HK1208439B - 5-azaindazole compounds and methods of use - Google Patents

Description

5-Azaindazole compounds and methods of use thereof

Technical Field

The present invention generally relates to 5-azaindazole compounds, i.e., inhibitors, for treating conditions mediated by Pim kinases (Pim-1, Pim-2, and/or Pim-3), and thus as cancer therapeutics. The present invention also relates to compositions, more specifically pharmaceutical compositions comprising these compounds, and methods of using the compositions, alone or in combination, to treat various forms of cancer and hyperproliferative disorders, as well as methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells or related pathological conditions.

Background Art

The Pim kinases are a family of three highly related serine and threonine protein kinases encoded by the genes Pim-1, Pim-2, and Pim-3. The gene name is derived from the phrase Proviral Insertion ( M oloney), which is a common integration site of murine Moloney virus, where the insertion results in overexpression of Pim kinases and a marked acceleration of T-cell lymphoma de novo or tumorigenesis in a transgenic Myc-driven lymphoma model (Cuypers et al. (1984) Cell, vol. 37(1) pp. 141-50; Selten et al. (1985) EMBO J. vol. 4(7) pp. 1793-8; van der Lugt et al. (1995) EMBO J. vol. 14(11) pp. 2536-44; Mikkers et al. (2002) Nature Genetics, vol. 32(1) pp. 153-9; van Lohuizen et al. (1991) Cell, vol. 65(5) pp. 737-52). These experiments showed synergy with the oncogene c-Myc and suggested that inhibition of Pim kinases could have therapeutic benefit.

Mouse genetics suggest that antagonizing the Pim kinases may have an acceptable safety profile; Pim 1-/-, Pim-2-/-, Pim-3-/- knockout mice are viable, although slightly less viable than wild-type littermates (Mikkers et al. (2004) Mol Cell Biol vol. 24(13) pp. 6104-154). The three genes produce six protein isoforms that contain a protein kinase domain and apparently no identifiable regulatory domain. All six isoforms are constitutively active protein kinases that do not require post-translational modification for activity, so the Pim kinases are primarily regulated at the transcriptional level (Qian et al. (2005) J Biol Chem, vol. 280(7) pp. 6130-7). Pim kinase expression is highly inducible by cytokines and growth factor receptors and the Pims are direct transcriptional targets of Stat proteins, which include Stat3 and Stat5. For example, Pim-1 requires gp130-mediated Stat3 proliferation signaling (Aksoy et al. (2007) Stem Cells, vol. 25(12) pp. 2996-3004; Hirano et al. (2000) Oncogene vol. 19(21) pp. 2548-56; Shirogane et al. (1999) Immunity vol. 11(6) pp. 709-19).

The Pim kinases function in cell proliferation and survival pathways parallel the PI3k/Akt/mTOR signaling axis (Hammerman et al. (2005) Blood vol. 105 (11) pp. 4477-83). In fact, several phosphorylation targets of the PI3k axis, including Bad and eIF4E-BP1, are cell growth and apoptosis regulators and are also phosphorylation targets of Pim kinases (Fox et al. (2003) Genes Dev vol. 17 (15) pp. 1841-54; Macdonald et al. (2006) Cell Biol vol. 7 pp. 1; Aho et al. (2004) FEBS Letters vol. 571 (1-3) pp. 43-9; Tamburini et al. (2009) Blood vol. 114 (8) pp. 1618-27). Pim kinases can affect cell survival because phosphorylation of Bad increases Bcl-2 activity and thus promotes cell survival. Similarly, phosphorylation of eIF4E-BP1 by mTOR or Pim kinases leads to inhibition of eIF4E, promoting mRNA translation and cell growth. In addition, Pim-1 has been suggested to promote cell cycle progression by phosphorylating CDC25A, p21, and Cdc25C (Mochizuki et al. (1999) J Biol Chem vol. 274 (26) pp. 18659-66; Bachmann et al. (2006) Int J Biochem Cell Biol vol. 38 (3) pp. 430-43; Wang et al. (2002) Biochim Biophys Acta vol. 1593 (1) pp. 45-55).

In transgenic mouse models, Pim kinases have been shown to synergize with c-Myc-driven and Akt-driven tumors (Verbeek et al. (1991) Mol Cell Biol vol. 11 (2) pp. 1176-9; Allen et al. Oncogene (1997) vol. 15 (10) pp. 1133-41; Hammerman et al. (2005) Blood vol. 105 (11) pp. 4477-83). Pim kinases are involved in the transforming activity of oncogenes identified in acute myeloid leukemia (AML), including Flt3-ITD, BCR-abl, and Tel-Jak2. Expression of these oncogenes in BaF3 cells results in upregulation of Pim-1 and Pim-2 expression, which leads to IL-3-independent growth, and subsequent Pim inhibition causes apoptosis and cell growth arrest (Adam et al. (2006) Cancer Research 66(7): 3828-35). Pim overexpression and deregulation have also been shown to be a common event in a variety of hematopoietic cancers, including leukemias and lymphomas (Amson et al. (1989) Proc Natl Acad Sci USA 86(22)8857-61); Cohen et al. (2004) Leuk Lymphoma 45(5)951-5; Hüttmann et al. (2006) Leukemia 20(10)1774-82) and multiple myeloma (Claudio et al. (2002) Blood 100(6)2175-86). Pim 1 has been shown to be overexpressed and associated with prostate cancer progression (Cibullet et al. (2006) J Clin Pathol 59(3)285-8; Dhanasekaran et al. (2001) Nature 412 (6849) 822-6). In mouse models, Pim 1 expression increases with disease progression (Kim et al. (2002) Proc Natl Acad Sci USA 99 (5) 2884-9). Pim-1 has been reported to be the most highly expressed mRNA in a subset of human prostate tumor samples with a c-Myc-driven gene signature (Ellwood-Yen et al. (2003) Cancer Cell 4 (3) 223-38). Pim-3 has also been shown to be overexpressed and to have a functional role in pancreatic cancer and hepatocellular carcinoma (Li et al. (2006) Cancer Research 66 (13) 6741-7; Fujii et al. (2005) Int J Cancer, 114 (2) 209-18).

In addition to oncology therapeutic and diagnostic applications, Pim kinases may play a role in normal immune system function and Pim inhibition may treat a variety of different immunological conditions, including inflammation, autoimmune diseases, allergies, and immunosuppression in organ transplantation (Aho et al. (2005) Immunology 116(1):82-8).

Summary of the Invention

The present invention relates to 5-azaindazole compound inhibitors of formula I for use in the treatment of disorders mediated by Pim kinases (Pim-1, Pim-2 and/or Pim-3).

The compound of formula I has the pyrazolo[4,3-c]pyridine(5-azaindazole) structure:

and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof. Various substituents, including R ¹ and R ^2, are as defined herein.

One aspect of the present invention is a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, glidant, diluent or excipient. The pharmaceutical composition may further comprise a chemotherapeutic agent.

The present invention includes methods for treating diseases or disorders mediated by Pim kinases, comprising administering to a patient suffering from the disease or disorder a therapeutically effective amount of a compound of Formula I, wherein the disease or disorder is selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorders. The method further comprises administering an additional therapeutic agent selected from chemotherapeutic agents, anti-inflammatory agents, immunomodulators, neurotropic factors, drugs for treating cardiovascular disease, drugs for treating liver disease, antiviral agents, drugs for treating blood disorders, drugs for treating diabetes, and drugs for treating immunodeficiency disorders.

The present invention includes the use of a compound of formula I in the preparation of a medicament for treating cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorders, wherein the medicament mediates Pim kinases.

The present invention includes kits for treating conditions mediated by Pim kinases, comprising: a) a first pharmaceutical composition comprising a compound of Formula I; and b) instructions for use.

The present invention includes compounds of Formula I for use as medicaments and for treating diseases or disorders selected from cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction and neurological disorders, and diseases or disorders mediated by Pim kinases.

The present invention includes processes for preparing compounds of formula I.

DETAILED DESCRIPTION

Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structures and chemical formulae. While the present invention is described in conjunction with the enumerated embodiments, it should be understood that they are not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to encompass all variations, modifications, and equivalent forms that may be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize that a variety of methods and materials similar to or equivalent to the methods and materials described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. If one or more of the references, patents, and similar materials introduced herein differ or conflict with the present application (including but not limited to defined terms, term usage, described techniques, etc.), the present application shall prevail. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described in this application can be used to implement or test the present invention, appropriate methods and materials will be described below. All publications, patent applications, patents, and other references mentioned in this application are incorporated herein by reference in their entirety. Unless otherwise stated, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

When specifying the number of substituents, the term "one or more" refers to the range from one substituent to the maximum possible number of substituents, that is, the replacement of one hydrogen by a substituent to the replacement of all hydrogens. The term "substituent" represents an atom or group of atoms that replaces a hydrogen atom on the parent molecule. The term "substituted" means that the specified group carries one or more substituents. When any group can carry multiple substituents and various possible substituents are provided, the substituents are independently selected and do not need to be the same. The term "unsubstituted" means that the specified group does not carry a substituent. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from possible substituents. When specifying the number of substituents, the term "one or more" refers to the range from one substituent to the maximum possible number of substituents, that is, the replacement of one or more, for example, two, three or four hydrogens (including replacement of all hydrogens) by a substituent.

As used herein, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon radical having 1 to 12 carbon atoms (C ₁ -C ₁₂ ), wherein the alkyl radical may be optionally substituted independently with one or more substituents as described below. In another embodiment, the alkyl radical has 1 to 8 carbon atoms (C ₁ -C ₈ ), or has 1 to 6 carbon atoms (C ₁ -C ₆ ). Examples of alkyl groups include, but are _not limited to, methyl (Me, _-CH3 ), ethyl (Et, _-CH2CH3 ), 1-propyl (n-Pr, n _- propyl _{, -CH2CH2CH3} ), 2-propyl (i-Pr, isopropyl, -CH( _CH3 ) ₂ ), 1-butyl (n-Bu, n- _butyl , _{-CH2CH2CH2CH3 )} , 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH( _CH3 ) ₂ ) _, 2 _- butyl (s-Bu, sec-butyl, -CH( _CH3 ) _CH2CH3 ), ₂ -methyl-2-propyl (t-Bu, tert-butyl, -C( _CH3 ) ₃ ) _{, 1} -pentyl ( _{n -} pentyl, _{-CH2CH2CH2CH2CH3} ), 2-pentyl (-CH( _CH3 ) _{CH2 3-} Pentyl (-CH( _{CH2CH3) 2} ), 2-Methyl-2-butyl (-C( _CH3 ) _2CH2CH3 ), 3-Methyl- ₂ -butyl ( _-CH ( _CH3 )CH( _{CH3 ) 2 )} , 3-Methyl- ₁ -butyl ( _-CH2CH2CH ( _CH3 ) ₂ ), 2-Methyl-1-butyl ( _-CH2CH ( _{CH3 ) CH2CH3} ), 1 _{- hexyl} (-CH2CH2CH2CH2CH2CH3 ₎ , 2 _- hexyl ₍ -CH( _CH3 )CH2CH2CH2CH3), 3 _- hexyl ( _-CH ( _{CH2CH3 ) ( CH2CH2CH3 ) ) ,} 2-methyl _{- 2} -pentyl (-C( _{CH3 ) 2CH2CH2CH 3} ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ , 1-heptyl, 1-octyl, and the like.

As used herein, the term "alkylene" refers to a saturated, linear or branched divalent hydrocarbon group having 1 to 12 carbon atoms ( _C1 - _C12 ), wherein the alkylene group may be optionally substituted independently with one or more substituents described below. In another embodiment, the alkylene group has 1 to 8 carbon atoms ( _C1 - _C8 ), or 1 to 6 carbon atoms ( _C1 - _C6 ). Examples of alkylene groups include, but are _not limited to, methylene ( _-CH2- ), ethylene ( _{-CH2CH2- )} , propylene ( _-CH2CH2CH2- ), and the _like .

The term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical having 2 to 8 carbon atoms ( _C2 - _C8 ) and having at least one site of unsaturation (i.e., a carbon-carbon ^sp2 double bond), wherein the alkenyl group may be optionally substituted independently with one or more substituents described herein, and includes groups having "cis" and "trans" orientations (or "E" and "Z" orientations). Examples include, but are not limited to, ethylenyl (-CH= _CH2 ), allyl ( _-CH2CH = _CH2 ), and the like.

The term "alkenylene" refers to a straight or branched divalent hydrocarbon radical having 2 to 8 carbon atoms ( _C2 - _C8 ) and having at least one site of unsaturation (i.e., a carbon-carbon ^sp2 double bond), wherein the alkenylene radical may be optionally and independently substituted with one or more substituents described herein, and includes groups having "cis" and "trans" orientations (or "E" and "Z" orientations). Examples include, but are not limited to, vinylene (-CH=CH-), allylene ( _-CH2CH =CH-), and the like.

The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group having 2-8 carbon atoms ( _C2 - _C8 ) and at least one site of unsaturation (i.e., a carbon-carbon sp triple bond), wherein the alkynyl group may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C≡CH), propynyl (propargyl, _-CH2C≡CH ), and the like.

The term "alkynylene" refers to a straight or branched divalent hydrocarbon group having 2 to 8 carbon atoms ( _C2 - _C8 ) and at least one site of unsaturation (i.e., a carbon-carbon sp triple bond), wherein the alkynylene group may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynylene (-C≡C-), propynylene (propargylene, _-CH2C≡C- ), and the like.

The terms "carbocycle,""carbocyclyl,""carbocyclicring," and "cycloalkyl" refer to a monovalent non-aromatic saturated or partially unsaturated ring having 3 to 12 carbon atoms ( _C3 - _C12 ) as a monocycle or 7 to 12 carbon atoms as a bicycle. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms may be arranged as a bicyclo[5,6] or [6,6] system, or as a bridged system such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Spiro moieties are also included within the scope of this definition. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Carbocyclyl groups are optionally substituted independently with one or more substituents described herein.

"Aryl" refers to a monovalent aromatic hydrocarbon radical having 6 to 20 carbon atoms ( _C6 - _C20 ) derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented as "Ar" in the exemplary structures. Aryl groups include bicyclic groups containing an aromatic ring fused to a saturated, partially unsaturated ring, or an aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Aryl groups are optionally substituted independently with one or more substituents described herein.

"Arylene" refers to a divalent aromatic hydrocarbon radical having 6 to 20 carbon atoms ( _C6 - _C20 ) derived by removing two hydrogen atoms from two carbon atoms in a parent aromatic ring system. Some arylene groups are represented as "Ar" in the exemplary structures. Arylene groups include bicyclic groups containing an aromatic ring fused to a saturated, partially unsaturated ring, or an aromatic carbocyclic ring. Typical arylene groups include, but are not limited to, groups derived from benzene (phenylene), substituted benzenes, naphthyl, anthracenyl, biphenylene, indenylene, indanylene, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like. Arylene groups are optionally substituted independently with one or more substituents described herein.

The terms "heterocycle," "heterocyclyl," and "heterocyclic ring" are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in the ring) carbocyclic group having from 3 to about 20 ring atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, and the remaining ring atoms are C, wherein one or more ring atoms are optionally substituted independently with one or more substituents described below. The heterocycle may be a monocycle having from 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having from 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), such as a bicyclic [4,5], [5,5], [5,6], or [6,6] system. Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968) (especially Chapters 1, 3, 4, 6, 7, and 9); "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present) (especially Volumes 13, 14, 16, 19, and 28); and J. Am. Chem. Soc. (1960) 82: 5566. "Heterocyclyl" also includes groups in which a heterocyclic group is fused to a saturated, partially unsaturated ring, or an aromatic carbocyclic or heterocyclic ring. Examples of heterocycles include, but are not limited to, morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidin-1-yl, alkyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolyl, quinolizinyl, and N-pyridyl urea. Spiro moieties are also included within the scope of this definition. Examples of heterocyclic groups in which two ring atoms are substituted with oxo (=0) moieties are oxopyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclic groups herein are optionally substituted independently with one or more substituents described herein.

The term "heteroaryl" refers to monovalent aromatic groups of 5, 6 or 7 members, as well as fused ring systems comprising 5-20 ring atoms (wherein at least one ring is aromatic), containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The heteroaryl groups described herein are optionally substituted independently with one or more substituents described herein.

The heterocycle or heteroaryl group can be carbon-linked (carbon-linked) or nitrogen-linked (nitrogen-linked) when appropriately attached. By way of example and not limitation, a carbon-linked heterocycle or heteroaryl group is attached at the 2, 3, 4, 5, or 6 position of a pyridine; the 3, 4, 5, or 6 position of a pyridazine; the 2, 4, 5, or 6 position of a pyrimidine; the 2, 3, 5, or 6 position of a pyrazine; the 2, 3, 4, or 5 position of a furan, tetrahydrofuran, thiophene (thiofuran or thiophene), pyrrole, or tetrahydropyrrole; the 2, 4, or 5 position of an oxazole, imidazole, or thiazole; the 3, 4, or 5 position of an isoxazole, pyrazole, or isothiazole; the 2 or 3 position of an aziridine; the 2, 3, or 4 position of an azetidine; the 2, 3, 4, 5, 6, 7, or 8 position of a quinoline; or the 1, 3, 4, 5, 6, 7, or 8 position of an isoquinoline.

By way of example and not limitation, nitrogen-linked heterocycles or heteroaryls are attached at the following positions: position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole; position 2 of isoindole or isoindoline; position 4 of morpholine; and position 9 of carbazole or β-carboline.

The terms "treat" and "treatment" refer to therapeutic treatments and preventative measures, wherein the purpose is to prevent or slow down (mitigate) the development or spread of undesirable physiological changes or disorders such as cancer. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, relieving symptoms, reducing the extent of lesions, stabilizing (i.e., not worsening) the disease state, delaying or slowing the progression of the disease, improving or alleviating the disease state, and improving (partially or completely), whether these results are detectable or undetectable. "Treatment" can also mean prolonged survival compared to the expected survival of those not receiving treatment. Those in need of treatment include those already suffering from a disease or disorder and those susceptible to the disease or disorder or those for whom the disease or disorder is to be prevented.

The phrase "therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a specific disease, condition, or disorder described herein, (ii) reduces, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down to some extent and preferably stop) cancer cells from infiltrating into peripheral organs; inhibit (i.e., slow down to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate one or more symptoms associated with cancer to some extent. A drug can be cytostatic and/or cytotoxic if it prevents the growth of existing cancer cells and/or kills existing cancer cells. For cancer treatment, efficacy can be measured, for example, by evaluating time to disease progression (TTP) and/or determining a response rate (RR).

The term "cancer" refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancy. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma); lung cancer, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung, and squamous cell carcinoma of the lung; peritoneal cancer; hepatocellular carcinoma; gastric or stomach cancer, including gastrointestinal cancer; pancreatic cancer; glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer; hepatoma; breast cancer; colon cancer; rectal cancer; colorectal cancer; endometrial or uterine cancer; salivary gland cancer; kidney cancer or renal cancer; prostate cancer; vulval cancer; thyroid cancer; hepatic carcinoma; anal cancer; penile cancer; and head and neck cancer.

"Chemotherapeutic agents" are compounds that can be used to treat cancer, regardless of their mechanism of action. Chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, spindle poison plantalkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizing drugs, and kinase inhibitors. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. Examples of chemotherapeutic agents include: erlotinib (Genentech/OSI Pharm.), docetaxel (Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum (II), CAS No. 15663-27-1), carboplatin (CAS No. 41575-94-4), paclitaxel (Bristol-Myers Squibb) Oncology, Princeton, N.J.), trastuzumab (Genentech), temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentaazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide, CAS No. 85622-93-1, Schering Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethylamine,), doxorubicin (), Akti-1/2, HPPD, and rapamycin.

Other examples of chemotherapeutic agents include: oxaliplatin (Sanofi), bortezomib (Millennium Pharm.), sunitinib (SU11248, Pfizer), letrozole (Novartis), imatinib mesylate (Novartis), XL-518 (MEK inhibitor, Exelixis, WO 2007/044515), ARRY-886 (MEK inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, Wyeth), rapamycin analogs, mTOR inhibitors such as everolimus, MEK inhibitors (GDC-0973), Bcl-2 inhibitors such as navitoclax ((ABT-263) or ABT-199), lapatinib (GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR ^™ , SCH 66336, Schering Plough), sorafenib (BAY43-9006, Bayer Labs), gefitinib (AstraZeneca), irinotecan (CPT-11, Pfizer), tipifarnib (ZARNESTRA ^™ , Johnson & Johnson), ABRAXANE ^™ (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 11), vandetanib (rINN, ZD6474, AstraZeneca), chloranmbucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (Telik), thiotepa, and cyclosphosphamide alkyl sulfonates. sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethylenimine and methylamelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, and triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthyl mustard, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, mustard); nitroureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, calicheamicin γ 1I, calicheamicin ω 1I (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); anthracycline antibiotics (dynemicin, dynemicin A); bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromophore enediyne antibiotic chromophores. chromophore), aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin n), detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, daunorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenal drugs such as aminoglutethimide, mitotane, and trilostane; and folic acid supplements. acid replenisher, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, OR; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (particularly T-2 toxin, verracurin A, baculocin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");cyclophosphamide;thiotepa;6-thioguanine;mercaptopurine; methotrexate platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; novantrone; teniposide; edatrexate; daunorubicin; aminopterin; capecitabine (Roche); ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the foregoing.

The following are also included within the definition of "chemotherapeutic agent": (i) antihormonal drugs used to modulate or inhibit the effects of hormones on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifine citrate; (ii) aromatase inhibitors that inhibit the aromatase enzyme (which regulates estrogen production in the adrenal glands), such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, and dapoxetine. (iii) anti-androgen drugs, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors, such as MEK inhibitors (WO 2007/044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-α, Raf and H-Ras, such as oblimersen (Genta Inc.); (vii) ribozymes such as VEGF expression inhibitors (for example) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, and rIL-2; topoisomerase 1 inhibitors such as rmRH; (ix) anti-angiogenic drugs such as bevacizumab (Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Also included in the definition of "chemotherapeutic agent" are therapeutic antibodies, such as alemtuzumab (bevacizumab, Genentech); cetuximab (Imclone); panitumumab (Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (2C4, Genentech), trastuzumab (Genentech), and tositumomab (Corixa, GlaxoSmithKline).

Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents for use in combination with the compounds of formula I of the present invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol), cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin), ipilimumab, labetuzumab, lebrikizumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab olizumab), pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan), tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.

"Metabolites" are products produced by the metabolism of a particular compound or its salt in vivo. Metabolites of a compound can be identified using conventional techniques known in the art, and their activity can be determined using assays such as those described herein. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like of the administered compound. Thus, the present invention includes metabolites of compounds of the invention, including compounds produced by a method comprising contacting a compound of Formula I of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

The term "package insert" refers to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or precautions concerning the use of such therapeutic products.

The term "chiral" refers to molecules that have the property that their mirror image partner is non-superimposable, whereas the term "achiral" refers to molecules that are superimposable on their mirror image partner.

The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the orientation of the atoms or groups in space.

"Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereoisomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography.

"Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow those of S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its one or more chiral centers. The prefixes d and l or (+) and (-) are used to specify the sign of the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. A compound prefixed with (+) or d is right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric substances that are optically inactive. Enantiomers can be separated from a racemic mixture by chiral separation methods, such as supercritical fluid chromatography (SFC). The configurational assignment of chiral centers in the separated enantiomers may be tentative and is depicted in the structures of Tables 1 and 2 for illustrative purposes, while the stereochemistry is determined, for example, by x-ray crystallographic data.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid and base addition salts. The phrase "pharmaceutically acceptable" indicates that the substance or composition is chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal to be treated with the formulation.

The term "pharmaceutically acceptable acid addition salts" refers to those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from the classes of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid "mesylic acid", ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

The term "pharmaceutically acceptable base addition salts" refers to those formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

"Solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term " _EC50 " is half maximal effective concentration and represents the plasma concentration of a particular compound required to obtain 50% of the maximum value of a specific effect in vivo.

The term "Ki" is the inhibition constant and represents the absolute affinity of a particular inhibitor for a receptor. It is measured using a competition binding assay and is equal to the concentration at which the particular inhibitor occupies 50% of the receptors in the absence of a competing ligand (e.g., a radioligand). Ki values can be converted to pKi values in a logarithmic manner (-log Ki), where higher values indicate exponentially greater potency.

The term " _IC50 " is the half-maximal inhibitory concentration and represents the concentration of a particular compound required to achieve 50% inhibition of a biological process in vitro. _IC50 values can be converted logarithmically to _pIC50 values (-log _IC50 ), where higher values indicate exponentially greater potency. _IC50 values are not absolute values, but rather depend on experimental conditions, such as the concentration used, and can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099).

The terms "the inventive compound" and "compounds of the present invention" and "compounds of Formula I" include compounds of Formula I and stereoisomers, geometric isomers, tautomers, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs thereof.

Any formula or structure given herein, including compounds of Formula I, is also intended to represent hydrates, solvates, and polymorphs of the compound, or mixtures thereof.

The arbitrary formula or structure (comprising Formula I compound) that the application provides also contemplate the unlabeled form and isotope-labeled form of the compound of representation.Isotope-labeled compound has the structure described in the formula that the application provides, and different is that one or more atoms are replaced by the atom with selected atomic mass or mass number.The example of the isotope that can be incorporated into the compounds of this invention comprises the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to ² H (deuterium D), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.Various isotope-labeled compounds of this invention for example wherein combine radioactive isotope for example ³ H, ¹³ C and ¹⁴ C those compounds. The isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) (including drug or substrate tissue distribution assays), or in patients undergoing radioactive therapy. Deuterium-labeled or deuterium-substituted compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium can provide some therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. ¹⁸ F-labeled compounds can be used in PET or SPECT studies. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by the following procedures disclosed in the examples and the preparation methods described below, using readily available isotopically labeled reagents instead of non-isotopically labeled reagents. In addition, substitution with heavier isotopes, particularly deuterium (i.e., ² H or D), can provide some therapeutic benefits due to greater metabolic stability, such as an increase in half-life in vivo or a reduction in dosage requirements or an improvement in therapeutic index. It should be understood that deuterium in this context is considered to be a substituent in compound of formula (I). The concentration of the heavier isotope (particularly deuterium) can be defined by an isotopic enrichment factor. In the compounds of the present invention, an atom that is not specifically designated as a specific isotope is any stable isotope representing that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be a hydrogen with a natural abundance isotopic composition. Therefore, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to represent deuterium.

5-Azaindazole compounds

The present invention provides 5-azaindazole compounds of Formula I, including Formulas Ia-i, and pharmaceutical formulations thereof, which can be used to treat diseases, conditions, and/or disorders regulated by Pim kinases.

The compound of formula I has the following structure:

and its stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts, wherein:

R ¹ is a five-membered or six-membered heteroaryl group, which is optionally substituted with one or more groups independently selected from the following: F, Cl, Br, -CN, -NO ₂ , OH, C ₁ -C ₁₂ alkyl, -NH(C ₁ -C ₁₂ alkyl), -N(C ₁ -C ₁₂ alkyl) ₂ , -O(C ₁ -C ₁₂ alkyl), -S(C ₁ -C ₁₂ alkyl), -S(O) ₂ (C ₁ -C ₁₂ alkyl), -S(O) ₂ N(C ₁ -C ₁₂ alkyl) ₂ , -(C ₁ -C ₁₂ alkylene)-(C ₃ -C ₁₂ carbocyclyl), -(C ₁ -C ₁₂ alkylene)-(C ₂ -C ₂₀ heterocyclyl), -(C ₂ -C ₈ alkenylene)-(C ₃ -C ₁₂ carbocyclyl), -(C ₂ -C -C ₈ alkenylene)-(C ₂ -C ₂₀ heterocyclyl), C ₆ -C ₂₀ aryl, -(C ₆ -C ₂₀ arylene)-(C ₂ -C ₂₀ heterocyclyl), -(C ₆ -C ₂₀ arylene)-(C ₁ -C ₁₂ alkylene)-(C ₂ -C ₂₀ heterocyclyl), C ₃ -C ₁₂ carbocyclyl, C ₂ -C ₂₀ heterocyclyl and C ₁ -C ₂₀ heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CHCH ₂ NH ₂ , -CH ₂ CH(CH ₃ )NH ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CN, -CHF ₂ , -CF _3. -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NO ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , ＝O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -CH ₂ OCH ₃ , -S(O) ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and

R ² is phenyl or six-membered heteroaryl, wherein the phenyl or the six-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, -CN, -NO ₂ , OH, C ₁ -C ₁₂ alkyl, -NH(C ₁ -C ₁₂ alkyl), -N(C ₁ -C ₁₂ alkyl) ₂ , -O(C ₁ -C ₁₂ alkyl), -S(C ₁ -C ₁₂ alkyl), -S(O) ₂ (C ₁ -C ₁₂ alkyl), -S(O) ₂ N(C ₁ -C ₁₂ alkyl) ₂ , -(C ₁ -C ₁₂ alkylene)-(C ₃ -C ₁₂ carbocyclyl), -(C ₁ -C ₁₂ alkylene)-(C ₂ -C ₂₀ heterocyclyl), -O(C ₂ -C ₂₀ heterocyclyl), -NH(C ₂ -C ₂₀ heterocyclyl), -N(C ₁ -C ₁₂ alkyl)(C ₂ -C ₂₀ heterocyclyl), -(C ₂ -C ₈ alkenylene)-(C ₃ -C ₁₂ carbocyclyl), -(C ₂ -C ₈ alkenylene)-(C ₂ -C ₂₀ heterocyclyl), C ₆ -C ₂₀ aryl, -(C ₆ -C ₂₀ arylene)-(C ₂ -C ₂₀ heterocyclyl), -(C ₆ -C ₂₀ arylene)-(C ₁ -C ₁₂ alkylene)-(C ₂ -C ₂₀ heterocyclyl), C ₃ -C ₁₂ carbocyclyl, C ₂ -C ₂₀ heterocyclyl and C ₁ -C ₂₀ heteroaryl, wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CHCH ₂ NH ₂ , -CH ₂ CH(CH ₃ )NH ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CN, -CHF ₂ , -CF ₃ , -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ ,-CONHCH ₃ ,-CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NO ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -CH ₂ OCH ₃ , -S(O) ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino.

Exemplary embodiments of Formula I include R ¹ selected from the following structures:

The wavy lines represent connection points;

R ³ is selected from H, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CHCH ₂ NH ₂ , -CH ₂ CH(CH ₃ )NH. ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CN, -CF ₃ , -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -CH ₂ OCH ₃ , -S(O) ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and oxetanyl;

R ⁴ is independently selected from F, Cl, Br, I, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CHCH ₂ NH ₂ , -CH ₂ CH(CH ₃ )NH ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CN, -CF ₃ , -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ ,-CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NO ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CHF ₂ , -NHCH ₂ CF ₃ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHC(O)OCH ₂ CH ₃ , -NHC(O)OCH ₂ Cl ₃ , -NHC(O)OC ₆ H ₅ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , ＝O, —OH, —OCH ₃ , —S(O) ₂ N(CH ₃ ) ₂ , —SCH ₃ , —CH ₂ OCH ₃ , —S(O) ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino;

And n is 0, 1, 2 or 3.

Exemplary embodiments of compounds of Formula I include R ² being a six-membered heteroaryl having the structure:

The wavy lines represent connection points;

^Xa is N or ^CRa ;

X ^b is N or CR ^b ;

X ^c is N or CR ^c ;

^Xd is N or ^CRd ;

wherein 0 or 1 of X ^a , X ^b , X ^c and X ^d is N;

^Ra , ^Rb , ^Rc and ^Rd are independently selected from H, _C2 - _C20 heterocyclyl and -NH( _C2 - _C20 heterocyclyl), wherein the heterocyclyl is optionally substituted with one or more groups selected from F, Cl, Br, I, _-CH3 , _-CH2CH3 , -CH( _{CH3 ) 2} , -C( _CH3 ) ₃ , -CH2CH ₍ CH3 _{) 2} , _{-CH2NH2 , -CH2NHCH3} , _{-CH2CH2NH2 ,} -CH2CHCH2NH2, _{-CH2CH ( CH3 )} NH2, _{-CH2OH , -CH2CH2OH} , _-C ( _CH3 ) _2OH , -CH(OH ₎ CH( _{CH3 ) 2 ,} -C _{( CH3} ) _2CH2 OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CN, -CF ₃ , -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NO ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CHF ₂ , -NHCH ₂ CF ₃ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHC(O)OCH ₂ CH ₃ , -NHC(O)OCH ₂ Cl ₃ , -NHC(O)OC ₆ H ₅ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , ＝O, -OH, -OCH ₃ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -CH ₂ OCH ₃ , -S(O) ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino;

or wherein X ^a is CR ^a and X ^b is CR ^b , and ^Ra and R ^b form a six-membered ring.

Exemplary embodiments of compounds of Formula I include R ² selected from the following structures:

Exemplary embodiments of compounds of Formula I include R ² selected from the following structures:

Wherein R ^e is selected from H, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CHCH ₂ NH ₂ , -CH ₂ CH(CH ₃ )NH. ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CN, -CF ₃ , -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH) _CH3 , _-CONH2 , _-CONHCH3 , -CON(CH3) ₂ , -C( _CH3 ) _2CONH2 , -S(O _{) 2N} ( _CH3 ) ₂ , _-SCH3 , _-CH2OCH3 , -S(O _{) 2CH3 ,} cyclopropyl, cyclobutyl, cyclopentyl, _cyclohexyl , cycloheptyl, and oxetanyl.

Exemplary embodiments of compounds of Formula I include those wherein ^Ra is a heterocyclic group selected from the following structures:

wherein the heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of F, -OH, -OCH ₃ , =O, -NH ₂ , -CH ₃ , -CH ₂ CH ₃ and oxetan-3-yl.

Exemplary embodiments of compounds of Formula I include ^R2 being phenyl, optionally substituted with one or more groups selected from the group consisting of F, Cl, Br, _-CH3 , and _-NH2 .

Exemplary embodiments of compounds of Formula I include the structure of Formula Ia:

Exemplary embodiments of compounds of Formula I include the structure of Formula Ib:

Exemplary embodiments of compounds of Formula I include the structure of Formula Ic:

Exemplary embodiments of compounds of Formula I include structures of Formula Id:

Exemplary embodiments of compounds of Formula I include compounds of Tables 1 and 2.

Biological evaluation

The determination of the Pim kinase activity of the compounds of formula I can be carried out by a number of direct and indirect detection methods. The Pim kinase binding activity of certain exemplary compounds described herein, including isoforms Pim-1, Pim-2 and Pim-3, (Example 901) and in vitro anti-tumor cell activity (Example 902) were determined. The Pim binding activity IC ₅₀ values of certain exemplary compounds of the present invention are less than about 1 micromolar (μM). The tumor cell-based activity EC ₅₀ values of certain compounds of the present invention are less than about 1 micromolar (μM). Formula I compounds with Ki/IC ₅₀ /EC ₅₀ below 1 μM in the assays described in Examples 901 and 902 can be used therapeutically as Pim kinase inhibitors (Pim-1, Pim-2 and/or Pim-3).

The exemplary compounds of Formula I in Tables 1 and 2 were prepared, characterized, and tested for Pim kinase inhibition according to the methods of the present invention. These compounds have the following structures and corresponding names (ChemBioDraw Ultra, Version 11.0, CambridgeSoft Corp., Cambridge MA).

Table 1

Table 2

The present invention includes compositions (for example, pharmaceutical compositions), which include compounds of formula I and/or its solvates, hydrates and/or salts, and carriers (pharmaceutical carriers). The present invention also includes compositions (for example, pharmaceutical compositions), which include compounds of formula I and/or its solvates, hydrates and/or salts, and carriers (pharmaceutical carriers), further including second chemotherapeutic agents such as those described herein. The present compositions can be used to inhibit abnormal cell growth or treat hyperproliferative disorders such as cancer in mammals (for example, people). For example, the compounds of this invention and compositions can be used to treat multiple myeloma, lymphoma, acute myeloid leukemia, prostate cancer, breast cancer, hepatocellular carcinoma, pancreatic cancer and/or colorectal cancer in mammals (for example, people).

The present invention includes methods for inhibiting abnormal cell growth or treating hyperproliferative disorders such as cancer in mammals (e.g., humans), comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, and/or a solvate, hydrate, and/or salt thereof, or a composition thereof. For example, the present invention includes methods for treating multiple myeloma, lymphoma, acute myeloid leukemia, prostate cancer, breast cancer, hepatocellular carcinoma, pancreatic cancer, and/or colorectal cancer in a mammal (e.g., a human), comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, and/or a solvate, hydrate, and/or salt thereof, or a composition thereof.

The present invention includes methods for inhibiting abnormal cell growth or treating hyperproliferative disorders such as cancer in mammals (e.g., humans), comprising administering to the mammal a therapeutically effective amount of a compound of Formula I in combination with a second chemotherapeutic agent such as those described herein, and/or a solvate, hydrate and/or salt thereof, or a combination thereof. For example, the present invention includes methods for treating multiple myeloma, lymphoma, acute myeloid leukemia, prostate cancer, breast cancer, hepatocellular carcinoma, pancreatic cancer and/or colorectal cancer in a mammal (e.g., humans), comprising administering to the mammal a therapeutically effective amount of a compound of Formula I in combination with a second chemotherapeutic agent such as those described herein, and/or a solvate, hydrate and/or salt thereof, or a combination thereof.

The present invention includes a method of treating lymphoma in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, and/or a solvate, hydrate, and/or salt thereof, or a composition thereof, alone or in combination with a second chemotherapeutic agent, such as an anti-B-cell antibody therapeutic (e.g., Rituxan and/or Dacetuzumab), gemcitabine, corticosteroids (e.g., prednisolone and/or dexamethasone), a chemotherapeutic cocktail (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), and/or IC E (isfosfamide, cyclophosphamide, etoposide)), combinations of biologics and chemotherapeutic drugs (e.g., Rituxan-ICE, Dacetuzumab-Rituxan-ICE, R-Gem and/or D-R-Gem), Akt inhibitors, PI3K inhibitors (e.g., GDC-0941 (Genentech) and/or GDC-0980 (Genentech)), rapamycin, rapamycin analogs, mTOR inhibitors such as everolimus or sirolimus, MEK inhibitors (e.g., GDC-0973), Bcl-2 inhibitors (e.g., ABT-263 or ABT-199).

The present invention includes a method of treating multiple myeloma in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, and/or a solvate, hydrate, and/or salt thereof, or a combination thereof, alone or in combination with a second chemotherapeutic agent, such as melphalan, "imides" (immunomodulators such as thalidomide, lenalidomide, and/or pomolidamide), corticosteroids (e.g., dexamethasone and/or prednisolone), and bortezomib or other proteasome inhibitors.

The present invention includes a method of treating multiple myeloma, chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML) in a mammal (e.g., a human), comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, and/or a solvate, hydrate and/or salt thereof, or a composition thereof, alone or in combination with a second chemotherapeutic agent, such as cytarabine (araC), an anthracycline antibiotic (e.g., daunorubicin and/or idarubicin), an anti-myeloid antibody therapeutic drug (e.g., SGN-33), an anti-myeloid antibody-drug conjugate (e.g., ).

The present invention includes a method of treating chronic lymphocytic leukemia (CLL) in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, and/or a solvate, hydrate, and/or salt thereof, or a composition thereof, alone or in combination with a second chemotherapeutic agent, such as fludarabine, cyclophosphamide, an anti-B-cell antibody therapeutic (e.g., Rituxan and/or Dacetuzumab).

The present invention includes a method of treating chronic myeloid leukemia (CML) in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, and/or a solvate, hydrate, and/or salt thereof, or a composition thereof, alone or in combination with a second chemotherapeutic agent, such as a BCR-abl inhibitor (e.g., imatinib, nilotinib, and/or dasatinib).

The present invention includes a method for treating myeloproliferative disorders (MDS) and myeloproliferative diseases (including polycythemia vera (PV), essential thrombocythemia (ET) or myelofibrosis (MF)) in mammals (e.g., humans), which comprises administering to the mammal a therapeutically effective amount of a compound of Formula I, and/or its solvates, hydrates and/or salts, or a combination thereof, alone or in combination.

The present invention includes methods of using the compounds of the present invention for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells, tissues or related pathological conditions.

The compounds of the present invention (hereinafter referred to as "active compounds") can be administered by any method capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical administration, inhalation administration and rectal administration.

The amount of the active compound administered will depend on the subject being treated, the severity of the disorder or illness, the rate of administration, the disposal of the compound and the consideration of the prescribing physician. However, with a single dose or separate dosage, an effective dose is from about 0.001 to about 100 mg/kg body weight/day, preferably from about 1 to about 35 mg/kg/day. For a 70 kg person, this will amount to about 0.05-7 g/day, preferably from about 0.05 to about 2.5 g/day. In some cases, dosage levels below the aforementioned lower limit of the range may be sufficient, and in other cases, larger dosages may be used without causing any harmful side effects, provided that first this larger dose is divided into several small doses for administration in one day.

