hydroxymethyl)-4-(1-((6-methoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate. [01217] To a solution of 6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (640 mg, 3.59 mmol) in THF (50 mL) were added TEA (3.6 g, 36.00 mmol) and triphosgene (443 mg, 1.49 mmol) and stirred at 0^oC for 5 min. Then tert-butyl (R)-4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (1 g, 2.99 mmol) was added slowly at 0 ^oC. The mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (50 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title compound (1 g, 62 %) as a white solid. ESI-MS (M+H) ⁺:538.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 1H), 8.67 (s, 1H), 8.15 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 4.95 (s, 1H), 4.05 (d, J = 6.2 Hz, 6H), 4.03 – 3.96 (m, 3H), 3.91 – 3.78 (m, 2H), 3.65 – 3.56 (m, 2H), 3.22 – 3.06 (m, 4H), 3.02 – 2.90 (m, 2H), 1.43 (s, 9H). Step 2: Preparation of (R)-4-(3-(hydroxymethyl)piperazin-1-yl)-N-(6-methoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01218] To a mixture of tert-butyl (R)-2-(hydroxymethyl)-4-(1-((6-methoxy-2-methyl- 2H-pyrazolo[3,4-b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (900 mg, 1.67 mmol) in DCM (50 mL) were added HMDS (4 g, 25.05 mmol), TMSOTf (7.4 g, 33.40 mmol) at 0 ^oC . The mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mLx2). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title compound (470.91 mg, 64 %) as a white solid. ESI-MS (M+H) ⁺:439.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1H), 8.67 (s, 1H), 8.15 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 5.01 (s, 1H), 4.06 (d, J = 6.4 Hz, 6H), 4.03 – 3.97 (m, 2H), 3.76 – 3.63 (m, 2H), 3.50 – 3.45 (m, 2H), 3.17 – 3.08 (m, 3H), 3.01 – 2.87 (m, 3H), 2.80 – 2.71 (m, 1H). Example 425 – Preparation of (R)-4-(3-(hydroxymethyl)piperazin-1-yl)-N-(2-methyl- 2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (hydroxymethyl)piperazine-1-carboxylate. [01219] A mixture of tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate (2.66 g, 17.26 mmol), 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (4.1 g, 18.98 mmol) in DIEA (3 mL) was stirred at 140 ^oC for 16 h. The mixture was diluted with water (100 mL), extracted with EA (100 mL×3). The organic layer was washed with brine (100 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was diluted with EA, stirred at r.t for 1 h. The precipitate was filtered to afford title product (3.2 g, 55.67%) as a yellow solid. ESI-MS (M+H) ⁺: 335.2.¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 5.9 Hz, 1H), 6.09 (d, J = 6.0 Hz, 1H), 4.39 (s, 1H), 4.22 (s, 1H), 4.01 – 3.92 (m, 1H), 3.89 – 3.85 (m, 1H), 3.69 (d, J = 12.6 Hz, 1H), 3.55 (t, J = 8.3 Hz, 2H), 3.43 (d, J = 11.5 Hz, 1H), 3.26 – 3.16 (m, 1H), 3.10 – 3.02 (m, 2H), 2.92 – 2.90 (m, 2H), 1.49 (s, 9H). Step 2: Preparation of tert-butyl (R)-2-(hydroxymethyl)-4-(1-((2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01220] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (hydroxymethyl)piperazine-1-carboxylate (200 mg, 0.59 mmol), 2-methyl-2H-indazol-5- amine (108.7 mg, 0.72 mmol), triphosgene (213.8 mg, 0.72 mmol) and TEA (725.2 mg, 7.18 mmol) in THF (20 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (20 mL), stirred at r.t for 1 h. The precipitate was filtered to afford title product (200 mg, 65.7%) as a yellow solid. ESI-MS (M+H) ⁺: 508.4. Step 3: Preparation of (R)-4-(3-(hydroxymethyl)piperazin-1-yl)-N-(2-methyl-2H-indazol-5- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01221] A mixture of tert-butyl (R)-2-(hydroxymethyl)-4-(1-((2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (190 mg, 0.37 mmol) in 4M HCl /EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (77.76 mg, yield: 51.63 %) as a white solid. ESI-MS (M+H) ⁺: 408.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (s, 1H), 8.21 (d, J = 7.8 Hz, 2H), 7.99 (d, J = 1.4 Hz, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.55 (d, J = 9.1 Hz, 1H), 7.22 (dd, J = 9.2, 2.0 Hz, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.13 (s, 3H), 3.98 (t, J = 8.6 Hz, 2H), 3.70 (d, J = 12.2 Hz, 1H), 3.61 (d, J = 11.4 Hz, 1H), 3.45 – 3.39 (m, 2H), 3.11 (t, J = 8.6 Hz, 2H), 3.05 – 2.98 (m, 1H), 2.94 – 2.77 (m, 3H), 2.71 – 2.62 (m, 1H). Example 426 – Preparation of (R)-N-(7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01222] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 7-methoxy-2-methylimidazo[1,2- a]pyrimidin-6-amine (110 mg, 0.62 mmol) and TEA (471 mg, 4.70 mmol) in THF (8 mL) was added triphosgene (140 mg, 0.47 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:6) to give title product (80 mg, Y: 48.8%) as a yellow solid. ESI-MS (M+H) ⁺: 523.3. Step 2: Preparation of (R)-N-(7-methoxy-2-methylimidazo[1,2-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate. [01223] A mixture of tert-butyl (R)-4-(1-((7-methoxy-2-methylimidazo[1,2- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (60 mg, 0.11 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (24 mg, Y: 49.5 %) as a white solid. ESI-MS (M+H) ⁺: 423.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 9.28 (s, 1H), 8.29 (s, 2H), 7.92 (d, J = 5.9 Hz, 1H), 7.44 (s, 1H), 6.53 (d, J = 6.0 Hz, 1H), 4.06 (s, 3H), 4.02 – 3.92 (m, 3H), 3.19 – 3.06 (m, 4H), 3.05 – 2.96 (m, 2H), 2.94 – 2.85 (m, 1H), 2.77 – 2.69 (m, 1H), 2.24 (s, 3H), 1.15 (d, J = 5.9 Hz, 3H). Example 427 – Preparation of (S)-N-(6-fluoro-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 5-bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole. [01224] To a solution of 5-bromo-6-fluoro-2H-indazole (2 g, 9.34 mmol) in DCM (20 mL) were added PPTS (0.7 g, 2.80 mmol) and DHP (2.35 g, 28.05 mmol) at 0 ^oC. The mixture was stirred at r.t for 4 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL×3). The organic phase was washed with brine (50 mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA = 1: 1) to give the title compound (2.2 g, yield: 78 %) as a yellow solid. ESI-MS (M+H) ⁺:298.9. Step 2: Preparation of 1-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)propan-2-one. [01225] To a solution of 5-bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (2.1 g, 7.04 mmol) in 1,4-Dioxane (21 mL) were added diphenylmethanimine (1.53 g, 8.45 mmol) ,BINAP (430 mg, 0.7 mmol), Pd(OAc)₂(159 mg, 0.7 mmol) and Cs₂CO₃ (6.89 g, 6.3 mmol). The mixture was stirred at 100 ℃ for 5 h. The mixture was diluted with water (30 mL), extracted with EA (30 mL×3). The organic phase was washed with brine (50 mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA = 3: 1) to give the title compound (700 mg, yield: 25 %) as a yellow solid. ESI-MS (M+H)⁺:400.2. Step 3: Preparation of 6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-amine. [01226] To a solution of N-(6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-yl)- 1,1-diphenylmethanimine (700 mg, 1.75 mmol) in MeOH (10 mL) were added NH₂OH^.HCl (182 mg, 5.26 mmol) and NaOAc (431 mg, 0.53 mmol). The mixture was stirred at rt for 2 h. The mixture was quenched with water (30 mL), extracted with EA (30 mL×3). The organic layers was washed with brine (50 mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA = 1: 1) to give the title compound (400 mg, yield: 97 %) as a yellow solid. ESI-MS (M+H)⁺:236.1. Step 4: Preparation of tert-butyl (2S)-4-(1-((6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H- indazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01227] To a solution of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (50 mg, 0.16 mmol) and 6-fluoro-2-(tetrahydro-2H-pyran- 2-yl)-2H-indazol-5-amine (44 mg, 0.19 mmol) in THF (1 mL) was added TEA (79 mg, 0.78 mmol). Triphosgene (56 mg, 0.19 mmol) in THF (1 mL) was added the mixture at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL×3). The organic layers was washed with brine (10 mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo. The crude was purified by Prep-HPLC (0.1 % NH₄HCO₃ in water / CH₃CN) to give title product (40 mg, yield: 43 %) as a yellow solid. ESI-MS (M+H) ⁺: 580.4. Step 5: Preparation of (S)-N-(6-fluoro-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01228] To a mixture of tert-butyl (2S)-4-(1-((6-fluoro-2-(tetrahydro-2H-pyran-2-yl)- 2H-indazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine- 1-carboxylate (40 mg, 0.71 mmol) in DCM (2 mL) was added TFA(0.5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.1 % TFA in water / CH₃CN) to give title product (2.65 mg, yield: 7 %) as a white solid. ESI-MS (M+H) ⁺: 396.2.¹H NMR (400 MHz, CD₃OD-d₄) δ 8.48 (d, J = 7.4 Hz, 1H), 8.02 - 7.96 (m, 2H), 7.34 (d, J = 10.8 Hz, 1H), 6.58 (d, J = 6.2 Hz, 1H), 4.13 (t, J = 8.6 Hz, 2H), 3.78 (d, J = 13.2 Hz, 2H), 3.41 (d, J = 12.4 Hz, 2H), 3.26 -3.09 (m, 4H), 2.91 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H). Example 428 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01229] To a mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 2-methyl-2H-indazol-5- amine (66.41 mg, 0.45 mmol) in THF (10 mL) were added TEA (136.35 mg, 1.35 mmol) and triphosgene (266.40 mg, 0.9 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (120 mg, 52.81%) as a white solid. ESI-MS (M+H) ⁺: 506.0. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01230] A mixture of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (120 mg, 0.24 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The precipitate was filtered and lyophilized to give title product (98 mg, 92.59%) as a white solid. ESI-MS (M+H) ⁺:406.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.32 (s, 1H), 7.98 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.54 – 7.53 (m, 1H), 6.96 (d, J = 7.4 Hz, 1H), 4.39 (t, J = 8.6 Hz, 2H), 4.32 – 4.29 (m, 1H), 4.29 – 4.24 (m, 4H), 3.59 – 3.51 (m, 4H), 3.27 – 3.21 (m, 2H), 1.43 (d, J = 6.6 Hz, 6H). Example 429 – Preparation of (R)-N-(2,6-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate.

s_{tep 3 step 4}

s_{tep 6 step}

Compound 429 2 FA Step 1: Preparation of N-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine. [01231] To a mixture of 2-fluoro-4-iodo-5-methylpyridine (50 g, 210.97 mmol) in DIEA (500 mL) was added (2,4-dimethoxyphenyl)methanamine (35.23 g, 210.97 mmol). The mixture was stirred at 120 ^oC for 16 h. The mixture was diluted with water (200 mL) and extracted with EA (200 mL*3). The combined organic layer was washed with brine (400 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA = 100:0 to 2:1) to give the title compound (60 g, Y: 74.40 %) as a white solid. ESI-MS (M+H) ⁺: 385.3. Step 2: Preparation of 4-iodo-5-methylpyridin-2-amine. [01232] A mixture of N-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine (10 g, 26.04 mmol) in TFA (100 mL) was stirred at r.t for 16 h. The mixture was concentrated in vacuo, the residue was diluted with water (100 mL), adjust pH to 9 by sat. Na₂CO₃, extracted with DCM (300 mL *3), the organic layer was concentrated vacuo to give title product (2.5 g, 91.52%) as a yellow solid. ESI-MS (M+H) ⁺: 235.3. Step 3: Preparation of 1,2-diamino-4-iodo-5-methylpyridin-1-ium 2,4,6- trimethylbenzenesulfonate. [01233] To a solution of 4-iodo-5-methylpyridin-2-amine (10 g, 42.74 mmol) in CHCl₃ (100 mL) was added O-(mesitylsulfonyl)hydroxylamine (18.38 g, 85.48 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The precipitate was filtered and dried in vacuo to give crude title product (8.5 g, 44.29%) as a white solid. ESI-MS (M+H) ⁺: 250.0. Step 4: Preparation of 7-iodo-2,6-dimethyl-[1,2,4]triazolo[1,5-a]pyridine. [01234] To a mixture of 1,2-diamino-4-iodo-5-methylpyridin-1-ium2,4,6- trimethylbenzenesulfonate (8.5 g, 18.93 mmol) in Ac₂O (100 mL) was added 4- methylbenzenesulfonic acid (4.88 g, 28.40 mmol). The mixture was stirred at 100 ^oC for 16 h. The mixture was concentrated in vacuo and diluted with H₂O (20 mL) and the precipitate was filtered and dried in vacuo to give crude title product (4.8 g, Y: 92.87%) as a white solid. ESI-MS (M+H)⁺: 274.0. Step 5: Preparation of N-(2,6-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1,1- diphenylmethanimine. [01235] To a mixture of 7-iodo-2,6-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (4.8 g, 17.58 mmol), diphenylmethanimine (4.77 g, 26.37 mmol) and BINAP (2.19 g, 3.52 mmol) in 1,4-dioxane (50 mL) were added Cs₂CO₃ (11.46 g, 35.16 mmol) and Pd(OAc)₂ (397.31 mg, 1.76 mmol). The mixture was stirred at 110 ^oC for 16 h under N₂. The mixture was diluted with H₂O (50 mL) and extracted with EA (50 mL x 3). The organic phase was washed with brine (50 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (4.5 g, 78.50%) as a brown solid. ESI-MS (M+H) ⁺:327.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 7.75 – 7.50 (m, 5H), 7.38 – 7.24 (m, 5H), 6.69 (s, 1H), 2.32 (s, 3H), 2.17 (s, 3H). Step 6: Preparation of 2,6-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride. [01236] A mixture of N-(2,6-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1,1- diphenylmethanimine (4.5 g, 13.80 mmol) in 4M HCl/EA (50 mL) was stirred at r.t for 2 h. The mixture was filtrated and the filtrate was concentrated vacuo to give title product (2.5 g, 91.52%) as a yellow solid. ESI-MS (M+H⁺): 163.5. Step 7: Preparation of tert-butyl (R)-4-(1-((2,6-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-7- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01237] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol), 2,6-dimethyl-[1,2,4]triazolo[1,5- a]pyridin-7-amine hydrochloride (93.40 mg, 0.47 mmol) in THF (5 mL) were added TEA (142.41 mg, 1.41 mmol) and triphosgene (278.24 mg, 0.94 mmol) at 0 ^oC. The mixture was stirred at rt for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (60 mg, 25.23%) as a white solid. ESI-MS (M+H) ⁺: 507.4. Step 8: Preparation of (R)-N-(2,6-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate. [01238] To a mixture of tert-butyl (R)-4-(1-((2,6-dimethyl-[1,2,4]triazolo[1,5- a]pyridin-7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (60 mg, 0.12 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (6.31 mg, 10.56%) as a white solid. ESI-MS (M+H) ⁺:407.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 8.65 (s, 1H), 8.37 (s, 1H), 8.25 (s, 2H), 7.90 (d, J = 6.0 Hz, 1H), 6.55 (d, J = 6.1 Hz, 1H), 4.03 – 3.98 (m, 2H), 3.17 – 3.12 (m, 2H), 3.04 – 2.76 (m, 5H), 2.63 – 2.53 (m, 2H), 2.39 (d, J = 4.8 Hz, 6H), 1.06 (d, J = 6.1 Hz, 3H).

Example 430 – Preparation of N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4- ((3R,5S)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

step 1

step 4

: Preparation of ethyl 2,5-dimethyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate. [01239] To a mixture of 5-methyl-1H-1,2,4-triazol-3-amine (8.5 g, 86.73 mmol) in EtOH (120 mL) were added ethyl 3-oxobutanoate (11.3 g, 86.73 mmol) and (CH₂O)_n (2.6 g, 86.73 mmol). The mixture was stirred at 80^oC for 16 h. The mixture was concentrated in vacuo. The residue was diluted with H₂O (100 mL) and extracted with EA (100 mL*3). The organic layer was washed with brine (200 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to get title product (18.0 g, yield: 93.5%) as a white solid. ESI-MS (M+H)⁺: 223.2.¹H NMR (400 MHz, DMSO- d₆) δ 10.32 (s, 1H), 4.73 (s, 2H), 4.15 – 4.07 (m, 2H), 2.30 (s, 3H), 2.15 (s, 3H), 1.25 – 1.18 (m, 3H). Step 2: Preparation of ethyl 2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate. [01240] To a solution of ethyl 2,5-dimethyl-4,7-dihydro-[1,2,4]triazolo[1,5- a]pyrimidine-6-carboxylate (18.0 g, 81.08 mmol) in THF (200 mL) was added MnO₂ (35.2 g, 405.40 mmol). The mixture was stirred at 70^oC for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to give title product (9.4 g, Y: 52.7%) as a white solid. ESI-MS (M+H)⁺: 221.2. Step 3: Preparation of 2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid. [01241] To a mixture of ethyl 2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6- carboxylate (9.4 g, 42.73 mmol) in THF: EtOH: H₂O (5:1:1, 140 mL) was added LiOH (5.1 g, 213.64 mmol). The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo. The crude was diluted with water (50 mL), adjust pH to 5 with 1M HCl and the precipitate was filtered, dried to give the title compound (4.1 g, Y: 50.0 %) as a yellow solid. ESI-MS (M+H) ⁺:193.1. Step 4: Preparation of tert-butyl (R)-4-(1-((2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01242] To a mixture of 2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (136 mg, 0.71 mmol) in toluene (5 mL) were added TEA (191 mg, 1.89 mmol), DPPA (363 mg, 1.32 mmol). The mixture was stirred at r.t for 1 h and warmed up to 90^oC and stirred for 1 h. Tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) was added to the mixture and stirred at 100 ^oC for 4 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to give the title compound (60 mg, Y: 25.0 %) as a white solid. ESI-MS (M+H) ⁺:508.2. Step 5: Preparation of (R)-N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01243] To a solution of tert-butyl (R)-2-methyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5- a]pyridin-7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (50 mg, 0.10 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and lyophilized to give title compound (43 mg, 81.9 %) as a red solid. ESI-MS (M+H)⁺:408.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.53 (s, 1H), 7.85 – 7.83 (m, 1H), 6.96 – 6.94 (m, 1H), 4.49 – 4.40 (m, 2H), 4.31 – 4.18 (m, 2H), 3.63 – 3.53 (m, 5H), 3.42 – 3.35 (m, 2H), 2.84 (s, 3H), 2.71 (s, 3H), 1.44 (d, J = 6.5 Hz, 3H). Example 431 – Preparation of (S)-N-(7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01244] A mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (120 mg, 0.38 mol), 7-fluoro-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-amine (91 mg, 0.45 mmol), triphosgene (35 mg, 0.45 mmol), and TEA (457 mg, 4.53 mmol) in THF (12 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered and triturated with MeOH (5 mL) to afford title product (140 mg, 72.24 %) as a yellow solid. ESI-MS (M+H) ⁺: 511.4.¹H NMR (400 MHz, CDCl₃) δ 12.29 (d, J = 2.3 Hz, 1H), 9.62 (d, J = 6.7 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.30 (d, J = 10.2 Hz, 1H), 6.37 (d, J = 6.1 Hz, 1H), 4.39 – 4.30 (m, 1H), 4.21 – 4.15 (m, 2H), 3.97 (d, J = 13.2 Hz, 1H), 3.54 (d, J = 11.9 Hz, 1H), 3.44 (d, J = 12.5 Hz, 1H), 3.28 – 3.20 (m, 1H), 3.16 – 3.12 (m, 2H), 3.12 – 3.07 (m, 1H), 3.00 – 2.93 (m, 1H), 2.56 (s, 3H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01245] A mixture of tert-butyl (S)-4-(1-((7-fluoro-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (130 mg, 0.25 mmol) in 4M HCl /EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (70.86 mg, yield: 63.55 %) as a white solid. ESI-MS (M+H) ⁺: 411.2.¹H NMR (400 MHz, D₂O) δ 9.08 (d, J = 6.4 Hz, 1H), 7.71 (dd, J = 8.0, 5.1 Hz, 2H), 6.78 (d, J = 7.4 Hz, 1H), 4.31 (t, J = 8.5 Hz, 2H), 4.17 – 4.10 (m, 2H), 3.58 – 3.48 (m, 3H), 3.43 (t, J = 8.5 Hz, 2H), 3.38 – 3.27 (m, 2H), 2.56 (d, J = 1.5 Hz, 3H), 1.34 (d, J = 6.6 Hz, 4H). Example 432 – Preparation of (R)-N-(2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01246] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) in THF (20 mL) were added 2,7- dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (101 mg, 0.62 mmol), TEA (313 mg, 3.10 mmol), triphosgene (110 mg, 0.37 mmol) (in THF (1 mL)) in 0℃. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give title product (70 mg, yield: 43 %) as a white solid. ESI-MS (M+H) ⁺:507.0.¹H NMR (400 MHz, CDCl₃) δ 11.81 (s, 1H), 9.49 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.40 (s, 1H), 6.36 (d, J = 6.0 Hz, 1H), 4.37 – 4.31 (m, 1H), 4.22 – 4.16 (m, 2H), 3.99 – 3.92 (m, 1H), 3.56 – 3.49 (m, 1H), 3.47 – 3.43 (m, 1H), 3.27 – 3.21 (m, 1H), 3.16 – 3.09 (m, 3H), 3.00 – 2.94 (m, 1H), 2.56 (s, 3H), 2.53 (s, 3H), 1.49 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (R)-N-(2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01247] To a mixture of tert-butyl (R)-4-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (50 mg, 0.098 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (9.53 mg, 21%) as a white solid. ESI-MS (M+H) ⁺:407.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.37 (s, 1H), 8.51 (s, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.39 (s, 1H), 6.48 (d, J = 6.1 Hz, 1H), 4.06 – 3.98 (m, 2H), 3.78 – 3.70 (m, 2H), 3.43 – 3.36 (m, 2H), 3.24 – 3.13 (m, 2H), 3.11 – 3.05 (m, 2H), 2.95 – 2.87 (m, 1H), 2.49 (s, 3H), 2.45 (s, 3H), 1.36 (d, J = 6.5 Hz, 3H). Example 433 – Preparation of (R)-4-(3-(hydroxymethyl)piperazin-1-yl)-N-(6-methoxy-2- methyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

C^{ompound 433} Step 1: Preparation of tert-butyl (R)-2-(hydroxymethyl)-4-(1-((6-methoxy-2-methyl-2H- indazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [01248] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (hydroxymethyl)piperazine-1-carboxylate (200 mg, 0.59 mmol), 2,7-dimethyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine (150 mg, 0.72 mmol), triphosgene (210 mg,0.72 mmol) and TEA (720 mg, 7.18 mmol) in THF (20 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water (30 mL), stirred at r.t for 1 h. The precipitate was filtered and triturated with MeOH (5 mL) to afford title product (200 mg, 62.1%) as a yellow solid. ESI-MS (M+H) ⁺: 538.3. Step 2: Preparation of (R)-4-(3-(hydroxymethyl)piperazin-1-yl)-N-(6-methoxy-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01249] A mixture of tert-butyl (R)-2-(hydroxymethyl)-4-(1-((6-methoxy-2-methyl- 2H-indazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (190 mg, 0.35 mmol) in 4M HCl / EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (19.54 mg, yield: 12.77 %) as a yellow solid. ESI-MS (M+H) ⁺: 438.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.00 (s, 1H), 6.49 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.00 (d, J = 8.2 Hz, 2H), 3.96 (s, 3H), 3.67 (d, J = 11.8 Hz, 1H), 3.58 (d, J = 11.8 Hz, 1H), 3.39 (d, J = 4.6 Hz, 2H), 3.11 (t, J = 8.5 Hz, 2H), 2.99 (d, J = 9.6 Hz, 1H), 2.88 (t, J = 11.6 Hz, 1H), 2.82 – 2.74 (m, 2H), 2.64 – 2.57 (m, 1H). Example 434 – Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2-(2-chloro-4-iodo-6-(trifluoromethyl)pyridin-3- yl)ethyl)carbamate. [01250] To a solution of 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (25 g, 81.43 mmol) in THF (400 mL) was added LDA (76 mL, 122.15 mmol, 1.6 M in THF) at -78°C. The mixture was stirred at -78°C for 1.5 h. Then tert-butyl 1,2,3-oxathiazolidine-3- carboxylate 2,2-dioxide (27.2 g, 122.15 mmol) was added to the reaction mixture and stirred at r.t for 16 h. The reaction mixture was quenched with sat. NH₄Cl (250 mL) and extracted with DCM (300 mL x3). The organics were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title compound (33 g, Y: 89.9%) a yellow solid. Step 2: Preparation of 2-(2-chloro-4-iodo-6-(trifluoromethyl)pyridin-3-yl)ethan-1-amine HCl salt. [01251] To a solution of tert-butyl (2-(2-chloro-4-iodo-6-(trifluoromethyl)pyridin-3- yl)ethyl)carbamate (30 g, 66.67 mmol) in 4M HCl/EA (200 mL) was stirred at RT for 2 h. The precipitate was filtered and concentrated in vacuo to give title compound (23 g, Y: 98.7%) as a yellow solid. ESI-MS (M+H) ⁺: 392.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.27 (s, 2H), 3.35 – 3.29 (m, 2H), 3.00 – 2.90 (m, 2H). Step 3: Preparation of 4-iodo-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine [01252] To a solution of 2-(2-chloro-4-iodo-6-(trifluoromethyl)pyridin-3-yl)ethan-1- amine HCl salt (21 g, 59.83 mmol) in ACN (300 mL) was added DIEA (24.77 g, 179.49 mmol). The mixture was stirred at 50^oC for 48 h. The mixture was diluted with H₂O (200 mL), extracted with DCM (200 mL*3), organic layer was concentrated in vacuo and purified by silica gel column (PE: EA = 3: 1) to give title compound (20 g, crude) as a brown solid. ESI-MS (M+H) ⁺: 314.9. Step 4: Preparation of 1-(4-iodo-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1- yl)ethan-1-one. [01253] To a mixture of 4-iodo-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine (11 g, 34.92 mmol) in DCM (150 mL) was added acetyl chloride (5.45 g, 69.84 mmol) at 0^oC, the mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (100 mL), extracted with DCM (100 mL*3), organic layer was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 3) to give title product (1.5 g, 10.0%) as a yellow solid. ESI-MS (M+H) ⁺: 356.9. Step 5: Preparation of tert-butyl (S)-4-(1-acetyl-6-(trifluoromethyl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [01254] A mixture of 1-(4-iodo-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-1-yl)ethan-1-one (1 g, 2.80 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (673 mg, 3.36 mmol), BINAP (349 mg, 0.56 mmol), Cs₂CO₃ (2.73 g, 8.4 mmol) and Pd₂(dba)₃ (256 mg, 0.28 mmol) in 1,4-dioxane (20 mL) was stirred at 100^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 5: 1) to give title product (500 mg, Y: 41.7%) as a yellow solid. ESI-MS (M +H) ⁺: 429.2.¹H NMR (400 MHz, DMSO-d₆) δ 6.89 (s, 1H), 4.23 – 4.12 (m, 1H), 3.95 (t, J = 8.4 Hz, 2H), 3.80 – 3.55 (m, 3H), 3.22 – 3.08 (m, 4H), 3.03 – 2.95 (m, 1H), 2.51 (s, 3H), 1.42 (s, 9H), 1.17 (d, J = 6.6 Hz, 3H). Step 6: Preparation of tert-butyl (S)-2-methyl-4-(6-(trifluoromethyl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01255] A mixture of tert-butyl (S)-4-(1-acetyl-6-(trifluoromethyl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.70 mmol) and KOH (196 mg, 350 mmol) in THF / MeOH / H₂O (2 mL / 2 mL / 1mL) was stirred at 50^oC for 16 h. The mixture was diluted with H₂O (10 mL), extracted with DCM (10 mL*3), organic layer concentrated in vacuo to give title product (300 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 387.3. Step 7: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate. [01256] To a mixture of tert-butyl (S)-2-methyl-4-(6-(trifluoromethyl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.26 mmol), 7-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine hydrochloride (64 mg, 0.69 mmol) and TEA (389 mg, 3.88 mmol) in THF (8 mL) was added triphosgene (115 mg, 0.39 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:7) to give title product (80 mg, Y: 53.6%) as a yellow solid. ESI-MS (M+H) ⁺: 578.3. Step 8: Preparation of (S)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride. [01257] A mixture of tert-butyl (S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (70 mg, 0.12 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo to give title product (58 mg, Y: 93.5 %) as a yellow solid. ESI-MS (M+H) ⁺: 478.0.¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (d, J = 2.9 Hz, 1H), 9.68 – 9.66 (m, 2H), 9.54 (s, 1H), 8.16 (s, 1H), 8.07 (d, J = 9.9 Hz, 1H), 7.09 (s, 1H), 4.09 (t, J = 8.6 Hz, 2H), 4.02 – 3.92 (m, 2H), 3.31 – 3.28 (m, 3H), 3.24 – 3.16 (m, 2H), 3.15 – 3.03 (m, 2H), 2.45 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H). Example 435 – Preparation of N-(2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4- ((3R,5S)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

C^{ompound 435} Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01258] To a solution of 2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-amine hydrochloride (179 mg, 0.90 mmol) and TEA (913 mg, 9.02 mmol) in THF (20 mL) was added triphosgene (267 mg, 0.90 mmol) at 0^oC, after 10 min, tert-butyl (2R,6S)-4-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) was added at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (90 mg, 38.31 %) as a white solid. ESI-MS (M+H) ⁺:521.3. Step 2: Preparation of N-(2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-((3R,5S)-3,5- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01259] To a mixture of tert-butyl (2R,6S)-4-(1-((2,6-dimethyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in EA (2 mL) was added 4 M HCl/EA (3 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (20 mg, Y: 30.95 %) as a yellow solid. ESI-MS (M+H) ⁺:421.2.¹H NMR (400 MHz, D₂O) δ 8.65 (s, 1H), 8.58 (s, 1H), 7.69 (d, J = 7.3 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 4.33 (t, J = 8.4 Hz, 2H), 4.23 (s, 3H), 4.22 – 4.16 (m, 2H), 3.56 – 3.41 (m, 4H), 3.26 – 3.16 (m, 2H), 1.32 (d, J = 6.6 Hz, 6H). Example 436 – Preparation of (S)-N-(2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

C^{ompound 436} Step 1: Preparation of tert-butyl (S)-4-(1-((2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01260] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 2,6-dimethyl-2H-pyrazolo[3,4- b]pyridin-5-amine (77 mg, 0.47 mmol) and TEA (471 mg, 4.70 mmol) in THF (8 mL) was added triphosgene (139.7 mg, 0.47 mmol) at 0^oC, the mixture was stirred at RT for 16 h . The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:7) to give title product (120 mg, Y: 75.5%) as a yellow solid. ESI-MS (M+H) ⁺: 507.4. Step 2: Preparation of (S)-N-(2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01261] A mixture of tert-butyl (S)-4-(1-((2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.20 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1% FA in water / CH₃CN) to give title product (45 mg, Y: 56.0 %) as a yellow solid. ESI-MS (M+H) ⁺: 407.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 6.55 (d, J = 6.1 Hz, 1H), 4.13 (s, 3H), 4.00 (t, J = 8.5 Hz, 2H), 3.68 – 3.61 (m, 2H), 3.14 (t, J = 8.5 Hz, 2H), 3.10 – 3.05 (m, 1H), 3.05 – 2.75 (m, 4H), 2.65 (s, 3H), 1.11 (d, J = 6.3 Hz, 3H). Example 437 – Preparation of (R)-N-(2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01262] To a solution of 2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-amine hydrochloride (187 mg, 0.94 mmol) and TEA (953 mg, 9.42 mmol) in THF (20 mL) was added triphosgene (279 mg, 0.94 mmol) at 0^oC, after 10 min, tert-butyl (R)-4-(2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) was added at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (140 mg, 58.66 %) as a white solid. ESI-MS (M+H) ⁺:507.3. Step 2: Preparation of (R)-N-(2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01263] To a mixture of tert-butyl (R)-4-(1-((2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin- 5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (130 mg, 0.25 mmol) in EA (2 mL) was added 4M HCl/EA (5 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with DCM: MeOH (8 mL, 5:1), then filtered and lyophilized to give title product (80 mg, 89.41 %) as a yellow solid. ESI-MS (M+H) ⁺:407.2.¹H NMR (400 MHz, D₂O) δ 8.57 (s, 1H), 8.53 (s, 1H), 7.70 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 4.33 (t, J = 8.5 Hz, 2H), 4.23 (s, 3H), 4.14 (t, J = 12.2 Hz, 2H), 3.58 – 3.42 (m, 5H), 3.39 – 3.25 (m, 2H), 1.34 (d, J = 6.6 Hz, 3H). Example 438 – Preparation of N-(2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

C^{ompound 438} Step 1: Preparation of tert-butyl 7-(1-((2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [01264] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol), 2,6-dimethyl-2H-pyrazolo[3,4- b]pyridin-5-amine (74 mg, 0.45 mmol) and TEA (451 mg, 4.50 mmol) in THF (8 mL) was added triphosgene (135 mg, 0.45 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:7) to give title product (80 mg, Y: 50.9%) as a yellow solid. ESI-MS (M+H) ⁺: 519.3. Step 2: Preparation of N-(2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01265] A mixture of tert-butyl 7-(1-((2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (60 mg, 0.12 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1% FA in water / CH₃CN) to give title product (21 mg, Y: 43.8 %) as a yellow solid. ESI-MS (M+H) ⁺: 419.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 6.49 (d, J = 6.1 Hz, 1H), 4.13 (s, 3H), 3.98 (t, J = 8.5 Hz, 2H), 3.30 – 3.22 (m, 2H), 3.14 – 3.11 (m, 2H), 3.08 (t, J = 8.5 Hz, 2H), 2.93 – 2.85 (m, 2H), 2.65 (s, 3H), 0.58 – 0.45 (m, 4H). Example 439 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((7-fluoro-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [01266] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 7-fluoro-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine (75.00 mg, 0.45 mmol) in THF (10 mL) were added TEA (136.35 mg, 1.35 mmol) and triphosgene (266.40 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (60 mg, 25.45%) as a white solid. ESI-MS (M+H) ⁺: 525.4. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01267] A mixture of tert-butyl (2R,6S)-4-(1-((7-fluoro-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (60 mg,0.11 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (10.34 mg, 22.17%) as a white solid. ESI- MS (M+H) ⁺:425.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (s, 1H), 9.44 (d, J = 6.8 Hz, 1H), 8.25 (s, 2H), 7.87 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 10.9 Hz, 1H), 6.55 (d, J = 6.2 Hz, 1H), 4.02 – 3.98 (m, 2H), 3.66 – 3.65 (m, 2H), 3.19 – 3.14 (m, 2H), 2.92 – 2.86 (m, 2H), 2.84 – 2.78 (m, 1H), 2.48 – 2.46 (m, 1H), 2.43 (s, 3H), 1.05 (d, J = 6.2 Hz, 6H). Example 440 – Preparation of N-(2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4- ((3R,5S)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01268] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 2,7-dimethyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine (73.19 mg, 0.45 mmol) in THF (10 mL) were added TEA (136.35 mg, 1.35 mmol) and triphosgene (266.4 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (60 mg, 25.64%) as a white solid. ESI-MS (M+H) ⁺: 521.4. Step 2: Preparation of N-(2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-((3R,5S)-3,5- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01269] A mixture of tert-butyl (2R,6S)-4-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (60 mg,0.12 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% NH₃.H₂O in water / CH₃CN) to give title product (3.89 mg, 7.72%) as a white solid. ESI-MS (M+H) ⁺:421.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.39 (s, 1H), 7.89 (d, J = 6.2 Hz, 1H), 7.61 (s, 1H), 6.53 (d, J = 6.3 Hz, 1H), 4.03 – 3.97 (m, 2H), 3.64 – 3.59 (m, 2H), 3.18 – 3.12 (m, 2H), 2.84 – 2.77 (m, 2H), 2.51 (s, 3H), 2.43 – 2.40 (m, 5H), 1.00 (d, J = 6.2 Hz, 6H). Example 441 – Preparation of (S)-N-(2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-4-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01270] A mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (200 mg, 0.63 mmol), 2,7-dimethyl-[1,2,4]triazolo[1,5- a]pyridin-6-amine (200 mg, 1.26 mmol), triphosgene (370 mg,1.26 mmol) and TEA (760 mg, 7.55 mmol) in THF (20 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered and triturated with MeOH (5 mL) to afford title product (100 mg, 31.37 %) as a yellow solid. ESI-MS (M+H) ⁺: 507.0. Step 2: Preparation of (S)-N-(2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01271] A mixture of tert-butyl (S)-4-(1-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (90 mg, 0.17 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H2O / ACN) to give title product (18 mg, yield: 25.04 %) as a yellow solid. ESI-MS (M+H) ⁺: 407.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 9.38 (s, 1H), 8.23 (s, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.60 (s, 1H), 6.54 (d, J = 6.1 Hz, 1H), 4.00 (t, J = 8.3 Hz, 2H), 3.62 (d, J = 12.1 Hz, 2H), 3.14 (t, J = 8.3 Hz, 2H), 2.99 (d, J = 11.0 Hz, 1H), 2.90 – 2.79 (m, 3H), 2.60 – 2.51 (m, 1H), 2.49 (s, 3H), 2.41 (s, 3H), 1.05 (d, J = 5.9 Hz, 3H). Example 442 – Preparation of (R)-N-(8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of 5-bromo-3-ethoxypyrazin-2-amine. [01272] A mixture of 3,5-dibromopyrazin-2-amine (11 g, 43.48 mmol) in EtOH (200 mL) was added EtONa (3.25 g, 47.83 mmol). The mixture was stirred at 80℃ for 16 h. The reaction mixture concentrated in vacuo and diluted with H₂O (100 mL) and extracted with DCM (100 mL x3). The organics were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title compound (10.3 g, crude) a yellow solid. ESI-MS (M+H) ⁺: 218.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.57 (s, 1H), 6.47 (s, 2H), 4.31 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). Step 2: Preparation of 1,2-diamino-5-bromo-3-ethoxypyrazin-1-ium. [01273] To a mixture of 5-bromo-3-ethoxypyrazin-2-amine (10.1 g, 78.91 mmol) in DCM (600 mL) was added O-(mesitylsulfonyl)hydroxylamine (33.93 g, 157.81 mmol) at 0℃, the mixture was stirred at rt for 16 h. The mixture was filtered, dried in vacuo to give title product (19 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 235.1.¹H NMR (400 MHz, DMSO-d₆) δ 16.02 – 15.99 (m, 1H), 9.02 (s, 2H), 7.89 (s, 1H), 6.97 (s, 2H), 4.44 (q, J = 7.0 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). Step 3: Preparation of 6-bromo-8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazine. [01274] To a mixture of 1,2-diamino-5-bromo-3-ethoxypyrazin-1-ium (18 g, 76.92 mmol) in AcO₂ (180 mL) was added HCl (20 mL) at 0℃. The reaction solution was stirred at 100℃ for 16 h. The mixture diluted with H₂O (600 mL) and the precipitate was filtered, washed with water and dried in vacuo to give title product (11 g, Y: 55.6%) as a white solid. ESI-MS (M+H) ⁺: 258.9.¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). Step 4: Preparation of N-(8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-1,1- diphenylmethanimine. [01275] To a mixture of 6-bromo-8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazine (5 g, 19.46 mmol), diphenylmethanimine (3.87 g, 21.40 mmol) , BINAP (2.4 g, 3.90 mmol), Pd₂(dba)₃ (1.79 g, 1.95 mmol) and Cs₂CO₃ (18.9 g, 58.37 mmol) in 1,4-dioxane (80 mL). The reaction solution was stirred at 100℃ for 16 h under N₂. The reaction was filtered, the filtrate was concentrated in vacuo to give title product (11 g, crude) as a yellow oil. ESI-MS (M+H) ⁺: 358.0. Step 5: Preparation of 8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-amine HCl salt. [01276] A mixture of N-(8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-1,1- diphenylmethanimine (10.2 g, 28.21 mmol) in 4M HCl/EA (25 mL) was stirred at RT for 2h. The mixture diluted with EA (100 mL) stirred for 16 h and filtered, the filtrate cake was dried in vacuo to give title product (2.5 g, Y: 45.2%) as a yellow solid. ESI-MS (M+H) ⁺: 194.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (s, 1H), 5.57 (s, 2H), 4.56 – 4.34 (m, 2H), 2.38 (s, 3H), 1.39 (s, 3H). Step 6: Preparation of tert-butyl (R)-4-(1-((8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01277] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 8-ethoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrazin-6-amine HCl salt (91.2 mg, 0.47 mmol) and TEA (475 mg, 0.47 mmol) in THF (8 mL) was added triphosgene (140 mg, 0.47 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:7) to give title product (110 mg, Y: 65.2%) as a yellow solid. ESI-MS (M+H) ⁺: 538.3. Step 7: Preparation of (R)-N-(8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01278] A mixture of tert-butyl (R)-4-(1-((8-ethoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine- 1-carboxylate (90 mg, 0.17 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (32 mg, Y: 43.8%) as a white solid. ESI-MS (M+H) ⁺: 438.7.¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 8.77 (s, 1H), 8.29 (s, 1H), 7.88 (d, J = 6.1 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 3.97 (t, J = 8.5 Hz, 2H), 3.63 – 3.60 (m, 2H), 3.11 (t, J = 8.5 Hz, 2H), 3.05 – 2.98 (m, 1H), 2.94 – 2.77 (m, 3H), 2.63 – 2.55 (m, 1H), 2.46 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H). Example 443 – Preparation of (S)-4-(3-methylpiperazin-1-yl)-N-(pyrrolo[1,2- b]pyridazin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-2-methyl-4-(1-(pyrrolo[1,2-b]pyridazin-4-ylcarbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01279] To a solution of pyrrolo[1,2-b]pyridazin-4-amine (50 mg, 0.38 mmol) in THF (20 mL) were added TEA (381 mg, 3.77 mmol) and triphosgene (113 mg, 0.38 mmol) at 0 ^oC. The mixture was stirred for 5 minutes. Tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered, washed with H₂O (5 mL) and triturated with MeOH (10 mL) to give title compound (100 mg, yield: 67%) as a grey solid. ESI-MS (M+H)⁺: 478.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.73 (s, 1H), 8.10 (d, J = 6.1 Hz, 1H), 8.07 (d, J = 5.3 Hz, 1H), 7.83 – 7.80 (m, 1H), 7.38 (d, J = 5.3 Hz, 1H), 6.83 (dd, J = 4.2, 2.8 Hz, 1H), 6.70 (dd, J = 4.3, 1.4 Hz, 1H), 6.58 (d, J = 6.2 Hz, 1H), 4.18 (s, 1H), 4.03 (t, J = 8.5 Hz, 2H), 3.78 (d, J = 13.2 Hz, 1H), 3.68 (d, J = 13.1 Hz, 1H), 3.61 (d, J = 12.8 Hz, 1H), 3.14 (ddd, J = 16.6, 14.1, 5.8 Hz, 4H), 2.97 (td, J = 11.8, 3.4 Hz, 1H), 1.43 (s, 9H), 1.18 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-4-(3-methylpiperazin-1-yl)-N-(pyrrolo[1,2-b]pyridazin-4-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01280] To a solution of tert-butyl (S)-2-methyl-4-(1-(pyrrolo[1,2-b]pyridazin-4- ylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (90 mg, 0.19 mmol) in EA (2 mL) was added 4M HCl/EtOAc (6 mL) at 0 ^oC. Then the mixture was stirred at r.t for 2 hours. The precipitate was filtered, and washed with EA (5 mL) and lyophilized to give title compound (68.43 mg, yield: 87%) as a grey solid. ESI-MS (M+H)⁺:378.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.66 (s, 1H), 9.45 (s, 1H), 9.26 (s, 1H), 8.16 (d, J = 6.1 Hz, 1H), 8.08 (d, J = 5.3 Hz, 1H), 7.82 (dd, J = 2.6, 1.6 Hz, 1H), 7.38 (d, J = 5.3 Hz, 1H), 6.84 (dd, J = 4.3, 2.7 Hz, 1H), 6.73 (d, J = 1.5 Hz, 1H), 6.71 (d, J = 6.2 Hz, 1H), 4.06 – 4.04 (m, 2H), 3.83 (d, J = 14.0 Hz, 2H), 3.38 – 3.25 (m, 3H), 3.19 (t, J = 8.5 Hz, 2H), 3.13 – 3.03 (m, 2H), 1.30 (d, J = 6.5 Hz, 3H).

