WO2025008061A1 - 1,6-naphthridine compounds as smarca2 inhibitors useful for the treatment of smarca4 deficient cancers - Google Patents

Abstract

The invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds as inhibitors of the SMARCA2 protein and to their use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC).

Description

1 ,6-NAPHTHRIDINE COMPOUNDS AS SMARCA2 INHIBITORS USEFUL FOR THE TREATMENT OF SMARCA4 DEFICIENT CANCERS

FIELD OF THE INVENTION

[0001] The invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds as inhibitors of the SMARCA2 protein and to their use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC).

BACKGROUND OF THE INVENTION

[0002] The S witch/ Sucrose Non-Fermentable (SWI/SNF), also known as BAF complex, is a multi-subunit complex that modulates chromatic structure through the activity of two mutually exclusive helicase/ ATPase catalytic subunits: SWI/SNF -Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2, BRAHMA or BRM) and SWI/ SNF -Related, Matrix- Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 (SMARCA4 or BRG1). The core and the regulatory subunits couple ATP hydrolysis to the perturbation of histone-DNA contacts, thereby providing access points to transcription factors and cognate DNA elements that facilitate gene activation and repression.

[0003] Mutations in the genes encoding the twenty canonical SWI/SNF subunits are observed in nearly 20% of all cancers with the highest frequency of mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical and endometrial), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma. Despite having a high degree of homology, and their presumed overlapping functions, SMARCA2 and SMARCA4 have been reported as having different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is infrequent in tumor development. In fact, numerous types of cancer have been shown to be SMARCA4-related (e.g., cancers having a SMARCA4-mutation or a SMARCA4-deficiency, such as lack of expression), including, e.g., lung cancer (such as non- small cell lung cancer or NSCLC).

[0004] SMARCA2 has been demonstrated as one of the top essential genes in SMARCA4- related or -mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells depend exclusively on SMARCA2 activity - i.e., there is a greater incorporation of SMARCA2 into the complex to compensate for the SMARCA4 deficiency. Thus, SMARCA2 may be targeted in SMARCA4-related/deficient cancers. The co-occurrence of the deficiency of the expression of two (or more) genes that leads to cell death is known as synthetic lethality. Accordingly, synthetic lethality can be leveraged in the treatment of certain SMARCA2/SMARCA4-related cancers.

[0005] There is an ongoing need for effective treatment for diseases that are treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, non-specific effects, and the inability to selectively target and modulate SMARCA2 remains an obstacle to the development of effective treatments. As such, small-molecule therapeutic agents that target SMARCA2 would be very useful.

[0006] An objective of the present invention is to provide compounds that are selective on SMARCA2 over SMARCA 4.

[0007] An objective of the present invention is to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient cancers.

[0008] An objective of the present invention is to provide compounds SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient NSCLC.

SUMMARY OF THE INVENTION

[0009] Embodiments of the present invention relate to certain uses and methods of use of 1,6- naphthyridine chemical entities having SMARCA2 modulating properties, and pharmaceutical compositions comprising these chemical entities, to the use of said chemical entities as inhibitors of the SMARCA2 protein, and to methods of treatment or use in the treatment of SMARCA4 deficient cancers, as described in the claims.

[0010] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

[0011] Embodiments of this invention are uses and methods of treatment using compounds of Formula (I),

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

R¹ is an optionally substituted heteroaryl selected from: (a) 5-membered heteroaryl selected from:

wherein each Ra is independently selected from: halo, C_1-4alkyl, C_1-4alkyl substituted with OH, C_1-4haloalkyl, and (C=O)CH₃; Rb is selected from: C1-4alkyl substituted with OH; OC1-4alkyl; OCH2CH2OH; and OCHF₂; or (c) 6-membered heteroaryl selected from:

wherein each Rd is independently C_1-4alkyl, C_1-4haloalkyl, and OC_1-4alkyl; Re is selected from: C_1-4alkyl, C_1-4alkyl substituted with OH or OCH₃, and C_1- 4haloalkyl; X is NH or O;

, wherein Ring A is a nitrogen linked monocyclic, polycyclic, bridged, spirocyclic or fused heterocycloalkyl selected from:

and each R^c is independently halo or CH3; or

nitrogen linked monocyclic, polycyclic, spirocyclic heterocycloalkyl selected from:

wherein R^k is selected from: (CH)(CH3)2, oxetan-3-yl,

10 R^f is H or CH₃; R^g is selected from:

R^h is Ci-4alkyl;

R' is selected from:

n is 0, 1, or 2; and pharmaceutically acceptable salts and stereoisomers thereof.

INCORPORATION BY REFERENCE

[0012] All publications, patents, patent applications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, patent application, or published nucleotide and amino acid sequence, was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0014] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0015] In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and/or” unless stated otherwise.

[0016] When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. As used herein, “about X” (where X is a numerical value) preferably refers to ±10% of the recited value, inclusive. For example, the phrase “about 8” refers to a value of 7.2 to 8.8, inclusive; as another example, the phrase “about 8%” refers to a value of 7.2% to 8.8%, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of “1 to 5” is recited, the recited range should be construed as including ranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, and the like. In addition, when a list of alternatives is positively provided, such a listing can also include embodiments where any of the alternatives may be excluded. For example, when a range of “1 to 5” is described, such a description can support situations whereby any of 1, 2, 3, 4, or 5 are excluded; thus, a recitation of “1 to 5” may support “1 and 3-5, but not 2”, or simply “wherein 2 is not included.”

[0017] Some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions and acceptable error margins, for such given value.

[0018] As used herein, the expression “one or more” refers to at least one, for example one, two, three, four, five or more, whenever possible and depending on the context.

[0019] Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0020] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0021] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4^th Ed.” Vols. A (2000) and B (2001), Plenum Press, New York.

[0022] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications, or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0023] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0024] Hereinbefore and hereinafter, the term “compound of Formula (I)” is meant to include the addition salts, and the stereoisomers thereof.

[0025] As used herein, “C_x-y” (where x and y are integers) refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents). Thus, a Ci-ealkyl group contains from 1 to 6 carbon atoms, a Cs-ecycloalkyl group contains from 3 to 6 carbon atoms, and so on. [0026] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo. [0027] The “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “Ci-ealkyl” or similar designations. [0028] By way of example, the term “Ci-4alkyl”, or “Ci-ealkyl” as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 4 or 1 to 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, and the like.

[0029] The term “haloalkyl” refers to an alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with one or more halogens. The term “haloalkyl” includes “haloCi-4alkyl”, “haloCi-ealkyl”, monohaloCi-4alkyl, monohaloCi-ealkyl, polyhaloCi-4alkyl, and polyhaloCi-ealkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi-4alkyl or haloCi-ealkyl may have one, two, three or more halogens. Examples of “haloalkyl” groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF₃)₂), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

[0030] “Amino” refers to a -NH2 group.

[0031] The term “aromatic” refers to a planar ring having a delocalized 7t-electron system containing 4n+2 n electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0032] The term “non-aromatic group” embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and fully saturated heterocyclyl ring systems. [0033] The terms “unsaturated” and “partially saturated” refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond i.e. the ring contains at least one multiple bond e.g. a C=C, C=C or N=C bond.

[0034] The term “fully saturated” refers to rings where there are no multiple bonds between ring atoms. Saturated heterocyclyl groups include piperidine, morpholine, thiomorpholine, piperazine. Partially saturated heterocyclyl groups include pyrazolines, for example 2- pyrazoline and 3-pyrazoline.

[0035] The term “aryl” refers to a monocyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having 6 atoms per ring (Carbon atoms in the aryl groups are sp2 hybridized.)

[0036] The term “phenyl” represents the following moiety:

[0037] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. An example of a “cycloalkyl” is “Cs-ecycloalkyl”. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

, and the like.

[0038] The term “heterocyclyl” or “heterocycloalkyl”, is as defined herein, contains at least one heteroatom typically selected from nitrogen, oxygen or sulphur, in particular containing up to 5, up to 4, up to 3, up to 2, or a single heteroatom. Where reference is made herein to a heterocyclyl or heterocycloalkyl ring system, the heterocyclyl or heterocycloalkyl ring can, unless the context indicates otherwise, be optionally substituted (i.e. unsubstituted or substituted) by one or more substituents as discussed herein. It is understood that a heterocyclyl or heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring. The radicals may be fused with an aryl or heteroaryl. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:

[0039] The heterocyclyl or heterocycloalkyl ring systems can be heteroaryl ring systems having from 5 to 12 ring members, more usually from 5 to 10 ring members.

[0040] The heterocyclyl rings also include bridged ring systems such as for example bridged cycloalkanes, such as for example norbornane (1,4-endo-methylene-cyclohexane), adamantane, oxa-adamantane; bridged morpholine rings such as for example 8-oxa-3- azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane; bridged piperazine rings such as for example 3,6-diazabicyclo[3.1.1]heptane; bridged piperidine rings such as for example 1,4-ethylenepiperidine. For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4^th Edition, Wiley Interscience, pages 131-133, 1992.

[0041] The term “heteroaryl” is used herein to denote a heterocyclyl ring system having aromatic character. The term “heteroaryl” embraces polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system may be attached to the remainder of the compound by an aromatic ring or by a non-aromatic ring.

[0042] Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings, or two fused five membered rings. The heteroaryl ring system may contain up to about five heteroatoms typically selected from nitrogen, oxygen, and sulphur. Typically, the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. It is understood that a heteroaryl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heteroaryl ring. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Illustrative examples of heteroaryl groups include:

[0043] A nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. Each ring may, in addition, contain up to about four other heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, for example 1, 2 or 3, more usually up to 2 nitrogens, for example a single nitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. [0044] Examples of non-aromatic heterocyclyl groups are groups having from 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, and typically have from 1 to 5 heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ring members), usually selected from nitrogen, oxygen and sulphur. The heterocyclyl groups can contain, for example, cyclic ether moieties (e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine), and combinations thereof (e.g. thiomorpholine).

[0045] The heterocyclyl and cycloalkyl rings also include bridged ring systems such as for example bridged cycloalkanes, such as for example norbornane (1,4-endo-methylene- cyclohexane), adamantane, oxa-adamantane; bridged morpholine rings such as for example 8- oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8- azabicyclo[3.2.1]octane; bridged piperazine rings such as for example 3,6-diazabicyclo[3.1.1]heptane; bridged piperidine rings such as for example 1,4- ethylenepiperidine. For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4^th Edition, Wiley Interscience, pages 131-133, 1992.

[0046] Lines drawn into ring systems indicate that the bond may be attached to any of the suitable and available ring atoms. The term “variable point of attachment” means that a group is allowed to be attached at more than one alternative position in a structure. The attachment will always replace a hydrogen atom on one of the ring atoms. In other words, all permutations of bonding are represented by the single diagram, as shown in the illustrations below.

[0047] The term “optional” or “optionally” means the event described subsequent thereto may or may not happen. This term encompasses the cases that the event may or may not happen.

[0048] In the compounds of the present disclosure the carbon atom indicated with a in the drawn formula, is a chiral center. When the carbon atom is indicated with “(*R)”, it means that it is a pure enantiomer but that it is unknown whether is it an R or S enantiomer.

Similarly, when the carbon atom is indicated with “(*S)”, it means that it is a pure enantiomer but that it is unknown whether is it an R or S enantiomer. [0049] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moi eties when the atoms joined by the bond are considered to be part of larger substructure.

[0050] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0051] The term a “therapeutically effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that, when administered to a mammal in need, is effective to at least partially ameliorate or to at least partially prevent diseases, disorders or conditions described herein.

[0052] As used herein, the term “composition” is intended to encompass a product comprising specified ingredients in specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. [0053] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0054] The term “antagonist” as used herein, refers to a small-molecule agent that binds to a receptor and subsequently decreases the agonist induced transcriptional activity of the receptor.

[0055] The term “agonist” as used herein, refers to a small-molecule agent that binds to a receptor and subsequently increases receptor transcriptional activity in the absence of a known agonist.

[0056] The term “inverse agonist” as used herein, refers to a small-molecule agent that binds to a receptor and subsequently decreases the basal level of receptor transcriptional activity that is present in the absence of a known agonist.

[0057] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0058] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0059] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[0060] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells. A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0061] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.

[0062] The term “angiogenesis” refers to the formation and the growth of new blood vessels. Normal angiogenesis occurs in the healthy body of a subject for healing wounds and for restoring blood flow to tissues after injury. The healthy body controls angiogenesis through a number of means, e.g., angiogenesis-stimulating growth factors and angiogenesis inhibitors. Many disease states, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal angiogenesis refers to angiogenesis greater than that in a normal body, especially angiogenesis in an adult not related to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels that feed diseased tissues and/or destroy normal tissues, and in the case of cancer, the new vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).

[0063] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. Biological samples also include those biological samples that are transgenic, such as transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus.

Isomers, salts, N-oxides, isotopically labeled derivatives

[0064] Hereinbefore and hereinafter, the term “compound of Formula (I)”, “compounds of the present disclosure or invention”, “compounds presented herein”, or similar terms, is meant to include the addition salts, and the stereoisomers thereof.

[0065] In certain embodiments, the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns. In some embodiments, a compound of the present disclosure is used as a single enantiomer. In some embodiments, a compound of the present disclosure is used as a racemic mixture. In some embodiments, a compound of the present disclosure possesses hindered rotation about a single bond resulting in atropisomers.

[0066] In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0067] For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced. Examples of tautomeric forms include, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/enediamines, nitroso/oxime, thioketone/enethiol, and nitro/aci -nitro.

keto enol enolate

[0068] Such forms in so far as they may exist, are intended to be included within the scope of the compounds presented herein. It follows that a single compound may exist in both stereoisomeric and tautomeric form.

[0069] Where compounds described herein contain one or more chiral centres and can exist in the form of two or more optical isomers, references to the compounds described herein include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) of two or more optical isomers, unless the context requires otherwise. When a compound has more than one chiral centre, and one chiral centre is indicated as having an absolute stereoconfiguration, the other chiral centre(s) include all optical isomeric forms, either as individual optical isomers, or mixtures (e.g. racemic mixtures) of two or more optical isomers, thereof, unless the context requires otherwise. The optical isomers may be characterized and identified by their optical activity (i.e. as + and - isomers depending on the direction in which they rotate plane polarized light, or d and 1 isomers) or they may be characterized in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.

[0070] Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)- pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)- camphorsulphonic, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.

[0071] Where compounds exist as two or more isomeric forms, one isomeric form, e.g., one enantiomer in a pair of enantiomers, may exhibit advantages over the other isomeric form, e.g. over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers.

[0072] When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound described herein is for instance specified as (S), this means that the compound is substantially free of the (R) isomer; when a compound described herein is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound described herein is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

[0073] As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise not indicated as having a particular configuration (e.g., R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.

[0074] The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

[0075] Enantiomers are stereoisomers that are non-superimposable mirror images of each [0076] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the present disclosure includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

[0077] Disubstituted cycloalkyl and heterocycloalkyl stereoisomers may be designated by nomenclature prefixes such as cis and trans. Cis and trans isomers are also called "geometric isomers". When a compound described herein is for instance specified as “cis”, this means that the two groups point in the same direction relative to the plane of the ring. In the “trans” isomer, they point in the opposite direction. Exemplified below are “cis” and “trans” isomers of 2,6-dimethyl-morpholine. There are two possible relative configurations based on the relative positions of the two substituents and whether they are on the same side or opposite faces of the cyclic structure.

Relative Configuration

(2R.6S) (2S.6R) (2S,6S) (2R.6R)

(cis)-2,6-dimethyl-morpholine (trans)-2,6-dimethyl-morpholine

A/-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1 ,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide

[0079] In the present invention, tri substituted piperidine moieties with stereocenters are defined as (3a, 4a, 5a) or (3a, 4β, 5a). For example:

(3a,4a,5a)-3,5-dimethyl-4-piperidinol (3a,4p,5a)-3,5-dimethyl-4-piperidinol

(3a,4a,5a)-3,5-dimethyl-4-piperidinol (3a,4b,5a)-3,5-dimethyl-4-piperidinol

(3p,4p,5p)-3,5-dimethyl-4-piperidinol (3p,4a,5p)-3,5-dimethyl-4-piperidinol

(3b,4b,5b)-3,5-dimethyl-4-piperidinol (3b,4a,5b)-3,5-dimethyl-4-piperidinol

[0080] The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

[0081] The methods and formulations described herein include the use of N-oxides (if appropriate), pharmaceutically acceptable salts, and combinations thereof, of compounds having the structures presented herein and having the same type of activity.

[0082] The salt forms of the compounds presented herein are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977) “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non- pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0083] The pharmaceutically acceptable salts include pharmaceutically acceptable acid and base addition salts and are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds described herein are able to form.

[0084] The salts of the present disclosure can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in “Pharmaceutical Salts: Properties, Selection, and Use”, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The compounds of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed. [0085] The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like) or organic acids such (as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid and the like) in an anion form.

[0086] Appropriate anions comprise, for example, acetate, 2,2-dichloroacetate, adipate, alginate, ascorbate (e.g. L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4- acetamidobenzoate, butanoate, bicarbonate, bitartrate, bromide, (+) camphorate, camphor- sulphonate, (+)-(15)-camphor-10-sulphonate, calcium edetate, camsylate, caprate, caproate, caprylate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecyl sulphate, edetate, estolate, esylate, ethane-l,2-disulphonate, ethanesulphonate, formate, fumarate, galactarate, gentisate, glucoheptonate, gluceptate, gluconate, D-gluconate, glucuronate (e.g. D-glucuronate), glutamate (e.g. L-glutamate), a-oxoglutarate, glycolate, glycollylarsanilate, hexylresorcinate, hippurate, hydrabamine, hydrobromide, hydrochloride, hydriodate, 2-hydroxyethane-sulphonate, hydroxynaphthoate, iodide, isethionate, lactate (e.g. (+)-L-lactate, (±)-DL-lactate), lactobionate, malate, (-)-L-malate, maleate, malonate, mandelate, (±)-DL-mandelate, mesylate, methansulfonate, methylbromide, methylnitrate, methyl sulfate, mucate, naphthalene-sulphonate (e.g.naphthalene-2-sulphonate), naphthalene- 1,5 -di sulphonate, 1 -hydroxy -2 -naphthoate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate (embonate), pantothenate, phosphate/diphosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacate, stearate, subacetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, teoclate, thiocyanate, toluenesulphonate (e.g. /?-toluenesulphonate), tosylate, triethiodide, undecylenate, valeric acids, as well as acylated amino acids and cation exchange resins. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

[0087] The compounds of the present disclosure containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases in a cation form. Appropriate basic salts comprise those formed with organic cations such as arginine, benzathine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, tromethamine, and the like; those formed with ammonium ion (i.e., NHC), quaternary ammonium ion N(CH3)4⁺, and substituted ammonium ions (e.g., NH3R , NH2R2 , NHR.3⁺, NR/); and those formed with metallic cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. Where the compounds described herein contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of the compounds presented herein.

[0088] Conversely said salt forms can be converted by treatment with an appropriate acid into the free form.

[0089] In some embodiments, sites on the compounds disclosed herein are susceptible to various metabolic reactions. Therefore, incorporation of appropriate substituents at the places of metabolic reactions will reduce, minimize or eliminate the metabolic pathways. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium or an alkyl group.

[0090] The compounds of the present disclosure include compounds that are isotopically labeled, i.e., with one or more isotopic substitutions. These compounds are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. A reference to a particular element includes within its scope all isotopes of the element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygen include within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. In another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may also be useful in a diagnostic context. Radiolabeled compounds described herein may comprise a radioactive isotope selected from the group of ²H, ³H, ⁿC, ¹⁸F, ¹²²1, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selected from the group of ²H, ³H, ⁿC and ¹⁸F. More preferably, the radioactive isotope is ²H. In particular, deuterated compounds are intended to be included within the scope of the present invention. In some embodiments, metabolic sites on the compounds described herein are deuterated. [0091] Throughout the specification, groups and substituents thereof can be chosen to provide stable moieties and compounds. [0092] Embodiments of the 1,6-naphthyridine compounds for use as described herein are compounds of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is an optionally substituted heteroaryl selected from: (a) 5-membered heteroaryl selected from:

wherein each Ra is independently selected from: halo, C1-4alkyl, C1-4alkyl substituted with OH, C_1-4haloalkyl, and (C=O)CH₃; Rb is selected from: C1-4alkyl substituted with OH; OC1-4alkyl; OCH2CH2OH; and OCHF2; or (c) 6-membered heteroaryl selected from:

wherein each Rd is independently C1-4alkyl, C1-4haloalkyl, and OC1-4alkyl; Re is selected from: C_1-4alkyl, C_1-4alkyl substituted with OH or OCH₃, and C_1- 4haloalkyl; X is N or O;

, wherein Ring A is a nitrogen linked monocyclic, polycyclic, bridged, spirocyclic or fused heterocycloalkyl selected from:

and each R^c is independently halo or CH3; or

Rh is C1-4alkyl; R' is selected from:

n is 0, 1, or 2; and pharmaceutically acceptable salts and stereoisomers thereof.

[0093] In some embodiments, R¹ is

[0095] In some embodiments,

[0096] In some embodiments, R¹ is

[0097] In some embodiments, X is N. In some embodiments, X is O.

[0098] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is

[0099] In some embodiments, R⁵ is

[0101] In some embodiments, the compound of Formula (I) is a compound as shown below in Table 1.

JAB7147WOPCT1 -57-

[0102] and pharmaceutically acceptable salts and stereoisomers thereof. [0103] In some embodiments, the 1,6-naphthyridine compound is selected from the group consisting of: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-5-((2- hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-6- methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3 ^,4 ^,5 ^)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((3α, 4β, 5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthyridin- 7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-5-((2- hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-6- methyl-5-(methylsulfonyl)nicotinamide; N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)- 6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α, 4β, 5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthyridin- 7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α, 4β, 5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthyridin- 7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-5-((2- hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(4-fluoro-6-((3α, 4β, 5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-6- methyl-5-((*S)-S-methylsulfonimidoyl)nicotinamide; and 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-6-methylnicotinamide; and pharmaceutically acceptable salts and stereoisomers thereof. Synthesis of Compounds [0104] In this section, as in all other sections of this application unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein. [0105] The synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions presented herein may vary. Techniques and materials recognized in the field are described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. [0106] The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics. [0107] In the reactions described herein, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. [0108] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyl dimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[0109] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.

[0110] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. [0111] Typically blocking/protecting groups may be selected from:

Fmoc

[0112] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosure.

General synthetic pathways

SCHEME 1

(io ("D

[0113] A suitably substituted ester compound of formula (II) is commercially available or synthetically accessible. An heteroaryl halide compound of formula (II), such as methyl 5- bromo-6-methyl-3 -pyridinecarboxylate, can be reacted in a palladium-catalyzed sulfination using triphenylphosphine; 1,10-phenanthroline; in the presence of K2S2O5 and sodium formate; tert-butyl ammonium bromide; a palladium catalyst such as palladium acetate, and the like; followed by in situ alkylation with, for example, 2-(2 -bromoethoxy )tetrahydro-27/- pyran; in a suitable solvent such as DMSO, ACN, and the like; at temperatures ranging from room temperature to 100 °C; to afford methyl 6-methyl-5-((3-((tetrahydro-27/-pyran-2- yl)oxy)propyl)sulfonyl)nicotinate. Deprotection of the pyran can be achieved under acidic conditions known to one skilled in the art such as HCl/MeOH, to provide methyl 5-((3- hydroxypropyl)sulfonyl)-6-methylnicotinate.

[0114] An ester compound of formula (II), wherein R¹ has a halide such as Br, for example, 5-bromonicotinic acid; can be further functionalized by reaction with n-butyllithium; and acetone; in a suitable solvent such as THF, and the like; at temperatures ranging from -78 °C to room temperature; to afford a compound of formula (II), where the Br is now replaced by C(OH)(CH₃)₂.

[0115] A commercially available or synthetically accessible ester compound of formula (II), where ring B is a suitably substituted heteroaryl can be reacted under basic conditions such as NaOH, LiOH, KOH, and the like; in a suitable solvent such as methanol (MeOH), ethanol (EtOH), THF, ACN, H2O, or a mixture thereof; at a temperature of 60 °C to 80 °C; for a period of 1-6 h; to afford an acid compound of formula (III).

[0116] An acid compound of formula (III), wherein R¹ has a halide such as Br (bromide), such as 5-bromonicotinic acid; can be further functionalized by reaction with BuLi, in a suitable solvent such as THF, and the like; and acetaldehyde; at temperatures of about -78 °C; for a period of 1 h; to provide a compound of formula (III), where the Br is now replaced by CH(OH)CH₃.

[0117] A commercially available or synthetically accessible ester compound of formula (II), where ring B is a suitably substituted halogeno-heteroaryl can be reacted in two steps, first with a suitable alkylthiolate such as, for example, sodium methylthiolate in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, room temperature; then in a second step, oxidation of the intermediate alkylsulfide can be achieved using a suitable oxidizing agent such as, for example, mCPBA, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 0 °C or room temperature. [0118] A commercially available or synthetically accessible ester compound of formula (II), where ring B bears a thiol group can be difluoromethylsulfonylated in 3 steps, first, by reaction with sodium 2-chloro-2,2-difluoroacetate, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 100 °C; then, in a second step, by hydrolizing the intermediate ester in conditions known in the art, such as, for example, LiOH, in a suitable solvent such as, for example, a mixture of THF and water, at a suitable temperature such as, for example, room temperature; and in a third step, by reacting the intermediate with a suitable oxidizing agent such as, for example, NaIO4, in the presence of a suitable catalyst such as, for example, RuCl₃, in a suitable solvent such as, for example, DCM, ACN, water, or a mixture thereof, at a suitable temperature such as, for example, room temperature. Alternatively, a commercially available or synthetically accessible ester compound of formula (II), where ring B is a methylsulfonyl-heteroaryl can be difluoromethylsulfonylated in 3 steps, first, by reaction with 2,2,2-trifluoroethyl trifluoroacetate in the presence of a suitable base such as, for example, LiHMDS, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, -78 °C; then, in a second step, by reacting the intermediate 3,3,3-trifluoro-2-oxo-propylsulfone with a suitable fluorinating agent such as, for example, l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS [140681-55-6]), in a suitable solvent such as, for example, ACN, at a suitable temperature such as, for example, room temperature to 60 °C; and in a third step, by reacting the intermediate 1, 1,3,3, 3-pentafluoro-2- oxo-propyl sulfone with a suitable base such as, for example, DIPEA, in a suitable solvent such as, for example, THF, water, or a mixture thereof, at a suitable temperature such as, for example, room temperature.

[0119] A commercially available or synthetically accessible ester compound of formula (II), where ring B is a heteroaryl substituted by an alkylthiolate can be reacted with a suitable oxidizing agent such as, for example, oxone, in a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, room temperature, to afford the corresponding alkylsulfonylated heteroaryl compound.

[0120] According to SCHEME 2, a compound of formula (IV), where Hal is Br or Cl and R⁵ is a suitably substituted heteroaryl, can be borylated employing conditions known to one skilled in the art such as Miyaura borylation conditions. For example, a compound of formula (IV), where Hal is Br or Cl, can be treated with a transition metal catalyst such as 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)C12), and the like; in a suitable solvent such as dimethylsulfoxide (DMSO) or 1,4-di oxane, and the like; and a base such as potassium acetate, and the like; and a boron source such as bis(pinacolato)diboron, pinacol borane, and the like; at a temperature ranging from 80 °C to 100 °C; for a period of 2- 8 h; to provide a compound of formula (V).

[0121] According to SCHEME 3, A compound of formula (VI) can be prepared in a metal mediated coupling reaction of a commercially available or synthetically accessible compound of formula (VII), where Hal is a suitable halogen such as Br (bromine); with a boronic acid or boronic ester such as potassium trifluoro(vinyl)borate; in the presence of a catalyst such as bis(triphenylphosphine)palladium(II) chloride, and the like; a base such as Cs2CO3, and the like; in a suitable solvent such as THF, 1,4-dioxane, toluene, water, or a mixture thereof; at temperatures ranging from 70 °C to 100 °C; for a period of 12-18 h. [0122] Halogenation of a compound of formula (VI), employing a chlorinating agent such as POCl3, and the like, in a suitable solvent such as 1,2-dichloroethane, chloroform, and the like, at temperatures ranging from 70-90 °C, can afford a compound of formula (VIII). A compound of formula (VIII) can be oxidized by treatment with osmium tetroxide and NaIO4, in a suitable solvent such as 1,4-dioxane, THF, water, or a mixture thereof, to provide a compound of formula (IX). A compound of formula (IX) where Hal is Cl, can be reacted in a metal mediated cross coupling reaction with a commercially available or synthetically accessible boronic acid of formula R5-B(OH) or its boronate d 5 2 erivative, where R is an optionally substituted heteroaryl as described in claim 1, employing methods known to the art. For example, a compound of formula (IX) can be reacted with 4-[3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]pyridine; a suitable base such as Cs2CO3, K2CO3, K3PO4, K₂HPO₄, KHCO₃, Na₂CO_3, NaHCO₃, and the like; a palladium catalyst such as bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like; in a suitable solvent such as 1,4-dioxane, DMF, acetonitrile (ACN), ethanol, water, or a mixture thereof; at a temperature ranging from 50 to 100 °C; for a period of about 16 to 24 h; to provide a compound of formula (X), where R5 is 3-(pyridin-4-yl)phenyl. A compound of formula (X) can be reacted with hydroxylamine in the presence of a base such as, for example, NaHCO3, in a suitable solvent, such as, for example, MeOH, at a suitable temperature such as, for example, room temperature, to afford a compound of formula (XI). Reduction of a compound of formula (XI) can be achieved using, for example, hydrogen gas, in the presence of a catalyst such as, for example, Raney Ni, in a suitable solvent such as, for example, MeOH, THF, or a mixture thereof, at a suitable temperature such as, for example, room temperature, to afford a compound of formula (XII). SCHEME 4

[0123] According to SCHEME 4, a compound of formula (VII), where Hal is Cl, can undergo a palladium-catalyzed cyanation employing conditions known to one skilled in the art. For example, a compound of formula (VII), can be reacted with a palladium catalyst such as Pd(dppf)Cl2.CH2Cl2, and the like; and zinc cyanide as the nucleophile; in a suitable solvent such as DMA, N,N-dimethylformamide (DMF), and the like; at a temperature of about 100 °C; for a period of 2-6 h; to provide a cyano compound of formula (XIII). [0124] Halogenation of a compound of formula (XIII) can be achieved employing methods previously described, such as using POCl3, to afford a compound of formula (XIV). A compound of formula (XIV) can be reduced using a suitable reducing agent such as DIBAL- H; in a suitable solvent such as DCM, toluene, and the like; at a temperature of -78 °C to room temperature; subsequent reaction with a suitable protecting group precursor such as, for example, Boc anhydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, room temperature can afford a compound of formula (XV). SCHEME 5

[0125] According to SCHEME 5, a compound of formula (XV), where PG is Boc and Hal is Cl, can be reacted in a metal mediated cross coupling reaction with a commercially available or synthetically accessible boronic acid of formula R5’ -B(OH)₂ or boronate derivative of formula (Va), where R5’ is an optionally substituted heteroaryl as described in claim 1, employing methods known to the art. For example, a compound of formula (XV) can be reacted with 6-fluoropyridine-2-boronic acid or 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine; a suitable base such as Cs₂CO₃, K₂CO₃, K₃PO₄, K₂HPO₄, KHCO3, Na2CO3, NaHCO3, and the like; a palladium catalyst such as bis(triphenylphosphine)palladium(II) chloride, and the like; in a suitable solvent such as 1,4- dioxane, DMF, acetonitrile (ACN), ethanol, water, or a mixture thereof; at a temperature ranging from 50 to 100 °C; for a period of about 16 to 24 h; to provide a compound of formula (XVI), where R5’ is 6-fluoropyridyl. [0126] A compound of formula (XVI), where R5’ is a suitable heteroaryl such as, for example, 2-pyridyl substituted with a suitable halogen leaving group such as, for example, F (fluorine), can be reacted with an optionally substituted heterocycloalkyl (including but not limited to a 4-8 membered heterocycloalkyl, fused, spiro, and bridged 8-10 membered heterocycloalkyl, each optionally one or two heteroatoms independently selected from N, S, and O) such as cis- 2,6-dimethylmorpholine; a base such as DIPEA, and the like, in a suitable solvent such as DMSO, ACN, and the like, at temperatures ranging from 50-130 °C, for a period of 12-24 h, to provide a compound of formula (XVII), wherein R5 is a suitable heteroaryl substituted with a nitrogen linked heterocycloalkyl. [0127] A compound of formula (XVII) can be alkylated on the R5 group in two steps: first by halogenating a compound of formula (XVII) with a suitable halogenating agent such as, for example, N-iodosuccinimide, in a suitable solvent such as, for example, hexafluoroisopropanol, at a suitable temperature such as, for example, 0 °C to room temperature; and in a second step, by reacting the intermediate halide with a suitable methylboron derivative such as, for example, trimethylboroxine, in the presence of a suitable base such as, for example, K2CO3, in the presence of a suitable catalyst such as, for example, Xantphos Pd G3 (CAS [1445085-97-1]), in a suitable solvent such as, for example, 1,4- dioxane or water, or a mixture thereof, at a suitable temperature such as, for example, 80 °C. [0128] Deprotection of a compound of formula (XVII), where PG is Boc, can be achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999, pgs 518-525. For example, deprotection under acidic conditions such as trifluoroacetic acid (TFA)/CH₂Cl₂, HCl/Dioxane, and the like, at room temperature for a period of 2 h, to provide a compound of formula (XII). SCHEME 6

[0129] According to SCHEME 6, a compound of formula (XV), where Hal is Cl, and PG is Boc, can be reacted with a suitable sulfinate such as, for example, sodium 1-methyl 3- sulfinopropanoate (CAS [90030-48-1]); in the presence of a suitable catalyst such as, for example, CuI; in a suitable solvent such as, for example, DMSO, and the like; at a suitable temperature such as, for example, 110 °C; to provide a compound of formula (XVIII). A compound of formula (XVIII) can be reacted with a commercially available or synthetically accessible suitably substituted 2-halogeno-R5, such as, for example, (cis)-4-(6-bromo-4- fluoropyridin-2-yl)-2,6-dimethylmorpholine; in the presence of a suitable phosphonium salt such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3]); in the presence of a suitable base such as, for example, K2CO3, and the like; in the presence of a suitable catalyst such as, for example, Pd(OAc)₂, and the like; in a suitable solvent such as, for example, 1,4-dioxane; at a suitable temperature such as, for example, 150 °C; to provide a compound of formula (XVII). Deprotection of the Boc protecting group on a compound of formula (XVII) can be achieved employing acidic conditions known to one skilled in the art or as previously described to provide a compound of formula (XII). [0130] In a similar fashion, a compound of Formula (XVIII), where Hal is Cl, and PG is Boc, can be reacted with a suitable substituted 2-halo-heteroaryl (R5’ -Hal), such as, for example, (2R,6S)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine, in the presence of a suitable phosphonium salt such as, for example, di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3]); in the presence of a suitable base such as, for example, K₂CO₃, and the like; in the presence of a suitable catalyst such as, for example, Pd(OAc)2, and the like; in a suitable solvent such as, for example, 1,4-dioxane; at a suitable temperature such as, for example, 150 °C to provide a compound of formula (XVI), where R5 is 6-((2R,6S)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl. SCHEME 7

[0131] According to SCHEME 7, a compound of formula (XVIII), where PG is Boc, can be deprotected employing acidic conditions known to one skilled in the art or as previously described to provide a compound of formula (XIX). A compound of formula (XIX) can be reacted with a suitably substituted commercially available or synthetically accessible carboxylic acid; employing conventional amide bond forming techniques such as coupling reactions which are well known to those skilled in the art. For example, a compound of formula (XIX) can be reacted with a carboxylic acid of formula R1CO2H, where ring B is a suitably substituted heteroaryl ring; in the presence of a suitable coupling agent such as, for example, HATU, HBTU, 1-propanephosphonic anhydride, and the like; in the presence of a suitable base such as TEA, DIPEA, and the like; in a suitable solvent such as, for example, DCM, DMF, and the like; at a suitable temperature such as, for example, room temperature; to provide a compound of formula (XX). A compound of formula (XX) can be reacted with a commercially available or synthetically accessible suitably substituted 2-halogeno-R5, such as, for example, 8-(4-chloropyrimidin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione; in the presence of a suitable phosphonium salt such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3]); in the presence of a suitable base such as, for example, K₂CO₃, and the like; in the presence of a suitable catalyst such as, for example, Pd(OAc)₂, and the like; in a suitable solvent such as, for example, 1,4-dioxane; at a suitable temperature such as, for example, 115 °C; to provide a compound of Formula (I).