The active compounds can be administered as a monotherapy or in combination with one or more chemotherapeutic agents, such as those described herein.Such conjoint treatment may be achieved by simultaneous, sequential or separate administration of the individual therapeutic components.

The pharmaceutical composition can be, for example, in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained-release formulation, solution, suspension, in a form suitable for parenteral administration as a sterile solution, suspension or emulsion, in a form suitable for topical administration as an ointment or cream, or in a form suitable for rectal administration as a suppository. The pharmaceutical composition can be in a unit dosage form suitable for single administration of the aforementioned dose. The pharmaceutical composition will comprise conventional pharmaceutical carriers or excipients and the compound of the present invention as the active ingredient. In addition, it may comprise other pharmaceutical or medicinal drugs, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions or suspensions of a compound of Formula I in sterile aqueous solutions (e.g., aqueous propylene glycol or dextrose solutions). Such dosage forms may be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents. If desired, the pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, etc. Therefore, for oral administration, tablets containing various excipients such as citric acid can be used together with various disintegrants such as starch, alginic acid, and certain complex silicates, and with binders such as sucrose, gelatin, and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often used for tableting purposes. Similar types of solid compositions can also be used in soft and hard filled gelatin capsules. Therefore, preferred materials include lactose or milk sugar and high molecular weight polyethylene glycol. When an aqueous suspension or elixir is required for oral administration, the active compound therein can be combined with various sweetening or flavoring agents, coloring materials or dyes, and if desired, with emulsifiers or suspending agents and diluents such as water, ethanol, propylene glycol, glycerol, or a combination thereof.

Methods for preparing various pharmaceutical compositions using specific amounts of active compounds are known, or will be apparent, to those skilled in the art. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15th Edition (1975).

Administration of compounds of formula I

Formula I compound of the present invention can be administered by any approach suitable for disease to be treated.Suitable approach includes oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), percutaneous, rectal, nasal, local (including oral and sublingual), vagina, intraperitoneal, intrapulmonary and intranasal.For local immunosuppressive therapy, the compound can be administered by lesion area administration (including perfusion or contacting the graft with an inhibitor before transplantation).It should be understood that preferred approach can change with the situation of, for example, receptor.When the compound is orally administered, it can be formulated into pills, capsules, tablets, etc. together with pharmaceutical carriers or excipients.When the compound is parenteral, it can be formulated into unit dose injection form together with medicinal parenteral vehicles as described below.

The dosage for treating human patients may be from about 10 mg to about 1000 mg of the compound of Formula I. A typical dosage may be from about 100 mg to about 300 mg of the compound. The dosage may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of the specific compound, including absorption, distribution, metabolism, and excretion. In addition, toxicity factors may affect the dosage and dosing regimen. When administered orally, the pill, capsule, or tablet may be taken daily or less frequently for a prescribed period of time. The dosing regimen may be repeated for multiple treatment cycles.

Methods of treatment using compounds of formula I

The compounds of the present invention can be used to treat hyperproliferative diseases, conditions and/or disorders, including but not limited to those characterized by overexpression of Pim kinases (e.g., Pim-1, Pim-2 and Pim-3 kinases). Accordingly, another aspect of the present invention includes a method for treating or preventing a disease or disorder that can be treated or prevented by inhibiting Pim kinases. In one embodiment, the method comprises administering a therapeutically effective amount of a compound of formula I, or a stereoisomer, geometric isomer, tautomer, or a pharmaceutically acceptable salt thereof, to a mammal in need. In one embodiment, a human patient is treated with a compound of formula I and a pharmaceutical carrier, adjuvant or vehicle, wherein the compound of formula I is present in an amount that detectably inhibits the activity of Pim kinases.

Cancers that can be treated according to the methods of the present invention include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, myeloid disorders, lymphoid disorders, hairy cell cancer, oral cavity and pharyngeal (oral) cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, small intestine cancer, colon-rectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, and Hodgkin's cancer and leukemia.

Another aspect of the present invention provides compounds of the present invention for use in treating a disease or disorder described herein in a mammal, such as a human, having the disease or disorder. The present invention also provides the use of compounds of the present invention in the preparation of a medicament for treating the diseases and disorders described herein in a warm-blooded animal, such as a mammal, such as a human, having the diseases and disorders described herein.

pharmaceutical preparations

In order to use the compounds of the present invention for therapeutic treatment of mammals (including humans), they are usually formulated into pharmaceutical compositions according to standard pharmaceutical practice. According to this aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention in combination with a pharmaceutically acceptable diluent or carrier.

Typical formulations are prepared by mixing the compounds of the present invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include the following substances, such as carbohydrates, waxes, water-soluble polymers and/or water-swellable polymers (swellable polymer), hydrophilic substances or hydrophobic substances, gelatin, oils, solvents, water, etc. The specific carrier, diluent or excipient used will depend on the mode and purpose of applying the compounds of the present invention. Solvents are usually selected based on solvents (GRAS) that are considered safe for mammals by those skilled in the art. Generally speaking, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that can be dissolved or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300) and the like and mixtures thereof. The formulation may also include one or more of the following substances: buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, aromas, flavorings and other known additives that provide a high-quality appearance of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or assist in the manufacture of pharmaceutical products (i.e., drugs).

The formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk drug substance (i.e., a compound of the invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the invention are typically formulated into a pharmaceutical dosage form that provides an easily controllable dose of the drug and enables the patient to comply with a prescribed regimen.

Depending on the method used to administer the drug, the pharmaceutical composition (or formulation) for administration can be packaged in a variety of ways. Generally, the articles for distribution include a container in which the pharmaceutical formulation in an appropriate form is stored. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-proof assemblage to prevent inadvertent access to the contents of the package. In addition, the container may have a label describing the contents of the container. The label may also include appropriate precautions.

Pharmaceutical preparations of the compounds of the present invention can be prepared for a variety of routes of administration and types. For example, a compound of Formula I with a desired purity can optionally be mixed with a pharmaceutical diluent, carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A.Ed.) in the form of a lyophilized formulation, a ground powder or an aqueous solution. Preparation can be carried out as follows: at ambient temperature at a suitable pH and at a suitable purity with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the receptor at the dosage and concentration employed). The pH of the preparation depends primarily on the specific use and the concentration of the compound, but can range from about 3 to about 8. A preparation having a pH of 5 in acetate buffer is a suitable embodiment.

The compound can typically be stored as a solid composition, a lyophilized formulation, or an aqueous solution.

The pharmaceutical compositions of the present invention will be formulated, dosed, and administered in a manner consistent with good medical practice (i.e., amount, concentration, schedule, process, vehicle, and route of administration). Factors considered in this context include the specific condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the drug, the method of administration, the schedule of administration, and other factors known to medical practitioners. The "therapeutically effective amount" of the compound administered will be governed by these considerations and is the minimum amount required to improve or treat a hyperproliferative condition.

As a general recommendation, the initial pharmaceutically effective amount of the inhibitor per parenteral dose is about 0.01-100 mg/kg per day, ie, about 0.1 to 20 mg/kg of patient body weight, with a typical initial range of 0.3 to 15 mg/kg/day of compound used.

Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; ); cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants such as TWEEN ^™ , PLURONICS ^™ or polyethylene glycol (PEG). The active pharmaceutical ingredient can also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions, hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release formulations of the compound of Formula I can be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compound of Formula I, wherein the matrix is in the form of a shaped article (e.g., a film or microcapsule). Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides (US 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT ^™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

The formulations include formulations suitable for the routes of administration detailed herein. The formulations may be suitably in unit dosage form and may be prepared by any method known in the pharmaceutical art. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). The method comprises the step of combining the active ingredient with a carrier that constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and tightly combining the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then, if necessary, molding the product.

Formulations of compounds of Formula I suitable for oral administration can be prepared as discrete units, such as pills, capsules, cachets, or tablets, each containing a predetermined amount of a compound of Formula I. Compressed tablets can be prepared by compressing a free-flowing form of the active ingredient (e.g., powder or granules) and optionally a binder, lubricant, inert diluent, preservative, surfactant, or dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient therefrom. Tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or dispersible granules, emulsions, hard or soft capsules such as gelatin capsules, syrups, or elixirs may be prepared for oral administration. Preparations of compounds of formula I intended for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions, which compositions may contain one or more agents, including sweeteners, flavorings, colorants, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient and a mixture of non-toxic physiologically acceptable excipients suitable for making tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; adhesives such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or can be coated by known techniques (including microencapsulation) to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a timed delay material such as glyceryl monostearate or glyceryl distearate alone or in combination with wax can be used.

For treatment of the eye or other external tissues such as the mouth and skin, the formulation is preferably applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w/w. When formulated as an ointment, the active ingredient may be employed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures of these alcohols. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other area of action. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsion of the present invention can be made up of known ingredients in a known manner. When the phase can only contain an emulsifier, it can also contain at least one emulsifier and a fat or oil or a mixture of both a fat and an oil. The hydrophilic emulsifier included together with the lipophilic emulsifier can act as a stabilizer. At the same time, the emulsifier containing or not containing a stabilizer constitutes a so-called emulsifying wax, which, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersed phase of the ointment formulation. Emulsifiers and emulsion stabilizers suitable for the formulation of the present invention include 60, 80, octadecanol/cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

Aqueous suspensions of the compound of Formula I contain the active substance in admixture with excipients suitable for preparing aqueous suspensions. Excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic, and dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (e.g., heptadecaethyl eneoxycetanol), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethyl ene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Pharmaceutical compositions of compounds of Formula I may be in the form of sterile injectable formulations, such as sterile injectable aqueous suspensions or oily suspension formulations. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as mentioned above according to methods known in the art. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol. The sterile injectable formulations may also be prepared as lyophilized powders. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspending media. For this purpose, any mild fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may also be used to prepare injectable formulations.

The amount of active ingredient that can be combined with carrier material to produce single dose form will vary with the host being treated and the specific mode of administration. For example, a timed release formulation intended for oral administration to humans can contain about 1 to 1000 mg of active ingredient, and is mixed with a suitable and appropriate amount of carrier material, which can account for about 5 to about 95% of the total composition (weight: weight). Pharmaceutical compositions can be prepared to provide an amount that is easily measured during administration. For example, an aqueous solution intended for intravenous infusion can contain about 3 to 500 μg of active ingredient per milliliter of solution, so that the infusion of a suitable volume occurs at a rate of about 30 milliliters/hr.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in the formulation at a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a liquid carrier.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have, for example, a particle size of 0.1 to 500 microns (inclusive between 0.1 and 500 microns, in increments of, for example, 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nasal passages or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents (e.g., compounds heretofore used to treat or prevent the conditions described below).

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Preparation can be packaged in unit dose or multidose container such as sealed ampoule or bottle, and can be stored under freeze drying (lyophilization) condition, only need to add sterile liquid carrier such as water before immediate use, for injection. Instant injection solution (Extemporaneous injection solutions and suspension) and suspensoid are prepared from sterile powder, granule and tablet of aforementioned kind. Preferred unit dose preparation is the preparation containing the active ingredient of the application's daily dose as described above or unit daily subdose (sub-dose) or its appropriate fraction.

The present invention also provides veterinary compositions, which contain at least one active ingredient as defined above and a veterinary carrier. A veterinary carrier is a substance used for the purpose of administering the composition and may be a solid, liquid or gaseous substance that is either inert or acceptable in the veterinary field and is compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

Combination therapy

The compound of formula I can be used alone or in combination with other therapeutic agents for treating diseases or disorders described herein, such as inflammation or hyperproliferative disorders (e.g., cancer). In some embodiments, in a pharmaceutical combination formulation or as a dosing regimen for combined therapy, the compound of formula I is combined with a second therapeutic compound having anti-inflammatory or anti-hyperproliferative properties or for treating inflammation, immunoreactive disorders or hyperproliferative disorders (e.g., cancer). The second therapeutic agent can be an NSAID anti-inflammatory drug. The second therapeutic agent can be a chemotherapeutic agent. The second compound of the pharmaceutical combination formulation or dosing method preferably has an activity complementary to that of the compound of formula I, so that they do not adversely affect each other. Such compounds are suitably present in an amount effective for the intended purpose. In one embodiment, the composition of the present invention comprises a combination of a compound of formula I or its stereoisomers, tautomers, solvates, metabolites, or pharmaceutically acceptable salts or prodrugs and a therapeutic agent such as an NSAID.

Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the composition can be administered in two or more administrations. Administration in combination includes simultaneous administration using separate formulations or a single pharmaceutical formulation, and sequential administration in either order, preferably with a period of time during which both (or all) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above co-administered drugs are those currently used and may be lowered due to the combined action (synergy) of the newly identified drug and other therapeutic agents or treatments.

Combination therapy can provide "synergy" and provide a "synergistic effect," that is, the effect achieved when the active ingredients are used together is greater than the sum of the effects that would result from the separate administration of the compounds. Synergy is achieved when the active ingredients are: (1) formulated simultaneously in a combined unit dosage formulation and administered or delivered simultaneously; (2) delivered as separate formulations by alternation or parallel administration; or (3) administered by some other regimen. When delivered in alternation therapy, synergy is achieved when the compounds are administered or delivered sequentially, for example, by separate injections in separate syringes, by separate pills or capsules, or by separate infusions. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially (i.e., serially), whereas in combination therapy, effective dosages of two or more active ingredients are administered together.

In a specific embodiment for the treatment of, the compound of Formula I or its stereoisomer, tautomer, solvate, metabolite or pharmaceutical salt or prodrug, can be used in conjunction with other therapeutic agents, hormone drugs or antibody drugs (such as medicine described in the application), or with surgical treatment and radiotherapy. The combination treatment according to the present invention thus includes administering at least one compound of Formula I or its stereoisomer, tautomer, solvate, metabolite or pharmaceutical salt or prodrug, and using at least one other cancer treatment method. The amount of the compound of Formula I and other pharmaceutically active therapeutic agents and the relevant administration time limit are selected to achieve the desired combination treatment effect.

Metabolites of compounds of formula I

The in vivo metabolites of Formula I described herein also fall within the scope of the present invention. Such products may be caused, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. of the administered compound. Thus, the present invention includes metabolites of compounds of Formula I, including compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolite thereof.

Metabolites are typically identified by preparing a radiolabeled (e.g., ¹⁴ C or ³ H) isotope of a compound of the invention, administering it parenterally to an animal, such as a rat, mouse, guinea pig, monkey, or to a human, at a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (usually about 30 seconds to 30 hours), and then isolating its conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies that bind to antigenic epitopes that survive in the metabolites). The structure of the metabolite is determined in a conventional manner, such as by MS, LC/MS, or NMR analysis. In general, analysis of metabolites is accomplished in the same manner as conventional drug metabolism studies known to those skilled in the art. The metabolites, as long as they are not otherwise present in vivo, are used for diagnostic determination of therapeutic doses of the compounds of the invention.

Products

In another embodiment of the present invention, there are provided articles and "kits" containing substances for treating the diseases and conditions described above. In one embodiment, the kit comprises a container comprising a compound of Formula I or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof. The kit may further comprise a label or package insert attached to or in the container. The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products, which contain information about indications, usage, dosage, administration, contraindications, and/or precautions related to the use of the therapeutic product. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The container can be formed from a variety of materials (such as glass or plastic). The container can be filled with a compound of Formula I or its formulation that is effective for treating the condition and can have a sterile access port (for example, the container can be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). At least one active drug in the composition is a compound of Formula I. The label or package insert indicates that the composition is used to treat a selected condition such as cancer. In addition, the label or package insert may indicate that the patient to be treated is a patient suffering from a disease such as a hyperproliferative disease, neurodegeneration, cardiac hypertrophy, pain, migraine or neurotraumatic disease or event. In one embodiment, the label or package insert indicates that the composition comprising the compound of Formula I can be used to treat a disease caused by abnormal cell growth. The label or package insert may also indicate that the composition can be used to treat other diseases. Alternatively or additionally, the article may also include a second container comprising a pharmaceutical buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and glucose solution. The kit may also include other substances that are desirable from a commercial and user perspective, including other buffers, diluents, filters, needles and syringes.

The kit may further comprise instructions for administering the compound of Formula I and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition (containing a compound of Formula I) and a second pharmaceutical formulation, the kit may further comprise instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially, or separately to a patient in need of the formulations.

In another embodiment, the kit is suitable for delivering a compound of formula I in a solid oral form, such as a tablet or capsule. Such a kit preferably includes a plurality of unit doses. The kit may include a dosage card for the intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid may be provided, which may be in the form of, for example, numbers, letters, or other markings, or with a calendar insert, which specifies the days in the treatment schedule to which the dosage may be administered.

According to one embodiment, the kit may include (a) a first container containing a compound of Formula I therein; and optionally (b) a second container containing a second pharmaceutical preparation therein, wherein the second pharmaceutical preparation comprises a second compound with anti-hyperproliferative activity. Alternatively or additionally, the kit may also include a third container comprising a pharmaceutical buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. It may also include other substances that are desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

In certain other embodiments where the kit comprises a combination of Formula I and a second therapeutic agent, the kit may comprise containers for holding the separate compositions, such as divided bottles or divided foil packets, however, the separate compositions may also be held in a single, undivided container. Typically, the kit comprises instructions for administering the separate components. The kit format is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosage intervals, or when titration of the individual components of the combination is desirable to the attending physician.

5-Azaindazole compounds of Formula I are also known as pyrazolo[4,3-c]pyridines and have the following numbering scheme:

The compounds of formula I can be synthesized by synthetic routes that include methods analogous to those well known in the chemical art, in particular with the aid of the description contained herein, as well as for the other heterocycles described: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta, 41: 1052-60, (1958); Arzneimittel-Forschung, 40(12): 1328-31, (1990), each of which is expressly incorporated by reference. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or in Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including the appendix (also available through the Beilstein online database)).

Synthetic chemistry transformations and protecting group methodology (protection and deprotection) and the necessary reagents and intermediates useful in synthesizing compounds of Formula I are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, ^3rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

Compounds of Formula I can be prepared individually or as compound libraries comprising at least two, e.g., 5 to 1,000 or 10 to 100, compounds. Compound libraries of Formula I can be prepared by procedures known to those skilled in the art using solution phase or solid phase chemistry, by a combinatorial "split and mix" approach, or by multiple parallel syntheses. Thus, according to another method of the present invention, a compound library comprising at least two compounds or pharmaceutically acceptable salts thereof is provided.

The accompanying drawings and examples provide exemplary methods for preparing compounds of formula I. It will be appreciated by those skilled in the art that other synthetic routes can be used to synthesize compounds of formula I. Although specific starting materials and reagents are described and discussed in the accompanying drawings, general procedures, and examples, other starting materials and reagents can be easily replaced to provide a variety of derivatives and/or reaction conditions. In addition, a variety of exemplary compounds prepared by the methods described can be further modified according to the present disclosure using conventional chemistry well known to those skilled in the art.

When preparing the compound of formula I, it may be necessary to protect the remote functional group (e.g., primary or secondary amine) of the intermediate. The need for the protection will vary with the properties of the remote functional group (remote functionality) and the conditions of the preparation method. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). The need for the protection is easily determined by those skilled in the art. For a general description of protecting groups and their uses, see T.W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Separation method

In the method for preparing the compound of formula I, it may be advantageous to separate the reaction products from each other and/or from the raw materials. The desired product in each step or multiple steps is separated and/or purified to the required uniformity by common techniques in the art. Typically, the above separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example, reversed-phase and normal-phase, size exclusion, ion exchange, high, medium, and low pressure liquid chromatography and apparatus, small-scale analysis, simulated moving bed (SMB), and preparative thin or thick layer chromatography and small-scale thin layer and flash chromatography techniques.

Another type of separation method involves treating the mixture with a reagent selected to bind to or make the desired product, unreacted starting materials, reaction by-products, etc. separable. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, etc. Alternatively, the reagent may be an acid (in the case of a basic substance), a base (in the case of an acidic substance), a binding agent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid/liquid ion extractant (LIX), etc. The choice of an appropriate separation method depends on the properties of the substances involved, such as boiling point and molecular weight (in distillation and sublimation), the presence or absence of polar functional groups (in chromatography), the stability of the substance in acidic and basic media (in multiphase extraction), etc.

A mixture of diastereoisomers can be separated into its individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated by converting the mixture of enantiomers into a mixture of diastereomers by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and then converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. In addition, some compounds of the present invention may be atropisomers (e.g., substituted biaromatic compounds) and are considered part of the present invention. Enantiomers can also be separated by using a chiral HPLC column.

Individual stereoisomers, e.g., enantiomers substantially free of their stereoisomers, can be obtained by resolution of the racemic mixture using methods such as the formation of diastereomers using an optically active resolving agent (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds of the invention can be separated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers and conversion to pure stereoisomers; and (3) direct separation of the substantially pure or enriched stereoisomers under chiral conditions. See "Drug Stereochemistry, Analytical Methods and Pharmacology", Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

In method (1), diastereomeric salts can be formed by reacting an enantiomerically pure chiral base such as strychnine, quinine, ephedrine, brucine, α-methyl-β-phenylethylamine (amphetamine), etc. with an asymmetric compound having an acidic functional group such as a carboxylic acid and a sulfonic acid. The separation of the diastereomeric salts can be achieved by fractional crystallization or ion chromatography. In order to separate the optical isomers of an amino compound, a chiral carboxylic acid or sulfonic acid such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid is added, which can cause the formation of diastereomeric salts.

Alternatively, the substrate to be resolved is reacted with one enantiomer of a chiral compound by method (2) to form a diastereomeric pair (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing agent such as a menthyl derivative, followed by separation and hydrolysis of the diastereomers to yield a pure or enriched enantiomer. Methods for determining optical purity involve preparing a chiral ester of the racemic mixture [such as preparing a menthyl ester, e.g., (-)-menthyl chloroformate, or preparing Mosher's ester, i.e., α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem. (1982) 47:4165) in the presence of a base and analyzing the ¹ H NMR spectrum for the presence of two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated by normal and reverse phase chromatography following the methods for separation of atropisomeric naphthyl-isoquinolines (WO 1996/15111). In method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) WJ Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). The enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation or circular dichroism.

General preparation procedures

Solution 1

Scheme 1 shows a general synthesis of compound 5. Substituted 6-chloro-5-azaindazoles (Y═Z═CH) can be prepared from 6-chloro-5-azaindazole 1 via, but not limited to, Buchwald, Goldberg, or nucleophilic aromatic substitution (SnAr) reactions. Addition of the ^R group via SnAr reaction with various amines or C—C bond formation with or without transition metal catalysis provides compound 4. Alternatively, compound 4 can be prepared from 6-chloro-5-azaindazole 1 to which the ^Ra group has been added to a pyridine precursor. Subsequent Stille or Suzuki reactions followed by deprotection can provide the target compound 5 with various R ^{and Ra} substitutions. In an alternative sequence, compound 5 can be synthesized from compound 2 in a three- or four-step process. First, compound 3 is obtained via stannylation followed by addition of ^R via Stille or Suzuki reaction with boronic acid/boronic acid esters. Second, the ^Ra group can be added via SnAr reaction with various amines or C—C bond formation with or without transition metal catalysis. Finally, deprotection under acidic, basic, oxidative or reductive conditions can generate compound 5. Similarly, substituted N-pyrimidinyl 5-azaindazoles (Y = N, Z = CH) and substituted N-pyrazinyl 5-azaindazoles (Y = CH, Z = N) 5 can be synthesized.

Option 2

Scheme 2 shows the general synthesis of compound 5. Protection of 6-chloro-5-azaindazole 1 under alkaline or acidic conditions can produce compound 6. Alternatively, the 6 position can be other halogens, such as Br or I or a leaving group. The protecting group (PG) includes but is not limited to tetrahydropyranyl, 2-(trimethylsilyl)ethoxy]methyl or acetyl, or other N-protecting groups known in the literature. Compound 6 is then subjected to a stannylation reaction and then to a Stille reaction to obtain compound 8. Compound 9 can be prepared by removing the protecting group under acidic or alkaline conditions. Substituted N-pyridyl 5-azaindazole 3 can be synthesized from 6-chloro-5-azaindazole 9 by (but not limited to) Buchwald, Goldberg or nucleophilic aromatic substitution (SnAr) reactions. The ^Ra group is added by SnAr reaction with various amines or C—C bond formation reaction in the presence or absence of transition metal catalysis, followed by deprotection to obtain compound 5.

Option 3

Scheme 3 shows a general synthesis of compound 12. Compound 10 can be synthesized from 6-chloro-5-azaindazole 9 by, but not limited to, Buchwald, Goldberg, or nucleophilic aromatic substitution (SnAr) reactions. Compound 10 can be cyanated under suitable conditions to give compound 13. The addition of the ^Ra group can be achieved by, but not limited to, SnAr reactions with various amines or C—C bond formation reactions with or without transition metal catalysis. Subsequent deprotection under various conditions can give compound 12. Alternatively, compound 12 can be prepared by first adding the ^Ra group and then the ^R group in a different order.

Option 4

Scheme 4 shows the general synthesis of compounds 15, 18, and 19. Compound 15 can be synthesized from compound 14 by, but not limited to, Buchwald, Goldberg, or affinity aromatic substitution (SnAr) reactions, followed by deprotection under suitable conditions if desired. Vinyl addition can be achieved by Suzuki or Stille reactions to provide compound 16. Compound 16 can be oxidatively cleaved in one step or stepwise to generate aldehyde 17. Subsequent fluorination or reduction reactions, followed by deprotection under suitable conditions if desired, can generate compound 18 or 19.

Example

Example 1 6-(1-ethylpyrazol-4-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 101

Step A: Preparation of 6-chloro-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine

Method I: A solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (3.78 g, 24.6 mmol), cesium carbonate (16.1 g, 49.2 mmol) and 2,6-difluoropyridine (3.40 g, 29.5 mmol) in dimethyl sulfoxide; 50.0 mL was stirred at 70 ° C for 2 h. The reaction was quenched by pouring into water and then extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluted at 25% EtOAc) to give the desired product 3.2 g in a yield of 52%. MS (ESI) m / z: 249.2 [M + H] ⁺

Method II: A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (13.778 mmol, 2115.9 mg), 2-bromo-6-fluoro-pyridine (15.156 mmol, 2667.3 mg), N,N′-dimethylethylenediamine (13.778 mmol; 1.215 g; 1.37 mL), copper iodide (13.778 mmol; 2650.5 mg) and potassium carbonate (15.156 mmol; 2.12 g) in 1,4-dioxane (10 mL) was evacuated with argon, then sealed and stirred at 100° C. for 20 hours. The mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated; the residue was purified on silica gel and eluted with 0-100% ethyl acetate in heptane to give 6-chloro-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine as an off-white solid (1.90 g, 55%). MS (ESI) m/z: 249 [M+H] ⁺

Step B: Preparation of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]piperazine-1-carboxylate

A solution of 6-chloro-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine (100 mg, 0.40 mmol) and 1-N-Boc-piperazine (380 mg, 2.0 mmol) in dimethyl sulfoxide (3.0 mL) was heated at 95 ° C for 4 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane-25% EtOAc) to give 110 mg of the desired product in a yield of 66%. MS (ESI) m/z: 415.1 [M+H] ⁺

Step C: 6-(1-ethyl-1H-pyrazol-4-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]piperazine-1-carboxylate (0.5112 mmol; 212.1 mg), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.022 mmol; 227.1 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.05112 mmol; 42.6 mg), palladium acetate hydrate (0.7668 mmol; 0.77 mL), and sodium carbonate decahydrate (0.7668 mmol; 0.77 mL) in acetonitrile (10 mL) was heated in a pressure tube under microwave conditions at 150° C. for 15 minutes. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified on silica gel eluting with 0-6% MeOH in DCM to afford tert-butyl 4-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate as a dark brown solid.

A mixture of tert-butyl 4-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate (0.2486 mmol; 118 mg) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to give 6-(1-ethyl-1H-pyrazol- ⁴ -yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 101 (47.5 mg, 50%). NMR (400MHz, DMSO) δ9.15-9.11(s,1H),8.67-8.65(s,1H),8.54-8.51(s,1H),8. 27-8.24(s,1H),7.91-7.88(s,1H),7.78-7.72(t,J＝8.1Hz,1H),7.24-7.18(d,J＝ 7.7Hz,1H),6.80-6.74(d,J＝8.4Hz,1H),4.26-4.17(q,J＝7.3Hz,2H),3.65-3.56 (m,4H),2.96-2.86(m,4H),1.46-1.41(t,J＝7.3Hz,3H); MS(ESI)m/z:375.1[M+H] ⁺

Example 2 6-(1-methyl-1H-pyrazol-4-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 102

The procedure described in Example 1 was followed, starting from 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole having the following structure:

102 was obtained in two steps as an off-white solid (174 mg, 32%). ¹ H NMR (400 MHz, DMSO) δ 9.17-9.07 (s, 1H), 8.71-8.57 (s, 1H), 8.56-8.47 (s, 1H), 8.26-8.15 (s, 1H), 7.91-7.82 (s, 1H), 7.80-7.69 (t, J = 8.1 Hz, 1H), 7.26-7.15 (d, J = 7.7 Hz, 1H), 6.81-6.73 (d, J = 8.4 Hz, 1H), 3.99-3.82 (s, 3H), 3.66-3.52 (m, 4H), 2.96-2.85 (m, 4H); MS (ESI) m/z: 361.2 [M+H] ⁺

Example 3 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(5-isopropylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine 103

Following the procedure described in Example 8 and starting from 1,4-diazepane, 103 was obtained as an off-white solid (29.4 mg, 24%). ¹ H NMR (400 MHz, DMSO) δ 9.36-9.28 (s, 1H), 9.09-9.04 (d, J = 2.0 Hz, 1H), 9.03-9.01 (s, 1H), 8.66-8.61 (s, 1H), 8.59-8.55 (d, J = 2.1 Hz, 1H), 8.30-8.24 (t, J = 2.0 Hz, 1H), 7.76-7.65 (t, J = 8.1 Hz, 1H), 7.23-7.16 (d, J = 7.7 Hz, 1H),6.65-6.58(d,J＝8.5Hz,1H),3.93-3.72(dt,J＝10.0,5.5Hz,4H),3.12-3.03(dt,J＝14.0,7.0Hz,1H),2. 99-2.90(m,2H),2.73-2.66(m,2H),1.91-1.80(m,2H),1.33-1.30(d,J＝6.9Hz,6H); MS(ESI)m/z:414.1[M+H] ⁺

Example 4 6-(5-ethylpyridin-3-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 104

Following the procedure described in Example 8 and starting from 6-(5-ethylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and piperazine, 104 was obtained over 2 steps as an off-white solid (22.3 mg, 18%). ¹ H NMR (400 MHz, DMSO) δ 9.35-9.27 (s, 1H), 9.16-9.08 (d, J = 2.0 Hz, 1H), 9.08-9.01 (s, 1H), 8.67-8.59 (s, 1H), 8.57-8.50 (d, J = 1.9 Hz, 1H), 8.30-8.21 (s, 1H), 7.85-7.73 (m, 2H), 7.66-7.44 (m, 2H), 7. 28-7.23(d,J＝7.7Hz,1H),6.85-6.78(d,J＝8.4Hz,1H),3.65-3.57(m,4H),2.98-2.81(m,4H),2.79 -2.70(q,J＝7.6Hz,2H),1.75-1.52(m,3H),1.32-1.24(t,J＝7.6Hz,3H).;MS(ESI)m/z:386.2[M+H] ⁺

Example 5 6-(5-isopropylpyridin-3-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 105

Following the procedure described in Example 8 and starting from piperazine, 105 was obtained as an off-white solid (26.6 mg, 22%). ¹ H NMR (400 MHz, DMSO) δ 9.37-9.27 (s, 1H), 9.12-9.06 (d, J = 2.0 Hz, 1H), 9.05-9.02 (s, 1H), 8.67-8.62 (s, 1H), 8.60-8.55 (d, J = 2.0 Hz, 1H), 8.34-8.27 (t, J = 2.0 Hz, 1H), 7.80-7.72 (t, J = 8.1 Hz, 1H). H),7.29-7.21(d,J＝7.7Hz,1H),6.86-6.77(d,J＝8.4Hz,1H),3.66-3.58(m,4H),3.12-3.03(dt ,J＝13.8,6.9Hz,1H),2.93-2.82(m,4H),1.34-1.30(d,J＝6.9Hz,6H); MS(ESI)m/z:400.2[M+H] ⁺

Example 6 1-(6-(6-(5-ethylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 106

Following the procedure described in Example 8 and starting from 6-(5-ethylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepan-6-ol, 106 was obtained as an off-white solid (49.4 mg, 12%). MS (ESI) m/z: 416.1 [M+H] ⁺

Example 7 (R)-1-(6-(6-(5-isopropylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 107

Following the procedure described in Example 8 and starting from tert-butyl N-[(3R)-3-piperidinyl]carbamate, 107 was obtained over 2 steps as an off-white solid (33.5 mg, 27%). ¹ H NMR (400 MHz, DMSO) δ 9.38-9.29 (s, 1H), 9.14-9.09 (d, J = 2.0 Hz, 1H), 9.06-9.00 (s, 1H), 8.67-8.61 (s, 1H), 8.60-8.55 (d, J = 2.0 Hz, 1H), 8.36-8.30 (s, 1H), 7.79-7.70 (t, J = 8.1 Hz, 1H), 7.23-7.14 (d, J = 7.7 Hz, 1H), 6.84-6.7 8(d,J＝8.5Hz,1H),4.31-4.13(m,3H),3.13-3.04(dt,J＝13.7,6.6Hz,3H),2.87-2.79(m,1H),2.80-2.72(m,2H) ,1.96-1.75(m,2H),1.68-1.52(dd,J＝24.1,11.8Hz,2H),1.33-1.30(d,J＝7.0Hz,7H);MS(ESI)m/z:414.1[M+H] ⁺

Example 8 (3S)-1-[6-[6-(5-isopropyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 108

Step A: Preparation of 3-bromo-5-isopropenyl-pyridine

[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex; 98.0% by mass, potassium acetate hydrate (7.4997 mmol; 3.7 mL), sodium carbonate decahydrate (7.4997 mmol; 3.7 mL), acetonitrile (15 mL), and 3,5-dibromopyridine (4.9998 mmol; 1184.4 mg) were heated in a pressure tube at 120°C under microwave conditions for 3 minutes in 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9998 mmol; 840.0 mg; 0.940 mL). The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified on silica gel using 0-10% MeOH in DCM to afford 3-bromo-5-isopropenyl-pyridine as a dark brown solid (512.6 mg, 52%).

Step B: Preparation of 3-(prop-1-en-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 3-bromo-5-isopropenyl-pyridine (5.1767 mmol; 1025.3 mg), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (7.7651 mmol; 1972 mg), potassium acetate (7.7651 mmol; 762.10 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.25884 mmol; 216 mg) in 1,4-dioxane (15 mL) was evacuated with nitrogen in a pressure tube for 1 minute, then sealed and heated at 85 ° C overnight. The reaction mixture was hot filtered through celite. The filter cake was washed with EtOAc. The filtrate was washed with water and brine. The organic layer was dried over MgSO ₄ and then concentrated to give 3-(prop-1-en-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, which was used without purification.

Step C: Preparation of 1-(6-fluoropyridin-2-yl)-6-(5-isopropylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of 6-chloro-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine (1.759 mmol; 437.3 mg), 3-isopropenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.638 mmol; 646.6 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.1759 mmol; 147 mg), potassium acetate hydrate (2.638 mmol; 1.3 mL), and sodium carbonate (2.638 mmol; 1.3 mL) in acetonitrile (10 mL) was heated in a pressure tube at 150° C. under microwave conditions for 5 minutes. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified on silica gel and eluted with 0-6% MeOH in DCM to give 1-(6-fluoro-pyridin-2-yl)-6-(5-isopropenyl-pyridin-3-yl)pyrazolo[4,3-c]pyridine.

To a solution of the above 1-(6-fluoro-pyridin-2-yl)-6-(5-isopropenyl-pyridin-3-yl)pyrazolo[4,3-c]pyridine in ethanol (50 mL) in a 250 mL round-bottom flask was added Pearlman's catalyst (0.3523 mmol; 247.4 mg). The flask was evacuated and connected to a hydrogen balloon. The mixture was stirred at room temperature for 16 hours. The mixture was filtered through celite. The filtrate was concentrated. The residue was purified on silica gel eluting with 0-5% MeOH in DCM to give 1-(6-fluoropyridin-2-yl)-6-(5-isopropylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine (479.2 mg, 82%).

Step D: tert-Butyl N-[(3S)-1-[6-[6-(5-isopropyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of 1-(6-fluoro-pyridin-2-yl)-6-(5-isopropyl-pyridin-3-yl)pyrazolo[4,3-c]pyridine (0.3032 mmol; 120.0 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (0.9095 mmol; 182.2 mg) and N-methylmorpholine (3.032 mmol; 310 mg; 0.337 mL) in 1-methyl-2-pyrrolidinone (3 mL) was heated overnight in a sealed pressure bottle at 120° C. The mixture was cooled to room temperature and then partitioned between EtOAc and water. The organic layer was concentrated to give tert-butyl N-[(3S)-1-[6-[6-(5-isopropyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate, which was used without purification.

The above tert-butyl N-[(3S)-1-[6-[6-(5-isopropyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for ¹ h. The mixture was concentrated and the residue was purified by reverse phase HPLC to give 108 (33.9 mg, 37%). NMR (400MHz, DMSO) δ9.35-9.30 (s, 1H), 9.13-9.10 (d, J = 2.0Hz, 1H), 9.06-9.02 (s, 1H), 8.66-8.61 (s, 1H), 8.58-8.55 ( d,J＝2.0Hz,1H),8.35-8.31(d,J＝1.9Hz,1H),7.78-7.70(t,J＝8.1Hz,1H),7.23-7.17(d,J＝7.7Hz,1H),6.84-6.78(d,J＝ 8.5Hz,1H),4.32-4.14(dd,J＝37.4,11.8Hz,2H),3.12-3.01(td,J＝12.8,5.7Hz,2H),2.87-2.70(ddd,J＝15.5,13.1,7. 6Hz, 2H), 1.96-1.74 (m, 2H), 1.64-1.51 (dd, J＝24.5, 11.5Hz, 2H), 1.33-1.31 (d, J＝7.0Hz, 6H); MS (ESI) m/z: 414.1 [M+H] ⁺

Example 9 5-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[43-c]pyridin-6-yl]thiazole 109

A solution of 5-[1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]thiazole (50 mg, 0.17 mmol) and 1-N-boc-piperazine (175 mg, 0.921 mmol) in dimethyl sulfoxide (2.0 mL) was heated at 95°C for 8 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford tert-butyl 4-[6-(6-(thiazol-5-yl)pyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]piperazine-1-carboxylate.

A mixture of tert-butyl 4-[6-(6-(thiazol-5-yl)pyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]piperazine-1-carboxylate in 4 mol/L hydrochloric acid and dioxane (1.5 mL, 6.0 mmol) and 1.0 mL of dioxane was stirred at room temperature for 14 h. The reaction mixture was concentrated. The crude product was subjected to reverse-phase HPLC to afford 109 (44 mg) in a 72% yield. MS(ESI)m/z: ^364.1.1 HNMR (400MHz, DMSO) δ9.20 (d, J = 8.2Hz, 2H), 8.94 (s, 1H), 8.64-8.59 (m, 1H), 8.43 (s, 1H), 7.77 (t ,J＝8.1Hz,1H),7.23(d,J＝7.7Hz,1H),6.81(d,J＝8.4Hz,1H),3.65-3.57(m,4H),2.96-2.88(m,4H)

Example 10 (3R)-1-[6-(6-(thiazol-5-yl)pyrazolo[43-c]pyridin-1-yl)-pyridin-2-yl]piperidin-3-amine 110

According to the preparation procedure of Example 9, 110 was obtained. MS(ESI)m/z:378.1. ¹ H NMR (400MHz, DMSO) δ9.19(d,J＝13.5Hz,2H),8.96(s,1H),8.60(d,J＝9.0Hz,2H),7.74(t,J＝8.1Hz,1H),7.18(d,J＝7.7Hz,1H),6.81(d,J＝8.5Hz,1H ),4.22(dd,J＝10.2,6.2Hz,2H),3.15-3.04(m,1H),2.91-2.74(m,2H),2. 00-1.90(m,1H),1.90-1.80(m,1H),1.79-1.50(m,3H),1.41-1.27(m,1H).