Example 444 – Preparation of (R)-N-(2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of 3-methoxypyridine 1-oxide. [01281] To a mixture of 3-methoxypyridine (50 g, 0.69 mol) in dichloromethane (500 mL) was added m-chloroperoxybenzoic acid (118.6 g, 0.6 mol) in batches in an ice-water bath, the mixture was stirred at room temperature overnight. The mixture was diluted with saturated Aqueous sodium sulfite solution (700 mL), after stirring for 30 minutes, was added saturated aqueous sodium bicarbonate solution (500 mL), extracted with dichloromethane (1200 mL×10), The organic layer was dried with Na₂SO₄ and concentration in vacuo to give the title compound (105 g, crude) as an off-white solid. ESI-MS (M+H) ⁺:126.1. Step 2: Preparation of 3-methoxy-4-nitropyridine 1-oxide. [01282] A solution of 3-methoxypyridine-N-oxide (105 g, 0.84 mol) and con. H₂ SO₄ (200 mL) was carefully prepared by adding the acid slowly to the solid N-oxide using an ice bath for cooling. After solution is effected, it is rapidly stirred and fuming nitric acid (202 mL) is added over 30 min. The reaction mixture was warmed to 75° C for 5 hours. The contents were poured onto ice and neutralized to pH 9 with cooling using 50% NaOH. The mixture was extracted three times with CH₂Cl₂, dried over Na₂ SO₄ and solvent evaporated under reduced pressure to produce an oil. The crude product was chromatographed on silica gel using CH₂ Cl₂ / MeOH (99:1) as the eluent to give title product (17.4 g 24.38 %) as a crystalline solid. ESI-MS (M+H) ⁺:171.1.¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J = 1.3 Hz, 1H), 7.93 (d, J = 7.1 Hz, 1H), 7.88 (dd, J = 7.1, 1.5 Hz, 1H), 4.03 (s, 3H). Step 3: Preparation of 3-methoxypyridin-4-amine. [01283] The compound 3-methoxy-4-nitropyridine 1-oxide (8 g, 94.05 mmol) was dissolved in methanol (500 mL), Nickel in water (20 mL) was added at room temperature and stirred under a hydrogen atmosphere overnight. The mixture was filtered, washed with MeOH and the filtrate was concentrated to give the title compound (6.7 g, crude) as a yellow oil. ESI-MS (M+H) ⁺:125.2.¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J = 13.9 Hz, 2H), 6.58 (s, 1H), 4.30 (s, 2H), 2.07 (s, 3H). Step 4: Preparation of tert-butyl (3-methoxypyridin-4-yl)carbamate. [01284] To a mixture of 3-methoxypyridin-4-amine (13.5 g, 108.75 mmol) in EA (300 mL) was added Boc₂O (30.85 g, 141.37 mmol). The reaction solution was stirred at 80 ℃ for 3 h. After cooled to r.t, the mixture was diluted with H₂O (500 mL), then the mixture was extracted with EA (400 mL * 3). The organic layer was washed with brine, dried over Na₂SO₄ and evaporated to give the title product (18.4 g, 75.45 %) as a yellow solid. ESI-MS (M+H) ⁺:225.1.¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 5.3 Hz, 1H), 8.02 (d, J = 5.1 Hz, 1H), 7.22 (s, 1H), 3.96 (s, 3H), 1.54 (s, 9H). Step 5: Preparation of 1-amino-4-((tert-butoxycarbonyl)amino)-3-methoxypyridin-1-ium 2,4- dinitrophenolate. [01285] To a mixture of tert-butyl (3-methoxypyridin-4-yl)carbamate (17.40 g, mmol) in ACN (250 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (30.90 g, 155.18 mmol). The reaction solution was stirred at 50^oC for 16 h. The mixture was concentrated to give title product (48 g, crude) as a yellow solid and used at next step without further operation. ESI- MS (M+H) ⁺:240.1. Step 6: Preparation of ethyl 5-((tert-butoxycarbonyl)amino)-6-methoxypyrazolo[1,5- a]pyridine-3-carboxylate (DP) and ethyl 5-((tert-butoxycarbonyl)amino)-4- methoxypyrazolo[1,5-a]pyridine-3-carboxylate (BP). [01286] To a mixture of 1-amino-4-((tert-butoxycarbonyl)amino)-3-methoxypyridin-1- ium 2,4-dinitrophenolate (48 g, 113.37 mmol) and ethyl propiolate (12.64 mL, 124.71 mmol) in DMF (600 mL) was added K₂CO₃ ( 21.94 g, 21.94 mmol). The reaction solution was stirred at rt. for 16 h. The mixture was concentrated and diluted with water (500 mL), extracted with DCM (600 mL×3). The organic layer was washed with brine, dried with Na₂SO₄ and concentration in vacuo to give crude. The crude was purified by silica gel column chromatography (PE: EA= 4:1-2:1) to give the DP (7.2 g, 18.94 %) as a yellow solid and the BP (7 g, 18.41 %) as a yellow solid. [01287] DP: ESI-MS (M+H) ⁺:336.1.¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 4.40 – 4.35 (m, 2H), 3.94 (s, 3H), 1.56 (s, 9H), 1.42 (s, 3H). [01288] BP: ESI-MS (M+H) ⁺:336.1¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.32 (s, 1H), 4.35 (t, J = 7.1 Hz, 2H), 3.89 (s, 3H), 1.56 (s, 9H), 1.40 (t, J = 7.1 Hz, 3H). Step 7: Preparation of 6-methoxypyrazolo[1,5-a]pyridin-5-amine. [01289] A solution of ethyl 5-((tert-butoxycarbonyl)amino)-6-methoxypyrazolo[1,5- a]pyridine-3-carboxylate (6.85 g, 20.43 mmol) in concentrated sulfuric acid (78 mL, 98%) and water (80 mL) were stirred at 100 ° C for 16 hours. The Sodium hydroxide aqueous solution (6M) was adjusted to a pH greater than 7, extracted with DCM (3 x 100 mL), dry over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA= 1: 3) to give the compound (1.3 g, 39.00 %) as a yellow solid. ESI-MS (M+H) ⁺:164.1.¹H NMR (400 MHz, CDCl₃) δ 7.95 (s, 1H), 7.71 (d, J = 2.2 Hz, 1H), 6.57 (s, 1H), 6.11 (d, J = 1.8 Hz, 1H), 3.88 (s, 3H). Step 8: Preparation of tert-butyl (R)-4-(1-((6-methoxypyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01290] To a solution of 6-methoxypyrazolo[1,5-a]pyridin-5-amine (92 mg, 0.56 mmol) and TEA (572 mg, 5.65 mmol) in THF (12 mL) was added triphosgene (167.7 mg, 0.56 mmol) at 0^oC, after 10 min, tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) was added at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (40 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (90 mg, 37.64 %) as a white solid. ESI-MS (M+H) ⁺:508.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.80 – 7.77 (m, 1H), 6.53 (d, J = 6.1 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 4.22 – 4.14 (m, 1H), 4.04 – 4.00 (m, 2H), 3.99 (s, 3H), 3.81 – 3.75 (m, 1H), 3.68 – 3.62 (m, 1H), 3.58 (d, J = 14.2 Hz, 1H), 3.21 – 3.12 (m, 3H), 3.10 – 3.04 (m, 1H), 2.98 – 2.89 (m, 1H), 1.42 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H). Step 9: Preparation of tert-butyl (R)-4-(1-((6-methoxypyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01291] To a mixture of tert-butyl (R)-4-(1-((6-methoxypyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.16 mmol) in EA (2 mL) was added 4M HCl/EA (3 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with DCM: MeOH (8 Ml, 10:1), then filtered and lyophilized to give title product (60 mg, 93.43 %) as an off-white solid. ESI-MS (M+H) ⁺:408.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 9.81 (d, J = 44.9 Hz, 2H), 8.43 (s, 1H), 8.32 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.82 (d, J = 1.4 Hz, 1H), 6.65 (d, J = 6.0 Hz, 1H), 6.44 (s, 1H), 4.06 – 4.01 (m, 2H), 3.99 (s, 3H), 3.85 – 3.76 (m, 2H), 3.37 – 3.27 (m, 3H), 3.20 – 3.03 (m, 4H), 1.33 (d, J = 6.4 Hz, 3H). Example 445 – Preparation of (R)-N-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

C^{ompound 445} Step 1: Preparation of 2,4-dimethylpyridin-3-amine. [01292] To a solution of 2,4-dimethyl-3-nitropyridine (25 g, 0.16 mol) in EtOH (250 mL) was added Pd/C (10% wt, 2.5 g). The mixture was stirred at r.t for 16 h under H₂. The mixture was filtered and the filtrate was concentrated in vacuo to give crude title product (16 g, 81.97%) as a brown solid. ESI-MS (M+H) ⁺: 123.1. Step 2: Preparation of 6-bromo-2,4-dimethylpyridin-3-amine. [01293] To a mixture of 2,4-dimethylpyridin-3-amine (16 g, 131.15 mmol) in CAN (160 mL) was added 1-bromopyrrolidine-2,5-dione (21.01 g, 118.04 mmol). The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo and purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (10 g, 38.12%) as a yellow solid. ESI-MS (M+H) ⁺: 201.3.¹H NMR (400 MHz, DMSO-d₆) δ 7.03 (s, 1H), 4.96 (s, 2H), 2.25 (s, 3H), 2.08 (s, 3H). Step 3: Preparation of 5-bromo-7-methyl-2H-pyrazolo[3,4-c]pyridine. [01294] To a mixture of 6-bromo-2,4-dimethylpyridin-3-amine (10 g, 50 mmol), KOAc (9.70 g, 100 mmol) in CHCl₃ (100 mL) was added Ac₂O (23.6 g, 200 mmol). The mixture was stirred at r.t for 1 h. Then tert-Butyl nitrite (10.30 g, 100 mmol) and 18-Crown-6 (1.32 g, 5 mmol) were added to the mixture and stirred at 70 ^oC for 16 h. The mixture was concentrated in vacuo, the residue in MeOH (100 mL) was added K₂CO₃ (34.50 g, 250 mmol) and stirred at r.t for 16 h. The mixture was diluted with H₂O (100 mL) and extracted with DCM (100 mL). The organic phase was washed with brine (100 mL x 3), dried over anhydrous Na₂SO₄ and concentrated to afford title product (6.5 g, 61.62%) as a yellow solid. ESI-MS (M+H) ⁺: 212.2. Step 4: Preparation of 5-bromo-2,7-dimethyl-2H-pyrazolo[3,4-c]pyridine. [01295] A mixture of 5-bromo-7-methyl-2H-pyrazolo[3,4-c]pyridine (6.5 g, 30.81 mmol) in EA (70 mL) was added trimethyloxonium tetrafluoroborate (5.47 g, 36.98 mmol). The mixture was stirred at r.t for 3 h. The mixture was diluted with H₂O (70 mL) and extracted with EA (70 mL x 3). The organic phase was washed with brine (70 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (6.0 g, 88.36%) as a yellow solid. ESI-MS (M+H) ⁺: 226.3. Step 5: Preparation of methyl 2,7-dimethyl-2H-pyrazolo[3,4-c]pyridine-5-carboxylate. [01296] To a mixture of 5-bromo-2,7-dimethyl-2H-pyrazolo[3,4-c]pyridine (6.0 g, 26.67 mmol) in MeOH (60 mL) were added TEA (8.08 mg, 80.01 mmol) and Pd(dppf)Cl₂ (1.94 g, 2.67 mmol). The mixture was stirred at 80 ^oC for 16 h under CO. The mixture was diluted with H₂O (60 mL) and extracted with EA (60 mL x 3). The organic phase was washed with brine (60 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (1 g, 18.29%) as a white solid. ESI-MS (M+H) ⁺: 206.5. Step 6: Preparation of 2,7-dimethyl-2H-pyrazolo[3,4-c]pyridine-5-carboxylic acid. [01297] To a mixture of methyl 2,7-dimethyl-2H-pyrazolo[3,4-c]pyridine-5- carboxylate (1 g, 4.88 mmol) in MeOH (5 mL), THF(10 mL) and H₂O (2 mL) was added LiOH (585.12 mg, 24.39 mmol). The reaction solution was stirred at RT for 16 h. After concentration to remove most of MeOH, the aqueous phase was adjusted to pH to 5, extracted with EA (10 mLx3). The organic layer was washed with brine, dried over Na₂SO_4, filtered and evaporated to give title product (400 mg, 42.91%) as a white solid. ESI-MS (M+H) ⁺: 148.5. Step 7: Preparation of tert-butyl (R)-4-(1-((2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01298] To a solution of 2,7-dimethyl-2H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (100 mg, 0.52 mmol) in Toluene (10 mL) were added TEA (158.64 mg, 1.57 mmol) and DPPA (286 mg, 1.04 mmol). The mixture was stirred at r.t for 1h. Then the mixture was stirred at 60 ^oC for another 1h. tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (198.43 mg, 0.62 mmol) was added to the mixture and stirred at 90 ^oC for 16h. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:3) to provide title product (80 mg, 30.40%) as a white solid. ESI-MS (M+H)⁺: 507.5. Step 8: Preparation of (R)-N-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01299] A solution of tert-butyl (R)-4-(1-((2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.16 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (2.23 mg, 3.08 %) as a white solid. ESI-MS (M+H) ⁺: 407.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 8.31 (s, 2H), 8.00 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.20 (s, 3H), 4.02 – 3.96 (m, 2H), 3.60 – 3.57 (m, 2H), 3.14 – 3.09 (m, 2H), 2.97 – 2.93 (m, 1H), 2.91 – 2.73 (m, 4H), 2.70 (s, 3H), 1.03 (d, J = 6.2 Hz, 3H). Example 446 – Preparation of (R)-N-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of 5-bromo-3-methylpyrazin-2-amine. [01300] To a mixture of 5-bromo-3-methylpyrazin-2-amine (23.3 g, 213.76 mmol) and NBS (38.05 g, 213.76 mmol) in CHCl₃ (250 mL) was stirred at RT for 3 h. The mixture diluted with H₂O (200 mL) and extracted with DCM (100 mL x3). The organics were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to give title product (45 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 190.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (s, 1H), 6.43 (s, 2H), 2.26 (s, 3H). Step 2: Preparation of 1,2-diamino-5-bromo-3-methylpyrazin-1-ium. [01301] To a mixture of 5-bromo-3-methylpyrazin-2-amine (20 g, 106.38 mmol) in DCM (900 mL) was added O-(mesitylsulfonyl)hydroxylamine (47.74 g, 212.77 mmol) at 0℃ , the mixture was stirred at rt for 16 h. The precipitate was filtered, dried in vacuo to give title product (34 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 205.0. Step 3: Preparation of 6-bromo-2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine. [01302] To a mixture of 1,2-diamino-5-bromo-3-methylpyrazin-1-ium (30 g, 159.57 mmol) in AcO₂ (300 mL) was added HCl (34 mL) at 0℃. The reaction solution was stirred at 120℃ for 8 h. The mixture diluted with H₂O (1000 mL) and the precipitate was filtered, washed with water and dried in vacuo to give title product (14 g, Y: 38.9%) as a yellow solid. ESI-MS (M+H) ⁺: 229.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.25 (s, 1H), 2.75 (s, 3H), 2.54 (s, 3H). Step 4: Preparation of N-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-1,1- diphenylmethanimine. [01303] A mixture of 6-bromo-2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (5 g, 21.8 mmol), diphenylmethanimine (4.3 g, 24.0 mmol), BINAP (2.7 g, 4.4 mmol), Pd₂(dba)₃ (2.1 g, 2.2 mmol) and Cs₂CO₃ (20.3 g, 65.5 mmol) in 1,4-dioxane (100 mL) was stirred at 100℃ for 16 h under N₂. The reaction was filtered, the filtrate was concentrated in vacuo to give title product (11 g, crude) as a brown solid. ESI-MS (M+H) ⁺: 328.3. Step 5: Preparation of 2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6-amine HCl salt. [01304] A mixture of N-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-1,1- diphenylmethanimine (10.1 g, 30.79 mmol) in 4M HCl / EA (100 mL) was stirred at RT for 3h. The mixture was diluted with EA (400 mL) and stirred for 16 h. The precipitate was filtered, and dried in vacuo to give title product (3.6 g, Y: 72.0%) as a brown solid. ESI-MS (M+H) ⁺: 164.2. Step 6: Preparation of tert-butyl (R)-4-(1-((2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01305] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol), 2,8-dimethyl-[1,2,4]triazolo[1,5- a]pyrazin-6-amine HCl salt (92.5 mg, 0.56 mmol) and TEA (854 mg, 8.46 mmol) in THF (12 mL) was added triphosgene (251 mg, 0.85 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:6) to give title product (110 mg, Y: 65.2%) as a yellow solid. ESI-MS (M+H) ⁺: 508.4. Step 7: Preparation of (R)-N-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01306] A mixture of tert-butyl (R)-4-(1-((2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (90 mg, 0.18 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo to give title product (42 mg, Y: 58.1%) as a white solid. ESI-MS (M+H) ⁺: 408.1.¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (t, J = 64.2 Hz, 2H), 9.09 (s, 1H), 7.97 (s, 1H), 6.72 (s, 1H), 4.16 – 4.00 (m, 2H), 3.97 – 3.72 (m, 2H), 3.45 – 3.29 (m, 3H), 3.29 – 2.98 (m, 4H), 2.76 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H). Example 447 – Preparation of (R)-N-(4-methoxypyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of 4-methoxypyrazolo[1,5-a]pyridin-5-amine. [01307] A mixture of ethyl 5-((tert-butoxycarbonyl)amino)-4-methoxypyrazolo[1,5- a]pyridine-3-carboxylate (6.6 g, 19.68 mmol) in concentrated sulfuric acid (70 mL, 98%) and water (70 mL) was stirred at 100 ° C for 16 hours. The sodium hydroxide aqueous solution (6 M) was adjusted to a pH greater than 7, extracted with DCM (3*100 mL), Dry over anhydrous sodium sulfate, filtered and concentrated invacuo to obtain the title compound (2.9 g, 90.30%) as a brown solid. ESI-MS (M+H) ⁺:164.1.¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J = 7.3 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 6.27 – 6.22 (m, 2H), 3.85 (s, 3H). Step 2: Preparation of tert-butyl (R)-4-(1-((4-methoxypyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01308] To a solution of 4-methoxypyrazolo[1,5-a]pyridin-5-amine (92 mg, 0.56 mmol) and TEA (572 mg, 5.65 mmol) in THF (12 mL) was added triphosgene (167 mg, 0.56 mmol) at 0^oC, after 10 min, tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) was added at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (40 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (130 mg, 54.37 %) as a white solid. ESI-MS (M+H) ⁺:508.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (s, 1H), 8.47 (d, J = 7.6 Hz, 1H), 8.00 – 7.95 (m, 2H), 7.92 (d, J = 2.3 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 6.1 Hz, 1H), 4.22 – 4.14 (m, 1H), 4.05 – 4.00 (m, 2H), 3.99 (s, 3H), 3.81 – 3.76 (m, 1H), 3.68 – 3.63 (m, 1H), 3.61 – 3.57 (m, 1H), 3.20 – 3.12 (m, 3H), 3.10 – 3.05 (m, 1H), 2.97 – 2.90 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H). Step 3: Preparation of (R)-N-(4-methoxypyrazolo[1,5-a]pyridin-5-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.. [01309] To a mixture of tert-butyl (R)-4-(1-((4-methoxypyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.24 mmol) in EA (3 mL) was added 4 M HCl/EA (5 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with DCM: MeOH (8 mL, 10:1), then filtered and lyophilized to give title product (80 mg, 83.05 %) as an off-white solid. ESI-MS (M+H) ⁺:408.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 9.60 (d, J = 54.1 Hz, 2H), 8.48 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.94 (d, J = 2.1 Hz, 2H), 6.69 – 6.68 (m, 1H), 6.64 – 6.62 (m, 1H), 4.12 – 4.03 (m, 2H), 4.00 (s, 3H), 3.88 – 3.77 (m, 2H), 3.41 – 3.30 (m, 3H), 3.24 – 3.05 (m, 4H), 1.32 (d, J = 6.4 Hz, 3H).

Example 448 – Preparation of (R)-N-(5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

S_{tep 4 p}

Step 1: Preparation of 5-bromo-4-methoxypyrimidin-2-amine. [01310] A mixture of 4-methoxypyrimidin-2-amine (25 g, 200 mmol) and NBS (35.6 g, 200 mmol) in CHCl₃ (250 mL) was stirred at RT for 5 h. The mixture was diluted with H₂O (500 mL) and the precipitate was filtered, washed with water and dried in vacuo to give title product (45 g, crude) as a white solid. ESI-MS (M+H) ⁺: 206.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 6.81 (s, 2H), 3.87 (s, 3H). Step 2: Preparation of 1,2-diamino-5-bromo-4-methoxypyrimidin-1-ium. [01311] To a mixture of 5-bromo-4-methoxypyrimidin-2-amine (25 g, 122.55 mmol) in DCM (1000 mL) was added O-(mesitylsulfonyl)hydroxylamine (52.70 g, 245.10 mmol) at 0℃, the mixture was stirred at rt for 16 h. The precipitate was filtered and dried in vacuo to give title product (40 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 220.9. Step 3: Preparation of 6-bromo-5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine. [01312] To a mixture of 1,2-diamino-5-bromo-4-methoxypyrimidin-1-ium (23 g, 105.0 mmol) in AcO₂ (230 mL) was added TsOH (3.6 g, 21.00 mmol) at 0℃. The reaction solution was stirred at 100 ℃ for 16 h. The mixture diluted with H₂O (200 mL) and the precipitate was filtered, washed with water and dried in vacuo to give title product (11 g, Y: 44.0%) as a yellow solid. ESI-MS (M+H) ⁺: 245.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 4.05 (s, 3H), 2.41 (s, 3H). Step 4: Preparation of N-(5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-1,1- diphenylmethanimine. [01313] A mixture of 6-bromo-5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine (5 g, 20.58 mmol) , diphenylmethanimine (4.1 g, 22.630 mmol) , BINAP (1.28 g, 2.06 mmol), Pd₂(dba)₃ (943 mg, 1.03 mmol) and Cs₂CO₃ (20.1 g, 61.73 mmol) in 1,4-dioxane (100 mL) was stirred at 110℃ for 16 h under N₂. The reaction was filtered, the filtrate concentrated in vacuo to give title product (11 g, crude) as a brown solid. ESI-MS (M+H) ⁺: 344.0. Step 5: Preparation of 5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine. [01314] A mixture of N-(5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)- 1,1-diphenylmethanimine (10.1 g, 29.36 mmol) in 4M HCl/EA (100 mL) was stirred at RT for 3h. The mixture diluted with 1M NaOH (50 mL), extracted with DCM:MeOH=10:1 (100 mL x3) The organic layer was concentrated in vacuo and purified by silica gel column (DCM:MeOH =1:100) to give title product (2 g, Y:38.1%) as a yellow solid. ESI-MS (M+H) ⁺: 180.1. Step 6: Preparation of tert-butyl (R)-4-(1-((5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate. [01315] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 5-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-amine (85 mg, 0.47 mmol) and TEA (475 mg, 4.70 mmol) in THF (8 mL) was added triphosgene (140 mg, 0.47 mmol) at 0^oC, the mixture was stirred at RT for 16 h . The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:6) to give title product (110 mg, Y: 67.0%) as a yellow solid. ESI-MS (M+H) ⁺: 524.3. Step 7: Preparation of (R)-N-(5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01316] A mixture of tert-butyl (R)-4-(1-((5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (90 mg, 0.17 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo to give title product (52.4 mg, Y: 72.0%) as a yellow solid. ESI-MS (M+H) ⁺: 424.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (s, 1H), 9.75 (s, 1H), 9.61 (d, J = 8.9 Hz, 1H), 9.35 (s, 1H), 7.89 (d, J = 6.1 Hz, 1H), 6.62 (d, J = 5.8 Hz, 1H), 4.17 (s, 3H), 4.04 – 3.99 (m, 2H), 3.40 – 3.26 (m, 4H), 3.25 – 3.01 (m, 5H), 2.45 (s, 3H), 1.32 (d, J = 6.3 Hz, 3H). Example 449 – Preparation of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [01317] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin- 6-amine (58 mg, 0.36 mmol) and TEA (456 mg, 4.51 mmol) in THF (8 mL) was added triphosgene (134 mg, 0.45 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:8) to give title product (70 mg, Y: 44.3%) as a white solid. ESI-MS (M+H) ⁺: 521.3. Step 2: Preparation of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(3,3-dimethylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01318] A mixture of tert-butyl 4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (60 mg, 0.12 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo to give title product (45 mg, Y: 92.8%) as a white solid. ESI-MS (M+H) ⁺: 421.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 9.57 (s, 2H), 9.22 (s, 1H), 8.31 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 6.67 (d, J = 5.8 Hz, 1H), 4.08 – 4.03 (m, 2H), 3.56 – 3.49 (m, 2H), 3.36 (s, 2H), 3.27 – 3.16 (m, 4H), 2.82 (s, 3H), 2.54 (s, 3H), 1.40 (s, 6H). Example 451 – Preparation of (R)-N-(7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin- 5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01319] A mixture of 7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (156 mg, 0.75 mmol), TEA (190 mg, 1.88 mmol) and DPPA (259 mg, 0.94 mmol) in tol (4 mL) was stirred at RT for 1 h, heated to 70 ^oC and stirred for 0.5h, tert-butyl (R)-4-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.63 mmol) was added to the mixture and stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 8) to give title product (50 mg, Y: 15.2%) as a yellow solid. ESI-MS (M+H) ⁺: 523.7. Step 2: Preparation of (R)-N-(7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01320] A mixture of tert-butyl (R)-4-(1-((7-methoxy-2-methyl-2H-pyrazolo[3,4- c]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (40 mg, 0.08 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (4.5 mg, Y: 14.1 %) as a yellow solid. ESI-MS (M+H) ⁺: 423.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.49 (s, 1H), 8.06 (s, 1H), 7.99 (d, J = 5.9 Hz, 1H), 7.67 (s, 1H), 6.56 (d, J = 6.0 Hz, 1H), 4.18 (s, 3H), 4.11 (s, 3H), 4.10 – 4.03 (m, 2H), 3.78 – 3.70 (m, 2H), 3.45 – 3.36 (m, 2H), 3.26 – 3.07 (m, 4H), 2.96 – 2.88 (m, 1H), 1.36 (d, J = 6.6 Hz, 3H). Example 452 – Preparation of (S)-N-(6-methoxypyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-methoxypyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01321] To a solution of 6-methoxypyrazolo[1,5-a]pyridin-5-amine (92 mg, 0.56 mmol) and TEA (572 mg, 5.65 mmol) in THF (12 mL) was added triphosgene(167 mg, 0.56 mmol) at 0^oC, after 10 min, tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) was added at 0 ^oC. The mixture was diluted with water (45 mL). The precipitate was filtered and triturated with MeOH (8 mL) to give the compound (60 mg, 25.09 %) as a white solid. ESI-MS (M+H) ⁺:508.0. Step 2: Preparation of (S)-N-(6-methoxypyrazolo[1,5-a]pyridin-5-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01322] To a mixture of tert-butyl (S)-4-(1-((6-methoxypyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (2 mL) was added HCl/EA (4 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with DCM: MeOH (8 mL, 10:1), then filtered and lyophilized to give title product (30 mg, 74.74 %) as an off-white solid. ESI-MS (M+H) ⁺:408.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 9.69 (d, J = 50.6 Hz, 2H), 8.43 (s, 1H), 8.34 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 6.1 Hz, 1H), 6.42 (d, J = 1.8 Hz, 1H), 4.06 – 4.01 (m, 2H), 3.99 (s, 3H), 3.82 – 3.78 (m, 2H), 3.32 (t, J = 11.0 Hz, 3H), 3.20 – 3.04 (m, 4H), 1.32 (d, J = 6.5 Hz, 3H). Example 453 – Preparation of (S)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01323] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin- 6-amine (61 mg, 0.38 mmol) and TEA (475 mg, 4.70 mmol) in THF (8 mL) was added triphosgene (140 mg, 0.47 mmol) at 0^oC, the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:8) to give title product (80 mg, Y: 49.2%) as a pink solid. ESI-MS (M+H) ⁺: 507.2. Step 2: Preparation of (S)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01324] A mixture of tert-butyl (S)-4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (70 mg, 0.14 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo to give title product (55 mg, Y: 97.9 %) as a yellow solid. ESI-MS (M+H) ⁺: 407.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (s, 1H), 9.72 (s, 1H), 9.59 (s, 1H), 9.22 (s, 1H), 8.32 (s, 1H), 8.00 (d, J = 6.1 Hz, 1H), 6.68 (d, J = 6.0 Hz, 1H), 4.06 – 4.03 (m, 2H), 3.84 – 3.80 (m, 2H), 3.38 – 3.29 (m, 3H), 3.20 (t, J = 8.2 Hz, 2H), 3.15 – 3.02 (m, 2H), 2.84 (s, 3H), 2.54 (s, 3H), 1.32 (d, J = 6.2 Hz, 3H). Example 454 – Preparation of (S)-N-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-4-(1-((3-methoxy-2-methylpyridin-4-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [01325] A mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.314 mmol), 2,8-dimethyl-[1,2,4]triazolo[1,5- a]pyrazin-6-amine (62 mg, 0.377 mmol), triphosgene (112 mg, 0.377 mmol) and TEA (381 mg, 3.774 mmol) in THF (5 mL) was stirred at 0 ^oC for 20 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo. The residue was beated with MeOH (5 mL*2) to afford title product (30 mg, 18.8%) as a white solid. ESI-MS (M+H) ⁺: 508.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 9.11 (s, 1H), 7.98 (d, J = 6.0 Hz, 1H), 6.56 (d, J = 6.1 Hz, 1H), 4.03 (t, J = 8.6 Hz, 2H), 3.79 (d, J = 13.3 Hz, 1H), 3.68 – 3.57 (m, 3H), 3.31 – 3.30 (m, 3H), 3.18 – 3.13 (m, 3H), 3.11 – 3.06 (m, 1H), 3.00 – 2.90 (m, 1H), 2.75 (s, 3H), 1.43 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01326] A mixture of tert-butyl (S)-4-(1-((3-methoxy-2-methylpyridin-4- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (30 mg, 0.059 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the solid was lyophilized to give title product (13.5 mg, 51.5 %) as a white solid. ESI-MS (M+H) ⁺: 408.0.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 9.11 (s, 1H), 8.02 (d, J = 6.2 Hz, 1H), 6.67 (d, J = 6.9 Hz, 1H), 4.10 – 4.02 (m, 2H), 3.82 (d, J = 13.2 Hz, 2H), 3.61 – 3.60 (m, 3H), 3.43 – 3.34 (m, 2H), 3.26 – 3.10 (m, 4H), 3.09 – 2.98 (m, 1H), 2.76 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H). Example 455 – Preparation of (S)-N-(7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01327] To a solution of 7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (63 mg, 0.38 mmol) and TEA (381 mg, 3.77 mmol) in THF (12 mL) was added triphosgene (112 mg, 0.38 mmol) at 0^oC, after 10 min, tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2-methylpiperazine-1-carboxylate (100 mg,0.31 mmol) was added at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo, the residue was purified by silica gel column (PE: EA = 1:3) to give the compound (100 mg, 63 %) as a white solid. ESI- MS (M+H) ⁺:511.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (d, J = 8.2 Hz, 1H), 7.74 – 7.69 (m, 1H), 7.69 – 7.65 (m, 1H), 7.49 (d, J = 11.2 Hz, 1H), 4.22 (t, J = 6.4 Hz, 2H), 3.80 – 3.70 (m, 2H), 3.65 – 3.57 (m, 2H), 3.22 – 3.17 (m, 2H), 2.69 – 2.65 (m, 1H), 2.44 (s, 2H), 2.35 (s, 3H), 1.40 (s, 9H), 1.36 (s, 3H). Step 2: Preparation of (S)-N-(7-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01328] To a mixture of tert-butyl (S)-4-(1-((7-fluoro-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (80 mg, 0.16 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.05% FA in H₂O / ACN) to give title product (36.31 mg, 50%) as a white solid. ESI-MS (M+H) ⁺:411.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (d, J = 2.2 Hz, 1H), 9.42 (d, J = 6.8 Hz, 1H), 8.23 (s, 1H), 7.86 (d, J = 6.1 Hz, 1H), 7.77 (d, J = 10.9 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.02 – 3.97 (m, 2H), 3.62 (d, J = 12.3 Hz, 2H), 3.14 (t, J = 8.5 Hz, 2H), 3.00 (d, J = 11.6 Hz, 1H), 2.93 – 2.75 (m, 3H), 2.60 – 2.53 (m, 1H), 2.43 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H). Example 456 – Preparation of (S)-N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)- 4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01329] To a mixture of 2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (91 mg, 0.47 mmol) in toluene (5 mL) were added TEA (127 mg, 1.26 mmol), DPPA (242 mg, 0.88 mmol). The mixture was stirred at r.t for 1 h and warmed up to 90^oC and stirred for 1 h. tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) was added to the mixture and stirred at 100^oC for 4 h. The mixture was diluted with water (20 mL) and the precipitate was filtered and concentrated in vacuo to give the title compound (100 mg, Y: 63.5 %) as a brown solid. ESI-MS (M+H) ⁺:508.3. Step 2: Preparation of (S)-N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01330] To a solution of tert-butyl (S)-4-(1-((2,5-dimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (90 mg, 0.18 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (90 mg, 97.3 %) as a white solid. ESI-MS (M+H)⁺:408.2. ¹H NMR (400 MHz, MeOD-d₄) δ 9.63 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 6.58 (d, J = 6.0 Hz, 1H), 4.09 (t, J = 8.6 Hz, 2H), 3.86 – 3.80 (m, 2H), 3.52 – 3.46 (m, 2H), 3.29 – 3.21 (m, 2H), 3.19 – 3.15 (m, 2H), 3.01 (dd, J = 13.7, 10.5 Hz, 1H), 2.77 (s, 3H), 2.51 (s, 3H), 1.40 (d, J = 6.6 Hz, 3H). Example 457 – Preparation of (R)-N-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

C^{ompound 457} Step 1: Preparation of tert-butyl (R)-4-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01331] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol), 6-ethoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-amine (130 mg, 0.57 mmol) in THF (5 mL), TEA (143 mg, 1.42 mmol) was added triphosgene (168 mg, 0.57 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (10 mL) and filtered. The residue was triturated with MeOH (5mL), filtered and concentrated in vacuo to get title product (60 mg, Y: 23.7 %) as a brown solid. ESI-MS (M+H) ⁺:537.4. Step 2: Preparation of (R)-N-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01332] To a solution of tert-butyl (R)-4-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (50 mg, 0.10 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% NH₃.H₂O in water / ACN) to give title compound (6.96 mg, 17.1 %) as a yellow solid. ESI-MS (M+H)⁺:437.2. ¹H NMR (400 MHz, MeOD-d₄) δ 8.46 (s, 1H), 8.22 (s, 1H), 7.82 (d, J = 7.0 Hz, 1H), 6.93 (d, J = 7.1 Hz, 1H), 4.57 (q, J = 7.0 Hz, 2H), 4.41 – 4.35 (m, 2H), 4.26 – 4.19 (m, 2H), 4.17 (s, 3H), 3.61 – 3.50 (m, 5H), 3.41 – 3.35 (m, 2H), 1.48 (t, J = 7.0 Hz, 3H), 1.44 (d, J = 6.2 Hz, 3H). Example 458 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of tert-butyl 4-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01333] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 6-ethoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-amine (124 mg, 0.54 mmol), TEA (137 mg, 1.36 mmol) in THF (5 mL) was added triphosgene (161 mg, 0.54 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL), the precipitate was filtered and triturated with MeOH (5mL) to get title product (60 mg, Y: 24.1 %) as a brown solid. ESI-MS (M+H) ⁺:551.4. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01334] To a solution of tert-butyl 4-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% NH₃.H₂O in water / ACN) to give title compound (7.01 mg, 17.1 %) as a red solid. ESI-MS (M+H)⁺:451.3. ¹H NMR (400 MHz, MeOD-d₄) δ 8.47 (s, 1H), 8.13 (s, 1H), 7.87 – 7.83 (m, 1H), 6.88 (s, 1H), 4.55 (q, J = 7.1 Hz, 2H), 4.38 – 4.31 (m, 2H), 4.14 (s, 3H), 3.91 – 3.81 (m, 2H), 3.72 – 3.63 (m, 2H), 3.50 – 3.45 (m, 4H), 1.51 – 1.48 (m, 9H).

Example 459 – Preparation of N-(6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4- (4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of 4-bromo-5-methoxy-2-nitroaniline. [01335] To a mixture of 5-methoxy-2-nitroaniline (60 g, 357.14 mmol) in ACN (600 mL) were added NBS (63.4 g, 357.14 mmol). The reaction mixture was stirred at 70˚C for 2 h. The mixture was diluted with water (600 mL) and stirred at r.t for 20 min. The precipitate was filtered, washed with H₂O (400 mL) and dried to give the title product (80 g, 90%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.63 (s, 2H), 6.60 (s, 1H), 3.86 (s, 3H). Step 2: Preparation of 4-bromo-5-methoxybenzene-1,2-diamine. [01336] To a solution of 4-bromo-5-methoxy-2-nitroaniline (40 g, 161.94 mmol) in EtOH (800 mL) were added Fe (90.6 g, 1619.40 mmol), NH₄Cl (65.58 g, 1214.54 mmol) and H₂O (160 mL), the reaction was stirred at 90°C for 4 h. The precipitate was concentration in vacuo and triturated with PE: EA (250 mL, 4:1), then filtered and concentracted in vacuo to give title product (21 g, 59 %) as a brown solid. ESI-MS (M+H) ⁺:217.0.¹H NMR (400 MHz, DMSO-d₆) δ 6.66 (s, 1H), 6.34 (s, 1H), 4.68 (s, 2H), 4.25 (s, 2H), 3.63 (s, 3H). Step 3: Preparation of 5-bromo-6-methoxy-2H-benzo[d][1,2,3]triazole. [01337] To a solution of 4-bromo-5-methoxybenzene-1,2-diamine (21 g, 96.76 mmol) in H₂O (84 mL) and AcOH (21 mL) was added NaNO₂ (33.4 g, 483.87 mmol). The mixture was stirred at r.t for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The precipitate was triturated with EA: PE (150 mL, 2:1), then filtered and concentracted in vacuo to give title product (20 g, 90 %) as a brown solid. ESI-MS (M+H) ⁺:228.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.40 (s, 1H), 3.95 (s, 3H). Step 4: Preparation of 5-bromo-6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazole. [01338] To a solution of 5-bromo-6-methoxy-2H-benzo[d][1,2,3]triazole (20 g, 87.72 mmol) in toluene (200 mL) were added DMF-DMA (16 g, 131.58 mmol). The mixture was stirred at 100°C for 2 h. The reaction mixture was diluted with water (400 mL) and extracted with EA (400 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=5:1) to give title product (7 g, yield: 32 %) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.41 (s, 1H), 4.44 (s, 3H), 3.93 (s, 3H). Step 5: Preparation of N-(6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine. [01339] To a solution of 5-bromo-6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazole (7 g, 28.93 mmol) in 1,4-dioxane (200 mL) were added diphenylmethanimine (8 g, 43.39 mmol), Cs₂CO₃ (29 g, 86.79 mmol), Xantphos (3.4 g, 5.79 mmol), Pd₂(dba)₃ (2.75 g, 2.89 mmol). The mixture was stirred at 110 ℃ for 5 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to give title product (4 g, yield: 40 %) as a white solid. ESI-MS (M+H) ⁺:343.1.¹H NMR (400 MHz, CDCl₃) δ 7.82 – 7.76 (m, 2H), 7.55 – 7.47 (m, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.22 – 7.18 (m, 3H), 7.17 – 7.12 (m, 2H), 6.96 (s, 1H), 6.88 (s, 1H), 4.35 (s, 3H), 3.80 (s, 3H). Step 6: Preparation of 6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine. [01340] To a solution of N-(6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine (3.5 g, 10.23 mmol) in MeOH (70 mL) were added NaOAc (2.5 g, 30.69 mmol), NH₂OH.HCl (3.5 g, 51.17 mmol). The mixture was stirred at r.t for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=3:1) to give title product (1.7 g, yield: 92 %) as a white solid. ESI-MS (M+H) ⁺: 179.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.05 (s, 1H), 6.74 (s, 1H), 5.16 (s, 2H), 4.26 (s, 3H), 3.86 (s, 3H). Step 7: tert-butyl tert-butyl 7-(1-((6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [01341] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (150 mg, 0.45 mmol) in THF (20 mL) were added 6- methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine (97 mg, 0.54 mmol), TEA (455 mg, 4.50 mmol), triphosgene (160 mg,0.54 mmol) (in THF (0.5 mL) ) at 0℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE=3:1) to give title product (100 mg, yield: 41 %) as a white solid. ESI-MS (M+H) ⁺: 535.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 8.66 – 8.54 (m, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.30 (s, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.37 (s, 3H), 4.04 – 3.96 (m, 5H), 3.59 – 3.53 (m, 2H), 3.31 – 3.27 (m, 2H), 3.14 – 3.07 (m, 4H), 1.42 (s, 9H), 0.95 (t, J = 6.1 Hz, 2H), 0.86 (t, J = 6.1 Hz, 2H). Step 8: Preparation of N-(6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01342] To a solution of tert-butyl 7-(1-((6-methoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (80 mg, 0.15 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure to give title product (61.65 mg, 87%) as a white solid. ESI-MS (M+H) ⁺:435.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 9.75 (s, 2H), 8.59 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.31 (s, 1H), 6.61 (d, J = 6.1 Hz, 1H), 4.38 (s, 3H), 4.06 – 4.01 (m, 5H), 3.62 – 3.57 (m, 2H), 3.43 (s, 2H), 3.34 – 3.29 (m, 2H), 3.16 – 3.10 (m, 2H), 1.13 – 1.09 (m, 2H), 0.95 – 0.91 (m, 2H). Example 460 – Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methoxymethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate.