[0132] According to SCHEME 8, a compound of formula (XVI), where PG is Boc, and R5’ is a suitably substituted heteroaryl halide, can be deprotected employing methods known to one skilled in the art or as previously described, to provide a compound of formula (XXI). A compound of formula (XXI) can be reacted with a suitably substituted commercially available or synthetically accessible carboxylic acid; employing conventional amide bond forming techniques such as coupling reactions which are well known to those skilled in the art. For example, a compound of formula (XXI) can be reacted with a carboxylic acid of formula (III), where ring B is a suitably substituted phenyl ring; in the presence of a suitable coupling agent such as, for example, HATU, HBTU, 1-propanephosphonic anhydride, and the like; in the presence of a suitable base such as TEA, DIPEA, and the like; in a suitable solvent such as, for example, DCM, DMF, and the like; at a suitable temperature such as, for example, room temperature; to provide a compound of formula (XXII). [0133] In an alternate method, a compound of formula (XXII) can be prepared in two steps from a compound of formula (XXIII). In a first step, a compound of formula (XXIII) can be reacted in an amide bond forming reaction with a carboxylic acid of formula (III), where ring B is a suitably substituted phenyl ring; employing methods known to one skilled in the art or as previously described to provide a compound of formula (XXIV). Alternatively, an acid chloride derived from the acid of formula (III) can be reacted with a compound of formula (XXIII), in the presence of a base such as DIPEA, in a suitable solvent such as DCM, and the like; to provide a compound of formula (XXIV). In a second step, a compound of formula (XXIV) can be reacted in a coupling reaction with a suitable boronic acid such as R5’ -B(OH)₂, for example, 6-fluoro-pyridine-2-boronic acid or a boronate derivative such as 2-fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine; in the presence of a suitable base such as, for example, Na2CO3 or NaHCO3; in the presence of suitable catalyst such as bis(triphenylphosphine)palladium(II)chloride (CAS [13965-03-2]) or Pd(dppf)Cl2.CH2Cl2 (CAS [95464-05-4]); in a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as 85 °C; to provide a compound of formula (XXII). SCHEME 9

[0134] According to SCHEME 9, a compound of Formula (XXIV), where Hal is Cl, and R1 is a suitably substituted phenyl as described in Claim 1 can be reacted with a suitable sulfinate such as sodium 1-methyl 3-sulfinopropanoate (CAS [90030-48-1]); in the presence of a suitable catalyst such as CuI, and the like; in a suitable solvent such as DMSO, and the like; at temperatures ranging from 90 to 110 °C; to provide a compound of formula (XXV). [0135] A compound of formula (XXV), can be reacted with a suitably substituted heteroaryl halide of formula R5-Hal, wherein Hal is Br or Cl, and R5 is heteroaryl as defined in claim 1, in the presence of a suitable phosphonium salt such as, for example, di-tert- butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3]); in the presence of a suitable base such as K₂CO₃, and the like; in the presence of a suitable catalyst such as Pd(OAc)2, and the like; to provide a compound of Formula (I). SCHEME 10

[0136] According to SCHEME 10, a compound of formula (XXIV) can be reacted with a commercially available or synthetically accessible suitably substituted boronic acid or boronate derivative, such as (cis)-4-(3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)-2,6-dimethylmorpholine, for example, using standard Suzuki coupling conditions, in the presence of a suitable base such as, for example, sodium carbonate, in the presence of a suitable catalyst such as, for example, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (CAS [72287-26-4]), in a suitable solvent such as, for example, a mixture of water and 1,4-dioxane, at a suitable temperature such as, for example, 100 °C, to provide a compound of Formula (I), wherein R5 is defined as a C-linked heteroaryl, aryl, or heterocycloalkyl group. [0137] Alternatively, a compound of formula (XXIV) can be reacted with a suitable heteroalkyl organozinc derivative R5-Zn-Hal, wherein Hal is a suitable halide such as, for example, chloride, in the presence of a suitable catalyst such as, for example, Palladiumtetrakis(triphenylphosphine), in a suitable solvent such as, for example, THF or a mixture of THF and DMF, at a suitable temperature such as, for example, room temperature to provide a compound of Formula (I). SCHEME 11

[0138] According to SCHEME 11, a compound of formula (XII) can be reacted with a suitable commercially available or synthetically accessible carboxylic acid, employing conventional amide bond forming techniques such as coupling reactions which are well known to those skilled in the art. For example, a compound of formula (XII), where R5 is as described in claim 1, can be reacted with a suitable carboxylic acid, in the presence of a suitable coupling agent such as, for example, HATU (1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU, or 1- propanephosphonic anhydride; in the presence of a suitable base such as, for example, N- ethyldiisopropylamine (DIPEA), triethylamine (TEA), and the like; in a suitable solvent such as, for example, DCM, THF, DMF, and the like; at a suitable temperature such as, for example, ranging from 0 °C to room temperature, to provide a compound of Formula (I). [0139] Alternatively, compounds of Formula (I) can be prepared by reacting a compound of formula (XII) with a suitable activated form of a carboxylic acid, such as, for example, an acyl chloride, or its corresponding anhydride, in the presence of a suitable base such as, for example, DIPEA or Et₃N, in a suitable solvent such as, for example, DCM or DMF, at a suitable temperature such as, for example, 0 °C or room temperature. [0140] A compound of formula (XXII), wherein R5 is a suitable heteroaryl, such as, for example, 2-pyridyl, and Hal is a suitable halogen leaving group such as, for example, F (fluorine), can react with a suitable amine HNR9aR9b, in the presence of a suitable base such as, for example, DIPEA, in a suitable solvent such as, for example, DMSO, at a suitable temperature such as, for example, 90 °C or up to 150 °C, to provide a compound of Formula (I). [0141] Wherein when a compound of Formula (I) has a protecting group such as, for example, Boc, the protecting group can be removed employing conditions known to one skilled in the art. For example, reaction with a reagent such as, for example, pTsOH (p- toluenesulfonic acid), TFA, or HCl, in a suitable solvent such as, for example, DCM, or 1,4- dioxane, at a suitable temperature such as, for example, room temperature or 40 °C. [0142] Wherein a compound of Formula (I) has a protecting group on the R1 group such as, for example, Boc or THP, the protecting group can be removed by reaction with a suitable reagent such as, for example, HCl, pTsOH, or pyridinium p-toluenesulfonate, in a suitable solvent such as, for example, 1,4-dioxane, or EtOH, at a suitable temperature such as, for example, room temperature. Wherein when the protecting group is an ester, a compound of Formula (I) can be reacted with a suitable hydrolyzing agent such as, for example, LiOH or NaOH, in a suitable solvent such as, for example, THF, MeOH, water, or a mixture thereof, at a suitable temperature such as, for example, room temperature. [0143] The skilled person will realize that another sequence of the chemical reactions shown in the SCHEMES, may also result in the desired compound of Formula (I). [0144] The skilled person will realize that intermediates and final compounds shown in the schemes below may be further functionalized according to methods well-known by the person skilled in the art. [0145] The skilled person will realize that in the reactions described herein, in certain cases it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N2-gas atmosphere. [0146] It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before reaction work-up, meaning those series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, or extraction. [0147] The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.

[0148] The compounds of the invention as prepared in the processes described herein may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. Racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I), and the pharmaceutically acceptable addition salts thereof, involves liquid chromatography using a chiral stationary phase e.g., by supercritical fluid chromatography. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0149] In all these preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. The purity of the reaction products may be determined according to methodologies generally known in the art such as for example LC-MS, TLC, HPLC.

Methods of Treatment and Medical Uses, Pharmaceutical compositions and combinations [0150] The present invention also provides methods for the treatment or prevention of a proliferative disease (e.g., cancer, benign neoplasm, angiogenesis) in a subject. Such methods comprise the step of administering to the subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.

[0151] The subject being treated is a mammal. The subject may be a human. The subject may be a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. The subject may be a companion animal such as a dog or cat. The subject may be a livestock animal such as a cow, pig, horse, sheep, or goat. The subject may be a zoo animal. The subject may be a research animal such as a rodent, dog, or non-human primate. The subject may be a non- human transgenic animal such as a transgenic mouse or transgenic pig.

[0152] The proliferative disease to be treated or prevented using the compounds of Formula (I) will typically be associated with aberrant activity of SMARCA2. Aberrant activity of SMARCA2 may be an elevated and/or an inappropriate (e.g., abnormal) activity of SMARCA2. In certain embodiments, SMARCA2 is not overexpressed, and the activity of SMARCA2 is elevated and/or inappropriate. In certain other embodiments, SMARCA2 is overexpressed, and the activity of SMARCA2 is elevated and/or inappropriate. The compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, may inhibit the activity of SMARCA2 and be useful in treating and/or preventing proliferative diseases.

[0153] A proliferative disease may also be associated with inhibition of apoptosis of a cell in a biological sample or subject. All types of biological samples described herein or known in the art are contemplated as being within the scope of the invention. Inhibition of the activity of SMARCA2 is expected to cause cytotoxicity via induction of apoptosis. The compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, may induce apoptosis, and therefore, be useful in treating and/or preventing proliferative diseases.

[0154] In certain embodiments, the proliferative disease to be treated or prevented using the compounds of the present disclosure is cancer.

[0155] The cell described herein may be an abnormal cell. The cell may be in vitro or in vivo. The cell may be a proliferative cell.

[0156] In another aspect, the present invention provides methods of downregulating the expression of SMARCA2 in a biological sample or subject.

[0157] The present invention relates to the compounds of Formula (I) for use in a method of treatment of SMARCA4 deficient cancers, which method comprises administering to a subject in need thereof a compound of Formula (I).

[0158] The present invention relates to the compounds of Formula (I) for use in a method of treatment of SMARCA4 deficient NSCLC, which method comprises administering to a subject in need thereof a compound of Formula (I). [0159] In yet another aspect, the present invention provides the compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, for use in the treatment of a proliferative disease in a subject. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting cell growth. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inducing apoptosis in a cell. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting transcription.

[0160] One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, the amount of a compound of the present invention to be administered as a therapeutic agent for treating the disorders referred to herein will be determined on a case by case by an attending physician.

[0161] Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount may be from about 0.005 mg/kg to 50 mg/kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect may vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment, the compounds according to the invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

[0162] While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. [0163] The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington’s Pharmaceutical Sciences (18^th ed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, or a nose spray. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.

[0164] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

[0165] The exact dosage and frequency of administration depends on the particular compound used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

[0166] The methods described herein may also comprise the additional step of administering one or more additional pharmaceutical agents in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof. Thus, the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating proliferative diseases resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions.

[0167] Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound according to the present invention and one or more additional therapeutic agents, as well as administration of the compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound according to the present invention and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

[0168] Therefore, an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

[0169] The one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated, and the particular host being treated. The optimum method and order of administration and the dosage amounts, and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

[0170] The weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of Formula (I) and another anticancer agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.

EXAMPLES

[0171] The following examples further illustrate the present invention. The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods. Commercial sources include, but are not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific. Table 2. Abbreviations.

[0172] As understood by a person skilled in the art, compounds synthesized using the protocols as indicated may contain residual solvent or minor impurities. [0173] A skilled person will realize that, even where not mentioned explicitly in the experimental protocols below, typically after a column chromatography purification, the desired fractions were collected and the solvent was evaporated. [0174] In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context. [0175] When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained. [0176] For intermediates that may be used in a next reaction step as a crude or as a partially purified intermediate, theoretical mol amounts may be indicated in the reaction protocols described below. [0177] Example A: Preparation of the Intermediates and the final Compounds, and characterization thereof Preparation of intermediates [0178] For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below. Representative Synthetic Methods Method A: [0179] Carboxylic Acid (1.1 eq.) and DIPEA (3 eq.) were added to a solution of Amine (1 eq.) in DCM (2 mL). After 1 min, HATU (1.15 eq.) was added and the reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (12 g column, DCM/MeOH (9/1) in DCM, from 0 % to 25 %) to yield the title compound. Method B: [0180] HBTU (1.5 eq.) was added to a stirred solution of Carboxylic Acid (1 eq.), Amine (1 eq.), and DIPEA (3 eq.) in DMF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with Na₂CO₃ (1 M in water) and extracted with EtOAc. The organic layer was dried on MgSO₄, filtered, and evaporated. The residue was purified by reverse phase chromatography (72 % H2O – 28 % ACN -MeOH to 36 % H2O – 64 % ACN - MeOH - [0.1 % HCOOH]). The desired fractions were neutralized with solid Na₂CO₃ solid and extracted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated to yield the title compound. Method C: [0181] Amine (1.2 eq.) was added to a stirred solution of Carboxylic Acid (1 eq.), HATU (1.5 eq.), and DIPEA (3 eq.) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 72 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by flash column chromatography (silica 12g; MeOH in DCM from 0/100 to 3/97), followed by reverse phase chromatography (Phenomenex Gemini C1830 x 100 mm 5 µm Column; from 59 % [25 mM NH₄HCO₃] – 41 % [ACN:MeOH (1:1)] to 17 % [25 mM NH4HCO3] – 83 % [ACN:MeOH (1:1)]) to yield the title compound. Method E: [0182] Carboxylic Acid (1.2 eq.), Amine (1 eq.), and DIPEA (4 eq.) were dissolved in DMF (3 mL). After 15 min, HBTU (1.2 eq.) was added and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with aqueous Na₂CO₃ (1 M) and extracted with DCM. The organic layer was washed with brine, dried on MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g silica; DCM:MeOH (9:1)/DCM 0/100 to 25/75). The desired fractions were collected and concentrated in vacuo. The resulting product was triturated with ACN and filtered to give the title compound. Method F: [0183] 1-Propanephosphonic anhydride (50 % in EtOAc, CAS [68957-94-8], 1.3 eq.) was added to a suspension of Amine (1 eq.) and Carboxylic Acid (1.1 eq.) in dry DCM (5 mL) at room temperature, under nitrogen atmosphere. Et₃N (5 eq.) was then added dropwise to the orange suspension. The reaction mixture (clear yellow) was stirred at room temperature for 1 h. The solvent was evaporated and the residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane:EtOH/EtOAc 1/3100:0 -> 20:80) to give the title compound. Method I: [0184] Amine (10 eq.) was added to a solution of Intermediate 4 (1 eq.) in DMSO (1 mL) and the mixture was stirred at 120 °C for 18 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCCh. The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g; SiCh; DCM:Methanol (9: 1) in DCM, 0/100 to 40/60) to yield the title compound.

Method J:

[0185] Amine (6 eq.) was added to a solution of Intermediate 21 (1 eq.) and DIPEA (20 eq.) in DMSO (1 mL) and the mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCOs. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g column, gradient of DCMMeOH 9: 1 in DCM, from 0 % to 35 %) to yield a yellow solid. The solid was triturated in ACN, filtered, washed with Et2O, and dried in vacuo to yield the title compound.

Method K:

[0186] A solution of Intermediate 21 (1 eq.), Amine (3 eq.), and DIPEA (12 eq.) in dry DMSO (0.5 mL) was stirred at 120 °C overnight. After cooling, the reaction mixture was diluted with MeOH (2.5 mL) and filtered. The filtrate was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 μm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give the title compound.

Method M:

[0187] 1-Propanephosphonic anhydride (50 % in EtOAc, 1.7 eq.) was added to a solution of Amine (1 eq.), Carboxylic Acid (1.5 eq.), and EtsN (6 eq.) in DCM (5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and water, filtered, and purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 5 μm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to yield the title compound.

Method N:

[0188] Amine (3 eq.) was added to a solution of Intermediate 21 (1 eq.), DIPEA (1.3 eq.) in

DMSO (0.6 mL). The reaction mixture was stirred at 120 °C for 48 h. After cooling, the excess amine was evaporated under reduced pressure and the resulting solution was purified directly by reverse phase column chromatography (Stationary phase: RP XB ridge Prep Cl 8 OBD - 10 μm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN or MeOH) to yield the title compound.

Method P:

[0189] A solution of Intermediate 23 (3 eq.), EtsN (6 eq.) in DCM (1 mL) was added to Carboxylic Acid (1.7 eq.). 1-Propanephosphonic anhydride (50 % solution in EtOAc, 1.7 eq.) was added dropwise to the reaction mixture and it was stirred 16 hours at room temperature. The solvents were evaporated and the residue was purified by reverse phase column chromatography (Stationary phase: RP XBridge Prep C18 OBD - 10 μm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN or MeOH) to yield the title compound.

Preparation of intermediates

[0190] For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below.

Intermediate 1 :

[0191] Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DMA (2.24 L), Pd(dppf)C12.CH2C12 (CAS [95464-05-4], 22.4 g, 0.1 eq.), 7-chloro- 1/7-1, 6-naphthyridin-2-one (CAS [1345091-18-0], 224 g, 1240.37 mmol), zinc (16.22 g, 248.07 mmol, 0.2 eq.), and zinc cyanide (145.65 g, 1240.37 mmol, 1 eq.). The resulting solution was stirred for 4 h at 100 °C. The reaction mixture was cooled to room temperature. The solids were filtered out and washed with 2 x 100 mL of DMA. The reaction was then quenched by the addition of 5 L of water/ice. The solids were collected by filtration to afford Intermediate 1 (147 g, yield: 69 %) as a brown solid. Intermediate 2:

[0192] Into a 2-L 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed phosphorus oxychloride (1.47 L) and Intermediate 1 (147.00 g, 858.85 mmol). The resulting solution was stirred for 3 h at 80 °C. The reaction mixture was concentrated. The resulting solution was diluted with 2 L of DCM. The reaction was then quenched by the addition of 4 L of water/ice. The resulting solution was extracted with 3 x 3 L of DCM, the organic layer was dried over Na2SO4, and concentrated to afford Intermediate 2 (58 g, yield: 36 %) as a yellow solid.

Intermediate 3 :

[0193] Into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DCM (1.74 L), Intermediate 2 (58 g, 305.90 mmol). This was followed by the dropwise addition over 30 min of DIBAL-H (1 N, 765 mL, 2.5 eq.) while stirring at -78 °C. The resulting solution was stirred for 2 h at -78 °C. To this was added potassium sodium tartrate (257 g, 1224 mmol, 4 eq.) at -78 °C. The resulting solution was stirred for 1 h at room temperature. This was followed by the addition of di-tert-butyl dicarbonate (73.3 g, 336.50 mmol, 1.1 eq.). The resulting solution was stirred overnight at room temperature. The solids were filtered out and washed with 3 x 300 mL of DCM. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether 1/3 to 1/2) to afford Intermediate 3 (60.9 g, yield: 68 %) as a yellow solid.

Intermediate 4:

[0194] A suspension of Intermediate 3 (9900 mg, 33.702 mmol), 6-fluoropyridine-2-boronic acid (CAS [916176-61-9], 5699 mg, 40.442 mmol, 1.2 eq.), and sodium carbonate (10716 mg, 101.105 mmol, 3 eq.), in 1,4-di oxane (90 mL) and water (30 mL) was degassed by bubbling nitrogen through for 5 min. Bis(triphenylphosphine)palladium(II) chloride (CAS [13965-03-2], 1183 mg, 1.685 mmol, 0.05 eq.) was added and the mixture was further degassed with nitrogen for 5 min. The reaction mixture was stirred at 90 °C overnight under nitrogen atmosphere. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The solid residue was triturated in Et2O and filtered. The white solid was washed with a small amount of Et2O to give Intermediate 4 (7.47 g, yield: 58 %) as a white solid.

Intermediate 5:

[0195] A suspension of Intermediate 4 (5208 mg, 11.169 mmol), cis-2,6-dimethylmorpholine (CAS [6485-55-8], 5.7 mL, 44.676 mmol, 4 eq.), and DIPEA (5.8 mL, 33.507 mmol, 3 eq.) in dry DMSO (20 mL) was distributed in two pressure (microwave) vials. The vials were sealed, and the reaction mixture was stirred at 130 °C overnight. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was triturated in DCMZEt2O 1/1. The solid was filtered and washed with a small amount of Et2O. This solid was combined with the filtrate and was purified by column chromatography (Biotage Sfar 200 g; eluent: heptane :EtOH/EtO Ac 1/3 100:0 -> 20:80) to give Intermediate 5 (5.1 g, quantitative).

Intermediate 6:

[0196] HC1 (37 % in H2O, 40 mL, 484.24 mmol, 20 eq.) was added dropwise (1 drop/sec, slightly exothermic) to a yellow suspension of Intermediate 5 (10.85 g, 24.135 mmol) in 1,4- di oxane (100 mL) at room temperature. The reaction mixture turned red then yellow again and was stirred at room temperature for 16 h. The yellow suspension was evaporated to dryness and the residue was co-evaporated several times with toluene to give Intermediate 6 (HC1 salt, 12 g, quantitative) as an orange solid, dried under vacuum at 50 °C. Intermediate 7:

[0197] Iron(II) sulfate heptahydrate (CAS [7727-21-1], 31 mg, 0.093 mmol, 0.14 eq.) was added to a solution of 5-methylpyridine-2-carboxylic acid methyl ester (CAS [29681-38-7], 100 mg, 0.662 mmol) and TFA (64μL, 0.860 mmol, 1.3 eq.) in acetaldehyde (3.3 mL). The reaction mixture was cooled to 0 °C and a first portion of H2O2 (365μL, 3.572 mmol, 5.4 eq.) was added dropwise and the mixture was stirred for 30 min. A second portion of of H2O2 (365 μL, 3.572 mmol, 5.4 eq.) was then added dropwise and stirring was continued for 90 min. The reaction was slowly quenched at room temperature with 5 % aqueous Na2S20s, followed by addition of saturated aqueous NaHCCh. The mixture was extracted twice with EtOAc. The combined organic layer was washed with brine and the organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g silica; gradient of EtOAc in heptane from 0/100 to 10/90) to afford Intermediate 7 (75 mg, yield: 59 %) as a white solid.

Intermediate 8:

[0198] NaBEU (157 mg, 4.141 mmol, 2 eq.) was added to a solution of Intermediate 7 (400 mg, 2.07 mmol) in MeOH (10 mL) under nitrogen atmosphere at 0 °C and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4CI and the mixture was diluted with EtOAc. The layers were separated and the combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (80 g silica; gradient of EtOAc in heptane from 0/100 to 50/50) to afford Intermediate 8 (240 mg, yield: 59 %) as a colourless foam.

Intermediate 9:

[0199] NaOH (2 M in water, 1.229 mL, 2.459 mmol, 2 eq.) was added to a solution of Intermediate 8 (240 mg, 1.229 mmol, 1 eq.) in MeOH (6 mL) and the reaction mixture stirred 16 hours at room temperature. The reaction was adjusted to pH ~1 with HC1 (1 M in water), diluted with additional water, and extracted with EtOAc (3x). The combined organic extracts were dried over MgSCU, filtered, and concentrated in vacuo to afford Intermediate 9 (223 mg, yield: 100%), used without further purification.

Intermediate 10:

[0200] HC1 (37 % in H2O, 47 mL, 588.7 mmol, 20 eq.) was added dropwise (1 drop/sec, slightly exothermic) to a light brown solution of Intermediate 4 (10 g, 27.94 mmol) in 1,4- di oxane (300 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The precipitate that appeared during the reaction was filtered and the solid was washed with dioxane to give Intermediate 10 (HC1 salt, 8.3 g, quantitative) as a grey solid, dried under vacuum at 50 °C and used without further purification.

Intermediate 11 :

[0201] Intermediate 3 (1.03 g, 3.506 mmol) was added to a solution of sodium 1-methyl 3- sulfinopropanoate (CAS [90030-48-1], 1.22 g, 7.013 mmol, 2 eq.) and copper iodide (1.34 g, 7.013 mmol, 2 eq.) in DMSO (10 mL). The reaction mixture was stirred under nitrogen atmosphere at 110 °C for 1 h. After cooling, the reaction mixture was diluted with EtOAc and washed with water containing aqueous NH3 (1 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g column, gradient of EtOAc/heptane from 0/100 to 100/0) to give Intermediate 11 (801 mg, yield: 53 %) as an orange solid. Intermediate 12:

CIS

[0202] 2,6-Dibromo-4-nitropyridine (CAS [175422-04-5], 5 g, 17.737 mmol) and cis-2,6- dimethylmorpholine (CAS [6485-55-8], 2.42 mL, 19.511 mmol, 1.1 eq.) were dissolved in toluene (140 mL) and the solution was degassed by bubbling with nitrogen for 15 min. Cs₂CO₃ (8.67 g, 26.606 mmol, 1.5 eq.), rac-BINAP (CAS [98327-87-8], 1.10 g, 1.774 mmol, 0.1 eq.), and Pd(OAc)2 (CAS [3375-31-3], 398 mg, 1.774 mmol, 0.1 eq.) were then added and the resulting mixture was stirred at reflux under nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 250 ml). The combined organic layer was washed with brine, dried over MgSCU, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (120 g column, gradient of EtOAc/heptane from 0/100 to 40/60) to give Intermediate 12 (3.2 g, yield: 56 %) as an orange solid.

Intermediate 13:

CIS

[0203] Tetramethylammonium fluoride (CAS [373-68-2], 663 mg, 7.117 mmol, 1.5 eq.) was added to a solution of Intermediate 12 (1500 mg, 4.745 mmol) in DMF (40 mL) in a sealed tube. The mixture was stirred for 3 h at 65 °C. The reaction was quenched by addition of water and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried with MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (80 g column, gradient of EtOAc/heptane from 0/100 to 30/70) to give Intermediate 13 (1139 mg, yield: 81 %) as an orange solid. Intermediate 14:

[0204] Intermediate 11 (950 mg, 2.32 mmol), Intermediate 13 (1006 mg, 3.48 mmol, 1.5 eq.), and K2CO3 (481 mg, 3.48 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (24 mL) in a sealed tube under a nitrogen stream. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 58 mg, 0.232 mmol, 0.1 eq.) and Pd(OAc)₂ (CAS [3375-31-3], 26 mg, 0.116 mmol, 0.05 eq.) were added and the reaction mixture was stirred at 150 °C for 4 h. The mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over MgSCU, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g column, gradient of EtOAc/heptane from 0/100 to 100/0) to give Intermediate 14 (428 mg, yield: 39 %) as a yellow solid.

Intermediate 15:

[0205] Intermediate 14 (428 mg, 0.906 mmol) was dissolved in a solution of HC1 (4 M in 1,4- dioxane, 2.27 mL, 9.063 mmol, 10 eq.) and 1,4-dioxane (40 mL) and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue was triturated in Et₂O to yield Intermediate 15 (HC1 salt, 406 mg, quantitative) as an orange solid.

Intermediate 16:

[0206] Sodium methylthiolate (CAS [5188-07-8], 15 mg, 0.207 mmol, 1.2 eq.) was added to a solution of 2-pyridinecarboxylic acid, 4-chloro-5-methyl-, methyl ester (CAS [1104455-41- 5], 32 mg, 0.172 mmol) in DMF (0.5 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (10 mL) and washed with staturated aqueous NaHCCf. The organic layer was dried over MgSCU, filtered, and concentrated. The residue was purified by flash chromatography over silica gel (12 g column, gradient of EtOAc in heptane from 0 to 100 %) to give Intermediate 16 (25 mg, yield: 73 %) as a white solid.

Intermediate 17:

[0207] m-CPBA (2.465 g, 10 mmol, 2.5 eq.) was added portion wise to a solution of Intermediate 16 (789 mg, 4 mmol) in DCM (35 mL) at 0 °C. The reaction mixture was stirred for 20 h, allowing the temperature to rise to room temperature. The reaction was quenched with saturated aqueous Na2S20s (1 mL) while stirring. Saturated aqueous NaHCCh (5 mL) and DCM (10 mL) were added. The mixture was stirred for another 10 min, then the organic layer was separated. The aqueous layer was extracted twice with DCM (2 x 10 mL). The combined organic layer was dried over MgSCU, filtered, and concentrated. The residue was purified by column chromatography over silica gel (12 g column, gradient of MeOH in DCM from 0 to 5 %) to give Intermediate 17 (771 mg, yield: 83 %) as a white solid.

Intermediate 18:

[0208] NaOH (1 M in water, 5.0 mL, 5.038 mmol, 1.5 eq.) was added to solution of Intermediate 17 (770 mg, 3.359 mmol) in MeOH (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and KHSO4 (1 M in water) was added, reaching a pH ~2-3. The mixture was extracted with MeOHObCh (1 :9). The organic layer was dried on MgSO4, filtered, and concentrated in vacuo to give Intermediate 18 (630 mg, yield: 86 %) as a white solid, used without further purification.

Intermediate 19:

(3 a, 4a, 5 a)

[0209] Intermediate 19 was prepared according to Method J, starting from Intermediate 4 and

(3a,4a,5a)-3,5-dimethyl-4-piperidinol (CAS [1236030-00-4]).

Intermediate 20:

(3 a, 4a, 5 a) (HC1 salt)

[0210] HC1 (4 M in 1,4-dioxane, 2.13 mL, 8.51 mmol, 10 eq.) was added to Intermediate 19 (411 mg, 0.85 mmol) in 1,4-dioxane (20 mL) and water (5 mL) and the reaction mixture was stirred at 50 °C overnight. The reaction mixture was concentrated to give Intermediate 20 (HC1 salt, 452 mg, 92 % pure, quantitative). Intermediate 21 :

[0211] 1-Propanephosphonic anhydride (50 % in EtOAc, CAS [68957-94-8], 24.37 mL, 40.932 mmol, 1.7 eq.) was added to a suspension of Intermediate 10 (7000 mg, 24.078 mmol) and 5-(methylsulfonyl)nicotinic acid (CAS [893723-59-6], 5813 mg, 28.893 mmol, 1.2 eq.) in dry DCM (200 mL) at room temperature, under nitrogen atmosphere. Et₃N (24.1 mL, 173.358 mmol, 7.2 eq.) was then added dropwise over 5 min to the orange suspension. The reaction mixture was stirred at room temperature overnight. The solid that appeared was filtered and washed with Et₂O. The solid was stirred in water and MeOH for 2 h, filtered, and washed with toluene to give Intermediate 21 (7.1 g, 95 % pure, yield: 64 %) Intermediate 22:

(3α,4β,5α) [0212] Intermediate 22 was prepared according to Method J, starting from Intermediate 4 and (3α,4β,5α)-3,5-dimethyl-4-piperidinol (CAS [374067-78-4]). Intermediate 23:

[0213] Intermediate 23 was prepared in a similar manner as Intermediate 20, starting from Intermediate 22 instead of Intermediate 19. Intermediate 24 and Intermediate 25:

Intermediate 24: *R, pure stereoisomer but stereochemistry undetermined

Intermediate 25: *S, pure stereoisomer but stereochemistry undetermined [0214] NaOH (2 M in water, 19 mL, 38.034 mmol, 2 eq.) was added to a solution of methyl 5-(1-hydroxyethyl)-3-pyridinecarboxylate (CAS [38940-64-6], 3.45 g, 19.017 mmol) in MeOH (30 mL). The reaction mixture was stirred at room temperature for 18 h. The pH of the mixture was brought to 4 with aqueous HCl (1 M). The solvents were evaporated and DCM:MeOH (9:1) was added. The salts were filtered off and the filtrate was concentrated. The residue was purified by preparative SFC (i-Amylose-1 column; isocratic mode method: 10 % [MeOH + 0.1 % DEA] – 90 % [CO₂]) to yield Intermediate 24 (930 mg, yield: 29 %) and Intermediate 25 (631 mg, yield: 20 %), both as brown oils. Intermediate 26:

[0215] Dess-Martin periodinane (CAS [87413-09-0], 124 mg, 0.293 mmol, 1.5 eq.) was added to a solution of Compound 4 (100 mg, 0.195 mmol) in DCM (2 mL) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3, followed by brine. The organic layer was dried with MgSO4, filtered, and concentrated to yield Intermediate 26 (99 mg, yield: 95 %) as a yellow solid, used without further purification. Intermediate 27:

(3α,4β,5α) [0216] N-iodosuccinimide (199 mg, 0.884 mmol, 1 eq.) was added to a solution of Intermediate 22 (410 mg, 0.884 mmol) in hexafluoroisopropanol (10 mL) at 0 ºC. The reaction mixture was stirred at 0 ºC for 30 min, then at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica; EtOAc/heptane 0/100 to 50/50) to yield Intermediate 27 (450 mg, 66 % pure, yield: 57 %) as a yellow oil. Intermediate 28:

(3α,4β,5α) [0217] A solution of Intermediate 27 (450 mg, 66 % pure, 0.504 mmol), trimethylboroxine (CAS [823-96-1], 423 µL, 3.023 mmol, 6 eq.), and K₂CO₃ (418 mg, 3.023 mmol, 6 eq.) in 1,4-dioxane (0.5 mL) and water (0.3 mL) was degassed with nitrogen for 5 min. XantPhos Pd G3 (CAS [1445085-97-1], 48 mg, 0.050 mmol, 0.1 eq.) was added to the solution at room temperature and the mixture was stirred at 80 ºC for 12 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 100/0) followed by reverse phase column chromatography (Phenomenex Gemini C1830 x 100 mm 5 µm Column; from 81 % [0.1 % HCOOH] – 19 % ACN to 45 % [0.1 % HCOOH] – 55 % ACN) to yield Intermediate 28 (77 mg, yield: 32 %) as a yellow solid. Intermediate 29:

(3α,4β,5α) [0218] HCl (4 M in 1,4-dioxane, 419 µL, 1.675 mmol, 20 eq.) was added to a solution of Intermediate 28 (40 mg, 0.084 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated to yield Intermediate 29 (HCl salt, 42 mg, 90 % pure, quantitative) as an orange solid. Intermediate 30:

[0219] A suspension of Intermediate 21 (50 mg, 0.109 mmol), tert-butyl 1,7- diazaspiro[3.5]nonane-l-carboxylate (CAS [121693-62-7], 98 mg, 0.434 mmol, 4 eq.), and DIPEA (56μL, 0.326 mmol, 3 eq.) in dry DMSO (0.5 mL) was stirred at 90 °C overnight.

The reaction mixture was diluted with water and EtOAc. The resulting precipitate was filtered and washed with EtOAc, then dried under vacuum to afford Intermediate 30 (48 mg, yield: 68 %) as a light yellow solid.

Intermediate 31 :

[0220] Intermediate 31 was prepared according to Method K, starting from Intermediate 21 and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (CAS [1180509-95-8]).

Intermediate 32:

[0221] Intermediate 32 was prepared according to Method K, starting from Intermediate 21 and 3-(N-tert-butoxycarbonyl-N-methylamino)pyrrolidine (CAS [172478-00-1]).

Intermediate 33:

[0222] Intermediate 33 was prepared according to Method K, starting from Intermediate 21 and DL-3-(Boc-amino)pyrrolidine (CAS [99724-19-3]). Intermediate 34:

[0223] Intermediate 34 was prepared according to Method J, starting from Intermediate 21 and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (CAS [236406-55-6]). Intermediate 35:

[0224] Tert-butyl (pyrrolidin-2-ylmethyl)carbamate (CAS [149649-58-1], 176 mg, 0.879 mmol, 4 eq.) and DIPEA (115 µL, 0.665 mmol, 3 eq.) were added to a suspension of Intermediate 21 (100 mg, 0.222 mmol) in dry DMSO (1 mL) and the reaction mixture was stirred at 130 °C overnight. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated to give Intermediate 35, used directly in the next step without further purification. Intermediate 36:

[0225] A suspension of Intermediate 21 (50 mg, 0.109 mmol), 3-(Boc-amino)-3- methylpyrrolidine (CAS [147459-52-7], 87 mg, 0.434 mmol, 4 eq.) and DIPEA (56 µL, 0.326 mmol; 3 eq.) in dry DMSO (0.5 mL) was stirred at 90 °C overnight. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Redisep 4 g, DCM/DCM:MeOH 9:1, from 100/0 to 0/100) to afford Intermediate 36 (51 mg, yield: 76 %) as a dark yellow solid. Intermediate 37:

[0226] Into a 2-L 4-necked round-bottom flask purged and maintained under nitrogen atmosphere, was placed Intermediate 83 (99 g, 464.24 mmol, 1 eq.), EtOH (990 mL), and H₂O₂ (157.91 g, 4642.44 mmol, 10 eq.). This was followed by the addition of ammonium molybdate tetrahydrate (57.37 g, 46.42 mmol, 0.1 eq.) at 0 °C. The resulting solution was stirred for 1 h at 0 °C. The resulting solution was extracted with DCM (3 x 1 L) and the combined organic layer was washed with saturated aqueous Na₂S₂O₃ (3 x 1 L), dried over Na2SO4, and concentrated. The residue was purified by trituration with MTBE (1 L) to give Intermediate 37 (62 g, yield: 54 %) as a white solid. Intermediate 38:

[0227] Into a 2-L 4-necked round-bottom flask, were added Intermediate 37 (62 g, 252.80 mmol), THF (240 mL), H₂O (360 mL), and LiOH (30.27 g, 1264.01 mmol, 5 eq.) at room temperature. The resulting solution was stirred for 20 h at 40 °C. The resulting mixture was concentrated under reduced pressure and the residue was diluted with water (500 mL). The mixture was acidified to pH 3 with aqueous HCl (6 N). The precipitated solids were collected by filtration. The solid was purified by trituration with THF (600 mL) and the solid was collected by filtration to give Intermediate 38 (50.46 g, yield: 87 %) as a white solid. Intermediate 39:

(3α,4 ^,5α) [0228] Intermediate 39 was prepared according to Method J, starting from Intermediate 4 and (3α,4α,5α)-3,5-dimethyl-4-piperidinol (CAS [1236030-00-4]). Intermediate 40:

(3α,4 ^,5α) [0229] Intermediate 40 was prepared in a similar manner as Intermediate 29, using Intermediate 39 instead of Intermediate 28. Intermediate 41:

[0230] Iron(II) sulfate heptahydrate (CAS [7782-63-0], 545 mg, 1.632 mmol, 0.14 eq.) was added to a solution of methyl 5-chloro-2-pyridinecarboxylate (CAS [132308-19-1], 2 g, 11.656 mmol) in TFA (1.13 mL, 15.153 mmol, 1.3 eq.) and acetaldehyde (58 mL, 1037.411 mmol, 89 eq.). The mixture was cooled to 0 ºC and a first portion of H₂O₂ (6.43 mL, 62.944 mmol, 5.4 eq.) was added dropwise and the reaction mixture was stirred for 30 min at 0 °C. A second portion of H2O2 (6.43 mL, 62.944 mmol, 5.4 eq.) was added dropwise to the reaction mixture and it was stirred for an additional 90 min at 0 °C. The mixture was then warmed to room temperature. The reaction was quenched by slowly adding saturated aqueous Na₂S₂O₃, followed by addition of saturated aqueous NaHCO₃, and the mixture was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g silica; gradient EtOAc/heptane from 0/100 to 10/90) to afford Intermediate 41 (1.85 g, yield: 74 %) as a colorless oil. Intermediate 42:

[0231] NaOH (2 M in water, 8.7 mL, 17.321 mmol, 2 eq.) was added to a solution of Intermediate 41 (1.85 g, 8.66 mmol) in MeOH (45 mL). The reaction mixture was stirred at room temperature for 2 h. The pH of the mixture was brought to 1-2 with 1 M aqueous HCl. The mixture was diluted with water and extracted with EtOAc (x 3). The combined organic layer was separated, dried (MgSO4), filtered, and the solvents evaporated in vacuo to yield Intermediate 42 (1.49 g, yield: 86 %), used without further purification. Intermediate 43:

(3α,4β,5α) [0232] Benzoyl chloride (CAS [98-88-4], 1.8 mL, 15.507 mmol, 1.55 eq.), Et3N (7 mL, 50.222 mmol, 5 eq.), and DMAP (219 mg, 1.793 mmol, 0.18 eq.) were added to a solution of (3α,4β,5α)-3,5-dimethyl-1-(phenylmethyl)-4-piperidinol (CAS [374067-77-3], 2.2 g, 10.031 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried with MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (80 g, EtOAc/heptane 0/100 to 20/80) to yield Intermediate 43 (2.88g, yield: 88 %) as a white solid. Intermediate 44:

(3α,4β,5α) [0233] Palladium hydroxide (CAS [12135-22-7], 238 mg, 0.34 mmol, 0.04 eq.) was added to a solution of Intermediate 43 (2.88 g 8.905 mmol) in MeOH (50mL) under nitrogen atmosphere. The mixture was purged using vacuum and nitrogen. Then, the mixture was purged with hydrogen and stirred at room temperature under hydrogen atmosphere for 18 h. The reaction mixture was filtered through a short pad of celite and the solvent was removed in vacuo to yield Intermediate 44 (1.98 g, yield: 94 %) as a colorless oil. Intermediate 45:

(3α,4β,5α) [0234] Nitrogen was purged through a solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 1.236 g, 4.384 mmol) in 1,4-dioxane (37 mL). Cs2CO3 (3.14 g, 9.644 mmol, 2.2 eq.), Intermediate 44 (1.36 g, 5.041 mmol, 1.15 eq.), DavePhos (CAS [213697-53-1], 173 mg, 0.44 mmol, 0.1 eq.) and Pd2dba3 (CAS [51364-51-3], 200 mg, 0.218 mmol,0.05 eq.) were then added at room temperature while nitrogen was bubbled through. The vial was sealed and the mixture was stirred at 90 ºC for 3 h. Saturated aqueous NaHCO₃ and EtOAc were added to the reaction mixture and the layers were separated. The aqueous layer was extracted again with EtOAc (3 x). The combined organic layer was dried with MgSO4, filtered, and concentrated under vacuo. The residue was purified by column chromatography on silica gel (25 g, EtOAc/heptane from 0/100 to 25/75) to yield Intermediate 45 (1.686 g, yield: 84 %) as a yellow solid. Intermediate 46:

(3α,4β,5α) [0235] Tetramethylammonium fluoride (CAS [373-68-2], 543 mg, 5.83 mmol, 1.5 eq.) was added to a solution of Intermediate 45 (1.686 g, 3.882 mmol) in DMF (15 mL). The reaction mixture was stirred at 65 ºC for 3 h. After cooling, the mixture was diluted with EtOAc (15 mL) and water (15 mL). The layers were separated and the organic layer was washed with water (20 mL) and brine (15 mL). The organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (80 g, EtOAc/heptane from 0/100 to 30/100) to yield Intermediate 46 (1.265 g, yield: 79 %) as a yellow solid. Intermediate 47:

(3α,4β,5α) [0236] Intermediate 47 was prepared in a similar manner as Intermediate 14, starting from Intermediate 46 instead of Intermediate 13. Intermediate 48:

(3α,4β,5α) [0237] TFA (1.505 mL, 19.67 mmol, 30 eq.) was added to a solution of Intermediate 47 (384 mg, 0.656 mmol) in DCM (3 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to yield Intermediate 48 (295 mg, yield: 91 %), used without further purification. Intermediate 49:

(3α,4 ^,5α) [0238] Intermediate 49 was prepared according to Method A (in DMF), starting from Intermediate 48 and 2-methyl-6-(methylsulfonyl)-4-pyridinecarboxylic acid (CAS [1780757- 32-5]).