Example 11 6-(5-cyclopropylpyridin-3-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 111

Following the procedure described in Example 8 and starting from 6-(5-cyclopropylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and piperazine, 111 was obtained as an off-white solid (41.7 mg, 31%). ¹ H NMR (400 MHz, DMSO) δ 9.33-9.28 (s, 1H), 9.06-8.99 (d, J = 2.5 Hz, 2H), 8.66-8.61 (s, 1H), 8.50-8.45 (d, J = 2.1 Hz, 1H), 8.09-8.03 (t, J = 2.0 Hz, 1H), 7.81-7.73 (t, J = 8.1 Hz, 1H), 7. 29-7.20(d,J＝7.7Hz,1H),6.85-6.76(d,J＝8.5Hz,1H),3.65-3.56(m,4H),2.94-2.84(m ,4H),2.13-2.04(m,1H),1.12-1.04(m,2H),0.88-0.81(m,2H); MS(ESI)m/z:398.2[M+H] ⁺

Example 12 6-(5-cyclopropylpyridin-3-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 112

Following the procedure described in Example 8 and starting from 6-(5-cyclopropylpyridin-3-yl)-1-(6-fluoropyridin ^-2- yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepane, 112 was obtained as an off-white solid (30.9 mg, 22%). NMR (400MHz, DMSO) δ9.37-9.25(s,1H),9.04-8.98(s,2H),8.67-8.59(s,1H),8.51-8.45(d,J＝2.1Hz,1H) ,8.05-7.99(t,J＝2.1Hz,1H),7.74-7.66(dd,J＝14.5,6.5Hz,1H),7.24-7.15(t,J＝7.4Hz,1H),6.65-6.58 (d,J＝8.5Hz,1H),3.90-3.73(dt,J＝10.0,5.5Hz,4H),3.00-2.91(m,2H),2.75-2.65(dd,J＝13.3,7.3Hz,2 H),2.12-2.04(m,1H),1.91-1.81(m,2H),1.12-1.03(m,2H),0.88-0.81(m,2H).;MS(ESI)m/z:412.2[M+H] ⁺

Example 13 (S)-1-(6-(3-methylpiperazin-1-yl)pyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine 113

Following the procedure described in Example 8 and starting from 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and (S)-2-methylpiperazine, 113 was obtained as an off-white solid (26.3 mg, ²⁴ %). NMR (400MHz, DMSO) δ9.39-9.28(m,1H),9.20-9.11(d,J＝2.1Hz,1H),9.11-9.02(s,1H),8.72-8.61(m,2H),8.60-8.53(t,J＝2.1H z,1H),7.84-7.67(t,J＝8.1Hz,1H),7.32-7.18(d,J＝7.7Hz,1H),6.87-6.76(d,J＝8.5Hz,1H),5.08-4.98(dd,J＝8.2,6.2Hz,2H), 4.76-4.68(t,J＝6.3Hz,2H),4.48-4.35(m,1H),4.28-4.13(dd,J＝20.9,11.0Hz,2H), 3.06-2.88(ddd,J＝19.7,14.7,7.1Hz,2H), 2.87-2.73(m,2H),2.60-2.53(m,1H),2.39-2.31(d,J＝7.7Hz,1H),1.09-0.99(dd,J＝14.9,6.2Hz,3H); MS(ESI)m/z:428.2[M+H] ⁺

Example 14 6-(5-(oxetan-3-yl)pyridin-3-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 114

Following the procedure described in Example 8 and starting from 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and piperazine, 114 was obtained as an off-white solid (14.3 mg, 13%). ¹ H NMR (400 MHz, DMSO) δ 9.36-9.31 (s, 1H), 9.20-9.14 (d, J = 2.1 Hz, 1H), 9.10-9.05 (s, 1H), 8.70-8.62 (m, 2H), 8.57-8.52 (t, J = 2.0 Hz, 1H), 7.81-7.74 (t, J = 8.1 Hz, 1H), 7.28-7.22 (d, J = 7. 7Hz, 1H), 6.85-6.78 (d, J＝8.4Hz, 1H), 5.08-5.00 (dd, J＝8.3, 6.1Hz, 2H), 4.77-4.70 (t, J＝6. 3Hz,2H),4.47-4.38(m,1H),3.65-3.56(m,4H),2.99-2.75(m,4H).;MS(ESI)m/z:414.2[M+H] ⁺

Example 15 1-(6-(6-(5-cyclopropylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 115

Following the procedure described in Example 8 and starting from 6-(5-cyclopropylpyridin-3-yl)-1-(6-fluoropyridin- ² -yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepan-6-ol, 115 was obtained as an off-white solid (25.1 mg, 17%). NMR (400MHz, DMSO) δ9.31-9.27(s,1H),9.07-9.00(dd,J＝16.3,6.5Hz,2H),8.65-8.59(d,J＝5.6Hz,1H),8.48-8.44(t,J＝2 .8Hz,1H),8.09-8.03(t,J＝2.0Hz,1H),7.73-7.67(t,J＝8.1Hz,1H),7.20-7.14(d,J＝7.7Hz,1H),6.73-6.68(d,J＝8.5Hz,1 H),4.82-4.73(s,1H),4.03-3.87(m,3H),3.74-3.57(m,2H),3.02-2.93(t,J＝5.4Hz,2H),2.87-2.75(dd,J＝13.8,3.8Hz,1 H),2.70-2.60(dd,J＝13.8,5.9Hz,1H),2.15-2.03(m,1H),1.10-1.02(m,2H),0.92-0.82(m,2H); MS(ESI)m/z:428.2[M+H] ⁺

Example 16 1-(6-(6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 116

Following the procedure described in Example 8 and starting from 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3 ^- yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepan-6-ol, 116 was obtained as an off-white solid (7.2 mg, 6%). NMR (400MHz, DMSO) δ9.35-9.29(s,1H),9.23-9.16(dd,J＝8.9,2.0Hz,1H),9.11-9.04(d,J＝8.6Hz,1H),8.77-8.62(m,2H),8.55-8.46(dd, J＝15.4,8.6Hz,1H),7.74-7.67(t,J＝8.1Hz,1H),7.21-7.16(d,J＝7.7Hz,1H),6.77-6.68(dd,J＝8.5,2.9Hz,1H),5.69-5.45(d,J＝72.4Hz, 1H),5.06-5.00(dd,J＝8.1,6.2Hz,1H),4.81-4.70(dd,J＝13.5,6.7Hz,2H),4.48-4.40(m,1H),4.06-3.85(dd,J＝32.4,13.9Hz,3H),3.74- 3.53(m,2H),3.00-2.93(d,J＝2.3Hz,2H),2.83-2.77(dd,J＝13.8,3.8Hz,1H),2.70-2.62(dd,J＝13.2,6.0Hz,1H); MS(ESI)m/z:444.2[M+H] ⁺

Example 17 (S)-1-(3-chloro-6-(6-(5-ethylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 117

Step A: 2-[(6-chloropyrazolo[4,3-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane

To a mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (12.82 mmol; 1968 mg) in dichloromethane (50 mL) was added N,N-diisopropylethylamine (38.45 mmol, 6.7 mL). 2-(Trimethylsilyl)ethoxymethyl chloride (19.22 mmol; 3205 mg; 3.40 mL) was then added dropwise at room temperature. The resulting mixture was stirred overnight. The mixture was partitioned between DCM and water. The organic layer was concentrated and the residue was purified on silica gel eluting with 0-6% MeOH in DCM to give 2-[(6-chloropyrazolo[4,3-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (590 mg, 13%).

Step B: Trimethyl-[2-[[6-(5-vinyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl]silane

A mixture of 2-[(6-chloropyrazolo[4,3-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (1.074 mmol; 304.8 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-vinyl-pyridine (1.611 mmol; 372.3 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.1074 mmol; 89.5 mg), potassium acetate (1.611 mmol; 1.6 mL) and sodium carbonate (1.611 mmol; 1.6 mL) in acetonitrile (10 mL) was heated in a pressure tube at 150 ° C. under microwave for 5 minutes. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified on silica gel eluting with 0-6% MeOH in DCM to give trimethyl-[2-[[6-(5-vinyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl]silane (543.4 mg, 86%).

Step C: 6-(5-ethyl-pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine

To a solution of trimethyl-[2-[[6-(5-vinyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl]silane (543.4 mg) in ethanol (50 mL) in a 250 mL round-bottom flask was added Pearlman's catalyst (0.1850 mmol; 129.9 mg). The flask was evacuated and connected to a hydrogen balloon. The mixture was stirred at room temperature overnight. The mixture was filtered through celite. The filtrate was concentrated. The residue was purified on silica gel eluting with 0-5% MeOH in DCM to give 2-[[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (87 mg, 27%).

A solution of 2-[[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (0.2456 mmol; 106.8 mg) and anisole (1.228 mmol; 133 mg; 0.134 ml) in hydrochloric acid (4.0 M) and 1,4-dioxane (20 mmol; 5 ml) was stirred at room temperature overnight. The mixture was concentrated to give 6-(5-ethyl-pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine (~95.9 mg), which was used without purification.

Step D: 1-(5-chloro-6-fluoro-pyridin-2-yl)-6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridine

To a solution of 6- (5- ethyl - pyridin -3- bases) -1H- pyrazolo [4,3-c] pyridine (0.264 mmol; 95.9 mg) and 6- bromo -3- chloro -2- fluoro - pyridine (0.396 mmol; 83.4 mg) in 1,4- dioxane (10 mL) was added cesium carbonate (0.528 mmol; 172 mg), Xantphos (0.0449 mmol; 26.0 mg) and tris (dibenzylideneacetone) dipalladium (0) (0.0264 mmol; 24.2 mg) under nitrogen. The resulting mixture was sealed in a pressure tube and heated at 100 ° C for 17 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with DCM. The filtrate was concentrated. The residue was purified on silica gel eluting with 0-6% MeOH in DCM to give 1-(5-chloro-6-fluoro-pyridin-2-yl)-6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridine (54.9 mg, 59%).

Step E: tert-Butyl N-[(3S)-1-[3-chloro-6-[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of 1-(5-chloro-6-fluoro-pyridin-2-yl)-6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridine (0.155 mmol; 54.9 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (0.466 mmol; 93.2 mg) and N-methylmorpholine (1.55 mmol; 159 mg; 0.172 mL) in 1-methyl-2-pyrrolidone (3 mL) was heated in a sealed pressure bottle at 100° C. overnight. The mixture was poured into water. The precipitate was collected by filtration and dried under high vacuum to give tert-butyl N-[(3S)-1-[3-chloro-6-[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (66.6 mg, 80%), which was used without further purification.

To a solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.0446 mmol; 23.8 mg) in methanol (10 mL) was added a solution of hydrochloric acid (4.0 M) in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to give ¹¹⁷ (7.0 mg, 33%). NMR (400MHz, DMSO) δ9.36-9.31(s,1H),9.18-9.11(m,2H),8.74-8.65(s,1H),8.58-8.52(d,J＝1.9Hz,1H),8.34-8.30(s ,1H),8.02-7.97(d,J＝8.4Hz,1H),7.60-7.55(d,J＝8.4Hz,1H),3.95-3.81(dd,J＝27.5,10.2Hz,2H),3.06-2.97(t,J＝10 .2Hz,1H),2.93-2.84(t,J＝9.5Hz,1H),2.81-2.72(m,3H),1.98-1.90(d,J＝12.6Hz,1H),1.89-1.80(d,J＝13.3Hz,1H),1 .79-1.68(d,J＝12.9Hz,1H),1.68-1.48(s,2H),1.31-1.26(t,J＝7.6Hz,3H),1.26-1.20(m,1H); MS(ESI)m/z:434.2[M+H] ⁺

Example 18 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine 118

Following the procedure described in Example 8 and starting from 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepane, 118 was obtained as an off-white solid (22.8 mg, ¹⁸ %). NMR (400MHz, DMSO) δ9.36-9.33(s,1H),9.18-9.13(t,J＝4.0Hz,1H),9.10-9.05(s,1H),8.68-8.62(d,J＝5.1Hz,2 H),8.55-8.50(s,1H),7.74-7.69(dd,J＝13.8,5.6Hz,1H),7.23-7.18(d,J＝7.7Hz,1H),6.65-6.61(d,J＝8.5Hz,1 H),5.07-5.00(dd,J＝8.3,6.1Hz,2H),4.76-4.69(t,J＝6.3Hz,2H),4.48-4.36(m,1H),3.90-3.83(t,J＝5.8Hz,2H ),3.83-3.77(d,J＝5.3Hz,2H),3.01-2.93(m,2H),2.75-2.69(m,2H),1.89-1.83(m,2H); MS(ESI)m/z:428.2[M+H] ⁺

Example 19 3-Methyl-5-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[43-c]pyridin-6-yl]isothiazole 119

To a solution of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]piperazine-1-carboxylate (120 mg, 0.290 mmol) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.0290 mmol) in 1.0 mL of N,N-dimethylacetamide was added tributyl-(3-methylisothiazol-5-yl)stannane (224 mg, 0.579 mmol). The reaction mixture was heated at 150 ° C for 45 minutes in a microwave (Biotage Inc.). The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc and then washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 20% EtOAc) to give 4-[6-[6-(3-methylisothiazol-5-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (65 mg) in 47% yield.

A 1.0 mL solution of tert-butyl 4-[6-[6-(3-methylisothiazol-5-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylate (65 mg, 0.136 mmol) in 1,4-dioxane (2.0 mL, 8.0 mmol) and 1,4-dioxane was stirred at room temperature for 18 h. The reaction was concentrated under vacuum. Reverse-phase HPLC analysis of the crude product gave 118 (13 mg) in a 25% yield. ¹ H NMR (400MHz, DMSO) δ9.22 (s, 1H), 8.96 (s, 1H), 8.64 (s, 1H), 7.78 (t, J = 8.1Hz, 1H), 7.54 (s, 1H), 7.2 4(d,J＝7.7Hz,1H),6.82(d,J＝8.5Hz,1H),3.65-3.58(m,4H),2.98-2.90(m,4H).MS(ESI)m/z:378.1.

Example 20 5-[1-[6-(14-diazepan-1-yl)-pyridin-2-yl]pyrazolo[43-c]pyridin-6-yl]-3-methyl-isothiazole 120

According to the preparation of Example 19, 120 was obtained. MS (ESI) m/z: 392.1. ¹ H NMR (400 MHz, DMSO) δ 9.22 (s, 1H), 8.92 (d, J = 6.9 Hz, 1H), 8.64 (s, 1H), 7.74-7.67 (m, 1H), 7.54 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 3.86 (t, J = 5.9 Hz, 2H), 3.83-3.76 (m, 2H), 3.04-2.97 (m, 2H), 2.73 (t, J = 5.8 Hz, 2H), 1.90 (dd, J = 11.6, 5.8 Hz, 2H).

Example 21 (S)-1-(6-(6-(5-ethylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 121

Racemic 1-(6-(6-(5-ethylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin- ¹ -yl)pyridin-2-yl)-1,4-diazepan-6-ol (30 mg) was purified by chiral HPLC to give enantiomer 121 as an off-white solid (7.9 mg, 26%). NMR (400MHz, DMSO) δ9.35-9.28 (s, 1H), 9.16-9.10 (t, J = 4.0Hz, 1H), 9.07-9.04 (s, 1H), 8.67-8.6 1(s,1H),8.56-8.50(d,J＝1.8Hz,1H),8.33-8.28(s,1H),7.74-7.68(t,J＝8.1Hz,1H),7.21-7.17( d,J＝7.7Hz,1H),6.74-6.69(t,J＝7.5Hz,1H),4.91-4.77(s,1H),4.06-3.86(m,3H),3.75-3.57(m ,2H),3.04-2.96(m,2H),2.86-2.63(m,4H),1.31-1.25(t,J＝7.6Hz,3H); MS(ESI)m/z:416.1[M+H] ⁺

Example 22 (R)-1-(6-(6-(5-ethylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 122

Racemic 1-(6-(6-(5-ethylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin- ¹ -yl)pyridin-2-yl)-1,4-diazepan-6-ol (30 mg) was purified by chiral HPLC to give enantiomer 122 as an off-white solid (7.6 mg, 25%). NMR (400MHz, DMSO) δ9.34-9.28 (s, 1H), 9.14-9.10 (d, J = 1.8Hz, 1H), 9.07-9.03 (s, 1H), 8.67-8.60 ( s,1H),8.57-8.49(d,J＝1.8Hz,1H),8.33-8.27(s,1H),7.75-7.68(t,J＝8.1Hz,1H),7.22-7.16(d,J＝ 7.7Hz,1H),6.74-6.68(d,J＝8.5Hz,1H),4.90-4.74(s,1H),4.08-3.85(m,3H),3.76-3.55(m,2H),3 .03-2.95(t,J＝5.4Hz,2H),2.87-2.64(m,4H),1.30-1.26(t,J＝7.6Hz,3H); MS(ESI)m/z:416.1[M+H] ⁺

Example 23 6-(6-methylpyrazin-2-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 123

Step A: Preparation of trimethyl-(6-methylpyrazin-2-yl)stannane

A solution of 2-bromo-6-methyl-pyrazine (300 mg, 1.7 mmol), hexamethylditin (0.45 mL, 2.1 mmol) and (triphenylphosphine) (142 mg, 0.123 mmol) in 8.0 mL of 1,4-dioxane was charged with nitrogen for 5 minutes. The reaction mixture was stirred at 100 ° C for 18 hours. The reaction was filtered through celite. The crude product was used in the next step. MS (ESI) m / z: 259.1

Step B: tert-Butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylate

To a solution of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]piperazine-1-carboxylate (90 mg; 0.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) in N,N-dimethylacetamide; 2.0 mL was added trimethyl-(6-methylpyrazin-2-yl)stannane (112 mg; 0.436 mmol). The reaction mixture was heated in a microwave (Biotage) at 150 ° C for 45 minutes. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc and then washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 50% EtOAc) to afford 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester 60 mg, 58% yield.

A solution of tert-butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylate (60 mg, 0.1270 mmol) and hydrochloric acid (4 mol/L) in 1,4-dioxane (2.0 mL, 8.0 mmol) was stirred at room temperature for 18 h. The reaction mixture was concentrated and analyzed by reverse-phase HPLC to afford 123 (26 mg) in a 32% yield. MS(ESI)m/z:373.2. ¹ H NMR (400MHz, DMSO) δ9.59(s,1H),9.46(s,1H),9.31(s,1H),8.66(s,1H),8.62(s,1H),7.77(t,J＝8.1Hz ,1H),7.27(d,J＝7.7Hz,1H),6.80(d,J＝8.4Hz,1H),3.67-3.60(m,4H),2.96-2.89(m,4H),2.63(s,3H).

Example 24 (3S)-1-[6-[6-(3-methylisothiazol-5-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 124

According to the preparation of Example 19, 124 was obtained. MS (ESI) m/z: 392.2. ¹ H NMR (400 MHz, DMSO) δ 9.22 (s, 1H), 9.00 (s, 1H), 8.64 (s, 1H), 7.92 (s, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 4.36 (d, J = 8.9 Hz, 1H), 4 .13(d,J＝12.8Hz,1H),3.08-2.98(m,1H),2.89-2.77(m,2H),2.48(s,3H),1.97(d, J＝9.9Hz,1H),1.88-1.80(m,2H),1.60(dd,J＝24.6,11.9Hz,1H),1.42-1.29(m,1H).

Example 25 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 125

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1,4-diazepane, 125 was obtained as an off-white solid (21.5 mg, 17%). ¹ H NMR (400 MHz, DMSO) δ 9.15-9.09 (s, 1H), 8.55-8.48 (s, 1H), 8.29-8.21 (s, 1H), 7.92-7.86 (s, 1H), 7.71-7.65 (t, J = 8.0 Hz, 1H), 7.17-7.12 (d, J = 7.7 Hz, 1H), 6.62-6.56 (d, J = 8.5 Hz, 1H), 4. 24-4.19(d,J＝7.3Hz,2H),3.88-3.84(t,J＝6.0Hz,2H),3.82-3.77(m,2H),3.02-2.95(m,2H), 2.76-2.69(m,2H),1.90-1.86(m,2H),1.45-1.42(t,J＝7.3Hz,3H).;MS(ESI)m/z:389.2[M+H] ⁺

Example 26 (S)-6-(1-ethyl-1H-pyrazol-4-yl)-1-(6-(3-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 126

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and (S)-2-methylpiperazine, 126 was obtained as an off-white solid (19.7 mg, 16%). ¹ H NMR (400 MHz, DMSO) δ 9.18-9.09 (s, 1H), 8.72-8.60 (s, 1H), 8.56-8.47 (s, 1H), 8.30-8.25 (s, 1H), 7.96-7.89 (s, 1H), 7.78-7.71 (t, J = 8.1 Hz, 1H), 7.24-7.17 (d, J = 7.7 Hz, 1H), 6.82-6.75 (d, J = 8.4 Hz, 1H). z,1H),4.27-4.13(m,4H),3.09-3.01(d,J＝11.4Hz,1H),2.99-2.89(m,1H),2.89-2.76(m,2H),2.6 3-2.55(m,1H),1.47-1.39(t,J＝7.3Hz,3H),1.13-1.06(d,J＝6.2Hz,3H); MS(ESI)m/z:389.0[M+H] ⁺

Example 27 (S)-1-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)pyrrolidin-3-ol 127

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and (S)-pyrrolidin-3-ol, 127 was obtained as an off-white solid (18.6 mg, ¹⁴ %). NMR (400MHz, DMSO) δ9.19-9.05(s,1H),8.92-8.78(s,1H),8.55-8.46(s,1H),8.34-8.20(d,J＝8.3Hz,1H),7.99-7.91(s,1 H),7.73-7.64(t,J＝8.0Hz,1H),7.19-7.09(d,J＝7.7Hz,1H),6.42-6.35(d,J＝8.3Hz,1H),5.15-5.01(d,J＝3.7Hz,1H),4.57 -4.47(s,1H),4.26-4.16(q,J＝7.3Hz,2H),3.80-3.71(d,J＝6.4Hz,1H),3.72-3.60(s,2H),3.58-3.45(d,J＝10.6Hz,1H),2. 20-2.09(ddd,J＝13.1,8.6,4.6Hz,1H),2.06-1.97(d,J＝3.3Hz,1H),1.48-1.40(q,J＝7.5Hz,3H).;MS(ESI)m/z:376.2[M+H] ⁺

Example 28 (R)-1-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)pyrrolidin-3-ol 128

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and (R)-pyrrolidin-3-ol, 128 was obtained as an off-white solid (18.6 mg, ¹⁴ %). NMR (400MHz, DMSO) δ9.19-9.05(s,1H),8.92-8.78(s,1H),8.55-8.46(s,1H),8.34-8.20(d,J＝8.3Hz,1H),7.99-7.91(s,1 H),7.73-7.64(t,J＝8.0Hz,1H),7.19-7.09(d,J＝7.7Hz,1H),6.42-6.35(d,J＝8.3Hz,1H),5.15-5.01(d,J＝3.7Hz,1H),4.57 -4.47(s,1H),4.26-4.16(q,J＝7.3Hz,2H),3.80-3.71(d,J＝6.4Hz,1H),3.72-3.60(s,2H),3.58-3.45(d,J＝10.6Hz,1H),2. 20-2.09(ddd,J＝13.1,8.6,4.6Hz,1H),2.06-1.97(d,J＝3.3Hz,1H),1.48-1.40(q,J＝7.5Hz,3H).;MS(ESI)m/z:376.2[M+H] ⁺

Example 29 1-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-4-ol 129

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and piperidin-4-ol, 129 was obtained as an off-white solid (23.8 mg, ¹⁹ %). NMR (400MHz, DMSO) δ9.18-9.07(s,1H),8.70-8.60(s,1H),8.57-8.49(s,1H),8.30-8.22(s,1H),7.94-7.84(s,1H ),7.80-7.66(t,J＝8.1Hz,1H),7.26-7.10(d,J＝7.7Hz,1H),6.88-6.73(d,J＝8.4Hz,1H),4.87-4.71(d,J＝4.2Hz,1H ),4.26-4.18(q,J＝7.3Hz,2H),4.18-4.08(dt,J＝9.0,4.3Hz,2H),3.88-3.77(dt,J＝12.7,4.3Hz,1H),3.40-3.31( m,2H),1.98-1.88(dd,J＝8.7,4.4Hz,2H),1.59-1.47(m,2H),1.47-1.39(t,J＝7.3Hz,3H); MS(ESI)m/z:390.2[M+H] ⁺

Example 30 6-(6-methoxypyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[43-c]pyridine 130

According to the preparation of Example 23, 130 was obtained. MS (ESI) m/z: 389.2. ¹ H NMR (400 MHz, DMSO) δ 9.33 (s, 1H), 9.28 (s, 1H), 9.25 (s, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.08 (s, 3H), 3.65-3.58 (m, 5H), 2.90-2.83 (m, 4H).

Example 31 1-(6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)-6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 131

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2,2-dimethylpiperazine, 131 was obtained as an off-white solid (14.2 mg, 11%). ¹ H NMR (400 MHz, DMSO) δ 9.23-9.05 (s, 1H), 8.69-8.58 (s, 1H), 8.57-8.48 (d, J = 5.7 Hz, 1H), 8.33-8.20 (s, 1H), 7.98-7.88 (s, 1H), 7.75-7.68 (t, J = 8.1 Hz, 1H), 7.21-7.12 (d, J = 7.7 Hz, 1H), 6 .82-6.75(d,J＝8.5Hz,1H),4.25-4.17(q,J＝7.3Hz,2H),3.64-3.54(m,2H),3.46-3.41(s,2H) ,3.00-2.88(m,2H),1.47-1.39(t,J＝7.3Hz,3H),1.19-1.06(s,6H); MS(ESI)m/z:403.2[M+H] ⁺

Example 32 1-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-4-amine 132

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl piperidin-4-ylcarbamate, 132 was obtained over 2 steps as an off-white solid (15.2 mg, ¹² %). NMR (400MHz, DMSO) δ9.18-9.06(s,1H),8.68-8.62(s,1H),8.56-8.48(d,J＝4.4Hz,1H),8.31-8.21(s,1H),7.93- 7.85(s,1H),7.77-7.68(t,J＝8.1Hz,1H),7.23-7.14(d,J＝7.7Hz,1H),6.85-6.75(d,J＝8.5Hz,1H),4.36-4.26(d ,J＝13.1Hz,2H),4.27-4.16(q,J＝7.3Hz,2H),3.20-3.10(dd,J＝18.0,6.6Hz,2H),2.96-2.87(td,J＝9.9,4.9Hz,1 H),1.92-1.83(dd,J＝12.7,2.9Hz,2H),1.47-1.41(t,J＝7.3Hz,3H),1.41-1.30(m,2H); MS(ESI)m/z:389.2[M+H] ⁺

Example 34 (R)-1-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 134

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl (R)-piperidin-3-ylcarbamate, 134 was obtained over 2 steps as an off-white solid (15.3 mg, ¹² %). NMR (400MHz, DMSO) δ9.17-9.08(s,1H),8.72-8.65(s,1H),8.54-8.50(s,1H),8.49-8.43(s,1H),8.09-7.98(d,J＝15.0H z,1H),7.78-7.65(t,J＝8.1Hz,1H),7.23-7.12(d,J＝7.7Hz,1H),6.83-6.70(d,J＝8.5Hz,1H),4.37-4.29(d,J＝10.4Hz,1H ),4.26-4.11(m,3H),3.09-2.99(m,1H),2.89-2.72(m,2H),2.00-1.91(d,J＝9.4Hz,1H),1.90-1.73(m,2H),1.67-1.53(d d,J＝24.3,12.1Hz,1H),1.46-1.39(t,J＝7.3Hz,3H),1.39-1.28(ddd,J＝15.9,12.4,3.7Hz,1H); MS(ESI)m/z:389.2[M+H] ⁺

Example 35 (S)-1-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)pyrrolidin-3-amine 135

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- ^yl )-1H-pyrazole and (S)-tert-butyl pyrrolidin-3-ylcarbamate, 135 was obtained over 2 steps as an off-white solid (11.1 mg, 8.5%). NMR (400MHz, DMSO) δ9.14-9.09(s,1H),8.90-8.83(d,J＝16.8Hz,1H),8.57-8.46(d,J＝16.4Hz,1H),8.33 -8.23(d,J＝12.5Hz,1H),7.98-7.91(d,J＝8.6Hz,1H),7.71-7.65(t,J＝8.0Hz,1H),7.17-7.10(d,J＝7.7Hz ,1H),6.41-6.33(d,J＝8.3Hz,1H),4.26-4.16(q,J＝7.3Hz,2H),3.82-3.65(m,3H),3.65-3.54(s,1H),2.2 2-2.14(dt,J＝18.7,6.2Hz,1H),1.90-1.78(m,1H),1.47-1.41(q,J＝7.0Hz,3H); MS(ESI)m/z:375.2[M+H] ⁺

Example 36 (R)-1-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)pyrrolidin-3-amine 136

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and (R)-tert-butyl pyrrolidin-3-ylcarbamate, 136 was obtained over 2 steps as an off-white solid (14.5 mg, ¹² %). NMR(400MHz,DMSO)δ9.16-9.08(s,1H),8.90-8.85(s,1H),8.52-8.50(s,1H),8.29-8.25(s,1H),7 .99-7.92(m,1H),7.71-7.65(t,J＝8.0Hz,1H),7.16-7.10(d,J＝7.7Hz,1H),6.38-6.33(d,J＝8.3Hz, 1H),4.26-4.16(q,J＝7.3Hz,2H),3.83-3.65(m,3H),3.64-3.54(s,1H),2.22-2.12(dt,J＝12.6,6. 3Hz, 1H), 1.89-1.79 (td, J＝12.9, 6.4Hz, 1H), 1.47-1.41 (t, J＝7.3Hz, 3H); MS (ESI) m/z: 375.2[M+H] ⁺

Example 37 (3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 137

According to the preparation of Example 23, 137 was obtained. ¹ H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.62 (s, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 4.40 (d, J = 13.0Hz,1H),4.15(d,J＝11.2Hz,1H),3.17-3.07(m,1H),2.89-2.75(m,2H),2.64(s ,3H),1.98-1.81(m,2H),1.69-1.57(m,1H),1.40-1.27(m,1H).MS(ESI)m/z:387.2.

Example 38 1-[6-(14-diazepan-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridine 138

According to the preparation of Example 23, 138 was obtained. MS (ESI) m/z: 387.2. ¹ H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.62 (s, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.21 (t, J = 6.8 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 3.89 (dd, J = 15.6, 9.7 Hz, 4H), 3.08-3.00 (m, 2H), 2.78-2.70 (m, 2H), 2.61 (s, 3H), 1.93 (dd, J = 11.5, 6.0 Hz, 2H).

Example 39 (S)-1-(3-cyclopropyl-6-(6-(5-ethylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 139

Step A: tert-Butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.0801 mmol; 42.8 mg), potassium cyclopropyltrifluoroborate (0.120 mmol; 18.3 mg), butyldi(1-adamantyl)phosphine (0.0240 mmol; 9.07 mg), cesium carbonate (0.240 mmol; 78.3 mg), and palladium(II) acetate (0.0160 mmol; 3.60 mg) in water (0.5 mL) and toluene (4.5 mL) was degassed with argon for 1 minute. The reaction mixture was stirred in a pressure tube at 105° C. for 3 days. The layers were separated. The organic layer was concentrated. The residue was purified on silica gel eluting with 0-5% MeOH in DCM to give tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (32.2 mg, 74%).

Step B: To a solution of tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.0597 mmol; 32.2 mg) in methanol (10 mL) was added a 4.0 M solution of hydrochloric acid in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 139 as an off-white solid (20 mg, 7.4%). MS (ESI) m/z: 440.3 [M+H] ⁺

Example 40 1-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepan-4-amine 140

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl azepan-4-ylcarbamate, 140 was obtained over 2 steps as an off-white solid (16.2 mg, ¹² %). NMR (400MHz, DMSO) δ9.15-9.11(s,1H),8.70-8.65(d,J＝9.8Hz,1H),8.54-8.47(d,J＝8.1Hz,1H),8.28-8.25(d,J＝7.4Hz,1H),7.95-7.87(s,1H),7 .73-7.66(dd,J＝10.5,5.7Hz,1H),7.18-7.12(d,J＝7.7Hz,1H),6.60-6.5 4(t,J＝6.6Hz,1H),4.25-4.18(q,J＝7.3Hz,2H),3.95-3.86(s,1H),3.85- 3.77(m,1H),3.75-3.58(ddd,J＝20.2,14.0,9.4Hz,2H),2.94-2.85(dd,J ＝12.2,6.3Hz,1H),2.07-1.96(m,2H),1.83-1.74(m,1H),1.74-1.66(d,J ＝14.4Hz,1H),1.65-1.56(ddd,J＝13.0,9.1,4.5Hz,1H),1.46-1.41(t,J＝7.3Hz,3H),1.42-1.34(dd,J＝14.2,4.0Hz,1H); MS(ESI)m/z:403.2[M+H] ⁺

Example 41 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(5-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine 141

Following the procedure described in Example 8 and starting from (5-methylpyridin-3-yl)boronic acid and 1,4-diazepane, 141 was obtained over 2 steps as an off-white solid (23.3 mg, 22%). ¹ H NMR (400 MHz, DMSO) δ 9.33-9.29 (s, 1H), 9.08-8.99 (m, 2H), 8.64-8.61 (s, 1H), 8.53-8.48 (d, J = 1.5 Hz, 1H), 8.24-8.21 (s, 1H), 7.74-7.67 (t, J = 8.1 Hz, 1H), 7.21-7.16 (d, J = 7.7 Hz, 1H ),6.65-6.59(d,J＝8.5Hz,1H),3.88-3.83(t,J＝6.0Hz,2H),3.82-3.74(m,2H),3.02-2.95 (m,2H),2.75-2.69(m,2H),2.45-2.40(s,3H),1.92-1.83(m,2H); MS(ESI)m/z:386.2[M+H] ⁺

Example 42 (R)-6-(1-ethyl-1H-pyrazol-4-yl)-1-(6-(3-ethylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 142

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and (R)-tert-butyl 2-ethylpiperazine-1-carboxylate, 142 was obtained over ² steps as an off-white solid (12.7 mg, 10%). NMR (400MHz, DMSO) δ9.18-9.06(s,1H),8.67-8.59(s,1H),8.56-8.49(s,1H),8.31-8.25(s,1H),7.95- 7.90(s,1H),7.78-7.70(t,J＝8.1Hz,1H),7.23-7.15(d,J＝7.7Hz,1H),6.84-6.76(d,J＝8.5Hz,1H),4.27 -4.15(m,4H),3.10-3.03(d,J＝11.7Hz,1H),3.01-2.93(td,J＝11.8,3.0Hz,1H),2.86-2.77(td,J＝11.6, 3.0Hz,1H),2.68-2.56(m,2H),1.48-1.38(m,5H),0.94-0.87(t,J＝7.5Hz,3H); MS(ESI)m/z:403.2[M+H] ⁺

Example 43 N-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepan-3-amine 143

Following the procedure described in Example 8 and starting from 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl 3-aminoazepane-1-carboxylate, 143 was obtained over 2 steps as an off-white solid (3.6 mg, 2.8%). MS (ESI) m/z: 403.2 [M+H] ⁺

Example 44 1-(6-(Piperazin-1-yl)-pyridin-2-yl)-6-(pyrazin-2-yl)-pyrazolo[43-c]pyridine 144

To a solution of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]piperazine-1-carboxylate (40 mg, 0.096 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0095 mmol) in 1 mL of N,N-dimethylacetamide was added (2-pyrazinyl)tributyltin (0.064 mL, 0.19 mmol). The reaction mixture was heated at 150 ° C. in a biotage microwave for 45 minutes. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc and then washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 20% EtOAc) to afford 4-[6-(6-pyrazin-2-ylpyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester 30 mg, 67% yield.

A solution of tert-butyl 4-[6-(6-pyrazin-2-ylpyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]piperazine-1-carboxylate (30 mg, 0.065 mmol) in 1,4-dioxane (1.5 mL, 6.0 mmol) and 1.5 mL of 1,4-dioxane was stirred at room temperature for 18 h. The reaction mixture was concentrated and analyzed by reverse-phase HPLC to afford 144 (12 mg) in a 34% yield. MS(ESI)m/z:359.1. ^1H NMR (400MHz, DMSO) δ9.70 (s, 1H), 9.65 (d, J = 1.1Hz, 1H), 9.34 (s, 1H), 8.78-8.74 (m, 1H), 8.72 (d, J = 2.4Hz, 1H), 8.68 (d, J＝5.3Hz,1H),7.77(t,J＝8.1Hz,1H),7.25(d,J＝7.7Hz,1H),6.79(d,J＝8.4Hz,1H),3.67-3.61(m,4H),2.97-2.90(m,4H).

Example 45 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-tert-butyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 145

Step A: tert-Butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate

A solution of 2-bromo-6-fluoropyridine (500 mg, 2.8 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (568 mg, 2.8 mmol) in ethanol (10 mL) containing DIPEA (1.83 g, 14.2 mmol) was heated at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (100 mL). The solution was washed with brine, dried _{over Na₂SO₄} , and concentrated under reduced pressure to yield tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate as a colorless oil (500 mg, 50%). MS (ESI) m/z: 356 [M+H] ^⁺ .

Step B: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate (2.55 g, 7.16 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (1.0 g, 6.51 mmol) in 1,4-dioxane (20 mL) was added CuI (494 mg, 2.6 mmol), K ₂ CO ₃ (3.6 g, 26 mmol) and N ¹ , N ² -dimethylethane-1,2-diamine (460 mg, 5.2 mmol). The mixture was heated at 100 ° C for 3 hours, which was monitored by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using petroleum ether/EtOAc (2/1) as eluent to provide tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (1.6 g, 57%). MS (ESI) m/z: 429 [M+H] ⁺ .

Step C: 1-tert-Butyl-1H-pyrazole

A mixture of 1,1,3,3-tetramethoxypropane (3.7 g, 22.6 mmol), tert-butylhydrazine hydrochloride (2.8 g, 22.6 mmol), and concentrated HCl (6 mL, 72 mmol) in EtOH (30 mL) was heated at reflux overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over _MgSO₄ , and concentrated under reduced pressure to afford 1-tert-butyl-1H-pyrazole as a white solid (2.5 g, 89%). MS (ESI) m/z: 125 [M+H] ^⁺ .

Step D: 4-Bromo-1-tert-butyl-1H-pyrazole

To a suspension _{of Na₂CO₃} (3.6 g, 33.9 mmol) in _CH₂Cl₂ (30 _mL ) was added 1-tert-butyl-1H-pyrazole (2.1 g, 17 mmol) and _Br₂ (0.9 mL). The mixture was stirred at room temperature overnight. The formed solid was removed by filtration, and the filter cake was washed with _CH₂Cl₂ (30 mL) _. The filtrate was washed with water (20 mL) and brine (20 mL), dried ( _MgSO₄ ), and concentrated under reduced pressure to afford crude 4-bromo-1-tert-butyl-1H-pyrazole (2.9 g, 85%), which was used in the next step without further purification. MS (ESI) m/z: 203 [M+H] ^⁺ .

Step E: 1-tert-Butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of 4-bromo-1-tert-butyl-1H-pyrazole (3.3 g, 16.3 mmol), pinacol diboronate (8.3 g, 32.6 mmol), _PdCl₂ (dppf) (1.8 g, 2.4 mmol), and KOAc (3.2 g, 32.6 mmol) in 1,4-dioxane (60 mL) was heated at reflux for 15 hours. After the reaction was complete, the mixture was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using heptane/ethyl acetate (10%-50%) as the eluting solvent to provide 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (1.0 g, 25%). MS (ESI) m/z: 251 [M+H] ⁺ .

Step F: tert-Butyl 4-(6-(6-(1-tert-butyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

A mixture of 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (220 mg, 0.88 mmol), tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (377 mg, 0.88 mmol) and Pd(dppf) _Cl2 (64 mg, 0.088 mmol) in 1,4- _dioxane (20 mL) and _Na2CO3 (2.0 M, 5 mL) was heated at 100°C under nitrogen for 20 hours. The crude product was purified by silica gel chromatography using petroleum ether:EtOAc (50%-100%) as the eluent to yield tert-butyl 4-(6-(6-(1-tert-butyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (240 mg, 53%). MS (ESI) m/z: 517 [M+H] ⁺ .

Step G: A solution of tert-butyl 4-(6-(6-(1-tert-butyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (100 mg, 0.19 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with MeOH (10 mL), neutralized with 28% aqueous ammonia solution, concentrated and purified by preparative HPLC to give 145 as a white solid (45 mg, 56%). ¹ H-NMR (500MHz, CD ₃ OD)δ(ppm)9.03(s,1H),8.71(d,J＝6.5Hz,1H),8.36(s,1H),8.28(s,1H),7.98(s,1H),7.65-7.68(m,1H),7.25(d,J＝7.5Hz,1H),6.5 8(d,J＝8.5Hz,1H),3.90-3.94(m,4H),3.14-3.16(m,2H),2.91-2.94(m,2H),2.05-2.10(m,2H),1.68(s,9H); MS(ESI)m/z:417[M+H] ⁺ .

Example 46 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-isopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 146

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2-bromopropane, 146 was obtained as a yellow solid (90 mg, 75%) over 2 steps. ¹ H-NMR (500MHz, CD ₃ OD)δ(ppm)8.93(s,1H),8.54(s,1H),8.25(s,1H),8.10(s,1H),7.86(s,1H),7.55-7.59(m,1H),7.15(d,J＝7.5Hz,1H),6.47(d,J＝8.0Hz,1H), 4.56-4.63(m,1H),3.78-3.82(m,4H),3.06-3.08(m,2H),2.85-2.87(m,2H),1.98-2.02(m,2H),1.57(d,J＝6.5Hz,6H);MS(ESI)m/z:403[M+H] ⁺ .