Step 1: Preparation of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (methoxymethyl)piperazine-1-carboxylate. [01343] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (511 mg, 3.32 mol), tert-butyl (R)-2-(methoxymethyl)piperazine-1-carboxylate (840 mg, 3.65 mmol) in DIEA (0.5 mL) was stirred at 140 ^oC for 16 h. The crude was purified by silica gel column chromatography (MeOH: DCM= 6.8 %) to give title product (500 mg, 43.27%) as a yellow solid. ESI-MS (M+H) ⁺: 349.5. Step 2: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(methoxymethyl)piperazine-1- carboxylate. [01344] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (methoxymethyl)piperazine-1-carboxylate (150 mg, 0.43 mol), 7-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (85 mg, 0.52 mmol), triphosgene (153 mg,0.52 mmol) and TEA (522 mg, 5.17 mmol) in THF (15 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered to afford title product (50 mg, 21.57 %) as a yellow solid. ESI- MS (M+H) ⁺: 540.4. Step 3: Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methoxymethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate. [01345] A mixture of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(methoxymethyl)piperazine-1- carboxylate (40 mg, 0.07 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (27.3 mg, yield: 80 %) as a white solid. ESI-MS (M+H) ⁺: 440.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (d, J = 1.9 Hz, 1H), 9.19 (d, J = 7.4 Hz, 1H), 8.30 (s, 2H), 7.87 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 11.6 Hz, 1H), 6.50 (d, J = 6.2 Hz, 1H), 3.99 (t, J = 8.5 Hz, 2H), 3.65 – 3.56 (m, 2H), 3.34 – 3.29 (m, 2H), 3.28 (s, 3H), 3.12 (t, J = 8.5 Hz, 2H), 2.98 – 2.85 (m, 3H), 2.79 – 2.71 (m, 1H), 2.68 – 2.61 (m, 1H), 2.28 (s, 3H).

Example 461 – Preparation of N-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4- (4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate.

step 4

Step 1: Preparation of 6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine. [01346] To a mixture of 6-chloro-2H-pyrazolo[3,4-b]pyridine (20.0 g, 129.87 mmol) in EA (200 mL) was added trimethyloxonium tetrafluoroborate (23.1 g, 155.84 mmol). The mixture was stirred at r.t for 16 h. The mixture was diluted with Saturated sodium bicarbonate aqueous solution (200 mL) and extracted with EA (200 mL*3), the organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to get title product (18.0 g, Y: 82.5%) as a brown solid. ESI-MS (M+H)⁺: 168.5.¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 4.25 (s, 3H). Step 2: Preparation of 6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine. [01347] To a mixture of 6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine (18 g, 107.14 mmol) in EtOH (200 mL) was added EtONa (8.7 g, 128.57 mmol). The mixture was stirred at 70^oC for 16 h. The mixture was concentrated in vacuo and diluted with water (200 mL) and extracted with EA (200 mL*3), the organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to get title product (10.5 g, Y: 55.4%) as a brown solid. ESI-MS (M+H)⁺: 178.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). Step 3: Preparation of 5-bromo-6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine. [01348] To a mixture of 6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine (13.4 g, 82.21 mmol) in ACN (200 mL) was added NBS (17.6 g, 98.65 mmol). The mixture was stirred at 55^oC for 16 h. The mixture was diluted with water (200 mL) and extracted with EA (200 mL*3). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=10:1) to give the title compound (14.0 g, Y: 70.4 %) as a yellow solid. ESI-MS (M+H) ⁺:256.1. Step 4: Preparation of N-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,1- diphenylmethanimine. [01349] To a mixture of 5-bromo-6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine (9.0 g, 50.85 mmol) in 1,4-dioxane (100 mL) were added diphenylmethanimine (13.8 g, 76.27 mmol), BINAP (6.3 g, 10.17 mmol), Pd₂(dba)₃ (4.7 g, 5.08 mmol) and Cs₂CO₃ (33.2 g, 101.69 mmol). The mixture was stirred at 110^oC for 16 h under N₂. The mixture was diluted with water (100 mL) and extracted with EA (100 mL*3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 2: 1) to get title product (9.0 g, Y: 71.9%) as a yellow solid. ESI-MS (M+H)⁺:357.5.¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (s, 1H), 7.69 – 7.66 (m, 2H), 7.58 – 7.52 (m, 2H), 7.50 – 7.46 (m, 2H), 7.31 – 7.28 (m, 2H), 7.17 – 7.11 (m, 3H), 4.26 (q, J = 7.0 Hz, 2H), 3.98 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H). Step 5: Preparation of 6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine hydrochloride. [01350] To a mixture of N-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,1- diphenylmethanimine (9 g, 25.28 mmol) in EA (90 mL) was added 4 M HCl/EA (90 mL). The mixture was stirred at r.t for 2 h. The mixture was filtered and the residue was diluted with EA (100 mL). The mixture was stirred at r.t for 2 h and filtered to get title product (3.7 g, Y: 63.9%) as a yellow solid. ESI-MS (M+H)⁺:193.5. Step 6: Preparation of tert-butyl 7-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [01351] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (150 mg, 0.45 mmol), 6-ethoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-amine hydrochloride (105 mg, 0.55 mmol) , TEA (138 mg, 1.36 mmol) in THF (10 mL) was added triphosgene (162 mg, 0.55 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and the precipitate was filtered, triturated with MeOH (5 mL), filtered and concentrated in vacuo to get title product (40 mg, Y: 16.2 %) as a brown solid. ESI-MS (M+H) ⁺:549.4.¹H NMR (400 MHz, DMSO- d₆) δ 12.16 (s, 1H), 8.68 (s, 1H), 8.13 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.46 – 4.42 (m, 2H), 4.21 – 4.14 (m, 2H), 4.04 (s, 3H), 4.02 – 3.98 (m, 2H), 3.81 – 3.75 (m, 2H), 3.64 – 3.61 (m, 1H), 3.58 – 3.55 (m, 1H), 2.95 – 2.87 (m, 2H), 1.51 – 1.48 (m, 3H), 1.42 (s, 9H), 1.21 – 1.18 (m, 4H). Step 7: N-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4,7-diazaspiro[2.5]octan- 7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate. [01352] To a solution of tert-butyl 7-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (30 mg, 0.06 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (9.79 mg, 36.2 %) as a yellow solid. ESI-MS (M+H)⁺:449.3. ¹H NMR (400 MHz, MeOD-d4) δ 8.69 (s, 1H), 8.28 – 8.18 (m, 2H), 7.99 – 7.96 (m, 2H), 6.54 (d, J = 6.0 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.10 – 4.06 (m, 5H), 3.52 – 3.48 (m, 2H), 3.39 – 3.35 (m, 2H), 3.32 (s, 2H), 3.10 (t, J = 8.5 Hz, 2H), 1.57 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 6.4 Hz, 2H), 0.96 (t, J = 6.5 Hz, 2H).

Example 462 – Preparation of (S)-N-(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of N2-methyl-3-nitropyridine-2,4-diamine. [01353] To a solution of 2-chloro-3-nitropyridin-4-amine (1.0 g, 5.76 mmol) was added methanamine (10.0 mL,2M in ethanol) at 0 °C. The mixture was stirred at 30 °C for 16 hours. The mixture was concentrated in vacuo. The residue was triturated with tert-butyl methyl ether (5.0 mL) and filtered. The solid dried in vacuo to give title product (740 mg, yield: 72 %) as a yellow solid. ESI-MS (M+H)⁺: 169.2. Step 2: Preparation of tert-butyl (2-(methylamino)-3-nitropyridin-4-yl)carbamate. [01354] To a solution of N²-methyl-3-nitropyridine-2,4-diamine (740 mg, 4.40 mmol) in DCM (8.0 mL) were added TEA (1.3 g, 13.20 mmol) and DMAP (53.7 mg, 0.44 mmol), di-tert-butyl dicarbonate (1.9 g, 8.80 mmol), the mixture was stirred at rt for 16 h. The mixture was concentrated in vacuo,the crude was purified by silica gel column chromatography (PE:EA=10:1) to give title product (500 mg, yield: 42 %) as a yellow solid. ESI-MS (M+H)⁺: 269.2. Step 3: Preparation of tert-butyl (3-amino-2-(methylamino)pyridin-4-yl)carbamate. [01355] To a solution of tert-butyl (2-(methylamino)-3-nitropyridin-4-yl)carbamate (500 mg, 1.86 mmol) in MeOH (5.0 mL) was added 10% palladium on carbon (50 mg, 10% w/w).The mixture was stirred at rt for 16 h under hydrogen atmosphere. The mixure was filtrated through a pad of Celite and the filtrate was concentrated in vacuo to give title compound (400 mg, yield: 90 %) as a brown solid. ESI-MS (M+H)⁺: 239.2. Step 4: Preparation of tert-butyl (3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)carbamate. [01356] To a solution of tert-butyl (3-amino-2-(methylamino)pyridin-4-yl)carbamate (400 mg, 1.67 mmol) in trimethoxymethan (3.0 mL) was added HCOOH (115.9 mg, 2.51 mmol), the mixture was stirred at 100 °C for 1 h. The mixture was concentrated in vacuo,the crude was purified by silica gel column chromatography (PE:EA=1:1) to give title product (180 mg, yield: 43 %) as a yellow solid. ESI-MS (M+H)⁺: 249.1. Step 5: Preparation of 3-methyl-3H-imidazo[4,5-b]pyridin-7-amine. [01357] To a solution of tert-butyl (3-methyl-3H-imidazo[4,5-b]pyridin-7- yl)carbamate (180 mg, 0.72 mmol) in DCM (3.0 mL) was added TFA(1.0 mL) ,the mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo, the residue diluted with Na₂CO₃ solution (10.0 mL) ,extracted with EA (10 mL×3). The combined organic layers was washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give title product (50 mg, yield: 46 %) as a yellow solid. ESI-MS (M+H)⁺: 149.2. Step 6: Preparation of tert-butyl (S)-2-methyl-4-(1-((3-methyl-3H-imidazo[4,5-b]pyridin-7- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01358] To a solution of 3-methyl-3H-imidazo[4,5-b]pyridin-7-amine (50 mg, 0.33 mmol) in THF (8.0 mL) was added triphosgene (150.2 mg, 0.50 mmol) and TEA (2.0 mL) at 0°C , the mixture was stirred at 0°C for 0.5 h. Then the mixture was added tert-butyl (S)-4- (2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (107.4 mg, 0.33 mmol), the mixture was stirred at rt for 16 h. The mixture was concentrated in vacuo,the crude was purified by silica gel column chromatography (DCM:MeOH=20:1) to give title product (25 mg, yield: 15 %) as a yellow solid. ESI-MS (M+H)⁺: 493.3. Step 7: Preparation of (S)-N-(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01359] To a solution of tert-butyl (S)-2-methyl-4-(1-((3-methyl-3H-imidazo[4,5- b]pyridin-7-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (25 mg, 0.05 mmol) in DCM (1.0 mL) was added TFA (0.2 mL), the mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo,the crude was purified by Prep- HPLC (0.1% FA in H₂O/MeCN) to give title product (5.91 mg, yield: 29 %) as a yellow solid. ESI-MS (M+H)⁺: 393.3.¹H NMR (400 MHz, MeOD-d₄) δ 8.49 (s, 1H), 8.31 (d, J = 5.6 Hz, 1H), 8.09 (d, J = 5.6,2H), 8.07 (d, J =6.0,2H), 6.65 (d, J = 6.0 Hz, 1H), 4.17 (t, J = 8.4 Hz, 2H), 3.97 (s, 3H), 3.88 – 3.82 (m, 2H), 3.52 – 4.86 (m, 2H), 3.19 – 3.06 (m, 2H), 3.22 (t, J = 8.4 Hz, 2H), 3.13 – 3.02 (m, 1H), 1.41 (d, J = 6.4 Hz, 3H). Example 463 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl- 2H-benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01360] To a solution of 6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine (100 mg, 0.56 mmol) in THF (12 mL) were added TEA (3.3 mL, 23.74 mmol) and triphosgene (166.5 mg, 0.56 mmol) at 0°C , the mixture was stirred at 0°C for 0.5 h. Then the mixture was added tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine- 1-carboxylate (124.3 mg, 0.37 mmol), the mixture was stirred at rt for 16 h. The mixture was concentrated vacuo, the crude was purified by silica gel column chromatography (DCM:MeOH=20:1) to give title product (115 mg, yield:38 %) as a yellow solid. ESI-MS (M+H)⁺: 537.3. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01361] To a solution of tert-butyl 4-(1-((6-methoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (115 mg, 0.21 mmol) in DCM (2.0 mL) was added TFA(1.0 ml),the mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo, the crude purified by Prep-HPLC (0.1% FA in H₂O/MeCN) to give title product (61.19 mg, yield: 65 %) as a white solid. ESI-MS (M+H)⁺: 437.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.92 (s, 2H), 8.61 (s, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.31 (s, 1H), 6.62 (d, J = 6.0 Hz, 1H), 4.38 (s, 3H), 4.08 – 4.00 (m, 5H), 3.39-3.3 (m, 4H), 3.19-3.15 (m,2H), 1.38 (s,6H). Example 464 – Preparation of (S)-N-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of 2-methyl-5-nitro-2H-benzo[d][1,2,3]triazole. [01362] To a solution of 5-nitro-2H-benzo[d][1,2,3]triazole (14 g, 85.37 mmol) in EtOH (100 mL) were added EtONa-EtOH (20% wt) (52 mL, 153.67 mmol) and MeI (24 g, 170.73 mmol). The mixture was stirred at 80˚C for 16 h. T The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=5:1) to give title product (2 g, yield: 13 %) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (dd, J = 1.9, 0.7 Hz, 1H), 8.23 – 8.16 (m, 2H), 4.62 (s, 3H). Step 2: Preparation of 2-methyl-2H-benzo[d][1,2,3]triazol-5-amine. [01363] To a solution of 2-methyl-5-nitro-2H-benzo[d][1,2,3]triazole (200 mg, 1.12 mmol) in THF (10 mL) was added Pd/C (20 mg, 10% wt). The mixture was stirred at r.t for 2 h under H₂. The precipitate was filtered, washed with THF (50 mL) and the filtrate was concentrated to afford title product (150 mg, Y: 89 %) as a yellow solid. ESI-MS (M+H) ⁺: 149.1. Step 3: Preparation of tert-butyl (S)-2-methyl-4-(1-((2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01364] To a solution of 2-methyl-2H-benzo[d][1,2,3]triazol-5-amine (84 mg, 0.57 mmol) in THF (20 mL) were added and TEA (476 mg, 4.70 mmol) and triphosgene (167 mg, 0.57 mmol) and stirred at 0^oC for 5 min. Then tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) was added slowly at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (90 mg, 39 %) as a white solid. ESI-MS (M+H) ⁺: 493.7.¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.37 (dd, J = 9.1, 1.9 Hz, 1H), 6.58 – 6.48 (m, 1H), 4.44 (s, 3H), 4.21 – 4.14 (m, 1H), 4.04 – 3.97 (m, 2H), 3.82 – 3.76 (m, 1H), 3.70 – 3.57 (m, 2H), 3.22 – 3.06 (m, 4H), 3.00 – 2.91 (m, 1H), 1.43 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 4: Preparation of (S)-N-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01365] To a mixture of tert-butyl (S)-2-methyl-4-(1-((2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (70 mg, 0.14 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure to give title product (48.17 mg, 80%) as a white solid. ESI-MS (M+H) ⁺:393.2.¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (s, 2H), 8.22 (s, 1H), 7.89 (d, J = 9.1 Hz, 2H), 7.59 (s, 1H), 6.94 – 6.76 (m, 1H), 4.46 (s, 3H), 4.34 – 4.20 (m, 2H), 4.08 – 3.96 (m, 2H), 3.41 – 3.24 (m, 6H), 3.14 – 3.07 (m, 1H), 1.33 (d, J = 6.0 Hz, 3H). Example 465 – Preparation of (S)-N-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01366] To a solution of 2,7-dimethyl-2H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (90 mg, 0.47 mmol) in Toluene (10 mL) were added TEA (142.92 mg, 1.42 mmol) and DPPA (193.88 mg, 0.71 mmol). The mixture was stirred at rt for 1h. Then the mixture was stirred at 60 ^oC for another 1h. tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) was added to the mixture and stirred at 90 ^oC for 16h. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:3) to provide title product (50 mg, 21.02%) as a white solid. ESI-MS (M+H)⁺: 507.4. Step 2: Preparation of (S)-N-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01367] A mixture of tert-butyl (S)-4-(1-((2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.099 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (2.51 mg, 5.36%) as a white solid. ESI-MS (M+H) ⁺:407.2. ¹H NMR (400 MHz, MeOD-d₄) δ 8.35 (s, 1H), 8.03 (d, J = 5.8 Hz, 2H), 6.69 (d, J = 6.3 Hz, 1H), 4.32 (s, 3H), 4.21 – 4.14 (m, 2H), 3.94 – 3.86 (m, 2H), 3.57 – 3.35 (m, 4H), 3.28 – 3.24 (m, 2H), 3.12 – 3.04 (m, 1H), 2.92 (s, 3H), 1.41 (d, J = 6.6 Hz, 3H). Example 466 – Preparation of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-((3R,5S)- 3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01368] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol), 2,8-dimethylimidazo[1,2- a]pyrazin-6-amine (58 mg, 0.36 mmol) and TEA (457 mg, 4.50 mmol) in THF (8 mL) was added triphosgene (135 mg, 0.45 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 8) to give title product (100 mg, Y: 63.7%) as a pink solid. ESI-MS (M+H) ⁺: 521.3.¹H NMR (400 MHz, DMSO-d6)δ 11.86 (s, 1H), 8.91 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 6.58 (d, J = 6.2 Hz, 1H), 4.16 – 4.08 (m, 2H), 4.02 (t, J = 8.6 Hz, 2H), 3.59 (d, J = 12.4 Hz, 2H), 3.18 (t, J = 8.5 Hz, 2H), 2.99 (dd, J = 12.5, 4.1 Hz, 2H), 2.68 (s, 3H), 2.36 (s, 3H), 1.43 (s, 9H), 1.26 (d, J = 6.8 Hz, 6H). Step 2: Preparation of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-((3R,5S)-3,5- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01369] A mixture of tert-butyl (2R,6S)-4-(1-((2,8-dimethylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (90 mg, 0.17 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo to give title product (50 mg, Y: 68.8 %) as a white solid. ESI-MS (M+H) ⁺: 421.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.27 (s, 1H), 8.17 (s, 1H), 7.90 (d, J = 6.9 Hz, 1H), 6.97 (s, 1H), 4.47 – 4.14 (m, 4H), 3.64 – 3.44 (m, 4H), 3.24 (s, 2H), 2.88 (s, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.5 Hz, 6H). Example 467 – Preparation of (S)-N-(6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01370] To a solution of 6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine (101 mg, 0.565 mmol) in THF (5 mL) were added TEA (3 mL) and triphosgene (168 mg, 0.565 mmol) at 0°C. The mixture was stirred at 0°C for 1.0 h.Then tert-butyl (S)-4-(2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.376 mmol) in THF (2 mL) was added, the mixture was stirred at rt for 17 h. The mixture was concentrated in vacuo and the crude was triturated with MeOH (3.0 ml) to give title compound (160 mg, yield: 81 %) as a yellow solid. ESI-MS (M+H)⁺: 523.3. Step 2: Preparation of (S)-N-(6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01371] To a solution of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (160 mg, 0.306 mmol) in CH₂Cl₂ (2.5 mL) was added TFA (1 mL). The mixture was stirred at rt for 2 h. The mixture concentrated in vacuo, the crude was purified by Prep-HPLC (0.1% TFA in H₂O/MeCN) to give title product (133.45 mg, yield:78 %) as a white solid. ESI-MS (M+H)⁺: 423.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.31 (s, 1H), 9.25 (s, 1H), 8.88 (s, 1H), 8.61 (s, 1H), 8.01 (s, 1H), 7.30 (s, 1H), 6.62 (d, J = 3.2 Hz, 1H), 4.38 (s, 3H), 4.04 – 4.01 (m, 5H), 3.78 (d, J = 12.0 Hz, 2H), 3.38 (d, J = 12.0 Hz, 2H), 3.18 – 3.14 (m, 4H), 3.02 – 2.96 (m, 1H), 1.27 (d, J = 4.0 Hz, 3H). Example 468 – Preparation of (S)-N-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01372] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 6-ethoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-amine (86 mg, 0.38 mmol), TEA (476 mg, 4.72 mmol) in THF (10 mL) was added and triphosgene (112 mg, 0.38 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (10 mL), the precipitate was filtered and triturated with MeOH (5mL) to get title product (50 mg, Y: 23.7 %) as a brown solid. ESI- MS (M+H) ⁺:537.4. Step 2: Preparation of (S)-N-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01373] To a solution of tert-butyl (S)-4-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (50 mg, 0.10 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (6.66 mg, 16.2 %) as a white solid. ESI-MS (M+H)⁺:437.3.¹H NMR (400 MHz, MeOD-d₄) δ 8.71 – 8.65 (m, 1H), 8.02 – 7.96 (m, 2H), 6.64 – 6.59 (m, 1H), 4.55 – 4.48 (m, 2H), 4.14 – 4.08 (m, 5H), 3.85 – 3.77 (m, 2H), 3.49 (d, J = 10.3 Hz, 2H), 3.22 – 3.11 (m, 4H), 3.00 (t, J = 11.8 Hz, 1H), 1.59 – 1.54 (m, 3H), 1.41 – 1.38 (m, 3H). Example 469 – Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (2-hydroxypropan-2-yl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of 1-(tert-butyl) 2-methyl (R)-4-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1,2-dicarboxylate. [01374] A mixture of 1-(tert-butyl) 2-methyl (R)-piperazine-1,2-dicarboxylate (1.5 g, 6.148 mmol), 1-(4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethan-1-one (1.48 g, 6.148 mmol), Cs₂CO₃ (6 g, 18.443 mmol) and Binap (765 mg, 1.23 mmol ),Pd₂(dba)₃(563 mg, 0.615 mmol) in 1,4-dioxane (20 mL) was stirred at 100 °C for 16 h. The reaction was concentrated in vacuo and the crude was purified by silica gel column chromatography (EA: PE=5:1) to give the title compound (1.4 g, 56.5 %) as a yellow solid. ESI-MS (M+H)⁺: 405.1. ¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (d, J = 5.8 Hz, 1H), 6.55 (d, J = 5.9 Hz, 1H), 4.71 (d, J = 25.1 Hz, 1H), 4.05 – 3.79 (m, 4H), 3.68 (d, J = 5.9 Hz, 3H), 3.54 – 3.41 (m, 1H), 3.28 – 2.85 (m, 5H), 2.51 (s, 3H), 1.41 (d, J = 22.1 Hz, 9H). Step 2: Preparation of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(2- hydroxypropan-2-yl)piperazine-1-carboxylate . [01375] A mixture of 1-(tert-butyl) 2-methyl (R)-4-(1-acetyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1,2-dicarboxylate (2 g, 4.95 mmol) in THF(30 mL) was added MeLi (20 mL,49.5 mmol,2.5 M). The reaction mixture was stirred at -78 ^oC for 2 h. The reaction mixture was concentrated and the solid was purified by prep-HPLC (0.05% FA in H₂O / MeCN) to give the title compound (60 mg, 3.35 %) as yellow solid. ESI-MS (M+H⁺): 363.3.¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 6.20 (s, 1H), 4.65 – 4.43 (m, 1H), 4.15 – 4.03 (m, 1H), 3.80 – 3.72 (m, 1H), 3.60 (t, J = 8.3 Hz, 3H), 3.36 – 3.25 (m, 1H), 3.17 – 2.99 (m, 3H), 2.92 – 2.80 (m, 1H), 1.48 (s, 9H), 1.34 (s, 3H), 1.25 (s, 3H). Step 3: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(2-hydroxypropan-2- yl)piperazine-1-carboxylate. [01376] To a solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (33 mg, 0.20 mmol) and TEA (201mg, 1.99 mmol) in THF (12 mL) was added triphosgene (59 mg, 0.20 mmol) at 0^oC, after 10 min, tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- (2-hydroxypropan-2-yl)piperazine-1-carboxylate (60 mg, 0.17 mmol) was added at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (5 mL) to give the compound (60 mg, 64 %) as a grey solid. ESI-MS (M+H) ⁺:553.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 9.19 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 11.6 Hz, 1H), 6.47 (s, 1H), 4.62 (s, 1H), 4.08 – 3.90 (m, 4H), 3.76 (s, 1H), 3.57 – 3.44 (m, 2H), 3.32 – 3.25 (m, 2H), 3.21 – 3.13 (m, 2H), 2.28 (s, 3H), 1.38 (s, 9H), 1.15 (s, 6H). Step 4: Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-(2- hydroxypropan-2-yl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01377] To a solution of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(2-hydroxypropan-2- yl)piperazine-1-carboxylate (50 mg, 0.09 mmol) in EA (1 mL) was added 4M HCl/EtOAc (3 mL) at 0 ^oC. Then the mixture was stirred at r.t for 2 hours. The precipitate was filtered, and washed with EA (3 mL) and lyophilized to give title compound (33.65 mg, yield: 76%) as a white solid. ESI-MS (M+H)⁺:454.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 9.67 (s, 1H), 9.22 (s, 1H), 9.04 (s, 1H), 8.17 (s, 1H), 8.07 (d, J = 9.9 Hz, 1H), 7.98 (d, J = 6.1 Hz, 1H), 6.68 (d, J = 6.0 Hz, 1H), 4.08 – 4.06 (m, 2H), 3.92 – 3.84 (m, 2H), 3.34 – 3.27 (m, 2H), 3.25 – 3.16 (m, 3H), 3.14 – 3.04 (m, 2H), 2.46 (s, 3H), 1.30 (d, J = 14.3 Hz, 6H). [01378] Example 470 – Preparation of N-(7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)- 4-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of 5-bromo-4-ethoxypyridin-2-amine. [01379] To a mixture of 4-ethoxypyridin-2-amine (48 g, 347.83 mmol) in ACN (500 mL) was added 1-bromopyrrolidine-2,5-dione (61.91 g, 347.83 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (500 mL) and washed with EA (500 mL x 2). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to give title product (30 g, yield: 39.87 %) as a white solid. ESI-MS (M+H) ⁺:219.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (s, 1H), 6.09 (s, 1H), 6.02 (s, 2H), 4.04 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). Step 2: Preparation of 1,2-diamino-5-bromo-4-ethoxypyridin-1-ium 2,4,6- trimethylbenzenesulfonate. [01380] To a solution of 5-bromo-4-ethoxypyridin-2-amine (10 g, 46.30 mmol) in CHCl₃ (100 mL) was added and O-(mesitylsulfonyl)hydroxylamine (10.95 g, 50.93 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The precipitate was filtered and dried in vacuo to give crude title product (8 g, 74.47%) as a white solid. ESI-MS (M+H) ⁺: 234.0. Step 3: Preparation of 6-bromo-7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine. [01381] To a mixture of 1,2-diamino-5-bromo-4-ethoxypyridin-1-ium 2,4,6- trimethylbenzenesulfonate (8 g, 34.49 mmol) in Ac₂O (80 mL) was added O- (mesitylsulfonyl)hydroxylamine (1.19 g, 6.90 mmol). The mixture was stirred at 100 ^oC for 16 h. The mixture was concentrated in vacuo and diluted with H₂O (20 mL) and the precipitate was filtered and dried in vacuo to give crude title product (5 g, Y: 56.86%) as a white solid. ESI-MS (M+H)⁺: 259.0. Step 4: Preparation of N-(7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine. [01382] To a mixture of 6-bromo-7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (4.8 g, 18.82 mmol), diphenylmethanimine (5.11 g, 28.24 mmol) and BINAP (2.34 g, 3.76 mmol) in 1,4-dioxane (50 mL) were added Cs₂CO₃ (12.27 g, 37.64 mmol) and Pd(OAc)₂ (424.88 mg, 1.88 mmol). The mixture was stirred at 110 ^oC for 16 h under N₂. The mixture was diluted with H₂O (50 mL) and extracted with EA (50 mL x 3). The organic phase was washed with brine (50 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (1 g, 15.61%) as a brown solid. ESI-MS (M+H) ⁺:357.4. Step 5: Preparation of 7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine hydrochloride. [01383] A mixture of N-(7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1- diphenylmethanimine (1 g, 2.81 mmol) in 4M HCl/EA (10 mL) was stirred at rt for 2 h. The mixture was filtrated and filtrate cake was dried in vacuo to give title product (400 mg, 82.34%) as a brown solid. ESI-MS (M+H) ⁺: 193.5. Step 6: Preparation of tert-butyl 7-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [01384] To a mixture of 7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine hydrochloride (120 mg, 0.53 mmol), tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (173.68 mg, 0.53 mmol) and TEA (160.59 mg, 1.59 mmol) in THF (5 mL) was added triphosgene (313.76 mg, 1.06 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (60 mg, 17.22%) as a brown solid. ESI-MS (M+H) ⁺: 549.3. Step 7: Preparation of N-(7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01385] A mixture of tert-butyl 7-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (60 mg, 0.11 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (2.51 mg, 5.36%) as a white solid. ESI-MS (M+H) ⁺:449.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.36 (s, 1H), 7.80 (d, J = 5.9 Hz, 1H), 6.89 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 4.25 – 4.19 (m, 2H), 4.04 – 3.98 (m, 2H), 3.44 – 3.39 (m, 2H), 3.26 – 3.20 (m, 4H), 3.09 – 3.03 (m, 2H), 2.41 (s, 3H), 1.61 (t, J = 6.8 Hz, 3H), 0.91 – 0.82 (m, 4H).

Example 471 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methyl-2H-benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((6-methoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [01386] A mixture of 6-methoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine (129 mg, 0.723 mmol), triphosgene (215 mg, 0.723 mmol) and TEA (730 mg, 7 mmol) in THF (5 mL) was stirred at 0 ^oC for 20 min. Then tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (200 mg, 0.602 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo. The solid was triturated with MeOH (5 mL*2) to afford title product (80 mg, 24.8 %) as a white solid. ESI- MS (M+H) ⁺: 537.0.¹ H NMR (400 MHz, DMSO-d₆) δ 12.37 (s, 1H), 8.61 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.31 (s, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.37 (s, 3H), 4.15 – 4.08 (m, 2H), 4.07 – 4.01 (m, 5H), 3.58 (d, J = 12.4 Hz, 2H), 3.18 (t, J = 8.6 Hz, 2H), 3.01 – 2.95 (m, 2H), 1.43 (s, 9H), 1.26 (d, J = 6.8 Hz, 6H). Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01387] A mixture of tert-butyl (2R,6S)-4-(1-((6-methoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 2 h. The reaction mixture was concentrated and the solid was lyophilized to give title product (43.5 mg, 61.1 %) as a white solid. ESI-MS (M+H) ⁺: 437.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (s, 1H), 9.66 (s, 1H), 9.19 (s, 1H), 8.58 (s, 1H), 8.00 (d, J = 6.1 Hz, 1H), 7.32 (s, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.38 (s, 3H), 4.04 – 4.01 (m, 5H), 3.86 (d, J = 13.3 Hz, 2H), 3.39 – 3.30 (m, 2H), 3.20 (t, J = 8.5 Hz, 2H), 3.01 (t, J = 12.2 Hz, 2H), 1.31 (d, J = 6.5 Hz, 6H). Example 472 – Preparation of (S)-N-(8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-4-(1-((8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01388] A mixture of 8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-amine hydrochloride (173 mg, 0.755 mmol), triphosgene (224 mg, 0.755 mmol) and TEA (762 mg, 7.547 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (S)-4-(2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.629 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo. The solid was triturated with MeOH (5 mL*2) to afford title product (90 mg, 26.7 %) as a white solid. ESI-MS (M+H) ⁺: 538.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 8.83 (s, 1H), 7.94 (d, J = 6.1 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 4.05 – 3.97 (m, 2H), 3.67 – 3.57 (m, 3H), 3.26 – 3.04 (m, 6H), 2.47 (s, 3H), 1.46 – 1.42 (m, 12H), 1.19 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01389] A mixture of tert-butyl (S)-4-(1-((8-ethoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine- 1-carboxylate (80 mg, 0.149 mmol) in 4M HCl /EA (5 mL) was stirred at RT for 2 h. The reaction mixture was concentrated and the solid was lyophilized to give title product (60 mg, 85.2 %) as a white solid. ESI-MS (M+H) ⁺: 438.4.¹H NMR (400 MHz, DMSO-d₆) δ 9.52 – 9.09 (m, 2H), 8.82 (s, 1H), 7.97 (s, 1H), 6.67 (s, 1H), 4.56 (q, J = 7.0 Hz, 2H), 4.10 – 4.01 (m, 2H), 3.68 (s, 3H), 3.38 – 3.31 (m, 2H), 3.22 – 3.14 (m, 2H), 3.13 – 3.02 (m, 2H), 2.48 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H). Example 473 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(8-ethoxy-2- methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

C^{ompound 473} Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((8-ethoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [01390] A mixture of 8-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-amine hydrochloride (166 mg, 0.723 mmol), triphosgene (215 mg, 0.723 mmol) and TEA (730 mg, 7.229 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (2R,6S)-4-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (200 mg, 0.602 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo. The solid was triturated with MeOH (5 mL*2) to afford title product (80 mg, 24.1 %) as a white solid. ESI-MS (M+H) ⁺: 552.3.¹ H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 8.83 (s, 1H), 7.97 (d, J = 5.8 Hz, 1H), 6.59 (d, J = 6.1 Hz, 1H), 4.56 (q, J = 7.0 Hz, 2H), 4.14 – 4.07 (m, 2H), 4.03 (t, J = 8.4 Hz, 2H), 3.60 (d, J = 12.9 Hz, 2H), 3.22 – 3.15 (m, 2H), 3.03 – 2.96 (m, 2H), 2.47 (s, 3H), 1.47 – 1.42 (m, 12H), 1.26 (d, J = 6.8 Hz, 6H). Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(8-ethoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01391] A mixture of tert-butyl (2R,6S)-4-(1-((8-ethoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (80 mg, 0.145 mmol) in 4M HCl /EA (5 mL) was stirred at RT for 2 h. The reaction mixture was concentrated and the solid was lyophilized to give title product (51 mg, 72.1 %) as a white solid. ESI-MS (M+H) ⁺: 452.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.19 (s, 1H), 8.81 (s, 1H), 7.95 (d, J = 5.7 Hz, 1H), 6.70 (s, 1H), 4.56 (q, J = 7.1 Hz, 2H), 4.10 – 4.00 (m, 2H), 3.89 (d, J = 12.3 Hz, 2H), 3.39 – 3.29 (m, 2H), 3.28 – 3.14 (m, 2H), 3.13 – 2.94 (m, 2H), 2.48 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H), 1.31 (d, J = 6.4 Hz, 6H). Example 474 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-fluoro-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01392] To a solution of 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (70 mg, 0.36 mmol) in toluene (10 mL) were added DPPA (124 mg, 0.45 mmol) and TEA (91 mg, 0.90 mmol). The mixture was stirred at r.t for 1 h and 40 min at 70 ^o C. Then tert- butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (100 mg, 0.30 mmol) was added to the solution and stirred at 90 ^o C for 16 h. The precipitate was filtered, washed with toluene (5 mL) and dried to give title product (70 mg, yield: 43 %) as a white solid. ESI-MS (M+H) ⁺:524.3.¹H NMR (400 MHz, CDCl₃) δ 12.32 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.31 (d, J = 5.8 Hz, 1H), 7.95 (d, J = 6.0 Hz, 1H), 6.40 (d, J = 6.0 Hz, 1H), 6.18 (s, 1H), 4.31 – 4.24 (m, 2H), 4.22 – 4.15 (m, 2H), 3.48 – 3.42 (m, 2H), 3.20 – 3.13 (m, 2H), 3.05 – 2.98 (m, 2H), 2.43 (s, 3H), 1.50 (s, 9H), 1.37 (d, J = 6.8 Hz, 6H). Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-fluoro-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01393] To a mixture of tert-butyl (2R,6S)-4-(1-((6-fluoro-2-methylpyrazolo[1,5- a]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (50 mg, 0.095 mmol) in EA (5 mL) was added 4 M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure to give title product (41.54 mg, 95%) as a white solid. ESI-MS (M+H) ⁺: 424.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (s, 1H), 9.69 (s, 1H), 9.24 (s, 1H), 8.92 (d, J = 6.2 Hz, 1H), 8.21 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 6.69 (s, 1H), 6.32 (s, 1H), 4.16 – 4.08 (m, 2H), 3.91 – 3.84 (m, 2H), 3.38 – 3.30 (m, 2H), 3.25 – 3.15 (m, 2H), 3.10 – 2.99 (m, 2H), 2.34 (s, 3H), 1.31 (d, J = 6.5 Hz, 6H). Example 475 – Preparation of N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4- (3,3-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 4-(1-((2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01394] To a solution of 2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (87 mg, 0.45 mmol) and TEA (121 mg, 1.204 mmol) in tol (5 mL) was added DPPA (232 mg, 0.84 mmol), the mixture was stirred at RT for 1 h and 90 ^oC for 1 h, after 2 h, tert- butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (100 mg, 0.301 mmol) was added to the mixture and stirred at 110 ^oC for 4 h. The mixture was diluted with water (10 mL) extracted with EA (20 mL×3). The organic layer was washed with brine (20 mL), dried with Na₂SO₄ and concentrated in vacuo and triturate with MeOH (5 mL) to give title product (50 mg, yield: 31.88 %) as a yellow solid. ESI-MS (M+H) ⁺: 522.0. ¹H NMR (400 MHz, CDCl₃) δ 12.29 (s, 1H), 9.71 (s, 1H), 7.83 (d, J = 6.1 Hz, 1H), 6.24 (d, J = 6.2 Hz, 1H), 4.17 – 4.12 (m, 2H), 3.83 – 3.78 (m, 2H), 3.59 (t, J = 5.5 Hz, 2H), 3.48 (s, 2H), 3.31 – 3.26 (m, 2H), 2.79 (s, 3H), 2.59 (s, 3H), 1.51 (s, 9H), 1.46 (s, 6H). Step 2: Preparation of N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01395] A mixture of tert-butyl 4-(1-((2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (50 mg, 0.10 mmol) in 4M HCl/EA (2 mL, 4 M) was stirred at r.t for 2 h. The precipitate was filtered and dried to give title product (10.08 mg, 25.2 %) as a white solid. ESI-MS (M+H) ⁺: 422.1.¹H NMR (400 MHz, D₂O) δ 9.06 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 4.34 (t, J = 8.5 Hz, 2H), 3.89 – 3.85 (m, 2H), 3.68 (s, 2H), 3.49 – 3.42 (m, 4H), 2.61 (s, 3H), 2.52 (s, 3H), 1.43 (s, 6H).