(3α,4 ^,5α) [0239] A solution of Intermediate 47 (540mg, 0.922 mmol) in aqueous NaOH (2.5 M, 5.5 mL, 13.75 mmol, 15 eq.) was stirred at 72 ºC for 16 h. After cooling, the mixture was partitioned between EtOAc (25 mL) and saturated aqueous NaHCO₃. The layers were separated, and the organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g silica, DCM:MeOH (9:1) in DCM from 0 % to 25 %) to yield Intermediate 50 (401 mg, yield: 90 %) as a yellow solid. Intermediate 51:

(3α,4 ^,5α) [0240] Trifluoroacetic acid (1.5 mL, 19.601 mmol, 24 eq.) was added to a solution of Intermediate 50 (401 mg, 0.833 mmol) in DCM (3 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to yield Intermediate 51 (TFA salt, 508 mg, yield: 99 %) as a yellow solid, used without further purification. Intermediate 52:

(3 ^, 4 ^, 5 ^) [0241] (Methoxymethyl)triphenylphosphonium chloride (CAS [4009-98-7], 1518 mg, 4.341 mmol, 1.1 eq.) was dissolved THF (16 mL) and cooled to 0 °C under nitrogen atmosphere. Potassium tert-butoxide (1.0 M in THF, 4.14 mL, 4.144 mmol, 1.05 eq.) was added and the reaction mixture was stirred at room temperature for 1 h. Then, a solution of rel-1,1- dimethylethyl (3R,5S)-3,5-dimethyl-4-oxo-1-piperidinecarboxylate (CAS [1221821-84-6], 897 mg, 3.946 mmol, 1 eq.) in THF (8 mL) was added and the reaction mixture was stirred at room temperature overnight. Concentrated aqueous HCl was added until an acidic pH was reached, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with Et₂O (3 x). The combined organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography (24 g SiO2, heptane/EtOAc from 100/0 to 80/20) to afford Intermediate 52 (576 mg, yield: 60 %). Intermediate 53:

[0242] Intermediate 52 (576 mg, 2.387 mmol) was dissolved in MeOH (20 mL) and sodium borohydride (135 mg, 3.58 mmol, 1.5 eq.) was added. The reaction mixture was stirred at room temperature for 30 min, then was concentrated under reduced pressure. The residue was diluted in Et2O and washed with water. The aqueous layer was extracted twice with Et2O, and the combined organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography (12 g SiO₂, heptane/EtOAc from 90/10 to 50/50) to afford Intermediate 53 (389 mg, yield: 64 %) as a clear oil. Intermediate 54:

[0243] Intermediate 53 (389 mg, 1.519 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 10 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford Intermediate 54 (HCl salt, 385 mg, quantitative). Intermediate 55:

[0244] Intermediate 4 (200 mg, 0.564 mmol) and Intermediate 54 (200 mg, 0.792 mmol, 1.4 eq.) were dissolved in DMSO (5.6 mL) and DIPEA (0.292 mL, 1.693 mmol, 3 eq.) was added. The reaction mixture was stirred at 130 °C for 2 days. The reaction mixture was diluted with water and the mixture was extracted with EtOAc (3 x). The combined organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (12 g SiO2, DCM/MeOH from 100/0 to 90/10) to afford Intermediate 55 (112 mg, yield: 37 %) as an orange foam. Intermediate 56:

(3 ^, 4 ^, 5 ^) [0245] Intermediate 55 (112 mg, 0.211 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 4 mL, 4 M, 16 mmol) and DCM (2 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, then the precipitate was isolated by filtration, and dried under reduced pressure to afford Intermediate 56 (HCl salt, 117 mg, quantitative) as an off-white solid, used without further purification. Intermediate 57:

[0246] A suspension of Intermediate 4 (263 mg, 0.742 mmol), 2-methyl-6- (trifluoromethyl)morpholine (CAS [1342385-23-2], 502 mg, 2.968 mmol, 4 eq.), and DIPEA (384 µL, 2.226 mmol, 3 eq.) in dry DMSO (1 mL) was introduced in a thick wall vial. The vial was sealed and the reaction mixture was stirred at 130 °C for 4.5 days. The reaction mixture was diluted with water and DCM. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (SiO2, 25 g; heptane:EtOH/EtOAc 1/3 from 100:0 to 20:80) to give Intermediate 57 (311 mg, yield: 77 %) as an off-white solid. Intermediate 58:

[0247] HCl (37 % in water, 959 µL, 11.488 mmol, 20 eq.) was added dropwise to a solution of Intermediate 57 (311 mg, 0.574 mmol) in 1,4-dioxane (20 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated. The solid was co-evaporated with toluene to give Intermediate 58 (HCl salt, 273 mg, quantitative) as an orange solid, used without further purification. Intermediate 59:

[0248] A suspension of 4-methyl-4,6-diazaspiro[2.4]heptan-5-one (CAS [1338493-29-0], 368 mg, 2.917 mmol), 2,6-dibromopyridine (CAS [626-05-1], 1.38 g, 5.834 mmol, 2 eq.), Xantphos (CAS [161265-03-8], 675 mg, 1.167 mmol, 0.4 eq.), and Cs₂CO₃ (3.80 g, 11.668 mmol, 4 eq.) in dry 1,4-dioxane (15 mL) was degassed with nitrogen for 5 min. Pd(OAc)₂ (CAS [3375-31-3], 65 mg, 0.292 mmol, 0.1 eq.) was added and the reaction mixture was further degassed for 5 min. The vial was closed and the reaction mixture was stirred at 100 °C for 30 min in a microwave oven. The reaction mixture was diluted with DCM and the solid was filtered off. The filtrate was evaporated and the residue was purified by column chromatography (SiO2, 25 g; heptane:EtOH/EtOAc 1/3 from 100:0 to 20:80) to give Intermediate 59 (291 mg, yield: 35 %) as a yellow solid. Intermediate 60:

[0249] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS [72287-26-4], 76 mg, 0.103 mmol, 0.15 eq.) was added to a suspension of Intermediate 59 (291 mg, 1.031 mmol, 1.5 eq.), bis(pinacolato)diboron (CAS [73183-34-3], 314 mg, 1.238 mmol, 1.8 eq.), and KOAc (previously dried under vacuum at 50 °C, 304 mg, 3.094 mmol, 4.5 eq.) in dry 1,4- dioxane (6 mL), and the mixture was degassed by bubbling nitrogen through for 5 min. The vial was sealed and the reaction mixture was stirred at 90 °C for 2 h. The vial was opened and kept under nitrogen atmosphere while Intermediate 3 (202 mg, 0.688 mmol), K₂CO₃ (190 mg, 1.375 mmol, 2 eq.), and copper(I) chloride (69 mg, 0.688 mmol, 1 eq.) were added. The vial was sealed again and the reaction mixture was stirred at 75 °C for 18 h. After cooling, the reaction mixture was diluted with EtOAc and filtered. The solids were washed with EtOAc. Brine was added to the filtrate and the layers were separated. The aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (SiO₂, 25 g; heptane:EtOH/EtOAc 1/3 from 100:0 to 100:0) to give Intermediate 60 (124 mg, 41 % pure, yield: 16 %), as an off-white solid, still impure but used directly in the next step. Intermediate 61:

[0250] HCl (37 % in water, 0.28 mL, 3.312 mmol, 30 eq.) was added to a solution of Intermediate 60 (41 % pure, 124 mg, 0.11 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated to give Intermediate 61 (HCl salt, 62 mg) as a brown solid, used without further purification. Intermediate 62:

[0251] A solution of oxone (CAS [7069-62-8], 5.8 g, 9.2 mmol) in water (35 mL) was added in one portion to a solution of methyl 4-[(2-hydroxyethyl)thio]-2-pyridinecarboxylate (CAS [1500860-13-8], 0.98 g, 4.6 mmol) in MeOH (40 mL) at room temperature. The mixture was stirred at room temperature for 20 h. The mixture was diluted with EtOAc (150 mL) and water (250 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (150 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (40 g; MeOH/DCM from 0/100 to 20/80) to give Intermediate 62 (535 mg, yield: 47 %) as a white solid. Intermediate 63:

[0252] Sodium hydroxide (1 M in water, 6.5 mL, 6.5 mmol) was added to a stirred solution of Intermediate 62 (529 mg, 2.16 mmol) in MeOH (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was acidified with HCl (1 M in water) to pH=4 and extracted several times with EtOAc. The combined organic layer was evaporeated to give Intermediate 63 (662 mg, quantitative) as a white solid, used without further purification. Intermediate 64:

[0253] Intermediate 4 (2.67 g, 7.54 mmol) and 4-Boc-4,7-diazaspiro[2.5]octane (CAS [674792-08-6], 4 g, 18.84 mmol) were suspended in DMSO (80 mL), then DIPEA (3.9 mL, 22.61 mmol) was added. The mixture was stirred at 130 °C overnight. Then, the reaction mixture was diluted in EtOAc and washed with water. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by silica gel chromatography (DCM/MeOH from 100/0 to 98/2) to afford Intermediate 64 (1.72 g, yield: 42 % ). Intermediate 65:

[0254] Intermediate 64 (1.54 g, 2.82 mmol) was suspended in MeOH (15 mL) and HCl (6 M in iPrOH, 15 mL, 90 mmol) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated in vacuo and then co-evaporated once with toluene. The yellow powder was dried at 50 °C under reduced pressure to yield Intermediate 65 (1.49 g, yield: 100 %). Intermediate 66:

[0255] 2,6-Dibromopyridine (CAS [626-05-1], 200 mg, 0.84 mmol), 4-oxa-7- azaspiro[2.5]octan-6-one (CAS [1253790-21-4], 54 mg, 0.42 mmol), Xantphos (CAS [161265-03-8], 98 mg, 0.17 mmol), CS2CO3 (550 mg, 1.69 mmol), and Pd(0Ac)2 (CAS [3375-31-3], 9 mg, 0.042 mmol) were suspended in 1,4-dioxane (4.6 mL) and the suspension was degassed with nitrogen for 15 min. Then, the reaction mixture was stirred at 100 °C for 30 min under nitrogen atmosphere. The reaction mixture was diluted with DCM and filtered on a pad of dicalite. The solvents were evaporated in vacuo and the crude was purified by silica gel chromatography (24 g, heptane/EtOAc from 100/0 to 50/50) to yield Intermediate 66 (83 mg, yield: 68 %) as a white solid.

Intermediate 67:

[0256] Dichloro[l,T-bis(diphenylphosphino)ferrocene]palladium(II) (CAS [72287-26-4], 21 mg, 0.029 mmol) was added to a suspension of Intermediate 66 (83 mg, 0.29 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 88 mg, 0.34 mmol), and KOAc (dried under vacuum at 45 °C overnight, 85 mg, 0.86 mmol) in dry 1,4-dioxane (2 mL) and the mixture was degassed by bubbling nitrogen through for 5 min. The reaction mixture was stirred at 90 °C for 3.5 h. After cooling to 75 °C, the vial was opened and kept under nitrogen atmosphere while Intermediate 3 (56 mg, 0.19 mmol), K2CO3 (53 mg, 0.38 mmol), and CuCl (CAS [7758-89-6], 19 mg, 0.19 mmol) were added. The reaction mixture was stirred at 75 °C overnight. After cooling, the reaction mixture was diluted with brine and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was washed with brine, water, dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel chromatography (12 g, DCM/MeOH from 100/0 to 99/1) to yield Intermediate 67 (50 mg, yield: 57 %) as a yellow solid. Intermediate 68:

[0257] Intermediate 67 (50 mg, 0.11 mmol) was suspended in HC1 (6 M in iPrOH, 2 mL, 12 mmol) and MeOH (1 mL), and the orange reaction mixture was stirred at room temperature overnight. The solvents were evaporated under reduced pressure and the crude product was co-evaporated once with toluene to yield Intermediate 68 (46 mg, yield: 98 %) as a yellow- orange solid.

Intermediate 69:

[0258] Intermediate 69 was synthesized following a similar sequence of procedures as for the synthesis of Intermediate 68, starting from 2,6-dimethylmorpholin-3-one (CAS [93240-61-0]) instead of 4-oxa-7-azaspiro[2.5]octan-6-one.

Intermediate 70:

[0259] Intermediate 70 was synthesized following a similar sequence of procedures as for the synthesis of Intermediate 68, starting from 6-(trifluoromethyl)morpholin-3-one (CAS [1354953-95-9]) instead of 4-oxa-7-azaspiro[2.5]octan-6-one.

Intermediate 71 :

[0260] Intermediate 71 was synthesized following a similar sequence of procedures as for the synthesis of Intermediate 68, starting from 2,2-dimethylmorpholin-3-one (CAS [13882-78-5]) instead of 4-oxa-7-azaspiro[2.5]octan-6-one. Intermediate 72:

[0261] Sodium hydride (70 mg, 1.74 mmol) was added to a stirred solution of (L)-proline (CAS [147-85-3], 200 mg, 1.74 mmol) in DMSO (12 mL) at room temperature. The mixture was stirred at room temperature for 30 min. Then, 5-bromo-6-methyl-3-pyridinecarboxylic acid, methyl ester ([CAS: 1174028-22-8], 500 mg, 2.17 mmol), sodium methanesulfmate (CAS [20277-69-4], 1.8 g, 17.4 mmol), and copper iodide (CAS [7681-65-4], 331 mg, 1.74 mmol) were added and the mixture was stirred at 120 °C for 2 h. After cooling the reaction mixture was poured into a mixture of saturated aqueous NaHCCh and EtOAc. The formed precipitate was filtered, and the filtrate layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; MeOH/DCM from 0/100 to 5/95) to yield Intermediate 73 (278 mg, yield: 55 %) as a white solid.

Intermediate 73 :

[0262] A solution of sodium hydroxide (1 M in water, 9.2 mL, 9.2 mmol) was added to a stirred solution of Intermediate 72 (700 mg, 3.05 mmol) in MeOH (9 mL) at room temperature and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with aqueous HC1 (1 M in water) to pH~l and then extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 73 (545 mg, yield:79 %) as a white solid.

Intermediate 74:

[0263] 7-Bromo-l,6-naphthyridin-2(177)-one (CAS [1574395-48-4], 3.0 g, 13.33 mmol, 1.0 eq.), potassium trifluoro(vinyl)borate (CAS [13682-77-4], 2.15 g, 16.0 mmol, 1.2 eq.), bis(triphenylphosphine)palladium(II)chloride (CAS [13965-03-2], 280 mg, 0.4 mmol, 0.3 eq.), and Cs2CO3 (13.0 g, 40.0 mmol, 3.0 eq.) were taken up in DMF (40 mL) and water (10 mL) under nitrogen atmosphere. The mixture was stirred at 80 ºC for 16 h. After cooling, the reaction mixture was diluted with EtOAc and water. The organic layer was separated, dried (MgSO4), filtered, and the solvents were evaporated. The residue was purified by flash column chromatography (80 g SiO2, DCM:MeOH (9:1) in DCM, from 0 % to 30 %) to yield Intermediate 74 (1.267 g, yield: 49 %) as a white solid. Intermediate 75:

[0264] Phosphoryl chloride (CAS [10025-87-3], 1.65 mL, 17.67 mmol, 3.0 eq.) was added to a suspension of Intermediate 74 (1.014 g, 5.889 mmol, 1.0 eq.) in 1,2-dichloroethane (30 mL). The mixture was stirred at 80 ºC for 48 h. The mixture was diluted with aqueous saturated Na₂CO₃ and EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvents were evaporated to yield Intermediate 75 (981 mg, yield: 74 %) as a beige solid. Intermediate 76:

[0265] Osmium tetroxide (CAS [20816-12-0], 33 mg, 0.13 mmol) was added to a stirred mixture of Intermediate 75 (981 mg, 5.146 mmol, 1.0 eq.), sodium periodate (CAS [7790-28- 5], 4.4 g, 20.6 mmol, 4.0 eq.), and 2,6-dimethylpyridine (CAS [108-48-5], 1.2 mL, 10.3 mmol, 2.0 eq.) in water (14 mL) and 1,4-dioxane (55 mL) at 0 ºC. The mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO₃ and EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvents were evaporated to yield Intermediate 76 (822 mg, yield: 75 %) as a brown solid. Intermediate 77:

[0266] Intermediate 76 (200 mg, 1.038 mmol, 1.0 eq.), 4-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]pyridine acid (CAS [1009033-83-3], 467 mg, 0.494 mmol, 1.44 eq.), and sodium carbonate (330 mg, 3.115 mmol, 3.0 eq.) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) at room temperature in a pressure flask. The mixture was bubbled with nitrogen for 10 min. Then bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (CAS [95464-05-4], 42 mg, 0.052 mmol, 0.05 eq.) was added and the mixture was stirred at 85 ºC for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (silica 12 g; EtOAc/heptane from 0/100 to 80/20) to yield Intermediate 77 (90 mg, yield: 28 %) as a white solid. Intermediate 78:

[0267] Sodium bicarbonate (24 mg, 0.289 mmol, 1.0 eq.) and hydroxylamine hydrochloride (CAS [5470-11-1], 40 mg, 0.578 mmol, 2.0 eq.) were added to a solution of Intermediate 77 (90 mg, 0.289 mmol, 1.0 eq.) in MeOH (30 mL). This suspension was stirred at room temperature for 24 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvents were evaporated to yield Intermediate 78 (45 mg, yield: 47 %) as a beige solid., used without further purification. Intermediate 79:

[0268] Raney Ni (CAS [7440-02-0], 215 mg, 3.667 mmol, 4.0 eq.) was added to a stirred solution of Intermediate 78 (300 mg, 0.919 mmol, 1.0 eq.) in MeOH (6 mL) and THF (3 mL) at room temperature and under nitrogen atmosphere. Then, nitrogen atmosphere was replaced by hydrogen and the reaction mixture was stirred at room temperature for 4 h. The mixture was filtered over a pad of celite and the filtrate was evaporated to yield Intermediate 79 (170 mg, yield: 58 %) as a brown solid, used without further purification. Intermediate 80:

(3α, 4β, 5α) [0269] N-iodosuccinimide (CAS [516-12-1], 335 mg, 1.49 mmol, 1.0 eq.) was added to a solution of Intermediate 50 (717 mg, 1.49 mmol, 1.0 eq.) in 1,1,1,3,3,3-hexafluoro-2-propanol ([920-66-1], 4 mL) at 0 ºC and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and saturated aqueous Na₂S₂O₃. The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated. The crude product was purified by flash column chromatography (25 g SiO2, DCM:MeOH (9:1) in DCM from 0 % to 18 %) to yield Intermediate 80 (555 mg, yield: 60 %) as a yellow solid. Intermediate 81:

(3α, 4β, 5α) [0270] Trimethylboroxine (CAS [823-96-1], 264 µL, 0.19 mmol, 2.0 eq.), Cs₂CO₃ (CAS [534-17-8], 595 mg, 1.83 mmol, 2.0 eq.), and Pd(dppf)Cl₂ CH₂Cl₂ (CAS [95464-05-4], 75 mg, 91 µmol, 0.1 eq.) were added to a solution of Intermediate 80 (555 mg, 0.91 mmol) in 1,4-dioxane (10 mL) under nitrogen atmosphere. The mixture was stirred at 95 ºC for 16 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (25 g SiO2 column, DCM:MeOH (9:1) in DCM, rom 0/100 to 20/80) to yield Intermediate 81 (413 mg, yield: 90 %) as a colourless oil. Intermediate 82

(3α, 4β, 5α) [0271] Trifluoroacetic acid (CAS [76-05-1], 1.5 mL, 19.6 mmol, 23.5 eq.) was added to a stirred solution of Intermediate 81 (413 mg, 0.83 mmol, 1.0 eq.) in DCM (3 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h, then saturated aqueous NaHCO3 and DCM were added to the reaction mixture. The organic layer was separated, dried with MgSO₄, filtered, and concentrated to yield Intermediate 82 (321 mg, yield: 96 %) as a beige solid used without further purification. Intermediate 83:

[0272] A mixture of methyl 5-bromonicotinate (CAS [29681-44-5], 5.05 g, 26.367 mmol), Xantphos (CAS [161265-03-8], 2.667 g, 4.606 mmol, 0.2 eq.), and Pd2(dba)3 (CAS [51364- 51-3], 2.136 g, 0.1 eq.) was charged in a reaction vessel that was sealed, evacuated, and purged with nitrogen. Dry 1,4-dioxane (100 mL) was added, followed by 2-mercaptoethanol (CAS [60-24-2], 1.8 mL, 25.663 mmol, 1.1 eq.) and DIPEA (6 mL, 34.817 mmol, 1.5 eq.). The reaction mixture was stirred at 95 °C for 16 h. After cooling, the reaction mixture was filtered and the filtrated was concentrated. The crude residue was purified flash column chromatography (330 g SiO2; EtOAc/DCM 0/100 to 100/0) to give Intermediate 83 (5.18 g, quantitative). Intermediate 84:

[0273] Under nitrogen atmosphere, 5-bromonicotinic acid (CAS [20826-04-4], 600 mg, 2.970 mmol, 1.0 eq.) was dissolved in THF (15 mL), the reaction mixture was cooled to -78 ºC and was stirred for 10 min. n-Butyllithium (2.5 M in hexanes, 2.37 mL, 5.94 mmol, 2 eq.) was added dropwise and the reaction mixture was stirred at -78 ºC for 20 min. A solution of acetone (0.44 mL, 5.940 mmol, 2 eq.) in THF (1 mL) was added dropwise. The reaction mixture was stirred at -78 ºC for 1 h, then warmed to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous NH₄Cl, and KHSO₄ (1 M in water) was added dropwise over 10 min with vigorous stirring. The pH reached the value of 2-3. Then DCM and water were added. The organic layer was separated, concentrated, and the residue was purified by flash column chromatography (silica 25 g, DCM:MeOH (9:1) in DCM from 0/100 to 20/80) to yield Intermediate 84 (194 mg, yield: 32 %) as a beige solid. Intermediate 85:

[0274] Nitrogen was purged through a solution of 2,6-dibromo-4nitropyridine (CAS [175422- 04-5], 2 g, 7.1 mmol, 1.0 eq.) and tert-butyl 5,8-diazaspiro[2.5]octane-8-carboxylate (CAS [674792-08-6], 1.5 g, 7.1 mmol, 1.0 eq.) in 1,4-dioxane (30 mL). Then, Cs₂CO₃ (5 g, 15.35 mmol, 2.0 eq.), DavePhos (CAS [213697-53-1], 303 mg, 0.77 mmol, 0.05 eq.), and Pd2dba3 (CAS [51364-51-3], 330 mg, 0.36 mmol, 0.1 eq.) were added to the stirred solution at room temperature under nitrogen in a closed tube. The mixture was stirred at 90 ºC for 3.5 h, then saturated aqueous NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, dried with MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (80 g; EtOAc/heptane from 0/100 to 10/90) to yield Intermediate 85 (2.6 g, yield: 80 %) as a yellow solid. Intermediate 86:

[0275] Tetramethylammonium fluoride anhydrous (CAS [373-68-2], 887 mg, 9.5 mmol, 1.5 eq.) was added to a solution of Intermediate 85 (2.6 g, 6.3 mmol, 1.0 eq.) in DMF (50 mL) at room temperature in a sealed tube. The mixture was stirred for 3 h at 65 ºC. After cooling, the reaction mixture was diluted with EtOAc and water. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (80 g; EtOAc/heptane from 0/100 to 10/90) to yield Intermediate 86 (2.0 g, yield: 74 %) as an orange oil. Intermediate 87:

[0276] Intermediate 11 (0.65 g, 1.59 mmol, 1.0 eq.), Intermediate 86 (0.65 g, 1.68 mmol, 1.06 eq.), and K₂CO₃ (330 mg, 2.39 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (9 mL) in a sealed tube under nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 40 mg, 161.26 µmol, 0.1 eq.) and Pd(OAc)2 (CAS [3375-31-3], 18 mg, 80.18 µmol, 0.05 eq.) were added and the reaction mixture was stirred at 120 ºC for 14 h. After cooling, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (x 3). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g SiO2, EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 87 (470 mg, yield: 52 %) as a yellow oil. Intermediate 88:

[0277] HCl (4 M in 1,4-dioxane, 4.1 mL, 16.4 mmol, 20 eq.) was added to a solution of Intermediate 87 (0.47 g, 0.83 mmol) in DCM (7 mL). The reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated. The crude product was triturated with 1,4-dioxane and collected by filtration to yield Intermediate 88 (390 mg, yield: 96 %) as an orange solid. Intermediate 89:

[0278] 1,10-Phenanthroline (CAS [66-71-7], 132 mg, 0.72 mmol, 0.15 eq.), triphenylphosphine (CAS [603-35-0], 192 mg, 0.69 mmol, 0.15 eq.), potassium metabisulfite (CAS [16731-55-8], 2.17 g, 9.75 mmol, 2.2 eq.), formic acid sodium salt (CAS [141-53-7], 739 mg, 10.87 mmol, 2.5 eq.), and TBAB (CAS [1643-19-2], 1.75 g, 5.44 mmol, 1.25 eq.) were added to a solution of 5-bromo-6-methyl-3-pyridinecarboxylic acid methyl ester (CAS [1174028-22-8], 1.0 g, 4.35 mmol, 1.0 eq.) in DMSO (30 mL). The mixture was bubbled with nitrogen for 20 min. Palladium (II) acetate (CAS [3375-31-3], 55 mg, 0.24 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture temperature was allowed to cool to room temperature. Then, 2-(3- bromopropoxy)tetrahydro-2J/-pyran (CAS [33821-94-2], 0.9 mL, 5.35 mmol, 1.2 eq.) was added and the mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into water and extracted with DCM:MeOH (9: 1) (x 3). The combined organic layer was washed with water, dried over MgSCU, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (80 g SiCL; DCM:MeOH (9: 1) in DCM from 0/100 to 30/70) to yield Intermediate 89 (1045 mg, yield: 60 %) as a brown oil. Intermediate 90:

[0279] Pyridinium p-toluenesulfonate (CAS [24057-28-1], 100 mg, 0.40 mmol, 0.4 eq.) was added to a solution of Intermediate 89 (350 mg, 0.98 mmol, 1.0 eq.) in EtOH (5 mL) at room temperature and heated at 60 °C for 5 h. The reaction mixture was cooled and concentrated. The crude product was purified by flash column chromatography (12 g SiCL, DCM:MeOH (9: 1) in DCM from 0/100 to 30/70) to yield Intermediate 90 (171 mg, yield: 44 %) as a yellow oil. Intermediate 91 :

[0280] Dess-Martin periodinane (CAS [87413-09-0], 410 mg, 0.94 mmol, 1.5 eq.) was added portionwise to a stirred solution of Intermediate 90 (171 mg, 0.63 mmol, 1.0 eq.) in dry DCM (6 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 3 h. DCM and saturated aqueous NaHCCf were added, and the mixture was extracted with DCM (x 3). The combined organic layer was dried over MgSCU, filtered, and concentrated to yield Intermediate 91 (165 mg, yield: 97 %) as a colourless sticky solid.

Intermediate 92:

[0281] DAST (CAS [38078-09-0], 0.330 mL, 2.50 mmol, 4.0 eq.) was added to a solution of Intermediate 91 (165 mg, 0.61 mmol, 1.0 eq.) in DCM (4 mL), The reaction mixture was stirred at 60 °C for 3 h. After cooling, water was added to the reaction mixture. The layers were separated and the aqueous layer was extracted with DCM (x 3). The combined organic layer was dried (MgSCU), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (12 g SiCL, EtOAc/heptane from 0/100 to 40/60) to yield Intermediate 92 (85 mg, yield: 38 %) as a white solid.

Intermediate 93 :

[0282] LiOH (37 mg, 0.88 mmol, 3.0 eq.) was added to solution of Intermediate 92 (85 mg, 0.29 mmol, 1.0 eq.) in THF (2 mL) and H2O (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. EtOAc and HC1 (1 M in water) were added until pH 2-3 and the mixture was extracted with EtOAc (x 5). The combined organic layer was dried over MgSO₄, filtered, and concentrated to yield Intermediate 93 (50 mg, yield: 51 %) as a white solid. Intermediate 94:

[0283] Under nitrogen atmosphere, 5-bromonicotinic acid (CAS [20826-04-4], 1 g, 4.95 mmol, 1.0 eq.) was dissolved in dry THF (25 mL), and the solution was cooled to -78 ºC and stirred for 10 min. n-Butyllithium (1.6M hexanes, CAS [109-72-8], 6.19 mL, 9.90 mmol, 2.0 eq.) was added dropwise and the reaction mixture was stirred at -78 ºC for 20 min. A solution of acetaldehyde (CAS [75-07-0], 0.56 mL, 9.90 mmol, 2.0 eq.) in dry THF (1 mL) was then added dropwise. The reaction mixture was stirred at -78 ºC for 1 h, then warmed to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl. The layers were separated and the organic layer was concentrated. The residue was triturated with DCM:MeOH (9:1), filtered, and the filtrate was concentrated. The crude product was purified by reverse phase column chromatography (Phenomenex Gemini C1830 x 100 mm 5 µm; 95 % [25 mM NH4HCO3] - 5 % [ACN: MeOH 1:1] - 28 % [ACN: MeOH 1:1] to 63 % [25 mM NH₄HCO₃] - 37 % [ACN: MeOH 1:1]) to yield Intermediate 94 (502 mg, yield: 57 %) as a yellow oil. Intermediate 95:

[0284] Triethylamine (5.2 mL, 4.2 mmol, 2.0 eq.) was added to a stirred a solution of 2,6- dibromo-4-nitropyridine (CAS [175422-04-5], 600 mg, 2.1 mmol, 1.0 eq.) and 4-(Boc- amino)-3,3-difluoropiperidine (CAS [1263180-22-8], 578 mg, 2.4 mmol, 1.15 eq.) in toluene (14 mL) at room temperature. The mixture was stirred at 120 ºC for 9 h. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine (x 2), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 40/60) to yield Intermediate 95 (311 mg, yield: 33 %) as an orange solid. Intermediate 96:

[0285] Anhydrous tetramethylammonium fluoride (CAS [373-68-2], 100 mg, 1 mmol, 1.5 eq.) was added to a solution of Intermediate 95 (311 mg, 0.71 mmol, 1.0 eq.) in DMF (4 mL) at 65 ºC in a sealed tube. The mixture was stirred for 3 h. After cooling, the reaction mixture was diluted with EtOAc (100 mL) and water (150 mL). The organic layer was separated, washed once with water (100 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (12 g SiO₂, EtOAc/heptane from 0/100 to 30/70) to yield Intermediate 96 (202 mg, yield: 68 %) as a yellow oil. Intermediate 97:

[0286] Trifluoroacetic acid (1.33 mL, 17.4 mmol, 23.0 eq.) was added to a stirred solution of Intermediate 11 (300 mg, 0.73 mmol, 1.0 eq.) in DCM (5 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0ºC, and saturated aqueous Na₂CO₃ was added until pH 8. DCM was added and the aqueous layer was extracted with DCM (x 5). The combined organic layer was dried over MgSO4, filtered, and concentrated to yield Intermediate 97 (187 mg, yield: 81 %) as a yellow solid. Intermediate 98:

[0287] HATU (CAS [148893-10-1], 209 mg, 0.55 mmol, 1.25 eq.) was added to a solution of Intermediate 97 (187 mg, 0.44 mmol, 1.0 eq.), Intermediate 171 (104 mg, 0.48 mmol, 1.15 eq.), and DIPEA (0.3 mL, 1.71 mmol, 4.0 eq.) in DMF (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Saturated aqueous NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, dried (MgSO4), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (12 g SiO2, DCM:MeOH (9:1) in DCM from 0 % to 30 %), followed by reverse phase column chromatography (Phenomenex Gemini C1830 x 100 mm 5 µm; from 90 % H₂O (0.1 % HCOOH)- 10 % ACN-MeOH to 54 % H₂O (0.1 % HCOOH)-46 % ACN- MeOH) to yield Intermediate 98 (162 mg, yield: 71 %) as a yellow solid. Intermediate 99:

[0288] Intermediate 98 (148 mg, 0.3 mmol, 1.0 eq.), Intermediate 96 (120 mg, 0.3 mmol, 1.0 eq.), and K₂CO₃ (60 mg, 0.44 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (5 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 11 mg, 0.04 mmol, 0.15 eq.) and Pd(OAc)2 (CAS [3375-31-3], 6.5 mg, 0.03 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 120 ºC for 14 h. After cooling, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g SiO2; EtOAc/heptane, from 0/100 to 35/65) to yield Intermediate 99 (65 mg, yield: 32 %) as a yellow solid. Intermediate 100:

[0289] Nitrogen was bubbled through a solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 0.5 g, 1.77 mmol, 1.0 eq.) and 5-azaspiro [2.4] heptan-7-ol hydrochloride (CAS [1152110-85-4], 0.26 g, 1.77 mmol, 1.0 eq.) in 1,4-dioxane (8 mL) in a closed tube. Then, Cs₂CO₃ (1.25 g, 3.84 mmol, 2.1 eq.), DavePhos (CAS [213697-53-1], 0.076 mg, 0.19 mmol, 0.1 eq.), and Pd2dba3 (CAS [51364-51-3], 0.083 mg, 0.090 mmol, 0.05 eq.) were added. The mixture was stirred at 90 ºC for 3.5 h. Saturated aqueous NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, dried with MgSO₄, filtered, and concentrated. This crude product was purified by column of silica-gel (25 g; EtOAc/heptane from 0/100 to 10/90) to yield Intermediate 100 (337 mg, yield: 59 %) as an orange solid. Intermediate 101:

[0290] To a solution of Intermediate 100 (228 g, 0.72 mmol, 1.0 eq.) in DCM (2 mL) was added benzoyl chloride (CAS [98-88-4], 123 µL, 1.0 mmol, 1.46 eq.), Et3N (0.5 mL, 3.6 mmol, 5.0 eq.), and 4-(dimethylamino)pyridine (CAS [1122-58-3], 15.7 mg, 0.13 mmol, 0.18 eq.). The reaction mixture was stirred at room temperature for 24 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried with MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (12 g SiO₂, EtOAc/heptane from 0/100 to 10/90) to yield Intermediate 101 (293 mg, yield: 91 %) as a white solid. Intermediate 102:

[0291] Tetramethylammonium fluoride (CAS [373-68-2], 97 mg, 1.0 mmol, 1.42 eq.) was added to a solution of Intermediate 101 (293 mg, 0.7 mmol, 1.0 eq.) in DMF (4 mL) at 65 ºC in a sealed tube. The mixture was stirred for 3 h. After cooling, the reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (12 g SiO₂; EtOAc/heptane from 0/100 to 30/60) to yield Intermediate 102 (222 mg, yield: 80 %) as a yellow oil. Intermediate 103:

[0292] Intermediate 11 (338 mg, 0.82 mmol, 1.0 eq.), Intermediate 102 (323 mg, 0.82 mmol, 1.0 eq.), and K2CO3 (171 mg, 1.23 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (9 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 30 mg, 0.1 mmol) and Pd(OAc)₂ (CAS [3375-31-3], 18 mg, 0.083 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 120 ºC for 14 h. After cooling, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g SiO₂, heptane/EtOAc, from 0/100 to 35/65) to yield Intermediate 103 (235 mg, yield: 49 %) as a yellow solid. Intermediate 104:

[0293] Trifluoroacetic acid (0.75 mL, 9.8 mmol, 24.0 eq.) was added to a stirred solution of Intermediate 103 (235 mg, 0.41 mmol, 1.0 eq.) in DCM (2 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 ºC, and saturated aqueous Na₂CO₃ was added until pH 8. DCM was added and the aqueous layer was extracted with DCM (x 5). The combined organic layer was dried over MgSO4, filtered, and concentrated to yield Intermediate 104 (195 mg, yield: 98 %) as a yellow solid. Intermediate 105:

[0294] Intermediate 104 (195 mg, 0.33 mmol, 1.0 eq.), Intermediate 171 (79 mg, 0.36 mmol, 1.1 eq.), and DIPEA (0.23 mL, 1.33 mmol, 3.7 eq.) were taken up in DMF (3 mL). HATU (CAS [148893-10-1], 158 mg, 0.41 mmol, 1.24 eq.) was added at room temperature and the reaction mixture was stirred for 2 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvents evaporated. The crude product was purified by flash column chromatography (12 g column, DCM:MeOH (9:1) in DCM, from 0 % to 30 %) to yield Intermediate 105 (117 mg, yield: 52 %) as a yellow solid. Intermediate 106:

[0295] Iodomethane (CAS [74-88-4], 866 mg, 6.1 mmol, 1.0 eq.) was added to a stirred solution of 2,6-dichloro-3H-pyrimidin-4-one (CAS [120977-94-8],1.0 g; 6.1 mmol, 1.0 eq.) and K2CO3 (1.68 g; 12.1 mmol, 2.0) in DMF (20 mL) at 0 ºC. The mixture was stirred for 2 h at 0 ºC. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 50/50) to yield Intermediate 106 (732 mg, yield: 67 %) as a white solid. Intermediate 107:

[0296] 2,2,6,6-Tetramethylmorpholine (CAS [19151-69-0], 234 mg, 1.64 mmol, 0.8 eq.) was added to a stirred solution of Intermediate 106 (366 mg, 2.045 mmol, 1.0 eq.) and DIPEA (1.014 mL, 6.14 mmol, 3.0 eq.) in DMSO (2 mL). The mixture was stirred at 130 ºC for 16 h. The mixture was diluted with water and extracted with EtOAc (x 3). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 24 g; EtOAc/heptane from 0/100 to 70/30) to yield Intermediate 107 (350 mg, yield: 59 %) as a yellow solid. Intermediate 108:

[0297] Intermediate 11 (200 mg, 0.5 mmol, 1.0 eq.), Intermediate 107 (139 mg, 0.48 mmol, 0.96 eq.), and K2CO3 (101 mg, 0.73 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (5 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 18 mg, 0.07 mmol, 0.14 eq.) and Pd(OAc)₂ (CAS [3375-31-3], 11 mg, 0.07 mmol, 0.07 eq.) were added and the reaction mixture was stirred at 120 ºC for 14 h. After cooling, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (x 3). The combined organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g SiO2, EtOAc/heptane, from 0/100 to 35/65) to yield Intermediate 108 (106 mg, yield: 42 %) as a yellow solid. Intermediate 109:

[0298] Trifluoroacetic acid (0.31 mL, 4.1 mmol, 20.0 eq.) was added to a stirred solution of Intermediate 108 (106 mg, 0.2 mmol, 1.0 eq.) in DCM (0.5 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0ºC, and a saturated Na₂CO₃ aqueous solution was added until pH 8. DCM was added and the aqueous layer was extracted with DCM (x 5). The combined organic layer was dried over MgSO4, filtered, and concentrated to yield Intermediate 109 (78 mg, yield: 90 %) as a yellow solid. Intermediate 110:

[0299] Cis-2,6-dimethylmorpholine (CAS [6485-55-8], 0.201 mL, 1.64 mmol, 0.8 eq.) was added to a stirred solution of Intermediate 106 (366 mg, 2.045 mmol, 1.0 eq.) and DIPEA (1.014 mL, 6.14 mmol) in DMSO (2 mL). The mixture was stirred at 130 ºC for 16 h. The mixture was diluted with water and extracted with EtOAc (x 3). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 24 g; EtOAc/heptane from 0/100 to 70/30) to yield Intermediate 110 (384 mg, yield: 72 %) as a yellow solid. Intermediate 111:

[0300] Intermediate 11 (200 mg, 0.49 mmol, 1.0 eq.), Intermediate 110 (126 mg, 0.49 mmol, 1.0 eq.), and K₂CO₃ (101 mg, 0.73 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (5 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 18 mg, 0.07 mmol, 0.14 eq.) and Pd(OAc)2 (CAS [3375-31-3], 11 mg, 0.05 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 120 ºC for 14 h. After cooling, the mixture was diluted with saturated aqueous NaHCO₃ and extracted with EtOAc (x 3). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (12 g SiO2, EtOAc/heptane, from 0/100 to 20/80) to yield Intermediate 111 (83 mg, yield: 35 %) as a yellow solid. Intermediate 112:

[0301] Trifluoroacetic acid (0.27 mL, 3.59 mmol, 20.0 eq.) was added to a stirred solution of Intermediate 111 (80 mg, 0.17 mmol, 1.0 eq.) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 ºC, and saturated aqueous NaHCO₃ was added until pH 8. DCM was added and the aqueous layer was extracted with DCM (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated to yield Intermediate 112 (68 mg, yield: 96 %) as a beige solid. Intermediate 113:

(TRANS) [0302] (2R,6S)-Rel-2-methyl-6-(trifluoromethyl)-morpholine, hydrochloride (1:1) (CAS [2417329-59-8], 260 mg, 1.54 mmol, 1.0 eq.) was added to a stirred solution of Intermediate 106 (344 mg, 1.9 mmol, 1.23 eq.) and DIPEA (0.95 mL, 5.7 mmol, 3.7 eq.) in DMSO (2 mL). The mixture was stirred at 130 ºC for 16 h. The mixture was diluted with water and extracted with EtOAc (x 3). The organic layer was dried over MgSO₄, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 24 g; EtOAc/heptane from 0/100 to 70/30) to yield Intermediate 113 (264 mg, 35 %) as a yellow oil. Intermediate 114:

(TRANS) [0303] Intermediate 11 (145 mg, 0.35 mmol, 1.0 eq.), Intermediate 113 (110 mg, 0.35 mmol, 1.0 eq.), and K2CO3 (73 mg, 0.53 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (5 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 14 mg, 0.05 mmol, 0.14 eq.) and Pd(OAc)2 (CAS [3375-31-3], 8 mg, 0.03 mmol, 0.085 eq.) were added and the reaction mixture was stirred at 120 ºC for 14 h. The mixture was then cooled to room temperature, the mixture was diluted with saturated aqueous NaHCO₃ and extracted with EtOAc (x 3). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g, SiO₂, gradient of heptane in EtOAc, from 0 % to 35 %) to yield Intermediate 114 (90 mg, yield: 47 %) as a yellow solid. Intermediate 115:

(TRANS) [0304] Trifluoroacetic acid (0.26 mL, 3.3 mmol, 20.0 eq.) was added to a stirred solution of Intermediate 114 (90 mg, 0.17 mmol, 1.0 eq.) in DCM (0.5 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 ºC, and a saturated Na2CO3 aqueous solution was added until pH 8. DCM was added and the aqueous layer was extracted with DCM (x 5). The combined organic layer was dried over MgSO₄, filtered, and concentrated to yield Intermediate 115 (60 mg, yield: 81 %). Intermediate 116:

[0305] Tert-butyl N-(3,3-difluoropiperidin-4-yl) carbamate (CAS [1263180-22-8], 0.217 g, 0.92 mmol, 2.0 eq.) was added to a solution of Intermediate 190 (0.215 g, 0.46 mmol, 1.0 eq.) and DIPEA (0.227 mL, 1.38 mmol, 1.5 eq.) in DMSO (1 mL). The mixture was stirred at 120 ºC for 3 h. After cooling, the reaction mixture was diluted with DCM and washed with water. The organic layer was dried over MgSO4, and concentrated. The crude product was triturated with ACN and the solid was collected by filtration to yield Intermediate 116 (203 mg, yield: 65 %) as a beige solid. Intermediate 117:

[0306] Sodium hydride (60 % in mineral oil, 139 mg, 3.47 mmol, 0.8 eq.) was added to a stirred solution of (L)-proline (CAS [147-85-3], 398 mg, 3.46 mmol, 0.8 eq.) in DMSO (30 mL) at room temperature and the mixture was stirred at room temperature for 30 min. Then, methyl 5-bromo-6-hydroxynicotinate (CAS [381247-99-0].1.0 g, 4.3 mmol, 1.0 eq.), sodium methanesulfinate (CAS [20277-69-4], 3.51 g, 34.4 mmol, 8.0 eq.), and copper iodide (658 mg, 3.45 mmol, 0.8 eq.) were added and the mixture was stirred at 120 ºC for 4 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (x 2) and the solvents were evaporated. The crude product was purified by flash column chromatography (12 g SiO2; DCM:MeOH (9:1) in DCM, from 0 to 20 %) to yield Intermediate 117 (478 mg, yield: 47 %) as a white solid. Intermediate 118:

[0307] Iodomethane (CAS [74-88-4], 441 mg, 3.1 mmol, 3.6 eq.) and silver carbonate (CAS [534-16-7], 310 mg, 1.1 mmol, 1.25 eq.) was added to a stirred solution of Intermediate 117 (200 mg, 0.86 mmol, 1.0 eq.) in CHCl3 at room temperature. The mixture was stirred at 50 ºC for 2 days. The mixture was cooled, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 30/70) to yield Intermediate 118 (50 mg, 23 %) as a white solid and its N-alkylated isomer (130 mg, 60 %) as a white solid. Intermediate 119:

[0308] NaOH (1 M in water, 0.4 mL, 0.4 mmol, 2.0 eq.) was added to solution of Intermediate 118 (50 mg, 0.2 mmol, 1.0 eq.) in MeOH (1.2 mL), and the reaction mixture was stirred at room temperature for 16 h. KHSO4 (1 M in water, 1.4 mL) was added dropwise over 10 min with vigorous stirring. The pH reached the value of 2-3. This solution was concentrated to yield Intermediate 119 (45 mg, yield: 95 %, crude) as a white solid, used without further purification in the next step. Intermediate 120:

[0309] Pyrrole-3-carboxylic acid (CAS [931-03-3], 3 g, 27 mmol, 1 eq.) and 1,1-bis-(1,1- dimethylethoxy)-N,N,N,triethylamine (CAS [36805-97-7], 26 mL, 108 mmol, 1 eq.) were dissolved in toluene (57 mL) at room temperature. The mixture was stirred at 85 ºC for 16 h. The solvent was removed in vacuo. The residue was diluted in EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiO₂; EtOAc/heptane from 0/100 to 30/70) to yield Intermediate 120 (1.78 g, yield: 39 %) as a white solid. Intermediate 121:

[0310] N-chlorosuccinimide (CAS [128-09-6], 2.8 g, 20.9 mmol, 2 eq.) was added to a stirred solution of Intermediate 120 (1.75 g, 10.5 mmol 1 eq.) in ACN (20 mL). The mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc. The combined organic layers were dried over. MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO₂; EtOAc/heptane from 0/100 to 10/90) to yield Intermediate 121 (370 mg, yield: 14 %) as a white solid. Intermediate 122:

[0311] Isopropylsulfonyl chloride (CAS [1310-66-3], 0.64 mL, 2.3 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 121 (370 mg, 1.6 mmol, 1 eq.) and KHDMS (CAS [40949-94-8], 4.7 mL, 4.7 mmol, 3 eq.) in dry THF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (5 mL) and extracted with EtOAc. The organic layer was washed with brine (5 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g SiO2; EtOAc/heptane from 0/100 to 80/20). The desired fractions were collected and concentrated in vacuo to yield Intermediate 122 (362 mg, yield: 64 %) as a colourless oil. Intermediate 123:

[0312] HCl (4 M in 1,4-dioxane, CAS [7647-01-0], 7.9 mL, 31.6 mmol, 30 eq.) was added dropwise to the stirred solution of Intermediate 122 (360 mg, 1 mmol) in 1,4-dioxane (5 mL) at room temperature and the mixture was stirred at room temperature for 72 h. The mixture was concentrated in vacuo to yield Intermediate 123 (300 mg, yield: 99 %) as a white solid. Intermediate 124:

(3α, 4β, 5α) [0313] N-chlorosuccinimide (CAS [128-09-6], (77 mg, 0.58 mmol, 1.5 eq.) was added to a solution of Intermediate 47 (227 mg, 0.387 mmol, 1 eq.) in 1,1,1,3,3,3-hexafluoro-2-propanol (CAS [920-66-1], 11 mL) at 0 ºC. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and saturated aqueous NaS2O3, dried over MgSO4, filtered, and the solvent concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2, MeOH in DCM from 0 to 3 %) to yield Intermediate 124 (172 mg, yield: 72 %) as an orange powder. Intermediate 125:

(3α, 4β, 5α) [0314] An aqueous solution of NaOH (2.5 M in water, 2.8 mL, 2.0 mmol, 18 eq.) was added to a solution of Intermediate 124 (172 mg, 0.28 mmol, 1 eq.) in THF (3 mL) at room temperature. The mixture was stirred at 75 ºC for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The pH was brought to 10 with the addition of Na2CO3 (1 M in water). The aqueous layer was extracted with EtOAc (2 x20 mL). The organic layer was dried over MgSO₄, filtered, and the solvents evaporated in vacuo to yield Intermediate 125 (112 mg, yield: 78 %) as a yellow powder. Intermediate 126:

(3α, 4β, 5α) [0315] HCl (4 M in 1,4-dioxane, 0.92 mL, 3.7 mmol, 20 eq.) was added to a solution of Intermediate 125 (112 mg, 0.184 mmol, 1 eq.) in 1,4-dioxane (2 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo to yield Intermediate 126 (97 mg, yield: 99 %) as an orange solid. Intermediate 127:

[0316] 1,10-Phenanthroline (CAS [66-71-7], 132 mg, 0.73 mmol, 0.17 eq.), triphenylphosphine (CAS [603-35-0], 192 mg, 0.69 mmol, 0.16 eq.), potassium metabisulfite (CAS [16731-55-8], 2.17 g, 9.7 mmol, 2.2 eq.), formic acid sodium salt (CAS [141-53-7], 739 mg, 10.9 mmol, 2.5 eq.), and TBAB (CAS [1643-19-2], 1.75 g, 5.4 mmol, 1.2 eq.) were added to a solution of 5-bromo-6-methyl-3-pyridinecarboxylic acid, methyl ester (CAS [1174028-22-8], 1 g, 4.35 mmol, 1 eq.) in DMSO (30 mL). The mixture was bubbled with nitrogen for 20 min. Then, palladium (II) acetate (CAS [3375-31-3], 55 mg, 0.24 mmol, 0.06 eq.) was added and the reaction mixture was stirred at 100 ºC for 2 h. The reaction mixture was allowed to cool to room temperature. Finally, 2-(2-bromoethoxy)tetrahydro-2H-pyran (CAS [17739-45-6], 0.8 mL, 5.35 mmol, 1.2 eq.) was added and the mixture was stirred at 60 ºC for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water (x 2) and brine (x 2), then dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (24 g SiO₂; EtOAc/heptane from 0/100 to 50/50) to yield Intermediate 127 (456 mg, yield: 30 %) as a yellow solid. Intermediate 128:

[0317] HCl (4 M in 1,4-dioxane, 3.32 mL, 13.3 mmol, 10 eq.) was added to a solution of Intermediate 127 (456 mg, 1.3 mmol, 1 eq.) in 1,4-dioxane (8 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 128 (400 mg, yield: 96 %) as a yellow solid. Intermediate 129:

[0318] An aqueous solution of NaOH (1 M, 3.8 mL, 3.84 mmol, 3 eq.) was added to a stirred solution of Intermediate 128 (400 mg, 1.28 mmol, 1 eq.) in THF (10 mL). The mixture was stirred at room temperature for 72 h. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with HCl (1 M in water) to pH=1 and extracted with EtOAc (x 2). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 129 (220 mg, yield: 67 %) as a white solid. Intermediate 130:

[0319] HATU (CAS [148893-10-1], 4.97 g, 13.0 mmol, 1.5 eq.) was added to a stirred solution of methyl 2-(benzylamino)propanoate hydrochloride (CAS [16975-44-3], 2.0 g, 8.7 mmol, 1 eq.), 1-(Z-amino)cyclopropanecarboxylic acid (CAS [84677-06-5], 2.7 g, 8.7 mmol, 1 eq.), and DIPEA (4.6 mL, 26.1 mmol, 3 eq.) in DCM (45 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiO₂; EtOAc/heptane from 0/100 to 50 %) to yield Intermediate 130 (3.8 g, yield: 66 %) as a white solid. Intermediate 131:

[0320] Palladium on carbon (CAS [7440-05-3], 128 mg, 0.6 mmol, 0.1 eq.) was added to a stirred solution of Intermediate 130 (3.8 g, 6.0 mmol, 1 eq.) in EtOH (10 mL) under nitrogen atmosphere. The mixture was purged using vacuum and hydrogen. The mixture was stirred at room temperature under hydrogen atmosphere for 24 h. The reaction mixture was filtered through a short pad of celite. The filtrate was evaporated and the crude product was purified by flash column chromatography (80 g SiO2; EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 131 (1.7 g, yield: 80 %) as a white solid. Intermediate 132:

[0321] Borane-methyl sulfide complex (CAS [13292-87-0], 13.1 mL, 26.2 mmol, 3 eq.) was added to a solution of Intermediate 131 (2.7 g, 8.7 mmol, 1 eq.) in THF (15 mL) at room temperature. The reaction mixture was stirred at reflux for 16 h. The reaction mixture was cooled to 0 ºC and quenched with MeOH. Then, the reaction mixture was stirred at 70 ºC for 6 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (25 g SiO2, MeOH in DCM from 0 to 5 %) to yield Intermediate 132 (980 mg, yield: 50 %) as white solid. Intermediate 133:

[0322] Di-tert-butyl dicarbonate (CAS [24424-99-5], 2.5 mL, 12.8 mmol) was added to a stirred solution of Intermediate 132 (980 mg, 4.5 mmol) and Et3N (2.5 mL, 18.9 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO₃. The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g SiO2, EtOAc/heptane from 0/100 to 60/40) to yield Intermediate 133 (1.25 g, yield: 86 %) as a white solid. Intermediate 134:

[0323] Palladium on carbon (CAS [1314-15-4] (42 mg, 0.15 mmol, 0.1 eq.) was added to a stirred solution of Intermediate 133 (1.25 g, 3.9 mmol, 1 eq.) in MeOH (15 mL) under nitrogen atmosphere. The mixture was purged using vacuum and hydrogen. The mixture was stirred at room temperature under hydrogen atmosphere for 16 h. The mixture was filtered off through a pad of celite and the filtrate was evaporated in vacuo to yield Intermediate 134 (835 mg, yield: 93 %) as a yellow oil. Intermediate 135:

[0324] DavePhos (CAS [213697-53-1], 81 mg, 0.21 mmol, 0.1 eq.) and Pd2dba3 (CAS [51364-51-3] (94 mg, 0.10 mmol, 0.05 eq.) were added to a stirred solution of 2,6-dibromo-4- nitropyridine (CAS [175422-04-5], 580 mg, 2 mmol, 1 eq.), Intermediate 134 (489 mg, 2.16 mmol, 1.05 eq.), and Cs2CO3 (CAS [534-17-8], 1.4 g; 4.5 mmol, 2.2 eq.), in 1,4-dioxane (8 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at 100 ºC for 16 h. The mixture was diluted with H₂O, extracted with EtOAc. The organic layer was washed with brine (x 2), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g; EtOAc/heptane from 0/100 to 20/80) to yield Intermediate 135 (322 mg, yield: 36 %) as an orange oil. Intermediate 136:

[0325] Tetramethylammonium fluoride (CAS [373-68-2] (84 mg, 0.9 mmol, 1.2 eq.) was added to a solution of Intermediate 135 (320 mg, 0.75 mmol, 1 eq.) in dry DMF (3 mL) at room temperature. The mixture was stirred at 65 ºC for 3 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO₂, EtOAc/heptane from 0/100 to 20/80) to yield Intermediate 136 (259 mg, yield: 84 %) as an orange oil. Intermediate 137:

[0326] Pd(OAc)2 (CAS [3375-31-3], 14 mg, 0.06 mmol, 0.06 eq.) and di-tert- butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 31 mg, 0.128 mmol, 0.12 eq.) were added to a solution of Intermediate 11 (497 mg, 1.09 mmol, 1 eq.), Intermediate 136 (525 mg, 1.3 mmol, 1.2 eq.), and K2CO3 (265 mg, 1.9 mmol, 1.8 eq.) in 1,4-dioxane (4 mL) under a nitrogen atmosphere. The mixture was stirred at 120 ºC for 16 h. The mixture was diluted with H₂O and extracted with AcOEt. The organic layer was washed with brine (x 2), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (24 g SiO₂; EtOAc/heptane from 0/100 to 70/30) to yield Intermediate 137 (336 mg, yield: 52 %) as an orange oil. Intermediate 138:

[0327] HCl (4 M in 1,4-dioxane, 1.45 mL, 5.8 mmol, 10 eq.) was added to a solution of Intermediate 137 (336 mg, 0.580 mmol) in 1,4-dioxane (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to yield Intermediate 138 (260 mg, yield: 98 %) as an orange solid. Intermediate 139:

CIS [0328] Intermediate 6 (100 mg, 0.237 mmol) was added to a stirred solution of 4- acetylpicolinic acid (CAS [20857-22-1], 47 mg, 0.284 mmol, 1.2 eq.), HATU (CAS [94790- 37-1], 135 mg, 0.655 mmol, 1.5 eq.) and DIPEA (CAS [7087-68-5], 0.207 mL, 1.184 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was diluted with saturated NaHCO₃ aqueous solution and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash chromatography column (12 g silica, EtOAc/heptane, from 0 % to 95 %) and by reverse phase (Stationary phase: Phenomenex Gemini C18 (100 x 30 mm, 5 μm); Mobile phase: gradient from 59 % [25mM NH4HCO3] - 41 % [ACN:MeOH (1:1)] to 17 % [25mM NH4HCO3] - 83 % [ACN:MeOH (1:1)]) to yield Intermediate 139 (4 mg, yield: 3 %) as a yellow solid. Intermediate 140:

[0329] Iodomethane (CAS [74-88-4], 0.29 mL, 4.7 mmol, 3.6 eq.) and silver carbonate (CAS [534-16-7], (468 mg, 1.7 mmol, 1.3 eq.) were added to a stirred solution of methyl-6- hydroxinicotinate (CAS [66171-50-4], 200 mg, 1.3 mmol) in CHCl3 at room temperature. The mixture was stirred at room temperature for 72 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography over silica gel (25 g SiO₂; EtOAc/heptane from 0/100 to 30/70) to yield Intermediate 140 (135 mg, yield: 61 %) as a white solid. Intermediate 141:

[0330] Sodium hydroxide (2.3 mL, 2.35 mmol) was added to a stirred solution of Intermediate 140 (130 mg, 0.78 mmol) in MeOH (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with HCl (1 M in water) to pH=1 and then extracted with EtOAc (x 2). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 141 (102 mg, yield: 84 %) as a white solid. Intermediate 142:

[0331] Sodium hydride (60 % in mineral oil, 141 mg, 3.5 mmol) was added to a stirred solution of methyl-6-hydroxinicotinate (CAS [66171-50-4], 200 mg, 1.3 mmol) in ACN (4 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 20 min. Then, 2,2-difluoro-2-(fluorosulfonyl) acetic acid (CAS [1717-59-5], 0.23 mL, 2.22 mmol) was added dropwise. The heterogeneous mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g SiO₂, EtOAc/heptane from 0/100 to 20/80) to yield Intermediate 142 (150 mg, yield: 56 %) as a white solid. Intermediate 143:

[0332] An aqueous solution of NaOH (1 M, 2.2 mL, 2.2 mmol, 3 eq.) was added to a stirred solution of Intermediate 142 (150 mg, 0.74 mmol, 1 eq.) in MeOH (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with HCl (1 M in water) to pH=1 and then extracted with EtOAc (x 2). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 143 (115 mg, yield: 66 %) as a white solid. Intermediate 144:

[0333] DIAD (CAS [2446-83-5], 0.39 mL, 1.96 mmol, 1.5 eq.), dissolved in dry THF (1 mL), was added dropwise to a stirred solution of methyl 6-hydroxynicotinate (CAS [66171-50-4], 200 mg, 1.3 mmol, 1 eq.), 2-((tert-butyldimethylsilyl)oxy)ethanol (CAS [102229-10-7], 0.38 mL, 1.96 mmol, 1.5 eq.), and triphenylphosphine (CAS [603-35-0] (514 mg, 1.96 mmol, 1.5 eq.) in dry THF (6 mL) under nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (x 3). The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO₂; AcOEt/heptane from 0/100 to 30/70) to yield Intermediate 144 (165 mg, yield: 40 %) as a white solid. Intermediate 145:

[0334] Intermediate 145 was prepared following the same procedure as Intermediate 143, using Intermediate 144 instead of Intermediate 142. Intermediate 146:

[0335] HATU (CAS [148893-10-1], 195 mg, 0.48 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 145 (95 mg, 0.32 mmol, 1 eq.), Intermediate 6 (140 mg, 0.32 mmol, 1eq.), and DIPEA (0.24 mL, 1.28 mmol, 4 eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water, extracted with DCM, and washed with brine (x 2). The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2; EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 146 (165 mg, 82 %) as a yellow solid. Intermediate 147:

[0336] A mixture of 2-chloro-6-methyl-4-pyridinecarboxylic acid, methyl ester (CAS [3998- 90-1], 8.4 g, 45.26 mmol), 2-mercaptoethanol ([CAS 60-24-2], 3.8 mL, 54.18 mmol), potassium carbonate (8.8 g, 63.67 mmol), and dry acetone (266 mL) was refluxed for 36 h, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo, the residue was dissolved in Et2O and washed with brine. The organic layer was concentrated and the crude product was purified by flash column chromatography (120 g SiO2; EtOAc/heptane from 0/100 to 45/55) to afford Intermediate 147 (0.86 g, yield: 7 %) as a yellow solid. Intermediate 148:

[0337] TBDMSCl (CAS [18162-48-6], 684 mg, 4.54 mmol) was added in one portion to a solution of Intermediate 147 (860 mg, 2.27 mmol) and imidazole (CAS [288-32-4], 355 mg, 5.2 mmol) in THF (12 mL) at 5 ºC. The mixture was stirred at room temperature for 20 h. The mixture was diluted with saturated aqueous NaHCO₃ and Et₂O. The layers were separated and the organic layer was evaporated. The crude product was purified by flash column chromatography on silica gel (25 g; EtOAc/DCM from 0/100 to 5/95) to afford Intermediate 148 (640 mg, yield: 78 %) as oil. Intermediate 149:

[0338] A solution of mCPBA (CAS [937-14-4], 0.846 g, 3.77 mmol) in DCM (18 mL) was added dropwise over a period of 10 min to a solution of Intermediate 148 (640 mg, 1.87 mmol) in DCM (8 mL) at 5 ºC. Following the addition, the mixture was stirred at room temperature for 22 h. More mCPBA (218 mg, 0.97 mmol) in DCM (3 mL) was added dropwise over a period of 10 min at 5 ºC, and the mixture was stirred at room temperature for 22 h. The reaction was quenched by addition of saturated aqueous NaHCO3. The mixture was extracted with DCM. The organic layer was concentrated and the crude product was purified by flash column chromatography (12 g SiO₂; EtOAc/heptane, from 0/100 to 10/100) to afford Intermediate 149 (92 mg, yield: 13 %) as an oil. Intermediate 150:

[0339] A solution of Intermediate 149 (92 mg, 0.25 mmol) in a mixture of THF (1.3 mL), water (1.3 mL), and acetic acid (2.5 mL, 43.71 mmol) was stirred at room temperature for 3 days. The solvents were evaporated to afford Intermediate 150 (65 mg, yield: 79 %) as an oil, used without further purification. Intermediate 151:

[0340] NaOH (1 M in water, 0.4 mL, 0.4 mmol) was added to a solution of Intermediate 150 (64 mg, 0.25 mmol) in MeOH (1 mL) and the mixture was stirred at room temperature for 2 h. KHSO4 (1 M in water, 0.5 mL) was added and the mixture was stirred for 2 min, then concentrated in vacuo to afford Intermediate 151 (62 mg, yield: 71 %) as a yellow solid, used without further purification. Intermediate 152 and Intermediate 153: ( 2

(*S) Intermediate 153 [0341] 5-(1-Hydroxyethyl)-3-pyridinecarboxylic acid (CAS [1507931-60-3]) was separated into its stereoisomers by SFC (i-Amylose-1; isocratic 10 % [MeOH + 0.1 % DEA] – 90 % [CO₂]) to give Intermediate 152 and Intermediate 153, both as brown oils. Intermediate 154:

[0342] 1-Propanephosphonic anhydride solution (CAS [68957-94-8], 50 % in EtOAc, 5.57 mL, 9.35 mmol) was added dropwise to a suspension of Intermediate 10 (2 g, 5.5 mmol), Intermediate 171 (1.42 g, 6.6 mmol), and Et3N (5.5 mL, 39.6 mmol) in DCM (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The solid that appeared was filtered, washed with DCM, and dried under vacuum to yield Intermediate 154 (1.03 g, yield: 40 %) as a brown solid, used without further purification. Intermediate 155:

[0343] A suspension of Intermediate 154 (100 mg, 0.213 mmol), 1,2-diamino-2- methylpropane (CAS [811-93-8], 67 µL, 0.638 mmol, 3 eq.), and DIPEA (110 µL, 0.638 mmol, 3 eq.) in dry DMSO (1 mL) was introduced into a thick wall vial. The vial was sealed and the reaction mixture was stirred at 130 °C for 24 h. The reaction mixture was diluted with water and DCM. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried by filtration on Extrelut NT3, and evaporated to give Intermediate 155 (110 mg, yield: 90 %), used without further purification. Intermediate 156:

[0344] Intermediate 3 (5 g, 17.021 mmol) and Na₂CO₃ (7.2 g, 68.1 mmol) were added to a stirred solution of phenyl boronic acid (CAS [98-80-6], 6.2 g, 51.1 mmol) in 1,4-dioxane (240 mL) at room temperature under nitrogen atmosphere. Then, Pd(dppf)Cl2.CH2Cl2 (CAS [95464-05-4], 697 mg, 0.8 mmol) was added and the mixture was stirred at 85 ºC under nitrogen atmosphere for 16 h. After cooling, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂350 g; heptane/EtOAc 100/0 to 0/100) to yield Intermediate 156 (3.507 g, yield: 49 %) as a sticky paste. Intermediate 157:

[0345] Intermediate 156 (3.507 g, 10.456 mmol) was dissolved in HCl (6 M in iPrOH, 34.8 mL, 209.12 mmol) and the resulting mixture was stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure to give Intermediate 157 (HCl salt, 2.965 g, yield: 92 %) as a beige solid, used without further purification. Intermediate 158:

[0346] 5-Bromo-6-methylnicotinic acid (CAS [1190862-72-6], 282 mg, 1.308 mmol), HATU (CAS [148893-10-1], 497 mg, 1.308 mmol), and DIPEA (1.145 mL, 6.539 mmol) were combined in anhydrous DMF (3 mL) under nitrogen atmosphere and the mixture was stirred at room temperature for 1 min Intermediate 6 (500 mg, 1.09 mmol) was then added in one portion and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water. The solid that formed was filtered and washed with water to give Intermediate 158 (556 mg, yield: 93 %) as a tan solid, used without further purification. Intermediate 159:

[0347] Diisopropyl azodicarboxylate (CAS [2446-83-5], 4.5 mL, 22.9 mmol, 2.14 eq.) was added to a mixture of 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol (CAS [20931-50-4], 2.2 g 13.8 mmol, 1.28 eq.), 6-chloro-3-hydroxypyridazine (CAS [19064-67-6], 1.4 g, 10.7 mmol), Et3N (1.9 mL, 13.8 mmol, 1.28 eq.), and triphenyl phosphine (CAS [603-35-0], 6.4 g, 22.9 mmol, 2.14 eq.) in dry THF (65 mL). The mixture was stirred at room temperature for 3 h. The solvent was evaporated in vacuo and the crude product was suspended in heptane/EtOAc (5:1 v/v). The precipitate was filtered off and the filtrate was concentrated to dryness. The crude product was purified by flash column chromatography (silica 120 g; EtOAc/heptane, from 0/100 to 20/80) to yield Intermediate 159 (379 mg, yield: 13 %) as a white solid. Intermediate 160:

[0348] A solution of Intermediate 159 (376 mg, 1.4 mmol) and thiourea (CAS [62-56-6], 159 mg, 2.1 mmol, 1.5 eq.) in methyl ethyl ketone (CAS [78-93-3], 5 mL) was stirred at 90 ºC for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, dried over MgSO₄, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 40 g; EtOAc/heptane from 0 % to 15 %), followed by reverse phase column chromatography (Phenomenex Gemini C18100 x 30 mm, 5 μm; gradient from 72 % [25 mM NH₄HCO₃] - 28 % ACN to 36 % [25 mM NH4HCO3] - 64 % ACN) to yield Intermediate 160 (159 mg, yield: 41 %) as a yellow solid. Intermediate 161 :

[0349] H2O2 (30 % in water, 0.030 mL, 0.3 mmol, 0.5 eq.) was added dropwise at room temperature to a solution of Intermediate 160 (159 mg, 0.6 mmol) in a mixture of water (2.6 mL) containing NaOH (31 mg, 0.8 mmol, 1.3 eq.) and EtOH (2.6 mL). The mixture was stirred at room temperature for 16 h. The mixture was recharged with H2O2 (30 % aqueous solution, 0.015 mL, 0.1 mmol, 0.25 eq.) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated in vacuo and the residue was diluted with EtOAc (200 mL). The layers were separated. The aqueous layer was co-evaporated with ACN to yield Intermediate 161 (180 mg, yield: 91 %) as a white solid. Intermediate 162:

[0350] Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 22 mg, 0.09 mmol, 0.23 eq.) and palladium (II) acetate (CAS [3375-31-3], 12 mg, 0.06 mmol, 0.1 eq.) were added to a mixture of Intermediate 161 (180 mg, 0.6 mmol, 1.5 eq.), Intermediate 3 (109 mg, 0.4 mmol), and K2CO3 (78 mg, 0.6 mmol) in 1,4-di oxane (3 mL) under nitrogen atmosphere. The mixture was stirred at 120 °C for 18 h. After cooling ,the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 162 (145 mg, yield: 76 %) as a white solid.

Intermediate 163:

[0351] A solution of HC1 (4 M in 1,4-di oxane, 1.4 mL, 5.6 mmol, 19 eq.) was added to a stirred solution of Intermediate 162 (145 mg, 0.3 mmol) in DCM (1.5 mL). The mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to yield Intermediate 163 (.2 HCl, 134 mg, yield: 96 % yield) as a white solid. Intermediate 164:

[0352] A solution of 5-mercapto-3-pyridinecarboxylic acid, methyl ester (CAS [74470-37-4], 1.01 g, 5.96 mmol) in anhydrous DMF (12 mL) was treated with sodium 2-chloro-2,2- difluoroacetate (CAS [1895-39-2], 1.63 g, 10.6 mmol, 1.8 eq.) and sodium carbonate (4.89 g, 46.13 mmol, 7.7 eq.). The reaction mixture was stirred at 100 ºC for 1 h. The reaction mixture was cooled to room temperature and treated with saturated aqueous NaHCO₃ (50 mL). The mixture was extracted with DCM (2 x 50 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2, 80 g; gradient of DCM:MeOH 9:1 in DCM from 0 % to 100 %) to yield Intermediate 164 (325 mg, yield: 24 %) as a white solid. Intermediate 165:

[0353] Lithium hydroxide monohydrate (CAS [1310-66-3], 70 mg, 1.63 mmol, 1.5 eq.) was added to a solution of Intermediate 164 (226 mg, 1.03 mmol) in THF (2 mL) and water (0.5 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. The solvents were concentrated to dryness. The crude product was acidified with HCl (1 N in water, 1.1 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to dryness to yield Intermediate 165 (157 mg, yield: 74 %) as a white solid. Intermediate 166:

[0354] Ruthenium (III) chloride hydrate (CAS [14898-67-0], 20 mg, 0.015 mmol, 0.06 eq.) was added to a stirred solution of Intermediate 165 (247 mg, 1.2 mmol) and sodium periodate (CAS [7790-28-5], 1 g, 4.67 mmol, 3.8 eq.) in DCM (22 mL), ACN (22 mL), and water (44 mL). The mixture was stirred at room temperature for 16 h. Volatiles were removed under reduced pressure. The aqueous residue (pH<7) was extracted with DCM (3 x 15 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to dryness to yield Intermediate 166 (249 mg, yield: 86 %) as a white solid. Intermediate 167:

[0355] A solution of 4-mercapto-2-pyridinecarboxylic acid, methyl ester (CAS [74470-47-6], 293 mg, 1.73 mmol) in anhydrous DMF (5 mL) was treated with sodium 2-chloro-2,2- difluoroacetate (CAS [1895-39-2], 800 mg, 5.24 mmol, 3 eq.) and cesium carbonate (CAS [534-17-8], 1.7 g, 5.21 mmol, 3 eq.). The reaction mixture was stirred at 100 ºC for 16 h. The reaction mixture was cooled to room temperature and treated with saturated aqueous NaHCO₃ (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was dried over MgSO₄, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO₂, 25 g; gradient of DCM:MeOH 9:1 in DCM from 0 % to 100 %) to yield Intermediate 167 (135 mg, yield: 35 %) as a yellow oil. Intermediate 168:

[0356] Intermediate 168 was prepared following the same procedure as Intermediate 165, using Intermediate 167 instead of Intermediate 164. Intermediate 169:

[0357] Intermediate 169 was prepared following the same procedure as Intermediate 166, using Intermediate 168 instead of Intermediate 165. Intermediate 170:

[0358] CuI (CAS [7681-65-4], 1.98 g, 2.21 mmol, 1.1 eq.) was added to a stirred solution of 5-bromo-6-methyl-nicotinic acid methyl ester (CAS [1174028-22-8], 2.176 g, 9.46 mmol) and sodium methanesulfinate (CAS [20277-69-4], 3.88 g, 38.0 mmol, 4 eq.) in DMSO (28.5 mL) at room temperature in a sealed tube. The reaction mixture was stirred at 120 ºC for 16 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO₃ and DCM. The layers were separated and the organic layer was washed with brine (5 x 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (80 g, silica; EtOAc/heptane from 0/100 to 50/50) to yield Intermediate 170 (899 mg, yield: 35 %) as a white solid. Intermediate 171:

[0359] NaOH (1 M in water, 9.2 mL, 9.2 mmol, 3 eq.) was added to a stirred solution of Intermediate 170 (700 mg, 3.05 mmol) in MeOH (9 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water and washed with EtOAc. The aqueous layer was acidified with HCl (1 M in water) to pH=1 and then extracted with EtOAc (2 x 25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 171 (545 mg, yield: 79 %) as a white solid. Intermediate 172:

[0360] Acetaldehyde (CAS [75-07-0], 4.825 g, 109.524 mmol, 1.5 eq.) and p-toluenesulfonic acid monohydrate (CAS [6192-52-5], 25 g, 131.429 mmol, 1.8 eq.) were added to a solution of 4-penten-2-ol (CAS [625-31-0], 7.5 mL, 73.016 mmol) in toluene (260 mL) at 0 ºC. The reaction mixture was slowly warmed to room temperature and then stirred at 70 ºC for 3 h. The reaction mixture was diluted with Na2CO3 (1 M in water) and extracted with EtOAc (2 x 150 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated. The crude product was purified by silica gel column chromatography (12 g silica, EtOAc/heptane 20/80) to yield Intermediate 172 (11.76 g, yield: 57 %) as an orange oil. Intermediate 173:

(2 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ [0361] Cs2CO3 (CAS [534-17-8], 4.4 g, 13.51 mmol, 1.2 eq.) was added to a mixture of hydroxy-6-chloropyridazine (CAS [19064-67-6], 1.46 g, 11.19 mmol) and Intermediate 172 (3.82 g, 13.43 mmol, 1.2 eq.) in DMF (36 mL). The mixture was stirred at 100 ºC for 72 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSO₄, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 120 g; EtOAc/heptane from 0/100 to 50/50) to yield Intermediate 173 (1.0 g, yield: 33 %) as a white solid. Intermediate 174:

(2 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ [0362] Intermediate 173 (500 mg, 2.06 mmol) and thiourea (CAS [62-56-6], 236 mg, 3.10 mmol, 1.5 eq.) were diluted in methyl ethyl ketone (CAS [78-93-3], 6 mL) and the mixture was stirred at 90 ºC for 6 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSO₄, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; EtOAc/heptane from 0/100 to 15/85) to yield Intermediate 174 (325 mg, yield: 60 %) as a yellow solid.