Example 47 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-cyclobutyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 147

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and bromocyclobutane, 147 was obtained as a yellow solid (40 mg, 35%) over 2 steps. ¹ H-NMR (500MHz, CD ₃ OD)δ(ppm):9.02(s,1H),8.66(s,1H),8.34(s,1H),8.18(s,1H),7.95(s,1 H),7.66-7.69(m,1H),7.25(d,J＝7.5Hz,1H),6.59(d,J＝8.5Hz,1H),4.91-4 .96(m,1H),3.90-3.95(m,4H),3.20-3.22(m,2H),3.00-3.02(m,2H),2.52 -2.63(m,4H),2.08-2.13(m,2H),1.92-1.99(m,2H); MS(ESI)m/z:415[M+H] ⁺ .

Example 48 5-(1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-2-methylpyridazin-3(2H)-one 148

A solution of 4-chloro-1H-pyridazin-6-one (6.000 mmol; 783.2 mg), iodomethane (7.200 mmol; 1032 mg; 0.453 mL) and potassium carbonate (9.000 mmol; 1256 mg) in DMF (12 mL) was stirred at room temperature overnight. The mixture was filtered. The filtrate was partitioned between EtOAc and water. The organic layer was concentrated. The residue was purified on silica gel eluting with 0-40% EtOAc in DCM to give 5-chloro-2-methyl-pyridazin-3-one as an off-white solid (514.7, 59%).

To a mixture of 5-chloro-2-methyl-pyridazin-3-one (3.560 mmol; 514.7 mg), pinacol diboron (5.687 mmol; 1459 mg) and potassium acetate (7.121 mmol; 720.5 mg) in 1,4-dioxane (12 mL) in a pressure tube under nitrogen was added X-PHOS (0.4273 mmol; 142.3 mg) and tris(dibenzylideneacetone)dipalladium(0) (0.1780 mmol; 163.0 mg). The tube was sealed and heated at 90° C. for 2 h. The reaction mixture was filtered through celite. The filter cake was washed with EtOAc. The filtrate was washed with water and brine. The organic layer was dried over MgSO ₄ and then concentrated to give 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3-one, which was used without further purification.

A mixture of 6-chloro-1-[6-(1,4-diazacycloheptan-1-yl)-pyridin-2-yl]pyrazolo[4,3-c]pyridine (0.3190 mmol; 104.9 mg), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3-one (0.4786 mmol; 113.0 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.03190 mmol; 26.6 mg), potassium acetate (0.4786 mmol; 0.48 mL), and sodium carbonate (0.4786 mmol; 0.48 mL) in acetonitrile (10 mL) was heated in a microwave at 150° C. for 15 minutes in a pressure tube. The mixture was filtered through celite. The filtrate was concentrated. The residue was purified on silica gel using 10% MeOH in DCM containing 1% NH ₄ OH. The obtained product (29 mg, purity>90%) was further purified by reverse phase HPLC to afford 148 as an off-white solid (10.9 mg, 8.5%). ¹ H NMR (400 MHz, DMSO) δ 9.39-9.31 (s, 1H), 9.08-9.01 (s, 1H), 8.72-8.65 (s, 1H), 8.56-8.51 (d, J=2.1 Hz, 1H), 8.31-8.22 (s, 1H), 7.76-7.69 (t, J=8.1 Hz, 1H), 7.42-7.38 (d, J=2.1 Hz, 1H ),7.22-7.18(d,J＝7.7Hz,1H),6.69-6.62(d,J＝8.5Hz,1H),3.87-3.79(m,4H),3.74-3.72 (s,3H),3.05-3.00(m,2H),2.83-2.77(m,2H),1.94-1.87(m,2H); MS(ESI)m/z:403.2[M+H] ⁺

Example 49 6-(6-ethylpyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[43-c]pyridine 149

According to the preparation of Example 23, 149 was obtained. MS (ESI) m/z: 387.2. ¹ H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 9.50 (s, 1H), 9.33 (s, 1H), 8.66 (d, J = 3.9 Hz, 2H), 7.77 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 3.67-3.58 (m, 4H), 2.91 (dd, J = 8.9, 4.5 Hz, 6H), 1.36 (t, J = 7.6 Hz, 3H).

Example 50 1-[6-(14-diazepan-1-yl)-pyridin-2-yl]-6-(6-ethylpyrazin-2-yl)pyrazolo[43-c]pyridine 150

According to the preparation procedure of Example 23, 150 was obtained. MS (ESI) m/z: 401.2. ¹ H NMR (400MHz, DMSO) δ9.60 (d, J = 6.4Hz, 1H), 9.49 (s, 1H), 9.32 (s, 1H), 8.66 (d, J＝2.8Hz,2H),7.72(dd,J＝14.7,6.6Hz,1H),7.20(d,J＝7.7Hz,1H),6.62(d,J＝ 8.5Hz,1H),3.91(t,J＝6.0Hz,2H),3.85-3.78(m,2H),3.01-2.94(m,2H),2.90 (q,J＝7.6Hz,3H),2.72-2.64(m,3H),1.94-1.84(m,2H),1.35(t,J＝7.6Hz,3H).

Example 51 3-ethyl-5-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[43-c]pyridin-6-yl]pyrimidin-4-one 151

According to the preparation of Example 23, 151 was obtained. MS (ESI) m/z: 403.2. ¹ H NMR (400 MHz, DMSO) δ 9.80 (s, 1H), 9.23 (s, 1H), 9.02 (s, 1H), 8.65 (s, 1H), 8.59 (s, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.65-3.57 (m, 4H), 2.96-2.83 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H).

Example 52 2-(4-(1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)ethanol 152

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and ethylene oxide, 152 was obtained over 2 steps as a light yellow solid (102 mg, 71%). ¹ H NMR (500 MHz, CDCl ₃ )δ(ppm)8.941-8.942(d,J＝0.5Hz,1H),8.57(s,1H),8.17(s,1H),8.07(s,1H),7.86(s,1H) ,7.57-7.60(t,J＝16Hz,1H),7.22-7.26(t,J＝20.5Hz,1H),6.36-6.37(d,J＝8Hz,1H),4.30-4 .32(t,J＝9.5Hz,2H),4.05-4.07(t,J＝9.5Hz,2H),3.77-3.82(m,4H),3.11-3.13(t,J＝10.5H z,2H),2.88-2.91(t,J＝11.5Hz,2H),2.26(s,2H),1.97-2.01(m,2H); MS(ESI)m/z:405[M+H] ⁺ .

Example 53 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 153

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 1-bromo-2-fluoroethane, 153 was obtained over 2 steps as a yellow solid (60 mg, 87.5%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.12(s,1H),8.63(s,1H),8.51(s,1H),8.28(s,1H),7.95(s,1H),7.49-7 .66(m,1H),7.13-7.15(d,J＝7.5Hz,1H),6.55-6.57(d,J＝8.5Hz,1H),4.88-4.90( m,1H),4.73-4.80(m,1H),4.54-4.58(m,1H),4.49-4.52(m,1H),3.77-3.83(m,4H ),2.97-2.99(m,2H),2.70-2.72(m,2H),1.87-1.89(m,2H); MS(ESI)m/z:407[M+H] ⁺ .

Example 54 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 154

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2,2,2-trifluoroethyl trifluoromethanesulfonate, 154 was obtained over 2 steps as a white solid (45 mg, 31%). ¹ H NMR (500 MHz, CDCl ₃ )δ(ppm)9.060-9.062(d,J＝1Hz,1H),8.76(s,1H),8.24(s,1H),8.16(s,1H),8.05(s ,1H),7.60-7.63(t,J＝16Hz,1H),7.26-7.28(t,J＝7.5Hz,1H),6.42-6.43(d,J＝8.5H z,1H),4.75-4.78(t,J＝16.5Hz,2H),3.86-3.92(m,4H),3.15-3.17(t,J＝10.5Hz,2H ),2.90-2.92(t,J＝11.5Hz,2H),2.01-2.03(t,J＝11.5Hz,2H); MS(ESI)m/z:443[M+H] ⁺ .

Example 55 2-(4-(1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)acetonitrile 155

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2-bromonitrile, 155 was obtained as a white solid (25 mg, 18.5%) over 2 steps. ¹ H NMR (500MHz, CDCl ₃ )δ(ppm)9.064-9.065(d,J＝0.5Hz,1H),8.75(s,1H),8.25(s,1H),8.19(s,1 H),8.05(s,1H),7.61-7.64(t,J＝16.5Hz,1H),7.28(s,1H),6.43-6.45(d,J ＝8.5Hz,1H),5.15(s,2H),3.88-3.92(m,4H),3.17-3.19(t,J＝11Hz,2H),2. 92-2.94(t,J＝11Hz,2H),2.02-2.05(t,J＝12Hz,2H); MS(ESI)m/z:400[M+H] ⁺ .

Example 56 (3S)-1-[6-[6-(6-ethylpyrazin-2-yl)pyrazolo[4S-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 156

Step A: Preparation of 6-(6-ethylpyrazin-2-yl)-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine

To a solution of 6-chloro-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine (85 mg; 0.34 mmol) and tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol) in N,N-dimethylacetamide; 2.0 mL was added (6-ethylpyrazin-2-yl)-trimethyl-stannane (185 mg, 0.684 mmol). The reaction was purged with _N2 for 5 minutes and then heated at 150 °C in a biotage microwave for 45 minutes. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc and then washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 50% EtOAc) to give 6-(6-ethylpyrazin-2-yl)-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine (45 mg) in 41% yield. MS (ESI) m/z: 321.2

Step B: (S)-tert-Butyl(1-(6-(6-(6-ethylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-yl)carbamate

A solution containing 6-(6-ethylpyrazin-2-yl)-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine (75 mg, 0.23 mmol) and tert-butyl N-[(3S)-3-piperidinyl]carbamate (234 mg, 1.17 mmol) in 2.0 mL of methyl sulfoxide was heated at 95 ° C. The reaction was quenched with water and then extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluted at 65% EtOAc) to give tert-butyl (S)-(1-(6-(6-ethylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-yl)carbamate (80 mg) in 68% yield.

Step C: A solution of tert-butyl (S)-(1-(6-(6-ethylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-yl)carbamate (80 mg, 0.16 mmol) in hydrochloric acid (4 mol/l) in 1,4-dioxane (2.0 ml, 8.0 mmol) and 2.0 mL of 1,4-dioxane was stirred at room temperature for 18 h. The reaction was concentrated and purified by reverse phase HPLC to give 156 (47 mg) in ⁵⁰ % yield. NMR (400MHz, DMSO) δ9.55(s,1H),9.49(s,1H),9.33(s,1H),8.66(d,J＝4.9Hz,2H),7.75(t,J ＝8.1Hz,1H),7.21(d,J＝7.7Hz,1H),6.82(d,J＝8.5Hz,1H),4.42(d,J＝13.1Hz,1H),4.12(d,J＝ 10.6Hz,1H),3.17-3.06(m,1H),2.93(q,J＝7.5Hz,2H),2.88-2.71(m,2H),1.84(ddd,J＝17.0 ,13.4,8.1Hz,2H),1.58(dd,J＝24.7,11.5Hz,1H),1.35(t,J＝7.6Hz,3H).MS(ESI)m/z:401.2.

Example 57 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 157

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2-(methylsulfonyl)ethyl 4-methylbenzenesulfonate, 157 was obtained over 2 steps as a white solid (50 mg, 40.6%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.16(s,1H),8.58(s,1H),8.56(s,1H),8.39(s,1H),8.02(s,1H),7.76-7.79(t,J＝16Hz ,1H),7.23-7.24(d,J＝7.5Hz,1H),6.71-6.73(d,J＝8.5Hz,1H),4.64-4.67(t,J＝13.5Hz,2H),4. 01-4.03(t,J＝9.5Hz,2H),3.89-3.87(t,J＝11.5Hz,2H),3.76-3.79(t,J＝14Hz,2H),3.32(s,2H) ,3.17-3.20(t,J＝10.5Hz,2H),2.94(s,3H),2.13-2.14(d,J＝4.5Hz,2H); MS(ESI)m/z:467[M+H] ⁺ .

Example 58 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 158

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and oxetan-3-ylmethyl 4-methylbenzenesulfonate, 158 was obtained over 2 steps as a yellow solid (38 mg, 51%). ¹ H-NMR (500 MHz, CD ₃ OD)δ(ppm):9.16-9.19(m,1H),8.86-8.77(m,3H),8.43-8.47(m,1H),7.66- 7.73(m,1H),7.18-7.26(m,1H),6.63-6.66(m,1H),4.81-4.83(m,2H),4.60 -4.64(m,2H),3.75-3.97(m,7H),3.61-3.64(m,1H),3.46-3.48(m,1H),3.1 0-3.12(m,1H),2.88-2.90(m,1H),1.98-2.07(m,2H); MS(ESI)m/z:431[M+H] ⁺ .

Example 59 2-(4-(1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-1-yl)acetamide 159

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2-bromoacetonitrile, 159 was obtained as a white solid (12 mg, 36%) over 2 steps. ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.11(s,1H),8.64(s,1H),8.46(s,1H),8.20(s,1H),7.91(s,1H),7.64-7.70(m,1H),7.14-7.16(d,J＝12.5Hz,3H),6. 56-6.59(d,J＝14Hz,1H),4.83(s,1H),3.78-3.88(m,6H),2.74-2.78(m,3H),1.88-1.92(t,J＝20Hz,2H); MS(ESI)m/z:418[M+H] ⁺ .

Example 60 6-(6-methylpyrazin-2-yl)-1-[6-(1,23,6-tetrahydropyridin-4-yl)-pyridin-2-yl]pyrazolo[4,3-c]pyridine 160

Step A: 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a solution of 1-(6-bromo-pyridin-2-yl)-6-chloro-pyrazolo[4,3-c]pyridine (150 mg, 0.485 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate (180 mg, 0.581 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (32 mg, 0.039 mmol) in 5.0 mL of acetonitrile was added 1.00 M aqueous potassium acetate (0.73 mL, 0.73 mmol) and 1.00 M aqueous sodium carbonate (0.73 mL, 0.73 mmol). The reaction mixture was stirred at 95° C. for 2 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 35% EtOAc) to give 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (185 mg) in 92% yield. MS (ESI) m/z: 412.2

Step B: 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3,6-dihydro-2h-pyridine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (200 mg, 0.486 mmol) and tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.049 mmol) in 5.0 mL of N,N-dimethylacetamide was added trimethyl-(6-methylpyrazin-2-yl)stannane (250 mg, 0.971 mmol). The reaction mixture was heated at 150 ° C in a microwave for 40 minutes. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluted at 65% EtOAc) to give the desired product 165 mg in 72% yield.

Step C: A solution of tert-butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3,6-dihydro-2h-pyridine-1-carboxylate (40 mg, 0.085 mmol) in 1,4-dioxane (1.0 mL, 4.0 mmol) and 1.0 mL of 1,4-dioxane was stirred at room temperature for 18 h. The reaction was concentrated. The crude product was diluted in water and washed with EtOAc to remove the triphenylphosphine oxide by-product. The aqueous layer was concentrated and subjected to reverse phase HPLC to give 16017 mg, 52% yield. ¹ H NMR(400MHz,DMSO)δ9.73(s,1H),9.48(s,1H),9.34(s,1H),8.72(s,1H),8.64(s,1H),8. 03(t,J＝7.9Hz,1H),7.93(d,J＝8.1Hz,1H),7.57(d,J＝7.7Hz,1H),7.02(s,1H),3.14(s,2H

Example 61 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 161

Step A: tert-Butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate

A mixture of 2-bromo-6-fluoropyridine (500 mg, 2.8 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (568 mg, 2.8 mmol) in DIPEA (1.83 g, 14.2 mmol) and ethanol (10 mL) was heated at 100°C for 16 hours. After cooling, the solvent was removed under reduced pressure, and the residue was _diluted with EtOAc (100 mL) and washed with brine. The organic layer was dried over _Na₂SO₄ and concentrated under reduced pressure to give tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate as a colorless oil (500 mg, 50%). MS (ESI) m/z: 356 [M+H] ⁺ .

Step B: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate (2.55 g, 7.16 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (1.0 g, 6.51 mmol) in 1,4-dioxane (20 mL) was added CuI (494 mg, 2.6 mmol), K ₂ CO ₃ (3.6 g, 26 mmol) and N ¹ ,N ² -dimethylethane-1,2-diamine (460 mg, 5.2 mmol). The mixture was heated at 100 ° C for 3 hours, which was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/EtOAc (2/1) as the eluent to provide tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (1.6 g, 57%). MS (ESI) m/z: 429 [M+H] ⁺ .

Step C: tert-Butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (500 mg, 1.16 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (679 mg, 3.5 mmol), Pd(dppf) _Cl2 (47.5 mg, 0.058 mmol) and _{aqueous Na2CO3} (saturated, 3 mL) in 1,4-dioxane (10 mL) was heated at 100°C under nitrogen for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/EtOAc (1/1) as eluent to provide tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (360 mg, 67%). MS (ESI) m/z: 461 [M+H] ⁺ .

Step D: tert-Butyl 4-(6-(6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

A suspension of 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (200 mg, 0.43 mmol), (bromomethyl)cyclopropane (100 mg, 0.65 mmol) and K ₂ CO ₃ (120 mg, 0.87 mmol) in DMF (10 mL) was stirred at room temperature for 18 hours. The reaction mixture was extracted with EtOAc (100 mL), washed with brine (50 mL), dried over MgSO ₄ , and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether/EtOAc (2/1) as eluent to afford tert-butyl 4-(6-(6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (200 mg, 89.6%). MS (ESI) m/z: 515 [M+H] ⁺ .

Step E: A solution of tert-butyl 4-(6-(6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (200 mg, 0.39 mmol) in HCl/MeOH (2 M, 10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 161 as a yellow solid (70 mg, 43.5%). ¹ H NMR (500MHz, CDCl ₃ )δ(ppm)9.055-9.057(d,J＝1Hz,1H),8.74(s,1H),8.23(s,1H),8.17(s,1H) ,7.97(s,1H),7.60-7.63(t,J＝16Hz,1H),7.28(s,1H),6.41-6.43(d,J＝8Hz

++-,1H),4.04-4.06(d,J＝7Hz,2H),3.89-3.94(m,4H),3.17-3.19(t,J＝11Hz,2H),2.91-2.93(t,J＝11.5Hz,2H) ,2.03-2.06(t,J＝12.5Hz,2H),1.35-1.36(m,1H),0.69-0.73(m,2H),0.43-0.46(m,2H); MS(ESI)m/z:415[M+H] ⁺ .

Example 62 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 162

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 1,1-difluoro-2-iodoethane, 162 was obtained over 2 steps as a light yellow solid (21 mg, 14.5%). ¹ H NMR (500 MHz, CDCl ₃ )δ(ppm)9.060-9.062(d,J＝1Hz,1H),8.74(s,1H),8.24(s,1H),8.11(s,1H),8.04( s,1H),7.61-7.64(t,J＝16Hz,1H),7.26-7.28(t,J＝10.5Hz,1H),6.42-6.44(d,J＝8 .5Hz,1H),6.04-6.26(m,1H),4.51-4.57(m,2H),3.89-3.93(m,4H),3.17-3.19(t, J＝11Hz,2H),2.92-2.94(t,J＝11Hz,2H),2.02-2.05(m,2H); MS(ESI)m/z:425[M+H] ⁺ .

Example 63 1-(6-(1,4-diazepan-1-yl)pyrazin-2-yl)-6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 163

Step A: tert-Butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate

A mixture of 2,6-dibromopyrazine (5.0198 mmol; 1194.1 mg), tert-butyl 1,4-diazepane-1-carboxylate (5.271 mmol; 1055.6 mg) and triethylamine (15.06 mmol; 1539 mg; 2.12 mL) in IPA (10 mL) was heated at 120 ° C in a sealed pressure bottle overnight. The mixture was cooled to room temperature and then concentrated. The residue was purified on silica gel eluted with 0-100% EtOAc in heptane to give tert-butyl 4-(6-bromopyrazine-2-yl)-1,4-diazepane-1-carboxylate (1.6965 g, 95%). MS (ESI) m / z: 357 [M + H] ⁺

Step B: tert-Butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl]-1,4-diazepane-1-carboxylate

A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.0 mmol; 307 mg), tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate (2.199 mmol; 785.5 mg), N,N′-dimethylethylenediamine (4.0 mmol; 352.4 mg; 0.398 mL), cuprous iodide (2.0 mmol; 380.72 mg), and potassium carbonate (2.1990 mmol; 307 mg) in 1,4-dioxane (15 mL) was evacuated with nitrogen, then sealed and stirred overnight at 110° C. The mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated; the residue was purified on silica gel eluting with 0-100% EtOAc in heptane to afford tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl]-1,4-diazepane-1-carboxylate as an off-white solid (217.2 mg, 25%). MS (ESI) m/z: 430 [M+H] ⁺

Step C: tert-Butyl 4-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate

A mixture of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2526 mmol; 108.6 mg), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.3789 mmol; 84.16 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.02526 mmol; 21.1 mg), potassium acetate (0.3789 mmol; 0.38 mL), and sodium carbonate (0.3789 mmol; 0.38 mL) in acetonitrile (10 mL) was heated in a pressure tube under microwave conditions at 150° C. for 15 minutes. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified on silica gel eluting with 0-5% MeOH in DCM containing 1% _NH₄OH to afford tert-butyl 4-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (127 mg, ~100%).

Step D: To a solution of tert-butyl 4-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2596 mmol; 127.1 mg) in methanol (5 mL) was added a 4.0 M solution of hydrochloric acid in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 163 as an off ^- white solid (34.9 mg, 34%). NMR (400MHz, DMSO) δ9.17-9.12(s,1H),8.60-8.56(s,1H),8.55-8.52(s,1H),8.39 -8.36(s,1H),8.27-8.24(s,1H),8.12-8.08(s,1H),7.91-7.85(s,1H),4.25-4.17 (q,J＝7.3Hz,2H),3.92-3.80(dt,J＝10.3,5.5Hz,4H),3.05-2.95(m,2H),2.79-2.7 1(m,2H),1.95-1.82(m,2H),1.46-1.40(t,J＝7.3Hz,3H); MS(ESI)m/z:390.2[M+H] ⁺

Example 64 3-(1-(6-(1,4-diazepan-1-yl)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-5-methylpyridin-2-ol 164

Step A: tert-Butyl 4-[6-[6-(2-Fluoro-5-methyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate

A mixture of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2526 mmol; 108.6 mg), 2-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.3789 mmol; 89.84 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.02526 mmol; 21.1 mg), potassium acetate (0.3789 mmol; 0.38 mL), and sodium carbonate (0.3789 mmol; 0.38 mL) in acetonitrile (10 mL) was heated in a pressure tube under microwave conditions at 150° C. for 15 minutes. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified on silica gel eluting with 0-5% MeOH in DCM containing 1% _NH₄OH to afford tert-butyl 4-[6-[6-(2-fluoro-5-methyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (106.6 mg, 84%).

Step B: To a solution of tert-butyl 4-[6-[6-(2-fluoro-5-methyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2113 mmol; 106.6 mg) in methanol (5 mL) was added a 4.0 M solution of hydrochloric acid in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 164 as a by-product (18.7 mg, 22%). ^1H NMR (400MHz, DMSO) δ9.89-9.85(s,1H),9.25-9.20(s,1H),8.64-8.60(s,1H),8.56-8.52(d,J＝2.6Hz,1H),8.41-8.38(s,1H),8.08-8.05(s,1H) ),7.33-7.30(s,1H),3.95-3.84(m,4H),2.99-2.93(m,2H),2.71-2.66 (m,2H),2.15-2.13(s,3H),1.88-1.81(m,2H); MS(ESI)m/z:403.2[M+H] ⁺

Example 65 6-(6-cyclopropylpyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[43-c]pyridine 165

According to the preparation of Example 23, 165 was obtained. MS (ESI) m/z: 399.2. ¹ H NMR (400 MHz, DMSO) δ 9.40 (s, 1H), 9.32 (s, 1H), 9.28 (s, 1H), 8.66 (s, 1H), 8.62 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 3.66-3.59 (m, 4H), 2.91-2.85 (m, 4H), 2.35-2.27 (m, 1H), 1.21-1.06 (m, = 4H).

Example 66 6-(6-methylpyrazin-2-yl)-1-[6-(4-piperidinyl)-pyridin-2-yl]pyrazolo[43-c]pyridine 166

Step A: tert-Butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidine-1-carboxylate

A mixture of 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (125 mg, 0.266 mmol) and palladium onactivated carbon (reduced 10%) (28 mg, 0.0266 mmol) in 10.0 mL of ethanol was stirred at 40 ° C. under a balloon of H ₂ for 18 h. The reaction was filtered through celite and washed with MeOH. The crude product was used in the next step.

Step B: A mixture of tert-butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidine-1-carboxylate (B, 110 mg, 0.2332 mmol) in 4 mol/L hydrochloric acid in 1,4-dioxane (2.0 mL, 8.0 mmol) and 2.0 mL of 1,4-dioxane was stirred at room temperature for 18 h. The reaction was concentrated and analyzed by reverse phase HPLC to afford 166 (13 mg), a 13% yield. ¹ H NMR(400MHz,DMSO)δ9.80(s,1H),9.46(s,1H),9.34(s,1H),8.71(s,1H),8.63 (s,1H),7.99(t,J＝7.9Hz,1H),7.87(d,J＝8.1Hz,1H),7.29(d,J＝7.5Hz,1H),3. 15(d,J＝12.0Hz,2H),2.94(tt,J＝11.8,3.5Hz,1H),2.76-2.67(m,2H),2.66(s, 3H), 2.01 (d, J＝12.1Hz, 2H), 1.85 (qd, J＝12.2, 3.8Hz, 2H). MS (ESI) m/z: 372.2.

Example 67 (3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]pyrrolidin-3-amine 167

According to the preparation of Example 23, 167 was obtained. MS (ESI) m/z: 373.2. ¹ H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 9.45 (s, 1H), 9.30 (s, 1H), 8.64 (s, 1H), 8.62 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 6.39 (d, J = 8.3 Hz, 1H), 3.74 (dd, J = 28.2, 23.7 Hz, 4H), 2.64 (s, 3H), 2.19 (td, J = 12.6, 7.1 Hz, 1H), 1.92-1.78 (m, 2H).

Example 68 (3R)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]pyrrolidin-3-amine 168

According to the preparation of Example 23, 168 was obtained. MS (ESI) m/z: 373.2. ¹ H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 9.45 (s, 1H), 9.30 (s, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 6.39 (d, J = 8.3 Hz, 1H), 3.74 (dd, J = 27.9, 23.5 Hz, 4H), 2.64 (s, 3H), 2.19 (td, J = 12.6, 7.1 Hz, 1H), 1.90-1.80 (m, 2H).

Example 69 1-[6-(3-methylpiperazin-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 169

According to the preparation of Example 23, 169 was obtained. MS (ESI) m/z: 387.2. ¹ H NMR (400 MHz, DMSO) δ 9.56 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.63 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 4.37 (d, J = 12.1 Hz, 1H), 4.1 7(d,J＝10.7Hz,1H),3.08(d,J＝11.7Hz,1H),2.98(td,J＝11.9,2.9Hz,1H),2.83(dd,J＝22.0 ,9.9Hz,1H),2.63(s,3H),2.62-2.54(m,1H),2.34(d,J＝12.3Hz,1H),1.04(d,J＝6.3Hz,3H).

Example 70 6-(6-tert-Butylpyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 170

According to the preparation of Example 23, 170 was obtained. MS (ESI) m/z: 415.2. ¹ H NMR (400 MHz, DMSO) δ 9.65 (s, 1H), 9.56 (d, J = 1.2 Hz, 1H), 9.32 (s, 1H), 8.81 (d, J = 1.3 Hz, 1H), 8.65 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 3.70-3.58 (m, 4H), 3.00-2.89 (m, 4H), 1.43 (s, 9H).

Example 71 6-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 171

Step A: N-[1-(6-Bromo-pyridin-2-yl)-6-methyl-3-piperidinyl]carbamic acid tert-butyl ester

A solution containing 2-bromo-6-fluoropyridine (0.95 mL, 6.65 mmol) and tert-butyl 6-methylpiperidin-3-ylcarbamate (750 mg, 3.32 mmol) in methyl sulfoxide 5.0 ml was heated at 95 ° C for 18 h. The reaction was quenched with water and then extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluted at 30% EtOAc) to give tert-butyl N-[1-(6-bromo-pyridin-2-yl)-6-methyl-3-piperidinyl]carbamate (480 mg) in 39% yield. MS (ESI) m/z: 371.2

Step B: tert-Butyl N-[1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-6-methyl-3-piperidinyl]carbamate

A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.651 mmol), tert-butyl N-[1-(6-bromo-pyridin-2-yl)-6-methyl-3-piperidinyl]carbamate (422 mg, 1.14 mmol), tetrakis(dibenzylideneacetone)dipalladium(0) (59 mg, 0.065 mmol), xantphos (78 mg, 0.130 mmol) and sodium tert-butoxide (129 mg, 1.30 mmol) in 6.0 mL of toluene was stirred at 100 ° C for 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/heptane) to give the desired product (185 mg) in 64% yield. MS (ESI) m/z: 443.2

Step C: According to the preparation procedure of Example 23, 171 was obtained. MS(ESI)m/z:401.2.1HNMR(400MHz,DMSO)δ9.47(d,J＝6.7Hz,2H),9.33(s,1H), 8.66(s,1H),8.62(s,1H),7.75(t,J＝8.1Hz,1H),7.21(d,J＝7.7Hz,1H),6.75(d, J＝8.5Hz,1H),5.05-4.92(m,1H),4.06(d,J＝7.8Hz,1H),2.71(dd,J＝6.1,3.3Hz ,2H),2.65(s,3H),1.92-1.70(m,2H),1.70-1.41(m,2H),1.27(t,J=6.5Hz,3H).

Example 72 1-[6-[6-(6-ethylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-14-diazepan-6-ol 172

According to the preparation of Example 56, 172 was obtained. MS (ESI) m/z: 417.2. ¹ H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 9.47 (d, J = 4.1 Hz, 1H), 9.32 (s, 1H), 8.65 (d, J = 4.1 Hz, 2H), 7.71 (t, J = 8.1 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 4.73 (s, 1H), 4.11 (dt, J = 13.8, 5.1 Hz, 1H ),4.06-3.97(m,1H),3.92(s,1H),3.86-3.70(m,1H),3.52(dd,J＝14.6,6.9Hz,1H),3.00(t,J＝5.4Hz ,2H),2.92(q,J＝7.5Hz,2H),2.78(dd,J＝13.8,3.9Hz,1H),2.69-2.59(m,1H),1.35(t,J＝7.6Hz,3H).

Example 73 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 173

Step A: 1-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) _-1H -pyrazole (516 mg, 2.66 mmol), _CF2ClCO2Na (486 mg, 3.19 mmol), and 18-crown-6 (141 mg, 0.532 mmol) in _CH3CN (150 mL) was heated at reflux for 20 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over _MgSO4 , and concentrated under reduced pressure to give crude 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg), which was used in the next step without further purification. MS (ESI) m/z: 245 [M+H] ⁺ .

Step B: Following the procedure described in Example 45 and starting from tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 173 was obtained as a white solid (80 mg, 35%) over 3 steps. ¹ H-NMR (500MHz, CD ₃ OD)δ(ppm)9.06(s,1H),8.73(s,1H),8.50(s,1H),8.34(s,1H),8.15(s,1H),7.50-7.67(m,2H),7.23(d,J＝7.5Hz,1H),6 .58(d,J＝8.0Hz,1H),3.87-3.90(m,4H),3.13-3.15(m,2H),2.91-2.94(m,2H),2.03-2.08(m,2H); MS(ESI)m/z:411[M+H] ⁺ .

Example 74 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 174

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and cyclopropylboronic acid, 174 was obtained over 2 steps as a yellow solid (40 mg, 25%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.13(s,1H),8.64(s,1H),8.52(s,1H),8.26(s,1H),7.98(s,1H),7.66-7.70 (t,J＝16Hz,1H),7.14-7.17(t,J＝14.5Hz,1H),6.58-6.66(m,1H),6.06-6.12(m,1H),5 .21-5.28(m,2H),4.84-4.85(d,J＝10Hz,2H),3.35-3.90(m,7H),2.97-2.99(t,J＝10.5 Hz,1H),2.71-2.73(t,J＝12Hz,1H),1.87-1.89(t,J＝10Hz,2H); MS(ESI)m/z:401[M+H] ⁺ .

Example 75 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(pyrimidin-5-yl)-1H-pyrazolo[4,3-c]pyridine 175

Step A: tert-Butyl 4-(6-(6-(pyrimidin-5-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

A mixture of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (427 mg, 1.0 mmol), pyrimidin-5-ylboronic acid (372 mg, 3.0 mmol), PdCl ₂ (dppf) (73 mg, 0.1 mmol) and aqueous NaHCO ₃ (318 mg, 3.0 mmol) in 1,4-dioxane (5.0 mL) was evacuated with nitrogen in a sealed tube and stirred at 100° C. for 16 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was chromatographed on silica gel using petroleum ether:EtOAc (5:1 to 1:1) as eluent to afford tert-butyl 4-(6-(6-(pyrimidin-5-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (350 mg, 74% yield). ESI (MS) m/z = 473 [M+H] ⁺

Step B: A suspension of tert-butyl 4-(6-(6-(pyrimidin-5-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (320 mg, 0.68 mmol) in HCl in MeOH (3.0 N, 20 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 175 as a light yellow solid (220 mg, 87% yield). ¹ HNMR(500MHz,DMSO-d ₆ )δ(ppm)9.43(s,1H),9.39(s,1H),9.35(d,J＝3.0Hz,1H),9.28(d,J＝3.0Hz,1H),9.06(d,J＝11.5Hz,1H),8.66(d,J＝5.5Hz,1H),7.70(dd,J＝8.0and 16.5Hz,1H),7.17(dd,J＝7.5and 11.0Hz,1H),6.61(t,J＝8.0Hz,1H),3.83(s,2H),3.77(s,2H),3.56(m,1H),2.95(t ,J＝5.0Hz,2H),2.70(t,J＝6.0Hz,2H),1.84(t,J＝5.0Hz,2H).ESI(MS)m/z:373[M+1] ⁺ .

Example 76 (S)-1-(3-chloro-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 176

Step A: 6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (11.5 g, 0.075 mol) and 3,4-dihydro-2H-pyran (19 g, 0.225 mol) and Tos-OH (0.13 g 0.75 mmol) in 1,4-dioxane (175 mL) was heated at 110 ° C overnight. The mixture was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:0 to 20:1) to give a mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 6-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[4,3-c]pyridine (13.5 g, yield 76%). MS (ESI) m/z: m/z: 238 [M+1] ⁺

Step B: 1-(Tetrahydro-2H-pyran-2-yl)-6-(tetrabutylstannyl)-1H-pyrazolo[4,3-c]pyridine

To a mixture of 6-chloro-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (19.506 mmol; 4636.1 mg) in 1,4-dioxane (40 mL) was added lithium chloride (117.03 mmol; 4961.5 mg), bis(tributyltin) (23.407 mmol; 14293 mg; 12.45 mL), tris(dibenzylideneacetone)dipalladium(0) (0.97528 mmol; 893.09 mg) and tris(tributyltin) (23.407 mmol; 14293 mg; 12.45 mL). Cyclohexylphosphine (2.3407 mmol; 656.40 mg). The resulting mixture was sealed in a pressure tube and heated at 120 ° C overnight. The mixture was filtered through celite. The filter cake was washed with DCM. The filtrate was concentrated, and the residue was purified on silica gel eluting with 0-60% EtOAc in DCM to give 1-(tetrahydro-2H-pyran-2-yl)-6-(tetrabutylstannyl)-1H-pyrazolo[4,3-c]pyridine as a clear oil (7.1768 g, 74%).

Step C: 6-(6-Methylpyrazin-2-yl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine

A mixture of tributyl-(1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-6-yl)stannane (7.139 mmol; 3514.5 mg), 2-chloro-6-methyl-pyrazine (10.71 mmol; 1377 mg), tricyclohexylphosphine (0.5140 mmol; 144.1 mg) and tris(dibenzylideneacetone)dipalladium(0) (0.2142 mmol; 196.1 mg) in N,N-dimethylacetamide (15 mL) was evacuated with argon for 1 minute. The reaction mixture was sealed in a pressure bottle and heated at 130° C. overnight. The mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica gel eluting with 0-100% EtOAc in DCM to afford 6-(6-methylpyrazin-2-yl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine as a clear oil (1.3608 g, 60%).

Step D: 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine

To a solution of 6-(6-methylpyrazin-2-yl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (4.29 mmol; 1360.8 mg) in methanol (10 mL) was added a 4.0 M solution of hydrochloric acid in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified on silica gel eluting with 0-5% MeOH in DCM to give 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine as an off-white solid (759.5 mg, 88%).

Step E: 1-(5-chloro-6-fluoro-pyridin-2-yl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine

To a mixture of 6-(6-methylpyrazine-2-yl)-1H-pyrazolo[4,3-c]pyridine (1.325mmol; 279.9mg) and 6-bromo-3-chloro-2-fluoro-pyridine (1.988mmol; 418.3mg) in 1,4-dioxane (10mL) was added cesium carbonate (3.975mmol; 1295mg), Xantphos (0.2253mmol; 130.4mg) and tris(dibenzylideneacetone)dipalladium(0) (0.1325mmol; 121.3mg) under argon. The resulting mixture was sealed in a pressure tube and stirred at 105°C overnight. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with DCM. The filtrate was concentrated. The residue was purified on silica gel eluting with 0-6% MeOH in DCM to give 1-(5-chloro-6-fluoro-pyridin-2-yl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (217.1 mg, 48%).

Step F: tert-Butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of 1-(5-chloro-6-fluoro-pyridin-2-yl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine; (0.6372 mmol; 217.1 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (1.912 mmol; 382.9 mg) and N-methylmorpholine (3.186 mmol; 326 mg; 0.354 mL) in 1-methyl-2-pyrrolidone (3 mL) was heated in a sealed pressure bottle at 100° C. overnight. The mixture was poured into water. The precipitate was collected by filtration and purified on silica gel eluting with 0-6% MeOH in DCM to give tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (229.4 mg, 69%).

Step G: To a solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.140 mmol; 72.7 mg) in methanol (5 mL) was added a 4.0 M solution of hydrochloric acid in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 176 as an off-white solid (23.3 mg, ⁴⁰ %). NMR (400MHz, DMSO) δ9.67-9.61(s,1H),9.47-9.42(s,1H),9.34-9.28(s,1H),8.71-8.67(s,1H),8.64-8.61(s,1H),8 .01-7.94(d,J＝8.4Hz,1H),7.57-7.51(d,J＝8.4Hz,1H),3.91-3.83(d,J＝8.8Hz,1H),3.81-3.72(d,J＝12.3Hz,1H),3. 25-3.19(m,1H),2.97-2.89(m,1H),2.77-2.71(dd,J＝11.9,9.1Hz,1H),2.67-2.62(d,J＝8.6Hz,3H),1.98-1.87(dd,J ＝16.2,6.5Hz,2H),1.84-1.40(dd,J＝32.9,22.1Hz,3H),1.36-1.23(td,J＝13.5,4.6Hz,1H); MS(ESI)m/z:421.1[M+H] ⁺

Example 77 6-[1-(6-(Piperazin-1-yl)-pyridin-2-yl)pyrazolo[43-c]pyridin-6-yl]pyrazine-2-carbonitrile 177

According to the preparation of Example 23, 177 was obtained. MS (ESI) m/z: 384.1. ¹ H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 9.61 (s, 1H), 9.38 (s, 1H), 9.29 (s, 1H), 8.71 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 3.68-3.60 (m, 4H), 3.02-2.95 (m, 4H).

Example 78 1-(6-(1,4-diazepan-1-yl)pyrazin-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 178

Step A: tert-Butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate

A mixture of 2,6-dibromopyrazine (0.47 g, 2 mmol), tert-butyl 1,4-diazepane-1-carboxylate (0.4 g, 2 mmol), and DIPEA (0.78 g, 6 mmol) in EtOH (10 mL) was heated at 100 ° C for 15 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (5%-50%) as eluent to obtain tert-butyl 4-(6-bromopyrazine-2-yl)-1,4-diazepane-1-carboxylate as a colorless oil (0.5 g, 70%). MS (ESI) m/z: 357 [M+H] ⁺ .

Step B: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate (0.45 g, 1.26 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (192 mg, 1.26 mmol) in dioxane (10 mL) was added CuI (19 mg, 0.1 mmol), N ¹ ,N ² -dimethylethane-1,2-diamine (6.3 mmol, 0.55 g), and K ₂ CO ₃ (3.78 mmol, 0.53 g). The reaction mixture was heated at 100° C. and monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using petroleum ether/ethyl acetate (5% to 50%) as the eluent to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (0.4 g, 74%). MS (ESI) m/z: 430 [M+H] ⁺ .