Example 476 – Preparation of (R)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of 6,8-dibromo-2-methylimidazo[1,2-a]pyrazine. [01396] To a mixture of 3,5-dibromopyrazin-2-amine (24 g, 94.86 mmol) in IPA (240 mL) were added 1-bromo-2,2-dimethoxypropane (34.72 g, 189.72 mmol) and PPTS (2.38 g, 9.49 mmol). The reaction solution was stirred at 80℃ for 48 h. The mixture was filtered and dried in vacuo to give title product (15 g, yield: 54.2%) as a brown solid. ESI-MS (M+H) ⁺: 291.8. Step 2: Preparation of t 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine. [01397] A mixture of 6,8-dibromo-2-methylimidazo[1,2-a]pyrazine (14 g, 47.95 mmol) in MeOH (300 mL) was added NaH (2.3 g, 95.89 mmol), the mixture was stirred at r.t for 16 h. The mixture diluted with H₂O (300 mL), extracted with DCM (600 mL x3), organic layer was concentrated in vacuo to give title product (14 g, crude) as a brown solid. ESI-MS (M+H) ⁺: 243.9. Step 3: Preparation of N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-1,1- diphenylmethanimine. [01398] To a mixture of 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine (6 g, 24.69 mmol) and diphenylmethanimine (4.92 g, 27.16 mmol) in 1,4-dioxane (80 mL) were added BINAP (3.08 g, 4.94 mmol), Pd₂(dba)₃(2.26 g, 2.47 mmol) and Cs₂CO₃ (24.07 g, 74.07 mmol). The reaction solution was stirred at 110℃ for 16 h under N₂. The reaction was concentrated in vacuo and purified by silica gel column chromatography (PE: EA=2:3) to give title product (5.8 g, Y: 68.5%) as a yellow oil. ESI-MS (M+H) ⁺: 343.0. Step 4: Preparation of 8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-amine HCl salt. [01399] A mixture of N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-1,1- diphenylmethanimine (5.3 g, 12.21 mmol) in EA (40 mL) and 4M HCl/EA (30 mL) was stirred at RT for 2h. The mixture was diluted with EA (250 mL), stirred at r.t for 16h. The precipitate was filtered and dried in vacuo to give title product (2.7 g, y: 97.6%) as a yellow solid. ESI-MS (M+H) ⁺: 179.1. Step 5: Preparation of tert-butyl (R)-4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01400] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 8-methoxy-2-methylimidazo[1,2- a]pyrazin-6-amine HCl salt (84 mg, 0.47 mmol) and TEA (475 mg, 4.70 mmol) in THF (15 mL) was added triphosgene (111.7 mg, 0.38 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 8) to give title product (110 mg, Y: 67.1%) as a yellow solid. ESI-MS (M+H) ⁺: 523.4. Step 6: Preparation of (R)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01401] A mixture of tert-butyl (R)-4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (90 mg, 0.17 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (36 mg, Y: 49.5 %) as a white solid. ESI-MS (M+H) ⁺: 423.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.65 (s, 1H), 8.22 (s, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.87 (d, J = 0.7 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.04 (s, 3H), 4.01 – 3.95 (m, 2H), 3.62 – 3.58 (m, 3H), 3.12 (t, J = 8.6 Hz, 2H), 2.97 (d, J = 11.1 Hz, 1H), 2.88 – 2.75 (m, 3H), 2.32 (s, 3H), 1.04 (d, J = 6.3 Hz, 3H). Example 477 – Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-ethoxy-2- methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

C^{ompound 477} Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [01402] To a mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol), 6-ethoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-amine (83 mg, 0.36 mmol) in THF (10 mL) were added TEA (456 mg, 4.52 mmol) and triphosgene (107 mg, 0.36 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and the precipitate was filtered and triturated with MeOH (5mL) to get title product (50 mg, Y: 30.1 %) as an off-white solid. ESI-MS (M+H) ⁺:551.4. Step 2: Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01403] To a solution of tert-butyl (2S,6R)-4-(1-((6-ethoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (40 mg, 0.07 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (7 mg, 17.7 %) as a white solid. ESI-MS (M+H)⁺:451.2. ¹H NMR (400 MHz, MeOD-d₄) δ 8.65 (s, 1H), 7.99 (s, 1H), 7.95 (d, J = 6.1 Hz, 1H), 6.62 (d, J = 6.2 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.14 – 4.09 (m, 5H), 3.88 (d, J = 13.8 Hz, 2H), 3.52 – 3.46 (m, 2H), 3.16 (t, J = 8.5 Hz, 2H), 2.94 – 2.86 (m, 2H), 1.55 (t, J = 7.1 Hz, 3H), 1.39 (d, J = 6.6 Hz, 6H). Example 478 – Preparation of N-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

C^{ompound 478} Step 1: Preparation of tert-butyl 7-(1-((2-methylimidazo[1,2-a]pyrimidin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [01404] To a mixture of 7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine hydrochloride (66.60 mg, 0.45 mmol), tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (150 mg, 0.45 mmol) and TEA (136.35 mg, 1.35 mmol) in THF (5 mL) was added triphosgene (266.40 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/1 to 1/100) to afford title product (60 mg, 26.46%) as a yellow solid. ESI-MS (M+H) ⁺: 505.2. Step 2: Preparation of N-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01405] A mixture of tert-butyl 7-(1-((2-methylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (60 mg,0.12 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% HCl in water / CH₃CN) to give title product (2.61 mg, 4.94%) as a yellow solid. ESI-MS (M+H) ⁺:405.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.22 (s, 1H), 8.48 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.55 (s, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.11 – 4.02 (m, 2H), 3.45 – 3.39 (m, 2H), 3.27 – 3.23 (m, 2H), 3.22 – 3.16 (m, 2H), 3.15 – 3.08 (m, 2H), 2.42 (s, 3H), 0.88 – 0.77 (m, 4H). Example 479 – Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 7-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [01406] To a mixture of 2,7-dimethylimidazo[1,2-a]pyridin-6-amine hydrochloride (88.65 mg, 0.45 mmol), tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (150 mg, 0.45 mmol) and TEA (136.35 mg, 1.35 mmol) in THF (5 mL) was added triphosgene (266.40 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/1 to 1/100) to afford title product (60 mg, 25.79%) as a yellow solid. ESI-MS (M+H) ⁺: 518.3. Step 2: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01407] A mixture of tert-butyl 7-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (60 mg, 0.12 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (1.44 mg, 2.59%) as a yellow solid. ESI-MS (M+H) ⁺:418.4.¹H NMR (400 MHz, MeOD-d₄) δ 9.25 (s, 1H), 8.40 (s, 1H), 7.91 (d, J = 5.5 Hz, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 6.52 (d, J = 5.6 Hz, 1H), 4.11 – 3.98 (m, 2H), 3.49 – 3.41 (m, 2H), 3.29 – 3.26 (m, 2H), 3.26 – 3.21 (m, 2H), 3.13 – 3.04 (m, 2H), 2.54 (s, 3H), 2.42 (s, 3H), 0.95 – 0.77 (m, 4H). Example 480 – Preparation of N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of tert-butyl 4-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [01408] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (120 mg, 0.36 mmol), 2,8-dimethylimidazo[1,2-a]pyridin- 6-amine (85 mg, 0.43 mmol), triphosgene (128 mg, 0.43 mmol) and TEA (438 mg, 4.34 mmol) in THF (12 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered to afford title product (50 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 520.3. Step 2: Preparation of N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3,3-dimethylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01409] A mixture of tert-butyl 4-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (50 mg, 0.10 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title product (15.5 mg, yield: 37.01 %) as a white solid. ESI-MS (M+H) ⁺: 420.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 8.82 (d, J = 1.3 Hz, 1H), 7.89 (d, J = 6.1 Hz, 1H), 7.66 (s, 1H), 6.94 (s, 1H), 6.50 (d, J = 6.2 Hz, 1H), 3.97 (t, J = 8.6 Hz, 2H), 3.17 – 3.08 (m, 4H), 2.99 (s, 2H), 2.87 – 2.81 (m, 2H), 2.44 (s, 3H), 2.30 (s, 3H), 1.90 (s, 1H), 1.08 (s, 6H). Example 481 – Preparation of (S)-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide dihydrochloride.

C^{ompound 481} Step 1: Preparation of tert-butyl (S)-4-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01410] To a solution of 2,8-dimethylimidazo[1,2-a]pyridin-6-amine hydrochloride (140 mg, 0.74 mmol) in THF (20 mL) were added TEA (951 mg, 9.40 mmol) and triphosgene(167 mg, 0.56 mmol) at 0^oC, after 5 min, tert-butyl (S)-4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol) was added slowly at 0 ^oC. The mixture was stirred at r.t for 5 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (60 mg, 25 %) as a white solid. ESI-MS (M+H) ⁺: 506.3.¹H NMR (400 MHz, CDCl₃) δ 11.60 (s, 1H), 8.81 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.29 (s, 1H), 6.82 (s, 1H), 6.36 (d, J = 6.1 Hz, 1H), 4.42 – 4.24 (m, 1H), 4.21 – 4.12 (m, 2H), 4.01 – 3.90 (m, 1H), 3.58 – 3.48 (m, 1H), 3.47 – 3.38 (m, 1H), 3.29 – 3.19 (m, 1H), 3.14 – 3.05 (m, 3H), 3.00 – 2.90 (m, 1H), 2.59 (s, 3H), 2.45 (s, 3H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H). [01411] Step 2: Preparation of (S)-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide dihydrochloride. [01412] To a mixture of tert-butyl (S)-4-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure to give title product (32.15 mg, 67%) as a white solid. ESI-MS (M+H) ⁺:406.2.¹H NMR (400 MHz, DMSO-d₆) δ 14.45 (s, 1H), 12.13 (s, 1H), 9.59 (s, 1H), 9.46 (s, 1H), 9.26 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 6.71 (s, 1H), 4.12 – 4.02 (m, 2H), 3.86 – 3.80 (m, 2H), 3.37 – 3.30 (m, 3H), 3.25 – 3.18 (m, 2H), 3.14 – 3.05 (m, 2H), 2.59 (s, 3H), 2.48 (s, 3H), 1.31 (d, J = 6.5 Hz, 3H). Example 482 – Preparation of (R)-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

C^{ompound 482} Step 1: Preparation of tert-butyl (R)-4-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01413] A mixture of 2,8-dimethylimidazo[1,2-a]pyridin-6-amine hydrochloride (149 mg, 0.755 mmol), triphosgene (224 mg, 0.755 mmol) and TEA (762 mg, 7.547 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.629 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo to afford title product (100 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 506.3. Step 2: Preparation of (R)-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01414] A mixture of tert-butyl (R)-4-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.158 mmol) in 4M HCl /EA (5 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (52 mg, 63.3 %) as a white solid. ESI-MS (M+H) ⁺: 406.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.82 (s, 1H), 8.29 (s, 2H), 7.93 (d, J = 6.0 Hz, 1H), 7.66 (s, 1H), 6.94 (s, 1H), 6.57 (d, J = 6.1 Hz, 1H), 3.97 (t, J = 8.5 Hz, 2H), 3.69 (d, J = 12.6 Hz, 2H), 3.21 – 3.03 (m, 5H), 3.00 – 2.91 (m, 1H), 2.85 – 2.76 (m, 1H), 2.44 (s, 3H), 2.31 (s, 3H), 1.18 (d, J = 6.3 Hz, 3H). Example 483 – Preparation of N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-((3R,5S)- 3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide dihydrochloride.

Step 1: Preparation of 6-bromo-2,8-dimethylimidazo[1,2-a]pyridine. [01415] To a solution of 5-bromo-3-methylpyridin-2-amine (20 g, 106.95 mmol) in IPA (400 mL) were added 1-bromo-2,2-dimethoxypropane (29 g, 160.42 mmol), PPTS (2.7 g, 10.70 mmol) at 0℃. The mixture was stirred at 85 ℃ for 48 h. The precipitate was filtered, washed with IPA (50 mL) and dried to give crude product. The residue was dissolved in H₂O (50 mL), adjusted PH= 11 by sat. Na₂CO₃. The precipitate was filtered, washed with H₂O (20 mL) and dried to give title product (12 g, 49%) as a white solid. ESI-MS (M+H) ⁺:227.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J = 0.8 Hz, 1H), 7.66 (s, 1H), 7.18 (s, 1H), 2.45 (s, 3H), 2.34 (s, 3H). Step 2: Preparation of N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1-diphenylmethanimine. [01416] To a solution of 6-bromo-2,8-dimethylimidazo[1,2-a]pyridine (11 g, 48.46 mmol) in 1,4-dioxane (200 mL) were added diphenylmethanimine (13 g, 72.69 mmol), Cs₂CO₃ (31 g, 96.92 mmol), BINAP (6 g, 9.69 mmol), Pd(OAc)₂ (1.1 g, 4.84 mmol). The mixture was stirred at 115 ℃ for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to give title product (12 g, yield: 75 %) as a yellow oil. ESI-MS (M+H) ⁺:326.1. Step 3: Preparation of 2,8-dimethylimidazo[1,2-a]pyridin-6-amine hydrochloride. [01417] To a solution of N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (11 g, 33.84 mmol) in EA (100 mL) was added 4M HCl/EA (100 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered, washed with EA (100 mL) and dried in vacuo to give title product (6 g, 90%) as a white solid. ESI-MS (M+H) ⁺: 162.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 8.01 (s, 1H), 7.32 (s, 1H), 2.53 (s, 3H), 2.45 (s, 3H). Step 4: Preparation of tert-butyl (2R,6S)-4-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01418] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (150- mg, 0.45 mmol) in THF (20 mL) were added 2,8-dimethylimidazo[1,2-a]pyridin-6-amine hydrochloride (130 mg, 0.67 mmol), TEA (910 mg, 9.00 mmol), triphosgene (160 mg, 0.54 mmol) (in THF (0.5 mL) ) at 0℃. The reaction mixture was stirred at r.t for 5 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (40 mg, 17 %) as a white solid. ESI-MS (M+H) ⁺: 520.3.¹H NMR (400 MHz, CDCl₃) δ 11.60 (s, 1H), 8.82 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.29 (s, 1H), 6.83 (s, 1H), 6.40 (d, J = 6.1 Hz, 1H), 4.30 – 4.23 (m, 2H), 4.19 – 4.12 (m, 2H), 3.47 – 3.42 (m, 2H), 3.18 – 3.11 (m, 2H), 3.05 – 2.98 (m, 2H), 2.59 (s, 3H), 2.46 (s, 3H), 1.50 (s, 9H), 1.37 (d, J = 6.8 Hz, 6H). Step 5: Preparation of N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-((3R,5S)-3,5- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide dihydrochloride. [01419] To a mixture of tert-butyl (2R,6S)-4-(1-((2,8-dimethylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (30 mg, 0.10 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure to give title product (16.11 mg, 60%) as a white solid. ESI-MS (M+H) ⁺:420.2.¹H NMR (400 MHz, DMSO-d₆) δ 14.28 (s, 1H), 12.14 (s, 1H), 9.52 (s, 1H), 9.28 (s, 1H), 9.06 (s, 1H), 8.16 (s, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.76 (s, 1H), 6.70 (s, 1H), 4.08 – 3.99 (m, 2H), 3.92 – 3.83 (m, 2H), 3.35 – 3.31 (m, 2H), 3.23 – 3.16 (m, 2H), 3.04 – 2.96 (m, 2H), 2.58 (s, 3H), 2.49 (s, 3H), 1.30 (d, J = 6.4 Hz, 6H). Example 484 – Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [01420] To a solution of 2,7-dimethylimidazo[1,2-a]pyridin-6-amine (47 mg, 0.29 mmol) and TEA (292 mg, 2.89 mmol) in THF (15 mL) was added triphosgene (86 mg, 0.29 mmol) at 0^oC, after 10 min, tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (80 mg, 0.24 mmol) was added at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and concentrated in vacuo to give the compound (50 mg, 40 %) as a white solid. ESI- MS (M+H) ⁺:520.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 9.06 (s, 1H), 8.73 (s, 1H), 8.23 (s, 1H), 7.83 (d, J = 6.1 Hz, 1H), 6.41 (d, J = 6.3 Hz, 1H), 3.99 – 3.93 (m, 2H), 3.72 – 3.68 (m, 2H), 3.59 – 3.56 (m, 2H), 3.54 (s, 2H), 3.30 – 3.29 (m, 2H), 2.39 (s, 3H), 2.32 (s, 3H), 1.43 (s, 9H), 1.38 (s, 6H). Step 2: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3,3-dimethylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01421] To a mixture of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (40 mg, 0.08 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% NH₃.H₂O in H₂O / ACN) to give title product (9.53 mg, 28%) as a white solid. ESI-MS (M+H) ⁺:420.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.69 (s, 1H), 9.06 (s, 1H), 7.87 (d, J = 6.1 Hz, 1H), 7.61 (s, 1H), 7.30 (s, 1H), 6.50 (d, J = 6.2 Hz, 1H), 3.98 (t, J = 8.5 Hz, 2H), 3.18 – 3.10 (m, 4H), 3.00 (s, 2H), 2.87 – 2.80 (m, 2H), 2.39 (s, 3H), 2.28 (s, 3H), 1.90 (s, 1H), 1.08 (s, 6H). Example 485 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2- a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 2,2-dimethyl-4-(1-((2-methylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01422] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 2-methylimidazo[1,2-a]pyrimidin-6- amine (66.60 mg, 0.45 mmol) and TEA (136.35 mg, 1.35 mmol) in THF (5 mL) was added triphosgene (266.40 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/1 to 1/100) to afford title product (60 mg, 26.35%) as a yellow solid. ESI-MS (M+H) ⁺: 507.2. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyrimidin- 6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01423] A mixture of tert-butyl 2,2-dimethyl-4-(1-((2-methylimidazo[1,2-a]pyrimidin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.12 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in water / CH₃CN) to give title product (2.76 mg, 4.42%) as a yellow solid. ESI-MS (M+H) ⁺:407.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.21 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.55 (s, 1H), 6.56 (d, J = 6.0 Hz, 1H), 4.13 – 4.03 (m, 2H), 3.50 – 3.44 (m, 2H), 3.42 – 3.37 (m, 2H), 3.29 – 3.26 (m, 2H), 3.17 – 3.09 (m, 2H), 2.42 (s, 3H), 1.48 (s, 6H). Example 486 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-b]pyridazin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of methyl 6-chloro-3-methoxypyridazine-4-carboxylate. [01424] To a solution of methyl 3,6-dichloropyridazine-4-carboxylate (15.00 g, 72.46 mmol) in THF (150 mL) was added Sodium Methoxide (30% in MeOH, 18.2 mL) at 0°C. The reaction mixture was stirred at 0°C for 0.5 h. The mixture was quenchend with Saturated ammonium chloride solution (150 mL) and diluted with water (150 mL), extracted with EA (500 mL×3). The combined organic layers was washed with brine (500 mL) ,dried over Na₂SO_4, filtered and concentrated in vacuo to give title compound (11.00 g, , yield: 74 %) as a yellow solid. ESI-MS (M+H)⁺: 202.9. Step 2: Preparation of methyl 3-methoxy-6-(prop-1-yn-1-yl)pyridazine-4-carboxylate. [01425] To a solution of methyl 6-chloro-3-methoxypyridazine-4-carboxylate (3.00 g, 14.81 mmol) in DMF (30 mL) were added CuI (282 mg, 1.48 mmol), Pd(PPh₃)₂Cl₂ (1.04 mg, 1.48 mmol), TEA (4.33 g, 59.23 mmol) and prop-1-yne (29.62 ml , 29.62 mmol, 1mol/L in THF), the mixture was stirred at 80°C for 2 h in seal tube. The mixture was diluted with water (50 mL) and extracted with EA (100 mL×3). The combined organic layers was washed with brine (50 mL×8), dried over Na₂SO_4.,filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE:EA =10:1) to give title compound (3.40 g, Y:41.8%) as a yellow solid. ESI-MS (M+H)⁺: 207.1. Step 3: Preparation of 1-amino-3-methoxy-4-(methoxycarbonyl)-6-(prop-1-yn-1- yl)pyridazin-1-ium. [01426] To a solution of (aminooxy)sulfonic acid (4.00 g, 35.37 mmol) in H₂O (36 mL) was added KHCO₃ (1.77 g, 17.69 mmol). The mixture was stirred at rt for 10 min. Then methyl 3-methoxy-6-(prop-1-yn-1-yl)pyridazine-4-carboxylate (2.41 g, 11.67 mol) was added, the mixture was stirred at 70°C for 16 h. The mixture was added KI (2.94 g, 7.34 mmol) was added, the mixture was concentrated in vacuo and the residue dissolve in ACN (26 mL) was added DBU (6 mL). The mixture was stirred at rt for 4 h. The mixture was was concentrated in vacuo and diluted with water (50 mL) ,extracted with EA (100 mL×3). The combined organic layers weas washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (DCM:MeOH =100:1) to give title compound (260 mg, yield:7 %) as a yellow solid. ESI-MS (M+H)⁺: 222.0. Step 4: Preparation of 6-methoxy-2-methylpyrazolo[1,5-b]pyridazine-5-carboxylic acid. [01427] To a solution of methyl 6-methoxy-2-methylpyrazolo[1,5-b]pyridazine-5- carboxylate (240 mg, 1.08 mmol) in MeOH:H₂O=3:1 (12 mL) was added LiOH^.H₂O (364 mg, 8.68 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with water (10 mL) and adjusted pH = 1 with (2M) HCl aq, extracted with DCM (30 mL×3) .The combined organic layers was washed with brine (30 mL) , dried over Na₂SO_4, filtered and concentrated in vacuo to give title compound (230 mg, yield: 94 %) as a yellow solid. ESI-MS (M+H)⁺: 208.0. Step 5: Preparation of tert-butyl 4-(1-((6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01428] To a solution of 6-methoxy-2-methylpyrazolo[1,5-b]pyridazine-5-carboxylic acid (200 mg, 0.965 mmol) in toluene (7 mL) were added TEA (293 mg, 2.90 mmol) and DPPA (664 mg, 2.41 mmol). The mixture was stirred at rt for 3 h,then heated to 90°C for 1 h. Then tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (254 mg, 0.772 mmol) was added, the mixture was stirred at 90°C for 6 h. The mixture was diluted with water (20 mL) and extracted with DCM:MeOH =10:1( 30 ml ×3 ) , dried over Na₂SO₄, filtered and concentrated in vacuo. The crude was purified by was purified by silica gel column chromatography (DCM:MeOH =30:1) to give title compound (80 mg yield: 13.4 %) as a yellow solid. ESI-MS (M+H)⁺: 537.2. Step 6: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methylpyrazolo[1,5- b]pyridazin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01429] To a solution of tert-butyl 4-(1-((6-methoxy-2-methylpyrazolo[1,5- b]pyridazin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in DCM (1.0 mL) was added TFA (0.5 ml) . The mixture was stirred at rt for 2 h. The mixture concentrated in vacuo,the crude was purified by Prep-HPLC (0.1% TFA in H₂O/MeCN) to give the title compound (17.14 mg, yield: 20 %) as a white solid. ESI-MS (M+H)⁺: 437.1.¹H NMR (400 MHz, DMSO-d₆)δ 12.41 (s, 1H), 8.51 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 6.30 (s ,1H), 4.10 (s, 3H), 4.04– 3.96 (m, 2H), 3.38 – 3.33 (m, 2H), 3.19 (s, 2H), 3.17 – 3.12 (m, 4H), 2.32 (s, 3H), 1.27(s, 6H).

Example 487 – Preparation of (R)-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide

Step 1: Preparation of tert-butyl (R)-4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01430] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (120 mg, 0.37 mmol), 2,7-dimethylimidazo[1,2-a]pyridin-6- amine (89 mg, 0.45 mmol), triphosgene (133 mg, 0.45 mmol) and TEA (457 mg, 4.53 mmol) in THF (12 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered to afford title product (50 mg, 43%) as a yellow solid. ESI-MS (M+H) ⁺: 506.3. Step 2: Preparation of (R)-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01431] A mixture of tert-butyl (R)-4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.10 mmol) in 4M HCl / EA (20 mL) was stirred at RT for 2 h. The precipitate was filtered and dried to give title product (13.49 mg, 33.73 %) as a white solid. ESI-MS (M+H) ⁺:406.2.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 9.39 (s, 1H), 7.99 (d, J = 6.5 Hz, 2H), 7.77 (s, 1H), 6.69 (d, J = 6.2 Hz, 1H), 4.08 (t, J = 8.3 Hz, 2H), 3.85 – 3.81 (m, 2H), 3.44 – 3.35 (m, 2H), 3.31 – 3.19 (m, 3H), 3.17 – 3.04 (m, 2H), 2.57 (s, 3H), 2.45 (s, 3H), 1.31 (d, J = 6.5 Hz, 3H). Example 488 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methyl-2H-benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (4-methyl-5-nitropyridin-2-yl)carbamate. [01432] To a solution of 4-methyl-5-nitropyridin-2-amine (10 g, 65.36 mmol) in THF (100 mL) was added NaH (3.4 g, 84.97 mmol) at 0 ℃. The mixture was stirred at 0 ^oC for 1 h. Then Boc₂O (21.4 g, 98.04 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (120 mL) and extracted with ethyl acetate (100 mL*3). The organic extracts were concentrated to dryness to give title product (9.5 g, 57.6 %) as a white solid. ESI-MS (M+H) ⁺: 254.1.¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H), 8.92 (s, 1H), 7.88 (s, 1H), 2.59 (s, 3H), 1.49 (s, 9H). Step 2: Preparation of tert-butyl (5-amino-4-methylpyridin-2-yl)carbamate. [01433] A solution of tert-butyl (4-methyl-5-nitropyridin-2-yl)carbamate (600 mg, 2.37 mmol) in dry ethanol (20 mL) was added 10% Pd/C (100 mg). The reaction mixture was stirred at r.t for 4 h under H₂. The solution was filtered through a celite pad to remove the catalyst and the filtrate was evaporated to dryness to give title product (450 mg, 85.1 %) as a yellow solid. ESI-MS (M+H) ⁺: 224.1. Step 3: Preparation of tert-butyl (5-acetamido-4-methylpyridin-2-yl)carbamate. [01434] To a solution of tert-butyl (5-amino-4-methylpyridin-2-yl)carbamate (8.4 g, 37.67 mmol) in DCM (100 mL) were added Ac₂O (4.2 g, 41.43 mmol).The reaction mixture was stirred at RT for 5 h. The mixture was concentrated in vacuo and purified by column gel chromatography (PE/EA=3/2) to give title product (7.5 g, 75.2 %) as a yellow solid. ESI-MS (M+H) ⁺: 266.1.¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 9.38 (s, 1H), 8.12 (s, 1H), 7.66 (s, 1H), 2.18 (s, 3H), 2.04 (s, 3H), 1.47 (s, 9H). Step 4: Preparation of tert-butyl (1-acetyl-1H-pyrazolo[3,4-c]pyridin-5-yl)carbamate. [01435] To a solution of tert-butyl (5-acetamido-4-methylpyridin-2-yl)carbamate (7 g, 26.42 mmol) in CHCl₃ (80 mL) were added KOAc (3.1 g, 31.7 mmol), Ac₂O (10.8 g, 105.66 mmol). The reaction mixture was stirred at 70 ^oC for 1 h. Then 2-methyl-2-nitropropane (5.44 g, 52.83 mmol ) and 18-crown-6 (700 mg, 2.64 mmol) was added to the reaction mixture and stirred at 65 ^oC for 16 h. The mixture was concentrated in vacuo and purified by column gel chromatography (PE/EA=1/2) to give title product (1.5 g, 20.6 %) as a yellow solid. ESI-MS (M+H) ⁺: 277.1.¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 9.25 (s, 1H), 8.55 (d, J = 0.5 Hz, 1H), 8.23 (d, J = 1.2 Hz, 1H), 2.71 (s, 3H), 1.50 (s, 9H). Step 5: Preparation of tert-butyl (2H-pyrazolo[3,4-c]pyridin-5-yl)carbamate. [01436] To a solution of tert-butyl (1-acetyl-1H-pyrazolo[3,4-c]pyridin-5-yl)carbamate (1.5 g, 5.43 mmol) in DCM (15 mL) was added NH₃ in MeOH (7 mL, 7 M). The reaction mixture was stirred at r.t for 16 h. The mixture was concentrated to give title product (1.2 g, 94 %) as a white solid. ESI-MS (M+H) ⁺: 235.1.¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 8.75 (s, 1H), 8.13 (s, 1H), 8.04 (d, J = 0.9 Hz, 1H), 1.49 (s, 9H). Step 6: Preparation of tert-butyl (2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)carbamate. [01437] To a solution of tert-butyl (2H-pyrazolo[3,4-c]pyridin-5-yl)carbamate (1.27 g, 5.43 mmol) in EA (15 mL) was added trimethyloxonium tetrafluoroborate (803 mg, 5.43 mmol). The mixture was stirred at r.t for 1 h. The mixture was concentrated in vacuo and purified by column gel chromatography (PE/EA=1/1) to give title product (1 g, 74 %) as a yellow solid. ESI-MS (M+H) ⁺: 249.2.¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H), 8.91 – 8.87 (m, 1H), 8.34 (s, 1H), 7.91 – 7.87 (m, 1H), 4.21 (s, 3H), 1.48 (s, 9H). Step 7: Preparation of 2-methyl-2H-pyrazolo[3,4-c]pyridin-5-amine hydrochloride. [01438] To a solution of tert-butyl (2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamate (80 mg, 0.323 mmol) in HCl in EA (3 mL,4 M). The mixture was stirred at RT for 16 h. The reaction mixture was dried in vacuo to give title product (50 mg, 84.7 %) as a yellow solid. ESI-MS (M+H) ⁺: 149.2.¹H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 8.50 (s, 1H), 7.24 (s, 1H), 4.31 (s, 3H). Step 8: Preparation of tert-butyl (S)-2-methyl-4-(1-((2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01439] A mixture of 2-methyl-2H-pyrazolo[3,4-c]pyridin-5-amine hydrochloride (60 mg, 0.326 mmol), triphosgene (97 mg, 0.326 mmol) and TEA (329 mg, 3.261 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (86 mg, 0.272 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL×3). The organic layer was concentrated in vacuo. The solid was triturated with MeOH (3 mL*2) to afford title product (27 mg, pure: 71%) as a white solid. ESI-MS (M+H) ⁺: 493.2. Step 9: Preparation of (S)-N-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01440] A mixture of tert-butyl (S)-2-methyl-4-(1-((2-methyl-2H-pyrazolo[3,4- c]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (20 mg, 0.041 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 2 h. The reaction mixture was concentrated and the solid was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (7 mg, 40.2 %) as a white solid. ESI-MS (M+H) ⁺: 393.2.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.89 (s, 1H), 8.23 (d, J = 7.7 Hz, 2H), 8.04 (d, J = 5.9 Hz, 1H), 6.60 (d, J = 6.0 Hz, 1H), 4.27 (s, 3H), 4.12 (t, J = 8.5 Hz, 2H), 3.79 (d, J = 13.3 Hz, 2H), 3.49 – 3.41 (m, 2H), 3.27 – 3.13 (m, 4H), 2.95 (dd, J = 13.5, 10.4 Hz, 1H), 1.37 (d, J = 6.5 Hz, 3H). Example 489 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2- methylimidazo[1,2-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

C^{ompound 489} Step 1: Preparation of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((2-methylimidazo[1,2- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [01441] To a mixture of 2-methylimidazo[1,2-a]pyrimidin-6-amine (66.88 mg, 0.45 mmol), tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) and TEA (136.35 mg, 1.35 mmol) in THF (5 mL) was added triphosgene (266.40 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/1 to 1/100) to afford title product (50 mg, 21.96%) as a yellow solid. ESI-MS (M+H) ⁺: 507.4. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2- a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01442] A mixture of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((2-methylimidazo[1,2- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (50 mg, 0.10 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (9.9 mg, 21.90%) as a yellow solid. ESI-MS (M+H) ⁺:407.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 9.28 (d, J = 2.5 Hz, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.18 (s, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.69 (s, 1H), 6.60 (d, J = 6.1 Hz, 1H), 4.03 – 3.97 (m, 2H), 3.77 – 3.74 (m, 2H), 3.18 – 3.10 (m, 4H), 2.71 – 2.64 (m, 2H), 2.35 (s, 3H), 1.15 (d, J = 6.2 Hz, 6H). Example 490 – Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

C^{ompound 490} Step 1: Preparation of tert-butyl (2S,6R)-2,6-dimethyl-4-(1-((2-methylpyrazolo[1,5-a]pyridin- 5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01443] A mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol), phenyl (2- methylpyrazolo[1,5-a]pyridin-5-yl)carbamate (120 mg, 0.45 mmol) and TEA (91 mg, 0.90 mmol) in THF (20 mL) was stirred at 70 ^oC for 16 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE: EA=1:2) to give the title compound (120 mg, yield: 79%) as a green solid. ESI-MS (M+H) ⁺:506.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 8.12 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 7.5, 2.3 Hz, 1H), 6.28 (d, J = 2.3 Hz, 1H), 6.22 (s, 1H), 4.04 – 3.99 (m, 2H), 3.60 (d, J = 12.4 Hz, 2H), 3.31 – 3.28 (m, 2H), 3.16 – 3.13 (m, 2H), 3.00 (d, J = 8.2 Hz, 2H), 2.33 (s, 3H), 1.43 (s, 9H), 1.25 (d, J = 6.2 Hz, 6H). Step 2: Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(2-methylpyrazolo[1,5- a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01444] To a solution of tert-butyl (2S,6R)-2,6-dimethyl-4-(1-((2-methylpyrazolo[1,5- a]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.20 mmol) in EA (2 mL) was added 4M HCl/EA (6 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.05% FA in H₂O / ACN) to give title product (18.91 mg, 21%) as a pink solid. ESI-MS (M+H) ⁺:406.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 8.44 (d, J = 7.4 Hz, 1H), 8.26 (s, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.83 (s, 1H), 6.85 (dd, J = 7.5, 2.1 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 6.21 (s, 1H), 3.97 (t, J = 8.5 Hz, 2H), 3.62 (d, J = 12.1 Hz, 2H), 3.13 (t, J = 8.5 Hz, 2H), 2.87 – 2.80 (m, 2H), 2.43 (t, J = 11.5 Hz, 2H), 2.33 (s, 3H), 1.02 (d, J = 6.2 Hz, 6H). Example 491 – Preparation of (S)-4-(3-methylpiperazin-1-yl)-N-(2-methylpyrazolo[1,5- a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Boc H C^{ompound 491} Step 1: Preparation of tert-butyl (S)-2-methyl-4-(1-((2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01445] A mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), phenyl (2-methylpyrazolo[1,5- a]pyridin-5-yl)carbamate (125 mg, 0.47 mmol) and TEA (95 mg, 0.94 mmol) in THF (10 mL) was stirred at 70 ^oC for 16 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (EA) to give the title compound (120 mg, yield: 78%) as a white solid. ESI-MS (M+H) ⁺:492.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 7.5, 2.3 Hz, 1H), 6.55 (d, J = 4.1 Hz, 1H), 6.53 (d, J = 4.3 Hz, 1H), 6.21 (s, 1H), 3.99 (t, J = 6.9 Hz, 2H), 3.79 (d, J = 13.1 Hz, 2H), 3.58 – 3.43 (m, 4H), 2.95 (dd, J = 12.3, 3.3 Hz, 2H), 2.87 – 2.82 (m, 1H), 2.33 (s, 3H), 1.42 (s, 9H), 1.20 (d, J = 4.0 Hz, 3H). Step 2: Preparation of (S)-4-(3-methylpiperazin-1-yl)-N-(2-methylpyrazolo[1,5-a]pyridin-5- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01446] To a solution of tert-butyl (S)-2-methyl-4-(1-((2-methylpyrazolo[1,5- a]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.20 mmol) in EA (2 mL) was added 4M HCl/EA (6 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.05% FA in H₂O / ACN) to give title product (39.29 mg, 45%) as a pink solid. ESI-MS (M+H) ⁺:392.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 8.45 (d, J = 7.4 Hz, 1H), 8.26 (s, 1H), 7.92 (d, J = 6.1 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 7.5, 2.3 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 6.21 (s, 1H), 3.97 (t, J = 8.5 Hz, 2H), 3.62 (d, J = 12.0 Hz, 2H), 3.12 (t, J = 8.5 Hz, 2H), 2.99 (d, J = 11.5 Hz, 1H), 2.91 – 2.76 (m, 3H), 2.59 – 2.53 (m, 1H), 2.33 (s, 3H), 1.05 (d, J = 6.3 Hz, 3H). Example 492 – Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide diformate.

C^{ompound 492} Step 1: Preparation of tert-butyl (2S,6R)-2,6-dimethyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [01447] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol), 2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine (67 mg, 0.36 mmol) and TEA (456 mg, 4.52 mmol) in THF (10 mL) was added triphosgene (107 mg, 0.36 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and the precipitate was filtered, triturated with MeOH (5mL) to get title product (70 mg, Y: 45.8 %) as a brown solid. ESI-MS (M+H) ⁺:508.4. Step 2: Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate. [01448] To a solution of tert-butyl (2S,6R)-2,6-dimethyl-4-(1-((2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The precipiate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (37 mg, 62.7 %) as a white solid. ESI-MS (M+H)⁺:408.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.57 (d, J = 2.4 Hz, 1H), 8.86 (d, J = 2.5 Hz, 1H), 8.40 (s, 2H), 8.02 (d, J = 5.8 Hz, 1H), 6.61 (d, J = 6.1 Hz, 1H), 4.12 (t, J = 8.5 Hz, 2H), 3.87 – 3.81 (m, 2H), 3.39 – 3.34 (m, 2H), 3.21 (t, J = 8.2 Hz, 2H), 2.83 – 2.75 (m, 2H), 2.55 (s, 3H), 1.32 (d, J = 6.5 Hz, 6H). Example 493 – Preparation of (S)-N-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-2-methyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate. [01449] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine (70 mg, 0.38 mmol), TEA (476 mg, 4.72 mmol) in THF (10 mL) was added triphosgene (112 mg, 0.38 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and the precipitate was filtered, triturated with MeOH (5 mL), filtered and concentrated in vacuo to get title product (70 mg, Y: 45.1 %) as a brown solid. ESI-MS (M+H) ⁺:494.4. Step 2: Preparation of (S)-N-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01450] To a solution of tert-butyl (S)-2-methyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (60 mg, 0.12 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (35 mg, 65.5 %) as a white solid. ESI-MS (M+H)⁺:394.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.55 (d, J = 2.5 Hz, 1H), 8.83 (d, J = 2.6 Hz, 1H), 8.49 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.11 (t, J = 8.5 Hz, 2H), 3.80 – 3.75 (m, 2H), 3.41 – 3.34 (m, 2H), 3.22 – 3.13 (m, 4H), 2.90 (dd, J = 13.4, 10.4 Hz, 1H), 2.55 (s, 3H), 1.34 (d, J = 6.5 Hz, 3H). Example 494 – Preparation of N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4- (4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide HCl salt.

Step 1: Preparation of tert-butyl 7-(1-((2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [01451] To a solution of 2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (87 mg, 0.45 mmol) and TEA (122 mg, 1.21 mmol) in tol (5 mL) was added DPPA (233 mg, 0.85 mmol), the mixture was stirred at RT for 1 h and 90 ^oC for 1 h, after 2 h, tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.303 mmol) was added to the mixture and stirred at 110 ^oC for 4 h. The mixture was diluted with water (10 mL) extracted with EA (20 mL×3). The organic layer was washed with brine (20 mL), dried with Na₂SO₄ and concentrated in vacuo, triturate with MeOH (5 mL) to give title product (50 mg, yield: 31.79 %) as a yellow solid. ESI-MS (M+H) ⁺: 520.3. Step 2: Preparation of N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide HCl salt. [01452] A mixture of tert-butyl 7-(1-((2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (50 mg, 0.09 mmol) in HCl/EA (2 mL, 4 M) was stirred at r.t for 2 h. The precipitate was filtered and dried to give title product (7.9 mg, 20.94 %) as a yellow solid. ESI-MS (M+H) ⁺: 420.2.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 9.45 (s, 1H), 7.91 (d, J = 6.4 Hz, 1H), 6.74 (d, J = 6.0 Hz, 1H), 4.18 – 4.10 (m, 2H), 3.71 – 3.67 (m, 2H), 3.60 – 3.55 (m, 2H), 3.38 – 3.34 (m, 2H), 3.29 – 3.22 (m, 2H), 2.68 (s, 3H), 2.49 (s, 3H), 1.13 – 1.09 (m, 2H), 1.00 – 0.96 (m, 2H). Example 495 – Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-fluoro-2- methyl-2H-benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol- 5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01453] To a solution of 6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine hydrochloride (91 mg, 0.45 mmol) and TEA (457 mg, 4.52 mmol) in THF (15 mL) was added triphosgene (134 mg, 0.45 mmol) at 0^oC, after 10 min, tert-butyl (S)-4-(2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.37 mmol) was added at 0^oC to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (40 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (110 mg, 57.17 %) as a white solid. ESI-MS (M+H) ⁺:525.3. Step 2: Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-fluoro-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01454] To a mixture of tert-butyl (S)-4-(1-((6-fluoro-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.19 mmol) in EA (2 mL) was added HCl/EA (5 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % HCl in water / ACN) to give title product (30 mg, Y: 63.51 %) as a white solid. ESI-MS (M+H) ⁺:425.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (d, J = 2.8 Hz, 1H), 9.20 (s, 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.58 (d, J = 10.4 Hz, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.86 (d, J = 11.2 Hz, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.44 (s, 3H), 4.05 (t, J = 8.5 Hz, 2H), 3.94 – 3.85 (m, 2H), 3.45 – 3.40 (m, 2H), 3.23 – 3.16 (m, 2H), 2.94 – 2.85 (m, 2H), 1.27 (d, J = 6.4 Hz, 6H). Example 496 – Preparation of (S)-N-(6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)- 4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

4

4M

Step 1: Preparation of 4-bromo-5-fluoro-2-nitroaniline. [01455] To a mixture of 5-fluoro-2-nitroaniline (10.0 g, 64.10 mmol) in AcOH (50 mL) was added NBS (11.4 g, 64.10 mmol) under N₂ at 25℃, then the reaction was stirred at 110℃ for 1.5 h. The reaction was diluted with EA (100 mL) and washed with water (100 mLx3) and brine (100 mL). The organic extract was dried over Na₂SO₄, and the solvent was removed to afford the crude product. The crude product was purified by column flash chromatography (EA/PE=0%~5%) to afford the title product (10.0 g, 66.6 % yield) as a yellow solid. ESI-MS (M+H) ⁺: 235.0¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J = 7.4 Hz, 1H), 7.71 (s, 2H), 6.93 (d, J = 11.0 Hz, 1H). Step 2: Preparation of 4-bromo-5-fluorobenzene-1,2-diamine. [01456] To a solution of 4-bromo-5-fluoro-2-nitroaniline (22.7 g, 96.59 mmol) in EtOH/H₂O=5/1 (600 mL) were added NH₄Cl (38.7 g, 0.72 mol) and Fe (53.94 g, 0.96 mol). The mixture was stirred at 90 ^oC for 4 h. The mixture was filtered and the filtrate was concentrated. The crude was triturated with PE: EA (500 mL, 10:1), then filtered and lyophilized to give title product (29 g, 73.52 %) as a yellow solid. ESI-MS (M+H) ⁺:207.0. Step 3: Preparation of 5-bromo-6-fluoro-2H-benzo[d][1,2,3]triazole. [01457] To a solution of 4-bromo-5-fluorobenzene-1,2-diamine (20 g, 97.55 mmol) in AcOH:H2O=1:4 (100 mL) was added NaNO₂ (33.6 g, 0.49 mol). The mixture was stirred at r.t for 1 h.The mixture was diluted with water (100 mL). The precipitate was filtered to give the compound (16 g, 75.93 %) as a yellow solid. ESI-MS (M+H) ⁺:217.9.¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J = 6.1 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H). Step 4: Preparation of 5-bromo-6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazole. [01458] To a solution of 5-bromo-6-fluoro-2H-benzo[d][1,2,3]triazole (15 g, 69.44 mmol) in Toluene (160 mL) was added DMF-DMA (13.84 mL, 104.16 mmol). The mixture was stirred at 120^oC for 1 h. The reaction was concentrated and purified by SGC (PE/EA=0- 100%) to give product (7 g, 43.82 %) as yellow solid. ESI-MS (M+H) ⁺:232.0.¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 6.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 4.41 (s, 3H). Step 5: Preparation of N-(6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine. [01459] To a solution of 5-bromo-6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazole (500 mg, 212.17mmol), diphenylmethanimine (6.5 g, 28.26 mmol), Cs₂CO₃ (27.83 g, 84.77 mmol) and Pd(OAc)₂ (2.59 g, 2.83 mmol) in 1,4-dioxane(100 mL) was added BINAP (3.27 g, 5.65 mmol), the mixture was stirred for 16 h at 100^oC under N₂. The mixture was purified by silica gel column chromatography (PE: EA= 1: 2) to give title product (10 g, crude) as a yellow solid. ESI-MS (M+H) ⁺:331.2. Step 6: Preparation of 6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine hydrochloride. [01460] The mixture of N-(6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine (9 g, 27.24 mmol) in 4M HCl/EA (100 mL) was stirred at r.t for 16 h. The precipitate was filtered and triturated with EA (500 mL) and filtered to give the title compound (3 g, 54.35 %) as a white solid. ESI-MS (M+H) ⁺:167.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (d, J = 10.7 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 4.42 (s, 3H). Step 7: Preparation of tert-butyl (S)-4-(1-((6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01461] To a solution of 6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine hydrochloride (91 mg, 0.45 mmol) and TEA (457 mg, 4.52 mmol) in THF (15 mL) was added triphosgene (134 mg, 0.45 mmol) at 0^oC, after 10 min, tert-butyl (S)-4-(2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.37 mmol) was added at 0^oC to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (40 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (110 mg, 57.17 %) as a white solid. ESI-MS (M+H) ⁺:511.3. Step 8: Preparation of (S)-N-(6-fluoro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01462] To a mixture of tert-butyl (S)-4-(1-((6-fluoro-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.19 mmol) in EA (2 mL) was added HCl/EA (5 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (30 mg, Y: 63.51 %) as a white solid. ESI-MS (M+H) ⁺:411.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.64 (d, J = 7.1 Hz, 1H), 8.26 (s, 1H), 7.91 (d, J = 5.9 Hz, 1H), 7.83 (d, J = 11.1 Hz, 1H), 6.58 (d, J = 6.0 Hz, 1H), 4.44 (s, 3H), 4.04 – 4.00 (m, 2H), 3.74 – 3.69 (m, 2H), 3.23 – 3.13 (m, 4H), 3.08 – 2.94 (m, 2H), 2.87 – 2.73 (m, 1H), 1.18 (d, J = 6.2 Hz, 3H).