Intermediate 175:

(2 a, 4 fl, 6a)

[0363] H2O2 (30 % in water, CAS [7722-84-1], 60 μL, 0.59 mmol, 1.6 eq.) was added dropwise at room temperature to a solution of Intermediate 174 (130 mg, 0.54 mmol) dissolved in a mixture of water (4.4 mL) containing NaOH (28 mg, 0.7 mmol) and EtOH (2.4 mL). The mixture was stirred at room temperature for 16 h. Then the mixture was cooled to 0 °C, and H2O2 (30 % aqueous solution, 30 μL, 0.6 mmol, 0.8 eq.) was added. The mixture was stirred at room temperature for 60 min. The solvent was evaporated in vacuo and the residue was washed with EtOAc. The aqueous phase was co-evaporated with ACN to afford Intermediate 175 (130 mg, yield: 86 %) as a white solid.

Intermediate 176:

(2 a, 4 fl, 6a)

[0364] Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 17 mg, 0.069 mmol, 0.1 eq.) and palladium(II) acetate (CAS [3375-31-3], 8 mg, 0.036 mmol, 0.05 eq.) were added to a mixture of Intermediate 175 (300 mg, 1.02 mmol, 1.49 eq.), Intermediate 3 (200 mg, 0.68 mmol), and K2CO3 (145 mg, 1.05 mmol, 1.5 eq.) in 1,4-dioxane (5 mL) under nitrogen atmosphere. The mixture was stirred at 120 °C for 18 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; EtOAc/heptane 0/100 to 50/50) to yield Intermediate 176 (130 mg, yield: 39 %) as a white solid. Intermediate 177:

HCl (4 M in 1,4-dioxane, 1.4 mL, 5.6 mmol, 20 eq.) was added to a stirred solution of Intermediate 176 (130 mg, 0.28 mmol) in DCM (2.8 mL). The mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to yield Intermediate 177 (.2 HCl, 122 mg, yield: 97 %) as a yellow solid, contaminated with some (2 ^, 4 ^, 6 ^) isomer. Intermediate 178:

[0365] Intermediate 158 (175 mg, 0.32 mmol), sodium methanethiolate (CAS [5188-07-8], 71 mg, 0.96 mmol), and DMF (1.75 mL) were combined under nitrogen atmosphere and the mixture was stirred at 100 °C for 1.5 h. After cooling, the reaction mixture was diluted with water until a light brown solid precipitated. The suspension was stirred at room temperature for 5 min, then filtered, and washed with additional water. The solid was collected and dried under vacuum at 45 °C to give Intermediate 178 (120 mg, yield: 73 %) as a light brown solid. Intermediate 179:

[0366] Intermediate 158 (175 mg, 0.32 mmol) and Xantphos Pd G4 (CAS [1621274-19-8], 15 mg, 0.016 mmol, 0.05 eq.) were dissolved in THF (1.6 mL) under nitrogen atmosphere.2- Mercaptoethanol (CAS [60-24-2], 25 µL, 0.352 mmol, 1.1 eq.) and Et3N (49 µL, 0.352 mmol, 1.1 eq.) were added sequentially. The mixture was stirred at 60 °C for 1.5 h. After cooling, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic layer was dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (12 g SiO2, 0-15 % MeOH/DCM) to give Intermediate 179 (165 mg, yield 95 %) as a yellow solid. Intermediate 180:

[0367] 5-Bromonicotinic acid (CAS [20826-04-4], 264 mg, 1.308 mmol, 1.2 eq.), HATU (CAS [148893-10-1], 497 mg, 1.308 mmol, 1.2 eq.), and DIPEA (1.15 mL, 6.539 mmol, 6.0 eq.) were combined in dry DMF (8 mL) under nitrogen atmosphere and the mixture was stirred for 1 min. Intermediate 6 (500 mg, 1.09 mmol) was added in one portion, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water until precipitation was complete, then the suspension was stirred for 10 min, filtered, and the solid was washed with to give a tan solid, dried under vacuum to give Intermediate 180 (543 mg, yield: 93 %) as a tan solid.

Intermediate 181 :

[0368] Intermediate 180 (220 mg, 0.412 mmol) and sodium methanethiolate (CAS [5188-07- 8], 91 mg, 1.237 mmol) were combined in DMF (3.3 mL) and the mixture was stirred at 100 °C under nitrogen atmosphere for 1.5 h. After cooling, the mixture was diluted with water until a light precipitate formed. The suspension was stirred for 10 min then filtered to give a light brown solid, which was dried under vacuum to give Intermediate 181 (106 mg, yield: 51 %).

Intermediate 182:

[0369] Intermediate 180 (125 mg, 0.23 mmol) and Xantphos Pd G4 (CAS [1621274-19-8], 11 mg, 0.012 mmol, 0.05 eq.) were dissolved in dry THF (1.2 mL) under argon atmosphere. 2- Mercaptoethanol (CAS [60-24-2], 18 μL, 0.26 mmol, 1.1 eq.) and EbN (36 μL, 0.26 mmol, 1.1 eq.) were then added and the mixture was stirred at 60 °C for 1.5 h. After cooling, the reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography (12 g silica gel, 0-12 % MeOH in DCM) to afford Intermediate 182 (135 mg, yield: 108 %) as a green oil.

Intermediate 183:

[0370] Sodium hydride (270 mg, 6.7 mmol) was added to a stirred solution of (L)-proline (CAS [147-85-3], 773 mg, 6.7 mmol) in DMSO (25 mL) at room temperature. The mixture was stirred at room temperature for 30 min. Then, 5-bromo-6-methyl-3-pyridinecarboxylic acid, methyl ester (CAS [1174028-22-8], 1.93 g 8.3 mmol), sodium methanesulfmate (CAS [20277-69-4], 7 g, 68.5 mmol), and copper iodide (CAS [7681-65-4], 1.3 g, 6.8 mmol) were added and the mixture was stirred at 120 °C for 2 h. After cooling, the mixture was poured in saturated aqueous NaHCCE and EtOAc. The mixture was filtered, and the filtrate layers were separated. The aqueous layer was extracted with EtOAc (x2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 183 (850 mg, yield: 42 %) as a yellow solid.

Intermediate 184:

[0371] A homogeneous solution of Intermediate 183 (0.492 g, 2.146 mmol) and 2,2,2- trifluoroethyl trifluoroacetate (CAS [407-38-5], 0.5 mL, 3.734 mmol) in dry THF (20 mL) was cooled to -78 °C under a nitrogen atmosphere and was treated dropwise with LiHMDS (CAS [4039-32-1], 3.6 mL, 3.6 mmol, 1 M in THF). After stirring at -78 °C for 5 min, the reaction mixture was allowed to slowly warm to room temperature over the course of 1 h. The mixture was then cooled to 0 °C and the reaction was quenched by addition of saturated aqueous NaHCCL. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried (MgSO4), filtered, and concentrated to yield Intermediate 184, used directly without further purification.

Intermediate 185:

[0372] A solution of Intermediate 184 in ACN (30 mL) was cooled to 0 °C and treated with l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bi s(tetrafluorob orate) (CAS [140681-55-6], 2.947 g, 8.319 mmol) in one portion. The reaction mixture was warmed to room temperature and then stirred at 60 °C for 40 min. After cooling, the reaction mixture was concentrated to dryness. The crude material was suspended in EtOAc (500 mL), sonicated to break up all particulates, filtered through celite, and the filtrate was concentrated to yield Intermediate 185, used directly without further purification.

Intermediate 186:

[0373] A solution of Intermediate 185 in THF (20 mL) and water (5 mL) was treated with DIPEA (1.0 mL, 5.803 mmol) and was stirred at room temperature for 15 min. The reaction mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried (MgSCU), filtered, and concentrated. The crude material was purified by flash column chromatography (40 g SiCh, EtOAc/heptane 0/100 to 100/0) to yield Intermediate 186 (0.27 g, 47 % over 3 steps) as a colorless oil that crystallized to white needles upon standing.

Intermediate 187:

[0374] A suspension of Intermediate 186 (0.522 g, 1.968 mmol) in MeOH (5 mL) was treated with aqueous NaOH (0.7 mL, 2.1 mmol, 3 M in water) and stirred at 50 °C for 40 min. After cooling, the reaction mixture was concentrated to yield Intermediate 187 (0.518 g, 96 %, sodium salt) as an orange solid, used without further purification. Intermediate 188:

[0375] A solution of 2-chloropyrimidine (CAS [1722-12-9], 4.58 g, 40.0 mmol) in THF (120 mL) was cooled to -60 °C under nitrogen atmosphere. Then, a 0.79 M THF-toluene solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (CAS [898838-07-8], 61 mL, 48.2 mmol) was added dropwise and the resulting mixture was stirred for 1.5 h at -60 °C. Zinc chloride (CAS [7646-85-7], 1 M in diethyl ether, 60 mL, 60 mmol) was added and the reaction mixture was allowed to come to room temperature and stirred for another 1.5 h to prepare the intermediate organozinc. In a separate flask, Intermediate 3 (2 g, 6.81 mmol) and Pd(PPhs)4 (CAS [14221-01-3], 393 mg, 0.340 mmol, 0.05 eq.) were placed under nitrogen atmosphere and treated with the prepared solution of organozinc (ca. 0.16 M, 128 mL, 20.4 mmol, 3 eq.). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Triturating the residue with ACN gave Intermediate 188 (1.46 g, yield: 56 %) as white solid.

Intermediate 189:

[0376] Intermediate 188 (0.650 g, 1.75 mmol) was dissolved in HC1 (4 N in 1,4-dioxane, 8.7 mL, 34.8 mmol, 20 eq.) and 1,4-dioxane (23 mL) and the mixture was stirred at room temperature for 16 h. The crude mixture was concentrated in vacuo and the residue was triturated in diethyl ether and filtered to yield Intermediate 189 (HC1 salt, 0.475 g, yield: 99 %) as a brownish solid.

Intermediate 190:

[0377] HBTU (CAS [94790-37-1], 0.575 g, 1.516 mmol, 1.1 eq.) was added to a stirred solution of Intermediate 189 (0.475 g, 1.378 mmol), Intermediate 171 (0.326 g, 1.516 mmol, 1.1 eq.), and DIPEA (0.96 mL, 5.513 mmol, 4 eq.) in DMF (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with 1 M aqueous Na2CO3.The organic layer was dried over MgSO4, filtered, and concentrated. The product was triturated in ACN and filtered to afford Intermediate 190 (0.477 g, yield: 71 %) as an off-white solid.

Intermediate 191 :

[0378] 1, 3, 8-Triazaspiro[4.5]decane-2, 4-dione (CAS [13625-39-3], 0.767 g, 4.53 mmol, 2 eq.) was added to a solution of 4-benzyloxy-2-chloropyrimidine (CAS [108381-28-8], 0.5 g, 2.26 mmol) and DIPEA (0.75 mL, 4.53 mmol, 2 eq.) in DMSO (2 mL). The mixture was stirred at 120 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with H2O. The organic layer was dried over MgSCU, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (25 g SiCh, heptane/EtOAc from 100/0 to 0/100) to afford Intermediate 191 (622 mg, yield: 74 %).

Intermediate 192:

[0379] Intermediate 191 (622 mg, 1.76 mmol) and EtsN (0.060 mL 0.421 mmol, 0.24 eq.) were dissolved in MeOH (15 mL). Pd/C (10 % , CAS [7440-05-3], 59 mg, 0.055 mmol) was added and the suspension was stirred under hydrogen atmosphere (1 atm) at room temperature for 16 h. The catalyst was filtered off through a pad of Celite that was further rinsed with MeOH (5 x 40 mL). The filtrate was concentrated to yield Intermediate 192 (414 mg, yield: 68 %) as a solid. Intermediate 193:

[0380] Phosphorous(V) oxychloride (CAS [10025-87-3], 0.176 mL, 1.89 mmol, 1.2 eq.) was added to a solution of Intermediate 192 (0.414 g, 1.57 mmol) and Et3N (0.22 mL 1.57 mmol, 1 eq.) in DMF (14 mL). The resulting mixture was stirred at 50 ºC under nitrogen atmosphere for 2 h. The mixture was poured onto ice, basified with 1 M aqueous Na₂CO₃, and extracted several times with EtOAc. The combined organic layer was dried over MgSO₄, filtered, and the solvents evaporated in vacuo to yield Intermediate 193 (446 mg, yield: 91 %) as a solid, used without further purification. Intermediate 194:

[0381] Intermediate 3 (0.2 g, 0.68 mmol) was dissolved in a solution of HCl (4 M in 1,4- dioxane, 6 mL, 24 mmol) and 1,4-dioxane (4 mL) and the mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo to yield Intermediate 194 (HCl salt, 197 mg, yield: 78 %) as pale brown solid, used without further purification. Intermediate 195:

[0382] HBTU (CAS [94790-37-1], 1.5 g, 4 mmol) was added to a solution of Intermediate 194 (0.9 g, 3.4 mmol), Intermediate 171 (0.87 g, 4 mmol), and DIPEA (2.8 mL, 16.9 mmol) in DCM (15 mL) at room temperature and the mixture was stirred for 2 h at room temperature. The mixture was diluted with DCM and washed with Na2CO3 (1 M in water). The organic layer was dried (MgSO₄), filtered, and the solvent evaporated in vacuo. The crude product was triturated in ACN and the solid was filtered to give a first crop of Intermediate 195. The mother liquor was purified by flash column chromatography (25 g SiO2; DCM/MeOH 9/1 in DCM, from 0/100 to 20/80). The pure fractions were collected, the solvent was evaporated, and the product was triturated in ACN, filtered, dried, and combined with the first crop to yield Intermediate 195 (0.915 g, yield: 67 %) as a solid. Intermediate 196:

[0383] Intermediate 195 (0.665 g, 1.70 mmol) and sodium 1-methyl 3-sulfinopropanoate (CAS [90030-48-1], 0.60 g, 3.44 mmol, 2 eq.) were dissolved in DMF (6 mL) and the miwture was degassed by bubbling nitrogen. Copper iodide (CAS [7681-65-4], 650 mg, 3.41 mmol, 2 eq.) was added. The vial was sealed and the reaction mixture was stirred at 100 ºC for 1 h. After cooling ,the reaction mixture was partitioned between EtOAc (25 mL), water (25 mL) and 25 % ammonia (5 mL). The organic layer was separated, washed with brine (3 x 5 mL), dried over MgSO4, and filtered. The solvent was evaporated and the residue was purified by flash column chromatography (25 g SiO2, MeOH/DCM from 0/100 to 5/95) to yield Intermediate 196 (0.26 g, yield: 30 %) as a white solid. Intermediate 197:

[0384] 4-Boc-4,7-diazaspiro[2.5]octane (CAS [674792-08-6], 1.92 g, 9.07 mmol, 2 eq.) was added to a solution of 4-benzyloxy-2-chloropyrimidine (CAS [108381-28-8], 1.33 g, 4.53 mmol) and DIPEA (1.5 mL, 9.07 mmol, 2 eq.) in DMSO (4 mL). The reaction mixture was stirred at 120 ºC for 2 h. After cooling, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO₂25 g, heptane/EtOAc from 100/0 to 50/50) to afford Intermediate 197 (1.38 g, yield: 75 %) as an oil. Intermediate 198:

[0385] Intermediate 197 (1.38 g, 3.48 mmol) and Et₃N (0.116 mL 0.833 mmol, 0.24 eq.) were dissolved in MeOH (25 mL). Pd/C (10 %, CAS [7440-05-3], 116 mg, 0.109 mmol) was added and the suspension was stirred under hydrogen atmosphere (1 atm) at room temperature for 16 h. The catalyst was filtered off through a pad of Celite that was further rinsed with MeOH (5 x 40 mL). The filtrate was concentrated to yield Intermediate 198 (1.06 g, yield: 98 %) as a solid, used without further purification.

Intermediate 199:

[0386] Intermediate 199 was prepared following the same procedure as Intermediate 193, using Intermediate 198 instead of Intermediate 192

Intermediate 200:

[0387] Intermediate 199 (335 mg, 1.031 mmol) was dissolved in 1,4-dioxane (5 mL) under nitrogen atmosphere. AcOK (CAS [127-08-2], 253 mg, 2.58 mmol, 2.5 eq.), bis(pinacolato)diboron (CAS [73183-34-3], 288 mg, 1.14 mmol, 1.1 eq.), tricyclohexylphosphine (CAS [2622-14-2], 12 mg, 0.041 mmol, 0.04 eq.), and Pd(OAc)2 (CAS [3375-31-3], 5 mg, 0.021 mmol, 0.02 eq.) were added to the solution. The reaction mixture was stirred at 110 °C for 1 h under nitrogen atmosphere. After cooling, the mixture was kept under nitrogen atmosphere and K2CO3 (285 mg, 2.063 mmol, 2 eq.), CuCl (CAS [7758-89-6], 102 mg, 1.031 mmol, 1 eq.), and Intermediate 3 (303 mg, 1.031 mmol, 1 eq.) were added. The reaction mixture was stirred at 110 °C for 16 h. After cooling, the mixture was diluted with water and EtOAc. The organic layer was separated, dried over MgSCU, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiCL, heptane/EtOAc from 0/100 to 80/20) to yield Intermediate 200 (100 mg, yield: 18 %) as a foam.

Intermediate 201 :

[0388] TFA (0.278 mL, 3.64 mmol, 22.6 eq.) was added to a stirred solution of Intermediate

200 (0.100 g, 0.161 mmol) in DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated with toluene (2 x 15 mL) to yield Intermediate

201 (TFA salt, 92 mg, yield: 98 %) as a thick oil.

Intermediate 202:

[0389] Sodium hydride (CAS [7646-69-7], 56 mg, 1.41 mmol, 0.8 eq.) was added to a stirred solution of (L)-proline (CAS [147-85-3], 162 mg, 1.41 mmol, 0.8 eq.) in DMSO (12 mL) under nitrogen atmosphere and the mixture was stirred at room temperature for 30 min. Methyl 5-bromo-6-(trifluoromethyl)nicotinate (CAS [1198016-45-3], 562 mg, 1.76 mmol), sodium methanesulfmate (CAS [20277-69-4], 1.44 g, 14.08 mmol, 8 eq.), and copper iodide (CAS [7681-65-4], 270 mg, 1.41 mmol, 0.8 eq.) were added. The reaction vessel was closed and the mixture was stirred at 120 °C for 2 h. After cooling, the reaction mixture was poured into water and DCM. The solids were filtered off. The layers of the filtrate were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiCL, DCM/MeOH from 100/0 to 90/10) to afford Intermediate 202 (149 mg, yield: 29 %) as a white solid.

Intermediate 203 :

[0390] Lithium hydroxide monohydrate (CAS [1310-66-3], 88 mg, 2.10 mmol, 4 eq.) was added to a solution of Intermediate 202 (149 mg, 0.526 mmol) in THF (6 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The pH was brought to neutral by addition of 1 M aqueous KHSO4. DCM was added and the organic layer was separated, dried over MgSCU, and filtered. The solvents were removed in vacuo to yield Intermediate 203 (131 mg, yield: 91 %) as a white solid, used without further purification. Intermediate 204:

[0391] To a solution of methyl 5-bromo-6-methylnicotinate (CAS [1174028-22-8], 2 g, 8.70 mmol) in DCE (25 mL) under nitrogen atmosphere, was added N-bromosuccinimide (CAS [128-08-5], 4.6 g, 26 mmol, 3 eq.), followed by 2, 2'-azobis(2 -methylpropionitrile) (CAS [78- 67-1], 0.43 g, 2.6 mmol, 0.3 eq.). The reaction mixture was stirred at 90 °C for 16 h. After cooling, the solvent was evaporated and the crude product was purified by flash column chromatography (80 g SiCL, heptane/(heptane:EtOAc, 5: 1), from 100/0 to 90/10) to give Intermediate 204 (1.3 g, yield: 38 %) as a colourless oil.

Intermediate 205:

[0392] Intermediate 204 (1.14 g, 2.94 mmol) was dissolved in DCM (30 mL) under nitrogen atmosphere and silver tetrafluoroborate (CAS [14104-20-2], 1.7 g, 8.8 mmol, 3 eq.) was added. The reaction mixture was stirred at 40 °C for 16 h. The solid was filtered off and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography (12 g SiCE, heptane/(heptane:EtOAc, 5: 1), from 100/0 to 90/10) to give Intermediate 205 (840 mg, yield: 99 %) as a white solid.

Intermediate 206:

[0393] Under nitrogen atmosphere, sodium hydride (CAS [7646-69-7], 48 mg, 1.20 mmol, 0.8 eq.) was added to a stirred solution of (L)-proline (CAS [147-85-3], 138 mg, 1.20 mmol, 0.8 eq.) in DMSO (7 mL), and the mixture was stirred at room temperature for 30 min.

Intermediate 205 (400 mg, 1.50 mmol), sodium methanesulfmate (CAS [20277-69-4], 1.23 g, 12.0 mmol, 8 eq.), and copper iodide (CAS [7681-65-4], 229 mg, 1.20 mmol, 0.8 eq.) were added. The reaction vial was sealed and the mixture was stirred at 120 °C for 16 h. After cooling, the reaction mixture was poured into water and EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiO2, heptane/EtOAc from 100/0 to 85/15) to afford Intermediate 206 (110 mg, yield: 27 %) as a white solid.

Intermediate 207:

[0394] Lithium hydroxide monohydrate (CAS [1310-66-3], 70 mg, 1.70 mmol, 4 eq.) was added to a solution of Intermediate 206 (110 mg, 0.41 mmol) in THF (3 mL) and water (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The pH was brought to neutral by addition of 1 M aqueous KHSO4. The mixture was extracted with DCM. The organic layer was dried MgSCU, filtered, and the solvents evaporated in vacuo to yield Intermediate 207 (86 mg, yield: 82 %) as a white solid.

Intermediate 208:

[0395] Cis-2,6-dimethylmorpholine (CAS [6485-55-8], 1.14 ml, 9.20 mmol, 2 eq.) was added to a solution of 4-benzyloxy-2-chloropyrimidine (CAS [108381-28-8], 1.56 g, 4.60 mmol) and DIPEA (1.52 mL, 9.20 mmol, 2 eq.) in DMSO (5 mL). The mixture was stirred at 120 °C for 2 h. After cooling, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was collected, dried over MgSCU, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (80 g SiCh, heptane/EtOAc from 100/0 to 80/20) to afford Intermediate 208 (1.14 g, yield: 82 %) as a solid.

Intermediate 209:

[0396] Intermediate 209 was prepared following the same procedure as Intermediate 198, using Intermediate 208 instead of Intermediate 197. Intermediate 210:

[0397] Intermediate 210 was prepared following the same procedure as Intermediate 193, using Intermediate 209 instead of Intermediate 192. Intermediate 211:

[0398] Intermediate 210 (223 mg, 1.031 mmol) was dissolved in 1,4-dioxane (4 mL) under nitrogen atmosphere. AcOK (CAS [127-08-2], 251 mg, 2.55 mmol, 2.5 eq.), bis(pinacolato)diboron (CAS [73183-34-3], 285 mg, 1.12 mmol, 1.1 eq.), tricyclohexylphosphine (CAS [2622-14-2], 11 mg, 0.041 mmol, 0.04 eq.), and Pd(OAc)2 (CAS [3375-31-3], 5 mg, 0.021 mmol, 0.02 eq.) were added. The reaction was stirred at 110 ºC for 30 min under nitrogen atmosphere. The mixture was allowed to cool to room temperature and kept under nitrogen atmosphere. K2CO3 (282 mg, 2.04 mmol, 2 eq.), CuCl (CAS [7758-89-6], 101 mg, 1.02 mmol, 1 eq.), and Intermediate 3 (300 mg, 1.02 mmol, 1 eq.) were added. The reaction mixture was stirred at 110 ºC for 16 h. After cooling, the mixture was diluted with water and EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiO₂, heptane/EtOAc from 0/100 to 60/40) to yield Intermediate 211 (136 mg, yield: 29 %) as a foam. Intermediate 212:

(CIS) [0399] Intermediate 211 (0.136 g, 0.302 mmol) was dissolved in HCl (4 N in 1,4-dioxane, 4.1 mL, 16.4 mmol, 54 eq.) and 1,4-dioxane (3.5 mL) and the mixture was stirred at room temperature for 16 h. The crude suspension was concentrated in vacuo to give Intermediate 212 (HCl salt, 0.118 g, yield: 91 %) as a solid. Intermediate 213 and Intermediate 214:

Intermediate 213 Intermediate 214 [0400] In a sealed tube, Cs2CO3 (2.16g, 6.64 mmol, 2.1 eq.) was added to a mixture of 5- bromo-2-hydroxypyridine (CAS [13466-38-1], 550 mg, 3.16 mmol) and 2,2,6,6- tetramethyloxan-4-yl methanesulfonate (CAS [1160656-10-9], 1.5 g, 6.32 mmol, 2 eq.) in DMF (5 mL). The reaction mixture was stirred at 120 ºC for 18 h. The mixture was diluted with 1 M aqueous Na2CO3 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (25 g SiO₂, heptane/EtOAc from 100/0 to 80/20) to yield Intermediate 214 (32 mg, yield: 3 %) and Intermediate 213 (220 mg, yield: 21 %), both as white solids. Intermediate 215:

[0401] Intermediate 213 (220 mg, 0.700 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 256 mg, 1.01 mmol, 1.44 eq.), Pd(dppf)Cl₂.CH₂Cl₂ (CAS [95464-05-4], 29 mg, 0.035 mmol, 0.05 eq.), and AcOK ([127-08-2], 213 mg, 2.18 mmol, 3.1 eq.) were dissolved in 1,4-dioxane (2 mL) under nitrogen atmosphere. The reaction vessel was sealed and the reaction mixture was stirred at 90 ºC for 3 h. The mixture was diluted with 1 M aqueous Na₂CO₃ and extracted with EtOAc (2 x). The combined organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiO2, heptane/EtOAc from 100/0 to 50/50) to give Intermediate 215 (253 mg, yield: 100 %) as a white solid. Intermediate 216:

[0402] 2-Isopropoxypyridine-5-boronic acid pinacol ester (CAS [871839-91-7], 175 mg, 0.664 mmol, 1.3 eq.) and 1 M aqueous Na2CO3 (1.5 mL, 1.5 mmol, 3 eq.) were added to a stirred solution of Intermediate 3 (150 mg, 0.511 mmol) in 1,4-dioxane (3 mL) at room temperature. The reaction mixture was degassed by bubbling with nitrogen before addition of Pd(PPh₃)Cl₂ (CAS [13965-03-2], 18 mg, 0.026 mmol, 0.05 eq.). The reaction mixture was stirred at 85 ºC under nitrogen atmosphere for 4 h. After cooling, the mixture was diluted with water. The mixture was extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (12 g SiO2, DCM/MeOH from 100/0 to 95/5) to yield Intermediate 216 (200 mg, yield: 98 %) as an orange gum. Intermediate 217:

[0403] Intermediate 216 (0.20 g, 0.51 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 1.3 mL, 5.09 mmol, 10 eq.) and 1,4-dioxane (1 mL). The suspension was stirred at room temperature for 20 h. Solvent was removed in vacuo to yield Intermediate 217 (210 mg, yield: 100 %) as a yellow solid, used without further purification. Intermediate 218 and Intermediate 219:

(2 ^, 4 ^, 6 ^) (2 ^, 4 ^, 6 ^) Intermediate 218 Intermediate 219 [0404] Cs2CO3 (2.86 g, 8.79 mmol, 1.2 eq.) was added to a solution of 5-bromo-2-hydroxy-3- methylpyridine (CAS [89488-30-2], 1.38 g, 7.33 mmol) and (2R,6S)-rel-tetrahydro-2,6- dimethyl-2H-pyran-4-ol, 4-(4-methylbenzenesulfonate) (CAS [1306785-92-1], 2.5 g, 8.79 mmol, 1.2 eq.) in DMF (20 mL). The reaction mixture was stirred at 70 ºC for 48 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (40 g SiO2; heptane/EtOAc from 100/0 to 50/50) to yield Intermediate 218 (1.72 g, yield: 77 %) as a colourless oil and Intermediate 219 (170 mg, yield: 8 %) as a white solid. Intermediate 220:

(2 ^, 4 ^, 6 ^) [0405] Intermediate 218 (700 mg, 2.33 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 855 mg, 3.37 mmol, 1.4 eq.), Pd(dppf)Cl₂.DCM (CAS [95464-05-4], 95 mg, 0.131 mmol, 0.05 eq.), and AcOK (CAS [127-08-2], 712 mg, 8.16 mmol, 3.1 eq.) were taken up in 1,4- dioxane (15 mL) under nitrogen atmosphere. The reaction vessel was sealed and the reaction mixture was stirred at 90 ºC for 3 h. After cooling, the mixture was diluted with 1 M aqueous Na₂CO₃ and extracted with EtOAc. The combined organic layer was dried over MgSO₄, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiO2, heptane/EtOAc from 100/0 to 50/50) to give Intermediate 220 (576 mg, yield: 64 %) as a white solid, contaminated with some (2 ^, 4 ^, 6 ^) isomer. Intermediate 221 and Intermediate 222:

(2 ^, 4 ^, 6 ^) (2 ^, 4 ^, 6 ^) Intermediate 221 Intermediate 222 [0406] Cs₂CO₃ (CAS [534-17-8], 2.86 g, 8.79 mmol, 1.2 eq.) was added to a solution of 5- bromo-4-methyl-2(1H)pyridinone (CAS [164513-38-6], 1.38 g, 7.33 mmol) and (2R,6S)-rel- tetrahydro-2,6-dimethyl-2H-pyran-4-ol, 4-(4-methylbenzenesulfonate) (CAS [1306785-92-1], 2.5 g, 8.79 mmol, 1.2 eq.) in DMF (20 mL). The reaction mixture was stirred at 70 ºC for 48 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (40 g SiO2; heptane/EtOAc from 100/0 to 50/50) to yield Intermediate 221 (1.80 g, yield: 81 %) as a colourless oil and Intermediate 222 (113 mg, yield: 5 %) as a white solid. Intermediate 223:

(2 ^, 4 ^, 6 ^) [0407] Intermediate 221 (700 mg, 2.33 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 855 mg, 3.37 mmol, 1.4 eq.), Pd(dppf)Cl2.DCM (CAS [95464-05-4], 95 mg, 0.131 mmol, 0.05 eq.), and AcOK (CAS [127-08-2], 712 mg, 8.16 mmol, 3.1 eq.) were taken up in 1,4- dioxane (15 mL) under nitrogen atmosphere. The reaction vessel was sealed and the mixture was stirred at 90 ºC for 3 h. After cooling, the mixture was diluted with 1 M aqueous Na₂CO₃ and extracted with EtOAc. The combined organics layer was dried over MgSO₄, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiO2, heptane/EtOAc from 100/0 to 50/50) to give Intermediate 223 (517 mg, yield: 61 %) as a white solid, contaminated with some (2 ^, 4 ^, 6 ^) isomer. Intermediate 224:

(2 ^, 4 ^, 6 ^) [0408] Cs₂CO₃ (CAS [534-17-8], 2.86 g, 8.79 mmol, 1.2 eq.) was added to a solution of 5- bromo-6-methyl-2(1H)pyridinone (CAS [54923-31-8] (1.38 g, 7.33 mmol) and (2R,6S)-rel- tetrahydro-2,6-dimethyl-2H-pyran-4-ol, 4-(4-methylbenzenesulfonate) (CAS [1306785-92-1], 2.5 g, 8.79 mmol, 1.2 eq.) in DMF (20 mL). The reaction mixture was stirred at 70 ºC for 48 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (40 g SiO₂; heptane/EtOAc from 100/0 to 50/50) to yield Intermediate 224 (1.88 g, yield: 84 %) as a colourless oil. Intermediate 225:

(2 ^, 4 ^, 6 ^) [0409] Intermediate 224 (904 mg, 3.01 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 1.10 g, 4.34 mmol, 1.4 eq.), Pd(dppf)Cl2.DCM (CAS [95464-05-4], 123 mg, 0.15 mmol, 0.5 eq.), and AcOK (CAS [127-08-2], 920 mg, 9.37 mmol, 3.1 eq.) were taken up in 1,4-dioxane (15 mL) under nitrogen atmosphere. The reaction vessel was sealed and the reaction mixture was stirred at 90 ºC for 3 h. The mixture was diluted with 1 M aqueous Na₂CO₃ and extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiO₂; heptane/EtOAc from 100/0 to 50/50) to give Intermediate 225 (990 mg, yield: 92 %) as a white solid. Intermediate 226 and Intermediate 227:

(2 ^, 4 ^, 6 ^) (2 ^, 4 ^, 6 ^) [0410] Intermediate 226 and Intermediate 227 were prepared following the same procedure as Intermediate 221 and Intermediate 222, respectively, using 5-bromo-2-hydroxypyridine (CAS [13466-38-1]) instead of 5-bromo-4-methyl-2(1H)pyridinone. Intermediate 228:

(2 ^, 4 ^, 6 ^) [0411] Intermediate 228 was prepared following the same procedure as Intermediate 225, using Intermediate 227 instead of Intermediate 224. Intermediate 229:

(2 α, 4 β, 6 α)Intermediate 228 (250 mg, 0.75 mmol, 1.1 eq.) and 1 M aqueous Na₂CO₃ (2.0 mL, 2.0 mmol, 3 eq.) were added to a stirred solution of Intermediate 3 (200 mg, 0.682 mmol) in 1,4-dioxane (7 mL) at room temperature under nitrogen atmosphere. Then, Pd(PPh₃)₂Cl₂ (CAS [13965-03-2], 24 mg, 0.034 mmol, 0.05 eq.) was added, and the mixture was stirred at 90 ºC under nitrogen atmosphere for 4 h. After cooling, the mixture was diluted with water and was extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (12 g SiO2, heptane/EtOAc 100/0 to 0/100) to yield Intermediate 229 (243 mg, yield: 69 %) as a brown solid. Intermediate 230:

(2 ^, 4 ^, 6 ^) ^ [0412] Intermediate 229 (0.243 g, 0.523 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 2.6 mL, 10.4 mmol, 20 eq.) and 1,4-dioxane (2 mL) and the mixture was stirred at room temperature for 3 h. The solvents were evaporated in vacuo to yield Intermediate 230 (HCl salt, 239 mg, yield: 99 %) as a brown solid, used without further purification. Intermediate 231:

[0413] Methyl 5-bromo-6-(trifluoromethyl)nicotinate (CAS [1198016-45-3], 500 mg 1.76 mmol) was dissolved in 1,4-dioxane (10 mL) under nitrogen atmosphere. DIPEA (0.92 mL, 5.28 mmol, 3 eq.) and 2-mercaptoethanol (CAS [60-24-2], 0.12 mL 1.76 mmol, 1 eq.) were added. Then, Xantphos (CAS [161265-03-8], 102 mg, 0.18 mmol, 0.1 eq.) and Pd₂(dba)₃ (CAS [ 32005-36-0], 30 mg 0.05 mmol, 0.03 eq.) were added and the reaction mixture was stirred at 110 ºC for 16 h under nitrogen atmosphere. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The crude product was purified by flash chromatography column (25 g SiO2, DCM/MeOH from 100/0 to 90/10) to yield Intermediate 231 (420 mg, yield: 74 %) as a yellow oil. Intermediate 232:

[0414] m-CPBA (CAS [937-14-4], 77 % pure, 335 mg 1.49 mmol, 1 eq.) was added portionwise at 0 ºC to a solution of Intermediate 231 (420 mg, 1.49 mmol) in DCM (10 mL). The mixture was then stirred for 16 h at room temperature. More DCM (30 mL) was added and m-CPBA (77 % pure, 1.5 g, 6.7 mmol, 4.5 eq.) was added portionwise over 24 h, until the reaction was complete. The mixture was diluted with DCM and 1 M aqueous Na₂CO₃ was added with stirring. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (25 g SiO₂, DCM/MeOH from 100/0 to 90/10) to afford Intermediate 232 (287 mg, yield: 55 %). Intermediate 233:

[0415] Lithium hydroxide monohydrate (CAS [1310-66-3], 85 mg, 1.99 mmol, 4 eq.) was added to a solution of Intermediate 232 (156 mg, 0.49 mmol) in THF (2 mL) and water (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The pH was brought to 5 by addition of 1 M aqueous KHSO₄ and the mixture was concentrated to dryness. The crude product was purified by reverse phase column chromatography (Phenomenex Gemini C1830 x 100 mm 5 µm; from 95 % [25 mM NH4HCO3] - 5 % [ACN:MeOH (1:1)] to 63 % [25 mM NH4HCO3] - 37 % [ACN:MeOH (1:1)]) to give Intermediate 233 (130 mg, yield: 86 %). Intermediate 234:

[0416] In a sealed reactor, tetrakistriphenylphosphine palladium (0) (CAS [14221-01-3], 1.07 g, 0.927 mmol, 0.1 eq.) was added to a solution of methyl 4-bromopicolinate (CAS [29681- 42-3], 2 g, 9.258 mmol), triisopropylsilianethiol (CAS [156275-96-6], 2.4 mL, 11.179 mmol, 1.2 eq.), and cesium carbonate (3.6 g, 11.09 mmol, 1.2 eq.) in toluene (70 mL). The reaction mixture was purged with nitrogen and stirred at 110 ºC for 5 h. The reaction mixture was filtered through a pad of celite and rinsed with EtOAc. The filtrate was concentrated in vacuo to yield Intermediate 234 (4.0 g, yield: 54 %) as an orange oil. Intermediate 235:

[0417] Sodium 2-chloro-2,2-difluoroacetate (CAS [1895-39-2], 4.3 g, 28.261 mmol, 5.9 eq.) and caesium carbonate (9.1 g, 28.051 mmol, 5.9 eq.) were added to a solution of Intermediate 234 (4.0 g, 4.752 mmol) in anhydrous DMF (20 mL). The reaction mixture was stirred at 100 ºC for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and the mixture was extracted with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (80 g column, EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 235 (520 mg, yield: 48 %) as an orange sticky solid. Intermediate 236:

[0418] Ammonium carbamate (CAS [1111-78-0], 1.8 g, 23.056 mmol, 19 eq.) was added portion wise to a stirred solution of Intermediate 235 (259 mg; 1.182 mmol) and (diacetoxyiodo)benzene (CAS [3240-34-4], 7.5 g; 23.056 mmol, 19 eq.) in MeOH (10 mL) and DCM (10 mL). The reaction mixture was stirred at room temperature while bubbling O2 for 16 h. The reaction mixture was stirred at 50 °C for 2 h. The solvents were evaporated and the residue was taken up in water and EtOAc. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (40 g, EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 236 (95 mg, yield: 31 %) as a white solid.

Intermediate 237:

RAC

[0419] Lithium hydroxide monohydrate (25 mg, 0.573 mmol, 1.5 eq.) was added to a solution of Intermediate 236 (95 mg, 0.38 mmol) in THF (3 mL) and water (1.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to the aqueous layer and it was acidified with HC1 (1 M in water, 0.4 mL) and extracted with EtOAc. The organic layer was dried on MgSO4, filtered, and evaporated to yield Intermediate 237 (60 mg, yield: 66 %) as a white solid.