Step C: tert-Butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate

A mixture of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate (400 mg, 0.93 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (271 mg, 1.4 mmol), Pd(dppf) _Cl2 (81 mg, 0.093 mmol) and _Na2CO3 solution (2.0 M, 1.5 mL) in 1,4-dioxane (6 mL) was heated under argon in a sealed bottle at 120°C _for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (10%-60%) as the eluent to afford tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (180 mg, 42%). MS (ESI) m/z: 462 [M+H] ⁺ .

Step D: tert-Butyl 4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate

To a solution of tert-butyl 4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate (100 mg, 0.22 mmol) in DMF (10 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (100 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (10% to 60%) as eluent to afford tert-butyl 4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (80 mg, 80%). MS (ESI) m/z: 544 [M+H] ⁺ .

Step E: To a solution of tert-butyl 4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate (80 mg, 0.147 mmol) in 1,4-dioxane (6 mL) was added HCl/1,4-dioxane solution (3.8 M, 6 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase preparative HPLC to give 178 as a white solid (55 mg, 84%). ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.17(s,1H),8.60(s,1H),8.54(s,1H),8.37(d,J＝6.0Hz,2H),8.09(s,1H),8.02(s,1H),5.26(Q,J＝9.2Hz,2H) ,3.86(s,2H),3.81(s,2H),3.01(t,J＝5.5Hz,2H),2.76(t,J＝5.5Hz,2H),1.89(t,J＝5.5Hz,2H).MS(ESI)m/z:444[M+H] ⁺ .

Example 79 1-(2-(1,4-diazepan-1-yl)pyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo-[4,3-c]pyridine 179

Following the procedure described in Example 78 and starting from 2,4-dichloropyrimidine, 179 was obtained over 5 steps as a white solid (80 mg, 9.5%). ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.18(s,1H),8.68(s,1H),8.64(s,1H),8.45(d,J＝4.5Hz,1H),8.39(s,1H),8.04(s,1H),7.12(d,J＝5.0Hz,1H),5.27(Q, J＝9.2Hz,2H),3.98(s,2H),3.89(s,2H),3.13(s,1H),2.95(s,1H),2.82(s,2H),2.01(s,1H),1.81(s,1H).MS(ESI)m/z:444[M+H] ⁺ .

Example 80 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 180

Following the procedure described in Example 61 and starting from tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate, 180 was obtained over 1 step as a yellow solid (62 mg, 65.9%). ¹ H NMR (500 MHz, MeOD) δ (ppm) 9.084-9.086 (d, J=1 Hz, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 8.15 (s, 2H), 7.77-7.80 (t, J=16.5 Hz, 1H), 7.36-7.38 (d, J=8 Hz, 1H), 6.71-6.73 (d, J=8 Hz, 1H), 4.16-4.70 (d, J=8 Hz, 1H), 4.70-4.70 (d, J=8 Hz, 1H). .19(t,J＝11Hz,2H),3.97-3.99(t,J＝12.5Hz,2H),3.51-3.53(t,J＝11Hz,2H),3.37-3.39(t, J＝11Hz,2H),2.29-2.31(t,J＝11Hz,2H),1.32-1.34(t,J＝14.5Hz,2H); MS(ESI)m/z:361[M+H] ⁺ .

Example 81 (S)-1-(3-cyclopropyl-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 181

Step A: tert-Butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.2225 mmol; 115.9 mg), potassium cyclopropyltrifluoroborate (0.3337 mmol; 50.90 mg), butyldi(1-adamantyl)phosphine (0.06674 mmol; 25.19 mg), cesium carbonate (0.6674 mmol; 217.4 mg), and palladium(II) acetate (0.04449 mmol; 9.994 mg) in water (0.5 mL) and toluene (4.5 mL) was degassed with argon for 1 minute. The reaction mixture in a sealed tube was stirred at 105° C. for 3 days. The layers were separated. The organic layer was concentrated. The residue was purified on silica gel eluting with 0-5% MeOH in DCM to afford tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (129 mg, -100%).

Step B: To a solution of tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.2224 mmol; 117.1 mg) in methanol (5 mL) was added a 4.0 M solution of hydrochloric acid in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 181 as an off-white solid (46.0 mg, ⁴⁹ %). NMR (400MHz, DMSO) δ9.75-9.71(s,1H),9.47-9.44(s,1H),9.33-9.29(s,1H),8.67-8.61(d,J＝9.6Hz,2H),7.55-7.5 1(d,J＝8.2Hz,1H),7.49-7.43(d,J＝8.2Hz,1H),3.86-3.78(d,J＝10.8Hz,1H),3.65-3.58(s,1H),3.16-3.09(s,1H),2 .89-2.81(m,1H),2.68-2.65(s,3H),2.12-2.04(m,1H),2.02-1.93(d,J＝8.9Hz,2H),1.81-1.69(m,1H),1.48-1.37(d ,J＝8.7Hz,1H),1.20-1.11(m,1H),1.09-0.99(m,1H),0.91-0.84(m,1H),0.75-0.67(s,1H); MS(ESI)m/z:427.2[M+H] ⁺

Example 82 6-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 182

Compound 182 was obtained from the second peak of Example 71 by SFC chiral separation. MS(ESI)m/z:401.2.1H NMR (400MHz, DMSO) δ9.48(s,1H),9.45(s,1H),9.33(s,1H),8.67(s,1H),8.62(s,1H),7.77(t,J＝8.1Hz,1H),7.23(d,J＝7.7Hz,1H),6.75(d,J＝8.5H z,1H),5.03(s,1H),4.09(d,J＝8.8Hz,1H),2.80(dd,J＝19.2,10.2Hz,2H), 2.64(s,3H),1.94-1.72(m,3H),1.66-1.51(m,1H),1.27(d,J＝6.8Hz,3H).

Example 83 6-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 183

Compound 183 was obtained from the first peak of the SFC chiral separation of Example 71. MS(ESI)m/z:401.2.1H NMR (400MHz, DMSO) δ9.48(s,1H),9.45(s,1H),9.33(s,1H),8.67(s,1H),8.62(s,1H),7.76(t,J＝8.1Hz,1H),7.22(d,J＝7.7Hz,1H),6.75(d,J＝8. 5Hz,1H),5.01(s,1H),4.13-3.92(m,2H),2.81-2.73(m,2H),2.65(s,3H) ,1.96-1.69(m,2H),1.55(dd,J＝14.9,8.1Hz,1H),1.26(d,J＝6.8Hz,3H).

Example 84 1-[6-(5-methyl-14-diazepan-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridine 184

According to the preparation of Example 23, 184 was obtained. MS (ESI) m/z: 401.2. 1H NMR (400 MHz, DMSO) δ 9.65 (s, 1H), 9.45 (s, 1H), 9.31 (s, 1H), 8.65 (s, 1H), 8.62 (s, 1H), 7.70 (t, J = 8.1 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.59 (d, J = 8.5 Hz, 1H), 4.01 (d, J = 12.7 Hz, 2H), 3.86-3.73(m,1H),3.62(t,J＝10.1Hz,1H),3.20(d,J＝13.9Hz,1H),2.98-2.87(m,1H),2.7 1-2.62(m,1H),2.61(s,3H),2.13-2.02(m,1H),1.54-1.40(m,1H),1.00(d,J＝6.4Hz,3H).

Example 85 1-[6-(3-methylpiperazin-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridine 185

Compound 185 was obtained from the second peak of Example 69 by SFC chiral separation. MS(ESI)m/z:387.2.1H NMR(400MHz,DMSO)δ9.56(s,1H),9.47(s,1H),9.32(s,1H),8.66(s,1H),8 .63(s,1H),7.77(t,J＝8.1Hz,1H),7.25(d,J＝7.7Hz,1H),6.82(d,J＝8.5Hz, 1H),4.39(d,J＝12.3Hz,1H),4.19(d,J＝11.3Hz,1H),3.12(d,J＝11.8Hz,1H) ,3.07-2.98(m,1H),2.94-2.82(m,2H),2.63(s,3H),1.06(d,J＝6.3Hz,3H).

Example 86 (S)-1-(3-methoxy-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 186

Step A: tert-Butyl N-[(3S)-1-(6-bromo-3-methoxy-pyridin-2-yl)-3-piperidinyl]carbamate

A mixture of 6-bromo-2-fluoro-3-methoxy-pyridine (2.030 mmol; 418.1 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (3.044 mmol; 609.7 mg) and N-methylmorpholine (6.089 mmol; 622 mg; 0.676 mL) in 1-methyl-2-pyrrolidone (5 mL) was heated at 120 ° C overnight in a sealed bottle. The mixture was poured into water and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica gel and eluted with 0-40% EtOAc in heptane to give tert-butyl N-[(3S)-1-(6-bromo-3-methoxy-pyridin-2-yl)-3-piperidinyl]carbamate (743.5 mg, 95%).

Step B: tert-Butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.4734 mmol; 100.0 mg), tert-butyl N-[(3S)-1-(6-bromo-3-methoxy-pyridin-2-yl)-3-piperidinyl]carbamate (0.5681 mmol, 219.5 mg), N,N′-dimethylethylenediamine (0.4734 mmol; 41.73 mg; 0.0471 mL), copper iodide (0.4734 mmol; 91.08 mg) and potassium carbonate (0.5208 mmol; 72.70 mg) in 1,4-dioxane (10 mL) was evacuated with argon, then sealed and stirred at 100° C. overnight. The mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated; the residue was purified on silica gel eluting with 0-100% EtOAc in DCM to afford tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate as a brown solid (142.5 mg, 58%).

Step C: To a solution of tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.2758 mmol; 142.5 mg) in methanol (10 mL) was added a 4.0 M solution of hydrochloric acid in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 186 as an off-white solid (105.6 mg, ⁹¹ %). NMR (400MHz, DMSO) δ9.66-9.62(s,1H),9.48-9.44(s,1H),9.33-9.28(s,1H),8.65-8.61(d,J=3. 5Hz,2H),7.54-7.45(dd,J＝21.6,8.5Hz,2H),4.02-3.96(d,J＝10.3Hz,1H),3.90-3.84(d,J＝11.7H z,4H),3.03-2.96(d,J＝9.0Hz,1H),2.89-2.82(m,1H),2.65-2.61(s,3H),1.98-1.86(t,J＝10.6H z,2H),1.78-1.67(d,J＝10.2Hz,1H),1.45-1.35(dd,J＝19.2,8.9Hz,1H); MS(ESI)m/z:417.2[M+H] ⁺

Example 87 1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]azepan-3-amine 187

According to the preparation of Example 23, 187 was obtained. MS (ESI) m/z: 401.2. 1H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.62 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 4.39-4.29 (m, 1H), 4.06 (d, J = 12.5 Hz, 1H), 2.63 (s, 3H), 2.11 (s, 1H), 1.76 (s, 3H), 1.44 (d, J = 10.3 Hz, 1H), 1.27 (d, J = 9.6 Hz, 1H).

Examples 88 and 89 (R)-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl)-1,4-diazepan-6-ol 188 and (S)-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl)-1,4-diazepan-6-ol 189

Step A: 1-(6-bromopyridin-2-yl)-1,4-diazepan-6-ol

A mixture of 2-bromo-6-fluoropyridine (477 mg, 2.7 mmol), 1,4-diazepan-6-ol (350 mg, 3 mmol), and DIPEA (1.94 g, 15 mmol) in ethanol (10 mL) was heated at 100 ° C for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with brine. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 1-(6-bromopyridin-2-yl)-1,4-diazepan-6-ol as a colorless oil (400 mg, 48.9%). MS (ESI) m / z: 272 [M + H] ⁺ .

Step B: tert-Butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate

A mixture of 1-(6-bromopyridin-2-yl)-1,4-diazepan-6-ol (400 mg, 1.47 mmol), Boc ₂ O (354 mg, 1.62 mmol), and Et ₃ N (157 mg, 1.55 mmol) in DCM (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was washed with brine, dried over Na ₂ SO ₄ , and concentrated under reduced pressure to afford tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-1,4-diazepan-1-carboxylate as a colorless oil (500 mg, 91%). MS (ESI) m/z: 372 [M+H] ⁺ .

Step C: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (550 mg, 1.48 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (207 mg, 1.34 mmol) in 1,4-dioxane (20 mL) was added CuI (102 mg, 0.54 mmol), K ₂ CO ₃ (743 g, 5.4 mmol) and N ¹ , N ² -dimethylethane-1,2-diamine (95 mg, 1.08 mmol). The reaction mixture was heated at 100 ° C for 3 hours, which was monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether/EtOAc (2/1) as eluent to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as a light yellow solid (160 mg, 24.3%). MS (ESI) m/z: 445 [M+H] ⁺ .

Step D: tert-Butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate

A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (160 mg, 0.36 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (140 mg, 0.72 mmol), Pd(dppf)Cl ₂ (147 mg, 0.18 mmol) and aqueous Na ₂ CO ₃ solution (2.0 M, 1 mL) in 1,4-dioxane (10 mL) was heated at 100° C. under nitrogen for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc as eluent to give tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as a yellow solid (60 mg, 35%). MS (ESI) m/z: 477 [M+H] ⁺ .

Step E: (±)-tert-Butyl 6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

A suspension of tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (150 mg, 0.32 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.48 mmol) and K ₂ CO ₃ (87 mg, 0.64 mmol) in DMF (10 mL) was stirred at room temperature for 18 hours, which was monitored by LCMS. After completion of the reaction, the reaction mixture was quenched with EtOAc (100 mL), washed with brine (50 mL), dried over MgSO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/EtOAc (1/1) as eluent to afford tert-butyl (±)-6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (82 mg, 46.5%). MS (ESI) m/z: 559 [M+H] ⁺ .

Step F: (R)-tert-Butyl 6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and (S)-tert-Butyl 6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

(±)-tert-Butyl 6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo-[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate was separated by chiral preparative HPLC to afford (S)-6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)- tert-Butyl (R)-6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (70 mg).

Step G: A mixture of (S)-tert-butyl 6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (70 mg, 0.13 mmol) in HCl/MeOH (4.0 M, 10 mL) was stirred at room temperature for 3 hours, which was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to afford (R)-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 188 as a white solid (30 mg, 52.6%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.16(s,1H),8.74(s,1H),8.55(s,1H),8.49(s,1H),8.21(s,1H),7.69( t,J＝16Hz,1H),7.17(d,J＝7.5Hz,1H),6.66(d,J＝8Hz,1H),5.18-5.24(m,2H),4. 93(d,J＝5.5Hz,1H),3.96(t,J＝8.5Hz,1H),3.88(m,2H),3.56-3.64(m,2H),2.98 (t,J＝10.5Hz,2H),2.80-2.84(m,1H),2.64-2.72(m,1H); MS(ESI)m/z:459[M+H] ⁺ .

Step H: Following the procedure described in Step G and starting from (R)-tert-butyl 6-hydroxy-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate, 189 was obtained as a yellow solid (41 mg, 71.9%). ^1H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.16(s,1H),8.74(s,1H),8.55(s,1H),8.49(s,1H),8.21(s,1H),7.69( t,J＝16Hz,1H),7.17(d,J＝7.5Hz,1H),6.66(d,J＝8Hz,1H),5.18-5.24(m,2H),4. 93(d,J＝5.5Hz,1H),3.96(t,J＝8.5Hz,1H),3.88(m,2H),3.56-3.64(m,2H),2.98 (t,J＝10.5Hz,2H),2.80-2.84(m,1H),2.64-2.72(m,1H); MS(ESI)m/z:459[M+H] ⁺ .

Example 90 6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-N-(4-piperidinyl)pyridin-2-amine 190

According to the preparation of Example 23, 190 was obtained. MS (ESI) m/z: 387.2. 1H NMR (400 MHz, DMSO) δ 9.45 (s, 1H), 9.42 (s, 1H), 9.32 (s, 1H), 8.64 (s, 2H), 8.35 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 4.17 (s, 1H), 3.08-2.97 (m, 2H), 2.71 (d, J = 9.7 Hz, 1H), 2.67 (s, 3H), 2.06 (s, 2H), 1.64 (d, J = 9.1 Hz, 2H).

Example 91 1-[6-[(2R)-2-methylpiperazin-1-yl]-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridine 191

According to the preparation procedure of Example 71, 191 was obtained. MS(ESI)m/z:387.2.1H NMR (400MHz, DMSO) δ9.52(s,1H),9.48(s,1H),9.32(s,1H),8.66(s,1H),8.62(s,1H),7.76(t,J＝8.1Hz,1H),7.26(d,J＝7.7Hz,1H),6.75(d,J＝8.5H z,1H),4.60(s,1H),4.06(d,J＝12.1Hz,1H),3.19-3.08(m,3H),2.99(dt,J ＝19.3,7.8Hz,2H),2.84-2.74(m,1H),2.64(s,3H),1.28(d,J＝6.6Hz,3H).

Example 92 (3S,5S)-5-Fluoro-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 192

According to the preparation procedure of Example 23, 192 was obtained. MS (ESI) m/z: 405.2.

Example 93 1-[6-(3-methylpiperazin-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 193

Compound 193 was obtained from the first peak of the SFC chiral separation of Example 69. MS(ESI)m/z:387.2.1H NMR (400MHz, DMSO) δ9.54(s,1H),9.47(s,1H),9.33(s,1H),8.67(s,1H),8.64(s,1H),7.80(t,J＝8.1Hz,1H),7.28(d,J＝7.7Hz,1H),6.86(d,J＝8.5H z,1H),4.43(d,J＝12.4Hz,1H),4.25(d,J＝12.0Hz,1H),3.17-3.06(m,1H), 3.03-2.91(m,2H),2.83-2.71(m,1H),2.64(s,3H),1.12(d,J=6.3Hz,3H).

Example 94 1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-4-amine 194

According to the preparation of Example 23, 194 was obtained. MS (ESI) m/z: 387.2. 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.64 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 4.43 (d, J = 13.3 Hz, 2H), 2.65 (s, 3H), 1.98 (d, J = 10.4 Hz, 2H), 1.48 (dd, J = 20.4, 11.1 Hz, 2H).

Example 95 2-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 195

Following the preparation of Example 71, 195 was obtained. MS(ESI)m/z:401.2.1H NMR (400MHz, DMSO) δ9.47(d,J＝5.9Hz,2H),9.33(s,1H),8.66(s,1H),8.62(s,1H),7.78(t,J＝8.1Hz,1H),7.21(d,J＝7.7Hz,1H),6.77(d,J＝8.5Hz,1H) ,4.66-4.55(m,1H),4.42(d,J＝13.7Hz,1H),3.10-3.00(m,2H),2.64(s,3H ),1.92-1.83(m,1H),1.65(dt,J＝21.6,10.4Hz,3H),1.19(d,J＝6.8Hz,3H).

Example 96 1-[6-[(2S)-2-methylpiperazin-1-yl]-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridine 196

According to the preparation of Example 71, 196 was obtained. MS (ESI) m/z: 387.1. 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 9.48 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.63 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.61 (s, 1H), 4.07 (d, J = 12.0 Hz, 1H), 2.98 (dd, J = 20.6, 13.3 Hz, 2H), 2.79 (t, J = 10.8 Hz, 1H), 2.64 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H).

Example 97 1-(5-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine 197

Following procedure 1 described in Example 8 and starting from 6-bromo-3-chloro-2-fluoropyridine and tert-butyl 1,4-diazepane-1-carboxylate, 197 was obtained over 4 steps as an off-white solid (31.6 mg, 48%). ¹ H NMR (400 MHz, DMSO) δ 9.66-9.61 (s, 1H), 9.48-9.42 (s, 1H), 9.33-9.27 (s, 1H), 8.66-8.60 (d, J = 7.9 Hz, 2H), 7.53-7.49 (d, J = 8.1 Hz, 1H), 7.39-7.34 (d, J = 8.1 Hz, 1H), 3.94-3.8 4(m,4H),3.10-3.06(m,2H),2.91-2.84(m,2H),2.65-2.61(s,3H),2.03-1.91(tt,J＝11 .5,5.6Hz,3H),1.05-0.92(m,3H),0.78-0.71(q,J＝5.7Hz,2H); MS(ESI)m/z:427.2[M+H] ⁺

Example 98 (3S,5R)-5-Fluoro-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 198

According to the preparation procedure of Example 23, 198 was obtained. MS (ESI) m/z: 405.1.1H NMR(400MHz,DMSO)δ9.58(s,1H),9.47(s,1H),9.33(s,1H),8.67(s,1H),8.63 (s,1H),7.78(t,J＝8.1Hz,1H),7.25(d,J＝7.7Hz,1H),6.85(d,J＝8.5Hz,1H),5 .10(d,J＝47.2Hz,1H),4.71(t,J＝13.0Hz,1H),4.29(d,J＝9.9Hz,1H),2.96-2. 86(m,1H),2.65(s,3H),2.20(d,J＝11.5Hz,1H),1.69(dt,J＝24.6,11.4Hz,1H).

Example 99 2-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-28-diazaspiro[4,5]decane 199

According to the preparation of Example 23, 199 was obtained. MS (ESI) m/z: 427.1. 1H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 9.46 (s, 1H), 9.31 (s, 1H), 8.64 (d, J = 6.3 Hz, 2H), 7.73 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 3.86 (s, 2H), 3.00-2.83 (m, 6H), 2.63 (s, 3H), 2.02 (t, J = 7.0 Hz, 2H), 1.67 (s, 4H).

Example 100 8-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-28-diazaspiro[4,5]decane 200

According to the preparation of Example 23, 200 was obtained. MS (ESI) m/z: 427.1. 1H NMR (400 MHz, DMSO) δ 9.62 (s, 1H), 9.48 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.64 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 3.91-3.80 (m, 2H), 3.78-3.68 (m, 2H), 3.13-3.07 (m, 2H), 2.89 (s, 2H), 2.65 (s, 3H), 1.79 (t, J = 7.2 Hz, 2H), 1.71 (t, J = 5.3 Hz, 4H).

Example 101 (S)-2-(3-aminopiperidin-1-yl)-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)nicotinonitrile 201

Step A: 1-(5-Bromo-6-fluoro-pyridin-2-yl)-6-chloro-pyrazolo[4,3-c]pyridine and 6-chloro-1-(6-fluoro-5-iodo-pyridin-2-yl)pyrazolo[4,3-c]pyridine

A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.045 mmol; 314.0 mg), 3-bromo-2-fluoro-6-iodo-pyridine (2.249 mmol; 679.0 mg), N,N′-dimethylethylenediamine (0.2045 mmol; 18.02 mg; 0.0203 mL), copper iodide (2.045 mmol; 393.3 mg), and potassium carbonate (2.249 mmol; 314.0 mg) in 1,4-dioxane (10 mL) was evacuated with argon, then sealed and stirred at 100° C. for 20 hours. The mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated; the residue was purified on silica gel and eluted with 0-100% EtOAc in heptane to give a mixture of 1-(5-bromo-6-fluoro-pyridin-2-yl)-6-chloro-pyrazolo[4,3-c]pyridine (-80 mg, 12%) and 6-chloro-1-(6-fluoro-5-iodo-pyridin-2-yl)pyrazolo[4,3-c]pyridine (-163 mg, 21%).

Step B: 6-(6-Chloropyrazolo[4,3-c]pyridin-1-yl)-2-fluoro-pyridine-3-carbonitrile

A suspension of 1-(5-bromo-6-fluoro-pyridin-2-yl)-6-chloro-pyrazolo[4,3-c]pyridine (0.7437 mmol; 243.6 mg), zinc cyanide (0.4462 mmol; 53.47 mg; 0.0289 mL) and tetrakis(triphenylphosphine)palladium(0) (0.03719 mmol; 43.1 mg) in DMF (5 mL) was degassed and then heated at 120° C. for 3 hours. The mixture was cooled to room temperature and then partitioned between EtOAc and brine. The organic layer was concentrated and the residue was purified on silica gel eluting with 0-60% EtOAc in heptane to give 6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-fluoro-pyridine-3-carbonitrile as a white solid (143.2 mg, 70%).

Step C: Trimethyl-(6-methylpyrazin-2-yl)stannane

A mixture of 2-chloro-6-methyl-pyrazine (3.357 mmol; 431.6 mg), hexamethylditin (4.03 mmol; 1361 mg; 0.861 mL) and tetrakis(triphenylphosphine)palladium(0) (0.2756 mmol; 318.5 mg) in 1,4-dioxane (10 mL) was evacuated with argon. The resulting mixture was sealed in a pressure tube and heated at 100 ° C overnight. The mixture was cooled to room temperature and filtered through celite. The filter cake was washed with DCM. The filtrate was concentrated to give trimethyl-(6-methylpyrazine-2-yl)stannane, which was used without purification.

Step D: tert-Butyl N-[(3S)-1-[3-cyano-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of [(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-3-cyano-pyridin-2-yl]-3-piperidinyl]carbamic acid (0.5166 mmol; 205.5 mg), trimethyl-(6-methylpyrazin-2-yl)stannane (0.7749 mmol; 199.1 mg) and tetrakis(triphenylphosphine)palladium(0) (0.05166 mmol; 59.8 mg) in N,N-dimethylacetamide (12 mL) was evacuated with argon. The reaction mixture was sealed in a pressure bottle and heated at 150° C. for 2 hours. The mixture was cooled to room temperature and then partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica gel eluting with 0-5% MeOH in DCM to give tert-butyl N-[(3S)-1-[3-cyano-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate as a yellow solid (248.6 mg, 94%).

Step E: To a solution of tert-butyl N-[(3S)-1-[3-cyano-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.4859 mmol; 248.6 mg) in dichloromethane (8 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for ⁴ hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to give 201 as an off-white solid (361.6 mg, 18%). NMR(400MHz,DMSO)δ9.61-9.55(s,1H),9.48-9.44(s,1H),9.37-9.33(s,1H),8.80- 8.75(s,1H),8.66-8.62(s,1H),8.26-8.19(m,2H),7.48-7.44(d,J＝8.4Hz,1H),4.29 -4.19(dd,J＝10.7,6.9Hz,2H),3.00-2.94(m,1H),2.66-2.62(s,3H),2.03-1.89(dd, J＝18.5,10.2Hz,2H),1.80-1.66(m,1H),1.49-1.37(m,1H); MS(ESI)m/z:412.2[M+H] ⁺

Example 102 (5S)-5-amino-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4S-c]pyridin-1-yl]-pyridin-2-yl]piperidin-2-one 202

Step A: tert-Butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-6-oxo-3-piperidinyl]carbamate

A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (75 mg, 0.36 mmol), tert-butyl N-[(3S)-1-(6-bromo-pyridin-2-yl)-6-oxo-3-piperidinyl]carbamate (158 mg, 0.426 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.036 mmol), xantphos (42 mg, 0.071 mmol) and sodium tert-butoxide (70 mg, 0.71 mmol) in 6.0 mL of toluene was stirred at 100° C. for 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 100% EtOAc) to afford tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-6-oxo-3-piperidinyl]carbamate (50 mg) in 28% yield.

Step B: A mixture of tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-6-oxo-3-piperidinyl]carbamate (45 mg, 0.15 mmol) in 1,4-dioxane (2.0 ml, 8.0 mmol) solution of hydrogen chloride (4 mol/l) and 1,4-dioxane 2.0 mL was stirred at room temperature for 18 h. The reaction was diluted with water and then washed with EtOAc. The aqueous layer was basified to pH 10 with 1 M NaOH and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to reverse phase HPLC to give 202 (11 mg), 18% yield. MS(ESI)m/z:401.1.1HNMR(400MHz,DMSO)δ9.61(s,1H),9.47(s,1H),9.35(s,1H),8.73(s ,1H),8.63(s,1H),8.04(t,J＝8.1Hz,1H),7.83(d,J＝7.9Hz,1H),7.76(d,J＝8.1Hz,1H),4.2 4(dd,J＝12.2,3.8Hz,1H),3.94(dd,J＝12.3,6.3Hz,1H),3.49(s,1H),2.75(dd,J＝12.2,5. 3Hz,1H),2.69(s,3H),2.63-2.55(m,1H),2.10(dd,J＝13.0,4.3Hz,1H),1.85-1.72(m,1H).

Example 103 2-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 203

Compound 203 was obtained from the first peak of the SFC chiral separation of Example 71. MS(ESI)m/z:401.1.1H NMR (400MHz, DMSO) δ9.47(d,J＝7.6Hz,2H),9.32(s,1H),8.66(s,1H),8.62(s,1H),7.76(t,J＝8.1Hz,1H),7.21(d,J＝7.7Hz,1H),6.77(d,J＝8.5Hz, 1H),4.62-4.49(m,1H),4.41(d,J＝13.7Hz,1H),3.09-2.97(m,2H),2.64( s,3H),1.86(d,J＝13.0Hz,1H),1.74-1.49(m,3H),1.17(d,J＝6.8Hz,3H).

Example 104 2-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 204

Compound 204 was obtained from the second peak of SFC chiral separation of Example 71. MS (ESI) m/z: 401.1.1H NMR (400MHz, DMSO) δ9.47(d,J＝5.4Hz,2H),9.32(d,J＝0.9Hz,1H),8.65(d,J＝10 .3Hz,1H),8.61(d,J＝5.5Hz,1H),7.81-7.73(m,1H),7.21(d,J＝7.7Hz,1H),6.77 (d,J＝8.5Hz,1H),4.63-4.52(m,1H),4.41(d,J＝14.2Hz,1H),3.10-2.99(m,2H) ,2.64(s,3H),1.86(d,J＝12.0Hz,1H),1.76-1.52(m,3H),1.19(d,J＝6.8Hz,3H).

Example 105 (S)-1-(3-methyl-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 205

Step A: 6-Bromo-2-fluoro-3-methyl-pyridine

To a solution of diisopropylamine (22.001 mmol; 2240 mg; 3.13 mL) in THF (40 mL) was added a solution of N-butyllithium (2.5 mol/L) in hexane (24.001 mmol; 9.6 mL) at 0°C. The reaction was stirred at 0°C for 0.5 h and then cooled to -78°C. A solution of 2-bromo-6-fluoro-pyridine (20.001 mmol; 3520.0 mg) in THF (10 mL) was added dropwise. The mixture was stirred at -78°C for 3 h. Iodomethane (22.001 mmol; 3122.8 mg; 1.37 mL) was slowly added. The mixture was warmed to room temperature with stirring for 1 hour. The reaction was quenched with water (~50 mL) and stirred overnight. The layers were separated. The organic layer was concentrated and the residue was purified on silica gel eluting with 0-5% EtOAc in heptane to give 6-bromo-2-fluoro-3-methyl-pyridine as a white solid (2.08 g, 55%).

Step B: Following the procedure described in Example 86 and starting from tert-butyl N-[(3S)-3-piperidinyl]carbamate, 6-bromo-2-fluoro-3-methyl-pyridine and 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine, 205 was obtained over 3 steps as an off-white solid (4.4 mg, 4.5%). ¹ H NMR (400 MHz, DMSO) δ 9.75-9.70 (s, 1H), 9.48-9.44 (s, 1H), 9.33-9.29 (s, 1H), 8.68-8.61 (d, J = 12.1 Hz, 2H), 8.38-8.15 (s, 1H), 7.78-7.74 (d, J = 8.1 Hz, 1H), 7.59-7.55 (d, J = 8.0 Hz,1H),2.90-2.84(m,1H),2.67-2.63(s,3H),2.37-2.32(s,3H),2.04-1.95(d,J＝9.2Hz ,2H),1.80-1.68(d,J＝9.4Hz,1H),1.57-1.47(d,J＝8.6Hz,1H); MS(ESI)m/z:433.1[M+H] ⁺

Example 106 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]-14-diazepan-5-one 206

According to the preparation procedure of Example 102, 206 was obtained. MS (ESI) m/z: 401.1.

Example 107 1-(3-methoxy-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 207

Step A: 1-(6-Bromo-3-methoxy-pyridin-2-yl)-1,4-diazepan-6-ol

A mixture of 6-bromo-2-fluoro-3-methoxy-pyridine (2.660 mmol; 547.9 mg), 1,4-diazepan-6-ol dihydrobromide (3.989 mmol; 1109 mg) and N,N'-diisopropylethylamine (10.64 mmol; 1389 mg; 1.87 mL) in isopropanol (10 mL) was heated at 100 ° C in a sealed pressure bottle overnight. The mixture was cooled to room temperature and concentrated. The residue was purified on silica gel eluting with 0-10% MeOH in DCM to give 1-(6-bromo-3-methoxy-pyridin-2-yl)-1,4-diazepan-6-ol (301.2 mg, 37%).

Step B: 4-(6-Bromo-3-methoxy-pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylic acid tert-butyl ester

A mixture of 1-(6-bromo-3-methoxy-pyridin-2-yl)-1,4-diazepan-6-ol (0.9968 mmol; 301.2 mg), tert-butoxycarbonyl tert-butyl carbonate (1.495 mmol; 326.3 mg), and sodium bicarbonate (9.968 mmol; 837.4 mg) in dichloromethane (20 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified on silica gel eluting with 0-40% EtOAc in DCM to give tert-butyl 4-(6-bromo-3-methoxy-pyridin-2-yl)-6-hydroxy-1,4-diazepan-1-carboxylate (262.5 mg, 65%).

Step C: Following the procedure described in Example 86 and starting from 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine and 4-(6-bromo-3-methoxy-pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylic acid tert-butyl ester, 207 was obtained over 2 steps as an off-white solid (4.4 mg, 4.5%). MS (ESI) m/z: 433.1 [M+H] ⁺

Example 108 5-(1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-methylpyrazin-2-amine 208

Step A: tert-Butyl N-[(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of 6-chloro-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine (2.998 mmol; 745.3 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (4.496 mmol; 900.5 mg), and N-methylmorpholine (8.993 mmol; 919 mg; 0.999 mL) in 1-methyl-2-pyrrolidone (10 mL) was heated at 100° C. overnight in a sealed pressure bottle. The mixture was poured into water. The precipitate was collected by filtration and then purified on silica gel eluting with 0-40% EtOAc in heptane to give tert-butyl N-[(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-3-piperidinyl]carbamate (1.0738 g, 84%).

Step B: tert-Butyl 4-[6-(6-Tetrabutylstannylpyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-1,4-diazepane-1-carboxylate (1.234 mmol; 529.4 mg) in 1,4-dioxane (40 mL) was added lithium chloride (7.406 mmol; 314.0 mg), bis(tributyltin) (1.481 mmol; 904.5 mg; 0.7879 mL), tris(dibenzylideneacetone)dipalladium(0) (0.06172 mmol; 56.52 mg) and tricyclohexylphosphine (0.1481 mmol; 41.54 mg) under argon. The reaction mixture was sealed in a pressure tube and heated at 120 ° C overnight. The mixture was cooled to room temperature and filtered through celite. The filter cake was washed with DCM. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-40% EtOAc in heptane to afford tert-butyl 4-[6-(6-tetrabutylstannylpyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-1,4-diazepane-1-carboxylate as a clear oil (400.0 mg, 47%).

Step C: 4-[6-[6-(5-Amino-6-methyl-pyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazepane-1-carboxylic acid tert-butyl ester

A mixture of 4-[6-(6-tetrabutylstannylpyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-1,4-diazepane-1-carboxylic acid tert-butyl ester (0.5852 mmol; 400 mg), 5-bromo-3-methyl-pyrazin-2-amine (1.170 mmol; 220.1 mg), tricyclohexylphosphine (0.1405 mmol; 39.39 mg) and tris(dibenzylideneacetone)dipalladium(0) (0.05852 mmol; 53.59 mg) in N,N-dimethylacetamide (30 mL) was evacuated with argon for 1 minute. The reaction mixture was sealed in a Biotage microwave tube and heated under microwave at 150° C. for 45 minutes. The mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica gel eluting with 10% MeOH in DCM to give 4-[6-[6-(5-amino-6-methyl-pyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazepane-1-carboxylic acid tert-butyl ester (115.0 mg, 39%).

Step D: To a solution of tert-butyl 4-[6-[6-(5-amino-6-methyl-pyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazepane-1-carboxylate (0.2293 mmol; 115 mg) in methanol (10 mL) was added a 4.0 M solution of hydrochloric acid in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 208 as an off-white solid (4.0 mg, 4.3%). MS (ESI) m/z: 402.1 [M+H] ⁺

Example 109 (S)-5-(1-(6-(3-aminopiperidin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-methylpyrazin-2-amine 209

Following the procedure described in Example 108 and starting from tert-butyl (S)-piperidin-3-ylcarbamate, 209 was obtained over 4 steps as an off-white solid (52.8 mg, 56%). ¹ H NMR (400 MHz, DMSO) δ 9.34-9.29 (s, 1H), 9.20-9.13 (s, 1H), 8.89-8.84 (s, 1H), 8.58-8.54 (s, 1H), 7.77-7.69 (t, J = 8.1 Hz, 1H), 7.22-7.15 (d, J = 7.7 Hz, 1H), 6.81-6.73 (d, J = 8.5 Hz, 1H), 6.60-6.51 (s, 2H), 4.45-4.37 (d, J = 13.2 Hz, 1H), 4.18- 4.11(d,J＝10.5Hz,1H),3.16-3.08(dd,J＝17.5,6.7Hz,1H),2.87-2.74(dt,J＝22.9,9.5Hz,2H),2.47-2.38(s,3H),1.9 6-1.90(d,J＝12.7Hz,1H),1.87-1.79(m,1H),1.65-1.53(d,J＝12.8Hz,1H),1.38-1.28(m,1H); MS(ESI)m/z:402.1[M+H] ⁺

Example 110 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]cyclohexylamine 210

Compound 210 was obtained from the third peak of the SFC chiral separation of a mixture of four diastereomers. MS (ESI) m/z: 386.1. 1H NMR (400 MHz, DMSO) δ 9.68 (s, 1H), 9.49 (s, 1H), 9.37 (s, 1H), 8.74 (s, 1H), 8.66 (s, 1H), 8.07-8.02 (m, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 2.65 (s, 3H), 2.35-2.21 (m, 1H), 2.19-2.02 (m, 3H), 1.96-1.72 (m, 4H).

Example 111 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]cyclohexylamine 211

Compound 211 was obtained from the first peak of a mixture of four diastereomers by SFC chiral separation. MS (ESI) m/z: 386.1. 1H NMR (400 MHz, DMSO) δ 9.68 (s, 1H), 9.49 (s, 1H), 9.37 (d, J = 0.8 Hz, 1H), 8.74 (s, 1H), 8.66 (s, 1H), 8.07-8.02 (m, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 2.65 (s, 3H), 2.36-2.22 (m, 2H), 2.19-2.03 (m, 4H), 1.93-1.72 (m, 4H).

Example 112 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]cyclohexylamine 212

Compound 212 was obtained from the second peak of the SFC chiral separation of a mixture of four diastereomers. MS(ESI)m/z:386.1.1H NMR(400MHz,DMSO)δ9.72(s,1H),9.49(s,1H),9.37(s,1H),8.75(s,1H),8. 66(s,1H),8.06-8.01(m,1H),7.92(d,J＝8.1Hz,1H),7.29(d,J＝7.4Hz,1H), 3.26(s,1H),3.04(t,J＝12.1Hz,1H),2.66(s,3H),2.25-2.02(m,4H),1.95( dd,J＝27.3,12.1Hz,1H),1.71-1.53(m,2H),1.46(dd,J＝22.9,10.7Hz,1H).

Example 113 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]cyclohexylamine 213

Compound 213 was obtained from the fourth peak of SFC chiral separation of a mixture of four diastereomers. MS (ESI) m/z: 386.1. 1H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 9.49 (s, 1H), 9.37 (s, 1H), 8.74 (s, 1H), 8.66 (s, 1H), 8.06-8.00 (m, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 3.25 (s, 1H), 3.04 (t, J = 12.1 Hz, 1H), 2.66 (s, 3H), 2.27-2.02 (m, 4H), 1.94 (dd, J = 25.3, 12.8 Hz, 1H), 1.73-1.39 (m, 3H).

Example 114 1-[6-(26-diazaspiro[3.4]octan-6-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridine 214

According to the preparation of Example 23, 214 was obtained. MS (ESI) m/z: 399.1. 1H NMR (400 MHz, DMSO) δ 9.80 (s, 1H), 9.45 (s, 1H), 9.30 (s, 1H), 8.64 (d, J = 3.3 Hz, 1H), 8.39 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.42 (d, J = 8.3 Hz, 1H), 3.73 (dd, J = 21.9, 13.3 Hz, 6H), 3.62 (d, J = 8.5 Hz, 2H), 2.65 (s, 3H), 2.32 (t, J = 6.8 Hz, 2H).

Example 115 (S)-1-(3-fluoro-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 215

Step A: tert-Butyl N-[(3S)-1-(6-chloro-3-fluoro-pyridin-2-yl)-3-piperidinyl]carbamate

A mixture of 2,6-dichloro-3-fluoro-pyridine (3.802 mmol, 631.1 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (3.992 mmol; 799.6 mg), potassium carbonate (7.605 mmol; 1051 mg), N,N'-dimethylethylenediamine (0.3802 mmol; 33.52 mg; 0.0409 mL), and copper (I) iodide (3.802 mmol; 724.1 mg) in 1,4-dioxane (15 mL) was evacuated with argon, then sealed in a pressure tube and heated overnight at 105° C. The reaction was cooled to room temperature and then filtered through celite. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-20% EtOAc in heptane to afford tert-butyl N-[(3S)-1-(6-chloro-3-fluoro-pyridin-2-yl)-3-piperidinyl]carbamate (279.2 mg, 22%) as a white solid.