Example 497 – Preparation of (S)-N-(2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of 4-bromo-5-methyl-2-nitroaniline. [01463] To a solution of 5-methyl-2-nitroaniline (10 g, 65.72 mmol) in CH₃CN (30 mL) was added NBS (11.7 g, 65.72 mmol) in portions under 0^oC under stirring. The mixture was stirred at room temperature for 1 h. The mixture was filtered to give the title product (15.3 g, yield: 100%) as an orange solid. ESI-MS (M+H) ⁺: 233.1.¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.48 (s, 2H), 6.98 (s, 1H), 2.27 (s, 3H). Step 2: Preparation of 4-bromo-5-methylbenzene-1,2-diamine. [01464] To a solution of 4-bromo-5-methyl-2-nitroaniline (15.3 g, 66.23 mmol) in EtOH (100 mL) and H₂O (20 mL) were added NH₄Cl (26.6 g, 496.75 mmol) and Fe (37.1 g, 662.34 mmol). The mixture was stirred at 80^oC for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=90%:10%) to give title product (8.1 g, yield: 87%) as a yellow solid. ESI-MS (M+H) ⁺: 202.8.¹H NMR (400 MHz, DMSO-d₆) δ 6.66 (s, 1H), 6.43 (s, 1H), 4.51 (s, 4H), 2.08 (s, 3H). Step 3: Preparation of 5-bromo-6-methyl-2H-benzo[d][1,2,3]triazole. [01465] To a solution of 4-bromo-5-methylbenzene-1,2-diamine (7 g, 34.81 mmol) in H₂O (20 mL) and AcOH (12 mL) was added NaNO₂ (12.2 g, 174.04 mmol). The mixture was stirred at room temperature for 1 h. The pH of mixture was adjusted to ~8 by ammonium hydroxide. The mixture was then diluted with H₂O (100 mL) and extracted with EA (150 mL*3). The organic layer was collected and washed by brine (200 mL), dried over Na₂SO₄, filtered and concentrated to give crude product (2.9 g, yield:39%) as brown solid. ESI-MS (M+H) ⁺: 212.1. Step 4: Preparation of 5-bromo-2,6-dimethyl-2H-benzo[d][1,2,3]triazole. [01466] To a solution of 5-bromo-6-methyl-2H-benzo[d][1,2,3]triazole (2.5 g, 11.79 mmol) in toluene (20 mL) was added DMF-DMA (2 mL). The mixture was stirred at 120^oC for 1 h. The mixture was diluted with H₂O (20 mL), and extracted with EA (30 mL*3). The organic layer was collected and washed by brine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=80%:20%) to give the title product (553 mg, yield: 21%) as a yellow solid. ESI-MS (M+H) ⁺: 228.0.¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.93 (s, 1H), 4.47 (s, 3H), 2.49 (s, 3H). Step 5: Preparation of N-(2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine. [01467] To a solution of 5-bromo-2,6-dimethyl-2H-benzo[d][1,2,3]triazole (450 mg, 1.99 mmol) in 1,4-dioxane (30 mL) were added diphenylmethanimine (433 mg, 2.39 mmol), Cs₂CO₃ (1945 mg, 5.97 mmol), XantPhos (231 mg, 0.40 mmol) and Pd₂(dba)₃ (183 mg, 0.20 mmol). The mixture was stirred at 110^oC for 5 h. The mixture was diluted with H₂O (30 mL), extracted with EA (50 mL*3). The organic layer was collected and washed by brine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=80%:20%) and triturated with DCM:MeOH=10%:90% to give title product (326 mg, yield: 50%) as a yellow solid. ESI-MS (M+H) ⁺: 327.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.75 – 7.71 (m, 2H), 7.62 (s, 1H), 7.58 – 7.46 (m, 3H), 7.28 (t, J = 7.5 Hz, 3H), 7.20 (dd, J = 7.6, 1.6 Hz, 2H), 6.78 (s, 1H), 4.33 (s, 3H), 2.30 (s, 3H). Step 6: Preparation of 2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-amine. [01468] To a solution of N-(2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine (200 mg, 0.61 mmol) in MeOH (10 mL) was added hydroxylamine hydrochloride (212 mg, 3.07 mmol), CH₃COONa (151 mg, 1.84 mmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=0%:100%) to give title product (126 mg, yield: 50%) as yellow solid. ESI-MS (M+H) ⁺: 163.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (s, 1H), 6.77 (s, 1H), 5.12 (s, 2H), 4.29 (s, 3H), 2.21 (d, J = 0.5 Hz, 3H). Step 7: Preparation of tert-butyl (S)-4-(1-((2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01469] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 2,6-dimethyl-2H- benzo[d][1,2,3]triazol-5-amine (70 mg, 0.38 mmol), TEA (476 mg, 4.72 mmol) in THF (10 mL) was added triphosgene (112 mg, 0.38 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL), the precipitate was filtered and triturated with MeOH (5 mL) to get title product (60 mg, Y: 74.0 %) as a brown solid. ESI-MS (M+H) ⁺:507.3. Step 8: Preparation of (S)-N-(2,6-dimethyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01470] To a solution of tert-butyl (S)-4-(1-((2,6-dimethyl-2H-benzo[d][1,2,3]triazol- 5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (60 mg, 0.12 mmol) in EA (3 mL) was added 4M HCl/EA (3 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (16 mg, 29.9 %) as a white solid. ESI-MS (M+H)⁺:407.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.74 (s, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.41 (s, 3H), 4.02 – 3.98 (m, 2H), 3.64 – 3.59 (m, 2H), 3.13 (t, J = 8.5 Hz, 2H), 3.00 (d, J = 11.2 Hz, 1H), 2.90 – 2.77 (m, 3H), 2.60 – 2.54 (m, 1H), 2.52 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H).

Example 498 – Preparation of (S)-N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01471] To a solution of 6-fluoro-2,7-dimethyl-2H-indazol-5-amine (81 mg, 0.45 mmol) and TEA (457 mg, 4.52 mmol) in THF (12 mL) was added triphosgene (134 mg, 0.45 mmol) at 0^oC, after 10 min, tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (120 mg, 0.37 mmol) was added at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (150 mg, 76.02 %) as a white solid. ESI-MS (M+H) ⁺:524.4. Step 2: Preparation of (S)-N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01472] To a mixture of tert-butyl (S)-4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (130 mg, 0.25 mmol) in EA (2 mL) was added HCl/EA (6 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (40 mg, Y: 38.04 %) as a white solid. ESI-MS (M+H) ⁺:424.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (d, J = 2.9 Hz, 1H), 8.27 (d, J = 7.2 Hz, 2H), 8.21 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 6.55 (d, J = 6.1 Hz, 1H), 4.12 (s, 3H), 4.00 (t, J = 8.6 Hz, 2H), 3.69 – 3.65 (m, 2H), 3.15 – 3.12 (m, 2H), 3.09 – 3.00 (m, 2H), 3.00 – 2.91 (m, 2H), 2.73 – 2.66 (m, 1H), 2.45 – 2.41 (m, 3H), 1.13 (d, J = 6.3 Hz, 3H). Example 499 – Preparation of (S)-N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin- 6-yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-4-(1-((8-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01473] To a solution of 8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-amine (112 mg, 0.57 mmol) in THF (5 mL) were added TEA (572 mg, 5.66 mmol) and triphosgene (168 mg, 0.57 mmol) at 0 ^oC. After stirred at 0 ^oC for 5 min, tert-butyl (S)-4-(2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (150 mg 0.47 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL*3). The organic layer was concentrated in vacuo to provide the title product (124 mg, 48.6 %) as a yellow solid. ESI-MS (M+H) ⁺: 542.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 9.07 (s, 1H), 7.95 (d, J = 6.1 Hz, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.00 (t, J = 8.6 Hz, 2H), 3.77 (d, 1H), 3.20 – 3.12 (m, 4H), 3.10 – 3.05 (m, 4H), 2.35 (s, 3H), 1.43 – 1.42 (m, 9H), 1.19 (d, J = 1.4 Hz, 3H). Step 2: (S)-N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01474] A solution of tert-butyl (S)-4-(1-((8-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (124 mg, 0.23 mmol) in 4 M HCl / EA (5 mL) was stirred at r.t for 2 h. The reaction mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % FA in H₂O / CH₃CN) to afford the title product (19 mg, 16.4 %) as a yellow solid. ESI-MS (M+H) ⁺:442.0.¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 9.07 (s, 1H), 8.22 (s, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.84 (s, 1H), 7.36 – 7.35 (m, 2H), 6.55 (d, J = 6.1 Hz, 1H), 3.99 (t, J = 8.5 Hz, 2H), 3.64 – 3.63 (m, 1H), 3.15 (t, J = 8.4 Hz, 2H), 3.01 (d, J = 11.6 Hz, 1H), 2.94 – 2.78 (m, 4H), 2.58 – 2.56 (m, 1H), 2.35 (s, 3H), 1.06 (d, J = 6.2 Hz, 3H). Example 500 – Preparation of N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6- yl)-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((8-(difluoromethyl)-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [01475] To a solution of 8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-amine (107 mg, 0.54 mmol) in THF (5 mL) were added TEA (548 mg, 5.42 mmol) and triphosgene (161 mg, 0.54 mmol) at 0^oC. After stirred at 0^oC for 5 min, tert-butyl (2S,6R)-4-(2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL*3). The organic layer was concentrated in vacuo and triturated with MeOH (5 mL) to provide the title product (48 mg, 19.1 %) as a white solid. ESI-MS (M+H) ⁺: 556.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 9.08 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 7.84 (s, 1H), 7.50 – 7.40 (m, 2H), 6.58 (d, J = 6.2 Hz, 1H), 4.15 – 4.08 (m, 2H), 4.02 (t, J = 8.6 Hz, 2H), 3.60 (d, J = 12.5 Hz, 2H), 3.18 (t, J = 8.0 Hz, 2H), 3.00 (dd, J = 12.5, 4.3 Hz, 2H), 2.36 (d, J = 11.2 Hz, 3H), 1.43 (s, 9H), 1.26 (d, J = 6.8 Hz, 6H). Step 2: Preparation of N-(8-(difluoromethyl)-2-methylimidazo[1,2-a]pyridin-6-yl)-4- ((3S,5R)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01476] A solution of tert-butyl (2S,6R)-4-(1-((8-(difluoromethyl)-2- methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,6-dimethylpiperazine-1-carboxylate (48 mg, 0.086 mmol) in 4M HCl / EA (5 mL) was stirred at r.t for 2 h. The precipitate was filtered and lyophilized to afford the title product (35 mg, 89.4 %) as a white solid. ESI-MS (M+H) ⁺:456.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.41 (s, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.27 – 7.20 (m, 2H), 4.30 – 4.28 (m, 4H), 3.56 – 3.52 (m, 3H), 3.33 – 3.31 (m, 2H), 3.14 – 3.11 (m, 1H), 2.59 (s, 3H), 1.42 (d, J = 6.5 Hz, 6H). Example 501 – Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-((3S,5R)- 3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate

Step 1: Preparation of 6-bromo-2,7-dimethylimidazo[1,2-a]pyridine. [01477] To a mixture of 5-bromo-4-methylpyridin-2-amine (20 g, 107.53 mmol) in IPA (200 mL) were added 1-bromo-2,2-dimethoxypropane (21.53 g, 118.28 mmol) and PPTS (63.61 g, 129.04 mmol). [01478] The mixture was stirred at 85^oC for 16 h. The mixture was diluted with water (200 mL), adjusted pH to 10 with sat.NaOH and extracted with EA (200 mL*3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 5: 1) to get title product (11 g, Y: 45.87%) as a white solid. ESI-MS (M+H) ⁺: 227.0. Step 2: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1-diphenylmethanimine. [01479] To a mixture of 6-bromo-2,7-dimethylimidazo[1,2-a]pyridine (11 g, 49.11 mmol), diphenylmethanimine (13.33 g, 73.67 mmol) and BINAP (6.12 g, 9.82 mmol) in 1,4- dioxane (110 mL) were added Cs₂CO₃ (32.02 g, 98.22 mmol) and Pd(OAc)₂ (1.11 g, 4.91 mmol). The mixture was stirred at 110 ^oC for 16 h under N₂. The mixture was diluted with H₂O (100 mL) and extracted with EA (100 mL x 3). The organic phase was washed with brine (100 mL*3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (4 g, 25.06%) as a brown solid. ESI-MS (M+H) ⁺:326.4. Step 3: Preparation of 2,7-dimethylimidazo[1,2-a]pyridin-6-amine hydrochloride. [01480] A mixture of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (4 g, 12.31 mmol) in 4M HCl/EA (50 mL) was stirred at r.t for 2 h. The precipitate was filtrated, washed with EA and dried in vacuo to give title product (700 mg, 90.49%) as a yellow solid. ESI-MS (M+H⁺): 162.2. Step 4: Preparation of tert-butyl (2S,6R)-4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01481] To a mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 2,7-dimethylimidazo[1,2- a]pyridin-6-amine hydrochloride (106.38 mg, 0.54 mmol) in THF (10 mL) were added TEA (136.35 mg, 1.35 mmol) and triphosgene (267.30 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford title product (80 mg, 34.25%) as a brown solid. ESI-MS (M+H) ⁺: 520.3. Step 5: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-((3S,5R)-3,5- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01482] A mixture of tert-butyl (2S,6R)-4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (80 mg, 0.15 mmol) in 4M HCl / EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in water / CH₃CN) to give title product (3.75 mg, 4.69%) as a brown solid. ESI-MS (M+H) ⁺:420.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.48 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.18 – 4.13 (m, 2H), 3.95 – 3.90 (m, 2H), 3.55 – 3.49 (m, 2H), 3.28 – 3.22 (m, 2H), 2.98 – 2.92 (m, 2H), 2.66 (s, 3H), 2.51 (s, 3H), 1.40 (d, J = 6.6 Hz, 6H). Example 502 – Preparation of (R)-N-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-2-methyl-4-(1-((2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01483] A mixture of 2-methyl-2H-pyrazolo[3,4-c]pyridin-5-amine hydrochloride (104 mg, 0.566 mmol), triphosgene (168 mg, 0.566 mmol) and TEA (572 mg, 5.66 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (150 mg, 0.472 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL×3). The organic layer was concentrated in vacuo. The solid was trirurated with MeOH (3 mL*2) to afford title product (70 mg, 30.2 %) as a white solid. ESI-MS (M+H) ⁺: 493.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 8.94 (s, 1H), 8.38 (s, 1H), 8.19 – 8.16 (m, 1H), 7.97 – 7.94 (m, 1H), 6.56 – 6.49 (m, 1H), 4.22 (s, 3H), 4.04 – 3.98 (m, 2H), 3.82 – 3.55 (m, 4H), 3.19 – 3.07 (m, 4H), 2.96 – 2.88 (m, 1H), 1.42 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (R)-N-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01484] A mixture of tert-butyl (R)-2-methyl-4-(1-((2-methyl-2H-pyrazolo[3,4- c]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (50 mg, 0.102 mmol) in 4M HCl /EA (4 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the solid was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (20 mg, 44.9 %) as a white solid. ESI-MS (M+H) ⁺: 393.0. ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 8.94 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.93 (d, J = 6.0 Hz, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.22 (s, 3H), 4.00 (t, J = 8.5 Hz, 2H), 3.59 (d, J = 11.5 Hz, 2H), 3.12 (t, J = 8.6 Hz, 2H), 2.97 (d, J = 10.9 Hz, 1H), 2.89 – 2.76 (m, 3H), 2.56 – 2.52 (m, 1H), 1.04 (d, J = 6.3 Hz, 3H). Example 503 – Preparation of (S)-N-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-2-methyl-4-(1-((2-methylimidazo[1,2-a]pyrimidin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01485] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol), 2-methylimidazo[1,2-a]pyrimidin-6- amine (69.81 mg, 0.47 mmol) and TEA (142.41 mg, 1.41 mmol) in THF (5 mL) was added triphosgene (278.24 mg, 0.94 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/1 to 1/100) to afford title product (60 mg, 25.95%) as a brown solid. ESI-MS (M+H) ⁺: 493.2. Step 2: Preparation of (S)-N-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01486] A mixture of tert-butyl (S)-2-methyl-4-(1-((2-methylimidazo[1,2-a]pyrimidin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg,0.12 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% TFA in water / CH₃CN) to give title product (5.66 mg, 9.32%) as a brown solid. ESI-MS (M+H) ⁺:393.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.65 (d, J = 2.4 Hz, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 6.2 Hz, 1H), 7.91 (s, 1H), 6.72 (d, J = 6.3 Hz, 1H), 4.23 – 4.17 (m, 2H), 3.97 – 3.89 (m, 2H), 3.55 – 3.34 (m, 4H), 3.30 – 3.27 (m, 2H), 3.12 (dd, J = 13.8, 10.5 Hz, 1H), 2.56 (s, 3H), 1.41 (d, J = 6.6 Hz, 3H). Example 504 – Preparation of (S)-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of tert-butyl (S)-4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01487] To a solution of 2,7-dimethylimidazo[1,2-a]pyridin-6-amine (49 mg, 0.30 mmol) and TEA (305 mg, 3.02 mmol) in THF (15 mL) was added triphosgene (89 mg, 0.38 mmol) at 0^oC, after 10 min, tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (80 mg, 0.25 mmol) was added at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and concentrated in vacuo to give the compound (50 mg, 40 %) as a white solid. ESI- MS (M+H) ⁺:506.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.69 (s, 1H), 9.09 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.65 (s, 1H), 7.34 (s, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.00 (t, J = 7.5 Hz, 2H), 3.78 (d, J = 13.2 Hz, 2H), 3.66 (d, J = 12.9 Hz, 1H), 3.59 (d, J = 13.0 Hz, 2H), 3.17 (d, J = 5.2 Hz, 4H), 2.33 (s, 6H), 1.42 (s, 9H). Step 2: Preparation of (S)-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01488] To a mixture of tert-butyl (S)-4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.05% NH_3.H₂O in H₂O / ACN) to give title product (8.63 mg, 27 %) as a white solid. ESI-MS (M+H) ⁺: 406.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 9.06 (s, 1H), 7.87 (d, J = 6.1 Hz, 1H), 7.61 (s, 1H), 7.30 (s, 1H), 6.51 (d, J = 6.2 Hz, 1H), 3.98 (t, J = 8.6 Hz, 2H), 3.58 (d, J = 12.2 Hz, 2H), 3.13 (t, J = 8.6 Hz, 2H), 2.91 (d, J = 11.2 Hz, 1H), 2.85 – 2.68 (m, 3H), 2.48 – 2.42 (m, 1H), 2.39 (s, 3H), 2.28 (s, 3H), 1.00 (d, J = 6.3 Hz, 3H). Example 505 – Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-ethoxy-2- methyl-2H-benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol- 5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01489] A mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (80 mg, 0.24 mmol), 6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-amine (55 mg, 0.29 mmol), triphosgene (86 mg, 0.29 mmol) and TEA (292 mg, 2.89 mmol) in THF (8 mL) was stirred at 0 ^oC for 15 min. The mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered to afford title product (40 mg, 30.30 %) as a yellow solid. ESI-MS (M+H) ⁺: 551.3. Step 2: Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01490] A mixture of tert-butyl (2S,6R)-4-(1-((6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (30 mg, 0.05 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (16.57 mg, yield: 73.64 %) as a gray solid. ESI-MS (M+H) ⁺: 451.3.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.61 (s, 1H), 8.31 (s, 1H), 7.92 (d, J = 5.9 Hz, 1H), 7.27 (s, 1H), 6.61 (d, J = 5.9 Hz, 1H), 4.37 (s, 3H), 4.23 – 4.17 (m, 2H), 4.03 (t, J = 8.4 Hz, 2H), 3.75 (s, 2H), 3.22 – 3.13 (m, 4H), 2.75 (t, J = 12.2 Hz, 2H), 1.55 (t, J = 6.9 Hz, 3H), 1.20 (d, J = 6.4 Hz, 6H). Example 506 – Preparation of (R)-N-(6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01491] A mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (80 mg, 0.25 mmol), 6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-amine (58 mg, 0.30 mmol), triphosgene (89 mg, 0.30 mmol) and TEA (305 mg, 3.02 mmol) in THF (8 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered to afford title product (40 mg, 29.85 %) as a yellow solid. ESI-MS (M+H) ⁺: 537.3. Step 2: Preparation of (R)-N-(6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01492] A mixture of tert-butyl (R)-4-(1-((6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (30 mg, 0.05 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (4.71 mg, yield: 21.60 %) as a white solid. ESI-MS (M+H) ⁺: 437.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 8.63 (s, 1H), 8.16 (s, 1H), 7.88 (d, J = 6.1 Hz, 1H), 7.28 (s, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.37 (s, 3H), 4.21 (t, J = 6.9 Hz, 2H), 4.02 (t, J = 8.6 Hz, 2H), 3.66 (d, J = 12.0 Hz, 2H), 3.15 (d, J = 8.8 Hz, 3H), 3.03 – 2.91 (m, 3H), 2.71 (d, J = 11.7 Hz, 1H), 1.54 (t, J = 6.9 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H). Example 507 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of 4-bromo-5-ethoxy-2-nitroaniline. [01493] A mixture of 5-ethoxy-2-nitroaniline (24 g, 138.87 mmol) and NBS (23.5 g, 138.87 mmol) in ACN (200 mL) was stirred at 70 ^oC for 16 h. The mixture was diluted with water (200 mL), extracted with EA (200 mL×3). The organic layer was washed with brine (200 mL), dried with Na₂SO₄ and concentrated in vacuo to give title product (33 g, yield: 96.24 %) as a yellow solid. ESI-MS (M+H) ⁺: 261.0.¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 6.14 (s, 1H), 4.10 (q, J = 7.0 Hz, 2H), 1.52 (t, J = 7.0 Hz, 3H). Step 2: Preparation of 4-bromo-5-ethoxybenzene-1,2-diamine. [01494] A mixture of 4-bromo-5-ethoxy-2-nitroaniline (32 g, 123.08 mmol), NH₄Cl (49.8 g, 923.1 mmol) and Fe (68 g, 1230.76 mmol) in EtOH / H₂O (500 mL /100 mL) was stirred at 90 ^oC for 4 h. The precipitate was filtered and the filtrate was concentarted in vacuo. The residue was diluted with water (500 mL), extracted with EA (500 mL×3). The organic layer was washed with brine (500 mL), dried with Na₂SO₄ and concentrated in vacuo to give title product (24 g, 84.41 %) as a black solid. ESI-MS (M+H) ⁺: 233.0.¹H NMR (400 MHz, CDCl₃) δ 6.88 (s, 1H), 6.35 (s, 1H), 3.98 (q, J = 6.9 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H). Step 3: Preparation of 5-bromo-6-ethoxy-2H-benzo[d][1,2,3]triazole. [01495] A mixture of 4-bromo-5-ethoxybenzene-1,2-diamine (23 g, 100 mmol), NaNO₂ (34.5 g, 500 mmol) , in AcOH / H₂O (100 mL / 400 mL) was stirred at RT for 20 min. The mixture was diluted with water (200 mL), extracted with EA (200 mL×3). The organic layer was washed with brine (200 mL), dried with Na₂SO₄ and concentrated in vacuo to give title product (20 g, yield: 82.98 %) as a brown solid. ESI-MS (M+H) ⁺: 244.0. Step 4: Preparation of 5-bromo-6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazole. [01496] A mixture of 5-bromo-6-ethoxy-2H-benzo[d][1,2,3]triazole (18 g, 74.69 mmol), CH₃I (21.21 g, 149.38 mmol) and EtONa (9.1 g, 134.44 mmol) in EtOH (200 mL) was stirred at 70 ^oC for 16 h. The mixture was diluted with water (200 mL), extracted with EA (200 mL×3). The organic layer was washed with brine (200 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 23 %) to give title product (4.8 g, yield: 25.20 %) as a white solid. ESI-MS (M+H) ⁺: 258.1.¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.10 (s, 1H), 4.44 (s, 3H), 4.15 (q, J = 7.0 Hz, 2H), 1.54 (t, J = 7.0 Hz, 3H). Step 5: Preparation of N-(6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine. [01497] A mixture of 5-bromo-6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazole (4.7 g, 18.43 mmol), diphenylmethanimine (5 g, 27.65 mmol), Pd₂(dba)₃ (1.68 g, 1.84 mmol), Xantphos (2.13g, 3.68 mmol) and Cs₂CO₃ (12.02 g, 36.86 mmol) in 1,4-dioxane (50 mL) was stirred at 110 ^oC for 5 h under N₂. The mixture was diluted with water (100 mL), extracted with EA (100 mL×3). The organic layer was washed with brine (100 mL), dried with Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 70 %) to give title product (1.7 g, yield: 25.91 %) as a yellow oil. ESI-MS (M+H) ⁺: 357.0.¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 7.4 Hz, 2H), 7.48 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.22 – 7.14 (m, 5H), 6.97 (s, 1H), 6.91 (s, 1H), 4.36 (s, 3H), 3.97 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H). Step 6: Preparation of 6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-amine hydrochloride. [01498] A mixture of N-(6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-1,1- diphenylmethanimine (1.6 g, 4.49 mmol) in HCl / EA (4M, 20 mL) was stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (700 mg, yield: 68.38 %) as a white solid. ESI-MS (M+H) ⁺: 193.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (s, 1H), 7.29 (s, 1H), 4.36 (s, 3H), 4.17 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H). Step 7: Preparation of tert-butyl 4-(1-((6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01499] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (120 mg, 0.36 mmol), 6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-amine hydrochloride (83 mg, 0.43 mmol), triphosgene (129 mg, 0.43 mmol) and TEA (438 mg, 4.34 mmol) in THF (12 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered to afford title product (50 mg, 25.25 %) as a yellow solid. ESI- MS (M+H) ⁺: 551.2. Step 8: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01500] A mixture of tert-butyl 4-(1-((6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (40 mg, 0.07 mmol) in HCl / EA (4M, 2 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (17.63 mg, yield: 55.96 %) as a white solid. ESI-MS (M+H) ⁺: 451.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 8.63 (s, 1H), 8.31 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.27 (s, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.37 (s, 3H), 4.21 (t, J = 6.9 Hz, 2H), 4.04 – 3.99 (m, 2H), 3.23 – 3.19 (m, 2H), 3.12 (t, J = 8.5 Hz, 2H), 3.04 (s, 2H), 2.95 – 2.91 (m, 2H), 1.54 (t, J = 6.9 Hz, 3H), 1.15 (s, 6H). Example 508 – Preparation of N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl 7-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [01501] A mixture of 2,8-dimethylimidazo[1,2-a]pyridin-6-amine hydrochloride (143 mg, 0.727 mmol), triphosgene (216 mg, 0.727 mmol) and TEA (734 mg, 7.273 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.606 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo to afford title product (90 mg, crude) as a yellow solid. ESI-MS (M+H) ⁺: 518.0. Step 2: Preparation of N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01502] A mixture of tert-butyl 7-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (80 mg, 0.155 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the solid was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (39 mg, 47.5 %) as a white solid. ESI-MS (M+H) ⁺: 418.2.¹ H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 9.45 – 9.21 (m, 3H), 8.16 (s, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.75 (s, 1H), 6.66 (d, J = 6.2 Hz, 1H), 4.02 (t, J = 8.5 Hz, 2H), 3.63 – 3.56 (m, 2H), 3.46 – 3.42 (m, 2H), 3.40 – 3.33 (m, 2H), 3.15 (t, J = 8.4 Hz, 2H), 2.57 (s, 3H), 2.48 (s, 3H), 1.09 – 1.02 (m, 2H), 0.97 – 0.89 (m, 2H). Example 509 – Preparation of (S)-N-(2,7-dimethyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01503] To a solution of 2,7-dimethyl-2H-indazol-5-amine (60 mg, 0.37 mmol) in THF (10 mL) were added and TEA (376 mg, 3.72 mmol), triphosgene (110mg, 0.37 mmol) and stirred at 0^oC for 5 min. Then tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) was added slowly at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (5 mL) to give the compound (100 mg, 63 %) as a white solid. ESI-MS (M+H) ⁺: 506.2.¹H NMR (400 MHz, CDCl₃) δ 11.59 (s, 1H), 7.95 (dd, J = 12.3, 3.7 Hz, 2H), 7.79 (s, 1H), 7.04 (s, 1H), 6.34 (d, J = 6.0 Hz, 1H), 4.41 – 4.29 (m, 1H), 4.23 – 4.13 (m, 5H), 4.01 – 3.90 (m, 1H), 3.59 – 3.48 (m, 1H), 3.46 – 3.37 (m, 1H), 3.30 – 3.18 (m, 1H), 3.12 – 3.03 (m, 3H), 2.98 – 2.89 (m, 1H), 2.62 (s, 3H), 1.49 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(2,7-dimethyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01504] To a mixture of tert-butyl (S)-4-(1-((2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.16 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure to give title product (55.87 mg, 79%) as a white solid. ESI-MS (M+H) ⁺:406.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 2H), 8.26 (s, 1H), 7.79 (dd, J = 37.4 Hz, 2H), 7.13 (s, 1H), 6.84 – 6.83 (m, 1H), 4.40 – 4.10 (m, 6H), 4.09 – 3.91 (m, 3H), 3.42 – 3.31 (m, 4H), 3.15 – 3.08 (m, 1H), 2.49 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H). Example 510 – Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-4-((3S,5R)-3,5- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((2,7-dimethyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate. [01505] To a solution of 2,7-dimethyl-2H-indazol-5-amine (60 mg, 0.36 mmol) in THF (10 mL) were added and TEA (364 mg, 3.60 mmol), triphosgene (107 mg, 0.36 mmol) and stirred at 0^oC for 5 min. Then tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) was added slowly at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (70 mg, 40 %) as a white solid. ESI-MS (M+H) ⁺: 520.0.¹H NMR (400 MHz, CDCl₃) δ 11.59 (s, 1H), 8.00 – 7.93 (m, 2H), 7.79 (s, 1H), 7.04 (s, 1H), 6.41 – 6.36 (m, 1H), 4.31 – 4.24 (m, 2H), 4.22 – 4.16 (m, 5H), 3.46 – 3.39 (m, 2H), 3.17 – 3.10 (m, 2H), 3.04 – 2.96 (m, 2H), 2.62 (s, 3H), 1.50 (s, 9H), 1.37 (d, J = 6.8 Hz, 6H). Step 2: Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-4-((3S,5R)-3,5-dimethylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01506] To a mixture of tert-butyl (2S,6R)-4-(1-((2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (50 mg, 0.096 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (30.29 mg, 67%) as a white solid. ESI-MS (M+H) ⁺: 420.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.84 (s, 1H), 6.97 (s, 1H), 6.51 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 3.99 – 3.94 (m, 2H), 3.63 – 3.61 (m, 2H), 3.14 – 3.09 (m, 2H), 2.90 – 2.83 (m, 2H), 2.49 – 2.40 (m, 5H), 1.03 (d, J = 6.3 Hz, 6H). Example 511 – Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-4-(3,3- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [01507] To a solution of 2,7-dimethyl-2H-indazol-5-amine (47 mg, 0.29 mmol) and TEA (292 mg, 2.89 mmol) in THF (10 mL) was added triphosgene (86 mg, 0.29 mmol) at 0^oC, after 10 min, tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (80 mg, 0.24 mmol) was added at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and triturated with MeOH (5 mL) to give the compound (100 mg, 80%) as a white solid. ESI-MS (M+H) ⁺:520.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 6.1 Hz, 1H), 7.84 (d, J = 1.4 Hz, 1H), 6.97 (s, 1H), 6.40 (d, J = 6.3 Hz, 1H), 4.13 (s, 3H), 3.94 (t, J = 8.6 Hz, 2H), 3.72 – 3.67 (m, 2H), 3.58 – 3.54 (m, 2H), 3.53 (s, 2H), 3.29 – 3.25 (m, 2H), 2.48 (s, 3H), 1.43 (s, 9H), 1.38 (s, 6H). Step 2: Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-4-(3,3-dimethylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01508] To a mixture of tert-butyl 4-(1-((2,7-dimethyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in EA (2 mL) was added 4M HCl/EA (6 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep- HPLC (0.05% FA in H₂O / ACN) to give title product (38.90 mg, 56 %) as a white solid. ESI-MS (M+H) ⁺:420.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.84 (d, J = 1.4 Hz, 1H), 6.97 (s, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 4.01 – 3.95 (m, 2H), 3.26 – 3.22 (m, 2H), 3.13 – 3.07 (m, 4H), 2.99 – 2.95 (m, 2H), 2.48 (s, 3H), 1.18 (s, 6H). Example 512 – Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 7-(1-((2,7-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. [01509] To a solution of 2,7-dimethyl-2H-indazol-5-amine (59 mg, 0.36 mmol) and TEA (368 mg, 3.64 mmol) in THF (10 mL) was added triphosgene (108 mg, 0.36 mmol) at 0^oC, after 10 min, tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol) was added at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and concentrated in vacuo to give the compound (50 mg, 32 %) as a white solid. ESI- MS (M+H) ⁺:518.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.18 (s, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.84 (s, 1H), 6.97 (s, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 3.96 (t, J = 8.6 Hz, 2H), 3.58 – 3.55 (m, 2H), 3.29 – 3.27 (m, 2H), 3.12 – 3.06 (m, 4H), 2.48 (s, 3H), 1.42 (s, 9H), 0.94 (d, J = 4.5 Hz, 2H), 0.86 (d, J = 5.0 Hz, 2H). Step 2: Preparation of (N-(2,7-dimethyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan-7-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01510] To a mixture of tert-butyl 7-(1-((2,7-dimethyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (40 mg, 0.08 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep- HPLC (0.05% FA in H₂O / ACN) to give title product (29.01 mg, 78%) as a white solid. ESI- MS (M+H) ⁺:418.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.84 (d, J = 1.4 Hz, 1H), 6.97 (s, 1H), 6.48 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 3.95 (t, J = 8.6 Hz, 2H), 3.24 – 3.21 (m, 2H), 3.10 (s, 2H), 3.08 – 3.03 (m, 2H), 2.89 – 2.85 (m, 2H), 2.48 (s, 3H), 0.51 (t, J = 10.0 Hz, 4H). Example 513 – Preparation of N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4- ((3R,5S)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01511] To a mixture of 2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (87 mg, 0.45 mmol) in toluene (5 mL) were added TEA (122 mg, 1.20 mmol) and DPPA (232 mg, 0.84 mmol). The mixture was stirred at r.t for 1 h and warmed up to 90^oC and stirred for 1 h. Tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) was added to the mixture and stirred at 110 ^oC for 16 h. The mixture was diluted with water (10 mL) and the precipitate was filtered to give the title compound (40 mg, Y: 25.5 %) as a brown solid. ESI-MS (M+H) ⁺:522.4. Step 2: Preparation of N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4-((3R,5S)-3,5- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01512] To a solution of tert-butyl (2R,6S)-4-(1-((2,5-dimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (24 mg, 66.9 %) as a white solid. ESI-MS (M+H)⁺:422.3. ¹H NMR (400 MHz, MeOD-d₄) δ 9.64 (s, 1H), 8.51 – 8.41 (m, 1H), 7.98 (d, J = 5.7 Hz, 1H), 6.60 (d, J = 6.0 Hz, 1H), 4.11 (t, J = 8.3 Hz, 2H), 3.87 – 3.81 (m, 2H), 3.41 – 3.35 (m, 2H), 3.19 (t, J = 8.4 Hz, 2H), 2.84 – 2.77 (m, 5H), 2.52 (s, 3H), 1.34 (d, J = 6.5 Hz, 6H). Example 514 – Preparation of N-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4- ((3R,5S)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01513] To a mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol), 2,8-dimethyl- [1,2,4]triazolo[1,5-a]pyrazin-6-amine (59 mg, 0.36 mmol) and TEA (455 mg, 4.50 mmol) in THF (12 mL) was added triphosgene (107 mg, 0.36 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 6) to give title product (70 mg, Y: 44.7%) as a yellow solid. ESI-MS (M+H) ⁺: 522.4. Step 2: Preparation of N-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-((3R,5S)-3,5- dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01514] A mixture of tert-butyl (2R,6S)-4-(1-((2,8-dimethyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (60 mg, 0.16 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (23.96 mg, Y: 49.4 %) as a white solid. ESI-MS (M+H) ⁺: 422.2.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.68 (s, 1H), 8.29 (s, 1H), 7.62 (d, J = 5.9 Hz, 1H), 6.30 (d, J = 6.1 Hz, 1H), 3.76 (t, J = 8.0 Hz, 2H), 3.63 (d, J = 12.4 Hz, 2H), 3.31 – 3.19 (m, 2H), 2.86 (t, J = 8.0 Hz, 2H), 2.73 (t, J = 12.5 Hz, 2H), 2.53 (s, 3H), 2.32 (s, 3H), 1.22 (d, J = 6.5 Hz, 6H). Example 515 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(5-methoxy-2- methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

C^{ompound 515} Step 1: Preparation of N-(5-methoxy-2-methyl-[1,2,4]triazolo a]pyrimidin-6-yl)-1,1-

diphenylmethanimine. [01515] To a mixture of 6-bromo-5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidine (5.0 g, 20.58 mmol) in 1,4-dioxane (50 mL) were added diphenylmethanimine (5.6 g, 30.86 mmol), BINAP (2.6 g, 4.12 mmol), Pd₂(dba)₃ (1.9 g, 2.06 mmol) and Cs₂CO₃ (13.4 g, 41.15 mmol). The mixture was stirred at 110^oC for 16 h under nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with EA (100 mL*3), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 1: 4) to get title product (400 mg, Y: 5.7%) as a yellow solid. ESI-MS (M+H)⁺:343.1. Step 2: Preparation of 5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride. [01516] To a mixture of N-(5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)- 1,1-diphenylmethanimine (400 mg, 1.17 mmol) in EA (5 mL) was added 4 M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered and diluted with EA (5 mL). The mixture was stirred at r.t for 2 h and the precipitate was filtered to get title product (170 mg, Y: 67.3%) as a white solid. ESI-MS (M+H)⁺:180.1. Step 3: Preparation of tert-butyl (2R,6S)-4-(1-((5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [01517] To a mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (50 mg, 0.15 mmol), 5-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-amine HCl salt (39 mg, 0.18 mmol), TEA (228 mg, 2.26 mmol) in THF (5 mL) was added and triphosgene (54 mg, 0.18 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and the precipitate was filtered, triturated with MeOH (5mL) to get title product (40 mg, Y: 50.0 %) as a white solid. ESI-MS (M+H) ⁺:538.4. Step 4: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(5-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01518] To a solution of tert-butyl (2R,6S)-4-(1-((5-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,6-dimethylpiperazine-1-carboxylate (30 mg, 0.06 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (19 mg, 61.7 %) as a white solid. ESI-MS (M+H)⁺:438.3. ¹H NMR (400 MHz, MeOD-d₄) δ 9.51 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 6.60 (d, J = 6.1 Hz, 1H), 4.26 (s, 3H), 4.12 – 4.07 (m, 2H), 3.93 – 3.88 (m, 2H), 3.55 – 3.48 (m, 2H), 3.19 (t, J = 8.5 Hz, 2H), 2.95 – 2.88 (m, 2H), 2.48 (s, 3H), 1.40 (d, J = 6.6 Hz, 6H).