Intermediate 238:

[0420] A mixture of 2-chloropyrimidine (CAS [1722-12-9], 229 mg, 2 mmol) in THF (30 mL) was cooled at -60 °C under nitrogen atmosphere. Then, 2, 2,6,6- tetramethylpiperidinylmagnesium chloride lithium chloride complex (CAS [898838-07-8], 0.85 M in THF/toluene, 2.824 mL, 2.4 mmol) was added dropwise and the reaction mixture was stirred for 1.5 h at -60 °C under nitrogen atmosphere. Zinc chloride (CAS [7646-85-7], 1 M in Et2O, 3 mL, 3 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was used as such for the next step. Intermediate 239:

[0421] Intermediate 238 (0.18 M in THF/Et2O, 14.18 mL, 2.55 mmol, 3 eq.) was added to a solution of Intermediate 3 (0.250 g , 0.851 mmol) and tetrakis(triphenylphosphine)palladium (CAS [14221-01-3], 49 mg, 0.043 mmol, 0.05 eq.) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried (MgSO₄), filtered, and the solvent evaporated in vacuo. The residue was crystallized in ACN to yield Intermediate 239 (213 mg, yield: 65 %) as a solid. Intermediate 240:

[0422] A solution of tert-butyl 2,5-dimethyl-4-oxopiperidine-1-carboxylate (CAS [1204654- 37-4], 680 mg, 2.992 mmol) in EtOH (7 mL) and water (7 mL) was treated with sodium cyanide (CAS [143-33-9], 293 mg, 5.984 mmol, 2 eq.) and ammonium carbonate (CAS [506- 87-6], 1.43 g, 14.958 mmol, 5 eq.). The reaction mixture was stirred at 60 ºC for 16 h. The mixture was poured into water and the aqueous layer was extracted twice with EtOAc. The combined organic layer was washed with water and brine, dried (MgSO₄), filtered, and the solvent evaporated. The residue was purified by flash column chromatography on silica gel (80 g column, DCM/MeOH (9/1) in DCM from 0 % to 100 %) to yield Intermediate 240 (551 mg, yield: 62 %) as a solid. Intermediate 241:

[0423] Intermediate 240 (551 mg, 1.853 mmol) was dissolved in 1,4-dioxane (2.4 mL) and HCl (4 M in 1,4-dioxane, 2.3 mL, 9.26 mmol, 5 eq.) was added. The reaction mixture was stirred at room temperature for 16 h. The solvents were evaporated to yield Intermediate 241 (HCl salt, 429 mg; yield: quantitative) as a white solid. Intermediate 242: ((6R)-6-(aminomethyl)-4-(cyclopropylmethyl)morpholin-3-one).

[0424] Intermediate 242 may be prepared from 4-(cyclopropylmethyl)-6-[[[(1R)-1- phenylethyl]amino]methyl]-3-morpholinone hydrochloride (1:1) (CAS [1398377-83-7] by reaction with hydrogen (1 atm) in MeOH in the presence of Pd/C (10 %) at room temperature. Intermediate 243: ((3S)-3-ethyl-4-(2-hydroxyethyl)-1,4-diazepan-5-one).

[0425] Intermediate 243 may be prepared in 4 steps from N-(phenylmethyl)-β-alanine (CAS [5426-62-0]) by reacting it first with (2S)-2-aminobutanal (CAS [1243173-40-1]) in the presence of sodium borohydride in MeOH at room temperature; then, in a second step, by cyclizing the formed intermediate in the presence of sodium methoxide in MeOH at reflux temperature; then, in a third step, by reacting the formed intermediate with 2-bromoethanol (CAS [540-51-2], in the presence of sodium hydride in DMF at 0 °C; and finally by reaction with hydrogen (1 atm) in MeOH in the presence of Pd/C (10 %) at room temperature Intermediate 244: (2-azabicyclo[3.1.1]heptane-5-carbonitrile).

[0426] Intermediate 244 may be prepared from 1,1-dimethylethyl 5-cyano-2- azabicyclo[3.1.1]heptane-2-carboxylate (CAS [1882055-84-6]) by reaction with TFA in DCM at room temperature. Intermediate 245: ((5S)-3-methyl-1,7-dioxa-3,10-diazaspiro[4.6]undecan-2-one).

[0427] Intermediate 245 may be obtained by chiral separation by SFC of 3-methyl-1,7-dioxa- 3,10-diazaspiro[4.6]undecan-2-one (CAS [2173135-44-7]). Intermediate 246: ((3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-6(1H)-one).

[0428] Intermediate 246 may be prepared in two steps by reacting (3aR,6aR)-hexahydro-1- [(1R)-1-phenylethyl]pyrrolo[3,4-b]pyrrol-6(1H)-one (CAS [2007092-81-9]) with methyl iodide in the presence of sodium hydride in DMF at 0 °C; followed by reaction of the formed intermediate with hydrogen (1 atm) in the presence of Pd/C (10 %) in EtOH at 50 °C. Intermediate 247: ((3aR,7aS)-5-(2,2-difluoroethyl)octahydro-1H-pyrrolo[3,4-c]pyridine)

[0429] Intermediate 247 may be prepared in two steps from 1,1-dimethylethyl (3aS,7aS)- octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (CAS [1416263-25-6]) by reaction with 2,2-difluoroethyl 1,1,1-trifluoromethanesulfonate (CAS [74427-22-8]) in the presence of DIPEA in ACN at room temperature; followed by reacting the formed intermediate with TFA in DCM at room temperature. Intermediate 248: ((3aS,6aR)-2-(2-methylpropyl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one).

[0430] Intermediate 248 may be prepared in two steps from (3aR,6aR)-hexahydro-5-[(1R)-1- phenylethyl]pyrrolo[3,4-c]pyrrol-1(2H)-one (CAS [1893359-89-1]), first by reacting it with 1-bromo-2-methylpropane (CAS [78-77-3]) in the presence of sodium hydride in THF at 0 °C; followed by reaction of the formed intermediate with hydrogen (1 atm) in MeOH in the presence of Pd/C (10 %) at room temperature. Intermediate 249: (1-(isopropylimino)thiomorpholine 1-oxide).

[0431] Intermediate 249 may be prepared in two steps from 1-imino-1λ4-thiomorpholine-4- carboxylic acid, 1,1-dimethylethyl ester, 1-oxide (CAS [1609964-38-6]), first by reacting with acetone in the presence of 2-picoline-borane (CAS [3999-38-0]) and acetic acid in MeOH at room temperature; then by reaction of the formed intermediate with TFA in DCM at room temperature. Intermediate 250: (N-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide).

[0432] Intermediate 250 may be prepared in two steps, first by reacting 1,1-dimethylethyl 1- amino-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (CAS [1517323-66-8]) with acetyl chloride in the presence of DIPEA in DCM at room temperature; followed by reaction of the formed intermediate with TFA in DCM at room temperature. Intermediate 251: (2-(methoxymethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine)

[0433] Intermediate 251 may be prepared in 4 steps from ethyl 5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (CAS [1301713-93-8]) , first by reacting it with di-tert-butyl decarbonate (CAS [24424-99-5]) in the presence of Et3N in DCM at room temperature; then by reacting the formed intermediate with methyl iodide, in the presence of sodium hydride in THF at 0 °C; then by reducing the ester with sodium borohydride in THF at room temperature; and finally reacting the obtained intermediate with TFA in DCM at room temperature. COMPOUNDS [0434] The compounds in Table 3. were prepared from Intermediate 6 and the corresponding acid, following procedures similar to the methods shown in the table: Table 3.

Compound 5: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-((*R)-l-hydroxyethyl)-5-methylpicolinamide and Compound 6: N-((2-(6-((cis)-

2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-((*S)-l- hydroxy ethyl)-5-methylpicolinamide.

Compound 5 (*R, CIS; pure enantiomer but absolute stereochemistry undetermined)

Compound 6 (*S, CIS; pure enantiomer but absolute stereochemistry undetermined) [0435] Compound 4 was separated into its stereoisomers by preparative SFC (i-Amylose-1 column; isocratic mode method: 50 % [EtOH + 0.1 % DEA] - 50 % [CO2]) to give Compound 5 and Compound 6, both as yellow solids. Compound 7: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-5-methyl-4-(methylsulfonyl)picolinamide.

[0436] The title compound was prepared in a manner analogous to Method E using Intermediate 18 and Intermediate 15. Compound 8: N-((2-(6-((3 ^,4 ^,5 ^)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

(3 ^, 4 ^, 5 ^) [0437] Compound 8 was prepared according to Method M, using Intermediate 20 and 5- (methylsulfonyl)nicotinic acid (CAS [893723-59-6]). Compound 9: N-((2-(6-((3 ^,4 ^,5 ^)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

(3 ^, 4 ^, 5 ^) [0438] A mixture of Intermediate 21 (2.7 g, 5.863 mmol), (3α,4β,5α)-3,5-dimethyl-4- piperidinol (CAS [374067-78-4], 4.22 g, 25.467 mmol, 4.3 eq.), and DIPEA (28.2 mL, 161.954 mmol, 27.6 eq.) was stirred at 130 °C overnight. The reaction mixture was diluted with DCM (500 mL) and brine (300 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layer was dried on MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography (silica, 120 g; MeOH in DCM from 0 % to 10 %). The solid obtained was suspended in a mixture of EtOH, MeOH, and water, stirred for 30 min, and filtered to give Compound 9 (2.27 g, yield: 69 %) as a yellow solid. The compounds in Table 4 were prepared following Method N, using the amines listed in the table (in this table, compounds with no stereochemistry indicated are mixtures of stereoisomers). Table 4.

The compounds in Table 5 were prepared following Method P, using the acids listed in the table. In this table, all compounds have the (3 ^,4 ^,5 ^) stereochemistry for the dimethylpiperidinol group. Table 5.

Compound 137: N-((2-(6-((3 ^,4 ^,5 ^)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)- 1,6-naphthyridin-7-yl)methyl)-2-methyl-6-(methylsulfonyl)isonicotinamide.

(3 ^, 4 ^, 5 ^) [0439] Compound 137 was prepared according to Method A (in DMF), starting from Intermediate 40 and 2-methyl-6-(methylsulfonyl)-4-pyridinecarboxylic acid (CAS [1780757- 32-5]). Compound 138: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)-4-(2-hydroxypropan-2-yl)-5-methylpicolinamide.

[0440] Methylmagnesium bromide (3 M in Et2O, CAS [75-16-1], 144 µL, 0.431 mmol, 2.2 eq.) was added dropwise to a solution of Intermediate 26 (100 mg, 0.196 mmol) in dry THF (1 mL) at 0 ºC. More methylmagnesium bromide (3 M in Et₂O, 65 µL, 0.196 mmol, 1 eq.) was added at 0 ºC and the reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0 ºC and the reaction was quenched by addition of saturated aqueous NH₄Cl. The mixture was diluted with water and was extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g silica; EtOAc/heptane from 0/100 to 40/60) to yield Compound 138 (51 mg, yield: 47 %) as a yellow solid. Compound 139: N-((2-(6-((3 α,4 β,5 α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)- 1,6-naphthyridin-7-yl)methyl)-2-(methylsulfonyl)isonicotinamide.

(3 ^, 4 ^, 5 ^) [0441] Compound 139 was prepared according to Method A (in DMF), starting from Intermediate 23 and 2-(methylsulfonyl)-4-pyridinecarboxylic acid (CAS [1186663-27-3]). Compound 140: N-((2-(6-((3 ^,5 ^)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

(3 α, 4 α, 5 α) [0442] DIPEA (0.3 mL, 1.74 mmol) was added to a solution of Intermediate 21 (80 mg, 0.17 mmol) and (3a,4a,5a)-3,4,5-trimethyl-4-piperidinol, hydrochloride (1 : 1) (CAS [2306425-61- 4], 76 mg, 0.43 mmol) in DMSO (1 mL) and the reaction mixture was stirred at 130 °C overnight. The reaction mixture was diluted with DCM (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layer was dried over MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography (silica, MeOH in DCM 0 to 10 %) to yield Compound 140 (66 mg, yield: 67 %).

Compound 141 : (*R)-N-((2-(6-(2-(methoxymethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide and Compound 142: (*S)-N-((2- (6-(2-(methoxymethyl)pyrrolidin-l -yl)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5- (methylsulfonyl)nicotinamide.

Compound 141 : (*R) pure stereoisomer but absolute stereochemistry undetermined

Compound 142: (*S) pure stereoisomer but absolute stereochemistry undetermined [0443] Compound 141 and Compound 142 were prepared according to Method J, using Intermediate 21 and 2-(methoxymethyl)pyrrolidine (CAS [76946-27-5]), followed by preparative SFC (Stationary phase: Chiralcel Diacel OJ 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 % iPrNH₂).

Compound 143: N-((2-(6-(4-(4-methylpiperazin-l-yl)piperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0444] Compound 143 was prepared according to Method J, using Intermediate 21 and 1- methyl-4-(piperidin-4-yl)piperazine (CAS [436099-90-0]).

Compound 144 : N-((2-(6-((ci s)-2, 6-dimethylmorpholino)-4-fluoropyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-5-((*R)-l-hydroxyethyl)nicotinamide and Compound 145: N-((2- (6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5- ((* S)- 1 -hydroxy ethyl)nicotinamide.

Compound 144: (*R, CIS), pure stereoisomer but stereochemistry undetermined

Compound 145: (*S, CIS), pure stereoisomer but stereochemistry undetermined [0445] Compound 144 and Compound 145 were prepared according to Method B, using Intermediate 15 reacting with Intermediate 24 and Intermediate 25, respectively.

Compound 146: 4-acetyl-5-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)picolinamide.

CIS

[0446] Compound 146 was prepared according to Method C (in DMF), using Intermediate 6 and Intermediate 42.

The compounds in Table 6 were prepared following Method K, using Intermediate 21 and the indicated amine. Table 6.

Compound 150: N-((2-(6-(l,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0447] TFA (56 μL, 0.735 mmol, 10 eq.) was added to a suspension of Intermediate 30 (48 mg, 0.073 mmol) in DCM (0.5 mL) at room temperature. The reaction mixture was stirred at 40 °C for 72 h. The reaction mixture was evaporated and the residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN), followed by preparative SFC (Stationary phase: Torus Diol 30 x 150 mm , Mobile phase: CO2, MeOH) to yield Compound 150 (3 mg, yield: 7 %).

Compound 155: N-((2-(6-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0448] HC1 (4 M in 1,4-di oxane, 1.5 mL, 6 mmol, 88 eq.) was added to a solution of Intermediate 31 (45 mg, 0.068 mmol) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. The precipitate that appeared was filtered and washed with 1,4- dioxane. The solid was taken up in MeOH and evaporated to dryness to afford Compound 155 (HC1 salt, 34 mg, yield: 79 %) as an orange solid.

Compound 156: (Racemic)-N-((2-(6-(3-(methylamino)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0449] Compound 156 was prepared in a similar manner as Compound 155, using Intermediate 32 instead of Intermediate 31. Compound 157: (R)-N-((2-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0450] Compound 157 was prepared according to Method J, using Intermediate 21 and D- prolinol (CAS [68832-13-3]). Compound 158: N-((2-(4-fluoro-6-((3 α,4 β,5 α)-4-hydroxy-3,5-dimethylpiperidin-1- yl)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-2-methyl-6-(methylsulfonyl)isonicotinamide.

(3 α, 4 β, 5 α) [0451] A solution of Intermediate 49 (73 mg, 0.107 mmol) in aqueous NaOH (2.5 M, 0.43 mL,1.069 mmol, 10 eq.) was stirred at 65 ºC for 72 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (x 3). The combined organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (12 g silica, DCM/MeOH (9/1) in DCM, from 0 % to 30 %) to yield Compound 158 (19 mg, yield: 30 %) as a yellow solid. Compound 159: (Racemic)-N-((2-(6-(3-aminopyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0452] Compound 159 was prepared in a similar manner as Compound 155, using Intermediate 33 instead of Intermediate 31. Compound 160: N-((2-(6-(3 , 3 -dimethylpiperazin- 1 -yl)pyridin-2-yl)- 1 , 6-naphthyri din-7 - yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0453] 2,2-Dimethylpiperazine dihydrochloride (CAS [128427-07-6], 83 mg, 0.443 mmol, 4 eq.) and DIPEA (210 μL, 1.22 mmol, 11 eq.) were added to a suspension of Intermediate 21 (50 mg, 0.111 mmol) in dry DMSO (1 mL) and the reaction mixture was stirred at 90 °C overnight, then at 130 °C for 5 h. More 2,2-dimethylpiperazine dihydrochloride (83 mg, 0.443 mmol, 4 eq.) was added and the mixture was stirred at 140 °C for 24 h. The reaction mixture was diluted with EtOAc aqueous NaOH (1 M). The mixture was extracted twice with EtOAc. The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD- 5 μm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give Compound 160 (5 mg, yield: 9 %).

Compound 161 : N-((2-(6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0454] 2,5-Dioxa-8-azaspiro[3.5]nonane hemioxalate (CAS [1184185-17-8], 77 mg, 0.222 mmol, 2 eq.) and DIPEA (210 μL, 1.22 mmol, 11 eq.) were added to a suspension of Intermediate 21 (50 mg, 0.111 mmol) in dry DMSO (1 mL) and the reaction mixture was stirred at 90 °C overnight, then at 130°C for 5 h. More 2,5-dioxa-8-azaspiro[3.5]nonane hemioxalate (77 mg, 0.222 mmol, 2 eq.) was added and the reaction mixture was stirred at 140 °C overnight. The reaction mixture was diluted with EtOAc and aqueous NaOH (1 M). The mixture was extracted twice with EtOAc and twice with DCM. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 μm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN), followed by another preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 5 μm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, MeOH) to give Compound 161 (17 mg, yield: 29 %). Compound 162: 5-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-(2-hydroxypropan-2-yl)picolinamide.

CIS

[0455] Methylmagnesium bromide (3 M in Et2O, 116 μL, 0.348 mmol, 2.2 eq.) was added dropwise to a solution of Compound 146 (84 mg, 0.158 mmol) in dry THF (1 mL) at 0 °C. More methylmagnesium bromide (3 M in Et20, 53 pl, 0.158 mmol, 1 eq.) was added at 0 °C and the mixture was stirred at room temperature overnight. The mixture was cooled to 0 °C and the reaction was quenched by addition of saturated aqueous NEUCl. The mixture was diluted with water and was extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g silica, EtOAc/heptane from 0/100 to 40/60), followed by reverse phase column chromatography (Phenom enex Gemini C18 30 x 100 mm 5 pm Column; from 39 % [25 mM NH4HCO3] - 61 % [ACN:MeOH (1 : 1)] to 11 % [25 mM NH4HCO3] - 89 % [ACN:MeOH (1 : 1)]) to afford Compound 162 (15 mg, yield: 17 %) as a yellow solid.

Compound 163: N-((2-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0456] TFA (1 mL, 13.067 mmol, 83 eq.) was added to a solution of Intermediate 34 (101 mg, 0.157 mmol) in DCM (2 mL) and the reaction mixture was stirred at room temperature for 1.5 h. The reaction was quenched by addition of aqueous NaOH (1 M) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, DCM/(7 N NH₃ in MeOH:DCM 1 :9) 100/0 to 0/100) to afford Compound 163 (31 mg, yield: 36 %) as a yellow solid. Compound 164: (Racemic)-N-((2-(6-(2-(aminomethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0457] Intermediate 35 (136 mg, 0.22 mmol) was dissolved in TFA (1 mL, 13.067 mmol, 59 eq.) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and basified with aqueous NaOH (1 M) to pH 10. The mixture was extracted with DCM (5 x). The combined organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Stationary phase: RP XB ridge Prep Cl 8 OBD - 5 μm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give Compound 164 (19 mg, yield: 16 %).

Compound 165: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)nicotinamide.

CIS

[0458] Compound 165 was prepared according to Method M, using Intermediate 6 and

Intermediate 38.

Compound 166: N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-2-(methylsulfonyl)isonicotinamide.

(3a, 4β, 5a)

[0459] Compound 166 was prepared according to Method A (in DMF), using Intermediate 51 and 2-(methylsulfonyl)-4-pyridinecarboxylic acid (CAS [1186663-27-3]). Compound 167: N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-2-((2 -hydroxy ethyl)sulfonyl)isonicotinamide.

(3a, 4β, 5a)

[0460] Compound 167 was prepared according to Method M, using Intermediate 29 and 5- (methylsulfonyl)nicotinic acid (CAS [893723-59-6]).

Compound 168: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-4-((*R)-l -hydroxy ethyl)picolinamide and Compound 169: N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4-((* S)-l- hydroxyethyl)picolinamide.

Compound 168 (*R), CIS: pure stereoisomer but absolute stereochemistry undetermined

Compound 169 (*S), CIS: pure stereoisomer but absolute stereochemistry undetermined [0461] Sodium borohydride (15 mg, 0.403 mmol, 2 eq.) was added to a solution of Intermediate 139 (100 mg, 0.201 mmol) in MeOH (2 mL) and dry THF (2 mL) under nitrogen atmosphere at 0 °C and the mixture was stirred overnight at room temperature. The reaction was quenched by addition of saturated aqueous NH4CI and the mixture was extracted with EtOAc (x 3). The combined organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g silica, EtOAc/heptane from 0/100 to 50/50), followed by SFC (Amilose_2 column, SCP2: isocratic 10 % iPrOH/heptane + 0.1 % DEA) to afford impure Compound 168 and impure Compound 169. Both were purified again by reverse phase chromatography (Phenomenex Gemini Cl 8 30 x 100 mm 5 pm Column; from 50 % [25 mM NH4HCO3] - 50 % [ACN:MeOH (1 : 1)] to 25 % [25 mM NH4HCO3] - 75 % [ACN:MeOH (1 : 1)]) to yield Compound 168 (6 mg, yield: 6 %) and Compound 169 (10 mg, yield: 9 %), both as yellow solids.

Compound 170: (Racemic)-N-((2-(6-(3-amino-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0462] TFA (63 μL, 0.824 mmol, 10 eq.) was added to a suspension of Intermediate 36 (51 mg, 0.082 mmol) in DCM (0.5 mL) at room temperature. The reaction mixture was stirred at 40 °C for 72 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 μm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give Compound 170 (28 mg, yield: 65 %).

Compound 171 : N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisonicotinamide.

(3a, 4β, 5a)

[0463] 2-[(2-Hydroxyethyl)sulfonyl]-4-pyridinecarboxylic acid (CAS [1855331-07-5], 405 mg, 0.35 mmol) and DIPEA (305 μL, 1.75 mmol) were added to a solution of Intermediate 23 (106 mg, 0.29 mmol) in DMF (7 mL). The reaction mixture was stirred and treated with HATU (CAS [148893-10-1], 144 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSCU), filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (12 g SiCE; EtOAc/heptane, from 0/100 to 30/70), followed by reverse phase HPLC (Phenomenex Gemini I.D. (mm) 100 x 21.2, 5 urn (C18) 110A; from 72 % of H₂O (0.1 % HCOOH)- 28 % ACN: MeOH 1 : 1 to 36 % of H2O (0.1 % HCOOH) - 64 % ACN: MeOH 1 : 1) to afford Compound 171 (14 mg, yield: 8 %) as a yellow solid. Compound 172: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0464] DIPEA (0.35 mL, 1.94 mmol) was added to a stirred solution of Intermediate 171 (100 mg, 0.46 mmol) and HATU (CAS [148893-10-1] (221 mg, 0.58 mmol) in DMF (3.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. Then, Intermediate 6 (163 mg, 0.387 mmol) was added and the mixture was stirred at room temperature for 3 h, then at 50 °C for 5 h. More HATU (221 mg, 0.58 mmol) was added and the reaction mixture was stirred at 50 °C for 2 h. After cooling, the mixture was diluted with saturated aqueous NaHCCh and was extracted with EtOAc (x 3). The combined organic layer was dried over MgSCU, filtered, and evaporated. The residue was purified by flash column chromatography (silica 25 g; DCM/MeOH in DCM from 0/100 to 25/75), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 59 % [25 mM NH4HCO3] - 41 % [ACNMeOH (1 : 1)] to 17 % [25 mM NH4HCO3] - 83 % [ACN:MeOH (1 : 1)]) to afford Compound 172 (15 mg, yield: 7 %) as a yellow solid.

Compound 173 : N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)nicotinamide.

[0465] Intermediate 38 (140 mg, 0.24 mmol) and DIPEA (230 μL, 1.32 mmol) were added to a solution of Intermediate 15 (89 mg, 0.22 mmol) in DMF (3 mL). The reaction mixture was stirred and treated with HATU (CAS [148893-10-1], 105 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (12 g SiCL; DCM:MeOH (9: 1) in DCM from 0 % to 40 %) to afford Compound 173 (29 mg, yield: 22 %) as a yellow solid.

Compound 174: N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-4-(methylsulfonyl)picolinamide.

(3a, 4β, 5a)

[0466] HATU (CAS [148893-10-1], 90 mg, 0.155 mmol) was added to a solution of Intermediate 51 (75 mg, 0.123 mmol), 6-methyl-4-(methylsulfonyl)-2 -pyridinecarboxylic acid (CAS [2735727-68-9], 59 mg, 0.137 mmol), and DIPEA (0.11 mL, 0.632 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with AcOEt (x 3). The combined organic layer was dried over MgSCU, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g SiCL; AcOEt/DCM from 0/100 to 70/30) to yield Compound 174 (45 mg, yield: 62 %) as a yellow solid.

Compound 175: N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisonicotinamide.

(3a, 4β, 5a)

[0467] Intermediate 151 (61 mg, 0.25 mmol) and DIPEA (218 μL, 1.25 mmol) were added to a solution of Intermediate 23 (91 mg, 0.21 mmol) in DMF (3 mL). The reaction mixture reaction was stirred and treated with HATU (CAS [148893-10-1], 103 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc (x 3). The organic layer was separated, dried (MgSCU), filtered, and the solvents evaporated in vacuo. The crude product was purified twice by flash column chromatography (12 g SiO₂; DCM:MeOH (9:1) in DCM from 0 % to 40 %) to afford Compound 175 (19 mg, yield: 15 %) as a yellow solid. Compound 176: (Racemic)-N-((2-(6-(4-hydroxy-2,2-dimethylpyrrolidin-1-yl)pyridin-2-yl)- 1,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0468] A suspension of 5,5-dimethylpyrrolidin-3-ol (CAS [1784937-75-2], 183 mg, 1.589 mmol) and Intermediate 21 (170 mg, 0.377 mmol) in DIPEA (1 mL, 5.803 mmol) in a sealed vial was stirred overnight at 150 °C. After cooling, DMSO (0.5 mL) was added and the reaction mixture was stirred for 10 days at 150 °C. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The combined organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm; 0.5 % NH₄Ac solution in water + 10 % ACN, ACN), followed by flash column chromatography (SiO₂; DCM/DCM:MeOH 9:1, 100/0 to 0/100) to afford Compound 176 (5 mg, yield: 2 %). Compound 177: N-((2-(4-fluoro-6-((3 ^,4 ^,5 ^)-4-hydroxy-3,5-dimethylpiperidin-1- yl)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide.

(3 ^, 4 ^, 5 ^) [0469] Intermediate 38 (49 mg, 0.21 mmol) and DIPEA (201 µL, 1.16 mmol) were added to a solution of Intermediate 51 (88 mg, 0.19 mmol) in DMF (2 mL). The reaction mixture was stirred and treated with HATU (CAS [148893-10-1], 92 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (x 3). The combined organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified twice by flash column chromatography (12 g SiCh; DCM:MeOH (9: 1) in DCM from 0/100 to 100/0) to yield Compound 177 (21 mg, yield: 18 %) as a yellow solid.

Compound 178: N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-((*R)-l-hydroxyethyl)nicotinamide.

[0470] In a flask round bottom, Intermediate 51 (50 mg; 0.1 Immol) was added to a stirred solution of Intermediate 152 (19 mg; 0.11 mmol), HATU (CAS [148893-10-1], 64 mg; 0.17 mmol), and DIPEA (0.163 mL, 0.93 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with AcOEt. The organic layer was washed with brine (x 2), dried on MgSCU, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 70 % [25 mM NH4HCO3] - 30 % [ACN:MeOH (1 :1)] to 27 % [25 mM NH₄HCO₃] - 73 % [ACN:MeOH (1 : 1)]). The product was triturated in Et2O, filtered, and dried to yield Compound 178 (9 mg; yield: 16 %) as a white solid.

Compound 179: N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-((*S)-l-hydroxyethyl)nicotinamide.

[0471] Compound 179 was prepared following the same procedure as Compound 178, using Intermediate 153 instead of Intermediate 152. Compound 180: l-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)-lH-pyrrole-3-carboxamide.

[0472] 1 -Methanesulfonyl- U/-pyrrole-3 -carboxylic acid (CAS [1521806-48-3], 70 mg, 0.310 mmol, 1.1 eq.) and DIPEA (147 μL, 0.844 mmol, 3.0 eq.) were added to a solution of Intermediate 79 (120 mg, 0.281 mmol, 1.0 eq.) in DCM (20 mL). The reaction mixture was stirred for 1 min and HATU (CAS [148893-10-1], 123 mg, 0.324 mmol, 1.15 eq.) was added. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with saturated aqueous NaHCCE and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvents evaporated. The crude product was purified by flash chromatography (12 g SiO2, DCM:MeOH (9: 1) in DCM, from 0 % to 30 %) to yield Compound 180 (38 mg, yield: 27 %) as a beige solid.

Compound 181 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(methylsulfonyl)-lH-pyrrole-3-carboxamide.

[0473] 1 -Methanesulfonyl- IT/-pyrrole-3 -carboxylic acid (CAS [1521806-48-3], 48 mg, 0.252 mmol, 1.1 eq.) and DIPEA (120 μL, 0.687 mmol, 3.0 eq.) were added to a solution of Intermediate 6 (80 mg, 0.229 mmol, 1.0 eq.) in DCM (2 mL) and DMF (1 mL). The reaction mixture was stirred for 1 min and HATU (CAS [148893-10-1], 100 mg, 0.263 mmol, 1.15 eq.) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCCh and extracted with EtOAc. The organic layer was dried (MgSCU), filtered, and the solvents were evaporated. The crude product was purified by flash chromatography (12 g SiCE, DCM:MeOH (9: 1) in DCM, from 0 % to 25 %) to yield Compound 181 (37 mg, yield: 30 %) as a yellow solid. Compound 182: 4,5-dichloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(isopropylsulfonyl)-lH-pyrrole-3-carboxamide.

[0474] HATU (CAS [148893-10-1], 285 mg, 0.75 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 6 (211 mg, 0.5 mmol, 1 eq.), Intermediate 123 (143 mg, 0.5 mmol, 1 eq.), and DIPEA (0.26 mL, 1.5 mmol, 3 eq.) in DCM (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with 1 M aqueous Na2CC>3 and extracted with EtOAc (2 x 15 mL). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCh, MeOH in DCM from 0 to 2 %) to yield Compound 182 (170 mg, yield: 54 %) as a yellow powder.

Compound 183: N-((2-(6-((3a, 4β, 5a))-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)thiophene-2-carboxamide.

(3a, 4β, 5a)

[0475] A solution of Intermediate 23 (35 mg, 0.0718 mmol), EtsN (60 μL, 0.43 mmol, 6 eq.) in DCM (1 mL) was added to 5-(methylsulfonyl)-2-thiophenecarboxylic acid (CAS [60166- 86-1], 25 mg, 0.12 mmol, 1.7 eq.). 1-Propanephosphonic anhydride (CAS [68957-94-8], 50 % in EtOAc, 72 μL, 0.12 mmol, 1.7 eq.) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature overnight. DMSO (500 pL) was added and the DCM was evaporated under reduced pressure. The residual DMSO solution was purified by reverse phase column chromatography (RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm; 0.25 % NH4HCO3 solution in water, ACN) to give Compound 183 (21 mg, yield: 54 %). Compound 184: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-l-methyl-5-(methylsulfonyl)-lH-pyrazole-4-carboxamide.

CIS

[0476] Compound 184 was prepared following the same procedure as Compound 192, using Intermediate 6 instead of Intermediate 23 and l -methyl-5-(methylsulfonyl)- IT/-pyrazole-4- carboxylic acid (CAS [1227070-38-3]) instead of Intermediate 171.

Compound 185: N-((2-(3-chloro-4-fluoro-6-((3a, 4[3, 5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

(3a, 4β, 5a)

[0477] HATU (CAS [148893-10-1], 76 mg, 0.2 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 126 (97 mg, 0.05 mmol, 1 eq.), 5-(methylsulfonyl)nicotinic acid (CAS, [893723-59-6], 40 mg, 0.2 mmol, 1.1 eq.), and DIPEA (0.13 mL, 0.7 mmol, 3 eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCL, MeOH in DCM from 0 to 10 %), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 70 % [65 mM NH₄OAC + ACN (90: 10)] - 30 % ACN to 27 % [65 mM NH₄OAc + ACN (90: 10)] - 73 % ACN) to yield Compound 185 (43 mg, yield: 39 %) as a white powder. Compound 186: N-((2-(4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

(3a, 4β, 5a)

[0478] Intermediate 82 (80 mg, 0.2 mmol, 1.0 eq.) was added to a solution of 5-

(m ethyl sulfonyl) nicotinic acid (CAS [893723-59-6], 48 mg, 0.24 mmol, 1.2 eq.) and DIPEA (106μL, 0.6 mmol, 3.0 eq.) in DMF (3 mL), and the mixture was stirred for 1 min. Then, HATU (CAS [148893-10-1], 92 mg, 0.24 mmol, 1.2 eq.) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCCh and was extracted with DCM. The organic layer was dried with MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography (12 g SiO₂, DCM:MeOH (9: 1) in DCM, from 0/100 to 20/80) to yield Compound 186 (73 mg, yield: 61 %) as a yellow solid.

Compound 187: N-((2-(6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide.

(3a,4β,5a)

[0479] Compound 187 was prepared following Method M, starting from Intermediate 23 and Intermediate 38.

Compound 188: N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)nicotinamide.

[0480] Compound 188 was prepared following Method M, starting from Intermediate 65 and Intermediate 38.

Compound 189: N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0481] Intermediate 65 (120 mg, 0.227 mmol) and Intermediate 171 (50 mg, 0.232 mmol) were dissolved in DCM (2.4 mL), then 1-propanephosphonic anhydride (CAS [68957-94-8], 50 % in EtOAc, 230 μL, 0.386 mmol) was added under nitrogen atmosphere. EtsN (227 pL, 1.634 mmol) was then added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured over NaOH (1 M in water) and the mixture was extracted with EtOAc (3 x). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Redisep 4 g, DCM/DCM:NH3 7 N in MeOH 9: 1, 100/0 to 80/20), followed by reverse phase column chromatography (RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm; 0.25 % NH4HCO3 solution in water, MeOH) to afford Compound 189 (5 mg, yield: 4 %).

Compound 190: N-((2-(4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-(2-hydroxypropan-2-yl)nicotinamide.

(3a, 4β, 5a)

[0482] DIPEA (132 μL, 0.76 mmol, 3.0 eq.) and HATU (CAS [148893-10-1], 120 mg, 0.32 mmol, 1.2 eq.) were added to a solution of Intermediate 84 (50 mg, 0.28 mmol, 1.1 eq.) in DMF (3 mL). The reaction mixture was stirred for 1 min and Intermediate 82 (100 mg, 0.25 mmol, 1.0 eq.) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCCh and was extracted with DCM (x 3). The combined organic layer was dried with MgSCU, filtered, and concentrated. The crude product was purified by semipreparative SFC (Cell-1 column; isocratic 60 % [MeOH + 0.1 % DEA] - 40 % [CO2]) to yield Compound 190 (51 mg, yield: 32 %) as a yellow solid.

Compound 191 : N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0483] HATU (CAS [148893-10-1], 250 mg, 0.65 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 88 (188 mg, 0.43 mmol, 1 eq.), Intermediate 171 (75 mg, 0.34 mmol, 0.8 eq.), and DIPEA (0.6 mL, 3.5 mmol, 8 eq.) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc (2 x 15 mL). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCE, MeOH in DCM from 0/100 to 10/90) to yield Compound 191 (43 mg, yield: 17 %) as a yellow solid.

Compound 192: N-((2-(6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(3a, 4β, 5a)

[0484] Intermediate 23 (140 mg, 0.32 mmol) was added to a stirred solution of Intermediate 171 (78 mg, 0.35 mmol, 1.1 eq.), HATU (CAS [94790-37-1], 186 mg, 0.49 mmol, 1.5 eq.), and DIPEA (0.474mL; 2.71 mmol, 8.4 eq.) in DMF (5mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine (2 x 10 mL), dried over MgSO4, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; gradient of (MeOH:DCM 9: 1) in DCM from 0 % to 100 %), followed by reverse phase column chromatography (Phenom enex Gemini C18 100 x 30 mm, 5 pm; gradient from 90 % [0.1 % HCOOH] - 10 % [ACN:MeOH (1 : 1)] to 54 % [0.1 % HCOOH] - 46 % [ACN:MeOH (1 : 1)]) to yield Compound 192 (47 mg, yield: 25 %) as a yellow solid.

Compound 193: N-((2-(6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide.

(3a, 4β, 5a)

[0485] HATU (CAS [148893-10-1], 195 mg, 0.51 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 23 (150 mg, 0.34 mmol, 1 eq.), Intermediate 129 (92 mg, 0.38 mmol, 1.1 eq.), and DIPEA (0.18 mL, 1.03 mmol, 3eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with 1 M aqueous Na2COs and extracted with EtOAc (2 x 15 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2, MeOH in DCM from 0 to 6 %) to yield Compound 193 (58 mg, yield: 29 %) as a yellow solid.

Compound 194: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide.

[0486] HATU (CAS [148893-10-1], 60 mg, 0.16 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 15 (46 mg, 0.11 mmol, leq.), Intermediate 129 (30 mg, 0.12 mmol, 1.1 eq.), and DIPEA (0.06 mL, 0.31 mmol, 3eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with 1 M aqueous Na2CC>3 and extracted with EtOAc (2 x 15 mL). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO₂, MeOH in DCM from 0 to 6 %) to yield Compound 194 (20 mg, yield: 32 %) as a yellow solid. Compound 195: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide.

[0487] HATU (CAS [148893-10-1], 101 mg, 0.33 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 6 (75 mg, 0.18 mmol, 1 eq.), Intermediate 129 (48 mg, 0.19 mmol, 1.1 eq.), and DIPEA (0.09 mL, 0.53 mmol, 4 eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc (2 x 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2, MeOH in DCM from 0 to 5 %) to yield Compound 195 (23 mg, yield: 18 %) as a yellow solid. Compound 196: N-((2-(4-fluoro-6-((3α, 4β, 5α)-4-hydroxy-3,5-dimethylpiperidin-1- yl)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6- methylnicotinamide.

(3α, 4β, 5α) [0488] HATU (CAS [148893-10-1], 128 mg, 0.34 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 51 (139 mg, 0.31 mmol, 1 eq.), Intermediate 129 (82 mg, 0.38 mmol, 1.1 eq.), and DIPEA (0.16 mL, 0.9 mmol, 3 eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with DCM (2 x 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g SiCh, MeOH in DCM from 0 to 10 %) to yield Compound 196 (95 mg, yield: 48 %) as a yellow solid.