Step B: tert-Butyl N-[(3S)-1-[3-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.83325 mmol; 176 mg), tert-butyl N-[(3S)-1-(6-chloro-3-fluoro-pyridin-2-yl)-3-piperidinyl]carbamate (0.8378 mmol; 276.3 mg), cesium carbonate (1.6665 mmol; 543.00 mg), Xantphos (0.14165 mmol; 84.500 mg) and tris(dibenzylideneacetone)dipalladium(0) (0.083325 mmol; 77.074 mg) in 1,4-dioxane (10 mL) was evacuated with argon, then sealed and stirred overnight at 110° C. The mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-100% EtOAc in heptane to afford tert-butyl N-[(3S)-1-[3-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (113.1 mg, 16%).

Step C: A mixture of tert-butyl N-[(3S)-1-[3-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.1345 mmol; 113.1 mg) in TFA (1 mL) and dichloromethane (4 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to give 215 as an off ^- white solid (42.7 mg, 77%). NMR (400MHz, DMSO) δ9.58-9.55(s,1H),9.47-9.43(s,1H),9.33-9.30(s,1H),8.69-8.65(s,1H),8.64 -8.62(s,1H),8.35-8.30(s,1H),7.79-7.72(dd,J＝12.7,8.5Hz,1H),7.42-7.38(dd,J＝8.4,2.0Hz,1H ),4.05-3.97(d,J＝8.5Hz,2H),3.29-3.26(d,J＝10.8Hz,1H),3.02-2.95(m,2H),2.66-2.60(s,3H),2. 00-1.87(t,J＝14.1Hz,2H),1.80-1.67(m,1H),1.47-1.37(d,J＝10.5Hz,1H); MS(ESI)m/z:405.1[M+H] ⁺

Example 116 8-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-18-diazaspiro[4,5]decane 216

According to the preparation of Example 23, 216 was obtained. MS (ESI) m/z: 427.1. 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.62 (s, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 3.87-3.70 (m, 4H), 2.87 (t, J = 6.9 Hz, 2H), 2.63 (s, 3H), 1.79-1.68 (m, 2H), 1.68-1.60 (m, 3H), 1.60-1.52 (m, 3H).

Example 117 1-[6-(27-diazaspiro[3.4]octan-2-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridine 217

According to the preparation of Example 23, 217 was obtained. MS (ESI) m/z: 399.1. 1H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 9.46 (s, 1H), 9.31 (s, 1H), 8.65 (s, 1H), 8.63 (s, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 6.37 (d, J = 8.1 Hz, 1H), 4.16 (s, 4H), 3.20 (s, 2H), 3.02 (t, J = 7.1 Hz, 3H), 2.62 (s, 2H), 2.14 (t, J = 7.1 Hz, 2H).

Example 118 (S)-(2-(3-aminopiperidin-1-yl)-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-3-yl)methanol 218

Step A: (6-Bromo-2-fluoro-pyridin-3-yl)methanol

To a solution of diisopropylamine (22.001 mmol; 2240 mg; 3.13 mL) in THF (40 mL) was added a solution of N-butyllithium (2.5 mol/L) in hexane (24.001 mmol; 9.6 mL) at 0°C. The reaction was stirred at 0°C for 0.5 h and then cooled to -78°C. A solution of 2-bromo-6-fluoro-pyridine (20.001 mmol; 3520.0 mg) in THF (10 mL) was added dropwise. The mixture was stirred at -78°C for 2.5 h. Paraformaldehyde (40.002 mmol; 3603.3 mg) was quickly added. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated and the residue was purified on silica gel eluting with 0-50% EtOAc in heptane to give (6-bromo-2-fluoro-pyridin-3-yl)methanol (1.4888 g, 36%).

Step B: tert-Butyl N-[(3S)-1-[6-bromo-3-(hydroxymethyl)-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of (6-bromo-2-fluoro-pyridin-3-yl)methanol (1.766 mmol; 363.8 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (2.649 mmol; 530.5 mg) and N-methylmorpholine (5.298 mmol; 541 mg; 0.588 mL) in 1-methyl-2-pyrrolidone (10 mL) was heated at 130° C. in a sealed pressure bottle for 4 hours. The mixture was poured into water and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica gel eluting with 0-100% EtOAc in heptane to give tert-butyl N-[(3S)-1-[6-bromo-3-(hydroxymethyl)-pyridin-2-yl]-3-piperidinyl]carbamate (546.3 mg, 80%).

Step C: Following the procedure described in Example 86 and starting from 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine and tert-butyl N-[(3S)-1-[6-bromo-3-(hydroxymethyl)-pyridin-2-yl]-3-piperidinyl]carbamate, 218 was obtained over 2 steps as an off-white ^solid (40.8 mg, 68%). NMR (400MHz, DMSO) δ9.77-9.73(s,1H),9.49-9.45(s,1H),9.34-9.31(s,1H),8.69-8.67(s,1H),8.64-8.61(s,1H) ,8.03-7.98(d,J＝8.1Hz,1H),7.65-7.61(d,J＝8.1Hz,1H),4.59-4.52(d,J＝2.9Hz,2H),3.60-3.52(d,J＝12.4Hz,1H) ,3.51-3.43(d,J＝9.8Hz,1H),3.21-3.15(d,J＝10.4Hz,1H),3.00-2.92(s,1H),2.74-2.68(d,J＝12.0Hz,1H),2.67- 2.64(s,3H),1.98-1.89(d,J＝9.4Hz,2H),1.77-1.66(m,1H),1.37-1.26(d,J＝10.0Hz,1H); MS(ESI)m/z:417.1[M+H] ⁺

Example 119 1-(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)-1,4-diazepan-6-ol 219

A mixture of 1-[6-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.213 mmol; 79.9 mg), 1,4-diazepan-6-ol dihydrobromide (1.07 mmol; 297 mg) and cesium carbonate (2.13 mmol; 696 mg) in DMSO (2 mL) and IPA (4 mL) was heated at 120 ° C overnight in a sealed pressure bottle. The mixture was cooled to room temperature and then filtered through Celite (R). The filtrate was concentrated and the residue was purified by reverse phase HPLC to give 219 as an off-white solid (10.8 mg, ¹¹ %). NMR (400MHz, DMSO) δ9.59-9.53(s,1H),9.48-9.43(s,1H),9.38-9.33(s,1H),8.79-8.75(s,1H),8.66-8.62(s ,1H),8.22-8.17(d,J＝8.5Hz,1H),7.57-7.52(d,J＝8.5Hz,1H),4.76-4.67(s,1H),3.98-3.88(d,J＝10.4Hz,3H) ,3.75-3.66(d,J＝14.1Hz,1H),3.65-3.55(dd,J＝15.3,8.4Hz,1H),3.15-3.07(m,1H),3.06-2.99(m,1H),2.87 -2.79(dd,J＝13.7,3.4Hz,1H),2.76-2.68(dd,J＝13.6,5.8Hz,1H),2.69-2.62(s,3H);MS(ESI)m/z:471.1[M+H] ⁺

Example 120 (S)-1-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine 120

Step A: 1-[6-Fluoro-5-(trifluoromethyl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine

To a mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (1.008 mmol; 213.0 mg) in dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil; 1.210 mmol; 48.40 mg) at 0 ° C. The resulting mixture was stirred for 10 minutes. 2,6-difluoro-3-(trifluoromethyl)pyridine (1.008 mmol; 184.6 mg) was then added. The reaction was stirred and allowed to warm to room temperature and stirred for 4 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine and then concentrated. The residue was purified on silica gel eluted with 0-100% EtOAc in heptane. 1-[6-Fluoro-5-(trifluoromethyl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine was obtained as the most abundant isomer (173.6 mg, 46%).

Step B: tert-Butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-(trifluoromethyl)-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of 1-[6-chloro-5-(trifluoromethyl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.0876 mmol; 59.7 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (0.263 mmol; 52.6 mg) and N-methylmorpholine (0.263 mmol; 26.9 mg; 0.0292 mL) in 1-methyl-2-pyrrolidone (3 mL) was heated overnight at 120° C. in a sealed pressure bottle. The mixture was poured into water and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica gel eluting with 0-100% EtOAc in heptane to provide tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-(trifluoromethyl)-pyridin-2-yl]-3-piperidinyl]carbamate as a white solid (37.0 mg, 65%).

Step C: A mixture of tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-(trifluoromethyl)-pyridin-2-yl]-3-piperidinyl]carbamate (0.0569 mmol; 37.0 mg) in methanol (5 mL) and a 4.0 M solution of hydrogen chloride in 1,4-dioxane (5 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 220 as an off-white solid ( ^31.0 mg, 81%). NMR(400MHz,DMSO)δ9.67-9.63(s,1H),9.48-9.45(s,1H),9.36-9.33(s,1H),8.78-8.75(s,1H),8.65-8.6 2(s,1H),8.27-8.21(d,J＝8.5Hz,1H),7.71-7.65(d,J＝8.5Hz,1H),3.76-3.62(dd,J＝24.1,11.7Hz,2H),3. 25-3.19(d,J＝11.2Hz,1H),2.95-2.80(dd,J＝24.6,13.2Hz,2H),2.68-2.63(d,J＝9.0Hz,3H),2.00-1.88(d ,J＝14.4Hz,2H),1.73-1.63(d,J＝13.2Hz,1H),1.36-1.22(dd,J＝20.5,8.6Hz,1H); MS(ESI)m/z:455.1[M+H] ⁺

Example 121 (5S)-5-amino-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-2-one 221

Step A: tert-Butyl N-[(3S)-1-(6-chloro-3-methyl-pyridin-2-yl)-6-oxo-3-piperidinyl]carbamate

A 12 mL solution of dioxane containing 2-bromo-6-chloro-3-methylpyridine (487 mg, 2.24 mmol), tert-butyl N-[(3S)-6-oxo-3-piperidinyl]carbamate (400 mg, 1.87 mmol), copper (I) iodide (356 mg, 1.87 mmol), potassium carbonate (310 mg, 2.24 mmol), and N,N′-dimethylethylenediamine (329 mg, 3.73 mmol) was stirred at 110° C. for 18 h. The reaction was filtered through celite and concentrated. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 50% EtOAc) to give 350 mg of the desired product in 38% yield. MS (ESI) m/z: 340.1.

Step B: tert-Butyl N-[(3S)-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-6-oxo-3-piperidinyl]carbamate

A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (150 mg, 0.710 mmol), tert-butyl N-[(3S)-1-(6-chloro-3-methyl-pyridin-2-yl)-6-oxo-3-piperidinyl]carbamate (497 mg, 1.42 mmol), tris(dibenzylideneacetone)dipalladium(0) (65 mg, 0.071 mmol), xantphos (84 mg, 0.14 mmol) and sodium tert-butoxide (140 mg, 1.42 mmol) in toluene 3.0 mL was stirred at 110 °C for 18 h. The reaction mixture was stirred at 110°C for 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/heptane then MeOH/DCM eluted at 10% MeOH) to give 75 mg of the desired product in 20% yield. MS (ESI) m/z: 515.1.

Step C: A solution of tert-butyl N-[(3S)-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-6-oxo-3-piperidinyl]carbamate (63 mg, 0.12 mmol) in 1,4-dioxane (2.0 mL, 8.0 mmol) containing 4 mol/L hydrogen chloride and 2.0 mL of 1,4-dioxane was stirred at room temperature for 18 h. The reaction was concentrated in vacuo. Reverse-phase HPLC analysis of the crude product gave 22115 mg, a 29% yield. MS(ESI)m/z:415.1.1H NMR (400MHz, DMSO) δ9.61(s,1H),9.48(s,1H),9.35(s,1H),8.73(s,1H),8.64(s,1H),7.98(d,J＝8.2Hz,1H),7.93(d,J＝8.3Hz,1H),4. 27(s,1H),3.86(s,1H),3.59(d,J＝33.7Hz,1H),3.40(s,1H),2.68(t,J＝18.2Hz,3H),2.20(d,J＝13.0Hz,3H),2.10(s,1H),1.85(s,2H).

Example 122 (3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]pyrazin-2-yl]piperidin-3-amine 222

Step A: tert-Butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidinyl]carbamate

A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (80 mg; 0.38 mmol), tert-butyl N-[(3S)-1-(6-bromo-3-methoxy-pyrazin-2-yl)-3-piperidinyl]carbamate (181 mg, 0.4550 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), xantphos (45 mg, 0.076 mmol), and sodium tert-butoxide (75 mg, 0.76 mmol) in 3.0 mL of toluene was stirred at 110° C. for 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 75% EtOAc) to give 112 mg of the desired product in 57% yield. MS (ESI) m/z: 518.1.

Step B: A solution of tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidinyl]carbamate (75 mg, 0.15 mmol) in 4.0 mL of dichloromethane and trifluoroacetic acid (0.80 mL, 10 mmol) was stirred at room temperature for 4 h. The reaction was concentrated and purified by reverse phase HPLC to afford 222 (25 mg) in 41% yield. MS(ESI)m/z:418.2.1H NMR (400MHz, DMSO) δ9.45(s,2H),9.32(s,1H),8.67(s,1H),8.63(s,1H),8.15(s,1H),4.24(d,J＝10.2Hz,1H),4.06(d,J＝13.3Hz,1H ), 4.00 (s, 3H), 3.09 (dd, J = 24.2, 12.0Hz, 3H), 2.63 (s, 3H), 1.94 (d, J = 15.0Hz, 2H), 1.76 (d, J = 10.0Hz, 1H), 1.49 (d, J = 10.0Hz, 1H).

Example 123 3-[(3S)-3-amino-1-piperidinyl]-5-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]pyrazin-2-ol 223

A solution of tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidinyl]carbamate (30 mg, 0.058 mmol) in hydrogen chloride (4 mol/L) in 1,4-dioxane (1.0 ml, 4.0 mmol) and 1.0 mL of 1,4-dioxane was stirred at room temperature for 2 days. The reaction was concentrated and purified by reverse phase HPLC to give 223 (7 mg, 27% yield). MS(ESI)m/z:404.1.1H NMR (400MHz, DMSO) δ9.44(s,1H),9.28(s,1H),9.25(s,1H),8.61(s,1H),8.57(s,1H),7.23(s,1H),4.74(d,J＝11.1Hz,1H) ,4.44(d,J＝12.8Hz,1H),2.92(s,2H),2.62(s,3H),1.88(d,J＝16.7Hz,2H),1.68(d,J＝11.1Hz,1H),1.39(d,J＝9.5Hz,1H).

Example 124 1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 224

Step A: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

To a solution of tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate (2.55 g, 7.16 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (1.0 g, 6.51 mmol) in 1,4-dioxane (20 mL) of Example 45 was added CuI (494 mg, 2.6 mmol), K ₂ CO ₃ (3.6 g, 26 mmol) and N ¹ ,N ² -dimethylethane-1,2-diamine (460 mg, 5.2 mmol). The mixture was heated at 100° C. for 3 hours, which was monitored by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether/EtOAc (2/1) as eluent to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (1.6 g, 57%). MS (ESI) m/z: 429 [M+H] ⁺ .

Step B: tert-Butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (500 mg, 1.16 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (679 mg, 3.5 mmol), Pd(dppf) _Cl2 (47.5 mg, 0.058 mmol) and _{aqueous Na2CO3} solution (2.0 M, 3 mL) in 1,4-dioxane (10 mL) was heated at 100°C under nitrogen for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/EtOAc (1/1) as eluent to afford tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (360 mg, 67%). MS (ESI) m/z: 461 [M+H] ⁺ .

Step C: A solution of 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (440 mg, 0.93 mmol) in HCl/MeOH (2M, 10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 224 as a yellow solid (180 mg, 51.8%). ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.095-9.098(d,J＝1.5Hz,1H),8.61(s,1H),8.45(s,1H),8.14(s, 1H),7.87(s,1H),7.64-7.69(t,J＝13.5Hz,1H),7.13-7.16(d,J＝12.5Hz,1 H),6.55-6.58(d,J＝14.5Hz,1H),3.90-3.91(d,J＝8Hz,3H),3.78-3.87(m, 6H),3.01-3.05(t,J＝13Hz,2H),1.87-1.91(m,2H); MS(ESI)m/z:375[M+H] ⁺ .

Example 125 (3S)-3-amino-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-2-one 225

Step A: tert-Butyl N-[(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-2-oxo-3-piperidinyl]carbamate

A solution containing 1-(6-bromo-pyridin-2-yl)-6-chloro-pyrazolo[4,3-c]pyridine (200 mg, 0.646 mmol), tert-butyl N-[(3S)-2-oxo-3-piperidinyl]carbamate (166 mg, 0.775 mmol), copper(I) iodide (123 mg, 0.646 mmol), potassium carbonate (107 mg, 0.775 mmol), and N,N′-dimethylethylenediamine (114 mg, 1.29 mmol) was stirred at 110° C. for 4 h. The reaction was filtered through celite and concentrated. The crude product was purified by ISCO column (EtOAc/heptane, eluted at 70% EtOAc) to give 135 mg of the desired product in 47% yield. MS (ESI) m/z: 443.1.

Step B: tert-Butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-2-oxo-3-piperidinyl]carbamate

To a solution of tert-butyl N-[(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl]-2-oxo-3-piperidinyl]carbamate (125 mg, 0.282 mmol) and tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.028 mmol) in 5.0 mL of N,N-dimethylacetamide was added trimethyl-(6-methylpyrazin-2-yl)stannane (145 mg, 0.565 mmol). The reaction mixture was heated at 145 ° C. in a CEM microwave for 40 minutes. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used in the next step. MS (ESI) m / z: 501.1.

Step C: A solution of tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-2-oxo-3-piperidinyl]carbamate (140 mg, 0.280 mmol) in 4.0 ml of dichloromethane and trifluoroacetic acid (0.80 ml, 10 mmol) was stirred at room temperature for 3 h. The reaction was concentrated and diluted with water, then extracted with EtOAc. The aqueous layer was basified to pH 10 with 1 M NaOH and then extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to reverse phase HPLC to give 225 (44 mg, 39% yield). MS (ESI) m/z: 401.1.1H NMR(400MHz,DMSO)δ9.60(s,1H),9.47(s,1H),9.33(s,1H),8.72(s,1H),8.64(s ,1H),8.05(t,J＝8.1Hz,1H),7.82(d,J＝8.0Hz,1H),7.74(d,J＝8.1Hz,1H),4.46- 4.33(m,1H),4.14-4.02(m,1H),3.58(dd,J＝10.8,6.4Hz,1H),2.65(s,3H),2.24 (dt,J＝11.4,5.3Hz,1H),2.19-2.00(m,2H),1.77(ddd,J＝23.0,10.6,5.1Hz,1H).

Example 126 (3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]pyrazin-2-yl]piperidin-3-amine 226

Step A: 3,5-Dibromo-2-chloro-pyrazine

To a solution of 3,5-dibromopyrazin-2-amine (1.00 g, 3.95 mmol) in 6.0 ml of dichloromethane was added a solution of titanium tetrachloride (1 mol/l) in dichloromethane (3.95 mL, 3.95 mmol) at 0°C, followed by dropwise addition of tert-butyl nitrite (1.05 mL, 7.91 mmol). The reaction was warmed to room temperature and then 1 equivalent of _TiCl₄ was added and stirred for 1 h. The reaction was quenched with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was used in the next step. MS (ESI) m/z: 272.2.

Step B: tert-Butyl N-[(3S)-1-(6-bromo-3-chloro-pyrazin-2-yl)-3-piperidinyl]carbamate

A 5.0 mL solution of 3,5-dibromo-2-chloropyrazine (1.03 g, 3.60 mmol) and tert-butyl n-[(3S)-3-piperidinyl]carbamate (600 mg, 3.00 mmol) in methyl sulfoxide was heated to 85°C. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluting with 35% EtOAc) to afford 350 mg of the desired product in 30% yield. MS (ESI) m/z: 393.2.

Step C: tert-Butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidinyl]carbamate

A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (110 mg, 0.52 mmol), tert-butyl N-[(3S)-1-(6-bromo-3-chloro-pyrazin-2-yl)-3-piperidinyl]carbamate (252 mg, 0.62 mmol), tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.052 mmol), xantphos (62 mg; 0.10 mmol), and sodium tert-butoxide (103 mg, 1.04 mmol) in 5.0 mL of toluene was stirred at 110° C. for 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 75% EtOAc) to give 112 mg of the desired product in 41% yield. MS (ESI) m/z: 523.2.

Step D: A solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidinyl]carbamate (30 mg, 0.057 mmol) in 4.0 ml of dichloromethane and trifluoroacetic acid (0.80 ml, 10 mmol) was stirred at room temperature for 3 h. The reaction was concentrated, diluted with water, and extracted with EtOAc. The aqueous layer was basified to pH 10 with 1 M NaOH and then extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC to afford 226 (12 mg, 49% yield). MS (ESI) m/z: 422.1.

Example 127 (S)-1-(3-(difluoromethyl)-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-amine 227

Step A: [2-Fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-3-yl]methanol

A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (2.000 mmol; 422.4 mg), (6-bromo-2-fluoro-pyridin-3-yl)methanol (2.400 mmol; 494.4 mg), potassium carbonate (4.000 mmol; 552.8 mg), copper(I) iodide (2.000 mmol; 380.9 mg) and N,N'-dimethylethylenediamine (0.2000 mmol; 17.81 mg; 0.0217 mL) in 1,4-dioxane (15 mL) was evacuated with argon, then sealed in a pressure tube and heated overnight at 105° C. The mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-100% EtOAc in heptane to give [2-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-3-yl]methanol (79.5 mg, 12%).

Step B: 2-Fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridine-3-carbaldehyde

To a solution of [2-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-3-yl]methanol (0.236 mmol; 79.5 mg) in dichloromethane (10 mL) was added DESS-MARTIN periodinane (0.355 mmol; 155 mg). The mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was purified on silica gel eluting with 0-100% EtOAc in DCM to provide 2-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridine-3-carbaldehyde as a light yellow solid (69.7 mg, 88%).

Step C: 1-[5-(Difluoromethyl)-6-fluoro-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine

2-Fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridine-3-carbaldehyde (0.208 mmol; 69.7 mg) was dissolved in dichloromethane (10 mL) and cooled to 0°C. DEOXO- (1.04 mmol; 231 mg; 0.19 mL) was slowly added and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified on silica gel eluting with 0-100% EtOAc in DCM to give 1-[5-(difluoromethyl)-6-fluoro-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (34.8 mg, 47%).

Step D: tert-Butyl N-[(3S)-1-[3-(difluoromethyl)-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate

A mixture of 1-[5-(difluoromethyl)-6-fluoro-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.0977 mmol; 34.8 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (0.147 mmol; 29.3 mg), and N-methylmorpholine (0.244 mmol; 24.9 mg; 0.0271 mL) in 1-methyl-2-pyrrolidone (3 mL) was heated overnight at 100° C. in a sealed pressure bottle. The mixture was poured into water and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica gel eluting with 0-100% EtOAc in DCM to afford tert-butyl N-[(3S)-1-[3-(difluoromethyl)-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (-52.4 mg, 100%).

Step E: A mixture of tert-butyl N-[(3S)-1-[3-(difluoromethyl)-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-3-piperidinyl]carbamate (0.0977 mmol; 52.4 mg) in TFA (1 mL) and dichloromethane (4 mL) was stirred at room temperature. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 228 as ^an off-white solid (17.5 mg, 40%). NMR (400MHz, DMSO) δ9.73-9.66(s,1H),9.48-9.42(s,1H),9.36-9.29(s,1H),8.76-8.72(s,1H),8.65-8.61(d ,J＝4.9Hz,1H),8.20-8.15(d,J＝8.4Hz,1H),7.74-7.70(d,J＝8.3Hz,1H),7.34-7.05(t,J＝54.2Hz,1H),3.60-3. 47(dd,J＝17.4,12.4Hz,2H),3.06-2.97(t,J＝8.3Hz,1H),2.94-2.86(dd,J＝11.9,8.2Hz,1H),2.68-2.61(s,3H) ,1.98-1.86(d,J＝12.3Hz,2H),1.86-1.67(dd,J＝16.0,6.7Hz,2H),1.41-1.31(m,1H);MS(ESI)m/z:437.1[M+H] ⁺

Example 128 (3S)-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]pyrazin-2-yl]piperidin-3-amine 228

Step A: tert-Butyl N-[(3S)-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidinyl]carbamate

To a solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidinyl]carbamate (50 mg, 0.096 mmol), trimethylboroxine (36 mg, 0.29 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (8.0 mg, 0.0095 mmol) in 2.0 mL of acetonitrile was added 1.00 M aqueous sodium carbonate solution (0.19 mL, 0.19 mmol) and 1.00 M aqueous potassium acetate solution (0.19 mL, 0.19 mmol). The mixture was heated in a microwave at 140° C. for 40 minutes. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/heptane, eluting at 80% EtOAc) to afford 34 mg of the desired product in 70% yield. MS (ESI) m/z: 502.2.

Step B: A solution of tert-butyl N-[(3S)-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidinyl]carbamate (34 mg, 0.068 mmol) in hydrogen chloride (4 mol/L) in 1,4-dioxane (2.0 mL, 8.0 mmol) and 1,4-dioxane (2.0 mL) was stirred at room temperature for 18 hours. The crude product was purified by reverse phase HPLC to afford 228 (15 mg, 56% yield). MS(ESI)m/z:402.2.1H NMR (400MHz, DMSO) δ9.58(s,1H),9.44(s,1H),9.32(s,1H),8.71(s,1H),8.66(s,1H),8.63(s,1H),3.67(d,J＝12.3Hz,2H),3.19(t,J＝11.3Hz ,1H),2.93(s,1H),2.73(dd,J＝12.1,9.1Hz,1H),2.64(s,3H),2.54(s,3H),1.94(d,J＝10.2Hz,2H),1.74(d,J＝11.1Hz,1H),1.39-1.26(m,1H).

Example 129 (R)-1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 229

Following the procedure described in Example 124 and starting from 1,4-diazepan-6-ol, 2-bromo-6-fluoropyridine, 6-chloro-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 229 was obtained as a yellow solid (40 mg, 24.1%) over 6 steps. ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.09(s,1H),8.65(s,1H),8.44(s,1H),8.25(s,1H),7.98(s,1H ),7.63-7.68(m,1H),7.14-7.16(d,J＝12.5Hz,1H),6.61-6.64(d,J＝14H z,1H),4.10-4.14(m,1H),3.86-3.91(m,6H),3.55-3.66(m,2H),2.98-3 .04(m,3H),2.84-2.90(m,1H),2.69-2.71(m,1H); MS(ESI)m/z:391[M+H] ⁺ .

Example 130 4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepan-4-ol 230

A solution of tert-butyl 4-hydroxy-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepane-1-carboxylate (200 mg, 0.41 mmol) in HCl in MeOH (2.0 M, 10 mL) was stirred at room temperature for 1 hour, which was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give 230 as a light yellow solid (30 mg, 31%). ¹ H NMR (500 MHz, CDCl ₃ )δ(ppm)9.06(s,1H),8.85(s,1H),8.26(s,1H),8.06(s,1H),8.03(s,1H),7. 88-7.89(d,J＝4.5Hz,2H),7.56-7.58(t,J＝9Hz,1H),4.00(s,3H),3.31-3.38 (m,2H),3.10-3.13(t,J＝13Hz,1H),2.81-2.83(t,J＝12Hz,1H),2.37-2.46(m ,3H),2.10-2.17(m,4H),1.82-1.85(t,J＝14.5Hz,1H); MS(ESI)m/z:390[M+H] ⁺ .

Example 131 (S)-1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 231

Following the procedure described in Example 124 and starting from 1,4-diazepan-6-ol, 2-bromo-6-fluoropyridine, 6-chloro-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 231 was obtained as a yellow solid (43 mg, 23.5%) over 6 steps. ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.09(s,1H),8.65(s,1H),8.44(s,1H),8.25(s,1H),7.98(s,1H ),7.63-7.68(m,1H),7.14-7.16(d,J＝12.5Hz,1H),6.61-6.64(d,J＝14H z,1H),4.10-4.14(m,1H),3.86-3.91(m,6H),3.55-3.66(m,2H),2.98-3 .04(m,3H),2.84-2.90(m,1H),2.69-2.71(m,1H); MS(ESI)m/z:391[M+H] ⁺ .

Example 132 1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]pyrrolidine-34-diol 232

According to the preparation of Example 23, 232 was obtained. MS (ESI) m/z: 390.1. 1H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 9.46 (s, 1H), 9.31 (s, 1H), 8.64 (d, J = 8.1 Hz, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.42 (d, J = 8.3 Hz, 1H), 5.23 (d, J = 3.1 Hz, 2H), 4.18 (s, 2H), 2.66 (s, 3H).

Example 133 (S)-3-(3-aminopiperidin-1-yl)-1-methyl-5-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2(1H)-one 233

Step A: tert-Butyl N-[(3S)-1-(5-bromo-1-methyl-2-oxo-pyridin-3-yl)-3-piperidinyl]carbamate

A mixture of 3,5-dibromo-1-methyl-pyridin-2-one (2.000 mmol; 533.8 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (2.00 mmol; 401 mg), cesium carbonate (4.0 mmol; 1303 mg), Xantphos (0.3400 mmol; 202.8 mg) and tris(dibenzylideneacetone)dipalladium(0) (0.2000 mmol; 185.0 mg) in 1,4-dioxane (10 mL) was evacuated with nitrogen, then sealed and stirred overnight at 110° C. The mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-100% EtOAc in heptane to provide tert-butyl N-[(3S)-1-(5-bromo-1-methyl-2-oxo-pyridin-3-yl)-3-piperidinyl]carbamate as a yellow solid (458.6 mg, 59%).

Step B: tert-Butyl N-[(3S)-1-[1-methyl-5-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-oxo-pyridin-3-yl]-3-piperidinyl]carbamate

A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.49711 mmol; 105 mg), tert-butyl N-[(3S)-1-(5-bromo-1-methyl-2-oxo-pyridin-3-yl)-3-piperidinyl]carbamate (0.59653 mmol; 230.4 mg), N,N′-dimethylethylenediamine (0.049711 mmol; 4.382 mg; 0.00495 mL), copper iodide (0.49711 mmol; 95.629 mg) and potassium carbonate (0.99422 mmol; 138.79 mg) in 1,4-dioxane (10 mL) was evacuated with argon, then sealed and stirred overnight at 100° C. The mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated; the residue was purified on silica gel eluting with 0-6% MeOH in DCM to give tert-butyl N-[(3S)-1-[1-methyl-5-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-oxo-pyridin-3-yl]-3-piperidinyl]carbamate (116. mg, 45%).

Step C: A mixture of tert-butyl N-[(3S)-1-[1-methyl-5-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-oxo-pyridin-3-yl]-3-piperidinyl]carbamate (0.2245 mmol; 116.0 mg) in TFA (1 mL) and dichloromethane (4 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to give 233 as an off ^- white solid (51.6 mg, 54%). NMR (400MHz, DMSO) δ9.47-9.40(s,1H),9.36-9.30(s,1H),8.66-8.57(s,2H),8.48-8.40(s,1H),7.9 6-7.90(d,J＝2.5Hz,1H),6.96-6.90(d,J＝2.5Hz,1H),3.69-3.61(d,J＝6.6Hz,2H),3.58-3.52(s,3H) ,2.83-2.72(t,J＝9.7Hz,1H),2.63-2.58(s,3H),2.30-2.23(m,1H),1.88-1.81(d,J＝9.0Hz,1H),1.7 4-1.68(d,J＝13.3Hz,1H),1.63-1.53(d,J＝12.8Hz,1H),1.18-1.06(m,1H); MS(ESI)m/z:417.2[M+H] ⁺

Example 134 (R)-1-(3-methoxy-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo-[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 234

Following the procedure described in Example 88 and starting from 6-bromo-2-fluoro-3-methoxypyridine and 1,4-diazepan-6-ol, 234 was obtained over 6 steps as a yellow solid (40 mg, 16.5%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.14(s,1H),8.60(s,1H),8.50(s,1H),8.46(s,1H),8.18(s,1H),7 .42(d,J＝8.5Hz,1H),7.24(d,J＝8.5Hz,1H),5.19-5.24(m,2H),4.81(s,1H) ,4.16-4.20(m,1H),3.98-4.02(m,2H),3.96(s,3H),3.50-3.54(m,2H),2.9 4-3.02(m,2H),2.85-2.87(m,1H),2.71-2.75(m,1H); MS(ESI)m/z:489[M+H] ⁺ .

Example 135 1-(6-(azepan-4-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 235

Step A: tert-Butyl 4-(6-bromopyridin-2-yl)-4-hydroxyazepane-1-carboxylate

To a solution of 2,6-dibromopyridine (0.2 g, 0.84 mmol) in Et ₂ O (20 mL) was added a 2.5 M hexane solution of n-BuLi (3.7 mL, 0.928 mmol) at -78°C over 30 minutes. The mixture was stirred at -78°C for 30 minutes. A solution of tert-butyl 4-oxoazepane-1-carboxylate (180 mg, 084 mmol) in Et ₂ O (20 mL) was added dropwise over 15 minutes. After stirring the mixture for 1 hour, H ₂ O (100 mL) was added. The aqueous layer was extracted with EtOAc (100 mL x 2). The organic layer was washed with 10% NaOH solution and brine, dried over MgSO ₄ , and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether/EtOAc (9:1) as eluent to afford tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxyazepane-1-carboxylate as an oil (200 mg, 62.5%). MS (ESI) m/z: 371 [M+H] ⁺ .

Step B: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-4-hydroxyazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxyazepane-1-carboxylate (792 mg, 2.4 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (300 mg, 1.94 mmol) in 1,4-dioxane (20 mL) was added CuI (150 mg, 0.78 mmol), K ₂ CO ₃ (1.08 g, 7.8 mmol) and N ¹ , N ² -dimethylethane-1,2-diamine (138 mg, 1.56 mmol). The mixture was heated at 100 ° C for 3 hours, which was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether/EtOAc (4/1) as the eluent to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-4-hydroxyazepane-1-carboxylate as a white solid (550 mg, 58%). MS (ESI) m/z: 444 [M+H] ⁺ .

Step C: tert-Butyl 4-hydroxy-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)azepane-1-carboxylate

A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-4-hydroxyazepane-1-carboxylate (500 mg, 1.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (350 mg, 1.69 mmol), Pd(dppf)Cl ₂ (50 mg, 0.06 mmol) and aqueous Na ₂ CO ₃ solution (2.0 M, 2.0 mL) in 1,4-dioxane (30 mL) was stirred at 100° C. under nitrogen for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/EtOAc (2/1) as eluent to afford tert-butyl 4-hydroxy-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepane-1-carboxylate as a yellow oil (500 mg, 91%). MS (ESI) m/z: 490 [M+H] ⁺ .

Step D: A mixture of tert-butyl 4-hydroxy-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepane-1-carboxylate (140 mg, 0.29 mmol) and SOCl ₂ (10 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. MeOH (10 mL) and 10% Pd/C (0.1 g) were added to the residue. The mixture was stirred at room temperature for 5 hours under hydrogen (40 psi), which was monitored by LCMS. After the reaction was complete, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give the formate salt of 235 as a light yellow solid (8 mg, 7.4%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.15(s,1H),8.75(s,1H),8.58(s,1H),8.416-8.421(d,J＝2.5Hz,1H ),8.31(s,1H),8.01(s,1H),7.96-7.99(t,J＝15.5Hz,1H),7.82-7.83(d,J＝8H z,1H),7.26-7.28(d,J＝7Hz,1H),4.08-4.22(m,3H),3.13-3.31(m,6H),2.24( s,1H),2.17-2.19(d,J＝7.5Hz,2H),1.96-2.03(m,3H); MS(ESI)m/z:374[M+H] ⁺ .

Example 136 1-(6-(4-fluoroazepan-4-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]picolinate 236

Step A: 1-(6-(4-fluoroazepan-4-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine

To a solution of tert-butyl 4-hydroxy-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepane-1-carboxylate (150 mg, 0.3 mmol) in DCM (5 mL) was added diethylaminosulfur trifluoride (DAST, 0.12 mL, 0.9 mmol). The mixture was stirred at room temperature for 1 hour, which was monitored by LCMS. After the reaction was complete, it was concentrated under reduced pressure to give 1-(6-(4-fluoroazepan-4-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine as a light yellow oil (130 mg, 87%). MS (ESI) m/z: 493 [M+H] ⁺ .

Step B: A solution of 1-(6-(4-fluoroazepan-4-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (120 mg, 0.24 mmol) in HCl in MeOH (2.0 M, 10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give the formate salt of 236 as a light yellow solid (18 mg, 18.9%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.17(s,1H),8.68(s,1H),8.62(s,1H),8.39(s,1H),8.33(s,1H),8.1 0-8.13(t,J＝16Hz,1H),8.07(s,1H),7.95-7.97(d,J＝8.5Hz,1H),7.50-7.51(d ,J＝8Hz,1H),3.93(s,3H),3.07-3.29(m,4H),2.64-2.66(t,J＝10.5Hz,2H),2. 22-2.30(m,2H),2.05-2.06(t,J＝6Hz,1H),1.92(s,1H); MS(ESI)m/z:392[M+H] ⁺ .

Example 137 (S)-1-(3-methoxy-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo-[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 237

Following the procedure described in Example 88 and starting from 6-bromo-2-fluoro-3-methoxypyridine and 1,4-diazepan-6-ol, 237 was obtained over 6 steps as a yellow solid (40 mg, 16.3%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.14(s,1H),8.60(s,1H),8.50(s,1H),8.46(s,1H),8.18(s,1H),7 .42(d,J＝8.5Hz,1H),7.24(d,J＝8.5Hz,1H),5.18-5.24(m,2H),4.80(s,1H) ,4.16-4.20(m,1H),3.98-4.02(m,2H),3.96(s,3H),3.50-3.54(m,2H),2.9 4-3.02(m,2H),2.84-2.87(m,1H),2.71-2.75(m,1H); MS(ESI)m/z:489[M+H] ⁺ .

Example 138 (3S)-1-[3-cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]pyrazin-2-yl]piperidin-3-amine 238

According to the preparation of Example 128, 238 was obtained. MS (ESI) m/z: 428.2.1H NMR(400MHz,DMSO)δ9.61(s,1H),9.45(s,1H),9.33(s,1H),8.71(s,1H),8.63(s, 1H),8.62(s,1H),3.86(d,J＝9.5Hz,1H),3.74(d,J＝11.9Hz,1H),2.98(d,J＝9.0Hz ,1H),2.86-2.76(m,1H),2.65(s,3H),2.25(t,J＝8.9Hz,1H),1.96(d,J＝10.1Hz,2 H),1.83-1.64(m,2H),1.34(d,J＝9.9Hz,1H),1.09(ddd,J＝24.4,12.6,5.7Hz,4H).

Example 140 6-(6-methylpyrazin-2-yl)-1-(6-(4-(oxetan-3-yl)-1,4-diazepan-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 240

Step A: 6-Chloro-1-[6-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]-pyridin-2-yl]pyrazolo[4,3-c]pyridine

A mixture of 6-chloro-1-[6-(1,4-diazepan-1-yl)-pyridin-2-yl]pyrazolo[4,3-c]pyridine (0.4094 mmol; 134.6 mg), oxetan-3-one (0.4912 mmol; 35.40 mg) and molecular sieves (4A) in 1,2-dichloroethane (12 ml) was stirred at room temperature for 4 hours. STAB (0.6141 mmol; 137.0 mg) was added. The reaction was stirred for 3 days. The mixture was filtered through celite. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-5% MeOH in DCM to give 6-chloro-1-[6-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]-pyridin-2-yl]pyrazolo[4,3-c]pyridine (99.2 mg, 63%).