Example 516 – Preparation of (S)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01519] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 8-methoxy-2-methylimidazo[1,2- a]pyrazin-6-amine hydrochloride (82 mg, 0.38 mmol), TEA (476 mg, 4.72 mmol) in THF (15 mL) was added triphosgene (112 mg, 0.38 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (30 mL), the precipitate was filtered and triturated with MeOH (5 mL) to get title product (40 mg, Y: 24.7 %) as a yellow solid. ESI-MS (M+H) ⁺:523.4. Step 2: Preparation of (S)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01520] To a solution of tert-butyl (S)-4-(1-((8-methoxy-2-methylimidazo[1,2- a]pyrazin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine- 1-carboxylate (30 mg, 0.06 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep- HPLC (0.03% TFA in water / ACN) to give title compound (20 mg, 64.9 %) as a yellow solid. ESI-MS (M+H)⁺:423.3. ¹H NMR (400 MHz, MeOD-d4) δ 8.91 – 8.88 (m, 1H), 8.03 – 7.99 (m, 2H), 6.68 – 6.63 (m, 1H), 4.27 (s, 3H), 4.15 (t, J = 8.4 Hz, 2H), 3.88 – 3.82 (m, 2H), 3.55 – 3.47 (m, 2H), 3.29 – 3.28 (m, 2H), 3.22 (t, J = 8.4 Hz, 2H), 3.05 (dd, J = 13.8, 10.4 Hz, 1H), 2.52 (s, 3H), 1.42 – 1.38 (m, 3H). Example 517 – Preparation of N-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4- ((3R,5S)-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01521] To a mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol), 8-methoxy-2- methylimidazo[1,2-a]pyrazin-6-amine hydrochloride (78 mg, 0.36 mmol), TEA (456 mg, 4.52 mmol) in THF (10 mL) was added triphosgene (107 mg, 0.36 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL), the precipitate was filtered and triturated with MeOH (5 mL) to get title product (40 mg, Y: 24.8 %) as a white solid. ESI-MS (M+H) ⁺:537.4. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(8-methoxy-2- methylimidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01522] To a solution of tert-butyl (2R,6S)-4-(1-((8-methoxy-2-methylimidazo[1,2- a]pyrazin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (30 mg, 0.06 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (19 mg, 61.7 %) as a yellow solid. ESI-MS (M+H)⁺:437.3. ¹H NMR (400 MHz, MeOD-d₄) δ 8.92 (s, 1H), 8.04 – 8.00 (m, 2H), 6.69 – 6.66 (m, 1H), 4.28 (s, 3H), 4.15 (t, J = 8.4 Hz, 2H), 3.96 – 3.90 (m, 2H), 3.56 – 3.49 (m, 2H), 3.23 (t, J = 8.4 Hz, 2H), 2.98 – 2.90 (m, 2H), 2.54 (s, 3H), 1.39 (d, J = 6.6 Hz, 6H). Example 518 – Preparation of (S)-N-(7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl (S)-4-(1-((7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01523] To a solution of 7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridine-5- carboxylic acid (65 mg, 0.31 mmol) and TEA (95.34 mg, 0.94 mmol) in tol (10 mL) was added DPPA (129 mg, 0.47 mmol) at r.t, after 1 h, the mixture was warmed to 90 ^oC and stirred for 30 min, then tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE/EA=3:7) to give title product (60 mg, Y: 36.56 %) as a white solid. ESI-MS (M+H) ⁺:523.4. Step 2: Preparation of (S)-N-(7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01524] To a mixture of tert-butyl (S)-4-(1-((7-methoxy-2-methyl-2H-pyrazolo[3,4- c]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (50 mg, 0.10 mmol) in EA (2 mL) was added HCl/EA (3 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (10 mg, Y: 24.74 %) as a white solid. ESI-MS (M+H) ⁺:423.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 9.14 (s, 1H), 8.80 (s, 1H), 8.25 (s, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.69 (s, 1H), 6.62 (d, J = 6.1 Hz, 1H), 4.14 (s, 3H), 4.05 – 3.99 (m, 5H), 3.81 – 3.77 (m, 2H), 3.42 – 3.35 (m, 2H), 3.22 – 3.12 (m, 4H), 3.03 – 2.95 (m, 1H), 1.27 (d, J = 6.5 Hz, 3H). Example 519 – Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-ethoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01525] A mixture of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (159 mg, 0.72 mmol) in Tol (5 mL) were added TEA (182 mg, 1.81 mmol) and DPPA (199 mg, 0.72 mmol) . The mixture was stirred at 30 ℃ for 30 min and 60 ℃ for 30 min. Tert- butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (200 mg, 0.60 mmol) was added to the mixture and stirred at 90 ℃ for 16 h. The mixture was concentrated in vacuo and diluted with water (15 mL), extracted with DCM (15 mL*3). The organic layer was concentrated in vacuo to afford the title product (80 mg, 24.2 %) as a white solid. ESI-MS (M+H) ⁺: 550.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 6.59 (d, J = 6.1 Hz, 1H), 6.16 (s, 1H), 4.16 – 4.09 (m, 4H), 4.02 (t, J = 8.6 Hz, 2H), 3.58 (d, J = 12.3 Hz, 2H), 3.18 (t, J = 8.5 Hz, 2H), 2.99 (dd, J = 12.4, 3.8 Hz, 2H), 2.30 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H), 1.43 (s, 9H), 1.26 (d, J = 6.8 Hz, 6H). Step 2: 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin- 5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01526] A solution of tert-butyl (2S,6R)-4-(1-((6-ethoxy-2-methylpyrazolo[1,5- a]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in 4 M HCl / EA (5 mL) was stirred at r.t for 2h. The precipitate was filtered and lyophilized to afford the title product (55 mg, 84.6%) as a white solid. ESI-MS (M+H) ⁺: 450.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1H), 9.69 (s, 1H), 9.24 (d, J = 9.9 Hz, 1H), 8.27 (d, J = 13.0 Hz, 2H), 7.88 (d, J = 6.0 Hz, 1H), 6.65 (d, J = 6.1 Hz, 1H), 6.19 (s, 1H), 4.12 (q, J = 6.9 Hz, 2H), 4.01 (t, J = 8.4 Hz, 2H), 3.84 (s, 2H), 3.32 (s, 2H), 3.17 (t, J = 8.4 Hz, 2H), 3.05 – 2.95 (m, 2H), 2.31 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H), 1.31 (d, J = 6.4 Hz, 6H). Example 520 – Preparation of N-(2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9- diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide.

C^{ompound 520} Step 1: Preparation of tert-butyl 2-(1-((2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate. [01527] To a solution of tert-butyl 2-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6- oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (120 mg, 0.33 mmol) in THF (3 mL) was added DIEA (198 mg, 1.67 mmol), triphosgene (99 mg, 0.33 mmol) and 2- methylimidazo[1,2-a] pyridin-6-amine (74 mg, 0.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with H₂O (80 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum and the residue was purified by C18 column chromatography eluted with (0.05% FA in water / ACN) to afford tert-butyl 2-(1-((2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H- pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (50 mg, yield: 28%) as a yellow solid. ESI-MS (M+1) ⁺: 534.3. Step 2: Preparation of N-(2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9-diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide. [01528] To a mixture of tert-butyl 2-(1-((2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9- carboxylate (40 mg, 0.075 mmol) in DCM (1 mL) was added HCl/dioxane (1 mL, 6 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The residue was purified by C18 column chromatography eluted with (0.05% NH₄HCO₃ in water / ACN) to afford N-(2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9-diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide (10 mg, yield: 30%) as a yellow solid. ESI-MS (M+1) ⁺: 434.1.¹H NMR (400 MHz, CD₃OD) δ 8.85 (dd, J = 1.9, 0.8 Hz, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.51 (s, 1H), 7.37 (d, J = 9.5 Hz, 1H), 7.17 (dd, J = 9.5, 2.0 Hz, 1H), 6.16 (d, J = 6.2 Hz, 1H), 3.99 (dt, J = 9.9, 7.1 Hz, 2H), 3.76 – 3.60 (m, 5H), 3.53 (d, J = 10.7 Hz, 1H), 3.45 – 3.34 (m, 2H), 2.85 (dt, J = 10.1, 8.6 Hz, 4H), 2.39 – 2.35 (m, 3H), 2.22 (dd, J = 14.4, 9.8 Hz, 1H), 1.92 (dt, J = 13.0, 8.7 Hz, 1H). Example 521 – Preparation of (R)-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of N-(2-methylimidazo[1,2-a]pyrazin-6-yl)-1,1-diphenylmethanimine. [01529] A mixture of 6-bromo-2-methylimidazo[1,2-a]pyrazine (5 g, 23.58 mmol) and diphenylmethanimine (4.7 g, 25.94 mmol) in dioxane (80 mL) were added BINAP (2.93 g, 4.72 mmol), Pd₂(dba)₃(2.16 g, 2.36 mmol) and Cs₂CO₃ (23 g, 70.75 mmol). The reaction solution was stirred at 110℃ for 16 h under N₂. The reaction was concentrated in vacuo and purified by silica gel column chromatography (PE: EA=1:3) to give title product (5 g, Y: 67.8%) as a yellow solid. ESI-MS (M+H) ⁺: 313.2. Step 2: Preparation of 2-methylimidazo[1,2-a]pyrazin-6-amine HCl salt. [01530] A mixture of N-(2-methylimidazo[1,2-a]pyrazin-6-yl)-1,1- diphenylmethanimine (4 g, 12.78 mmol) in EA (40 mL) and 4M HCl/EA (20 mL) was stirred at RT for 1h. The mixture diluted with EA (250 mL) stirred at rt for 2 h, the precipitate was filtered and dried in vacuo to give title product (2 g, crude) as a yellow solid. ESI-MS (M+H) ⁺: 149.2. Step 3: Preparation of tert-butyl (R)-2-methyl-4-(1-((2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01531] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (150 mg, 0.47 mmol)，2-methylimidazo[1,2-a]pyrazin-6- amine HCl salt (130 mg, 0.71 mmol) and TEA (712 mg, 7.05 mmol) in THF (12 mL) was added triphosgene (167.6 mg, 0.56 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 9) to give title product (100 mg, Y: 43.1%) as a brown solid. ESI-MS (M+H) ⁺: 493.3. Step 4: Preparation of (R)-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01532] A mixture of tert-butyl (R)-2-methyl-4-(1-((2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.16 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (22 mg, Y: 34.5 %) as a yellow solid. ESI-MS (M+H) ⁺: 393.2.¹H NMR (400 MHz, DMSO- d₆+D₂O) δ 8.94 (d, J = 1.2 Hz, 1H), 8.71 (s, 1H), 8.38 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.89 (s, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.03 – 3.98 (m, 2H), 3.79 – 3.67 (m, 2H), 3.32 (d, J = 10.4 Hz, 2H), 3.20 – 3.03 (m, 4H), 2.97 – 2.88 (m, 1H), 2.39 (s, 3H), 1.27 (d, J = 6.4 Hz, 3H).

Example 522 – Preparation of (S)-N-(6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)- 4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01533] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-amine (72 mg, 0.38 mmol), TEA (476 mg, 4.72 mmol) in THF (20 mL) was added triphosgene (112 mg, 0.38 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (30 mL), the precipitate was filtered and triturated with MeOH (5 mL) to get title product (40 mg, Y: 24.0 %) as a yellow solid. ESI-MS (M+H) ⁺:537.4. Step 2: Preparation of (S)-N-(6-ethoxy-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01534] To a solution of tert-butyl (S)-4-(1-((6-ethoxy-2-methyl-2H- benzo[d][1,2,3]triazol-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (30 mg, 0.06 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (12 mg, 44.5 %) as a white solid. ESI-MS (M+H)⁺:437.3.¹H NMR (400 MHz, MeOD-d₄) δ 8.64 (s, 1H), 8.51 (s, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.14 (s, 1H), 6.55 (d, J = 6.0 Hz, 1H), 4.38 (s, 3H), 4.21 (q, J = 6.9 Hz, 2H), 4.10 (t, J = 8.6 Hz, 2H), 3.77 – 3.70 (m, 2H), 3.41 – 3.35 (m, 2H), 3.24 – 3.11 (m, 4H), 2.88 (dd, J = 13.3, 10.4 Hz, 1H), 1.63 (t, J = 6.9 Hz, 3H), 1.34 (d, J = 6.5 Hz, 3H). Example 523 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-((3R)- 3-(1-hydroxyethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

C^{ompound 523} Step 1: Preparation of 4-benzyl 1-(tert-butyl) (R)-2-(methoxy(methyl)carbamoyl)piperazine- 1,4-dicarboxylate. [01535] To a solution of (R)-4-((benzyloxy)carbonyl)-1-(tert- butoxycarbonyl)piperazine-2-carboxylic acid (10.00 g, 27.44 mmol) in DMA (140 mL) were added HATU (12.52 g, 32.93 mmol) and DIEA (7.09 g, 54.89 mmol). The mixture was stirred at r.t for 0.5 h. N,O-dimethylhydroxylamine hydrochloride (3.21 g, 32.93 mmol) was added to the mixture and stirred at rt for 1.5 h. The mixture was diluted with water (100 mL), extracted with EA (200 mLx3). The combined organic layers were washed with brine (100 mLx6) and dried over anhydrous Na₂SO_4, concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE=1:18) to give the title compound (9.7 g, Y: 86.7 %) as a white solid. ESI-MS (M+H)⁺: 408.1. Step 2: Preparation of 4-benzyl 1-(tert-butyl) (R)-2-acetylpiperazine-1,4-dicarboxylate. [01536] To a solution of 4-benzyl 1-(tert-butyl) (R)-2- (methoxy(methyl)carbamoyl)piperazine-1,4-dicarboxylate (9.70 g, 23.81 mmol) in dry THF (54 mL) was added Methylmagnesium Bromide (23.8 mL, 71.42 mmol, 3M) at -20°C. The mixture was stirred at -20°C for 1.5 h. The mixture was quenched with Saturated ammonium chloride solution (60 mL), extracted with EA (150 mLx3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE=1:15) to give the title compound (5.20 g, Y: 60.2%) as a yellow oil. ESI-MS (M+H-56)⁺: 307.0. Step 3: Preparation of 4-benzyl 1-(tert-butyl) (2R)-2-(1-hydroxyethyl)piperazine-1,4- dicarboxylate. [01537] To a mixture of 4-benzyl 1-(tert-butyl) (R)-2-acetylpiperazine-1,4- dicarboxylate (5.20 g, 14.35 mmol) in MeOH (120 mL) was added NaBH₄ (814 mg, 21.52 mmol). The mixture was stirred at r.t for 0.5 h. The mixture was diluted with water (150 mL) and extracted with DCM (200 mL x3). The combined organic layers were washed with brine (200 mL) ,dried over anhydrous Na₂SO₄ and concentrated in vacuo to give title compound (4.50 g, Y: 86.0%) as a yellow oil. ESI-MS (M+H-100)⁺: 265.1. Step 4: Preparation of 4-benzyl 1-(tert-butyl) (2R)-2-(1-((tert- butyldimethylsilyl)oxy)ethyl)piperazine-1,4-dicarboxylate. [01538] To a solution of 4-benzyl 1-(tert-butyl) (2R)-2-(1-hydroxyethyl)piperazine- 1,4-dicarboxylate (4.5 g, 12.35 mmol) in DCM (20 mL) were added TBSCl (5.58 g, 37.04 mmol) and Imidazole (5.04 g, 74.08 mmol), the mixture was stirred at rt for 16 h. The mixture was diluted with water (100 mL) and extracted with DCM (150 mL x3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE=1:20) to give the title compound (4.3 g, Y: 72.7%) as a yellow oil. ESI-MS (M+23)⁺: 501.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.36 – 7.31 (m, 5H), 5.09 (s, 2H), 3.88 – 3.83 (m, 4H), 3.04 – 2.92 (m, 3H), 1.38 (s, 9H), 1.23 (s, 1H), 1.17 – 1.05 (m, 3H), 0.80 (s, 9H), 0.00 (s, 3H), -0.04 (s, 3H). Step 5: Preparation of tert-butyl (2R)-2-(1-((tert-butyldimethylsilyl)oxy)ethyl)piperazine-1- carboxylate. [01539] To a solution of 4-benzyl 1-(tert-butyl) (2R)-2-(1-((tert- butyldimethylsilyl)oxy)ethyl)piperazine-1,4-dicarboxylate (4.3 g, 8.98 mmol) in MeOH (50 mL) was added 10% palladium on carbon (1.2 g, 10% w/w). The mixture was stirred at r.t for 2 h under hydrogen atmosphere. The mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo to give title compound (2.4 g, Y:77.4%) as a yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ 4.24 – 4.19 (m, 1H), 3.70 – 3.62 (m, 2H), 2.83 – 2.71 (m, 3H), 2.51 – 2.47 (m, 1H), 2.41 – 2.34 (s, 1H), 1.32 (s, 9H), 1.06 (d, J = 4.0 Hz, 3H), 0.78 (s, 9H), 0.00 (s, 3H), -0.04 (s, 3H). Step 6: Preparation of tert-butyl (2R)-4-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2-(1-((tert-butyldimethylsilyl)oxy)ethyl)piperazine-1-carboxylate. [01540] A solution of tert-butyl (2R)-2-(1-((tert- butyldimethylsilyl)oxy)ethyl)piperazine-1-carboxylate (172 mg, 0.5 mmol), 1-(4-bromo-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethan-1-one (100 mg, 0.417 mmol), Cs₂CO₃ (407 mg, 1.25 mmol) and RuphosG3 (35 mg, 0.042 mmol ) in 1,4-dioxane (10 mL) was stirred at 100 °C for 16 h. The reaction was concentrated in vacuo and the crude was purified by silica gel column chromatography (EA: PE=5:1) to give the title compound (170 mg, 80.9 %) as a brown solid. ESI-MS (M+H)⁺: 505.2.¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (d, J = 5.8 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.18 – 4.11 (m, 1H), 3.94 – 3.84 (m, 4H), 3.54 (dd, J = 27.5, 12.1 Hz, 2H), 3.16 – 3.07 (m, 1H), 3.06 – 2.96 (m, 3H), 2.86 – 2.78 (m, 1H), 2.51 (s, 3H), 1.40 (s, 9H), 1.16 (d, J = 6.1 Hz, 3H), 0.84 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H). Step 7: Preparation of tert-butyl (2R)-2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01541] To a solution of tert-butyl (2R)-4-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-(1-((tert-butyldimethylsilyl)oxy)ethyl)piperazine-1-carboxylate (340 mg, 0.675 mmol) in MeOH : H₂O (7 mL: 1 mL) was added KOH (113 mg, 2.02 mmol). The mixture was stirred at 50 ^oC for 3 h. The mixture was concentrated in vacuo to give title product (300 mg, crude) as a yellow solid. ESI-MS (M+H)⁺:463.0.¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (d, J = 5.9 Hz, 1H), 6.00 (d, J = 6.0 Hz, 1H), 5.86 (s, 1H), 4.14 – 4.07 (m, 1H), 3.88 – 3.79 (m, 2H), 3.47 (d, J = 13.0 Hz, 1H), 3.39 – 3.29 (m, 3H), 3.02 (t, J = 11.2 Hz, 1H), 2.94 – 2.87 (m, 2H), 2.82 – 2.75 (m, 1H), 2.71 – 2.63 (m, 1H), 1.35 (s, 9H), 1.12 (d, J = 6.1 Hz, 3H), 0.79 (s, 9H), 0.00 (s, 3H), -0.03 (s, 3H). Step 8: Preparation of tert-butyl (2R)-2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(1-((7- fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate. [01542] To a solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (21 mg, 0.13 mmol), triphosgene (39 mg, 0.13 mmol) and TEA (131 mg, 1.3 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (2R)-2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4- (2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.108 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was triturated with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo. The solid was purified by TLC (DCM: MeOH =10:1) to afford title product (30 mg, 42 %) as a white solid. ESI-MS (M+H) ⁺: 654.5.¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (d, J = 2.1 Hz, 1H), 9.19 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.42 (d, J = 11.6 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.16 – 4.09 (m, 1H), 4.03 – 3.99 (m, 1H), 3.95 – 3.90 (m, 2H), 3.71 – 3.59 (m, 2H), 3.20 – 3.11 (m, 4H), 3.01 – 2.91 (m, 2H), 2.29 (s, 3H), 1.41 (s, 9H), 1.16 (d, J = 6.1 Hz, 3H), 0.85 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H). Step 9: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-((3R)-3-(1- hydroxyethyl)piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01543] A solution of tert-butyl (2R)-2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(1- ((7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.092 mmol) and TFA(2 mL) in DCM (4 mL) was stirred at RT for 16 h. The reaction mixture was concentrated and the solid was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (14 mg, 27.5 %) as a white soild. ESI-MS (M+H) ⁺: 440.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.63 (d, J = 6.5 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J = 9.7 Hz, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.20 – 4.13 (m, 2H), 3.91 – 3.81 (m, 3H), 3.49 – 3.44 (m, 1H), 3.29 – 3.20 (m, 5H), 3.16 – 3.09 (m, 1H), 2.53 – 2.50 (m, 3H), 1.34 (d, J = 6.3 Hz, 3H). Example 524 – Preparation of (R)-N-(2,7-dimethyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((2,7-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate. [01544] To a solution of 2,7-dimethyl-2H-indazol-5-amine (49 mg, 0.30 mmol) and TEA (305 mg, 3.02 mmol) in THF (10 mL) was added triphosgene (89 mg, 0.30 mmol) at 0^oC, after 10 min, tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (80 mg, 0.25 mmol) was added at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and triturated with MeOH (5 mL) to give the compound (100 mg, 79 %) as a white solid. ESI-MS (M+H) ⁺:506.7.¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.18 (s, 1H), 7.95 (d, J = 6.1 Hz, 1H), 7.84 (d, J = 1.4 Hz, 1H), 6.97 (s, 1H), 6.51 (d, J = 6.2 Hz, 1H), 4.13 (d, J = 2.1 Hz, 2H), 3.98 (t, J = 8.6 Hz, 2H), 3.78 (d, J = 13.3 Hz, 1H), 3.63 (d, J = 12.7 Hz, 1H), 3.57 (d, J = 12.7 Hz, 1H), 3.17 – 3.11 (m, 2H), 3.05 (dd, J = 12.9, 3.7 Hz, 1H), 2.92 (td, J = 11.9, 3.5 Hz, 1H), 2.48 (s, 3H), 1.42 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (R)-N-(2,7-dimethyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01545] To a mixture of tert-butyl (R)-4-(1-((2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.16 mmol) in EA (2 mL) was added 4M HCl/EA (6 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.05% FA in H₂O / ACN) to give title product (68 mg, 94 %) as a white solid. ESI-MS (M+H) ⁺:406.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.68 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.84 (s, 1H), 6.97 (s, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 3.97 (t, J = 8.6 Hz, 2H), 3.62 (d, J = 11.8 Hz, 2H), 3.11 (t, J = 8.6 Hz, 2H), 3.02 (d, J = 11.2 Hz, 1H), 2.91 (t, J = 10.6 Hz, 2H), 2.86 – 2.79 (m, 1H), 2.64 – 2.55 (m, 1H), 2.48 (s, 3H), 1.07 (d, J = 6.3 Hz, 3H). Example 525 – Preparation of (S)-N-(5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of tert-butyl (S)-4-(1-((5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate. [01546] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 5-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-amine (82 mg, 0.38 mmol), TEA (476 mg, 4.72 mmol) in THF (10 mL) was added triphosgene (112 mg, 0.38 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL), the precipitate was filtered and triturated with MeOH (5 mL), to get title product (50 mg, Y: 30.8 %) as a yellow solid. ESI- MS (M+H) ⁺:524.3. Step 2: Preparation of (S)-N-(5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01547] To a solution of tert-butyl (S)-4-(1-((5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (8.72 mg, 24.3 %) as a white solid. ESI-MS (M+H)⁺:424.3.¹H NMR (400 MHz, MeOD-d₄) δ 9.30 (s, 1H), 8.47 (s, 1H), 7.76 (d, J = 5.6 Hz, 1H), 6.41 (d, J = 5.7 Hz, 1H), 4.18 (s, 3H), 3.98 (t, J = 8.2 Hz, 2H), 3.75 (d, J = 12.2 Hz, 2H), 3.49 – 3.41 (m, 2H), 3.27 – 3.15 (m, 2H), 3.07 (t, J = 8.2 Hz, 2H), 2.99 – 2.92 (m, 1H), 2.39 (s, 3H), 1.39 (d, J = 5.6 Hz, 3H). Example 526 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(8-methoxy-2- methylimidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01548] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (80 mg, 0.24 mmol), 8-methoxy-2-methylimidazo[1,2- a]pyrazin-6-amine hydrochloride (61 mg, 0.28 mmol) and TEA (291 mg, 2.89 mmol) in THF (8 mL) was added triphosgene (83 mg, 0.28 mmol), the mixture was stirred at 0 ^oC for 15 min and stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered to afford title product (50 mg, 37.5 %) as a yellow solid. ESI-MS (M+H) ⁺: 537.3. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(8-methoxy-2-methylimidazo[1,2- a]pyrazin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01549] A mixture of tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (40 mg, 0.07 mmol) in 4M HCl / EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered to give title product (27.56 mg, yield: 81.68 %) as a white solid. ESI- MS (M+H) ⁺: 437.2.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.89 (s, 1H), 8.19 (s, 1H), 8.00 (d, J = 6.1 Hz, 1H), 6.68 (d, J = 6.1 Hz, 1H), 4.18 (s, 3H), 4.06 (t, J = 8.6 Hz, 2H), 3.52 (s, 2H), 3.34 (s, 2H), 3.30 – 3.25 (m, 2H), 3.24 – 3.17 (m, 2H), 2.46 (s, 3H), 1.39 (s, 6H). Example 527 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methoxy-2-methyl- 2H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 4-(1-((7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01550] To a solution of 7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridine-5- carboxylic acid (81.02 mg, 0.39 mmol) and TEA (118.7 mg, 1.17 mmol) in tol (10 mL) was added DPPA (161 mg, 0.58 mmol) at r.t, after 1 h, the mixture was warmed to 90 ^oC and stirred for 30 min, then tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (130 mg, 0.39 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE/EA=3:7) to give title product (50 mg, Y: 23.83 %) as a white solid. ESI-MS (M+H) ⁺:537.2. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-methoxy-2-methyl-2H- pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01551] To a mixture of tert-butyl 4-(1-((7-methoxy-2-methyl-2H-pyrazolo[3,4- c]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (45 mg, 0.08 mmol) in EA (1 mL) was added HCl/EA (2.5 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (8 mg, Y: 21.86 %) as a white solid. ESI-MS (M+H) ⁺:437.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.69 (s, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.13 (s, 3H), 4.03 (s, 3H), 4.01 – 3.96 (m, 2H), 3.25 – 3.22 (m, 2H), 3.13 – 3.09 (m, 2H), 3.08 – 3.05 (m, 2H), 2.98 – 2.93 (m, 2H), 1.17 (s, 6H). Example 528 – Preparation of N-(7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)- 4-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01552] To a solution of 7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridine-5- carboxylic acid (62.70 mg, 0.30 mmol) and TEA (91.8 mg, 0.91 mmol) in tol (10 mL) was added DPPA (124,9 mg, 0.45 mmol) at r.t, after 1 h, the mixture was warmed to 90 ^oC and stirred for 30 min, then tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE/EA=3:7) to give title product (30 mg, Y: 18.54 %) as a white solid. ESI-MS (M+H) ⁺:535.4. Step 2: Preparation of tert-butyl 7-(1-((7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate 2,2,2-trifluoroacetate. [01553] To a mixture of tert-butyl 7-(1-((7-methoxy-2-methyl-2H-pyrazolo[3,4- c]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (25 mg, 0.05 mmol) in EA (1 mL) was added HCl/EA (2 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (12 mg, Y: 59.06 %) as a white solid. ESI-MS (M+H) ⁺:435.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.73 (s, 1H), 9.24 (s, 2H), 8.24 (s, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.69 (s, 1H), 6.60 (d, J = 6.1 Hz, 1H), 4.14 (s, 3H), 4.05 – 3.99 (m, 5H), 3.44 – 3.31 (m, 6H), 3.14 – 3.08 (m, 2H), 1.05 (t, J = 6.2 Hz, 2H), 0.95 (t, J = 6.3 Hz, 2H). Example 529 – Preparation of (S)-N-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4- (3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01554] A mixture of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (166 mg, 0.76 mmol) in Tol (5 mL) were added TEA (191 mg, 1.88 mmol) and DPPA (208 mg, 0.76 mmol). The mixture was stirred at 30 ℃ for 30 min and 60 ℃ for 30 min. Tert- butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.63 mmol) was added to the mixture and stirred at 90 ℃ for 16 h. The mixture was concentrated in vacuo and purified by TLC (PE / EA=1:4) to afford the title product (88 mg, 26.4 %) as a purple solid. ESI-MS (M+H) ⁺: 536.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 8.26 (d, J = 9.4 Hz, 2H), 7.87 (d, J = 6.0 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 6.15 (s, 1H), 4.12 (q, J = 6.9 Hz, 2H), 4.00 (t, J = 7.0 Hz, 2H), 3.79 (d, J = 14.0 Hz, 1H), 3.66 – 3.55 (m, 2H), 3.30 – 3.28 (m, 2H), 3.22 – 3.04 (m, 4H), 2.30 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H), 1.42 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01555] A solution of tert-butyl (S)-4-(1-((6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (88 mg, 0.16 mmol) in 4 M HCl / EA (5 mL) was stirred at r.t for 2 h. The reaction mixture was concentrated in vacuo and purified by Prep-HPLC (0.1 % FA in H₂O / CH₃CN) to afford the title product (19 mg, 26.4%) as a purple solid. ESI-MS (M+H) ⁺: 436.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (s, 1H), 8.25 (d, J = 7.5 Hz, 3H), 7.83 – 7.81 (m, 1H), 6.54 (d, J = 6.1 Hz, 1H), 6.15 (s, 1H), 4.11 (t, J = 6.9 Hz, 2H), 3.99 (t, J = 8.4 Hz, 2H), 3.57 – 3.55 (m, 2H), 3.12 (t, J = 8.7 Hz, 2H), 2.97 (d, J = 11.4 Hz, 1H), 2.89 – 2.74 (m, 4H), 2.30 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H), 1.04 (d, J = 6.3 Hz, 3H). Example 530 – Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4- (6-oxa-2,9-diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1- carboxamide.

C_{ompound 530} Step 1: Preparation of tert-butyl (R)-2-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane- 9-carboxylate. [01556] The tert-butyl 2-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-oxa-2,9-diazaspiro[4.5] decane- 9-carboxylate (200 mg) was purified by Chiral-SFC to afford tert-butyl (R)-2-(1-((8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6- oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (50 mg, the first fraction) as a yellow solid and tert-butyl (S)-2-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (50 mg, the second fraction). [01557] Note: The absolute configuration was not determined. The depicted stereoisomers were assigned at random. Step 2: Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9- diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide. [01558] To a mixture of tert-butyl (R)-2-(1-((8-fluoro-2-methylimidazo[1,2-a] pyridin- 6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (30 mg, 0.054 mmol) in DCM (1 mL) was added HCl/dioxane (1 mL, 6 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by C18 column chromatography eluted with (0.05% NH₄HCO₃ in water / ACN) to afford (S)-N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9-diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide (20 mg, yield: 80%) as a yellow solid. ESI-MS (M+1) ⁺: 452.2.¹H NMR (400 MHz, CD₃OD) δ 8.69 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 6.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 12.0, 1.6 Hz, 1H), 6.17 (d, J = 6.2 Hz, 1H), 3.99 (dt, J = 10.1, 7.1 Hz, 2H), 3.75 – 3.61 (m, 5H), 3.54 (d, J = 10.7 Hz, 1H), 3.43 – 3.34 (m, 2H), 2.95 – 2.77 (m, 4H), 2.39 (s, 3H), 2.27 – 2.20 (m, 1H), 1.93 (dt, J = 13.2, 8.8 Hz, 1H). Example 531 – Preparation of (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(6- oxa-2,9-diazaspiro[4.5]decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide.

Step 1: Preparation of (R)-N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9- diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide. [01559] To a mixture of tert-butyl (S)-2-(1-((8-fluoro-2-methylimidazo[1,2-a] pyridin- 6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (30 mg, 0.054 mmol) in DCM (1 mL) was added HCl/dioxane (1 mL, 6 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by C18 column chromatography eluted with (0.05% NH₄HCO₃ in water / ACN) to afford (R)-N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9-diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide (20 mg, 80%) as a yellow solid. ESI-MS (M+1) ⁺: 452.3.¹H NMR (400 MHz, CD₃OD) δ 8.68 (d, J = 1.5 Hz, 1H), 7.76 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 12.0, 1.5 Hz, 1H), 6.14 (d, J = 6.2 Hz, 1H), 3.97 (dt, J = 10.2, 7.1 Hz, 2H), 3.76 – 3.67 (m, 3H), 3.64 – 3.57 (m, 2H), 3.51 (d, J = 10.7 Hz, 1H), 3.41 – 3.33 (m, 2H), 2.85 (dt, J = 10.3, 8.6 Hz, 4H), 2.38 (s, 3H), 2.27 – 2.19 (m, 1H), 1.96 – 1.88 (m, 1H). Note: The absolute configuration was not determined. The depicted stereoisomers were assigned at random. Example 532 – Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(7-ethoxy-2- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide.

C^{ompound 532} Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [01560] To a mixture of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (150 mg, 0.45 mmol), 7-ethoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine (86.40 mg, 0.45 mmol) and TEA (136.35 mg, 1.35 mmol) in THF (5 mL) was added triphosgene (266.40 mg, 0.90 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/1 to 1/100) to afford title product (40 mg, 16.16%) as a yellow solid. ESI-MS (M+H) ⁺: 551.3. Step 2: Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(7-ethoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01561] A mixture of tert-butyl (2S,6R)-4-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (40 mg, 0.07 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% NH₃.H₂O in water / CH₃CN) to give title product (3.39 mg, 10.76%) as a yellow solid. ESI-MS (M+H) ⁺:451.4.¹H NMR (400 MHz, MeOD-d₄) δ 9.35 (s, 1H), 7.77 (d, J = 6.0 Hz, 1H), 6.86 (s, 1H), 6.43 (d, J = 6.0 Hz, 1H), 4.25 – 4.17 (m, 2H), 4.04 – 3.95 (m, 2H), 3.69 – 3.61 (m, 2H), 3.11 – 3.03 (m, 4H), 2.58 – 2.50 (m, 2H), 2.40 (s, 3H), 1.61 (t, J = 6.9 Hz, 3H), 1.20 (d, J = 6.4 Hz, 6H). Example 533 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-ethoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01562] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol), 7-ethoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine (83 mg, 0.36 mmol), TEA (456 mg, 4.52 mmol) in THF (20 mL) was added triphosgene (107 mg, 0.36 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (30 mL), the precipitate was filtered and triturated with MeOH (5 mL) to get title product (30 mg, Y: 18.1 %) as a yellow solid. ESI- MS (M+H) ⁺:551.4. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-ethoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01563] To a solution of tert-butyl 4-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (30 mg, 0.05 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (1.58 mg, 5.1 %) as a white solid. ESI-MS (M+H)⁺:451.2.¹H NMR (400 MHz, MeOD-d₄) δ 9.55 (s, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.16 (s, 1H), 6.61 (d, J = 6.0 Hz, 1H), 4.35 (q, J = 6.9 Hz, 2H), 4.13 (t, J = 8.5 Hz, 2H), 3.53 – 3.50 (m, 2H), 3.45 – 3.42 (m, 2H), 3.34 – 3.33 (m, 2H), 3.21 (t, J = 8.5 Hz, 2H), 2.52 (s, 3H), 1.67 (t, J = 6.9 Hz, 3H), 1.51 (s, 6H). Example 534 – Preparation of (R)-N-(2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

C^{ompound 534} Step 1: Preparation of 1,2-diamino-5-bromopyrazin-1-ium. [01564] To a mixture of 5-bromopyrazin-2-amine (9.5 g, 54.60 mmol) in DCM (5 mL) was added O-(mesitylsulfonyl)hydroxylamine (14.1 g, 65.52 mmol). The mixture was stirred at r.t for 16 h under Nitrogen atmosphere. The precipitate was filtered and concentrated in vacuo to give the title compound (12 g, Y: 56.5 %) as a brown solid. ESI-MS (M+H) ⁺:191.0. Step 2: Preparation of 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyrazine. [01565] To a solution of 1,2-diamino-5-bromopyrazin-1-ium (12 g, 30.85 mmol) in Ac₂O (108 mL) was added con. HCl (12 mL) at 0^oC. The reaction mixture was stirred at 100^oC for 16 h. The mixture was concentrated in vacuo and the residue was adjust pH to 9 and the precipitate was filtered and concentrated in vacuo to give the title compound (4.0 g, Y: 60.9 %) as a grey solid. ESI-MS (M+H) ⁺:213.1. Step 3: Preparation of methyl 2-methyl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylate. [01566] To a mixture of 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyrazine (500 mg, 2.35 mmol) in MeOH (5 mL) were added TEA (5 mL) was added Pd(dppf)Cl₂ (172 mg, 0.23 mmol). The mixture was stirred at 80^oC for 16 h under CO atmosphere. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (PE: EA= 1:2) to get title product (300 mg, 66.5%) as a brown solid. ESI-MS (M+H)⁺: 193.1. Step 4: Preparation of 2-methyl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid. [01567] To a solution of methyl 2-methyl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylate (300 mg, 1.56 mmol) in THF: MeOH: H₂O (v: v: v= 5: 1: 1, 7 mL) was added LiOH (188 mg, 7.81 mmol). The reaction mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo, the residue was adjust pH to 5, the precipitate was filtered and concentrated in vacuo to give the title compound (100 mg, Y: 36.0 %) as a white solid. ESI- MS (M+H) ⁺:179.2. Step 5: Preparation of tert-butyl (R)-2-methyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5-a]pyrazin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01568] To a mixture of 2-methyl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid (84 mg, 0.47 mmol) in toluene (10 mL) were added TEA (127 mg, 1.26 mmol), DPPA (242 mg, 0.88 mmol). The mixture was stirred at r.t for 1 h and warmed up to 90^oC and stirred for 1 h. Tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (100 mg, 0.31 mmol) was added to the mixture and stirred at 110^oC for 16 h. The mixture was diluted with water (20 mL) and the precipitate was filtered and concentrated in vacuo to give the title compound (30 mg, Y: 19.6 %) as a brown solid. ESI-MS (M+H) ⁺:494.3. Step 6: Preparation of (R)-N-(2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01569] To a solution of tert-butyl (R)-2-methyl-4-(1-((2-methyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% NH₃.H₂O in water / ACN) to give title compound (1.31 mg, 5.5 %) as a white solid. ESI-MS (M+H)⁺:394.3.¹H NMR (400 MHz, MeOD-d₄) δ 9.35 (d, J = 1.4 Hz, 1H), 8.93 (d, J = 1.3 Hz, 1H), 7.94 (d, J = 6.0 Hz, 1H), 6.53 (d, J = 6.1 Hz, 1H), 4.12 – 4.07 (m, 2H), 3.64 – 3.60 (m, 2H), 3.33 – 3.31 (m, 2H), 3.17 (t, J = 8.5 Hz, 2H), 3.07 – 3.03 (m, 1H), 2.92 – 2.90 (m, 2H), 2.58 (s, 3H), 1.14 (d, J = 6.4 Hz, 3H). Example 535 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(5-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 4-(1-((5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01570] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol), 5-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-amine (78 mg, 0.36 mmol), TEA (456 mg, 4.52 mmol) in THF (10 mL) was added triphosgene (107 mg, 0.36 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL), the precipitate was filtered and triturated with MeOH (5 mL) to get title product (50 mg, Y: 31.0 %) as a yellow solid. ESI- MS (M+H) ⁺:538.4. Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(5-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01571] To a solution of tert-butyl 4-(1-((5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (40 mg, 0.07 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (22.4 mg, 54.6 %) as a yellow solid. ESI-MS (M+H)⁺:438.3. ¹H NMR (400 MHz, MeOD-d₄) δ 9.56 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 6.63 (d, J = 6.0 Hz, 1H), 4.28 (s, 3H), 4.16 – 4.11 (m, 2H), 3.55 – 3.52 (m, 2H), 3.45 – 3.42 (m, 2H), 3.36 – 3.34 (m, 2H), 3.22 (t, J = 8.5 Hz, 2H), 2.50 (s, 3H), 1.51 (s, 6H). Example 536 – Preparation of (S)-N-(7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