Compound 197: 5-((3,3-difhioropropyl)sulfonyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan- 7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-6-methylnicotinamide.

[0489] Intermediate 93 (72 mg, 0.26 mmol, 1.0 eq.) and DIPEA (0.36 mL, 2.07 mmol, 8.0 eq.) were added to a solution of HATU (CAS [148893-10-1], 118 mg, 0.31 mmol, 1.2 eq.) in DMF (5 mL). The mixture was stirred for 1 min and Intermediate 88 (HC1 salt, 170 mg, 0.36 mmol, 1.4 eq.) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCCL and extracted with DCM (x 3). The combined organic layer was dried (MgSCU), filtered, and the solvents were evaporated. The crude product was purified by flash chromatography (25 g SiCL, EtOAc:MeOH (9: 1) in EtOAc from 0 % to 100 %) to yield Compound 197 (69 mg, yield: 42 %) as a yellow solid.

Compound 198: N-((2-(4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyri din-2 -yl)-l, 6-naphthyridin-7-yl)methyl)-5-((*R)-l -hydroxy ethyl)nicotinamide and

Compound 199: N-((2-(4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-((*S)-l-hydroxyethyl)nicotinamide.

(S*), (3a, 4β, 5a) [0490] Intermediate 94 (41 mg, 0.25 mmol, 1.2 eq.) and DIPEA (106 μL, 0.61 mmol, 3.0 eq.) were added to a solution of Intermediate 82 (80 mg, 0.2 mmol, 1.0 eq.) in DMF (3 mL). The mixture was stirred for 1 min and HATU (CAS [148893-10-1], 100 mg, 0.26 mmol, 1.3 eq.) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with DCM (x 3). The combined organic layer was dried with MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (12 g; SiO2, DCM:MeOH (9:1) in DCM 0/100 to 100/0), followed by SFC (i-Cellulose-C (Regis Technologies) 250 mm x 30 mm I.D.5 μm; isocratic CO2 (60 %) – iPrOH (40 %) + 0.1 % diethylamine) to yield Compound 198 (15 mg, yield: 13 %) as a yellow solid and Compound 199 (12 mg, yield: 10 %) as a yellow solid. Compound 200: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)-6-methyl-5-(S-methylsulfonimidoyl)nicotinamide.

(rac), (CIS) Compound 200 [0491] (Diacetoxyiodo)benzene (CAS [3240-34-4], 188 mg, 0.583 mmol, 2.5 eq.) and ammonium carbamate (CAS [1111-78-0], 36 mg, 0.466 mmol, 2.0 eq.) were added in one portion to a suspension of Intermediate 178 (120 mg, 0.233 mmol) in MeOH (1 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC (Waters XBridge BEH C18, 5 uM, 19 x 150 mm, 20-55 % ACN/H2O with pH 10 NH4OH) to give Compound 200 (42 mg, yield: 33 %) as a yellow solid. The compounds in Table 7 were prepared following procedures analogous to the one used for Compound 200, using the indicated thioether: Table 7.

Compound 205: N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0492] HATU (CAS [148893-10-1], 325 mg, 0.85 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 138 (257 mg, 0.57 mmol, 1 eq.), Intermediate 128 (98 mg, 0.45 mmol, 0.8 eq.), and DIPEA (0.4 mL, 2.3 mmol, 4 eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with DCM (2 x 15 mL). The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2, MeOH in DCM from 0 to 8 %) to yield Compound 205 (138 mg, yield: 40 %) as a yellow solid. Compound 206: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)-6-methyl-5-((*R)-S-methylsulfonimidoyl)nicotinamide and Compound 207: N- ((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)-6-methyl- 5-((*S)-S-methylsulfonimidoyl)nicotinamide.

(*S), (CIS) Compound 207 [0493] A batch of Compound 200 was separated into its stereoisomers by chiral SFC (IH 30 x 250 mm ID, 5 um; 25 % ACN/iPr2NH) to give Compound 206 and Compound 207. Compound 208: N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)-6-(trifluoromethyl)nicotinamide.

[0494] Compound 208 was prepared following the same procedure as Compound 229, using Intermediate 212 instead of Intermediate 201.

Compound 209: 6-methyl-5-(methylsulfonyl)-N-((2-(6-(6-oxo-4-oxa-7-azaspiro[2.5]octan-7- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide.

[0495] Compound 209 was prepared following Method M, starting from Intermediate 68 and

Intermediate 73.

Compound 211 : N-((2-(6-((3a, 4β, 5a))-4-(hydroxymethyl)-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(3a, 4β, 5a)

[0496] Intermediate 56 (58 mg, 0.111 mmol) and Intermediate 171 (29 mg, 0.133 mmol) were dissolved in DCM (1 mL), then 1-propanephosphonic anhydride (CAS [68957-94-8], 50 % in EtOAc, 0.132 mL, 0.222 mmol) and EtsN (0.092 mL, 0.665 mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and the mixture was extracted with EtOAc (3 x). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column flash chromatography on silica gel (12 g, DCM/DCM:MeOH 9: 1 from 100/0 to 0/100), followed by preparative SFC (Torus Diol 30 x 150 mm; CO2, MeOH + 20 mM NH4OH), and finally reverse phase column chromatography (RP XB ridge Prep Cl 8 OBD- 5 μm, 50 x 250 mm; 0.25 % NH4HCO3 solution in water, ACN) to give Compound 211 (3 mg, yield: 5 %).

Compound 212: 6-methyl-5-(methylsulfonyl)-N-((2-(6-(5-oxo-2- (trifluoromethyl)morpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide.

Racemic

[0497] Compound 212 was prepared following Method M, starting from Intermediate 70 and

Intermediate 73.

Compound 213 : (*R)-N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide and Compound 214: (*S)-N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(*S) Compound 214

[0498] Compound 205 was separated into its stereoisomers by SFC (Amylose-1, 5 pm; 250 x 30 mm; 50 % CO2 - 50 % EtOH + 0.1 % DEA) to yield Compound 213 as a yellow solid and Compound 214 as a white solid. Compound 215: 6-methyl-5-(methylsulfonyl)-N-((2-phenyl-1,6-naphthyridin-7- yl)methyl)nicotinamide.

[0499] HATU (CAS [148893-10-1], 0.185 g, 0.487 mmol) was added to a stirred solution of Intermediate 157 (0.1 g, 0.324 mmol), Intermediate 73 (77 mg, 0.3 mmol), and DIPEA (0.283 mL, 1.6 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc and the solution was washed with Na2CO3 (1 M in water). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm; 0.25 % NH4HCO3 solution in water, ACN) to yield Compound 215 (61 mg, yield: 43 % ) as a brown solid. Compound 216: N-((2-(6-(2,6-dimethyl-3-oxomorpholino)pyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0500] Compound 216 was prepared following Method M, starting from Intermediate 69 and Intermediate 73. Compound 217: 6-methyl-5-(methylsulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)oxy)pyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)nicotinamide.

[0501] Intermediate 215 (0.084 g, 0.230 mmol, 1.5 eq.) was dissolved in 1,4-dioxane (4 mL). The solution was bubbled with nitrogen while 1 M aqueous Na₂CO₃ (0.655 mL, 0.655 mmol, 4.2 eq.) and Intermediate 195 (0.060 g, 0.154 mmol) were added. Finally, Pd(PPh₃)₂Cl₂ (CAS [13965-03-2], 11 mg, 0.015 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 90ºC under nitrogen atmosphere for 24 h. Water and EtOAc were added at room temperature. The organic layer was separated, washed with brine, dried over MgSO₄, filtered, and evaporated in vacuo. The crude product was purified by flash column chromatography (12 g SiO2, heptane/EtOAc from 100/0 to 0/100) to give Compound 217 (24 mg, yield: 25 %) as a white solid, after recrystallization from ACN. Compound 218: N-((2-(6-(2,2-dimethyl-3-oxomorpholino)pyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0502] Compound 218 was prepared following Method M, starting from Intermediate 71 and Intermediate 73. Compound 219: N-((2-(6-(4-amino-3,3-difluoropiperidin-1-yl)-4-fluoropyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0503] Trifluoroacetic acid (CAS [76-05-1], 0.14 mL, 1.9 mmol, 20.0 eq.) was added to a stirred solution of Intermediate 99 (65 mg, 0.095 mmol, 1.0 eq.) in DCM (0.4 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 ºC, and a saturated Na₂CO₃ aqueous solution was added until pH 8. DCM was added, the layer was separated and the aqueous layer was re-extracted with DCM (x 5). The combined organic layer was dried over MgSO4, filtered, and concentrated, the crude product was purified by flash column chromatography on silica gel (12 g SiO₂; DCM:MeOH (9:1) in DCM from 0 % to 30 %) to yield Compound 219 (36 mg, yield: 63 %) as a yellow solid. Compound 220: 6-methyl-N-((2-(6-((trans)-2-methyl-6-(trifluoromethyl)morpholino)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide and Compound 221 : 6- methyl-N-((2-(6-((cis)-2 -methyl -6-(trifluoromethyl)morpholino)pyri din-2 -yl)-l, 6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

(CIS) Compound 221

[0504] 1-Propanephosphonic anhydride solution (CAS [68957-94-8], 50 % in EtOAc, 398 μL, 2.866 mmol, 1.3 eq.) was added to a suspension of Intermediate 171 (136 mg, 0.63 mmol, 1.1 eq.), and Intermediate 58 (273 mg, 0.573 mmol) in dry DCM (10 mL) at room temperature. EtsN (398 μL, 2.866 mmol, 5 eq.) was then added dropwise to the suspension. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with DCM and water. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was triturated in ACN and the solid was filtered and washed with a small amount of ACN to give an off-white solid. This solid was further purified by reverse phase HPLC (RP XBridge Prep C18 OBD-10 μm, 50 x 150 mm; 0.25 % NH4HCO3 solution in water, ACN) to give Compound 220 (27 mg, yield: 8 %) and Compound 221 (71 mg, yield: 20 %), both as pale yellow solids.

Compound 222 : N-((2-(4-fluoro-6-(7 -hydroxy-5 -azaspiro[2.4]heptan-5 -yl)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0505] A solution of Intermediate 105 (117 mg, 0.175 mmol, 1.0 eq.) and NaOH (2.5 M in water, 1.3 mL, 3.2 mmol, 18.0 eq.) in 1,4-dioxane (1.2 mL) was stirred at 78 °C for 16 h. After cooling, the reaction mixture was partitioned between EtOAc (10 mL) and saturated aqueous NaHCOs. The organic layer was separated, dried (MgSO4), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (25 g column, DCM:MeOH (9: 1) in DCM from 0 % to 25 %) to yield Compound 222 (55 mg, yield: 55 %) as a yellow solid.

Compound 223 : 6-methyl-N-((2-(l-methyl-6-oxo-2-(2,2,6,6-tetramethylmorpholino)-l,6- dihydropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0506] Intermediate 109 (78 mg, 0.15 mmol, 1.0 eq.), Intermediate 171 (37 mg, 0.17 mmol, 1.15 eq.), and DIPEA (0.1 mL, 0.61 mmol, 4.0 eq.) were taken up in DMF (3 mL) at room temperature. HATU (CAS [148893-10-1], 74 mg, 0.2 mmol, 1.15 eq.) was added in one portion while stirring. The reaction mixture was stirred for 2 h before it was diluted with saturated aqueous NaHCCh and extracted with EtOAc (x 3). The organic layer was separated, dried (MgSCU), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (12 g SiO₂, DCM:MeOH (9: 1) in DCM, from 0 % to 30 %), followed by reverse phase column chromatography (Phenom enex Gemini C18 30 x l00 mm 5 pm; from 90 % H₂O (0.1 % HCOOH) - 10 % ACN-MeOH to 54 % H₂O (0.1 % HCOOH) - 46 % ACN-MeOH) to yield Compound 223 (40 mg, yield: 43 %) as a yellow solid.

Compound 224: N-((2-(2-((cis)-2,6-dimethylmorpholino)-l-methyl-6-oxo-l,6- dihydropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5- (methylsulfonyl)nicotinamide.

(CIS)

[0507] Intermediate 112 (68 mg, 0.18 mmol, 1.0 eq.), Intermediate 171 (43 mg, 0.20 mmol, 1.1 eq.), and DIPEA (0.125 mL, 0.72 mmol, 4.0 eq.) were taken up in DMF (3 mL) at room temperature. HATU (CAS [148893-10-1], 84 mg, 0.22 mmol, 1.2 eq.) was added and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCCL and extracted with EtOAc (x 3). The organic layer was separated, dried (MgSCU), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (12 g SiCL, DCM:MeOH (9: 1) in DCM, from 0 % to 45 %) to yield Compound 224 (44 mg, yield: 41 %) as a yellow solid.

Compound 225: 6-methyl-N-((2-(6-(4-methyl-5-oxo-4,6-diazaspiro[2.4]heptan-6-yl)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[0508] 1-Propanephosphonic anhydride solution (CAS [68957-94-8], 50 % in EtOAc, 85 pL, 0.143 mmol, 1.3 eq.) was added to a suspension of Intermediate 171 (26 mg, 0.121 mmol, 1.1 eq.), and Intermediate 61 (77 % pure, 62 mg, 0.110 mmol) in dry DCM (5 mL) at room temperature. EtsN (77 μL, 0.551 mmol, 5 eq.) was then added dropwise to the suspension. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with DCM and water. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried by filtration on Extrelut NT3, and evaporated. The residue was purified by column chromatography (SiCL, 10 g; AcOEt/EtOH 3/l :heptanes from 0: 100 to 100:0), followed by reverse phase HPLC (RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm; 0.25 % NH4HCO3 solution in water, ACN) to give Compound 225 (15 mg, yield: 24 %) as a white solid.

Compound 226: N-((2-(6-(4,4-dimethyl-2-oxoimidazolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0509] Triphosgene (CAS [32315-10-9], 20 mg, 0.067 mmol, 0.35 eq.) was added to a solution of Intermediate 155 (100 mg, 90 % pure, 0.192 mmol) and DIPEA (33 μL, 0.192 mmol, 1 eq.) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (2 mL) and water (5 mL) was added. After vigorous stirring, the aqueous layer was pipetted out to leave the white solid in suspension in the organic layer. The solvent of the organic layer was evaporated and the residue was purified by reverse phase HPLC (RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm; 0.25 % NH4HCO3 solution in water, ACN) to give Compound 226 (25 mg, yield: 24 %).

Compound 227: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-((*R)-2-hydroxyethylsulfonimidoyl)nicotinamide and Compound 228: N-((2-(6- ((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-5-((*S)-2- hydroxy ethylsulfonimidoyl)nicotinamide.

(*S), (CIS) Compound 228

[0510] Compound 210 was separated into its stereoisomers by chiral SFC (OD 21 x 250 mm ID, 5 um; 25 % ACN/iPrNH2 - 75 % CO2) to give Compound 227 and Compound 228.

Compound 229: N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)-6-(trifluoromethyl)nicotinamide.

[0511] HBTU (CAS [94790-37-1], 0.066 g, 0.174 mmol, 1.1 eq.) was added to a stirred solution of Intermediate 201 (0.1 g, 0.174 mmol), Intermediate 203 (0.034 g, 0.127 mmol, 0.8 eq.), and DIPEA (0.083 mL, 0.617 mmol, 3 eq.) in DMF (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with 1 M aqueous Na₂CO₃. The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 59 % [25 mM NH₄HCO₃] - 41 % [ACN:MeOH (1 :1)] to 17 % [25 mM NH₄HCO₃] - 83 % [ACN:MeOH (1 : 1)]) to give Compound 229 (39 mg, yield: 40 %).

Compound 230: N-((2-(2-(2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0512] Intermediate 196 (164 mg, 0.324 mmol), Intermediate 193 (137 mg, 0.486 mmol, 1.5 eq.), and K2CO3 (67 mg, 0.486 mmol, 1.5 eq.) were taken up in 1,4-di oxane (3 mL) in a sealed tube under nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 12 mg, 0.049 mmol, 0.15 eq.) and Pd(OAc)₂ (CAS [3375-31-3], 7 mg, 0.032 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 115 °C for 16 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (x 3). The combined organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography (25 g SiO₂, DCM/MeOH from 100/0 to 90/10), followed by reverse phase column chromatography (Phenom enex Gemini C18 30 x 100 mm 5 pm; from 81 % [25 mM NH₄HCO₃] - 19 % [ACN:MeOH (1 :1)] to 45 % [25 mM NH₄HCO₃] - 55 % [ACN:MeOH (1 : 1)]) to give Compound 230 (40 mg, yield: 20 %).

Compound 231 : N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-6-(difluoromethyl)-5-(methylsulfonyl)nicotinamide.

[0513] Compound 231 was prepared following the same procedure as Compound 229, using Intermediate 207 instead of Intermediate 203.

Compound 232: N-((2-(2-(l,3-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0514] 1,3-Dimethyl-l, 3, 8-triazaspiro[4.5]decane-2, 4-dione hydrochloride (CAS [1206970- 39-9], 0.056 g, 0.240 mmol, 1.5 eq.) was added to a solution of Intermediate 190 (0.075 g, 0.160 mmol) and DIPEA (0.053 mL, 0.320 mmol, 2 eq.) in DMSO (2 mL). The mixture was stirred at 120 °C for 3 h. After cooling, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSCU, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (25 g SiCL, heptane/EtOAc from 100/0 to 0/100) to give Compound 232 (67 mg, yield: 66 %) after trituration in ACN, as a yellow solid.

Compound 233 : N-((2-(6-isopropoxypyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-

(methylsulfonyl)nicotinamide.

[0515] Compound 233 was prepared following the same procedure as Compound 229, using Intermediate 171 instead of Intermediate 203, and Intermediate 217 instead of Intermediate 201.

[0516] The compounds in Table 8 were prepared following the same procedure as Compound 232, using the indicated amine instead of 1,3 -dimethyl- 1, 3, 8-triazaspiro[4.5]decane-2, 4-dione hydrochloride.

Table 8.

Compound 244: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl (methyl )-6-methoxynicotinamide.

[0517] HATU (CAS [148893-10-1], 202 mg, 1.42 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 6 (150 mg, 0.35 mmol, 1 eq.), Intermediate 141 (54 mg, 0.35 mmol,

1 eq.), and DIPEA (0.25 mL, 1.4 mmol, 4 eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc (2 x 15 mL). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCh, EtOAc/heptane from 0/100 to 100/0) to yield Compound 244 (105 mg, yield:70 %) as a yellow.

Compound 246: 6-methyl-N-((2-(l-methyl-2-((trans)-2-methyl-6- (trifluoromethyl)morpholino)-6-oxo-l,6-dihydropyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide.

(TRANS)

[0518] Compound 246 was prepared following Method C (in DMF), using Intermediate 115 and Intermediate 171.

Compound 247: N-((2-(2-(6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0519] Compound 247 was prepared following the same procedure as Compound 232, using 6,6-dimethyl-l,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (CAS [1918951-38-8]) instead of 1,3-dimethyl-l, 3, 8-triazaspiro[4.5]decane-2, 4-dione hydrochloride, and with an additional purification by reverse phase column chromatography (Phenom enex Gemini Cl 8 30 x 100 mm 5 pm; from 90 % [0.1 % HCOOH] - 10 % ACN to 54 % [0.1 % HCOOH] - 46 % ACN). Compound 248: (*R)-N-((2-(2-(2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)pyrimidin-4-yl)- l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide and Compound 249: (*S)-N-((2-(2-(2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin- 7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(*S) Compound 249

[0520] Compound 242 was separated into its stereoisomers by preparative SFC (Cellulose-1, 5 μm, 250 x 30 mm; 35 % CO2 - 65 % MeOH + 0.1 % DEA) to give Compound 248 and Compound 249.

Compound 250: N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyri din-7- yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)-6-(trifluoromethyl)nicotinamide.

[0521] HBTU (CAS [94790-37-1], 0.046 g, 0.121 mmol, 1.1 eq.) was added to a stirred solution of Intermediate 212 (0.07 g, 0.110 mmol), Intermediate 233 (0.040, 0.132 mmol, 1.2 eq.), and DIPEA (0.058 mL, 0.330 mmol, 3 eq.) in DMF (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with 1 M aqueous Na2COs. The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 59 % [25 mM NH4HCO3] - 41 % ACN to 17 % [25 mM NH4HCO3] - 83 % ACN) to give Compound 250 (31 mg, yield: 44 %).

Compound 251 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(2-hydroxyethyl)-6-oxo-l,6-dihydropyridine-3-carboxamide.

[0522] Hydrochloric acid (4 M in 1,4-dioxane, 0.65 mL, 2.6 mmol) was added to a stirred solution of Intermediate 146 (165 mg, 0.26 mmol) in 1,4-dioxane (2 mL) and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and basified to pH=10 with saturated aqueous NaHCCh. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCL, MeOH in DCM from 0 to 10 %) to yield Compound 251 (94 mg, yield: 68 %) as a yellow solid.

Compound 252: 6-methyl-N-((2-(2-((6*R)-6-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide and Compound 258: 6-methyl-N-((2-(2-((6*S)-6-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

(*S, RS) Compound 258

[0523] Compound 245 was separated into its diastereoisomers by reverse phase column chromatography (Phenom enex Gemini C18 30 x l00 mm 5 pm; from 81 % [25 mM NH₄HCO₃] - 19 % ACN to 45 % [25 mM NH₄HCO₃] - 55 % ACN) to give Compound 252 and Compound 258. Compound 253: 6-(difluoromethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- 1,6-naphthyridin-7-yl)methyl)nicotinamide.

[0524] HATU (CAS [148893-10-1], 202 mg, 1.42 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 6 (150 mg, 0.35 mmol, 1 eq.), Intermediate 143 (72 mg, 0.35 mmol, 1 eq.), and DIPEA (0.25 mL, 1.4 mmol, 4 eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc (2 x 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2, EtOAc/heptane from 0/100 to 100/0), followed by reverse phase column chromatography (Phenomenex Gemini C1830 x 100 mm 5 µm; from 59 % [25 mM NH₄HCO₃] - 41 % ACN to 17 % [25 mM NH₄HCO₃] - 83 % ACN) to yield Compound 253 (56 mg, yield: 30 %) as a yellow solid. Compound 254: N-((2-(2-(4-amino-3,3-difluoropiperidin-1-yl)pyrimidin-4-yl)-1,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0525] Trifluoroacetic acid (CAS [76-05-1], 0.25 mL, 3.27 mmol, 22.0 eq.) was added to a stirred solution of Intermediate 116 (100 mg, 0.15 mmol, 1.0 eq.) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 ºC, and saturated aqueous NaHCO₃ was added until pH 8. DCM was added and the aqueous layer was extracted with DCM (x 3). The organic layer was separated, dried (MgSO₄), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (12 g SiCL, DCM:MeOH (9: 1) in DCM, from 0 % to 70 %) to yield Compound 254 (49 mg, yield: 55 %) as a yellow solid.

Compound 255: N-((2-(2-(4-acetamido-3,3-difluoropiperidin-l-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0526] Acetic anhydride (CAS [108-24-7], 0.06 mL; 0.66 mmol, 8.5 eq.) was added dropwise to a solution of Compound 254 (44 mg, 0.08 mmol, 1.0 eq.) and EtsN (0.12 mL; 0.88 mmol, 11.4 eq.) in DCM (30 mL). The reaction mixture was stirred at reflux (55 °C) for 1 h. Water and DCM were added, the layers were separated, and the aqueous layer was extracted with DCM (x 3). The combined organic layer was dried (MgSCU), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (12 g SiCL; DCM:MeOH (9: 1) in DCM, from 0 % to 90 %) to yield Compound 255 (28 mg, yield: 59 %) as a pale yellow solid.

Compound 256: (*R)-6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide and Compound 257: (*S)-6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

(*S) Compound 257 [0527] Compound 241 was separated into its stereoisomers by preparative SFC (Stationary phase: i-Cellulose-C, 5 μm, 250 x 30 mm; 40 % CO2 – 60 % MeOH + 0.1 % IPA) to give Compound 256 and Compound 257. Compound 259: N-((2-(6-(((2 α, 4 β, 6 α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-5- methylpyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide and Compound 284: N-((2-(6-(((2 α, 4 β, 6 α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-5- methylpyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0528] Intermediate 220 (220 mg, 0.634 mmol, 1.1 eq.) and 1 M aqueous Na₂CO₃ (1.7 mL, 1.7 mmol, 3 eq.) were added to a stirred solution of Intermediate 78 (225 mg, 0.576 mmol) in 1,4-dioxane (7 mL) at room temperature previously degassed by bubbling nitrogen. Then, Pd(PPh₃)Cl₂ (CAS [13965-03-2], 20 mg, 0.029 mmol, 0.05 eq.) was added, and the mixture was stirred at 90 ºC under nitrogen atmosphere for 4 h. After cooling, the mixture was diluted with water and was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (12 g SiO₂, DCM/MeOH from 100/0 to 90/10), followed by reverse phase column chromatography (Phenomenex Gemini C1830 x 100 mm 5 µm; from 59 % [25 mM NH4HCO3] - 41 % [ACN:MeOH (1:1)] to 17 % [25 mM NH4HCO3] - 83 % [ACN:MeOH (1:1)]) to yield Compound 259 (132 mg, yield: 39 %) as a white solid and impure Compound 284. This impure fraction was purified by preparative SFC (1-cellulose-B column (Regis Technologies), 5 μm, 250 x 30 mm; isocratic CO2 (60 %) – MeOH (40 %) + 0.1 % DEA) to afford Compound 284 (6 mg, yield: 2 %) as a white solid. Compound 260: (*R)-N-((2-(2-(l,3-dimethyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide and Compound 261 : (*S)-N-((2-(2-(l,3-dimethyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(*S) Compound 261

[0529] Compound 240 was separated into its stereoisomers by preparative SFC (Stationary phase: Cellulose-1, 5 μm, 250 x 30mm; 40 % CO2 - 60 % MeOH + 0.1 % DEA) to give

Compound 260 and Compound 261.

Compound 262: 6-methyl-N-((2-(2-((5*R,6*R)-6-methyl-2,4-dioxo-l,3,8- triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide and Compound 263: 6-methyl-N-((2-(2-((5*S,6*S)-6-methyl- 2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide

(*S, *S) Compound 263

[0530] Compound 252 was separated into its stereoisomers by preparative SFC (i-Cellulose- B, 5 μm, 250 x 30 mm; 40 % CO2 - 60 % MeOH + 0.1 % DEA) to give Compound 262 and Compound 263.

Compound 264: (*R)-N-((2-(2-(6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide and Compound 265: (*S)-N-((2-(2-(6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(*S) Compound 265

[0531] Compound 247 was separated into its stereoisomers by preparative SFC (i-Cellulose- B, 5 μm, 250 x 30 mm; 50 % CO2 - 50 % MeOH + 0.1 % DEA) to give Compound 264 and Compound 265.

Compound 266: 6-methyl-N-((2-(2-((5*R,6*R)-6-methyl-2,4-dioxo-l,3,8- triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide and Compound 267: 6-methyl-N-((2-(2-((5*S,6*S)-6-methyl- 2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide.

(*S, *R) Compound 266

(*S, *S) Compound 267

[0532] Compound 258 was separated into its stereoisomers by preparative SFC (i-Cellulose-

B, 5 μm, 250 x 30 mm; 40 % CO2 - 60 % MeOH + 0.1 % DEA) to give Compound 266 and

Compound 267.

Compound 268: 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-6-methylnicotinamide.

CIS

[0533] A suspension of Intermediate 6 (HC1 salt, 0.052 g, 0.135 mmol), Intermediate 187 (0.046 g, 0.168 mmol), and DIPEA (0.1 mL, 0.58 mmol) in DMSO (1.5 mL) was treated with HATU (CAS [148893-10-1], 0.058 g, 0.153 mmol) while stirring at room temperature. After 10 min, the reaction mixture was filtered and purified directly by reverse phase HPLC (Waters XBridge BEH Cl 8, 5 urn, 19 x 150 mm, 35-70 % ACN/H2O with 10 mM NH₄OH) to yield Compound 268 (0.017 g, yield: 22 %).

Compound 269: 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide.

CIS

[0534] Compound 269 was prepared following Method M (in DMF), using Intermediate 6 and Intermediate 166. Compound 270: (*R)-N-((2-(2-(6,8-dioxo-5,7,l l-triazadispiro[2.0.44.43]dodecan-l 1- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide and Compound 271 : (*S)-N-((2-(2-(6,8-dioxo-5,7,l l-triazadispiro[2.0.44.43]dodecan-l 1- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(*S) Compound 271

[0535] Compound 243 was separated into its stereoisomers by preparative SFC (Cellulose-1, 5 μm, 250 x 30 mm; 60 % CO2 - 40 % MeOH + 0.1 % DEA) to give Compound 270 and Compound 271.

Compound 272: N-((2-(6-(((2a, 4a, 6a)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide and Compound 273: N-((2-(6-(((2a, 4β, 6a)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(2a, 4β, 6a) Compound 273

[0536] Intermediate 195 (225 mg, 0.576 mmol) and 1 M aqueous Na2COs (1.7 mL, 1.7 mmol,

3 eq.) were added at room temperature to a stirred solution of Intermediate 223 (220 mg, 0.682 mmol, 1.1 eq.) in 1,4-dioxane (7 mL) previously degassed by bubbling nitrogen. Finally, Pd(PPh3)2Ch (CAS [13965-03-2], 20 mg, 0.029 mmol, 0.05 eq.) was added, and the mixture was stirred at 90 °C under nitrogen atmosphere for 3 h. After cooling, the mixture was diluted with water and was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (25 g SiCh, DCM/MeOH from 100/0 to 90/10), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 70 % [25 mM NH4HCO3] - 30 % [ACN:MeOH (1 :1)] to 27 % [25 mM NH₄HCO₃] - 73 % [ACN:MeOH (1 : 1)]), and finally by preparative SFC (i-Cellulose-C column (Regis Technologies), 5 pm, 250 x 30 mm; isocratic CO2 (40 %) - EtOH (60 %) + 0.1 % DEA) to afford Compound 272 (8 mg, yield: 2 %) and Compound 273 (104 mg, yield: 31 %), both as white solids.

Compound 274: N-((2-(6-(((2a, 4β, 6a)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridin- 3-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(2a, 4β, 6a)

[0537] Propylphosphonic anhydride solution (CAS [68957-94-8], 50 % in EtOAc, 402 pL, 0.678 mmol, 1.25 eq.) was added to a solution of Intermediate 230 (236 mg, 0.540 mmol), Intermediate 171 (142 mg, 0.659 mmol, 1.2 eq.), and DIPEA (357 μL, 2.16 mmol, 4 eq.) in DMF (6 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with 1 M aqueous ISfeCOs and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and solvents evaporated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2, DCM/MeOH from 100/0 to 90/10), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 81 % [0.1 % HCOOH] - 19 % ACN to 45 % [0.1 % HCOOH] - 55 % ACN) to give Compound 274 (43 mg, yield: 14 %) as a white solid. Compound 275: N-((2-(6-(((2a, 4β, 6a)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-2- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(2a, 4β, 6a)

[0538] Intermediate 195 (230 mg, 0.588 mmol) and 1 M aqueous Na2CO₃ (1.7 mL, 1.7 mmol, 3 eq.) were added at room temperature to a stirred solution of Intermediate 225 (225 mg, 0.647 mmol, 1.1 eq.) in 1,4-dioxane (7 mL) under nitrogen atmosphere. Then, PdfPPlr^Ch (CAS [13965-03-2], 21 mg, 0.029 mmol, 0.05 eq.) was added, and the mixture was stirred at 90 °C under nitrogen atmosphere for 4 h. After cooling, the mixture was diluted with water and was extracted with EtOAc. The organic layer was dried over MgSCU, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (25 g SiCh, DCM/MeOH 100/0 to 90/10), followed by reverse phase column chromatography (Phenom enex Gemini C18 30 x 100 mm 5 pm; from 63 % [25 mM NH4HCO3] - 37 % [ACN:MeOH (1 : 1)] to 18 % [25 mM NH₄HCO₃] - 82 % [ACN:MeOH (1 : 1)]), and finally by preparative SFC (i-amylose-1 (Regis Technologies), 5 μm, 250 x 30 mm; isocratic CO2 (40 %) - iPrOH (60 %) + 0.1 % DEA) to give Compound 275 (76 mg, yield: 22 %) as a white solid.

Compound 276: 4-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)picolinamide.

CIS

[0539] Compound 276 was prepared following Method M (in DMF), using Intermediate 6 and Intermediate 169. Compound 277: N-((2-(2-((trans)-2,4-dioxo-6-(trifluoromethyl)-l,3,8-triazaspiro[4.5]decan- 8-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide and Compound 278: N-((2-(2-((cis)-2,4-dioxo-6-(trifluoromethyl)-l,3,8- triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-

(methylsulfonyl)nicotinamide.

(CIS) Compound 278

[0540] 6-(Trifluoromethyl)-l, 3, 8-triazaspiro[4.5]decane-2, 4-dione (CAS [2239305-59-8], 0.027 g, 0.095 mmol, 2 eq.) was added to a solution of Intermediate 190 (0.095 g, 0.095 mmol) and DIPEA (CAS [7087-68-5], 0.039 mL, 0.238 mmol, 2.5 eq.) in DMSO (2 mL). The mixture was stirred at 120 °C for 3 h. After cooling the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSCU, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (25 g SiCh, DCM:MeOH (9: 1) in DCM from 0/100 to 100/0), followed by reverse phase column chromatography (Phenom enex Gemini C18 30 x l00 mm 5 pm; from 81 % [25 mM NH4HCO3] - 19 % ACN to 45 % [25 mM NH4HCO3] - 55 % ACN) to give the mixture of Compound 277 and Compound 278. These were separated by preparative SFC (i-Cellulose-C, 5 μm, 250 x 30 mm; 40 % CO2 - 60 % EtOH + 0.1 % DEA) to give Compound 277 (10 mg, yield: 15 %) and Compound 278 (8 mg, yield: 12 %). Compound 279 : N-((2-(2-(7 -hydroxy-5 -azaspiro[2.4]heptan-5 -yl)pyrimidin-4-yl)- 1,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[0541] 5-Azaspiro[2.4]heptan-7-ol hydrochloride (CAS [1152110-85-4], 32 mg, 0.213 mmol, 1.0 eq.) was added to a solution of Intermediate 190 (0.1 g; 0.213 mmol. 1,0 eq.) and DIPEA (0.14 mL; 0.85 mmol, 4.0 eq.) in DMSO (1 mL). The mixture was stirred at 120 °C for 16 h. The mixture was diluted with EtOAc and washed with water (x 2) and brine. The organic layer was dried over MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography (24 g SiCL; DCM:MeOH (9: 1) in DCM, from 0 % to 90 %) to yield Compound 279 (62 mg, yield: 45 %) as a yellow solid.

Compound 280: 6-methyl-5-(methylsulfonyl)-N-((2-(6-(oxetan-3-yloxy)pyridin-3-yl)-l,6- naphthyridin-7-yl)methyl)nicotinamide.

[0542] Intermediate 195 (231 mg, 0.590 mmol) and 1 M aqueous Na2CO₃ (1.7 mL, 1.7 mmol, 3 eq.) were added to a stirred solution of 2-(oxetan-3-yloxy)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (CAS [2353522-90-2], 180 mg, 0.650 mmol, 1.1 eq.) in 1,4- dioxane (6 mL) at room temperature under nitrogen atmosphere. Then, PdfPPhs^Ch (CAS [13965-03-2], 20 mg, 0.029 mmol, 0.05 eq.) was added, and the reaction mixture was stirred at 90 °C under nitrogen atmosphere for 3 h. After cooling the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (25 g SiO2, DCM/MeOH from 100/0 to 90/10), followed by reverse phase column chromatography (Phenom enex Gemini C18 30 x l00 mm 5 pm; from 72 % [25 mM NH4HCO3] - 28 % [ACN:MeOH (1 :1)] to 36 % [25 mM NH₄HCO₃] - 64 % [ACN:MeOH (1 : 1)]) to afford Compound 280 (24 mg, yield: 8 %) as a white solid. Compound 281 : (*R)-N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide and Compound 282: (*S)-N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(*S) Compound 282

[0543] Compound 279 was separated into its stereoisomers by semipreparative SFC (Whelk- 01 250 x 30 mm 5 um; isocratic 45 % [MeOH + 0.1 % DEA] - 55 % [CO2]) to yield Compound 281 and Compound 282, both as yellow solids.

Compound 283: N-((2-(6-(((2a, 4β, 6a)-2,6-dimethyltetrahydro-2H-pyran-4- yl)oxy)pyridazin-3-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-

(methylsulfonyl)nicotinamide.

(2a, 4β, 6a)

[0544] Propylphosphonic anhydride solution, 50 % in EtOAc (CAS [68957-94-8], 0.210 mL, 0.35 mmol, 1.2 eq.) was added to a mixture of Intermediate 177 (122 mg, 0.28 mmol), Intermediate 171 (72 mg, 0.34 mmol, 1.2 eq.), and DIPEA (185 μL, 1.12 mmol, 4 eq.) in DMF (4 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCCh and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (SiO? 12 g, MeOELDCM (1 :9) in DCM, from 0 % to 100 %), followed by preparative SFC (i-Cellulose-B 250 x 30 mm, 5 pm; isocratic CO2 (83 %) - MeOH (60 %) + 0.1 % diethylamine) to yield Compound 285 (4 mg, yield: 2 %) and Compound 283 (50 mg, yield: 32 %), both as white solids.

Compound 285: N-((2-(6-(((2a, 4a, 6a)-2,6-dimethyltetrahydro-2H-pyran-4- yl)oxy)pyridazin-3-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5- (methylsulfonyl)nicotinamide.

(2a, 4a, 6a)

[0545] The title compound was isolated from the reaction mixture from Compound 283.

Compound 286: 6-methyl-5-(methylsulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)oxy)pyridazin-3-yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide.

[0546] Propylphosphonic anhydride solution, 50 % in EtOAc (CAS [68957-94-8], 342 pL, 0.6 mmol, 2 eq.) was added to a mixture of Intermediate 163 (134 mg, 0.3 mmol), Intermediate 171 (74 mg, 0.3 mmol, 1.2 eq.), and DIPEA (190 μL, 1.1 mmol, 4 eq.) in DMF (6 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCOs. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 25 g; gradient of DCM:MeOH (9: 1) in DCM from 0/100 to 100/0), followed by reverse phase column chromatography (Phenom enex Gemini C18 100 x 30 mm, 5 pm; gradient from 59 % [25 mM NH4HCO3] - 41 % [ACN:MeOH (1 : 1)] to 17 % [25 mM NH₄HCO₃] - 83 % [ACN:MeOH (1 : 1)]), and finally trituration with Et2O to yield Compound 286 (87 mg, yield: 51 %) as a white solid. Compound 287: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-6-methoxy-5-(methylsulfonyl)nicotinamide.