Step B: A mixture of trimethyl-(6-methylpyrazin-2-yl)stannane (0.387 mmol; 99.3 mg), 6-chloro-1-[6-[4-(oxetane-3-yl)-1,4-diazepan-1-yl]-pyridin-2-yl]pyrazolo[4,3-c]pyridine (0.258 mmol; 99.2 mg) and tetrakis(triphenylphosphine)palladium(0) (0.0258 mmol; 29.8 mg) in N,N-dimethylacetamide (3 ml) was evacuated with argon. The reaction mixture was sealed in a Biotage pressure bottle and heated at 150° C. in a microwave for 45 minutes. The mixture was filtered through celite. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-10% MeOH in DCM. The material was further purified by reverse ^phase HPLC to give 240 as an off-white solid (23.3 mg, 20%). NMR (400MHz, DMSO) δ9.66-9.61(s,1H),9.47-9.44(s,1H),9.33-9.30(s,1H),9.06-9.03(s,0H),8.67-8.60(m,2H),8.52-8.50(s,1H) ,7.76-7.68(td,J＝8.1,3.4Hz,2H),7.25-7.20(d,J＝7.7Hz,1H),7.17-7.13(d,J＝7.7Hz,1H),6.66-6.59(dd,J＝8.3,6.0Hz,2H),4.55- 4.46(m,3H),4.41-4.33(dt,J＝15.0,6.0Hz,3H),3.98-3.86(d,J＝5.5Hz,4H),3.81-3.73(m,2H),3.67-3.60(dt,J＝11.7,5.8Hz,2H),2 .67-2.63(s,2H),2.62-2.59(s,3H),2.41-2.36(dd,J＝11.3,6.0Hz,3H),2.05-1.93(dt,J＝18.5,6.1Hz,3H);MS(ESI)m/z:443.2[M+H] ⁺

Example 141 (S)-3-(3-aminopiperidin-1-yl)-1-methyl-5-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2(1H)-one 241

Step A: tert-Butyl N-[(3S)-1-(6-bromo-4-methyl-3-oxo-pyrazin-2-yl)-3-piperidinyl]carbamate

A mixture of 3,5-dibromo-1-methyl-pyrazin-2-one (2.025 mmol; 542.4 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (2.025 mmol; 405.5 mg), cesium carbonate (4.049 mmol; 1319 mg), Xantphos (0.1721 mmol; 102.7 mg) and tris(dibenzylideneacetone)dipalladium(0) (0.1012 mmol; 93.63 mg) in 1,4-dioxane (10 mL) was evacuated with argon, then sealed and stirred overnight at 110° C. The mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-20% EtOAc in DCM to give tert-butyl N-[(3S)-1-(6-bromo-4-methyl-3-oxo-pyrazin-2-yl)-3-piperidinyl]carbamate as a yellow solid (451.0 mg, 58%).

Step B: tert-Butyl N-[(3S)-1-[4-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-oxo-pyrazin-2-yl]-3-piperidinyl]carbamate

A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.49711 mmol; 105 mg), tert-butyl N-[(3S)-1-(6-bromo-4-methyl-3-oxo-pyrazin-2-yl)-3-piperidinyl]carbamate (0.6016 mmol; 233 mg), N,N′-dimethylethylenediamine (0.049711 mmol; 4.382 mg; 0.00495 mL), copper iodide (0.49711 mmol; 95.629 mg), and potassium carbonate (0.99422 mmol; 138.79 mg) in 1,4-dioxane (10 ml) was evacuated with argon, then sealed and stirred at 100° C. overnight. The mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated; the residue was purified on silica gel with 0-? % MeOH in DCM solution was used as eluent to give tert-butyl N-[(3S)-1-[4-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-oxo-pyrazin-2-yl]-3-piperidinyl]carbamate (181.4 mg, 70%).

Step C: A mixture of tert-butyl N-[(3S)-1-[4-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-oxo-pyrazin-2-yl]-3-piperidinyl]carbamate (0.3505 mmol; 181.4 mg) in TFA (1 mL) and dichloromethane (4 ml) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to give 241 as an off-white solid (28.1 mg, ¹⁸ %). NMR (400MHz, DMSO) δ9.47-9.40(s,1H),9.36-9.30(s,1H),8.66-8.57(s,2H),8.48-8.40(s,1H),7.9 6-7.90(d,J＝2.5Hz,1H),6.96-6.90(d,J＝2.5Hz,1H),3.69-3.61(d,J＝6.6Hz,2H),3.58-3.52(s,3H) ,2.83-2.72(t,J＝9.7Hz,1H),2.63-2.58(s,3H),2.30-2.23(m,1H),1.88-1.81(d,J＝9.0Hz,1H),1.7 4-1.68(d,J＝13.3Hz,1H),1.63-1.53(d,J＝12.8Hz,1H),1.18-1.06(m,1H); MS(ESI)m/z:418.2[M+H] ⁺

Example 142 (S)-3-(3-aminopiperidin-1-yl)-1-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2(1H)-one 242

Following the procedure described in Example 124 and starting from tert-butyl (S)-piperidin-3-ylcarbamate, 3,5-dibromo-1-methylpyrazin-2(1H)-one, 6-chloro-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 242 was obtained as a yellow solid (60 mg, 18.1%) over 4 steps. ¹ HNMR(500MHz,DMSO-d ₆ )δ(ppm)9.09(s,1H),8.45(s,1H),8.37(s,1H),8.32(s,1H),8.00(s,1H ),7.64(s,1H),4.59-4.72(m,2H),3.91(s,3H),3.51(s,3H),2.98-3.04( m,1H),2.83-2.92(m,1H),2.80-2.81(m,1H),1.92-1.94(m,1H),1.78-1 .79(m,1H),1.61-1.62(m,1H),1.28-1.34(m,1H); MS(ESI)m/z:406(M+H) ⁺ .

Example 143 (R)-3-(3-aminopiperidin-1-yl)-1-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2(1H)-one 243

Following the procedure described in Example 124 and starting from tert-butyl (R)-piperidin-3-ylcarbamate, 3,5-dibromo-1-methylpyrazin-2(1H)-one, 6-chloro-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 243 was obtained as a yellow solid (58 mg, 17.9%) over 4 steps. ¹ HNMR(500MHz,DMSO-d ₆ )δ9.09(s,1H),8.45(s,1H),8.37(s,1H),8.32(s,1H),8.05(s,1H),7. 64(s,1H),4.59-4.72(m,2H),3.92(s,3H),3.51(s,3H),2.98-3.06(m, 1H),2.80-2.92(m,1H),2.80-2.81(m,1H),1.92-1.94(m,1H),1.78-1. 79(m,1H),1.60-1.62(m,1H),1.29-1.34(m,1H); MS(ESI)m/z:406(M+H) ⁺ .

Example 145 (3S)-3-amino-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4S-c]pyridin-1-yl]-pyridin-2-yl]piperidin-2-one 245

Following the preparation of Example 121, 245 was obtained. MS (ESI) m/z: 415.1. 1H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 9.48 (s, 1H), 9.35 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 4.41 (s, 1H), 3.69 (s, 1H), 3.54 (s, 1H), 2.66 (s, 3H), 2.17 (s, 4H), 1.87 (s, 2H).

Example 147 6-(1-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-amine 247

Step A: Tributyl-[1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]stannane

To a mixture of 6-chloro-1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridine 6 (3.1411 mmol; 781 mg) in 1,4-dioxane (40 mL) was added lithium chloride (18.847 mmol; 798.98 mg), bis(tributyltin) (3.7693 mmol; 2301.7 mg; 2.005 mL), tris(dibenzylideneacetone)dipalladium(0) (0.15705 mmol; 143.82 mg) and tricyclohexylphosphine (0.37693 mmol; 105.70 mg) under argon. The resulting mixture was sealed in a pressure tube and heated at 120 ° C overnight. The mixture was filtered through celite. The filter cake was washed with DCM. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-30% EtOAc in heptane to give tributyl-[1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]stannane (1.0933 g, 69%).

Step B: 6-Bromo-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine

A mixture of 2,6-dibromopyrazine (3.431 mmol; 816.1 mg), (4-methoxyphenyl)methanamine (3.431 mmol; 470.6 mg; 0.4452 mL) and N-methylmorpholine (8.577 mmol; 876 mg; 0.952 mL) in 1-methyl-2-pyrrolidone (10 mL) was heated at 100° C. overnight in a sealed pressure bottle. The mixture was poured into water and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica gel eluting with 0-100% EtOAc in DCM to give 6-bromo-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (768.8 mg, 29%).

Step C: 6-[1-(6-Fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine

A mixture of 6-bromo-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (0.9932 mmol; 768.8 mg), tributyl-[1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]stannane (2.173 mmol; 1093 mg), tricyclohexylphosphine (0.1192 mmol; 33.42 mg) and tris(dibenzylideneacetone)dipalladium(0) (0.04966 mmol; 45.47 mg) in N,N-dimethylacetamide (15 mL) was evacuated with argon for 1 minute. The reaction mixture was sealed and heated at 150 ° C. in a microwave for 45 minutes. The mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica gel eluting with 0-100% EtOAc in heptane to give 6-[1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (316.3 mg, 48%).

Step D: 4-[6-[6-[6-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazepane-1-carboxylic acid tert-butyl ester

A mixture of 6-[1-(6-fluoro-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (0.479 mmol; 316.3 mg), tert-butyl 1,4-diazepane-1-carboxylate (0.958 mmol; 192 mg), and N-methylmorpholine (1.20 mmol; 122 mg; 0.133 mL) in 1-methyl-2-pyrrolidone (5 mL) was heated overnight at 110° C. in a sealed pressure bottle. The mixture was poured into water and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica gel eluting with 0-100% EtOAc in DCM to afford 4-[6-[6-[6-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazepane-1-carboxylic acid tert-butyl ester (-291 mg, 100%).

Step E: To a mixture of tert-butyl 4-[6-[6-[6-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazepane-1-carboxylate (0.4789 mmol; 291 mg) in dichloromethane (5 mL) was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (5 mL) and tris(methoxy)ethanesulfonic acid (4.789 mmol; 733.3 mg; 0.4293 mL). The reaction mixture was stirred at room temperature for 3 days. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 247 as an off ^- white solid (50.3 mg, 27%). NMR (400MHz, DMSO) δ9.45-9.41(s,1H),9.26-9.22(s,1H),8.76-8.73(s,1H),8.64-8.58 (s,1H),7.99-7.96(s,1H),7.73-7.67(t,J＝8.1Hz,1H),7.16-7.12(d,J＝7.7Hz,1H),6.63 -6.58(d,J＝8.5Hz,1H),6.33-6.25(s,2H),3.89-3.82(dd,J＝11.0,5.2Hz,4H),3.03-2.9 8(m,2H),2.73-2.66(m,2H),1.91-1.84(dd,J＝11.5,5.8Hz,2H); MS(ESI)m/z:388.2[M+H] ⁺

Example 148 (S)-6-methyl-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 248

Step A: 1-(6-bromopyridin-2-yl)-1,4-diazepan-6-ol

To a mixture of 2-bromo-6-fluoropyridine (845 mg, 4.83 mmol) and 1,4-diazepan-6-ol (560 mg, 4.83 mmol) in EtOH (20 mL) was added DIPEA (5 mL). The reaction mixture was heated at 100 ° C for 15 hours, which was monitored by LCMS. After the reaction was complete, it was concentrated under reduced pressure. The crude material was used in the next step without further purification. MS (ESI) m / z: 272 [M + H] ⁺ .

Step B: tert-Butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate

To a mixture of 1-(6-bromopyridin-2-yl)-1,4-diazepan-6-ol (900 mg, 3.32 mmol) in MeOH (20 mL) was added TEA (5 mL) followed by Boc ₂ O (1.81 g, 8.30 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel chromatography using DCM:MeOH (20:1 to 10:1) as eluent to afford tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-1,4-diazepan-1-carboxylate as a white solid (1.11 g, 90%). MS (ESI) m/z: 372 [M+H] ⁺ .

Step C: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (800 mg, 2.16 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (330 mg, 2.16 mmol) in 1,4-dioxane (25 mL) was added CuI (164 mg, 0.86 mmol), N ¹ ,N ² -dimethylethane-1,2-diamine (240 mg, 2.7 mmol) and K ₂ CO ₃ (894 mg, 6.48 mmol). The mixture was heated at 100° C. and monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using DCM:MeOH (20:1 to 10:1) as eluent to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as a yellow solid (671 mg, 70%). MS (ESI) m/z: 445 [M+H] ⁺ .

Step D: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-oxo-1,4-diazepane-1-carboxylate

To a mixture of 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (650 mg, 1.46 mmol) in DCM (20 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoxin-3(1H)-one (1.24 g, 2.92 mmol) at 0° C. and stirred overnight. The reaction mixture was quenched with brine (40 mL) and extracted with DCM (100 mL×3). The combined extracts were concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (5% to 50%) as eluent to afford 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-oxo-1,4-diazepane-1-carboxylate as a yellow oil (516 mg, 80%). MS (ESI) m/z: 443 [M+H] ⁺ .

Step E: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate

To a mixture of 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-oxo-1,4-diazepane-1-carboxylate (460 mg, 1.04 mmol) in THF (25 mL) was added Grignard reagent CH ₃ MgBr (147 mg, 1.25 mmol) at −78° C. and stirred at −78° C. for 2 hours. The reaction mixture was quenched with 10% NH ₄ Cl solution (25 mL) and extracted with DCM (80 mL×3). The combined extracts were concentrated under reduced pressure. The residue was purified by silica gel chromatography using DCM:MeOH (20:1 to 10:1) as eluent to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow solid (357 mg, 75%). MS (ESI) m/z: 459 [M+H] ⁺ .

Step F: tert-Butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate

A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate (330 mg, 0.72 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (140 mg, 0.72 mmol), Pd(dppf)Cl2 (53 mg, 0.072 mmol) and _Na2CO3 solution (2.0 M, 0.72 mL) in 1,4- _dioxane (10 mL) was heated in a sealed bottle in a microwave oven at 120°C under argon for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using DCM:MeOH (20:1 to 10:1) as eluent to afford tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow solid (212 mg, 60%). MS (ESI) m/z: 491 [M+H] ⁺ .

Step G: (R)-tert-Butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

and (S)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

To a solution of tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate (200 mg, 0.41 mmol) in DMF (15 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (473 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 18 hours, quenched with brine, extracted with DCM (100 mL×3), and concentrated under reduced pressure. The residue was purified by preparative HPLC to give tert-butyl (±)-6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (183 mg, 78%). MS (ESI) m/z = 573 [M+H] ⁺ , which was separated by chiral preparative HPLC to give (R)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (51 mg) and (S)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (48 mg).

Step H: To a solution of (R)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (46 mg, 0.08 mmol) in MeOH (3 mL) was added HCl solution (concentrated, 3.0 mL) and stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to give 248 as a white solid (36 mg, 94%). ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.16(s,1H),8.77(s,1H),8.54(s,1H),8.50(s,1H),8.25(s,1H),7.67(t,1H),7.12(d,1H),6.72(d,1H),5.25-5.20(t,2H), 4.68(s,1H),4.03-4.00(m,2H),3.57-3.48(m,2H),3.08-3.06(m,2H),2.72(d,1H),2.60(d,1H),1.14(s,3H); MS(ESI)m/z:473[M+H] ⁺ .

Example 149 (R)-6-methyl-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 249

Following the procedure described in Example 148 and starting from (S)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate, 249 was obtained as a white solid (34 mg, 90%). ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.16(s,1H),8.77(s,1H),8.54(s,1H),8.50(s,1H),8.25(s,1H),7.67(t,1H),7.12(d,1H),6.72(d,1H),5.25-5.20(t,2H), 4.68(s,1H),4.03-4.00(m,2H),3.57-3.48(m,2H),3.08-3.06(m,2H),2.72(d,1H),2.60(d,1H),1.14(s,3H); MS(ESI)m/z:473[M+H] ⁺ .

Example 150 (S)-1-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(oxetan-3-yl)pyridin-2-yl)piperidin-3-amine 250

Step A: 2,6-difluoro-4-(oxetan-3-yl)pyridine

(2,6-Difluoro-4-pyridyl)boronic acid (4.0004 mmol; 635.67 mg), nickel(II) iodide (0.12001 mmol; 37.503 mg), trans-2-aminocyclohexanol hydrochloride (0.12001 mmol; 18.382 mg), and sodium hexamethyldisilazane (4.0004 mmol; 748.56 mg) were weighed into a CEM microwave vial. The mixture was capped and placed under a nitrogen atmosphere. Isopropyl alcohol (15 mL) was added and the mixture was stirred under nitrogen for 5 minutes. A solution of 3-iodooxetane (2.0002 mmol; 368 mg) in isopropyl alcohol (1.5 mL) was then added. The vial was heated at 100° C. in a microwave for 20 minutes. The mixture was diluted with EtOH (15 mL) and filtered through celite. The filter cake was washed with EtOH (2 x 10 mL).The mixture was concentrated and the residue was purified on silica gel eluting with 0-50% EtOAc in DCM to give 2,6-difluoro-4-(oxetan-3-yl)pyridine (80.1 mg, 23%).

Step B: 1-[6-Fluoro-4-(oxetan-3-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine

To a mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.468mmol; 98.9mg) and 2,6-difluoro-4-(oxetane-3-yl)pyridine (0.468mmol; 80.1mg) in DMF (5mL) was added cesium carbonate (0.562mmol; 183mg). The resulting mixture was stirred at room temperature. The mixture was filtered. The filtrate was partitioned between EtOAc and water. The organic layer was concentrated. The residue was purified on silica gel eluted with 0-6% MeOH in DCM to give 1-[6-fluoro-4-(oxetane-3-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine as a white solid (63.2mg, 31%).

Step C: A mixture of 1-[6-fluoro-4-(oxetan-3-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.1443 mmol; 63 mg), tert-butyl N-[(3S)-3-piperidinyl]carbamate (0.4329 mmol, 80.7 mg) and N-methylmorpholine (0.3607 mmol; 36.9 mg; 0.0401 mL) in 1-methyl-2-pyrrolidone (3 mL) was heated at 100 °C in a sealed pressure bottle overnight. The mixture was cooled to room temperature. The solvent was removed. The residue was treated with 20% TFA in DCM at room temperature for 2 h. The mixture was concentrated and the residue was purified by reverse phase HPLC to give 250 as an off-white solid (17.5 mg, ²⁶ %). NMR (400MHz, DMSO) δ9.61-9.57(s,1H),9.49-9.43(s,1H),9.36-9.29(s,1H),8.69-8.66(s,1H),8.65-8.61(s,1H),7.33-7.30 (s,1H),6.82-6.76(s,1H),5.02-4.95(m,2H),4.73-4.66(t,J＝6.3Hz,2H),4.42-4.35(d,J＝13.2Hz,1H),4.35-4.27(dd,J＝15. 0,7.2Hz,1H),4.20-4.13(d,J＝10.7Hz,1H),3.29-3.21(m,2H),3.08-3.01(m,1H),2.98-2.91(s,1H),2.66-2.61(s,3H),2.01- 1.83(m,3H),1.71-1.58(d,J＝13.4Hz,1H),1.51-1.40(d,J＝10.8Hz,1H),0.99-0.92(t,J＝7.3Hz,1H); MS(ESI)m/z:443.2[M+H] ⁺

Example 151 1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]hexahydropyrimidin-2-one 251

Step A: 1-(6-Bromo-pyridin-2-yl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine

A solution containing 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (250 mg, 1.18 mmol), 2-bromo-6-iodo-3-methoxypyridine (570 mg, 1.78 mmol), copper(I) iodide (225 mg, 1.18 mmol), potassium carbonate (196 mg, 1.42 mmol), and N,N′-dimethylethylenediamine (0.25 mL, 2.37 mmol) was stirred at 85° C. for 4 h. The reaction was filtered through celite and concentrated. The crude product was purified by ISCO column (EtOAc/heptane, eluting at 100% EtOAc) to give 280 mg of the desired product in 59% yield. MS (ESI) m/z: 397.1.

Step B: A solution containing 1-(6-bromo-5-methoxy-pyridin-2-yl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (50 mg, 0.126 mmol), tetrahydro-2-pyrimidinone (40 mg, 0.38 mmol), copper(I) iodide (126 mg, 0.126 mmol), potassium carbonate (21 mg, 0.15 mmol), and N,N′-dimethylethylenediamine (0.028 mL, 0.252 mmol) was stirred at 110° C. for 18 h. The reaction was filtered through celite and concentrated. The crude product was purified by reverse phase HPLC to afford 251 (8 mg, 14%). MS(ESI)m/z:417.1.1HNMR(400MHz,DMSO)δ9.61(s,1H),9.47(s,1H),9.33(s,1H),8.68(s,1H),8.63(s,1H),7.89(d, J＝8.7Hz,1H),7.77(d,J＝8.8Hz,1H),6.74(s,1H),3.86(s,3H),3.35(d,J＝5.4Hz,2H),2.63(s,3H),2.16-2.08(m,2H).

Example 152 1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]hexahydropyrimidin-2-one 252

Following the preparation of Example 151, 252 was obtained. MS (ESI) m/z: 387.2. 1H NMR (400 MHz, DMSO) δ 9.65 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.70 (s, 1H), 8.63 (s, 1H), 7.96-7.86 (m, 2H), 7.67 (d, J=7.5 Hz, 1H), 7.12 (s, 1H), 4.28-4.21 (m, 2H), 2.62 (s, 3H), 2.17-2.08 (m, 2H).

Example 153 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-ol 253

Following the procedure described in Example 124 and starting from azetidin-3-ol hydrochloride and 2-bromo-6-fluoropyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine, 253 was obtained as a white solid (70 mg, 30.4%) over 3 steps. ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.12(s,1H),8.77(s,1H),8.53(s,1H),8.27(s,1H),7.93(s,1H ),7.70-7.73(t,J＝15.5Hz,1H),7.21-7.22(d,J＝7.5Hz,1H),6.32-6.33( d,J＝8.5Hz,1H),5.79-5.80(d,J＝6Hz,1H),4.70-4.72(m,1H),4.39-4.4 2(t,J＝15Hz,2H),3.93(s,3H),3.88-3.91(m,2H); MS(ESI)m/z:348[M+H] ⁺ .

Example 154 3-(6-hydroxy-1,4-diazepan-1-yl)-1-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2(1H)-one 254

Following the procedure described in Example 124 and starting from 1,4-diazepan-6-ol, 3,5-dibromo-1-methylpyrazin-2(1H)-one, 6-chloro-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 254 was obtained as a yellow solid (80 mg, 7.2%) over 5 steps. ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.09(s,1H),8.43(s,1H),8.30(s,1H),8.29(s,1H),8.05(s,1H),8.00(s,1H),4.91(s,1H),4.49(m,1H),3.92(m,1H) ,3.89(s,3H),3.70-3.71(m,2H),3.51(s,3H),2.99-3.02(m,1H),2.90-2.91(m,1H),2.74-2.86(m,2H);MS(ESI)m/z:422[M+H] ⁺ .

Example 155 1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-ol 255

Following the procedure described in Example 88 and starting from azetidin-3-ol hydrochloride, 2-bromo-6-fluoropyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine, 255 was obtained over 4 steps as a white solid (30 mg, 9.6%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.16(s,1H),8.83(s,1H),8.555(s,1H),8.44(s,1H),8.09(s,1H), 7.70-7.73(t,J＝16Hz,1H),7.21-7.23(d,J＝7.5Hz,1H),6.32-6.34(d,J＝8Hz ,1H),5.78-5.80(d,J＝6.5Hz,1H),5.23-5.28(m,2H),4.71-4.72(d,J＝6Hz, 1H),4.39-4.42(t,J＝14.5Hz,2H),3.89-3.91(m,2H); MS(ESI)m/z:416[M+H] ⁺ .

Example 156 (1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-yl)methanamine 256

Following the procedure described in Example 124 and starting from tert-butyl azetidin-3-ylmethylcarbamate and 2-bromo-6-fluoropyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine, 256 was obtained as a yellow solid (31 mg, 26.4%) over 4 steps. ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.12(d,1H),8.78(s,1H),8.52(s,1H),8.23-8.26(d,J＝16.5Hz,1 H),7.957-7.963(d,J＝3Hz,1H),7.70-7.73(t,J＝16Hz,1H),7.19-7.21(d, J＝7.5Hz,1H),6.28-6.30(d,J＝8Hz,1H),4.17-4.22(m,2H),3.87-3.93(m, 5H),2.95-2.96(d,J＝6.5Hz,2H),2.87-2.89(m,1H); MS(ESI)m/z:361[M+H] ⁺ .

Example 157 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-amine 257

Following the procedure described in Example 124 and starting from tert-butyl azetidin-3-ylcarbamate, 2-bromo-6-fluoropyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine, 257 was obtained as a yellow solid (128 mg, 23%) over 4 steps. ¹ HNMR(500MHz,DMSO-d ₆ )δ(ppm)9.11(s,1H),8.79(s,1H),8.51(s,1H),8.25(s,1H),7.92(s,1H),7.69-7.71(t,J＝9Hz,1H),7.18-7.20(d,J＝9Hz,1H),6.29- 6.30(d,J=9Hz,1H),4.33-4.36(m,2H),3.92-3.93(m,1H),3.92(s,3H),3.74-3.77(m,2H),2.68-2.70(br,2H); MS(ESI)m/z:347[M+H] ⁺ .

Example 158 1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-amine 258

Following the procedure described in Example 88 and starting from tert-butyl azetidine-3-carbamate, 2-bromo-6-fluoropyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine, 258 was obtained as a yellow solid (80 mg, 15%) over 5 steps. ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.16(s,1H),8.84(s,1H),8.55(s,1H),8.45(s,1H),8.09(s,1H),7.70-7.74(t,J＝10Hz,1H),7.21-7.23(d,J＝10Hz,1H) ,6.33-6.35(d,J＝10Hz,1H),5.25-5.27(m,2H),4.36-4.39(m,4H),4.00-4.01(m,1H),3.85-3.87(m,2H); MS(ESI)m/z:415[M+H] ⁺ .

Example 159 1-[6-(4,4-difluoro-3-piperidinyl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 259

Step A: 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 1-(6-bromo-pyridin-2-yl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (125 mg, 0.340 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (100 mg, 0.51 mmol), palladium acetate (8.0 mg, 0.034 mmol) and sodium tert-butoxide (74 mg, 0.75 mmol) in tetrahydrofuran (8.0 ml, 99 mmol) was added tri-tert-butylphosphine (0.020 mL, 0.068 mmol). The mixture was degassed and heated at 48 ° C for 2 h. The reaction was quenched with water and then extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluted at 75% EtOAc) to give the desired product 100 mg in 60% yield. MS (ESI) m/z: 486.1.

Step B: tert-Butyl 4,4-difluoro-3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidine-1-carboxylate

To a solution of bis(2-methoxyethyl)aminosulfur trifluoride (White, A.R. et al (2004) J. Org. Chem., 69: 2573-2576, Sigma-Aldrich, 0.054 mL 0.295 mmol) in dichloromethane (1.0 mL, 16 mmol) was added dropwise a solution of 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (65 mg, 0.13 mmol) in 1.0 mL DCM at -78 ° C. The reaction mixture was warmed to room temperature overnight. The reaction was quenched with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluting with 60% EtOAc) to afford 38 mg of the desired product in 55% yield. MS (ESI) m/z: 508.1.

Step C: To a solution of tert-butyl 4,4-difluoro-3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidine-1-carboxylate (50 mg, 0.099 mmol) in 1,4-dioxane (2.00 mL, 23.4 mmol) was added a solution of hydrogen chloride (4 mol/L) in 1,4-dioxane (1.00 mL, 4.00 mmol). The reaction was stirred at room temperature for 18 h. The reaction was concentrated and purified by reverse phase HPLC to yield 25917 mg, 42% yield. MS(ESI)m/z:408.1.1H NMR(400MHz,DMSO)δ9.72(s,1H),9.46(s,1H),9.36(s,1H),8.74(s,1H),8. 63(s,1H),8.04(t,J＝7.8Hz,1H),7.98(d,J＝8.2Hz,1H),7.40(d,J＝7.4Hz,1 H),3.60-3.42(m,2H),3.18(d,J＝12.8Hz,1H),2.87(t,J＝12.6Hz,1H),2.67 (s,3H),2.36(d,J＝18.3Hz,1H),2.21-2.09(m,1H),1.99(d,J＝34.4Hz,1H).

Examples 160 and 163 (R)-1-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 260 and (S)-1-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepan-6-ol 263

Step A: 1-(3-bromo-6-iodopyridin-2-yl)-1,4-diazepan-6-ol

A solution of 3-bromo-2-fluoro-6-iodopyridine (1.00 g, 3.4 mmol), 1,4-diazepan-6-ol (510 mg, 4.4 mmol), and DIPEA (2 mL) in EtOH (6 mL) was stirred in a sealed tube at 100° C. for 20 hours. The reaction mixture was concentrated under reduced pressure to give a residue (1.18 g), which was used in the next step without further purification. MS (ESI) m/z: 398 [M+H] ⁺ .

Step B: tert-Butyl 4-(3-bromo-6-iodopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate

A solution of 1-(3-bromo-6-iodopyridin-2-yl)-1,4-diazepan-6-ol (1.18 g, 3 mmol), Boc ₂ O (980 mg, 4.5 mmol), and TEA (2 mL) in MeOH (15 mL) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc:petroleum ether (10% to 25%) as eluent to afford tert-butyl 4-(3-bromo-6-iodopyridin-2-yl)-6-hydroxy-1,4-diazepan-1-carboxylate as a white solid (980 mg, 60% over two steps). MS (ESI) m/z: 498 [M+H] ⁺ .

Step C: 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.00 g, 13.1 mmol) and DIPEA (3 mL) in DCM (10 mL) was added SEMCl (3 mL). The mixture was stirred at 30°C for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/petroleum ether (10% to 60%) as eluent to afford 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine as a colorless oil (3.44 g, 93%). MS (ESI) m/z: 284 [M+H] ⁺ .

Step D: 6-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]-pyridine

A suspension of 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (1.30 g, 4.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.16 g, 6 mmol) and Pd(dppf) _Cl2 (437 mg, 0.6 mmol) in aqueous _Na2CO3 (2.0 _M , 12 mL) and 1,4-dioxane (20 mL) was heated at 110°C for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate/heptane 50%-100% as eluent to afford 6-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine as a yellow oil (670 mg, 46%). 1 g of the starting material was recovered. MS (ESI) m/z: 316 [M+H] ⁺ .

Step E: 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

A mixture of 6-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (670 mg, 2.12 mmol), K ₂ CO ₃ (587 mg, 4.24 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4 mL) in DMF (4 mL) was stirred at ambient temperature for 20 hours. The reaction mixture was quenched with EtOAc (10 mL) and H ₂ O (10 mL), and extracted with EtOAc (10 mL×3). The extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate/heptane (10%-70%) as eluent to afford 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine as a white solid (800 mg, 95%). MS (ESI) m/z: 398 [M+H] ⁺ .

Step F: 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazolo[4,3-c]pyridine (800 mg, 2.02 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated under reduced pressure to give 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridine as a yellow oil (539 mg, 100%). MS (ESI) m/z: 268 [M+H] ⁺ .

Step G: tert-Butyl 4-(3-bromo-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo-[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate

A mixture of 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (539 mg, 2.02 mmol), tert-butyl 4-(3-bromo-6-iodopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (1.00 g, 2.02 mmol), N ¹ ,N ² -dimethylethane-1,2-diamine (535 mg, 6.06 mmol), CuI (768 mg, 4.04 mmol) and K ₂ CO ₃ (1.12 g, 8.08 mmol) in 1,4-dioxane (10 mL) was heated at 100° C. for 20 hours under N _2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/petroleum ether (20% to 80%) as eluent to afford tert-butyl 4-(3-bromo-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as a white solid (244 mg, 19%). MS (ESI) m/z: 637 [M+H] ⁺ .

Step H: (±)-tert-Butyl 6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

A mixture of tert-butyl 4-(3-bromo-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (244 mg, 0.38 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborinane (194 mg, 1.53 mmol), Pd ₂ dba ₃ (174 mg, 0.19 mmol), Pcy ₃ (107 mg, 0.38 mmol) and Cs ₂ CO ₃ (500 mg, 1.53 mmol) in 1,4-dioxane (10 mL) was heated in a microwave oven at 110° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/petroleum ether (20% to 80%) as eluent to afford (±)-tert-butyl 6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (120 mg, 55%). MS (ESI) m/z: 573 [M+H] ⁺ .

Step I: (S)-tert-Butyl 6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

and (R)-tert-butyl 6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

(S)-6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (160 mg) was separated by chiral preparative HPLC to give (S)-6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate. -4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (60 mg) and (R)-6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (60 mg).

Step J: A mixture of (S)-tert-butyl 6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (60 mg, 0.10 mmol) in HCl/MeOH (4 M, 10 mL) was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with MeOH (10 mL), neutralized with 28% ammonia solution, concentrated under reduced pressure and purified by preparative HPLC to give 260 as a white solid (40 mg, 82%). ¹ H-NMR (500MHz, CD ₃ OD)δ(ppm)9.03(s,1H),8.76(s,1H),8.35(d,J＝10.5Hz,2H),8.16(s,1H),7.62(d,J＝8Hz,1H),7.45(d,J＝7.5Hz,1H),5.03-5.08(m,2H ),4.14-4.21(m,1H),3.96-3.99(m,1H),3.51-3.68(m,3H),3.18-3.33(m,3H),2.99-3.08(m,1H),2.38(s,3H); MS(ESI)m/z:473[M+H] ⁺ .

Step K: A mixture of (R)-tert-butyl 6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (60 mg, 0.10 mmol) in HCl/MeOH (4 M, 10 mL) was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with MeOH (10 mL), neutralized with 28% ammonia solution, concentrated under reduced pressure and purified by preparative HPLC to afford 263 as a white solid (40 mg, 82%). ¹ H-NMR (500MHz, CD ₃ OD) δppm 8.97(s,1H),8.66(s,1H),8.31(d,J＝10.5Hz,2H),8.11(s,1H),7.62(d,J＝8Hz,1H),7.45(d,J＝7.5Hz,1H),5.07-5.02(m,2H),4. 21-4.14(m,1H),3.99-3.96(m,1H),3.68-3.51(m,3H),3.33-3.18(m,3H),3.08-2.99(m,1H),2.38(s,3H); MS(ESI)m/z:473[M+H] ⁺ .

Example 161 (S)-1-(6-(6-methoxy-6-methyl-1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 261

Step A: tert-Butyl 4-(6-bromopyridin-2-yl)-6-oxo-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (1.05 g, 2.83 mmol) obtained from Examples 88, 89, and 148 in DCM (35 mL) was added (1,1,1-acetoxy)-1,1-dihydro-1,2-benzidoyl-3(1H)-one (2.40 g, 5.66 mmol) at 0°C. The mixture was stirred overnight, quenched with brine (40 mL) and DCM (30 mL), extracted with DCM (100 mL × 3), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (5%-50%) as eluent to give tert-butyl 4-(6-bromopyridin-2-yl)-6-oxo-1,4-diazepane-1-carboxylate as a yellow oil (846 mg, 81%). MS (ESI) m/z: 370 [M + H] ⁺ .

Step B: tert-Butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-oxo-1,4-diazepane-1-carboxylate (800 mg, 2.17 mmol) in THF (40 mL) at -78°C was added _CH₃MgBr (169 mg, 1.44 mmol). The mixture was stirred at -78°C for 2 hours, quenched with 10% _NH₄Cl solution (35 mL), extracted with DCM (100 mL x 3), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using DCM:MeOH (20:1 to 10:1) as eluent to give tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow solid (636 mg, 76%). MS (ESI) m/z: 386 [M+H] ^⁺ .

Step C: tert-Butyl 4-(6-bromopyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate (600 mg, 1.56 mmol) in DMF (20 mL) was added NaH (94 mg, 3.90 mmol) at 0 ° C and stirred for 30 minutes. Dimethyl sulfate (295 mg, 2.34 mmol) was added to the mixture and stirred at room temperature for 15 hours. It was quenched with brine (20 mL), extracted with EtOAc (100 mL×3), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether: EtOAc (4:1～1:1) as eluent to obtain tert-butyl 4-(6-bromopyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow oil (554 mg, 89%). MS (ESI) m/z: 400 [M + H] ⁺ .

Step D: tert-Butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate

To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate (530 mg, 1.33 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (203 mg, 1.33 mmol) in 1,4-dioxane (30 mL) was added CuI (101 mg, 0.53 mmol), N ¹ ,N ² -dimethylethane-1,2-diamine (94 mg, 1.06 mmol) and K ₂ CO ₃ (734 mg, 5.32 mmol). The mixture was heated at 100° C. and monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using petroleum ether:EtOAc (3:1 to 1:1) as eluent to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow solid (446 mg, 71%). MS (ESI) m/z: 473 [M+H] ⁺ .

Step E: tert-Butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate

A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate (420 mg, 0.89 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (173 mg, 0.89 mmol), Pd(dppf)Cl ₂ (65 mg, 0.089 mmol) and Na ₂ CO ₃ solution (2.0 M, 0.9 mL) in 1,4-dioxane (15 mL) was heated in a sealed bottle in a microwave oven at 120° C. for 1 hour under argon. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether:EtOAc (3:1 to 1:1) as eluent to afford tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow solid (283 mg, 63%). MS (ESI) m/z: 505 [M+H] ⁺ .

Step F: (R)-tert-Butyl 6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

and (S)-tert-butyl 6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate

To a solution of tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate (265 mg, 0.53 mmol) in DMF (15 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (610 mg, 2.63 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with brine, extracted with DCM (100 mL × 3), and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford tert-butyl (±)-6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (264 mg, 85%). MS (ESI) m/z: 587 [M+H] ⁺ .

(±)-tert-Butyl 6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate was separated by chiral preparative HPLC to afford (R)-6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate. tert-Butyl (S)-6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (100 mg) and tert-butyl (S)-6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (95 mg).

Step G: To a solution of (R)-tert-butyl 6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (100 mg, 0.17 mmol) in MeOH (5 mL) was added HCl (concentrated, 5 mL). The mixture was stirred at room temperature for 4 hours. It was concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to give 261 as a white solid (75 mg, 91%). ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.16(s,1H),8.70(s,1H),8.55(s,1H),8.41(s,1H),8.14(s,1H),7.68(t,1H),7.16(d,1H),6.69(d,1H),5.27-5.2 2(m,2H),4.06-4.03(m,2H),3.67-3.54(m,2H),3.12(s,3H),3.02(s,2H),2.72(s,2H),1.14(s,3H); MS(ESI)m/z:487[M+H] ⁺ .

Example 162 (1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-yl)methanamine 262

Following the procedure described in Example 88 and starting from tert-butyl azetidin-3-ylmethylcarbamate, 2-bromo-6-fluoropyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine, 262 was obtained over 5 steps as a yellow solid (35 mg, 30.9%). ¹ H NMR (500 MHz, DMSO-d ₆ )δ(ppm)9.15(s,1H),8.83-8.86(d,J＝12Hz,1H),8.55(s,1H),8.43(s,1H),8 .10-8.12(d,J＝7Hz,1H),7.69-7.72(t,J＝16Hz,1H),7.19-7.20(d,J＝8Hz,1H) ,6.28-6.29(d,J＝8Hz,1H),5.23-5.25(d,J＝9.5Hz,2H),4.17-4.20(m,2H),3 .87-3.89(t,J＝12Hz,2H),2.84-2.86(d,J＝6.5Hz,3H); MS(ESI)m/z:429[M+H] ⁺ .

Example 164 (R)-1-(6-(6-methoxy-6-methyl-1,4-diazepan-1-yl)pyridin-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 264

Following the procedure described in Example 161 and starting from (S)-tert-butyl 6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate, 264 was obtained as a white solid (133 mg, 92%). ¹ H NMR (500MHz, DMSO-d ₆ )δ(ppm)9.16(s,1H),8.70(s,1H),8.55(s,1H),8.41(s,1H),8.14(s,1H),7.68(t,1H),7.16(d,1H),6.69(d,1H),5.27-5.2 2(m,2H),4.06-4.03(m,2H),3.67-3.54(m,2H),3.12(s,3H),3.02(s,2H),2.72(s,2H),1.14(s,3H); MS(ESI)m/z:487[M+H] ⁺ .

Example 165 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[43-c]pyridin-1-yl]-pyridin-2-yl]piperidin-4-ol 265

Step A: tert-Butyl 4-hydroxy-3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidine-1-carboxylate

To a solution of tert-butyl 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-4-oxo-piperidine-1-carboxylate (90 mg, 0.18 mmol) in tetrahydrofuran (8.0 ml) was added sodium borohydride (8.0 mg, 0.20 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/heptane, eluted at 100% EtOAc) to give 40 mg of the desired product in 44% yield. MS (ESI) m/z: 488.1.

Step B: To a solution of tert-butyl 4-hydroxy-3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidine-1-carboxylate (35 mg, 0.072 mmol) in 1,4-dioxane (2.00 mL, 23.4 mmol) was added a solution of hydrogen chloride (4 mol/L) in 1,4-dioxane (1.00 mL, 4.00 mmol). The reaction was stirred at room temperature for 18 h. The reaction was concentrated and purified by reverse phase HPLC to yield 265. MS (ESI) m/z: 388.1.

Example 166 1-(6-(2,5-diazaspiro[3.5]non-2-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 266

Following the procedure described in Example 124 and starting from tert-butyl 2,5-diazaspiro[3.5]nonane-5-carboxylate, 2-bromo-6-fluoropyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine, 266 was obtained over 4 steps as a yellow solid (10 mg, 5%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 9.12 (s, 1H), 8.85 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.69-7.72 (t, J=16 Hz, 1H), 7.18-7.19 (d, J=7.5 Hz, 1H), 6.33-6.34 (d, J=8 Hz, 1H), 4.00-4.01 (d, J=8 Hz, 1H), 4.70-4.71 (d, J=6 Hz, 1H), 4.98-4.99 (d, J=7 Hz, 1H), 4.84-4.97 (d, J=6 Hz, 1H), 4.50-4.51 (d, J=6 Hz, 1H), 4.51-4.53 (d, J=6 Hz, 1H), 4.5 ＝7Hz,2H),3.92(s,3H),3.87-3.88(d,J＝7Hz,2H),2.715-2.724(d,J＝4.5Hz,2H),1.76 -1.78(t,J＝11Hz,2H),1.59-1.60(d,J＝3.5Hz,2H),1.45(s,2H); MS(ESI)m/z:401[M+H] ⁺ .