C^{ompound 536} Step 1: Preparation of tert-butyl (S)-4-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01572] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol), 7-ethoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-amine (60.38 mg, 0.31 mmol) and TEA (93.93 mg, 0.93 mmol) in THF (5 mL) was added triphosgene (183.52 mg, 0.62 mmol) at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/1 to 1/100) to afford title product (50 mg, 30.09%) as a white solid. ESI-MS (M+H) ⁺: 537.3. Step 2: Preparation of (S)-N-(7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01573] A mixture of tert-butyl (S)-4-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (50 mg, 0.09 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (1.58 mg, 3.64%) as a white solid. ESI-MS (M+H) ⁺:437.3.¹H NMR (400 MHz, MeOD-d₄) δ 9.25 (s, 1H), 8.54 (s, 1H), 7.70 (d, J = 6.0 Hz, 1H), 6.76 (s, 1H), 6.40 (d, J = 6.0 Hz, 1H), 4.20 – 4.11 (m, 2H), 4.00 – 3.91 (m, 2H), 3.74 – 3.63 (m, 2H), 3.38 – 3.32 (m, 2H), 3.20 – 3.07 (m, 2H), 3.06 – 3.00 (m, 2H), 2.88 – 2.79 (m, 1H), 2.37 (s, 3H), 1.57 (t, J = 6.9 Hz, 3H), 1.34 (d, J = 6.5 Hz, 3H). Example 537 – Preparation of N-(5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl)-4-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of tert-butyl 7-(1-((5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [01574] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol), 5-methoxy-2-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-amine (79 mg, 0.36 mmol), TEA (456 mg, 4.52 mmol) in THF (10 mL) was added triphosgene (107 mg, 0.36 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL), the precipitate was filtered and triturated with MeOH (5 mL) to get title product (50 mg, Y: 31.1 %) as a yellow solid. ESI- MS (M+H) ⁺:536.3. Step 2: Preparation of N-(5-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate. [01575] To a solution of tert-butyl 7-(1-((5-methoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (40 mg, 0.07 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The reaction mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (11.39 mg, 27.8 %) as a white solid. ESI-MS (M+H)⁺:436.3.¹H NMR (400 MHz, MeOD-d₄) δ 9.53 (s, 1H), 7.98 (d, J = 6.0 Hz, 1H), 6.58 (d, J = 6.1 Hz, 1H), 4.26 (s, 3H), 4.13 – 4.09 (m, 2H), 3.64 – 3.61 (m, 2H), 3.53 – 3.50 (m, 2H), 3.46 – 3.44 (m, 2H), 3.19 – 3.14 (m, 2H), 2.48 (s, 3H), 1.15 – 1.13 (m, 2H), 1.11 – 1.09 (m, 2H). Example 538 – Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-fluoro-2,7- dimethyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Boc ^{Compound 538} Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01576] To a solution of 6-fluoro-2,7-dimethyl-2H-indazol-5-amine hydrochloride (65 mg, 0.36 mmol) and TEA (365 mg, 3.61 mmol) in THF (12 mL) was added triphosgene (107 mg, 0.36 mmol) at 0^oC, after 10 min, tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) was added at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (100 mg, 61.83 %) as a white solid. ESI-MS (M+H) ⁺:538.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (d, J = 2.9 Hz, 1H), 8.31 – 8.23 (m, 2H), 7.94 (d, J = 6.1 Hz, 1H), 6.56 (d, J = 6.0 Hz, 1H), 4.14 – 4.09 (m, 5H), 4.06 – 3.99 (m, 2H), 3.61 – 3.56 (m, 2H), 3.22 – 3.16 (m, 2H), 3.02 – 2.95 (m, 2H), 2.43 (s, 3H), 1.43 (s, 9H), 1.26 (d, J = 6.8 Hz, 6H). Step 2: Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-fluoro-2,7-dimethyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01577] To a mixture of tert-butyl (2S,6R)-4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (90 mg, 0.17 mmol) in EA (2 mL) was added HCl/EA (5 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (40 mg, Y: 61.44 %) as a white solid. ESI-MS (M+H) ⁺:438.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (d, J = 3.0 Hz, 1H), 8.27 (d, J = 7.5 Hz, 2H), 8.22 (s, 1H), 7.87 (d, J = 6.1 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.12 (s, 3H), 4.02 – 3.96 (m, 2H), 3.66 – 3.61 (m, 3H), 3.18 – 3.10 (m, 3H), 2.92 – 2.85 (m, 2H), 2.43 (d, J = 1.8 Hz, 3H), 1.04 (d, J = 6.3 Hz, 6H). Example 539 – Preparation of (S)-N-(6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (S)-4-(1-((6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01578] To a mixture of 6-methoxy-2-methylpyrazolo[1,5-b]pyridazine-5-carboxylic acid (130 mg, 0.629 mmol) in toluene (5 mL) were added DPPA (259 mg, 0.943 mmol) and TEA (191 mg, 1.887 mmol) at 0 ^oC. The mixture was stirred at 30 ^oC for 1 h. Then tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.629 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was triturated with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo. The residue was triturated with MeOH (5 mL*2) to afford title product (50 mg, 15.3 %) as a white solid. ESI-MS (M+H) ⁺: 523.4.¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 8.52 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 6.30 (s, 1H), 4.21 – 4.15 (m, 1H), 4.09 (s, 3H), 4.00 (t, J = 8.6 Hz, 2H), 3.78 (d, J = 13.2 Hz, 1H), 3.69 – 3.54 (m, 2H), 3.21 – 3.12 (m, 3H), 3.11 – 3.04 (m, 1H), 3.00 – 2.88 (m, 1H), 2.31 (s, 3H), 1.18 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-N-(6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01579] A mixture of tert-butyl (S)-4-(1-((6-methoxy-2-methylpyrazolo[1,5- b]pyridazin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (50 mg, 0.096 mmol) in 4 M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and lyophilized to give title product (29 mg, 66.1 %) as a white solid. ESI-MS (M+H) ⁺: 423.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (s, 1H), 9.43 – 8.99 (m, 2H), 8.52 (s, 1H), 8.02 (d, J = 6.1 Hz, 1H), 6.65 (d, J = 6.1 Hz, 1H), 6.31 (s, 1H), 4.10 (s, 3H), 4.02 (t, J = 8.7 Hz, 2H), 3.81 – 3.79 (m, 2H), 3.34 (d, J = 11.7 Hz, 2H), 3.25 (s, 1H), 3.20 – 3.14 (m, 2H), 3.13 – 2.99 (m, 2H), 2.32 (s, 3H), 1.29 (d, J = 6.2 Hz, 3H). [01580] Example 540 – Preparation of (R)-N-(7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01581] To a solution of 7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (72 mg, 0.38 mmol) and TEA (381 mg, 3.77 mmol) in THF (10 mL) was added triphosgene (113 mg, 0.38 mmol) at 0^oC, after 10 min, tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) was added at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and triturated with MeOH (5 mL) to give the compound (50 mg, 30 %) as a yellow solid. ESI-MS (M+H) ⁺:537.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 9.37 (s, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.16 (s, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.26 (q, J = 7.0 Hz, 2H), 4.20 – 4.15 (m, 1H), 4.04 – 3.98 (m, 2H), 3.79 (d, J = 13.1 Hz, 1H), 3.65 – 3.56 (m, 2H), 3.20 – 3.05 (m, 4H), 2.98 – 2.88 (m, 1H), 2.38 (s, 3H), 1.54 (t, J = 6.9 Hz, 3H), 1.42 (s, 9H), 1.18 (d, J = 7.1 Hz, 3H). Step 2: Preparation of (R)-N-(7-ethoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01582] To a mixture of tert-butyl (R)-4-(1-((7-ethoxy-2-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate (40 mg, 0.07 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.05% FA in H₂O / ACN) to give title product (9.95 mg, 29 %) as a white solid. ESI-MS (M+H) ⁺:437.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (s, 1H), 9.38 (s, 1H), 8.28 (s, 1H), 7.84 (d, J = 6.1 Hz, 1H), 7.16 (s, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.26 (q, J = 7.0 Hz, 2H), 4.00 (t, J = 8.6 Hz, 2H), 3.58 (d, J = 11.7 Hz, 4H), 3.14 (s, 2H), 2.94 (d, J = 11.4 Hz, 1H), 2.79 (d, J = 7.0 Hz, 2H), 2.38 (s, 3H), 1.54 (t, J = 6.9 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H). Example 541 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy-2- methyl-3,3a-dihydro-2H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine-1-carboxamide diformate.

Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((7-methoxy-2-methyl-3,3a-dihydro-2H- pyrazolo[3,4-c]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [01583] To a mixture of 7-methoxy-2-methyl-3,3a-dihydro-2H-pyrazolo[3,4- c]pyridine-5-carboxylic acid (40 mg, 0.22 mmol), TEA (67 mg, 0.66 mmol) and DPPA (90.7 mg, 0.33 mmol) in Tol (3 mL) was stirred at RT for 1 h, heated to 90 ^oC stirred for 0.5h, tert- butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (73 mg, 0.22 mmol) was added to the mixture and stirred at 90^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 8) to give title product (50 mg, Y: 42.7%) as a yellow solid. ESI-MS (M+H) ⁺: 537.3. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-methoxy-2-methyl-3,3a- dihydro-2H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide diformate. [01584] A mixture of tert-butyl (2R,6S)-4-(1-((7-methoxy-2-methyl-3,3a-dihydro-2H- pyrazolo[3,4-c]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (40 mg, 0.07 mmol) in 4M HCl/EA (2 mL) was stirred at RT for 1 h. The mixture concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH₃CN) to give title product (5 mg, Y: 15.6 %) as a white solid. ESI-MS (M+H) ⁺: 437.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.52 (s, 2H), 8.11 (s, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.65 (s, 1H), 6.59 (d, J = 6.1 Hz, 1H), 4.21 (s, 3H), 4.13 (s, 3H), 4.09 (d, J = 8.7 Hz, 2H), 3.78 (d, J = 13.5 Hz, 2H), 3.42 – 3.35 (m, 2H), 3.14 (t, J = 8.4 Hz, 2H), 2.83 (t, J = 12.0 Hz, 2H), 1.35 (d, J = 6.5 Hz, 6H). Example 542 – Preparation of (R)-N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (R)-4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01585] To a solution of 6-fluoro-2,7-dimethyl-2H-indazol-5-amine HCl salt (81 mg, 0.38 mmol) and TEA (457 mg, 4.52 mmol) in THF (12 mL) was added triphosgene (134 mg, 0.45 mmol) at 0^oC, after 10 min, tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.37 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (130 mg, 79.06 %) as a white solid. ESI-MS (M+H) ⁺:524.3. Step 2: Preparation of (R)-N-(6-fluoro-2,7-dimethyl-2H-indazol-5-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01586] To a mixture of tert-butyl (R)-4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.23 mmol) in EA (3 mL) was added HCl/EA (6 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (80 mg, Y: 82.43 %) as a white solid. ESI-MS (M+H) ⁺:424.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 9.07 (s, 1H), 8.75 (s, 1H), 8.26 (d, J = 12.3 Hz, 2H), 7.95 (d, J = 6.1 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 4.13 (s, 3H), 4.05 – 4.02 (m, 2H), 3.83 – 3.78 (m, 2H), 3.41 – 3.34 (m, 2H), 3.23 – 3.12 (m, 4H), 3.03 – 2.95 (m, 1H), 2.43 (d, J = 1.6 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 543 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-fluoro-2,7-dimethyl- 2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate. [01587] To a solution of 6-fluoro-2,7-dimethyl-2H-indazol-5-amine hydrochloride (80 mg, 0.45 mmol) in THF (20 mL) were added TEA (600 mg, 6.00 mmol) and triphosgene (110 mg, 0.37 mmol) at 0^oC, after 5 min, tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2,2-dimethylpiperazine-1-carboxylate (100 mg, 0.30 mmol) was added slowly at 0 ^oC to the mixture and stirred at r.t for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mLx3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA in H₂O/ ACN) to give title product (80 mg, 49 %) as a white solid. ESI-MS (M+H) ⁺: 538.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.24 – 12.01 (m, 1H), 8.27 (d, J = 8.9 Hz, 2H), 7.83 (d, J = 6.1 Hz, 1H), 6.40 (d, J = 6.3 Hz, 1H), 4.12 (s, 3H), 4.01 – 3.93 (m, 2H), 3.73 – 3.67 (m, 2H), 3.59 – 3.51 (m, 4H), 3.31 – 3.27 (m, 2H), 2.43 (d, J = 1.7 Hz, 3H), 1.43 (s, 9H), 1.38 (s, 6H). Step 2: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(6-fluoro-2,7-dimethyl-2H-indazol- 5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01588] To a mixture of tert-butyl 4-(1-((6-fluoro-2,7-dimethyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (80 mg, 0.15 mmol) in EA (5 mL) was added 4M HCl/EA (5 mL). The mixture was stirred at r.t for 2 h. Concentration under reduced pressure to give title product (42.51 mg, 59%) as a white solid. ESI-MS (M+H) ⁺:438.2.¹H NMR (400 MHz, MeOD-d₄) δ 8.42 (s, 1H), 7.81 (dd, J = 12.5, 7.2 Hz, 2H), 6.94 (d, J = 7.4 Hz, 1H), 4.44 – 4.37 (m, 2H), 4.27 (s, 3H), 4.00 – 3.92 (m, 2H), 3.80 – 3.74 (m, 2H), 3.60 – 3.53 (m, 2H), 3.50 – 3.46 (m, 2H), 2.50 (d, J = 2.0 Hz, 3H), 1.50 (s, 6H). Example 544 – Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-b]pyridazin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((6-methoxy-2-methylpyrazolo[1,5- b]pyridazin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate. [01589] To a mixture of 6-methoxy-2-methylpyrazolo[1,5-b]pyridazine-5-carboxylic acid (125 mg, 0.602 mmol) in toluene (5 mL) were added DPPA (248 mg, 0.904 mmol) and TEA (183 mg, 1.807 mmol) at 0 ^oC. The mixture was stirred at 30 ^oC for 1 h. Then tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (200 mg, 0.602 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was diluted with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo. The solid was triturated with MeOH (5 mL*2) to afford title product (70 mg, 21.7 %) as a white solid. ESI-MS (M+H) ⁺: 537.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.44 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 6.60 (d, J = 6.0 Hz, 1H), 6.31 (s, 1H), 4.10 (s, 3H), 4.08 – 4.04 (m, 2H), 4.04 – 3.99 (m, 2H), 3.25 – 3.24 (m, 2H), 3.20 – 3.17 (m, 2H), 3.03 – 2.99 (m, 2H), 2.32 (s, 3H), 1.43 (s, 9H), 1.26 (d, J = 6.8 Hz, 6H). Step 2: Preparation of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-b]pyridazin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01590] A mixture of tert-butyl (2S,6R)-4-(1-((6-methoxy-2-methylpyrazolo[1,5- b]pyridazin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (40 mg, 0.075 mmol) in 4 M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and lyophilized to give title product (30 mg, 85.2 %) as a white solid. ESI-MS (M+H) ⁺: 437.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (s, 1H), 9.73 (s, 1H), 9.26 (s, 1H), 8.51 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 6.67 (d, J = 6.1 Hz, 1H), 6.31 (s, 1H), 4.10 (s, 3H), 4.02 (t, J = 8.4 Hz, 2H), 3.85 (d, J = 13.3 Hz, 2H), 3.32 (s, 2H), 3.19 (t, J = 8.4 Hz, 2H), 3.02 (t, J = 12.2 Hz, 2H), 2.32 (s, 3H), 1.31 (d, J = 6.4 Hz, 6H). Example 545 – Preparation of N-(6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5-yl)-4- (4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 7-(1-((6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. [01591] To a mixture of 6-methoxy-2-methylpyrazolo[1,5-b]pyridazine-5-carboxylic acid (125 mg, 0.606 mmol) in toluene (5 mL) were added DPPA (250 mg, 0.909 mmol) and TEA (184 mg, 1.818 mmol) at 0 ^oC. The mixture was stirred at 30 ^oC for 1 h. Then tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.606 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was diluted with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo. The residue was triturated with MeOH (5 mL*2) to afford title product (40 mg, 12.4 %) as a white solid. ESI-MS (M+H) ⁺: 534.9.¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 8.51 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 6.30 (s, 1H), 4.09 (s, 3H), 3.97 – 3.93 (m, 2H), 3.59 – 3.49 (m, 4H), 3.17 (d, J = 5.2 Hz, 2H), 3.13 – 3.12 (m, 2H), 2.32 (s, 3H), 1.42 (s, 9H), 0.97 – 0.89 (m, 4H). Step 2: Preparation of N-(6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01592] A mixture of tert-butyl 7-(1-((6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (50 mg, 0.094 mmol) in 4 M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (11.7 mg, 32.5 %) as a yellow solid. ESI-MS (M+H) ⁺: 435.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.44 (s, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 6.53 (d, J = 6.1 Hz, 1H), 6.29 (s, 1H), 4.09 (s, 3H), 3.99 – 3.95 (m, 2H), 3.37 (s, 2H), 3.22 (s, 2H), 3.11 – 3.06 (m, 2H), 3.03 (s, 2H), 2.31 (s, 3H), 0.69 (d, J = 14.4 Hz, 4H).

Example 546 – Preparation of (R)-N-(6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5- yl)-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (R)-4-(1-((6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01593] To a mixture of 6-methoxy-2-methylpyrazolo[1,5-b]pyridazine-5-carboxylic acid (130 mg, 0.629 mmol) in toluene (5 mL) were added DPPA (259 mg, 0.943 mmol) and TEA (191 mg, 1.887 mmol) at 0 ^oC. The mixture was stirred at 30 ^oC for 1 h. Then tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.629 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was diluted with H₂O (15 mL) and extracted with DCM (15 mL×3). The organic layer was concentrated in vacuo. The residue was triturated with MeOH (5 mL*2) to afford title product (50 mg, 15.3 %) as a white solid. ESI-MS (M+H) ⁺: 523.3.¹H NMR (400 MHz, DMSO-d₆) δ 12.44 (s, 1H), 8.51 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 6.29 (s, 1H), 4.10 – 4.08 (m, 3H), 4.03 – 3.98 (m, 2H), 3.84 – 3.74 (m, 2H), 3.67 – 3.55 (m, 3H), 3.18 – 3.16 (m, 4H), 2.31 (s, 3H), 1.42 (s, 9H), 1.19 – 1.16 (m, 3H). Step 2: Preparation of (R)-N-(6-methoxy-2-methylpyrazolo[1,5-b]pyridazin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01594] A mixture of tert-butyl (R)-4-(1-((6-methoxy-2-methylpyrazolo[1,5- b]pyridazin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (60 mg, 0.115 mmol) in 4 M HCl /EA (3 mL) was stirred at RT for 2 h. The reaction mixture was concentrated and the residue was purified by prep- HPLC (0.1% FA in H₂O / ACN) to give title product (8.6 mg, 19.2 %) as a yellow solid. ESI- MS (M+H) ⁺: 423.0.¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.51 (s, 1H), 8.29 (s, 1H), 7.94 (d, J = 5.7 Hz, 1H), 6.53 (d, J = 6.0 Hz, 1H), 6.29 (s, 1H), 4.09 (s, 3H), 3.98 (t, J = 8.0 Hz, 2H), 3.60 (d, J = 11.4 Hz, 2H), 3.13 (t, J = 8.2 Hz, 2H), 2.97 (d, J = 11.0 Hz, 1H), 2.90 – 2.74 (m, 3H), 2.56 – 2.55 (m, 1H), 2.31 (s, 3H), 1.04 (d, J = 5.8 Hz, 3H). Example 547 – Preparation of (S)-N-(2,4-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

C^{ompound 547} Step 1: Preparation of 2,4-dimethylpyrazolo[1,5-a]pyridin-5-amine. [01595] A solution of ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5- a]pyridine-3-carboxylate (16 g, 48.05 mmol) and TES (11.14 g, 96.09 mmol) in 33% HBr in AcOH (240 mL) was stirred at 100 ^oC for 16 h. The mixture was concentrated in vacuo, the residue was diluted with water (50 mL), adjusted PH to 7~8 with NaCO_3. The precipitate was filtered and purified by silica gel column chromatography (PE = 100 %) to give the product (6 g, 77.08 %) as a yellow solid. ESI-MS (M+H) ⁺: 162.2. Step 2: Preparation of tert-butyl (S)-4-(1-((2,4-dimethylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01596] To a mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2-methylpiperazine-1-carboxylate (200 mg, 0.63 mmol), 2,4-dimethylpyrazolo[1,5-a]pyridin- 5-amine (121 mg, 0.75 mmol) and TEA (762 mg, 7.55 mmol) in THF (20 mL) was added triphosgene (224 mg, 0.75 mmol) at 0 ^oC, the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered to afford title product (200 mg, 62.86 %) as a yellow solid. ESI-MS (M+H) ⁺: 506.3.¹H NMR (400 MHz, CDCl₃) δ 11.75 (s, 1H), 8.19 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 6.1 Hz, 1H), 6.17 (s, 1H), 4.36 – 4.35 (m, 1H), 4.21 – 4.14 (m, 2H), 3.97 – 3.95 (m, 1H), 3.53 (d, J = 11.7 Hz, 1H), 3.44 (d, J = 12.4 Hz, 1H), 3.24 – 3.23 (m, 1H), 3.15 – 3.07 (m, 3H), 2.96 – 2.94 (m, 1H), 2.46 (s, 3H), 2.43 (s, 3H), 1.49 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H). Step 3: Preparation of (S)-N-(2,4-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-(3-methylpiperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01597] A mixture of tert-butyl (S)-4-(1-((2,4-dimethylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.39 mmol) in 4M HCl / EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% NH₃·H₂O in H₂O / ACN) to give title product (43.15 mg, yield: 27.32 %) as a yellow solid. ESI-MS (M+H) ⁺: 406.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 6.1 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 6.2 Hz, 1H), 6.29 (s, 1H), 3.97 (t, J = 8.5 Hz, 2H), 3.58 (d, J = 11.9 Hz, 2H), 3.12 (t, J = 8.5 Hz, 2H), 2.91 (d, J = 11.0 Hz, 1H), 2.78 – 2.72 (m, 2H), 2.48 – 2.42 (m, 2H), 2.38 (s, 3H), 2.35 (s, 3H), 1.00 (d, J = 6.3 Hz, 3H). [01598] Example 548 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-hydroxy-2- methylimidazo[1,2-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

C^{ompound 548} Step 1: Preparation of tert-butyl (2R,6S)-4-(1-((7-hydroxy-2-methylimidazo[1,2-a]pyrimidin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. [01599] A mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethylpiperazine-1-carboxylate (200 mg, 0.60 mmol), 7-methoxy-2- methylimidazo[1,2-a]pyrimidin-6-amine (128 mg, 0.72 mmol), triphosgene (214 mg, 0.72 mmol) and TEA (730 mg, 7.23 mmol) in THF (20 mL) was stirred at 0 ^oC for 15 min. Then the mixture was stirred at RT for 16 h. The mixture was diluted with water, stirred at r.t for 1 h. The precipitate was filtered and triturated with MeOH to afford title product (40 mg, yield: 12.72 %) as a gray solid ESI-MS (M+H) ⁺: 523.3. Step 2: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-hydroxy-2- methylimidazo[1,2-a]pyrimidin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01600] A mixture of tert-butyl (2R,6S)-4-(1-((7-hydroxy-2-methylimidazo[1,2- a]pyrimidin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (30 mg, 0.06 mmol) in 4M HCl / EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (21 mg, yield: 76.42 %) as a yellow solid. ESI-MS (M+H) ⁺: 423.1.¹H NMR (400 MHz, D₂O) δ 8.66 (s, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.01 (s, 1H), 6.68 (d, J = 7.3 Hz, 1H), 4.20 (t, J = 8.3 Hz, 2H), 4.10 (d, J = 14.0 Hz, 2H), 3.52 – 3.43 (m, 2H), 3.34 (t, J = 8.4 Hz, 2H), 3.14 (dd, J = 14.3, 11.7 Hz, 2H), 2.21 (d, J = 0.9 Hz, 3H), 1.31 (d, J = 6.6 Hz, 6H). Example 549 – Preparation of (S)-N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-5-methyl-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of 4-chloro-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. [01601] A mixture of 4-chloro-5-methyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.99 mmol) and Raney-Nickel (100 mg, 20%) in MeOH (30 mL) was stirred at 70^oC for 16 h under H₂. The mixture filtered and filtrate concentrated in vacuo and purified by silica gel column (PE: EA = 2: 1) to give title product (125 mg, Y: 24.7%) as a yellow solid. ESI-MS (M+H) ⁺: 169.0. Step 2: Preparation of (S)-5-methyl-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine. [01602] A mixture of 4-chloro-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.48 mmol) and (S)-2-methylpiperazinein (445 mg, 2.22 mmol) in DIEA (0.3 mL) was stirred at 140^oC for 72 h in a sealed tube. The mixture was concentrated in vacuo to give title product (300 mg, Y: 87.0%) as a yellow oil. ESI-MS (M+H) ⁺: 233.2. Step 3: Preparation of tert-butyl tert-butyl (S)-2-methyl-4-(5-methyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate. [01603] A mixture of (S)-5-methyl-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine (300 mg, 1.29 mmol), Boc₂O (280 mg, 1.29 mmol) and TEA (390 mg, 3.80 mmol) in DCM (10 mL) was stirred at 40^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (DCM: MeOH = 20: 1) to give title product (200 mg, Y: 46.6%) as a brown oil. ESI-MS (M+H) ⁺: 333.1. Step 4: Preparation of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin- 5-yl)carbamoyl)-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01604] To a mixture of tert-butyl (S)-2-methyl-4-(5-methyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.30 mmol), 6-methoxy-2- methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (82 mg, 0.46 mmol) and TEA (456 mg, 4.50 mmol) in THF (16 mL) was added triphosgene (107 mg, 0.36 mmol) at 0^oC. The mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA = 1: 8) to give title product (80 mg, Y: 51.3%) as a yellow solid. ESI-MS (M+H) ⁺: 537.4. Step 5: Preparation of (S)-N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5- methyl-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01605] A mixture of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (70 mg,0.13 mmol) in 4M HCl/EA (5 mL) was stirred at r.t for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in water / CH₃CN) to give title product (14.88 mg, 23.75%) as a white solid. ESI- MS (M+H) ⁺:437.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 4.06 (d, J = 7.1 Hz, 6H), 4.00 – 3.96 (m, 2H), 3.24 – 3.18 (m, 2H), 3.17 – 3.10 (m, 2H), 3.06 (t, J = 11.3 Hz, 2H), 2.97 – 2.72 (m, 3H), 2.16 (s, 3H), 1.08 (d, J = 6.0 Hz, 3H). Example 550 – Preparation of N-(2,8-dimethylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9- diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl 2-(1-((2,8-dimethylimidazo[1,2-a] pyridin-6-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9-carboxylate. [01606] To a solution of tert-butyl 2-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6- oxa-2,9-diazaspiro [4.5] decane-9-carboxylate (120 mg, 0.33 mmol) in THF (3 mL) was added DIEA (198 mg, 1.67 mmol), triphosgene (99 mg, 0.33 mmol) and 2,8- dimethylimidazo[1,2-a]pyridin-6-amine (80 mg, 0.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with H₂O (80 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by C18 column chromatography eluted with (0.05% FA in water / ACN) to afford tert-butyl 2-(1-((2,8-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H- pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (52 mg, yield: 28%) as a yellow solid. ESI-MS (M+1) ⁺: 548.2. Step 2: Preparation of N-(2,8-dimethylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9-diazaspiro [4.5] decan-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate. [01607] To a mixture of tert-butyl 2-(1-((2,8-dimethylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-6-oxa-2,9-diazaspiro [4.5] decane-9- carboxylate (40 mg, 0.075 mmol) in DCM (1 mL) was added HCl/dioxane (1 mL, 6 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hours. The resulting mixture was concentrated under vacuum. The residue was purified by C18 column chromatography eluted with (0.05% FA in water / ACN) to afford N-(2,8-dimethylimidazo[1,2-a] pyridin-6-yl)-4-(6-oxa-2,9-diazaspiro [4.5] decan-2- yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate (10 mg, yield: 30%) as a yellow solid. ESI-MS (M+1) ⁺: 448.3.¹H NMR (400 MHz, CD₃OD) δ 8.97 (d, J = 1.2 Hz, 1H), 8.32 (s, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 0.9 Hz, 1H), 7.32 (s, 1H), 6.21 (d, J = 6.2 Hz, 1H), 4.07 – 3.89 (m, 4H), 3.81 (d, J = 11.0 Hz, 1H), 3.75 – 3.59 (m, 4H), 3.46 – 3.34 (m, 2H), 3.27 (d, J = 12.9 Hz, 1H), 3.17 (t, J = 4.8 Hz, 2H), 2.55 (s, 3H), 2.46 (s, 3H), 2.41 – 2.33 (m, 1H), 2.04 (dt, J = 13.0, 8.9 Hz, 1H). Example 551 – Preparation of (S)-N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-6-methyl-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide 2,2,2-trifluoroacetate.

Step 1: Preparation of 6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide. [01608] To a mixture of 6-methyl-1H-pyrrolo[2,3-b]pyridine (23.0 g, 174.24 mmol) in EA (240 mL) was added m-CPBA (45.2 g, 261.36 mmol). The mixture was stirred at r.t for 16 h. The mixture was diluted with water (200 mL) and extracted with EA (200 mL*3). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to get title product (22.0 g, Y: 85.3 %) as a brown solid. ESI-MS (M+H) ⁺:149.1.¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 3.2 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.52 (d, J = 3.2 Hz, 1H), 3.36 (s, 3H). Step 2: Preparation of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine. [01609] A solution of 6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (20.0 g, 135.14 mmol) in POCl₃ (92 mL) was stirred at 90^oC for 16 h. The mixture was concentrated in vacuo, the residue was diluted with water (100 mL) and adjust pH to 9 by NaHCO₃ (aq). The mixture was extracted with EA (100 mL*3). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=1:1) to get title product (12.0 g, Y: 53.2 %) as a brown solid. ESI-MS (M+H) ⁺:167.1. Step 3: Preparation of tert-butyl 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [01610] To a mixture of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (4.0 g, 23.95 mmol) in DCM (40 mL) were added TEA (7.3 g, 71.86 mmol), Boc₂O (6.3 g, 28.74 mmol) at 0^oC. The mixture was stirred at r.t for 3 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL*3). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to get title product (2.2 g, Y: 34.4 %) as a brown solid which was used to the next step without further purification. ESI-MS (M+H) ⁺:267.1. Step 4: Preparation of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. [01611] To a mixture of tert-butyl 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine-1- carboxylate (2.0 g, 7.49 mmol) in MeOH (20 mL) was added Raney-Ni (2 g). The mixture was stirred at 70^oC for 16 h under Hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo, the residue was purified by flash chromatography (PE: EA= 4: 1) to get title product (200 mg, 15.8%) as a white solid. ESI-MS (M+H)⁺: 169.1. Step 5: Preparation of tert-butyl (S)-2-methyl-4-(6-methyl-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate. [01612] A mixture of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (180 mg, 1.07 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (213 mg, 1.07 mmol) in DIEA (1 mL) was stirred at 140^oC for 16 h in a sealed tube. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EA=100:0 to 0:100, then DCM/MeOH = 100: 0 to 90: 10) to get title product (100 mg, Y: 28.3 %) as a yellow solid. ESI-MS (M+H) ⁺:333.2. Step 6: Preparation of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin- 5-yl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate. [01613] To a mixture of tert-butyl (S)-2-methyl-4-(6-methyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (70 mg, 0.21 mmol), 6-methoxy-2- methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (45 mg, 0.25 mmol), TEA (319 mg, 3.16 mmol) in THF (10 mL) was added and triphosgene (75 mg, 0.25 mmol) at 0^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (20 mL) and the precipitate was filtered, triturated with MeOH (5 mL) to get title product (25 mg, Y: 22.1 %) as a white solid. ESI-MS (M+H) ⁺:537.2. Step 7: Preparation of (S)-N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- methyl-4-(3-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01614] To a solution of tert-butyl (S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (15 mg, 0.03 mmol) in EA (1 mL) was added 4M HCl/EA (1 mL). The reaction mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.03% TFA in water / ACN) to give title compound (6.95 mg, 45.2 %) as a white solid. ESI-MS (M+H)⁺:437.3.¹H NMR (400 MHz, MeOD-d₄) δ 8.71 (s, 1H), 7.99 (s, 1H), 6.45 (s, 1H), 4.13 (s, 3H), 4.11 – 4.05 (m, 5H), 3.79 – 3.72 (m, 2H), 3.49 – 3.44 (m, 2H), 3.28 – 3.21 (m, 1H), 3.19 – 3.12 (m, 1H), 3.06 (t, J = 8.5 Hz, 2H), 2.95 (dd, J = 13.6, 10.4 Hz, 1H), 2.52 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H).

Example 552 – Preparation of 4-((2S,6R)-2,6-dimethylpiperidin-4-yl)-N-(7-fluoro-2,8- dimethylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide diformate.

Step 1: Preparation of tert-butyl (2R,6S)-2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-1(2H)-carboxylate. [01615] To a mixture of tert-butyl (2R,6S)-2,6-dimethyl-4-oxopiperidine-1- carboxylate (2 g, 8.81 mmol) in THF (20 mL) was added LiHMDS (10.6 mL,10.6 mmol, 1M) at -78 ^oC, the reaction mixture was stirred at -78 ^oC for 0.5 h. Then N,N- phenylbistrifluoromethane-sulfonimide (3.5 g, 9.69 mmol ) was added to the mixture and stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EA: PE (1: 9) to give title product (1.5 g, 47.5 %) as a yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ 6.02 – 5.99 (m, 1H), 4.68 – 4.60 (m, 1H), 4.55 – 4.47 (m, 1H), 2.76 – 2.67 (m, 1H), 2.16 (d, J = 16.9 Hz, 1H), 1.43 (s, 9H), 1.27 (d, J = 6.9 Hz, 3H), 1.16 (d, J = 7.0 Hz, 3H). Step 2: Preparation of tert-butyl (2R,6S)-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate. [01616] To a solution of tert-butyl (2R,6S)-2,6-dimethyl-4- (((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 4.18 mmol) in 1,4-dioxane (30 mL) were added B2Pin2 (1.3 g, 5.01 mmol), Pd(dppf)Cl2 (340 mg, 0.042 mmol) and KOAc (1.2 g, 12.54 mmol). The mixture was charged with N₂ for three times and stirred at 90 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EA: PE= (1: 9) to give title product (1 g, 70.9 %) as a yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ 6.36 – 6.32 (m, 1H), 4.46 – 4.36 (m, 1H), 4.25 – 4.18 (m, 1H), 2.20 – 2.11 (m, 1H), 2.03 – 1.98 (m, 1H), 1.41 (s, 9H), 1.21 (s, 12H), 1.17 – 1.16 (m, 6H). Step 3: Preparation of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethyl-3,6-dihydropyridine-1(2H)-carboxylate. [01617] To a solution of 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (490 mg, 2.48 mmol) in 1,4-dioxane : H₂O (20 mL:3.5 mL) were added tert-butyl (2R,6S)-2,6- dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (1 g, 2.97 mmol), Pd(dppf)Cl₂ (242 mg, 0.248 mmol) and K₂CO₃ (1 g, 7.424 mmol). The mixture was charged with N₂ for three times and stirred at 85 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EA: PE= (5: 1) to give title product (220 mg, 27 %) as a yellow solid. ESI-MS (M+H) ⁺: 330.2.¹ H NMR (400 MHz, DMSO-d₆) δ 7.65 (d, J = 5.6 Hz, 1H), 6.37 (d, J = 5.7 Hz, 1H), 5.87 – 5.86 (m, 1H), 4.62 – 4.51 (m, 1H), 4.42 – 4.33 (m, 1H), 3.49 – 3.46 (m, 2H), 3.12 – 3.03 (m, 2H), 2.63 – 2.55 (m, 1H), 2.14 (d, J = 16.5 Hz, 1H), 1.44 (s, 9H), 1.28 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.9 Hz, 3H). Step 4: Preparation of tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperidine-1-carboxylate. [01618] A mixture of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.152 mmol) and Pd/C (10 mg, 10 % w.t) in MeOH (10 mL) was stirred at RT for 6 h under H₂. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give title product (30 mg, 59.6 %) as a yellow solid. ESI-MS (M+H) ⁺: 332.3.¹ H NMR (400 MHz, DMSO-d₆) δ 7.63 (d, J = 5.6 Hz, 1H), 6.51 – 6.40 (m, 1H), 6.39 – 6.35 (m, 1H), 4.27 (s, 1H), 4.19 – 4.10 (m, 1H), 3.51 – 3.44 (m, 2H), 3.04 – 2.97 (m, 2H), 2.11 – 2.02 (m, 1H), 1.75 – 1.67 (m, 1H), 1.60 – 1.55 (m, 1H), 1.51 – 1.45 (m, 2H), 1.43 – 1.41 (m, 9H), 1.25 – 1.19 (m, 6H). Step 5: Preparation of tert-butyl (2S,6R)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin- 6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperidine-1- carboxylate. [01619] A mixture of 7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-amine (32 mg, 0.189 mmol), triphosgene (54 mg, 0.181 mmol) and TEA (183 mg, 1.813 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,6-dimethylpiperidine-1-carboxylate (50 mg, 0.151 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL×3). The organic layer was concentrated in vacuo to afford title product (40 mg, crude) as a brown solid. ESI-MS (M+H) ⁺: 537.4. Step 6: Preparation of 4-((2S,6R)-2,6-dimethylpiperidin-4-yl)-N-(7-fluoro-2,8- dimethylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate. [01620] A mixture of tert-butyl (2S,6R)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperidine-1-carboxylate (40 mg, 0.075 mmol) in 4M HCl / EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the residue was purified by prep- HPLC (0.1% FA in H₂O / ACN) to give title product (9 mg, 22.8 %) as a white solid. ESI- MS (M+H) ⁺: 437.4.¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (d, J = 6.7 Hz, 1H), 8.33 (s, 2H), 8.14 – 8.06 (m, 1H), 7.56 (s, 1H), 7.05 – 6.85 (m, 1H), 4.17 – 4.08 (m, 2H), 3.50 – 3.32 (m, 3H), 3.22 – 3.12 (m, 2H), 2.44 (s, 3H), 2.39 (s, 3H), 2.26 (d, J = 15.0 Hz, 1H), 2.11 – 2.01 (m, 1H), 1.99 – 1.86 (m, 1H), 1.72 – 1.58 (m, 1H), 1.43 – 1.32 (m, 6H). Example 553 – Preparation of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4- ((2S)-2-methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (S)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-1(2H)-carboxylate. [01621] To a mixture of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (10 g, 0.047 mol) in THF (100 mL) was added LiHMDS (56 mL,0.056 mol, 1M) at -78 ^oC, the reaction mixture was stirred at -78 ^oC for 0.5 h. Then N,N-phenylbistrifluoromethane- sulfonimide (18.4 g, 0.052 mol ) was added to the mixture and stirred at RT for 2 h. The mixture was diluted with water (50 mL), extracted with EA (100 mL), the organic layer was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EA: PE (1: 9) to give title product (9 g, 55.6 %) as a yellow oil. Step 2: Preparation of tert-butyl (S)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3,6-dihydropyridine-1(2H)-carboxylate. [01622] To a solution of tert-butyl (S)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)- 3,6-dihydropyridine-1(2H)-carboxylate (7 g, 0.02 mol) in 1,4-dioxane (80 mL) were added B₂Pin₂ (6.2 g, 0.024 mol), Pd(dppf)Cl₂ (1.7 g,0.002 mol) and AcOK (6 g, 0.061 mol). The mixture was charged with N₂ for three times and stirred at 90 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EA: PE= (1: 9) to give title product (5 g, 76.3 %) as a yellow oil. ESI- MS (M+H-Boc) ⁺: 224.2. Step 3: Preparation of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-methyl- 3,6-dihydropyridine-1(2H)-carboxylate. [01623] To a solution of 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (817 mg, 4.12 mmol) in 1,4-dioxane : H₂O (20 mL:3 mL) were added tert-butyl (S)-6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.19 mmol), Pd(dppf)Cl₂ (337 mg, 0.41mmol) and K₂CO₃ (1.7 g, 12.32 mmol). The mixture was charged with N₂ for three times and stirred at 85 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EA: PE= (1: 3) to give title product (700 mg, 53.9 %) as a yellow solid. ESI-MS (M+H) ⁺: 316.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (d, J = 5.5 Hz, 1H), 6.37 – 6.32 (m, 1H), 4.52 – 4.40 (m, 1H), 4.10 – 3.98 (m, 1H), 3.46 – 3.39 (m, 3H), 3.12 – 2.95 (m, 3H), 2.53 – 2.49 (m, 1H), 2.24 – 2.09 (m, 1H), 1.49 – 1.37 (m, 9H), 1.21 – 1.06 (m, 3H). Step 4: Preparation of tert-butyl (2S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperidine-1-carboxylate. [01624] A mixture of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6- methyl-3,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.16 mmol) and Pd/C(10 mg, 20 % Wt) in MeOH (10 mL) was stirred at RT for 5 h under H₂. The reaction mixture was filtered over Celite. The filtrate was concentrated under reduced pressure to give title product (30 mg, 59.6 %) as a yellow solid. ESI-MS (M+H) ⁺: 318.2. Step 5: Preparation of tert-butyl (2S)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1-carboxylate. [01625] A mixture of 7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-amine (34 mg, 0.189 mmol), triphosgene (56 mg, 0.189 mmol) and TEA (191 mg, 1.893 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (2S)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-methylpiperidine-1-carboxylate (50 mg, 0.158 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL×3). The organic layer was concentrated in vacuo to afford title product (20 mg, crude) as a brown solid. ESI-MS (M+H) ⁺: 523.4. Step 6: Preparation of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4-((2S)-2- methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01626] A mixture of tert-butyl (2S)-4-(1-((7-fluoro-2,8-dimethylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1- carboxylate (50 mg, 0.096 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (1.67 mg, 3.7 %) as a white solid. ESI-MS (M+H) ⁺: 423.2. ¹H NMR (400 MHz, MeOD-d₄) δ 9.07 (d, J = 6.8 Hz, 1H), 8.38 (s, 1H), 8.14 – 8.07 (m, 1H), 7.54 (s, 1H), 6.96 – 6.84 (m, 1H), 4.22 – 4.10 (m, 2H), 3.56 – 3.35 (m, 2H), 3.26 – 3.18 (m, 3H), 3.17 – 2.98 (m, 1H), 2.46 (s, 3H), 2.39 (s, 3H), 2.15 – 2.01 (m, 2H), 1.99 – 1.64 (m, 2H), 1.46 (dd, J = 54.2, 6.7 Hz, 3H).