[0547] Compound 287 was prepared following Method A (in DMF), using Intermediate 119 and Intermediate 6.

Compound 288: 4-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)picolinamide, Compound 289: 4-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)picolinamide, and Compound 290: 4-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)picolinamide.

(*R, CIS) Compound 290

[0548] A solution of propylphosphonic anhydride (CAS [68957-94-8], 50 % in EtOAc, 0.2 mL, 0.333 mmol, 1.3 eq.) was added to a solution of Intermediate 237 (60 mg, 0.254 mmol), Intermediate 6 (139 mg, 0.3. mmol, 1.3 eq.), and DIPEA (171 μL, 1.036 mmol, 4 eq.) in DMF (2.6 mL). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with saturated aqueous NaHCCh and extracted with EtOAc. The combined organic layer was dried on MgSCU, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (25 g; EtOAc/heptane from 0/100 to 100/0) to yield Compound 288 (100 mg, yield: 68 %) as a yellow solid.

[0549] Compound 288 was separated into its stereoisomers by semipreparative SFC (i- Cellulose-Z; isocratic 55 % [iPrOH + 0.1 % DEA] - 45 % CO2) to give impure Compound 289 and Compound 290 (25 mg, yield: 17 %) as a yellow solid. The impure Compound 289 was purified by flash column chromatography (4 g SiCE, EtOAc/heptane from 0/100 to 100/0) to yield Compound 289 (11 mg, yield: 7 %) as a yellow solid.

Compound 291 : N-((2-(2-((5*R,6*R,9*S)-6,9-dimethyl-2,4-dioxo-l,3,8- triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5- (methylsulfonyl)nicotinamide, Compound 292: N-((2-(2-((5*S,6*S,9*R)-6,9-dimethyl-2,4- dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6- methyl-5-(methylsulfonyl)nicotinamide, Compound 293: N-((2-(2-((5*R,6*S,9*R)-6,9- dimethyl-2,4-di oxo-1, 3, 8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6-naphthyri din-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide, and Compound 294: N-((2-(2- ((5*S,6*R,9*S)-6,9-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

(5*S, 6*S, 9*R) Compound 292

(5*S, 6*R, 9*S) Compound 294

[0550] Intermediate 241 (0.412 g, 1.763 mmol, 2 eq.) was added to a solution of Intermediate 190 (0.413 g, 0.881 mmol) and DIPEA (0.36 mL, 2.204 mmol, 2.5 eq.) in DMSO (6 mL). The reaction mixture was stirred at 120 °C for 3 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSCU, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (25 g; DCM/MeOH (9/1) in DCM from 0 % to 100 %), followed by reverse phase column chromatography (Phenom enex Gemini C 18 30 x 100 mm 5 pm; from 72 % [25 mM NH4HCO3] - 28 % ACN to 36 % [25 mM NH4HCO3] - 64 % ACN) to yield the mixture Compound 291/Compound 292 and the mixture Compound 293/Compound 294.

[0551] The mixture Compound 291/Compound 292 was purified by SFC (i-Cellulose-C (Regis Technologies) 250 mm x 30 mm I.D. 5 pm; isocratic CO2 (70 %) - EtOH (30 %) + 0.1 % DEA) to yield Compound 291 (106 mg, yield: 19 %) and Compound 292 (112 mg, yield: 20 %), both as solids.

[0552] The mixture Compound 292/Compound 293 was purified by SFC (cellulose-3 (Regis Technologies) 250 mm x 30 mm I.D. 5 pm; isocratic CO2 (70 %) - EtOH (30 %) + 0.1 % DEA) to yield Compound 293 (5 mg, yield: 1 %) and Compound 294 (5 mg, yield: 1 %), both as solids. Compound 295: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-4-((2 -methoxy ethyl)sulfonyl)picolinamide.

[0553] Intermediate 6 (50 mg, 0.12 mmol) was added to a stirred solution of Intermediate 63 (40 mg, 0.13 mmol), HATU (CAS [148893-10-1], 0.07 g, 0.18 mmol), and DIPEA (0.16 mL, 0.95 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (x 2), filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90), followed by reverse phase column chromatography (Phenom enex Gemini I.D. (mm) 100 x 21.2, 5 urn (Cl 8) 110A; from 59 % of H₂O (0.1 % HCOOH) - 41 % ACN: MeOH 1 : 1 to 17 % of H₂O (0.1 % HCOOH)- 83 % ACN: MeOH 1 : 1) to yield Compound 295 (27 mg, yield: 39 %) as a yellow powder.

Example B: Analytical characterization methods of Intermediates and Compounds LCMS General procedure

[0554] The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

[0555] Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time. . .) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

[0556] Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]⁺ (protonated molecule) and/or [M-H]' (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4] , [M+HCOO]', etc. . .). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

[0557] Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica.

LCMS Method Codes (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes):

Table 9.

LC-MS results

Table 10: Retention time (Rt) in min., [M+H]⁺ peak (protonated molecule), LCMS method:

NMR

[0558] Some NMR experiments were carried out using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe head with z gradients and operating at 500 MHz for the proton and 125 MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Some NMR experiments were carried out using a Bruker Avance III 400 spectrometer at ambient temperature (298.6 K), using internal deuterium lock and equipped with reverse double-resonance (1H, 13C, SEI) probe head with z gradients and operating at 400 MHz for the proton. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. [0559] 1H NMR spectra were recorded on Bruker Avance III 400MHz and Avance NEO 400MHz spectrometers. CDCl₃ was used as solvent, unless otherwise mentioned. The chemical shifts are expressed in ppm relative to tetramethylsilane. [0560] Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Definitions for multiplicity are as follows: s = singlet, d = doublet, t= triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution. Table 11: 1H NMR results.

SFC methods: [0561] The SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time…) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.Analytical SFC-MS Methods (Flow expressed in mL/min; column temperature (Col T) in °C; Run time in minutes, Backpressure (BPR) in bars. “iPrNH2” means isopropylamine, “iPrOH” means 2-propanol, “EtOH” means ethanol, “min” mean minutes, “DEA” means diethylamine. Table 12. SFC Methods.

[0562] Analytical SFC data - Rt means retention time (in minutes), [M+H]⁺ means the protonated mass of the compound, method refers to the method used for (SFC) MS analysis of enantiomerically pure compounds. (No. or # means number.) Table 13: Analytical SFC data ; SFC results.

Melting points: Melting Points

[0563] For melting points, values are peak values and are obtained with experimental uncertainties that are commonly associated with this analytical method. Melting points were determined with a Mettler-Toledo MP50 or FP62 apparatus. Melting points were measured with a temperature gradient of 10 °C/minute. Maximum temperature was 300 °C.

Table 14: Melting Point Results.

[0564] Optical rotation: Optical rotations were measured at 20°C or 23°C on a Perkin Elmer 341 digital polarimeter at X = 589 nm (i.e., sodium D line), using a 0.2 mL cell (1 = 1 dm), and are given as [a]D (concentration in g/100 mL solvent). Table 15: Optical rotation Results.

High Resolution Mass Spectrometry [0565] HRMS Method Code: 1

[0566] Column: YMC: Pack ODS-AQ (3 μm, 4.6 x 50 mm), mobile phase: A: HCOOH 0.1 % in water, B: CH3CN, gradient: 95 % A to 5 % A in 4.8 min, held for 1 min, back to 95 % A in 0.2 min. Flow: 2.6, Column Temp: 35, Run Time: 6.8 min.

Table 16: HRMS results

Example C: Pharmacological Assays

[0567] The enzymatic assays described below measured the DNA or nucleosome-dependent ATPase activities of various SMARCA2 and SMARCA4 protein constructs by monitoring ADP production using the ADP Gio™ Kinase Assay kit (Promega, V9101). The assay was performed in two steps after the enzymatic reaction was completed. In a first step, the ATPase reaction was terminated and depleted of the remaining ATP. In a second step, ADP was converted to ATP and the newly synthesized ATP was measured using a luciferase/luciferin reaction. The light generated was measured by an Envision Luminescence reader.

SMARCA2 Low [Enzyme] ADP-Glo™ assay

[0568] An N-terminally truncated construct of SMARCA2 (470-1590, NM_003070.5) was modified to carry a cleavable N-terminal hexa-histidine tag and was exogenously expressed in Sf9 insect cells.

[0569] The following assay buffer was prepared fresh and used as indicated below: 20 mM Tris HCl pH 7.4 (Teknova, cat# T1074), 20 mM NaCl (VWR, cat# E529), 0.005% Tween-20 (Enzo, cat# 80-1929), 0.01% BSA (Sigma, cat# B8667), 1 mM DTT (VWR, cat# 0281) and 1.25 mM MgCh (Quality Biological, cat# 351-033-721). The enzyme mix and the ATP/DNA mix were prepared by diluting the respective stock solutions in the assay buffer to the indicated concentrations: (a) 3.33 nM SMARCA2 and (b) 187.5 pM ATP and 5 nM poly(dA- dT) linear double-stranded DNA (Sigma, cat# P0883).

[0570] Compound(s) dissolved in DMSO or vehicle controls and 3 pL of the assay buffer or enzyme mix were dispensed into individual wells of a white 384-well PerkinElmer Proxiplate plate (PerkinElmer, cat# 6008289). Plates were centrifuged at 1000 rpm for 1 minute and incubated for 30 minutes at room temperature. Afterwards, 2 pL of ATP/DNA mix was added, followed by centrifugation for 1 min at 1000 rpm and 180 minutes of incubation at room temperature. Next, 3 pL of ADP Gio™ reagent, supplemented with 11.25 mM MgCh and 0.1% CHAPS (G Biosciences, cat# DG097), was added. Then, plates were centrifuged for 1 min at 1000 rpm and incubated for 60 minutes at room temperature. Ultimately, 6 pL of the Kinase Detection Reagent supplemented with 0.1% CHAPS were dispensed and plates were centrifuged for 1 min at 1000 rμm, sealed, and incubated at least 30 minutes at room temperature.

SMARCA4 low salt buffer ADP-Glo assay:

[0571] An N-terminally truncated construct of SMARCA4 (494-1647, NM_003072.5) was modified to carry a cleavable N-terminal hexa-histidine tag and was exogenously expressed in Sf9 insect cells.

[0572] The following assay buffer was prepared fresh and used as indicated below: 20 mM Tris HCl pH 7.4 (Teknova, cat# T1074), 10 mM NaCl (VWR, cat# E529), 0.005% Tween-20 (Enzo, cat#80-1929), 1 mM EGTA (Boston BioProducts, cat# BM-723), 0.05% BSA (Sigma, cat# B8667), 1 mM DTT (VWR, cat# 0281). The enzyme mix and the ATP/DNA mix were prepared by diluting the respective stock solutions in the assay buffer to the indicated concentrations: (a) 33.3 nM SMARCA4 and (b) 250 pM ATP, 275 pM MgCh (Quality Biological, cat# 351-033-721) and 12.5 nM pUC19 plasmid DNA (Bayou Bioloabs, cat# P- 102).

[0573] Compound(s) dissolved in DMSO or vehicle controls and 3 pL of the assay buffer or enzyme mix were dispensed into individual wells of a white 384-well PerkinElmer Proxiplate plate (PerkinElmer, cat# 6008289). Plates were centrifuged at 1000 rpm for 1 minute and incubated for 30 minutes at room temperature. Afterwards, 2 pL of ATP/DNA mix was added, followed by centrifugation for 1 min at 1000 rpm at room temperature and 180 minutes of incubation at room temperature. Next, 3 pL of ADP-Glo™ reagent, supplemented with 13.15 mM MgCh and 0.1% CHAPS (G Biosciences, cat# DG097), was added. Then, plates were centrifuged for 1 min at 1000 rpm and incubated for 60 minutes at room temperature. Ultimately, 6 pL of the Kinase Detection Reagent supplemented with 0.1% CHAPS was dispensed and plates were centrifuged for 1 min at 1000 rμm, sealed, and incubated at least 30 minutes at room temperature.

SMARCA2 or 4/SMARCC1/SMARCC2/SMARCB1 ADP-Glo Assays:

[0574] The following assay buffer was prepared fresh and used as indicated below: 20 mM Tris HCl pH 7.5 (Invitrogen, cat# 15567-027), 20 mM NaCl (VWR, cat# E529), 0.25 mM MgCh (Sigma, cat# M1028, 1 mM DTT (Sigma, cat# 646563), 1 mM EGTA (Alfa Caesar, cat# J60767), 0.005% Pluronic F-127 (Sigma, cat# 540025) and 0.2 mg/mL BSA (Sigma, cat# B8667) in molecular biology grade water. The enzyme mix and ATP/nucleosomes mix were prepared by diluting the respective stock solutions in the assay buffer to the indicated concentrations: (a) 0.664 nM for SMARCA2 or SMARCA4 core complex and (b) 250 pM ATP and 2.5 nM Biotin-GatC2 nucleosomes (Epicypher, cat# 16-4112).

[0575] Compound(s) dissolved in DMSO or vehicle controls and 3 pL of the assay buffer or enzyme mix were dispensed into individual wells of a white 384-well PerkinElmer Proxiplate plate (PerkinElmer, cat# 6008289). Plates were centrifuged at 1000 rpm for 1 minute and incubated for 30 minutes at room temperature. Afterwards, 2 pL of ATP/nucleosomes mix was added, followed by centrifugation for 1 min at 1000 rpm and 180 minutes of incubation at room temperature. Next, 3 pL of ADP-Glo™ reagent, supplemented with 14.5 mM MgCh and 0.1% CHAPS (G Biosciences, eta# DG097), was added. Then, plates were centrifuged for 1 min at 1000 rpm and incubated for 60 minutes at room temperature. Ultimately, 6 pL of the Kinase Detection Reagent supplemented with 0.1% CHAPS were dispensed and plates were centrifuged for 1 min at 1000 rμm, sealed, and incubated at least 30 minutes at room temperature.

[0576] Results (indicated as IC50s) obtained from testing the compounds of the present disclosure in the above-described assays are indicated in the Table 17 below.

Table 17: Biological Assay Results

NT : Not tested

Example D: Prophetic formulations

[0577] “Active ingredient” (a.i.) as used throughout these examples relates to a compound of Formula (I), including any tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable addition salt thereof; in particular to any one of the exemplified compounds.

Typical examples of recipes for the formulation of the invention are as follows:

1. Tablets

Active ingredient 5 to 50 mg

Di-calcium phosphate 20 mg

Lactose 30 mg

Talcum 10 mg

Magnesium stearate 5 mg

Potato starch ad 200 mg

2. Suspension

[0578] An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

3. Injectable

[0579] A parenteral composition is prepared by stirring 1.5 % (weight/volume) of active ingredient in 0.9 % NaCl solution or in 10 % by volume propylene glycol in water.

4. Ointment Active ingredient 5 to 1000 mg

Stearyl alcohol 3 g

Lanoline 5 g

White petroleum 15 g Water ad 100 g

[0580] In this Example, active ingredient may be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

Claims

CLAIMS 1. A compound of Formula (I),

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is an optionally substituted heteroaryl selected from: (a) 5-membered heteroaryl selected from:

wherein each Ra is independently selected from: halo, C_1-4alkyl, C_1-4alkyl substituted with OH, C1-4haloalkyl, and (C=O)CH3; Rb is selected from: C1-4alkyl substituted with OH; OC1-4alkyl; OCH2CH2OH; and OCHF₂; or (c) 6-membered heteroaryl selected from:

wherein each Rd is independently C_1-4alkyl, C_1-4haloalkyl, and OC_1-4alkyl; Re is selected from: C_1-4alkyl, C_1-4alkyl substituted with OH or OCH₃, and C1-4haloalkyl; X is N or O;

, wherein Ring A is a nitrogen linked monocyclic, polycyclic, bridged, spirocyclic or fused heterocycloalkyl selected from:

and each R^c is independently halo or CH3; or

nitrogen linked monocyclic, polycyclic, spirocyclic heterocycloalkyl selected from:

Rh is C1-4alkyl; R' is selected from:

n is 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R¹ is

3. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

(i) R¹ is

or,

4. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

(i) X is O; or

(ii) X is N.

5. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

(i) n is 0; or

(ii) n is 1, or

(iii) n is 2.

6. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R⁵ is:

7. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

8. A compound of claim 1 selected from the group consisting of:

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5- methyl-4-(methylsulfonyl)picolinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5- (methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4- (methylsulfonyl)picolinamide;

(racemic)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-4-(l -hydroxy ethyl)-5-methylpicolinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4- ((*R)-1 -hydroxy ethyl)-5-methylpicolinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4- ((*S)-l-hydroxyethyl)-5-methylpicolinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-5-methyl-4-(methylsulfonyl)picolinamide;

N-((2-(6-((3a,4a,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((la,5a)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-(2 -methoxy ethyl)piperazin-l-yl)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(methyl(2-morpholinoethyl)amino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(2-(2 -hydroxy ethyl)morpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(4-hydroxy-6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(methyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(3-methoxy-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-(N-((2-(6-(3-(methoxymethyl)-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide; (S)-N-((2-(6-(2-(hydroxymethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(3-hydroxy-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-N-((2-(6-(3-methylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5-

(methylsulfonyl)nicotinamide;

(S)-N-((2-(6-(3-hydroxypyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-

(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(3-(hydroxymethyl)-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-3 -hydroxy -4-methylpyrrolidin-l-yl)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((trans)-3-hy droxy-4-methylpyrrolidin-l-yl)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(2-(hy droxymethyl)morpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-5-(methylsulfonyl)-N-((2-(6-(((l,2,4,4-tetramethyl-5-oxopyrrolidin-2- yl)methyl)amino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(6-(3-(4-methyl-4-oxido-l,4-azaphosphinan-l-yl)azetidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-N-((2-(6-(((4-(cy cl opropylmethyl)-5-oxomorpholin-2-yl)methyl)amino)pyri din-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(S)-N-((2-(6-(3 -ethyl -4-(2 -hydroxy ethyl)-5-oxo-l,4-diazepan-l-yl)pyridin-2-yl)-l, 6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(5-cyano-2-azabicyclo[3.1.1]heptan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(S)-N-((2-(6-(3-methyl-2-oxo-l,7-dioxa-3,10-diazaspiro[4.6]undecan-10-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3aR,6aR)-5-methyl-6-oxohexahydropyrrolo[3,4-b]pyrrol-l(2H)-yl)pyri din-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3aR,4S,7R,7aS)-4-methyloctahydro-2H-4,7-epoxyisoindol-2-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3aS,7aS)-5-(2,2-difluoroethyl)octahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3aR,6aS)-5-isobutyl-4-oxohexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((4-(2H-tetrazol-2-yl)butyl)amino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2R,5S)-5-(hydroxymethyl)-2,4-dimethylpiperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(S)-N-((2-(6-(methyl(l-(methylcarbamoyl)pyrrolidin-3-yl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3R,4R)-3-(hydroxymethyl)-4-(pyri din-2 -yl)pyrrolidin-l-yl)pyri din-2 -yl)-l, 6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((3S,4S)-4-(dimethylamino)tetrahydrofuran-3-yl)(methyl)amino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-N-((2-(6-(3-(2-(ethyl(methyl)amino)-2-oxoethoxy)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(S)-N-((2-(6-((2-hydroxypropyl)(propyl)amino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(3-cyclopropyl-3-hydroxyazetidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-5-(methylsulfonyl)-N-((2-(6-(6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidin-10-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)nicotinamide;

5-(methylsulfonyl)-N-((2-(6-(3-(trifluoromethyl)-5,6-dihydroimidazo[l,5-a]pyrazin-

7(8H)-yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(6-(3-(tert-butyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((3-fluorooxetan-3-yl)methyl)amino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemmic)-N-((2-(6-(5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(l -imino-1 -oxido-lX⁶-thi omorpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((2-((dimethyl(oxo)-V-sulfaneylidene)amino)ethyl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-( 1 -(isopropylimino)- 1 -oxido- 1 /J’-thi omorphol i no)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(l-acetamido-5,6-dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(3-fluoroazetidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide;

(Racemic)-N -((2-(6-(7, 7 -difluoro-3 -azabicy clo [4.1.0]heptan-3 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

5-(methylsulfonyl)-N-((2-(6-(4-(methylsulfonyl)piperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)nicotinamide; N-((2-(6-(4-hydroxy-4-(trifluoromethyl)piperi din-l-yl)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-5-(methylsulfonyl)-N-((2-(6-(quinuclidin-3-ylamino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(6-((2-(lH-imidazol-l -yl)ethyl)amino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-isopropyl-3-oxopiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-

5-(methylsulfonyl)nicotinamide;

5-(methylsulfonyl)-N-((2-(6-(5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridin-2(lH)- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

(Racemic)-N-((2-(6-(3-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)piperidin-l-yl)pyridin-

2-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-N-((2-(6-((l-methyl-2-oxoazepan-3-yl)amino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-((7-oxaspiro[3.5]nonan-l-yl)amino)pyridin-2-yl)-l,6-naphthyridin-

7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-N-((2-(6-(2-(3-methylisoxazol-5-yl)pyrrolidin-l -yl)pyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-5-(methylsulfonyl)-N-((2-(6-(2-(pyridin-3-yl)morpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(6-(4-(6-(hydroxymethyl)pyridin-3-yl)piperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-5-(methylsulfonyl)-N-((2-(6-((l-(tetrahydro-2H-pyran-4- yl)ethyl)amino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

(S)-N-((2-(6-(2-(methylcarbamoyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-(2 -hydroxy ethyl)piperi din- l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-5-(methylsulfonyl)-N-((2-(6-(l-oxo-2,7-diazaspiro[4.5]decan-7-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(6-((cis)-l,l-dioxidohexahydro-5H-thieno[2,3-c]pyrrol-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((4-isopropyl-4H-l,2,4-triazol-3-yl)methyl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(([l,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-((dimethylamino)methyl)-4-hydroxypiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-((l-(lH-l,2,4-triazol-l-yl)propan-2-yl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(3-(hydroxymethyl)-3-methylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-N-((2-(6-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(2-(methoxymethyl)-7, 8-dihydro-4H-pyrazolo[ 1 , 5-a] [ 1 ,4]diazepin-5(6H)- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(7-methyl-2,7-diazaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((l-(methoxymethyl)-2-oxabicyclo[2.1. l]hexan-4-yl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-5-(methylsulfonyl)-N-((2-(6-(4-(((tetrahydrofuran-2- yl)methyl)amino)piperidin-l -yl)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)nicotinamide;

N-((2-(6-(((l-(hydroxymethyl)cyclopropyl)methyl)(methyl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(7-methyl-6-oxa-2-azaspiro[3.4]octan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-5-(methylsulfonyl)-N-((2-(6-((5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-6- yl)amino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

(Racemic)-N-((2-(6-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((2-methyl-2-morpholinopropyl)amino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(2 -methyl-l-oxidothiomorpholino)pyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(((2,3-dihydrofuro[2,3-c]pyridin-3-yl)methyl)amino)pyridin-2-yl)-

1.6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(4-hydroxy-2-methylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-5-(methylsulfonyl)-N-((2-(6-((l-(oxetan-3-yl)pyrrolidin-3-yl)amino)pyridin-2-yl)-

1.6-naphthyridin-7-yl)methyl)nicotinamide;

(Racemic)-N-((2-(6-(3-methyl-5-oxopiperazin-l -yl)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3-(2 -methyl-lH-imidazol-1 -yl)propyl)amino)pyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-(cyclobutanecarbonyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide;

N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide; (S)-5-(methylsulfonyl)-N-((2-(6-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(lH)- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(6-(((6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazin-3-yl)methyl)amino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(3-hydroxy-4,4-dimethoxypiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(ethyl((tetrahydrofuran-2-yl)methyl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((2-(4-acetylpiperazin-l-yl)ethyl)amino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-(2-(dimethylamino)-2-oxoethyl)-4-hydroxypiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((2-(dimethylamino)-2-oxoethyl)amino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((l-(3-cyanopropyl)piperidin-4-yl)amino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

5-(methylsulfonyl)-N-((2-(6-((3-(2-oxopyrrolidin-l-yl)propyl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)nicotinamide;

(Racemic)-N-((2-(6-(4-hydroxy-3-(pyrrolidin-l-ylmethyl)piperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((2-(2-oxabicyclo[2.1.1]hexan-l-yl)ethyl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(3 -methoxy azetidin-1 -yl)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5- (methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(4-methoxy-3,3-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((((cis)-3-(dimethylamino)cyclobutyl)methyl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(((l,4-oxathian-2-yl)methyl)amino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((l-(methoxymethyl)-2-oxabicyclo[2.1. l]hexan-4-yl)methyl)amino)pyri din-2 - yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-N-((2-(6-(6-(hydroxymethyl)-2,2-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(3-(2H-tetrazol-5-yl)azetidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(6-(methoxymethyl)-2,2-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(([l, 3]dioxolo[4, 5-b]pyridin-6-ylmethyl)amino)pyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-N-((2-(6-((l-(dimethylamino)propan-2-yl)amino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-cyanopiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide;

(S)-N-((2-(6-(2-(dimethylcarbamoyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(methyl(l -methylpiperidin-4-yl)amino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(ethyl(2-morpholinoethyl)amino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)- 5-(methylsulfonyl)nicotinamide;

5 -(methyl sulfonyl)-N-((2-(6-(( 1 R, 5 S)-8-oxo- 1 , 5 ,6, 8-tetrahy dro-2H- 1,5- methanopyrido[l,2-a][l,5]diazocin-3(4H)-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)nicotinamide;

(Racemic)-N-((2-(6-(3,3-dimethyl-l-oxohexahydroimidazo[l,5-a]pyrazin-7(lH)- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

5-chloro-N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)pyrimidine-2-carboxamide;

N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(trifluoromethyl)picolinamide;

N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-iodopicolinamide;

N-((2-(6-((3a,4a,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2 -methyl -6-(methylsulfonyl)isonicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4- (2-hydroxypropan-2-yl)-5-methylpicolinamide;

N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2-(methylsulfonyl)isonicotinamide;

N-((2-(6-((3a,5a)-4-hydroxy-3,4,5-trimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(*R)-N-((2-(6-(2-(methoxymethyl)pyrrolidin-l -yl)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(*S)-N-((2-(6-(2-(methoxymethyl)pyrrolidin-l-yl)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-(4-methylpiperazin-l -yl)piperidin-l-yl)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-5-((*R)-l -hydroxy ethyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-((*S)-l-hydroxyethyl)nicotinamide;

4-acetyl-5-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)picolinamide;

N-((2-(6-((2-(dimethylamino)ethyl)(methyl)amino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-3,5-dimethylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-

5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-(dimethylamino)piperidin-l-yl)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)- 5-(methylsulfonyl)nicotinamide;

N-((2-(6-(l,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(3-(dimethylamino)pyrrolidin-l -yl)pyri din-2 -yl)-l, 6-naphthyri din- 7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((2 -hydroxy ethyl)(methyl)amino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)- 5-(methylsulfonyl)nicotinamide;

N-((2-(6-((2 -hydroxy -2 -methylpropyl)(methyl)amino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(methyl(l-methylpyrrolidin-3-yl)amino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(3-(methylamino)pyrrolidin-l -yl)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

(R)-N-((2-(6-(2-(hydroxymethyl)pyrrolidin-l-yl)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2 -methyl -6-(methylsulfonyl)isonicotinamide;

(Racemic)-N-((2-(6-(3-aminopyrrolidin-l -yl)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(3,3-dimethylpiperazin-l-yl)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5- (methylsulfonyl)nicotinamide;

N-((2-(6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

5 -chloro-N -((2-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)- 1 , 6-naphthyri din-7 - yl)methyl)-4-(2-hydroxypropan-2-yl)picolinamide;

N-((2-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)nicotinamide;

(Racemic)-N-((2-(6-(2-(aminomethyl)pyrrolidin-l -yl)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-5- ((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2-(methylsulfonyl)isonicotinamide;

N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2-((2 -hydroxy ethyl)sulfonyl)isonicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-4- ((*R)-1 -hydroxy ethyl)picolinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-4- ((* S)- 1 -hydroxy ethyl)picolinamide; (Racemic)-N-((2-(6-(3-amino-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisonicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-6- methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-4-(methylsulfonyl)picolinamide;

N-((2-(6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisonicotinamide;

(Racemic)-N-((2-(6-(4-hydroxy-2,2-dimethylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((*R)-l -hydroxy ethyl)nicotinamide;

N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((*S)-l-hydroxyethyl)nicotinamide;

1-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)phenyl)-l, 6-naphthyri din-7-yl)methyl)-lH- pyrrol e-3 -carb oxami de;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-l- (methylsulfonyl)-lH-pyrrole-3-carboxamide;

4, 5-di chi oro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-l-(isopropylsulfonyl)-lH-pyrrole-3-carboxamide;

N-((2-(6-((3a, 4β, 5a))-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)thiophene-2-carboxamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-l- methyl-5-(methylsulfonyl)-lH-pyrazole-4-carboxamide;

N-((2-(3-chloro-4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-

2-yl)-l, 6-naphthyri din-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-methylpyridin- 2-yl)-l, 6-naphthyri din-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3 a, 4β, 5 a)-4-hy droxy-3 , 5 -dimethylpiperidin- 1 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- ((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-6- methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-methylpyridin- 2-yl)-l, 6-naphthyri din-7-yl)methyl)-5-(2-hydroxypropan-2-yl)nicotinamide; N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3 a, 4β, 5 a)-4-hy droxy-3 , 5 -dimethylpiperidin- 1 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3 a, 4β, 5 a)-4-hy droxy-3 , 5 -dimethylpiperidin- 1 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-5- ((2 -hydroxy ethyl)sulfonyl)-6-methylnicotinamide;

N-((2-(4-fluoro-6-((3 a, 4β, 5 a)-4-hy droxy-3 , 5 -dimethylpiperidin- 1 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide;

5 -((3 , 3 -difluoropropyl)sulfonyl)-N-((2-(4-fluoro-6-(4, 7 -diazaspiro[2.5 ] octan-7 - yl)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-6-methylnicotinamide;

N-((2-(4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-methylpyridin-

2-yl)-l, 6-naphthyri din-7-yl)methyl)-5-((*R)-l -hydroxy ethyl)nicotinamide;

N-((2-(4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-methylpyridin-

2-yl)-l, 6-naphthyri din-7-yl)methyl)-5-((*S)-l -hydroxy ethyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-6- methyl-5-(S-methylsulfonimidoyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-5- (2-hydroxyethylsulfonimidoyl)-6-methylnicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-5- ((*R)-2-hydroxyethylsulfonimidoyl)-6-methylnicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-5- ((*S)-2 -hydroxy ethylsulfonimidoyl)-6-methylnicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-5- (S-methylsulfonimidoyl)nicotinamide;

N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-6- methyl-5-((*R)-S-methylsulfonimidoyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-6- methyl-5-((*S)-S-methylsulfonimidoyl)nicotinamide;

N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l, 6-naphthyri din-7-yl)methyl)-

5-(methylsulfonyl)-6-(trifluoromethyl)nicotinamide;

6-methyl-5-(methylsulfonyl)-N-((2-(6-(6-oxo-4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-

2-yl)-l, 6-naphthyri din-7-yl)methyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-5- (2 -hydroxy ethylsulfonimidoyl)nicotinamide;

N-((2-(6-((3a, 4β, 5a))-4-(hydroxymethyl)-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-

1, 6-naphthyri din-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-5-(methylsulfonyl)-N-((2-(6-(5-oxo-2-(trifluoromethyl)morpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

(*R)-N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

(*S)-N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-5-(methylsulfonyl)-N-((2-phenyl-l,6-naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(6-(2,6-dimethyl-3-oxomorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)- 6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-5-(methylsulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4- yl)oxy)pyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(6-(2,2-dimethyl-3-oxomorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)- 6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4-amino-3,3-difluoropiperi din-l-yl)-4-fluoropyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(6-((trans)-2-methyl-6-(trifluoromethyl)morpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(6-((cis)-2-methyl-6-(trifluoromethyl)morpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(4-fluoro-6-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(l-methyl-6-oxo-2-(2,2,6,6-tetramethylmorpholino)-l,6- dihydropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(2-((cis)-2,6-dimethylmorpholino)-l -methyl -6-oxo-l, 6-dihy dropyrimidin-4-yl)- l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(6-(4-methyl-5-oxo-4,6-diazaspiro[2.4]heptan-6-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(4,4-dimethyl-2-oxoimidazolidin-l -yl)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5- ((*R)-2-hydroxyethylsulfonimidoyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5- ((*S)-2 -hydroxy ethylsulfonimidoyl)nicotinamide;

N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-

5-(methylsulfonyl)-6-(trifluoromethyl)nicotinamide;

N-((2-(2-(2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6-naphthyridin-

7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-

6-(difluoromethyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(2-(l,3-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-isopropoxypyri din-3 -yl)-l,6-naphthyri din-7-yl)methyl)-6-methyl-5- (methylsulfonyl)nicotinamide;

6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

6-methyl-5-(methylsulfonyl)-N-((2-(2-(2-oxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

6-methyl-N-((2-(2-(l-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(2-(l -methyl -2-oxo-l, 3, 8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-

1.6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(2-(6,8-dioxo-2,5,7-triazaspiro[3.4]octan-2-yl)pyrimidin-4-yl)-l,6-naphthyridin-

7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-5-(methylsulfonyl)-N-((2-(2-(6-oxo-2,5,7-triazaspiro[3.4]octan-2- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(2-(l,3-dimethyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)pyrimidin-4- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(2-(2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-

7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(2-(6,8-dioxo-5,7,l l-triazadispiro[2.0.44.43]dodecan-l l-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-6- methoxynicotinamide;

6-methyl-N-((2-(2-(6-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(l-methyl-2-((trans)-2-methyl-6-(trifluoromethyl)morpholino)-6-oxo-

1.6-dihydropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-

(methylsulfonyl)nicotinamide;

N-((2-(2-(6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

(*R)-N-((2-(2-(2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

(*S)-N-((2-(2-(2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-

5-((2 -hydroxy ethyl)sulfonyl)-6-(trifluoromethyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-l - (2 -hydroxy ethyl)-6-oxo-l,6-dihydropyridine-3-carboxamide;

6-methyl-N-((2-(2-((6*R)-6-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

6-(difluoromethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)nicotinamide; N-((2-(2-(4-amino-3,3-difluoropiperidin-l-yl)pyrimidin-4-yl)-l,6-naphthyri din-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(2-(4-acetamido-3,3-difluoropiperidin-l-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

(*R)-6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(*S)-6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(2-((6*S)-6-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((2a, 4β, 6a)-2, 6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-5-methylpyri din-3 - yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

(*R)-N-((2-(2-(l,3-dimethyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)pyrimidin-4- yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

(*S)-N-((2-(2-(l,3-dimethyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)pyrimidin-4- yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(2-((5*R,6*R)-6-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(2-((5*S,6*S)-6-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

(*R)-N-((2-(2-(6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4- yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

(*S)-N-((2-(2-(6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)- l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(2-((5*R,6*R)-6-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

6-methyl-N-((2-(2-((5*S,6*S)-6-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide;

5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methylnicotinamide;

5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)nicotinamide;

(*R)-N-((2-(2-(6,8-dioxo-5, 7,1 l-triazadispiro[2.0.44.43]dodecan-l l-yl)pyrimidin-4-yl)- l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

(*S)-N-((2-(2-(6,8-dioxo-5, 7,1 l-triazadispiro[2.0.44.43]dodecan-l l-yl)pyrimidin-4-yl)- l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((2a, 4a, 6a)-2, 6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4-methylpyri din-3 - yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((2a, 4β, 6a)-2, 6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4-methylpyri din-3 - yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((2a, 4β, 6a)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((2a, 4β, 6a)-2, 6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-2-methylpyri din-3 - yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

4-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)picolinamide;

N-((2-(2-((trans)-2,4-dioxo-6-(trifluoromethyl)-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-

(methylsulfonyl)nicotinamide;

N-((2-(2-((cis)-2,4-dioxo-6-(trifluoromethyl)-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-

(methylsulfonyl)nicotinamide;

N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-5-(methylsulfonyl)-N-((2-(6-(oxetan-3-yloxy)pyridin-3-yl)-l,6-naphthyridin-

7-yl)methyl)nicotinamide;

(*R)-N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyrimidin-4-yl)-l,6-naphthyridin-

7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

(*S)-N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyrimidin-4-yl)-l,6-naphthyridin- 7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((2a, 4β, 6a)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((2a, 4a, 6a)-2, 6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-5-methylpyri din-3 - yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-(((2a, 4a, 6a)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

6-methyl-5-(methylsulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4- yl)oxy)pyridazin-3-yl)-l,6-naphthyridin-7-yl)methyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-6- methoxy-5-(methylsulfonyl)nicotinamide;

4-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)picolinamide;

4-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)picolinamide;

4-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)picolinamide;

N-((2-(2-((5*R,6*R,9*S)-6,9-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-

(methylsulfonyl)nicotinamide;

N-((2-(2-((5*S,6*S,9*R)-6,9-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-

(methylsulfonyl)nicotinamide;

N-((2-(2-((5*R,6*S,9*R)-6,9-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl-5-

(methylsulfonyl)nicotinamide; N-((2-(2-((5*S,6*R,9*S)-6,9-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)-l, 6-naphthyri din-7-yl)methyl)-6-methyl-5- (methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4- ((2 -methoxy ethyl)sulfonyl)picolinamide; and pharmaceutically acceptable salts or stereoisomers thereof.

9. A compound of claim 1 selected from the group consisting of:

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-5-

((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-6- methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(4-fluoro-6-((3a,4β,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-

((2 -hydroxy ethyl)sulfonyl)nicotinamide;

N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-6- methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide;

N-((2-(6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide;

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-5-

((2 -hydroxy ethyl)sulfonyl)-6-methylnicotinamide;

N-((2-(4-fluoro-6-((3a, 4β, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-6- methyl-5-((*S)-S-methylsulfonimidoyl)nicotinamide; and 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methylnicotinamide; and pharmaceutically acceptable salts and stereoisomers thereof.

10. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of the preceding claims and at least one pharmaceutically acceptable excipient.

11. A compound according to any one of claims 1 to 9 for use in therapy.

12. A compound according to any one of claims 1 to 9 for use in the treatment of a SMARCA4 deficient cancer.

13. The compound for the use of claim 12, wherein the SMARCA4 deficient cancer is SMARCA4 deficient non-small cell lung cancer (NSCLC).

14. A compound according to any one of claims 1 to 9 for use in the treatment of a disease state or condition mediated by the SMARCA2 protein.

15. The compound for the use of claim 14, wherein the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC).

16. Use of a compound as defined in any one of claims 1 to 9 for the manufacture of a medicament for the treatment of cancer or NSCLC.

17. An in vitro method of modulating SMARCA2 activity comprising contacting the SMARCA2 protein, or portion thereof, with a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9.

18. A method for the treatment of a SMARCA4 deficient cancer, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 to 9.

19. The method of claim 18, wherein the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.

20. A method for the treatment of a disease state or condition mediated by the SMARCA2 protein, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 to 9.

21. The method of claim 20, wherein the disease or condition is selected from a cancer or NSCLC.

22. The method of any one of claims 18 to 21, wherein the subject is a mammal.