Example 167 1-(6-(2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 267

Following the procedure described in Example 88 and starting from tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 2-bromo-6-fluoropyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine, 267 was obtained as a yellow solid (58 mg, 11%) over 5 steps. ¹ HNMR(500MHz,DMSO-d ₆ )δ(ppm)9.15(s,1H),8.81(s,1H),8.54(s,1H),8.47(s,1H),8.14(s,1H),7.70-7.73(t,J＝10Hz,1H),7.21-7.22(d,J＝10Hz,1H),6.31 -6.32(d,J＝9Hz,1H),5.23-5.27(m,2H),4.24(s,4H),4.07-4.08(m,1H),3.76-3.82(m,3H),3.42-3.43(br,1H); MS(ESI)m/z:441[M+H] ⁺ .

Example 168 1-(6-(2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 268

Following the procedure described in Example 124 and starting from tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 2-bromo-6-fluoropyridine, 6-chloro-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 268 was obtained as a yellow solid (87 mg, 26%) over 4 steps. ^1H NMR(500MHz,DMSO-d6)δ(ppm)9.10(s,1H),8.74(s,1H),8.51(s,1H),8.28(s,1H),7.98(s,1H),7.69-7.71(t,J＝9Hz,1H),7.20-7.21(d,J＝9 Hz,1H),6.30-6.31(d,J=9Hz,1H),4.24(s,3H),4.08(s,1H),3.86-3.93(m,3H),3.79-3.83(m,2H),3.35-3.42(m,3H); MS(ESI)m/z:373[M+H] ⁺ .

Example 169 1-(6-(2,5-diazaspiro[3.5]non-2-yl)pyridin-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 269

Following the procedure described in Example 88 and starting from tert-butyl 2,5-diazaspiro[3.5]nonane-5-carboxylate, 2-bromo-6-fluoropyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine, 269 was obtained over 5 steps as a yellow solid (8 mg, 5%). ¹ H NMR (500 MHz, DMSO-d6) δ (ppm) 9.15-9.16 (d, J = 5 Hz, 1H), 8.84 (s, 1H), 8.53-8.55 (d, J = 9.5 Hz, 1H), 8.48 (s, 1H), 8.28-8.29 (d, J = 7.5 Hz, 1H), 7.56-7.59 (t, J = 15.5 Hz, 1H), 7.05-7.09 (m, 2H), 6.55-6.70 (d, J = 10.5 Hz, 1H). 6.57(d,J＝8Hz,1H),5.21-5.26(m,2H),3.44-3.45(d,J＝4.5Hz,2H),3.33(s,1H),2.61-2.64(t,J＝ 13Hz,1H),1.90-1.97(m,2H),1.76(s,1H),1.57(s,1H),1.28-1.37(m,4H); MS(ESI)m/z:469[M+H] ⁺ .

Example 170 3-(Aminomethyl)-1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-ol 270

Step A: 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-one

To a solution of dimethyl sulfoxide (225 mg, 2.88 mmol) in DCM (10 mL) was added oxalyl chloride (366 mg, 2.88 mmol) at -60 ° C. After the mixture was stirred at -60 ° C for 0.5 hours, a solution of 1- (6- (6- (1-methyl -1H- pyrazol-4-yl) -1H- pyrazolo [4, 3-c] pyridin-1-yl) pyridin-2-yl) azetidine-3-ol (200 mg, 0.58 mmol) in DCM (10 mL) was added dropwise at -60 ° C. The reaction mixture was stirred at -60 ° C for 2 hours, and triethylamine (583 mg, 5.76 mmol) was added dropwise thereto. The reaction mixture was stirred at -60 ° C for 1 hour. It was concentrated under reduced pressure to give a white solid. The crude product (1.1 g), 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-one, was used in the next reaction without further purification. MS (ESI) m/z: 346 [M+H] ⁺ .

Step B: 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-3-(nitromethyl)azetidin-3-ol

To a solution of 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-one (1.1 g) in DCM (10 mL) was added nitromethane (1 mL) and triethylamine (0.5 mL) at 20 ° C. The mixture was stirred at ambient temperature for 2 hours. It was concentrated under reduced pressure to give a white solid. The crude product (1.3 g), 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-3-(nitromethyl)azetidin-3-ol, was used in the next step without further purification. MS (ESI) m/z: 407[M+H] ⁺ .

Step C: 3-(Aminomethyl)-1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-ol

To a solution of 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-3-(nitromethyl)azetidin-3-ol (100 mg, 0.25 mmol) in MeOH (5 mL) and H ₂ O (0.5 mL) was added Zn powder (129 mg, 2 mmol) and NH ₄ Cl (132 mg, 2.5 mmol). The reaction mixture was stirred at ambient temperature for 2 h and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford 270 as a red solid (60 mg, 64.8%). ^1H NMR(500MHz,DMSO-d6)δ(ppm)9.13(s,1H),8.75(s,1H),8.53(s,1H),8.34-8.40(m,2H),7.98(s,1H),7.72-7.75(m,1H),7.24-7. 25(m,1H),6.34-6.36(d,J＝8.5Hz,1H),4.23-4.25(d,J＝8.5Hz,2H),3.89-3.97(m,5H),3.06-3.10(m,2H);MS(ESI)m/z:377[M+H] ⁺ .

Examples 171 and 172 (R)-1-[6-(4,4-difluoro-3-piperidinyl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 271 and (S)-1-[6-(4,4-difluoro-3-piperidinyl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 272

The enantiomeric compounds 271 and 272 were separated by chiral SFC separation according to Example 159. NMR(400MHz,DMSO)δ9.72(s,1H),9.46(s,1H),9.36(s,1H),8.74(s,1H),8.63(s ,1H),8.04(t,J＝7.8Hz,1H),7.98(d,J＝8.2Hz,1H),7.40(d,J＝7.4Hz,1H),3.60- 3.42(m,2H),3.18(d,J＝12.8Hz,1H),2.87(t,J＝12.6Hz,1H),2.67(s,3H),2.36( d,J＝18.3Hz,1H),2.21-2.09(m,1H),1.99(d,J＝34.4Hz,1H).MS(ESI)m/z:408.1.

Example 173 (6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)methanol dihydrochloride 273

Step A: tert-Butyl 4-(6-(6-(6-formylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate

A solution of sodium periodate (260 mg, 1.22 mmol) in 5 mL of water was added to a solution of tert-butyl 4-[6-[6-[6-(1,2-dihydroxyethyl)pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylate (315 mg, 0.61 mmol) in 25 mL of tetrahydrofuran and 5 mL of water. The mixture was stirred for 24 hours, concentrated, and the residue partitioned between ethyl acetate and water. The organic extract was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified on a 12 g silica gel column eluting with a gradient of ethyl acetate in heptane to afford 245 mg (83%). MS (ESI) m/z: 505.2 [M+ _H₂O +H] ^⁺ .

Step B: tert-Butyl 4-(6-(6-(6-(hydroxymethyl)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate

Sodium borohydride (25 mg, 0.66 mmol) was added portionwise to a solution of tert-butyl 4-[6-[6-(6-formylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylate (162 mg, 0.33 mmol) in 6 ml of methanol. The mixture was stirred for 1 hour, concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water, 1% aqueous citric acid, water, and brine, dried over sodium sulfate, and concentrated. The residue was purified on a 12 g silica gel column eluted with a gradient of 0-7% methanol in DCM to give 125 mg (77%). MS (ESI) m/z: 489.2 [M+H] ⁺

Step C: Compound 273 was obtained by treating the reaction mixture with 4 M HCl in methanolic dioxane for 1-2 hours, collecting the mixture by filtration, dissolving in water, and lyophilizing. 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.52 (s, 1H), 9.28 (s, 2H), 8.81 (s, 1H), 8.71 (s, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.78 (s, 2H), 3.96 (d, J = 5.5 Hz, 4H), 3.33 (d, J = 5.1 Hz, 4H). MS (ESI) m/z: 389.2 [M+H] ⁺ .

Example 174 1-(6-(piperazin-1-yl)pyridin-2-yl)-6-(6-vinylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine dihydrochloride 274

Step A: tert-Butyl 4-(6-(6-(6-vinylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl 4-[6-[6-(6-chloropyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylate (493 mg, 1 mmol), potassium vinyl trifluoroborate (335 mg, 2.500 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride, DCM complex (55 mg, 0.07500 mmol) and triethylamine (0.63 ml, 4.500 mmol) in ethanol (9 mL) was degassed and heated at 105 ° C. in a sealed bottle for 2 hours. The mixture was left at room temperature for 20 hours. The precipitate was collected and washed with ethanol to give the crude material, 605 mg (99.8%). MS (ESI) m/z: 485.4 [M+H] ⁺

Step B: Compound 274 was obtained by treatment with 4M HCl in dioxane methanol for 1-2 hours, collected by filtration from the reaction mixture, dissolved in water and lyophilized. 1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),9.46(s,1H),9.37(s,1H),9.09(s,2H),8 .95(s,1H),8.72(s,1H),7.89(t,J＝8.1Hz,1H),7.39(d,J＝7.8Hz,1H),7.03(d d,J＝17.6,11.0Hz,1H),6.96(d,J＝8.4Hz,1H),6.50(d,J＝17.3Hz,1H),5.80(d ,J＝11.2Hz,1H),3.96(t,J＝5.3Hz,4H),3.27(s,4H).MS(ESI)m/z:385.2[M+H] ⁺

Example 175 6-(6-chloropyrazin-2-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine dihydrochloride 275

Step A: tert-Butyl 4-(6-(6-(tetrabutylstannyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate

To a mixture of tert-butyl 4-( _6- (6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate (10 g, 0.024 mol) in DMF (100 mL) was added LiCl (6.14 g, 0.145 mol), nBu ₆ Sn ₂ (15.3 g 0.0264 mol), Pd ₂ (dba) ₃ (0.44 g, 0.48 mmol), and Pcy ₃ (0.27 g, 0.96 mmol) under N 2. The resulting mixture was heated at 130 ° C overnight. The mixture was filtered through celite. The filtrate was extracted with petroleum ether (300 mL×6). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA=50:1) to give 8 (4.5 g, yield 28%) as a clear oil. 1H NMR (400MHz, CDCl ₃ )δ9.26(d,J＝1.2Hz,1H),8.67-8.60(m,1H),8.25(d,J＝0.6Hz,1H),7.68(t,J＝8.1Hz,1H),7.38(d,J＝7.8Hz,1H),6.56(d,J＝8.3Hz,1H),3. 66(s,9H),1.66-1.57(m,6H),1.52(s,8H),1.36(dd,J＝14.6,7.1Hz,6H),1.23-1.15(m,6H),0.88(t,J＝7.3Hz,9H).MS(ESI)m/z:671[M+H] ⁺

Step B: tert-Butyl 4-(6-(6-(6-chloropyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl 4-(6-(6-(tetrabutylstannyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate (27 g, 0.04 mol), 2,6-dichloropyrazine (8.9 g, 0.06 mol), Pd ₂ (dba) ₃ (0.37 g, 0.4 mmol), and Pcy ₃ (0.23 g, 0.8 mmol) in DMA (150 mL) was purged with N ₂ for 1 minute. The reaction mixture was heated at 130° C. overnight. The mixture was cooled to room temperature, water and some EA were added, stirred for 10 minutes, and filtered, washing with MTBE. The crude product was purified by silica gel column chromatography (PE:EA=1:1) to give 9 (6.1 g, 30%) as a yellow solid. 1H NMR (400MHz, DMSO) δ9.58(d,J＝18.5Hz,2H),9.33(s,1H),8.90(s,1H),8.69(s,1H),7.80(t,J＝8.1Hz,1 H),7.32(d,J＝7.8Hz,1H),6.85(d,J＝8.4Hz,1H),3.64(s,8H),1.55-1.38(m,9H).MS(ESI)m/z:493[M+H] ⁺

Step C: Compound 275 was obtained by deprotection of the Boc group using 4M HCl in dioxane methanol. The corresponding hydrochloride was collected by filtration from the reaction mixture, dissolved in water and lyophilized. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.51 (s, 1H), 9.38 (s, 1H), 9.12 (s, 2H), 8.91 (s, 1H), 8.73 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.97 (t, J = 5.3 Hz, 4H), 3.37 (s, 4H). MS (ESI) m/z: 393.0 [M+H] ⁺

Example 176 6-(6-(Benzyloxy)pyrazin-2-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 276

Step A: tert-Butyl 4-(6-(6-(6-(benzyloxy)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of 3-5 equivalents of benzyl alcohol, 1 equivalent of tert-butyl 4-(6-(6-chloropyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate, and 6-10 equivalents of potassium tert-butoxide in dioxane was heated at 90°C for 2-4 hours. The mixture was mixed with water and extracted with ethyl acetate. The organic extract was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified on a silica gel column eluted with a gradient of ethyl acetate in heptane or methanol in DCM to give tert-butyl 4-(6-(6-(benzyloxy)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate, dihydrochloride. MS (ESI) m/z: 603.4 [M+H] ⁺

Step B: Deprotection of the Boc group was achieved by treatment with 4M HCl in dioxane in methanol for 1-2 hours to afford compound 276. The corresponding hydrochloride was collected by filtration from the reaction mixture, dissolved in water and lyophilized. MS (ESI) m/z: 465.3 [M+H] ⁺

Example 177 1-(6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)ethane-1,2-diol 277

Step A: tert-Butyl 4-(6-(6-(6-(1,2-dihydroxyethyl)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl 4-[6-[6-(6-vinylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylate (513 mg; 1.06 mmol), N-methylmorpholine-N-oxide monohydrate (744 mg, 6.35 mmol), and a 2.5% solution of osmium tetroxide in tert-butanol (0.6 ml, 0.04764 mmol) in 20 ml of acetone and 2.5 ml of water was stirred at room temperature for 24 hours. The mixture was stirred, mixed with water, and extracted with EtOAc. The organic extract was washed with water, 5% aqueous citric acid, saturated aqueous _NaHCO₃ , brine, dried _{over Na₂SO₄} , and concentrated. The residue was triturated with diethyl ether, and the precipitate was collected by filtration and washed with diethyl ether to give tert-butyl 4-(6-(6-(6-(1,2-dihydroxyethyl)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate (424 mg, 67%). MS (ESI) m/z: 519.3 [M+H] ⁺

Step B: Compound 277 was obtained by treatment with 4M HCl in dioxane methanol for 1-2 hours, collected by filtration from the reaction mixture, dissolved in water and lyophilized. 1H NMR (400MHz, DMSO-d6) δ9.57 (s, 1H), 9.46 (s, 1H), 9.37 (d, J = 1.0Hz, 1H), 9.17 (s ,2H),8.81(s,1H),8.72(s,1H),7.88(t,J＝8.1Hz,1H),7.40(d,J＝7.8Hz,1H),6.9 6(d,J＝8.4Hz,1H),4.80(t,J＝5.5Hz,1H),3.98(t,J＝5.3Hz,4H),3.83(dd,J＝11.1 ,5.0Hz,1H),3.75(dd,J＝11.1,6.0Hz,1H),3.33(s,4H).MS(ESI)m/z:419.2[M+H] ⁺

Example 178 2-((6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)oxy)ethanol dihydrochloride 278

Following the procedure described in Example 176 and using 3-5 equivalents of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol, 278 was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.24 (m, 3H), 8.71 (s, 1H), 8.42 (s, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.49 (t, J = 5.0 Hz, 2H), 3.97 (t, J = 5.3 Hz, 4H), 3.89 (t, J = 5.0 Hz, 2H), 3.27 (s, 4H). MS (ESI) m/z: 419.2 [M+H] ⁺

Example 179 6-(6-(difluoromethyl)pyrazin-2-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine trifluoroacetate 279

Step A: tert-Butyl 4-(6-(6-(6-(difluoromethyl)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl 4-[6-[6-(6-formylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylate (49 mg, 0.10 mmol) and a (50% by mass) toluene solution (0.175 ml, 0.40 mmol) in 4 ml of DCM was stirred for 24 hours. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic extract was washed with water, 5% aqueous citric acid, water, and brine, dried over sodium sulfate, and concentrated. The crude residue was purified on a 4 g silica gel column eluted with a gradient of 0-70% ethyl acetate in heptane to give 38 mg of tert-butyl 4-(6-(6-(difluoromethyl)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate (74%). MS (ESI) m/z: 509.3 [M + H] ⁺

Step B: A solution of tert-butyl 4-[6-[6-[6-(difluoromethyl)pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperazine-1-carboxylate (16) (38 mg, 0.075 mmol) in 3 mL of trifluoroacetic acid was stirred for 2 hours. The mixture was concentrated in vacuo, the residue was triturated with ether, and the precipitate was collected by filtration. The solid material was washed with ether, air-dried, redissolved in water, and lyophilized to afford 279 as a trifluoroacetate salt (16 mg, 42%). 1H NMR(400MHz, DMSO-d6)δ9.86(s,1H),9.51(s,1H),9.41(s,1H),9.07(s,1H),8.89(d,J＝30.2Hz,2H),8.74(s,1H),7.89(t,J＝8.1Hz,1H), 7.41(d,J＝7.8Hz,1H),7.25(t,J＝54.2Hz,1H),6.96(d,J＝8.4Hz,1H),3.94(t,J＝5.3Hz,4H),3.36-3.31(m,4H).MS(ESI)m/z:409.2[M+H] ⁺

Example 180 (S)-(1-(6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)pyrrolidin-2-yl)methanol dihydrochloride 280

A mixture of 3-5 equivalents of (S)-pyrrolidin-2-ylmethanol, 1 equivalent of tert-butyl 4-(6-(6-(6-chloropyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate, and 6-10 equivalents of cesium fluoride in DMSO was heated at 105 ° C for 12-24 hours. The mixture was mixed with water and extracted with ethyl acetate. The organic extract was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified on a silica gel column with a gradient elution of ethyl acetate in heptane or DCM. The Boc group was deprotected with 4M HCl in dioxane in methanol. The crude product was collected by filtration, dissolved in water and lyophilized to give 280.1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),9.31-9.19(m,2H),9.10(s,1H),8.80( s,1H),8.73(s,1H),8.19(s,1H),7.89(t,J＝8.1Hz,1H),7.35(d,J＝7.8Hz,1H ),6.97(d,J＝8.5Hz,1H),4.21(d,J＝6.0Hz,1H),3.93(t,J＝5.3Hz,4H),3.58( m,1H),3.49(m,2H),3.22(d,J＝5.4Hz,4H),2.06(m,4H).MS(ESI)m/z:458.3.

Example 181 1-(6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)azetidin-3-ol 281

Following the procedure described in Example 180, 281 was obtained. 1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),9.22(s,1H),8.91(s,1H),8.64(s,1H),8. 27(s,1H),7.96(s,1H),7.77(t,J＝8.1Hz,1H),7.24(d,J＝7.7Hz,1H),6.83(d,J＝ 8.4Hz,1H),4.72-4.62(m,1H),4.37(dd,J＝8.7,6.7Hz,2H),3.89(dd,J＝8.9,4.6 Hz, 2H), 3.63 (t, J = 5.1Hz, 4H), 2.86 (dd, J = 6.3, 3.9Hz, 4H). MS (ESI) m/z: 430.3.

Example 182 2-[[6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-yl]amino]ethanol 282

Following the procedure described in Example 180, 282 was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 7.8 Hz, 3H), 9.21 (s, 1H), 8.78 (s, 1H), 8.70 (s, 1H), 8.13 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 3.97 (t, J = 5.2 Hz, 4H), 3.68 (t, J = 5.9 Hz, 2H), 3.60-3.51 (m, 2H), 3.25 (s, 4H). MS (ESI) m/z: 418.2

Example 183 (1S,2S)-2-((6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)amino)cyclopentanol 283

Following the procedure described in Example 180, 283 was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.22 (s, 2H), 9.19 (s, 1H), 8.74 (s, 1H), 8.69 (s, 1H), 8.09 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.01 (t, J = 5.1 Hz, 1H), z,2H),3.94(t,J＝5.2Hz,4H),3.25(s,4H),2.19(dq,J＝13.7,6.8Hz,1H),1.90(ddt,J＝14.6,8.9,4.2 Hz, 1H), 1.73 (tp, J＝10.3, 5.3Hz, 2H), 1.56 (ddq, J＝26.2, 13.5, 6.9, 6.0Hz, 2H). MS (ESI) m/z: 458.3.

Example 184 6-(6-(azetidin-1-yl)pyrazin-2-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 284

Following the procedure described in Example 180, 284 was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 18.9 Hz, 2H), 8.89 (s, 1H), 8.64 (s, 1H), 7.93 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 4.16 (t, J = 7.5 Hz, 4H), 3.60 (dd, J = 6.3, 3.8 Hz, 4H), 2.84 (dd, J = 6.1, 4.0 Hz, 4H), 2.44 (q, J = 7.5 Hz, 2H). MS (ESI) m/z: 414.2.

Example 185 N-ethyl-6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-amine 285

Following the procedure described in Example 180, 285 was obtained as the dihydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.24 (s, 2H), 9.17 (s, 1H), 8.73 (s, 1H), 8.70 (s, 1H), 8.03 (s, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.20 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 3.95 (t, J = 4.2 Hz, 4H), 3.44 (q, J = 7.2 Hz, 2H), 3.23 (t, J = 4.2 Hz, 4H), 1.27 (t, J = 7.2 Hz, 3H). MS (ESI) m/z: 402.2.

Example 186 2-((6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)oxy)ethylamine 286

Following the procedure described in Example 176, 286 was obtained as the trihydrochloride salt. MS (ESI) m/z: 418.3 [M+H] ⁺

Example 901 Pim kinase binding activity

PIM-1, -2, and -3 enzymes were generated as fusion proteins expressed in bacteria and purified by IMAC column chromatography (Sun, X., Chiu, J.F., and He, Q.Y. (2005) Expert Rev. Proteomics, 2:649-657). Fluorescently labeled Pim-specific peptide substrates were custom synthesized by American Peptide Company (Sunnyvale, CA). The reaction buffer contained 10 mM HEPES, pH 7.2, _{10 mM} MgCl₂, 0.01% Tween 20, and 2 mM DTT. The stop buffer contained 190 mM HEPES, pH 7.2, 0.015% Brij-35, 0.2% Coating Reagent 3 (Caliper Life Sciences, Hopkinton, MA), and 20 mM EDTA. The separation buffer contained 100 mM HEPES, pH 7.2, 0.015% Brij-35, 0.1% coating agent 3, 1:200 coating agent 8 (Caliper Life Sciences, Hopkinton, MA), 10 mM EDTA, and 5% DMSO.

The PIM reaction is carried out in a 384-well plate, and every hole final volume is 10 μ L. The standard enzyme reaction is initiated by adding 5 μ L 2X ATP and test compound into 5 μ L 2X enzymes and FAM-peptides, containing 20pM PIM1, 50pMPIM2 or 55pM PIM3, 1 μ M FAM-Peptide and 10 μ M ATP in reaction buffer. After incubation at room temperature for 90 minutes, the phosphorylation reaction is terminated by adding 10 μ L stop buffers. The product in each individual reaction is separated from the 12-sipper microfluidic chip (12-sipper microfluidicchip) (Caliper Life Sciences, Hopkinton, MA) that runs on Caliper (Caliper Life Sciences, Hopkinton, MA). By using Caliper ' s Optimizer software (Hopkinton, MA), voltage and pressure are selected, the separation of product and substrate is optimized. Separation conditions used a downstream voltage of -500 V, an upstream voltage of -2150 V, and a screening pressure of -1.2 psi. Product and substrate fluorophores were excited at 488 nm and detected at 530 nm. Substrate conversion was calculated from the electropherogram using HTS Well Analysis Software (Caliper Life Sciences, Hopkinton, MA). Ki values were calculated for the test compounds. Representative micromolar Ki values for PIM1, PIM2, PIM3, and LC3K of exemplary compounds are shown in Tables 3 and 4.

Example 902 In vitro cell proliferation potency assay

The BaF3 parental strain was obtained from the DSMZ repository. BaF3 strains transfected with PIM1 or PIM2 were generated. Mouse IL-3 was purchased from R&D Systems. G418 was purchased from Clontech. The culture medium for the BaF3 parental strain contained RPMI, 10% FBS, 2 mM L-glutamine, and 2 ng/mL mIL-3. The culture medium for the BaF3 PIM1&2 strain contained RPMI, 10% FBS, 2 mM L-glutamine, 250 μg/mL. The culture medium for the MM1.S (multiple myeloma) strain contained RPMI, 10% FBS, and 2 mM L-glutamine.

BaF3 (murine interleukin-3 dependent proto-B cell line) parental cells, BaF3PIM1 cells, BaF3PIM2 cells, and MM1.S (multiple myeloma) cells were seeded in 384-well plates at 2k/well, 5k/well, 5k/well, and 10k/well, respectively, at a concentration of 45 μL/well per well. Test compounds were added at 5 μL/well. BaF3 cells (parental and transfected) were incubated overnight, while MM1.S cells were incubated at 37°C, 5% _CO2 for 72 hours. Cell Titer Glo reagent (Promega) was added at 50 μL/well, the plates were incubated for 30 minutes, and their fluorescence values were read on the HT Analyst. _IC50 /EC50 values of the test compounds were calculated.

Representative compounds of the invention were tested as described above and found to exhibit Ki/ _IC50 / _EC50 as shown in Tables 3 and 4 below.

Table 3

Table 4.

Although the foregoing invention has been described in detail to a certain extent by way of illustration and examples for the purpose of understanding clarity, the description and examples should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific literature cited in this application are expressly incorporated herein by reference in their entirety.

Claims (5)

1. A compound, selected from 6-(1-Ethylpyrazol-4-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 6-(1-methylpyrazol-4-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(5-isopropyl-pyridin-3-yl)pyrazolo[4,3-c]pyridine 6-(5-ethylpyridin-3-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)pyrazolo[4,3-c]pyridine 6-(5-isopropyl-pyridin-3-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 1-[6-[6-(5-ethylpyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]-1,4-diazacycloheptane-6-ol (3R)-1-[6-[6-(5-isopropyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine] (3S)-1-[6-[6-(5-isopropyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine] 5-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]thiazole (3R)-1-[6-(6-(thiazo-5-yl)pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl]piperidin-3-amine 6-(5-Cyclopropyl-pyridin-3-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 6-(5-cyclopropyl-pyridin-3-yl)-1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]pyrazolo[4,3-c]pyridine 1-[6-[(3S)-3-methylpiperazin-1-yl]-pyridin-2-yl]-6-[5-(oxecyclobutane-3-yl)-pyridin-3-yl]pyrazolo[4,3-c]pyridine 6-[5-(oxecyclobutane-3-yl)-pyridin-3-yl]-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 1-[6-[6-(5-cyclopropyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazacycloheptane-6-ol 1-[6-[6-[5-(oxecyclobutane-3-yl)-pyridin-3-yl]pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazacycloheptane-6-ol (3S)-1-[3-chloro-6-[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine] 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-[5-(oxecyclobutane-3-yl)-pyridin-3-yl]pyrazolo[4,3-c]pyridine 3-Methyl-5-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]isothiazolium 5-[1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]pyrazolo[4,3-c]pyridin-6-yl]-3-methylisothiazolium (S)-1-[6-[6-(5-ethylpyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]-1,4-diazacycloheptane-6-ol] (R)-1-[6-[6-(5-ethylpyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]-1,4-diazacycloheptane-6-ol] 6-(6-methylpyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine (3S)-1-[6-[6-(3-methylisothiazo-5-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine] 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridine 6-(1-Ethylpyrazol-4-yl)-1-[6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]pyrazolo[4,3-c]pyridine (3S)-1-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]pyrrolidine-3-ol] (3R)-1-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]pyrrolidine-3-ol] 1-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-4-ol 6-(6-methoxypyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 1-[6-(3,3-dimethylpiperazin-1-yl)-pyridin-2-yl]-6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridine 1-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidin-4-amine(3S)-1-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine (3R)-1-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine] (3S)-1-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]pyrrolidine-3-amine] (3R)-1-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]pyrrolidine-3-amine] (3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine] 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (3S)-1-[3-Cyclopropyl-6-[6-(5-ethyl-pyridin-3-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine 1-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacycloheptane-4-amine 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(5-methyl-pyridin-3-yl)pyrazolo[4,3-c]pyridine 1-[6-[(3R)-3-ethylpiperazin-1-yl]-pyridin-2-yl]-6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridine N-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacycloheptane-3-amine] 1-(6-(piperazin-1-yl)-pyridin-2-yl)-6-(pyrazin-2-yl)-pyrazolo[4,3-c]pyridine 6-(1-tert-butylpyrazol-4-yl)-1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]pyrazolo[4,3-c]pyridine 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(1-isopropylpyrazol-4-yl)pyrazolo[4,3-c]pyridine 6-(1-Cyclobutylpyrazole-4-yl)-1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]pyrazolo[4,3-c]pyridine 5-[1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]pyrazolo[4,3-c]pyridin-6-yl]-2-methyl-pyridazin-3-one 6-(6-ethylpyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(6-ethylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 3-Ethyl-5-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrimidin-4-one 2-[4-[1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]pyrazolo[4,3-c]pyridin-6-yl]pyrazol-1-yl]ethanol 1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]-6-[1-(2-fluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 2-[4-[1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]pyrazolo[4,3-c]pyridin-6-yl]pyrazol-1-yl]acetonitrile (3S)-1-[6-[6-(6-ethylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine] 1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]-6-[1-(oxecyclobutane-3-ylmethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 2-[4-[1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]pyrazolo[4,3-c]pyridin-6-yl]pyrazol-1-yl]acetamide 6-(6-methylpyrazin-2-yl)-1-[6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-2-yl]pyrazolo[4,3-c]pyridine 6-[1-(cyclopropylmethyl)pyrazol-4-yl]-1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]pyrazolo[4,3-c]pyridine 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-[1-(2,2-difluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 1-[6-(1,4-diazacycloheptane-1-yl)pyrazin-2-yl]-6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridine 3-[1-[6-(1,4-diazacycloheptane-1-yl)pyrazin-2-yl]pyrazolo[4,3-c]pyridin-6-yl]-5-methylpyridin-2-ol 6-(6-Cyclopropylpyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 6-(6-methylpyrazin-2-yl)-1-[6-(4-piperidinyl)-pyridin-2-yl]pyrazolo[4,3-c]pyridine (3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]pyrrolidine-3-amine] (3R)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]pyrrolidine-3-amine] 1-[6-(3-methylpiperazin-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 6-(6-tert-butylpyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine-6-methyl-1-[6-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidine-3-amine 1-[6-[6-(6-ethylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazacycloheptane-6-ol 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-[1-(difluoromethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 6-(1-Cyclopropylpyrazole-4-yl)-1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]pyrazolo[4,3-c]pyridine 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-pyrimidin-5-yl-pyrazolo[4,3-c]pyridine (3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine] 6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-carboxylonite 1-[6-(1,4-diazacycloheptane-1-yl)pyrazin-2-yl]-6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 1-[2-(1,4-diazacycloheptane-1-yl)pyrimidin-4-yl]-6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(1H-pyrazol-4-yl)pyrazolo[4,3-c]pyridine (3S)-1-[3-Cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine 6-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine 6-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine 1-[6-(5-methyl-1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 1-[6-(3-methylpiperazin-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine 1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacycloheptane-3-amine (R)-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl)-1,4-diazacycloheptane-6-ol (S)-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-pyridin-2-yl)-1,4-diazacycloheptane-6-ol 6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-N-(4-piperidinyl)pyridin-2-amine 1-[6-[(2R)-2-methylpiperazin-1-yl]-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (3S,5S)-5-fluoro-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine] 1-[6-(3-methylpiperazin-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidin-4-amine 2-Methyl-1-[6-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]piperidin-3-amine 1-[6-[(2S)-2-methylpiperazin-1-yl]-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 1-[5-cyclopropyl-6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (3S,5R)-5-fluoro-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine 2-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-2,8-diazaspiro[4,5]decane 8-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-2,8-diazaspiro[4,5]decane 2-[(3S)-3-amino-1-piperidinyl]-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-3-carboxylonitrile (5S)-5-amino-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-2-one 2-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine 2-Methyl-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine (3S)-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazacycloheptane-5-one 1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazacycloheptane-6-ol 5-[1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]pyrazolo[4,3-c]pyridin-6-yl]-3-methylpyrazine-2-amine 5-[1-[6-[(3S)-3-amino-1-piperidinyl]pyridin-2-yl]pyrazolo[4,3-c]pyridin-6-yl]-3-methyl-pyrazin-2-amine 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]cyclohexylamine 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]cyclohexylamine 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]cyclohexylamine 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]cyclohexylamine 1-[6-(2,6-diazaspiro[3,4]oct-6-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (3S)-1-[3-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine 8-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,8-diazaspiro[4,5]decane 1-[6-(2,7-diazaspiro[3,4]oct-2-yl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine [2-[(3S)-3-amino-1-piperidinyl]-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-3-yl]methanol 1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-(trifluoromethyl)pyridin-2-yl]-1,4-diazacycloheptane-6-ol (3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-(trifluoromethyl)pyridin-2-yl]piperidin-3-amine (5S)-5-amino-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-2-one (3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]piperidine-3-amine 3-[(3S)-3-amino-1-piperidinyl]-5-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-ol 1-[6-(1,4-diazacycloheptane-1-yl)-pyridin-2-yl]-6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridine (3S)-3-amino-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-2-one (3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]piperidin-3-amine] (3S)-1-[3-(difluoromethyl)-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-3-amine (3S)-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]piperidin-3-amine] 1-[6-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazacycloheptane-6-ol 4-[6-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacycloheptane-4-ol 1-[6-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]-pyridin-2-yl]-1,4-diazacycloheptane-6-ol 1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]pyrrolidine-3,4-diol 3-[(3S)-3-amino-1-piperidinyl]-1-methyl-5-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-one 1-[3-methoxy-6-[6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]-1,4-diazacycloheptane-6-ol 1-[6-(azacycloheptane-4-yl)-pyridin-2-yl]-6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridine 1-[6-(4-fluorozacriane-4-yl)-pyridin-2-yl]-6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridine 1-[3-methoxy-6-[6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]-1,4-diazacycloheptane-6-ol (3S)-1-[3-Cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]piperidin-3-amine (S)-2-((6-(1-(2-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)oxy)-1-phenylethylamine 6-(6-methylpyrazin-2-yl)-1-[6-[4-(oxecyclobutane-3-yl)-1,4-diazacycloheptane-1-yl]-pyridin-2-yl]pyrazolo[4,3-c]pyridine 3-[(3S)-3-amino-1-piperidinyl]-1-methyl-5-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-one 3-[(3S)-3-amino-1-piperidinyl]-1-methyl-5-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-one 3-[(3R)-3-amino-1-piperidinyl]-1-methyl-5-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-one (R)-2-((6-(1-(2-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)oxy)-1-phenylethylamine (3S)-3-amino-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-2-one 1-(6-(2,6-diazaspiro[3.5]non-2-yl)pyridin-2-yl)-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine 6-[1-[6-(1,4-diazacycloheptane-1-yl)pyridin-2-yl]pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-amine (S)-6-methyl-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazacycloheptane-6-ol (R)-6-methyl-1-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazacycloheptane-6-ol (3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-4-(oxetane-3-yl)pyridin-2-yl]piperidin-3-amine 1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]hexahydropyrimidin-2-one 1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]hexahydropyrimidin-2-one 1-[6-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacyclobutane-3-ol 3-(6-hydroxy-1,4-diazacycloheptane-1-yl)-1-methyl-5-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-one 1-[6-[6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacyclobutane-3-ol [1-[6-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacyclobutane-3-yl]methylamine 1-[6-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacyclobutane-3-amine 1-[6-[6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacyclobutane-3-amine 1-[6-(4,4-difluoro-3-piperidinyl)-pyridin-2-yl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (R)-1-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazacycloheptane-6-ol (S)-1-(6-(6-methoxy-6-methyl-1,4-diazacycloheptane-1-yl)pyridin-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine [1-[6-[6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacyclobutane-3-yl]methylamine (S)-1-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazacycloheptane-6-ol (R)-1-(6-(6-methoxy-6-methyl-1,4-diazacycloheptane-1-yl)pyridin-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 3-[6-[6-(6-methylpyrazin-2-yl)pyrazol[4,3-c]pyridin-1-yl]pyridin-2-yl]piperidin-4-ol 1-[6-(2,5-diazaspiro[3,5]non-2-yl)pyridin-2-yl]-6-(1-methylpyrazol-4-yl)pyrazol[4,3-c]pyridine 1-[6-(2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 1-[6-(2,6-diazaspiro[3.3]hept-2-yl)-pyridin-2-yl]-6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridine 1-[6-(2,5-diazaspiro[3,5]non-2-yl)pyridin-2-yl]-6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridine 3-(aminomethyl)-1-[6-[6-(1-methylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridin-2-yl]azacyclobutane-3-ol (S)-1-(6-(4,4-difluoropiperidin-3-yl)pyridin-2-yl)-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (R)-1-(6-(4,4-difluoropiperidin-3-yl)pyridin-2-yl)-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine [6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-yl]methanol 1-(6-(piperazin-1-yl)-pyridin-2-yl)-6-(6-vinylpyrazin-2-yl)pyrazolo[4,3-c]pyridine 6-(6-chloropyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 6-(6-benzyloxypyrazin-2-yl)-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine 1-[6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-yl]ethane-1,2-diol 2-[6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-yl]oxyethanol 6-[6-(difluoromethyl)pyrazin-2-yl]-1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridine [(2S)-1-[6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-yl]pyrrolidine-2-yl]methanol 1-[6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-yl]azacyclobutane-3-ol 2-[[6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-yl]amino]ethanol (1S,2S)-2-[[6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-yl]amino]cyclopentanol 6-[6-(azacyclobutane-1-yl)pyrazin-2-yl]-1-(6-(piperazin-1-yl)pyridin-2-yl)pyrazolo[4,3-c]pyridine N-Ethyl-6-[1-(6-(piperazin-1-yl)pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-amine 2-[6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]pyrazin-2-yl]oxyethylamine 6-[1-(6-(piperazin-1-yl)-pyridin-2-yl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazin-2-one 3-(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-ol (S)-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-(piperidin-3-yl)pyridazin-3(2H)-one (R)-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-(piperidin-3-yl)pyridazin-3(2H)-one 6-(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-2,6-diazaspiro[3,5]nonane-2-carboxaldehyde (6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)methylamine 1-(6-(2,6-diazaspiro[3.5]non-6-yl)pyridin-2-yl)-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine 1-(6-(3-Fluoroperidin-3-yl)pyridin-2-yl)-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine 1-(6-(3-methoxypiperidin-3-yl)pyridin-2-yl)-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine N,N-Dimethyl-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-amine N-Methyl-6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-amine (R)-1-(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-ol (S)-1-(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-ol 3-(6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)prop-2-yn-1-ol 3-(6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)prop-1-ol. 2. A compound, selected from (S)-(3-aminopiperidin-1-yl)(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl ketone (R)-(3-aminopiperidin-1-yl)(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl ketone (1S,2S)-2-(6-(1-(pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yloxy)cyclopentanamine 3-(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yloxy)cyclohexylamine 1-(6-(4-fluoropiperidin-3-yl)pyridin-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (1S,2S)-N1-(6-(1-(pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)cyclopentane-1,2-diamine N-(azacyclobutan-3-yl)-6-(1-(pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-amine 6-(5-chloro-1-methyl-1H-pyrazol-4-yl)-1-(2-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine 3-(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yloxy)cyclohexylamine 3-(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yloxy)cyclohexylamine 1-(6-(6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3,4-diol 6-(6-methylpyrazin-2-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridazine 1-(2-Fluorophenyl)-6-(1-Methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine 6-(6-ethynylpyrazin-2-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 1-(4-(1-(2-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)piperidin-4-amine 1-(6-(piperazin-1-yl)pyridin-2-yl)-6-(6-(prop-1-ynyl)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine. 3. A pharmaceutical composition comprising a compound of any one of claims 1-2 and a pharmaceutically acceptable carrier or excipient. 4. The pharmaceutical composition of claim 3, for treating diseases or disorders selected from: cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunctions, and neurological disorders; wherein said diseases or disorders are mediated by Pim kinase. 5. Use of the compound of any one of claims 1-2 in the preparation of a medicament for treating cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine disorders, and neurological disorders, wherein the medicament mediates Pim kinase.