Example 554 – Preparation of 4-((2S,6R)-2,6-dimethylpiperidin-4-yl)-N-(6-methoxy-2- methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

Step 1: Preparation of 4-((2S,6R)-2,6-dimethylpiperidin-4-yl)-N-(6-methoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01627] To a solution of 6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (52 mg, 0.29 mmol) in THF (10 mL) were added TEA (299 mg, 2.96 mmol) and triphosgene (86 mg, 0.29 mmol) at 0^oC. After 10 min, tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,6-dimethylpiperidine-1-carboxylate (80 mg, 0.24 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (30 mL). The precipitate was filtered and concentrated in vacuo to give the compound (40 mg, 31%) as a brown solid. ESI-MS (M+H) ⁺:536.4. Step 2: Preparation of 4-((2S,6R)-2,6-dimethylpiperidin-4-yl)-N-(6-methoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01628] To a mixture of 4-((2S,6R)-2,6-dimethylpiperidin-4-yl)-N-(6-methoxy-2- methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide (30 mg, 0.06 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H2O / ACN) to give title product (8.68 mg, 33 %) as a white solid. ESI-MS (M+H) ⁺:436.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (d, J = 10.9 Hz, 1H), 8.67 (d, J = 2.5 Hz, 1H), 8.37 (s, 1H), 8.19 – 8.11 (m, 2H), 6.96 – 6.86 (m, 1H), 4.06 (d, J = 8.1 Hz, 8H), 3.26 – 3.11 (m, 2H), 3.08 – 2.76 (m, 3H), 1.96 (d, J = 12.8 Hz, 1H), 1.74 (d, J = 13.2 Hz, 1H), 1.69 – 1.59 (m, 1H), 1.47 – 1.29 (m, 1H), 1.19 – 1.06 (m, 6H). Example 555 – Preparation of N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)- 4-((2S)-2-methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (2S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin- 5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1- carboxylate. [01629] To a solution of 6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (100 mg, 0.32 mmol) and TEA (383 mg, 3.79 mmol) in THF (10 mL) was added triphosgene (113 mg, 0.38 mmol) at 0^oC, after 10 min, tert-butyl (2S)-4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2-methylpiperidine-1-carboxylate (100 mg, 0.32 mmol) was added at the mixture and stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and concentrated in vacuo to give the compound (70 mg, 42%) as a brown solid. ESI-MS (M+H) ⁺:522.3. Step 2: Preparation of N-(6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-((2S)-2- methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01630] To a mixture of tert-butyl (2S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1- carboxylate (50 mg, 0.10 mmol) in EA (1 mL) was added 4M HCl / EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (11.39 mg, 24 %) as a yellow solid. ESI-MS (M+H) ⁺:422.2.¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (d, J = 5.7 Hz, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.18 – 8.13 (m, 2H), 6.93 – 6.83 (m, 1H), 4.11 – 4.06 (m, 5H), 4.05 (s, 3H), 3.17 – 3.12 (m, 4H), 3.07 – 2.98 (m, 2H), 2.94 – 2.71 (m, 2H), 1.70 (d, J = 16.5 Hz, 1H), 1.61 (d, J = 12.8 Hz, 1H), 1.19 (d, J = 73.5 Hz, 3H). Example 556 – Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-((2S)-2- methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate .

Step 1: Preparation of tert-butyl (2S)-4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1-carboxylate. [01631] A mixture of 6-fluoro-2-methyl-2H-indazol-5-amine (31 mg, 0.189 mmol), triphosgene (56 mg, 0.189 mmol) and TEA (191 mg, 1.893 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (2S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperidine-1-carboxylate (50 mg, 0.158 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL×3). The organic layer was concentrated in vacuo to afford title product (45 mg, crude) as a brown solid. ESI-MS (M+H) ⁺: 509.3. H NMR (400 MHz, DMSO-d₆) δ 11.74 – 11.68 (m, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.31 (s, 1H), 8.11 – 8.03 (m, 1H), 7.46 (d, J = 12.0 Hz, 1H), 6.94 – 6.88 (m, 1H), 4.15 – 4.09 (m, 5H), 3.32 – 3.27 (m, 2H), 3.18 – 2.92 (m, 3H), 1.79 – 1.64 (m, 2H), 1.63 – 1.47 (m, 3H), 1.42 (s, 9H), 1.23 – 1.14 (m, 3H). Step 2: Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-((2S)-2-methylpiperidin-4- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01632] A mixture of tert-butyl (2S)-4-(1-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1-carboxylate (40 mg,0.079 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (17 mg, 47.6 %) as a white solid. ESI-MS (M+H) ⁺: 409.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.11 – 8.05 (m, 1H), 7.46 (d, J = 12.2 Hz, 1H), 6.91 – 6.84 (m, 1H), 4.14 – 4.05 (m, 5H), 3.17 – 3.11 (m, 3H), 3.08 – 2.94 (m, 3H), 1.95 – 1.80 (m, 1H), 1.79 – 1.56 (m, 3H), 1.18 (dd, J = 73.1, 6.1 Hz, 3H). [01633] Example 557 – Preparation of N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4- ((2S)-2-methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

Step 1: Preparation of tert-butyl (2S)-4-(1-((6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1-carboxylate. [01634] To a solution of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (78 mg, 0.38 mmol) and TEA (101 mg, 1.00 mmol) in tol (5 mL) was added DPPA (192 mg, 0.70 mmol) at 30 ^oC, the mixture was stirred at r.t for 0.5h and 60 ^oC for 0.5 h. Tert-butyl (2S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1-carboxylate (80 mg, 0.25 mmol) was added to the mixture and stirred at 90 ^oC for 16 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (EA: PE= 70 %) to give title product (60 mg, yield: 46.06 %) as a white solid. ESI-MS (M+H) ⁺: 521.3. Step 2: Preparation of N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-4-((2S)-2- methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide. [01635] A mixture of tert-butyl (2S)-4-(1-((6-methoxy-2-methylpyrazolo[1,5- a]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1- carboxylate (50 mg, 0.09 mmol) in 4M HCl /EA (2 mL) was stirred at RT for 2 h. The precipitate was filtered and diluted with water (2 mL), adjusted pH to 7~8 by 1N Na₂CO₃. The precipitate was filtered, washed with water (10 mL) and dried in vacuo to give title product (20.01 mg, yield: 52.93 %) as a white solid. ESI-MS (M+H) ⁺: 421.2.¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (d, J = 5.9 Hz, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 8.14 (t, J = 5.2 Hz, 1H), 6.88 (dd, J = 7.9, 5.7 Hz, 1H), 6.18 (s, 1H), 4.07 (t, J = 7.9 Hz, 2H), 3.97 (s, 3H), 3.17 – 2.98 (m, 5H), 2.85 – 2.75 (m, 1H), 2.31 (s, 3H), 2.03 – 1.42 (m, 4H), 1.32 – 1.11 (m, 3H). Example 558 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-((2S)- 2-methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

Step 1: Preparation of tert-butyl (2S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1-carboxylate. [01636] A mixture of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (62 mg, 0.379 mmol), triphosgene (112 mg, 0.379 mmol) and TEA (382 mg, 3.785 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl (2S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2-methylpiperidine-1-carboxylate (100 mg, 0.315 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL×3). The organic layer was concentrated in vacuo to afford title product (60 mg, crude) as a brown solid. ESI-MS (M+H) ⁺: 509.3. Step 2: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-((2S)-2- methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01637] A mixture of tert-butyl (2S)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1-carboxylate (40 mg, 0.079 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (20 mg, 55.9 %) as a brown solid. ESI-MS (M+H) ⁺: 409.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 9.20 (d, J = 7.4 Hz, 1H), 8.25 (s, 1H), 8.11 (d, J = 5.4 Hz, 1H), 7.73 (s, 1H), 7.43 (d, J = 11.6 Hz, 1H), 6.87 (dd, J = 9.5, 5.6 Hz, 1H), 4.09 (t, J = 8.6 Hz, 2H), 3.70 – 3.69 (m, 1H), 3.39 – 3.29 (m, 1H), 3.19 – 3.13 (m, 3H), 3.02 – 2.91 (m, 1H), 2.29 (s, 3H), 2.06 – 1.80 (m, 3H), 1.75 – 1.58 (m, 1H), 1.40 – 1.21 (m, 3H). Example 559 – Preparation of 4-((2S,6R)-2,6-dimethylpiperidin-4-yl)-N-(6-fluoro-2- methyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

Step 1: Preparation of tert-butyl (2S,6R)-4-(1-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperidine-1- carboxylate. [01638] To a solution of 6-fluoro-2-methyl-2H-indazol-5-amine (48 mg, 0.29 mmol) in THF (10 mL) were added TEA (299 mg, 2.90 mmol) and triphosgene (86 mg, 0.29 mmol) at 0^oC. After 10 min, tert-butyl (2S,6R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperidine-1-carboxylate (80 mg, 0.24 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (30 mL). The precipitate was filtered and concentrated in vacuo to give the compound (100 mg, 80%) as a pink solid. ESI-MS (M+H) ⁺:523.1.¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.32 (s, 1H), 8.07 (d, J = 5.5 Hz, 1H), 7.46 (d, J = 11.8 Hz, 1H), 6.96 – 6.90 (m, 1H), 4.36 – 4.26 (m, 1H), 4.21 – 4.15 (m, 1H), 4.12 (s, 3H), 4.07 (dd, J = 14.1, 8.7 Hz, 2H), 3.21 (d, J = 8.4 Hz, 1H), 3.20 – 3.12 (m, 2H), 2.18 – 2.09 (m, 1H), 1.82 – 1.74 (m, 1H), 1.65 (d, J = 12.1 Hz, 1H), 1.61 – 1.54 (m, 1H), 1.43 (d, J = 2.4 Hz, 9H), 1.25 (t, J = 6.1 Hz, 6H). Step 2: Preparation of 4-((2S,6R)-2,6-dimethylpiperidin-4-yl)-N-(6-fluoro-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate. [01639] To a mixture of tert-butyl (2S,6R)-4-(1-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperidine-1- carboxylate (80 mg, 0.15 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% TFA in H₂O / ACN) to give title product (60 mg, 95 %) as a white solid. ESI-MS (M+H) ⁺:423.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (d, J = 2.9 Hz, 1H), 8.88 – 8.55 (m, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.32 (s, 1H), 8.29 – 8.13 (m, 1H), 8.11 (d, J = 5.5 Hz, 1H), 7.47 (d, J = 12.1 Hz, 1H), 6.95 – 6.83 (m, 1H), 4.12 (s, 3H), 4.11 – 4.05 (m, 2H), 3.47 – 2.93 (m, 5H), 2.14 (d, J = 14.5 Hz, 1H), 1.94 (d, J = 13.5 Hz, 1H), 1.81 (t, J = 10.7 Hz, 1H), 1.57 (q, J = 12.8 Hz, 1H), 1.32 – 1.18 (m, 6H). Example 560 – Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro- 2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide formate.

C^{ompound 560} Step 1: Preparation of tert-butyl (2-(2,6-dichloro-4-iodopyridin-3-yl)ethyl)carbamate. [01640] To a solution of 2,6-dichloro-4-iodopyridine (50 g, 183 mmol) in THF (500 mL) was added LDA (137 mL, 275 mmol, 2.0 M in THF) dropwise at -65^oC, the reaction mixture was stirred at -65^oC for 1h, then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide (61.3 g, 275 mmol) was added to the mixture and stirred at r.t overnight. The mixture was quenched with sat. NH₄Cl (500 mL) and stirred at r.t for 4 h. Then extracted with EA (500 mL*2), the combined organic layer was washed with brine (800 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with PE/EA=2:1 (500 mL) to give title product (29 g, 38.2%) as a yellow solid. ESI-MS (M+H) ⁺:417.0. Step 2: Preparation of tert-butyl 6-chloro-4-iodo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxylate. [01641] A mixture tert-butyl (2-(2,6-dichloro-4-iodopyridin-3-yl)ethyl)carbamate (4.3 g, 10.3 mmol) in THF (90 mL) was added NaH (1.65 g, 41.2 mmol) at 0^oC. The mixture was stirred at 50 ^oC for 3 h. The mixture was diluted with sat. NH₄Cl (50 mL), extracted with DCM (50 mL*3). The organic layer was concentrated in vacuo and purified by silica gel column (PE: EA= 2: 1) to give title product (2.1 g, 53.4%) as a white solid. ESI-MS (M+H) ⁺:381.2. Step 3: Preparation of tert-butyl 4-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)-6- chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [01642] A mixture of tert-butyl 6-chloro-4-iodo-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine-1-carboxylate (2.1 g, 5.51 mmol), tert-butyl 2,2-dimethylpiperazine-1-carboxylate (1.77 g, 8.27 mmol), Cs₂CO₃ (5.37 g, 16.54 mmol), Xantphos (646 mg, 1.10 mmol) and Pd₂(dba)₃ (504 mg, 0.55 mmol) in 1,4-dioxane (30 mL) was stirred at 80 ^oC for 16 h under N₂. The mixture was concentrated in vucuo, and the residue was purified by silica gel column (PE: EA= 3: 1) to give title product (1.5 g, 58%) as a yellow solid. ESI-MS (M+H) ⁺:467.1. Step 4: Preparation of tert-butyl 4-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)-6- cyclopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. [01643] A mixture of tert-butyl 4-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1- yl)-6-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.5 g, 3.21 mmol), cyclopropylboronic acid (1381 mg, 16 mmol), K₃PO₄ (3405 mg, 16 mmol), Pcy₃ (270 mg, 0.96 mmol) and Pd(OAc)₂ (144 mg, 0.64 mmol) in Toluene (20 mL) and H₂O (2 mL) was stirred at 130^oC for 2 h under N₂ in a sealed tube. The mixture was cooled down to r.t and concentrated in vacuo. The residue was purified by silica gel column (PE: EA= 3: 1) to give title product (1.3 g, 86%) as a white solid. ESI-MS (M+H) ⁺:473.3.¹H NMR (400 MHz, DMSO-d₆) δ 6.32 (s, 1H), 3.77 (t, J = 8.3 Hz, 2H), 3.66 – 3.61 (m, 2H), 3.41 (t, J = 5.4 Hz, 2H), 3.34 (s, 2H), 3.04 (t, J = 8.3 Hz, 2H), 1.92 – 1.83 (m, 1H), 1.46 (s, 9H), 1.42 (s, 9H), 1.36 (s, 6H), 0.88 (s, 2H), 0.76 (dd, J = 7.8, 2.9 Hz, 2H). Step 5: Preparation of 6-cyclopropyl-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine hydrochloride. [01644] To a solution of tert-butyl 4-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1- yl)-6-cyclopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.3 g, 2.75 mmol) in EA (4 mL) was added 4M HCl/EA (12 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo to give title compound (750 mg, 99 %) as a yellow solid. ESI-MS (M+H) ⁺:273.2. Step 6: Preparation of tert-butyl 4-(6-cyclopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,2-dimethylpiperazine-1-carboxylate. [01645] To a solution 6-cyclopropyl-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine hydrochloride (750 mg, 2.76 mmol) in DCM (30 mL) were added TEA (1394 mg, 13.8 mmol) and Boc₂O (661 mg, 3.03 mmol) at 0^oC. Then DMAP (34 mg, 0.28 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column (PE: EA= 1:4) to give title compound (550 mg, 53 %) as a yellow solid. ESI-MS (M+H) ⁺:373.3.¹H NMR (400 MHz, DMSO-d₆) δ 5.94 (s, 1H), 5.66 (s, 1H), 3.65 – 3.58 (m, 2H), 3.40 – 3.36 (m, 2H), 3.29 (d, J = 8.8 Hz, 4H), 3.01 (t, J = 8.4 Hz, 2H), 1.79 – 1.71 (m, 1H), 1.42 (s, 9H), 1.35 (s, 6H), 0.77 – 0.66 (m, 4H). Step 7: Preparation of tert-butyl 4-(6-cyclopropyl-1-((7-fluoro-2,8-dimethylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate. [01646] To a solution of 7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-amine (58 mg, 0.32 mmol) in THF (10 mL) were added TEA (325 mg, 3.22 mmol) and triphosgene (95 mg, 0.32 mmol) at 0^oC. After 10 min, tert-butyl 4-(6-cyclopropyl-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (100 mg, 0.27 mmol) was added at 0 ^oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (30 mL). The precipitate was filtered and triturated with MeOH (5 mL) to give the compound (150 mg, 96%) as a pink solid. ESI-MS (M+H) ⁺:578.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 9.09 (d, J = 7.1 Hz, 1H), 7.68 (s, 1H), 6.33 (s, 1H), 3.99 – 3.91 (m, 2H), 3.71 – 3.66 (m, 2H), 3.58 – 3.53 (m, 2H), 3.51 (s, 2H), 3.22 (t, J = 8.5 Hz, 2H), 2.39 (d, J = 2.0 Hz, 3H), 2.29 (s, 3H), 2.02 – 1.96 (m, 1H), 1.43 (s, 9H), 1.38 (s, 6H), 0.99 – 0.90 (m, 4H). Step 8: Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2,8- dimethylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01647] To a mixture of tert-butyl 4-(6-cyclopropyl-1-((7-fluoro-2,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,2-dimethylpiperazine-1-carboxylate (130 mg, 0.23 mmol) in EA (2 mL) was added 4M HCl/EA (6 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (91 mg, 82 %) as a white solid. ESI-MS (M+H) ⁺:478.4.¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 9.10 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 7.69 (s, 1H), 6.51 (s, 1H), 3.99 (t, J = 8.4 Hz, 2H), 3.35 (d, J = 3.2 Hz, 2H), 3.17 (s, 2H), 3.16 – 3.11 (m, 2H), 3.07 (t, J = 8.5 Hz, 2H), 2.39 (s, 3H), 2.29 (s, 3H), 2.07 – 1.98 (m, 1H), 1.28 (s, 6H), 0.96 (d, J = 8.2 Hz, 4H). Example 561 – Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(6-fluoro- 2-methyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

Step 1: Preparation of tert-butyl 4-(6-cyclopropyl-1-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate. [01648] To a solution of 6-fluoro-2-methyl-2H-indazol-5-amine (53 mg, 0.32 mmol) in THF (10 mL) were added TEA (325 mg, 3.22 mmol) and triphosgene (95 mg, 0.32 mmol) at 0^oC. After 10 min, tert-butyl 4-(6-cyclopropyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,2-dimethylpiperazine-1-carboxylate (100 mg, 0.27 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (45 mL). The precipitate was filtered and concentrated in vacuo to give the compound (100 mg, 66 %) as a white solid. ESI-MS (M+H) ⁺:564.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 7.48 (d, J = 12.3 Hz, 1H), 6.34 (s, 1H), 4.12 (s, 3H), 3.98 – 3.92 (m, 2H), 3.71 – 3.67 (m, 2H), 3.56 – 3.53 (m, 2H), 3.51 (s, 2H), 3.23 – 3.16 (m, 2H), 2.14 – 1.83 (m, 1H), 1.43 (s, 9H), 1.38 (s, 6H), 0.93 (dd, J = 22.4, 5.6 Hz, 4H). Step 2: Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(6-fluoro-2-methyl- 2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01649] To a mixture of tert-butyl (2S)-4-(1-((6-methoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperidine-1- carboxylate (80 mg, 0.14 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered and washed with EA (3 mL) and lyophilized to give title product (66 mg, 79 %) as an orange solid. ESI-MS (M+H) ⁺:464.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 9.49 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.32 (s, 1H), 7.49 (d, J = 12.3 Hz, 1H), 6.54 (s, 1H), 4.12 (s, 3H), 4.01 (t, J = 8.3 Hz, 2H), 3.49 (s, 2H), 3.29 (s, 2H), 3.23 (s, 2H), 3.08 (t, J = 8.3 Hz, 2H), 2.10 – 2.01 (m, 1H), 1.40 (s, 6H), 1.02 – 0.92 (m, 4H). Example 562 – Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(6- methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine- 1-carboxamide formate.

C^{ompound 562} Step 1: Preparation of tert-butyl 4-(6-cyclopropyl-1-((6-methoxy-2-methylpyrazolo[1,5- a]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate. [01650] A mixture of 6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine (29 mg, 0.161 mmol), triphosgene (48 mg, 0.161 mmol) and TEA (163 mg, 1.613 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl 4-(6-cyclopropyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (50 mg, 0.134 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL×3). The organic layer was concentrated in vacuo. The residue was triturated with MeOH (3 mL) to afford title product (25 mg, 32.3 %) as a white solid. ESI-MS (M+H) ⁺: 576.1.¹H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.29 (d, J = 7.9 Hz, 2H), 6.25 (s, 1H), 6.16 (s, 1H), 3.97 – 3.90 (m, 5H), 3.71 – 3.64 (m, 2H), 3.56 – 3.46 (m, 4H), 3.22 – 3.15 (m, 2H), 2.31 (s, 3H), 2.07 – 1.97 (m, 1H), 1.43 (s, 9H), 1.37 (s, 6H), 0.97 (d, J = 6.6 Hz, 4H). Step 2: Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01651] A mixture of tert-butyl 4-(6-cyclopropyl-1-((6-methoxy-2- methylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,2-dimethylpiperazine-1-carboxylate (30 mg, 0.052 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC (0.1% FA in H₂O / ACN) to give title product (10.4 mg, 38.2 %) as a white solid. ESI-MS (M+H) ⁺: 476.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 8.32 – 8.23 (m, 3H), 6.39 (s, 1H), 6.16 (s, 1H), 4.00 – 3.94 (m, 5H), 3.23 – 3.18 (m, 2H), 3.06 – 3.00 (m, 4H), 2.98 – 2.91 (m, 2H), 2.31 (s, 3H), 2.10 – 2.02 (m, 1H), 1.17 (s, 6H), 1.01 – 0.93 (m, 4H). Example 563 – Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(6- methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine-1-carboxamide formate

Step 1: Preparation of tert-butyl 4-(6-cyclopropyl-1-((6-methoxy-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate. [01652] A mixture of 6-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-amine (29 mg, 0.161 mmol), triphosgene (48 mg, 0.161 mmol) and TEA (163 mg, 1.613 mmol) in THF (5 mL) was stirred at 0 ^oC for 5 min. Then tert-butyl 4-(6-cyclopropyl-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (50 mg, 0.134 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL×3).The organic layer was concentrated in vacuo. The residue was triturated with MeOH (3 mL) to afford title product (33 mg, 42.6 %) as a white solid. ESI-MS (M+H) ⁺: 577.1. Step 2: Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(6-methoxy-2-methyl- 2H-pyrazolo[3,4-b]pyridin-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate. [01653] A mixture of tert-butyl 4-(6-cyclopropyl-1-((6-methoxy-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (30 mg, 0.052 mmol) in 4M HCl /EA (3 mL) was stirred at RT for 3 h. The reaction mixture was concentrated and the residue was purified by prep- HPLC (0.1% FA in H₂O / ACN) to give title product (10 mg, 36.8 %) as a white solid. ESI- MS (M+H) ⁺: 477.3.¹ H NMR (400 MHz, DMSO-d₆) δ 11.22 (s, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 6.43 (s, 1H), 4.06 (d, J = 6.4 Hz, 6H), 4.00 – 3.95 (m, 2H), 3.28 – 3.22 (m, 2H), 3.08 – 2.98 (m, 6H), 2.12 – 2.03 (m, 1H), 1.21 (s, 6H), 1.03 – 0.97 (m, 4H). Example 564 – Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro- 2-methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide hydrochloride.

C^{ompound 564} Step 1: Preparation of tert-butyl 4-(6-cyclopropyl-1-((7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate. [01654] To a solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (37 mg, 0.23 mmol) in THF (10 mL) were added TEA (228 mg, 2.25 mmol) and triphosgene (68 mg, 0.23 mmol) at 0^oC. After 10 min, tert-butyl 4-(6-cyclopropyl-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (70 mg, 0.19 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) to give the compound (30 mg, 30%) as a white solid. ESI-MS (M+H) ⁺:564.4. Step 2: Preparation of 6-cyclopropyl-4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride. [01655] To a mixture of tert-butyl 4-(6-cyclopropyl-1-((7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (30 mg, 0.05 mmol) in EA (1 mL) was added 4M HCl/EA (3 mL). The precipitate was filtered and washed with EA (3 mL) and lyophilized to give title product (14.5 mg, 58 %) as a white solid. ESI-MS (M+H) ⁺:464.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 9.72 (s, 1H), 9.63 (s, 2H), 8.17 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 6.60 (s, 1H), 4.08 – 3.98 (m, 3H), 3.58 – 3.44 (m, 2H), 3.32 (s, 2H), 3.25 – 3.08 (m, 4H), 2.45 (s, 3H), 2.13 – 2.01 (m, 1H), 1.40 (s, 6H), 1.03 – 0.93 (m, 4H). Example 565 – Preparation of (2S)-2-methyl-4-1H,2H,3H-pyrrolo[2,3-b]pyridin-4- ylpiperazine-1-carboxylate derivatives.

Step 1: Preparation of 4-chloro-1H,2H,3H-pyrrolo[2,3-b]pyridine [01656] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (80.0 g, 526.27 mmol) in tetrahydrofuran (1.3 L), (methylsulfanyl)methane borane (80.05 g, 1.05 mol, 100.06 mL, 2.0 eq.) was added carefully at room temperature. The resulting mixture was stirred at 65 °C for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The crude residue was carefully quenched with methanol (800 mL) and the solvent was again evaporated under reduced pressure. The resulting solid was triturated in a mixture of EtOAc and MeOH (8:2, 1 L), filtered, and the filtrate was concentrated in vacuo. The crude product was then purified by flash column chromatography using a gradient of methyl tert-butyl ether (MTBE/MeOH, 0-100%) to give the title 4-chloro-1H,2H,3H-pyrrolo[2,3- b]pyridine (13.0 g, 92.0% purity, 77.36 mmol, 14.7% yield) as a yellow solid. MS (ES+, m/z): 155.0 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 7.67 (d, J = 5.8 Hz, 1H), 6.48 (d, J = 5.8 Hz, 1H), 4.9 - 4.67 (s, 1H), 3.66 (t, J = 8.5 Hz, 2H), 3.11 (t, J = 8.5 Hz, 2H). Step 2: Preparation of (3S)-3-methyl-1-1H,2H,3H-pyrrolo[2,3-b]pyridin-4-ylpiperazine [01657] 4-Chloro-1H,2H,3H-pyrrolo[2,3-b]pyridine (7.33 g, 47.61 mmol), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (9.53 g, 47.61 mmol, 1 eq.), and ethylbis(propan-2- yl)amine (18.45 g, 142.84 mmol, 3 eq.) were dissolved in n-butanol (250 mL). The reaction mixture was transferred to an autoclave and stirred overnight at 140 °C. After the reaction was complete (as confirmed by LCMS), the solvent was evaporated under reduced pressure, yielding crude (3S)-3-methyl-1-1H,2H,3H-pyrrolo[2,3-b]pyridin-4-ylpiperazine (18.0 g, 40.0% purity, 32.98 mmol, 69.3% yield) which was used in the next step without purification. [01658] MS (ES+, m/z): 219.2 [M+H]⁺ Step 3: Preparation of (2S)-2-methyl-4-1H,2H,3H-pyrrolo[2,3-b]pyridin-4-ylpiperazine-1- carboxylate [01659] Di-tert-butyl dicarbonate (7.91 g, 36.27 mmol, 0.9 eq.) was added dropwise to a stirred solution of (3S)-3-methyl-1-1H,2H,3H-pyrrolo[2,3-b]pyridin-4-ylpiperazine (8.8 g, 40.3 mmol) and ethylbis(propan-2-yl)amine (10.41 g, 80.6 mmol, 2 eq.) in dichloromethane (200 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was washed with water, dried over anhydrous sodium sulfate (Na₂SO₄), filtered, and concentrated in vacuo to give a crude residue. This residue was purified by flash column chromatography using a hexane/MTBE gradient (0-100%) to afford tert-butyl (2S)-2-methyl-4-1H,2H,3H-pyrrolo[2,3-b]pyridin-4-ylpiperazine-1- carboxylate (5.0 g, 95.0% purity, 14.92 mmol, 37% yield). MS (ES+, m/z): 319.2 [M+H]⁺. ¹H NMR (600 MHz,CDCl₃) δ 7.68 (d, J = 5.6 Hz, 1H), 6.07 (d, J = 6.2 Hz, 1H), 4.3 (s, 1H), 3.91 (d, J = 13 Hz, 1H), 3.61 - 3.51 (m, 2H), 3.45 (d, J = 11.8 Hz, 1H), 3.35 (d, J = 12.4 Hz, 1H), 3.18 (t, J=12.6 Hz, 1H), 3.04 (t, J = 8.1 Hz, 2H), 2.97 (dd, J = 12.1, 3.4 Hz, 1H), 2.89 - 2.79 (m, 1H), 1.47 (s, 9H), 1.28 (d, J = 6.8 Hz, 3H). Parallel synthesis:

A ^{B C D E} [01660] To a solution of 1.1 eq. of Amine (A) and 1.5 eq. DIPEA in 1 mL of dry DMA was added 1.3 eq. Phenyl chloroformate (B) in one portion. The reaction mixture was stirred at rt for 3 hours. To the resulting mixture 1 eq. of mono-Boc diamine (D) and 2.5 eq. of DMAP were added. The reaction mixture was sealed and stirred at 90 °C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 mL TFA was added and stirred at room temperature for 4 hours. The mixture was evaporated. The residue was dissolved in DMSO (appr.1 mL). The solution was filtered, analyzed by LCMS, and transferred for HPLC purification. [01661] The purification was performed using Agilent 1260 Infinity systems equipped with DAD and mass-detector. Waters Sunfire C18 OBD Prep Column, 100 A, 5 µm, 19 mm × 100 mm with SunFire C18 Prep Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm was used. Deionized Water (phase A) and HPLC-grade Methanol or Acetonitrile (phase B) were used as an eluent. In most cases TFA was used as an additive to improve the separation of the products. In these cases, TFA salts of the products were formed respectively. Table 2. LCMS data:

Attorney Docket No.: RGT-020WO

Example 566 – Preparation of 4-bromo-N-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl- 1H,2H,3H-pyrrolo[2,3-b]pyridine-1-carboxamide derivatives.

Step 1: Preparation of N-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylcarbamate [01661] A solution of 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (4.1 g, 24.84 mmol) and pyridine (3.93 g, 49.68 mmol, 2 eq.) in dry tetrahydrofuran (40 mL) was cooled to 0 °C using an ice-water bath. Phenyl carbonochloridate (3.87 g, 24.84 mmol, 1 eq.) solution in THF was added dropwise to the reaction mixture at 0 °C. The resulting mixture was stirred for 1 hour at 0 °C, and then the solvent was removed under reduced pressure. The crude product was crystallized from MTBE to give phenyl N-8-fluoro-2-methylimidazo[1,2- a]pyridin-6-ylcarbamate (4.3 g, 98.0% purity, 14.77 mmol, 59.5% yield). MS (ES+, m/z): 286.0 [M+H]⁺.¹H NMR (400 MHz, DMSO): 10.33 (s, 1H), 8.64 (s, 1H), 7.87 (s, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.3 - 7.2 (m, 3H), 7.12 (d, J = 12.3 Hz, 1H), 2.32 (s, 3H). Step 2: Preparation of 4-bromo-N-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-1H,2H,3H- pyrrolo[2,3-b]pyridine-1-carboxamide [01662] Phenyl N-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylcarbamate (4.3 g, 15.07 mmol), 4-bromo-1H,2H,3H-pyrrolo[2,3-b]pyridine (2.98 g, 15.07 mmol, 1 eq.), and triethylamine (2.29 g, 22.61 mmol, 1.5 eq.) were dissolved in dry N,N-dimethylformamide (40 mL). The mixture was stirred at 100 °C for 1 hour. After completion of the reaction, water (40 mL) was added to the mixture, resulting in the formation of precipitate. The precipitate was filtered, washed with water (10 mL), and dried. The filtrate was extracted with ethyl acetate (60 mL), and the organic layer was separated, washed with brine (20 mL), _{dried over anhydrous sodium sulfate (Na SO ), and concentrated under reduced pressure. The} 833 IPTS/128781189.2

Attorney Docket No.: RGT-020WO crude residue was triturated with a minimal amount of acetonitrile, and the resulting precipitate was filtered. The combined precipitates were dried in vacuo to give pure 4-bromo- N-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-1H,2H,3H-pyrrolo[2,3-b]pyridine-1- carboxamide (1.67 g, 4.28 mmol, 28.4% yield). MS (ES+, m/z): 390.0 [M+H]⁺.¹H NMR (400 MHz, CDCl3) 11.23 (s, 1H), 8.78 (s, 1H), 7.91 (d, J = 5.9 Hz, 1H), 7.39 (s, 1H), 7.06 (d, J = 5.4 Hz, 1H), 6.88 - 6.77 (m, 1H), 4.23 (t, J = 8.5 Hz, 2H), 3.15 (t, J = 8.5 Hz, 2H), 2.47 (s, 3H). Parallel synthesis:

[01663] To a mixture of 1 eq. of mono-Boc diamine (A) and 1.5 eq. ArBr (B) in 1 mL of dry Dioxane under an inert atmosphere were added 0.05 eq. RuPhosPdG4, 0.05 eq. RuPhos and 2.5 eq. Cs2CO3. The reaction mixture was stirred at 100 °C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 mL TFA was added and stirred at room temperature for 4 hours. The mixture was evaporated. The residue was dissolved in DMSO (appr.1 mL), treated with scavenger SiliaMetS DMT and filtered. The solution was analyzed by LCMS and transferred for HPLC purification. [01664] The purification was performed using Agilent 1260 Infinity systems equipped with DAD and mass-detector. Waters Sunfire C18 OBD Prep Column, 100 A, 5 μm, 19 mm × 100 mm with SunFire C18 Prep Guard Cartridge, 100 A, 10 μm, 19 mm × 10 mm was used. Deionized Water (phase A) and HPLC-grade Methanol or Acetonitrile (phase B) were used as an eluent. In most cases TFA was used as an additive to improve the separation of the products. In these cases, TFA salts of the products were formed respectively. Table 3. LCMS data:

834 IPTS/128781189.2

Biological Activity of the Compounds of the Present Disclosure [01666] The biological activity of the compounds of the present disclosure was determined utilizing the assay described herein. Example 567 – Measurement of compound effect on pre-mRNA splicing using a PMS1 HiBit assay [01667] CRISPR-Cas9 gene editing allows for cell line generation where an endogenous protein can be tagged with a small 11-amino acid HiBiT tag. When exposed to its larger LgBiT subunit, the HiBiT tag binds with high affinity to produce a complex with luciferase activity that will release luminescent signal when treated with furimazine substrate. This system allows for quantitative measurement of a desired protein upon treatment with compound. Materials • DMEM medium: Gibco #12100-046 • FBS Fetal Bovine Serum: Gibco #10091-148 • Nano-Glo HiBiT Lytic Detection System: Promega #N3050 • White, 384-well assay plate: Greiner #781080 • Plate reader: PerkinElmer Envision [01668] For compound preparation, test compounds were diluted from 10 mM stocks in 1:3.162 serial dilutions in DMSO. Then 100 nL test compounds at the serial dilutions were dispensed into 384-well assay plate using Echo dispenser. Positive control (HPE; Compound A, final concentration 2 μM) and negative control (ZPE; final 0.5% DMSO) were dispensed to respective columns. [01669] To prepare cell lines, HEK 293/PMS1-HiBiT cells were transferred to a 15 mL tube and centrifuged at 1000 rpm for 5 min to pellet the cells. The cells were resuspended to 100,000 cells/mL in the DMEM medium. Then 20 μL of cell suspension were dispensed into the assay plate containing compounds to give seed cell density at 2,000 cells/well. Assay plates were then centrifuged briefly and then incubated at 37 °C, 5% CO₂ for 48 hours. After incubation, the assay plate and its contents were equilibrated at room temperature for approximately 20 minutes. 20 μL of Nano-Glo HiBiT lytic reagent was added to the assay plate and the plates were centrifuged at 500 rpm for 1 minute and equilibrated for 15 min. The luminescence (RLU) signals in each well were recorded using Envision plate reader, then converted to percentage inhibition values using the signals in HPE and ZPE treated wells as the references. IC50 values were determined by curve fitting in Levenberg–Marquardt algorithm. [01670] The percent activity was calculated as: % Inhibition = (Value – ZPE)/(HPE – ZPE) x 100% [01671] In Table 4 below, A indicates an IC₅₀ < 0.1 µM, B indicates an IC₅₀0.1 µM to < 1.0 µM, and C indicates an IC₅₀ > 1.0 µM.

EQUIVALENTS [01672] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. [01673] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

CLAIMS WHAT IS CLAIMED: 1. A compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3-12 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted 8-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R¹ is independently selected from halogen, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_{3- 6}cycloalkyl, and 5-8 memebered heteroaryl; each R² is independently selected from halogen and C_1-6alkyl; R³ is selected from H and C_1-6alkyl; each R^a is independently selected from the group consisting of halogen, -OH, C_1-6alkyl, C_{1- 6}haloalkyl, oxo, C_3-6cycloalkyl, -C(O)O-C_1-6alkyl, -C(O)C_1-6haloalkyl, -C(O)O-C_1- 6alkylene-OC(O)-C1-6alkyl, and -N(R^cR^d), wherein the C1-6alkyl is optionally substituted with -OH, C_1-6alkoxy, C_3-6cycloalkyl, -N(R^cR^d), or -S(O)₂C_1-6alkyl, or two R^a attached to the same carbon atom, together with carbon atom to which they are attached, combine to form a C_3-6cycloalkyl; each R^b is independently selected from the group consisting of halogen, -OH, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6 alkoxy, C_1-6haloalkoxy, and C_3-6cycloalkyl, wherein the C_1-6 alkoxy is optionally substituted with C_3-6cycloalkyl; each R^c is independently selected from H, C_1-6alkyl, and C_3-6cycloalkyl, wherein the C_1-6alkyl is optionally substituted with -OH; each R^d is independently selected from H and C_1-6alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. 2. The compound of claim 1, wherein m and n are each 0. 3. The compound of claim 1 or 2, wherein Ring A is an optionally substituted 5-6 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4. The compound of any one of claims 1-3, wherein Ring A is selected from optionally substituted piperidinyl and optionally substituted pyrrolidinyl. 5. The compound of any one of claims 1-4, wherein each R^a is independently selected from C_1-6alkyl and -N(R^cR^d). 6. The compound of any one of claims 1-5, wherein each R^c is methyl and each R^d is H. 7. The compound of any one of claims 1-6, wherein each R^a is independently selected from methyl and -N(H)CH₃. 8. The compound of any one of claims 1-7, wherein p is 1 or 2. 9. The compound of any one of claims 1-8, wherein the portion of the compound

10. The compound of claim 9, wherein the portion of the compound represented by

. 11. The compound of any of claims 1-8, wherein the portion of the compound represented

12. The compound of any one of claims 1-8, wherein the portion of the compound

13. The compound of claim 1, wherein the compound is a compound of formula (Ia),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3; and the rest of the variables are as defined in claim 1. 14. The compound of claim 13, wherein p is 0.

15. The compound of claim 13, wherein p is 1 or 2. 16. The compound of claim 13 or 15, wherein each R^a is methyl. 17. The compound of claim 1, wherein the compound is a compound of formula (Ib),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in claim 1. 18. The compound of claim 17, wherein each R^a is -N(H)CH₃. 19. The compound of claim 17 or 18, wherein p is 1. 20. The compound of claim 1, wherein the compound is a compound of formula (Ic),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in claim 1. 21. The compound of claim 20, wherein p is 0. 22. The compound of claim 1, wherein the compound is a compound formula (Id),

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined as in claim 1. 23. The compound of any one of claims 1-22, wherein Ring B is an optionally substituted 9 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 24. The compound of any one of claims 1-23, wherein Ring B is selected from the group consisting of optionally substituted indazolyl, optionally substituted imidazo[1,2-a]pyridyl, and optionally substituted 2,7a-dihyrdobenzo[d]oxazolyl. 25. The compound of any one of claims 1-20, wherein each R^b is independently selected from the group consisting of halogen, C_1-6alkyl, C_1-6haloalkyl, and C_1-6alkoxy. 26. The compound of any one of claims 1-21, wherein each R^b is independently selected from the group consisting of fluoro, methyl, methoxy, ethoxy, -CHF₂, and -CF₃. 27. The compound of any one of claims 1-22, wherein q is 2 or 3. 28. The compound of any of claims 1-22, wherein the portion of the compound represented

R^b R^b q q R^{b b} q R N q N N N _N NH N _{N N} N N _{N N} b _{N N} ^b , ^b R^b N ^R , , ^{R R} _, ^q , R^b R^b q q R^b R^b q q R^b R^b q N NH N N , , ^Rb _{, H , NH} , R^{b b} N q R N q R^b N q NH NH N R^b N ^b R^b , ^q , R^b _{, NH} R , ^q ,

29. The compound of any one of claims 1-23, wherein the portion of the compound

30. The compound of claim 23, wherein the portion of the compound represented by

F N F

F O O O N N N N N N N N N N , N , N , N _{, O} , F F O F N N N N N O _, ^O _{, O , S ,} ^S , F O O N _{N N N N N N N N N} , , , , ,

31. The compound of any one of claims 1-24, wherein the portion of the compound

32. A compound of selected from those described in Table 1 or a pharmaceutically acceptable salt thereof. 33. A pharmaceutical composition comprising a compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 34. A compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, for use as a small molecule splicing modulator.

36. A pharmaceutical composition comprising a compound of any one of claims 1-32 and 34, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 37. A method of treating a disorder related to a nucleotide repeat expansion n a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutical composition of claim 33. 38. The method of claim 37, wherein the nucleotide repeat expansion comprises a nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CNN, ANN, TNN, and GNN, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C). 39. The method of claim 37, wherein the nucleotide repeat expansion comprises a nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CAG, CAG/CTG, GCG, GCN, CGG, CCG, CCCCGCCCCGCG, GCA, GGGGCC, CTG, GAA, ATTCT, TGGAA, GGCCTG, AAGGG, CCCTCT, ATTTT/ATTTC, and CCCTCT, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C). 40. The method of claim 38 or 39, wherein the nucleotide repeat expansion comprises a trinucleotide sequence repeated two or more times, wherein the trinucleotide sequence is selected from the group consisting of CAG, CTG, CGG, and GCN. 41. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutical composition of claim 33, wherein the disease is selected from the group consisting of Dentatorubropallidoluysian atrophy, Huntington's disease, spinal and bulbar muscular atrophy, SCA1 (Spinocerebellar ataxia Type 1), SCA2 (Spinocerebellar ataxia Type 2), SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease), SCA6 (Spinocerebellar ataxia Type 6), SCA7 (Spinocerebellar ataxia Type 7), SCA12 (Spinocerebellar ataxia Type 12), SCA17 (Spinocerebellar ataxia Type 17), FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor/ataxia syndrome), FRAXE (Fragile XE mental retardation), Baratela-Scott syndrome, FRDA (Friedreich's ataxia), DM1 (Myotonic dystrophy Type 1), DM2 (Myotonic dystrophy Type 2), SCA8 (Spinocerebellar ataxia Type 8), Fuchs endothelial corneal dystrophy, Desbuquois dysplasia, amyotrophic lateral sclerosis, frontotemporal dementia, GLS (glutaminase) disease, and SBMA/Kennedy disease. 42. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutical composition of claim 33, wherein the disease is Huntington’s disease. 43. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutical composition of claim 33, wherein the disease is Myotonic dystrophy 1. 44. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutical composition of claim 33, wherein the disease is selected from the group consisting of FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor/ataxia syndrome), and FRAXE (Fragile XE mental retardation).