HK1193807B

HK1193807B - Pyrazolo[3,4-c]pyridine compounds and methods of use

Info

Publication number: HK1193807B
Application number: HK14107129.3A
Authority: HK
Inventors: Steven Do; Huiyong Hu; Aleksandr Kolesnikov; Wendy Lee; Vickie Hsiao-Wei Tsui; Xiaojing Wang; Zhaoyang Wen
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2011-08-12
Filing date: 2012-08-10
Publication date: 2019-07-12

Description

Pyrazolo [3,4-c ] pyridine compounds and methods of use

Technical Field

The present invention relates generally to pyrazolo [3,4-c ] pyridine compounds, i.e. inhibitors, for the treatment of disorders mediated by Pim kinases (Pim-1, Pim-2 and/or Pim-3), thus useful as cancer therapies. The invention also relates to compositions, and more particularly to 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 associated pathological conditions.

Background

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 moloney proviral insert (ProviralInsertion,Moloney), which is a common integration site for murine moloney virus, wherein the insertion results in overexpression of Pim kinase and significant acceleration of T-Cell lymphoma from either neogenesis (de novo) or tumorigenesis in a transgenic Myc-driven lymphoma model (cuipers 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 show a synergistic effect with the oncogene c-Myc and suggest that inhibition of Pim kinase may have therapeutic benefit.

Mouse genetics suggests that antagonistic Pim kinases may have an acceptable safety profile; pim1-/-, Pim-2-/-, Pim-3-/-knockout mice are viable, albeit slightly inferior to wild-type littermates (Mikkers et al (2004) Molcell Biol vol.24(13) pp.6104-154). The three genes produce six protein subtypes, which contain a protein kinase domain and apparently have no recognizable regulatory domain. All six subtypes are constitutively active protein kinases that do not require modification for post-translational activity, and therefore Pim kinases are mainly 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 Pims is a direct transcriptional target for Stat proteins, which include Stat3 and Stat 5. For example, Pim-1 requires a gp 130-mediated Stat3 proliferation signal (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).

Pim kinase function in the cell proliferation and survival pathway parallels the PI3k/Akt/mTOR signaling axis (Hammerman et al (2005) Blood vol.105(11) pp.4477-83). Indeed, several phosphorylation targets of the PI3k axis, including Bad and eIF4E-BP1, are regulators of cell growth and apoptosis, and are also phosphorylation targets of Pim kinase (Fox et al (2003) Genes Dev vol.17(15) pp.1841-54; Macdonald et al (2006) CellBiol vol.7pp.1; Aho et al (2004) FEBS Letters vol.571(1-3) pp.43-9; Tamburti et al (2009) Blood vol.114(8) pp.1618-27). Pim kinase 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 kinase causes inhibition of eIF4E, promoting mRNA translation and cell growth. Furthermore, Pim-1 has been suggested to promote Cell cycle progression by phosphorylating CDC25A, p21 and Cdc25C (Mochizuki et al (1999) J Biol Chemvol.274(26) pp.18659-66; Bachmann et al (2006) Int J Biochem Cell Biol vol.38(3) pp.430-43; Wang et al (2002) Biophys Acta vol.1593(1) pp.45-55).

Pim kinase shows synergistic effects with c-Myc-driven and Akt-driven tumors in transgenic mouse models (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 kinase is involved in the transforming activity of the Cancer genes identified in Acute Myeloid Leukemia (AML) (which includes Flt3-ITD, BCR-abl and Tel-Jak 2.) expression of these Cancer genes in BaF3 cells causes upregulation of Pim-1 and Pim-2 expression which causes IL-3 independent growth and subsequent Pim inhibition causes apoptosis and Cell growth arrest (Adr. 2006) is also shown to be deregulated in the prostate Cancer Cell-expressing tumor (1986) model (70-19) as well as a prostate-19-expressing pancreatic Cancer (20-kidney-19) with the lymphokines-expressing prostate-19-kidney-19. vol.11. 7. pp.11. 7. pp.2006-83. Pim kinase (90. A) and a prostate Cancer-19. expressing a prostate Cancer (90-11. pp.7. 7. 2000) which has been shown to be deregulated in transgenic mouse model (20; and a prostate Cancer-20. prostate Cancer (kidney-20. colon. 20. colon et 8. and a prostate Cancer (kidney-19. colon. kidney-2. colon) and a prostate Cancer-2. kidney-2. kidney-19. and a prostate Cancer expressing prostate Cancer (90. kidney-2. and a prostate Cancer expressing prostate Cancer (90. kidney-19. a prostate Cancer expressing prostate Cancer (35. expressing prostate Cancer-19. 7. a prostate Cancer expressing prostate Cancer (35. a prostate Cancer) with a prostate Cancer expressing prostate Cancer (35. expressing prostate Cancer-kidney-19. expressing prostate Cancer-2. expressing prostate Cancer (35. a prostate Cancer-2. a prostate Cancer-kidney-19. a prostate Cancer-kidney-2. 7. a prostate Cancer-kidney-2. a prostate Cancer-kidney-19. expressing a prostate Cancer-kidney-19. a prostate Cancer-19. 2000. a prostate Cancer-2. a prostate Cancer expressing a prostate.

In addition to oncological therapeutic and diagnostic applications, Pim kinases may play an important role in normal immune system function and Pim inhibition may treat a variety of different immunological conditions including inflammation, autoimmune diseases, allergy and immunosuppression for organ transplantation (Aho et al. expression of human Pim family genes activating T-helper type 35 1, but not ther type2, cell differentiation. immunology (2005) vol.116(1) pp.82-8).

Disclosure of Invention

The present invention relates to pyrazolo [3,4-c ] pyridine compounds, i.e. inhibitors, of formula I, useful for the treatment of conditions mediated by Pim kinase (Pim-1, Pim-2 and/or Pim-3).

The compounds of formula I have the following structure:

and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof. Various substituents (which include R)¹And R²) As defined in the present application.

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 another chemotherapeutic agent.

Another aspect of the invention is a process for preparing a pharmaceutical composition comprising combining a compound of formula I with a pharmaceutically acceptable carrier.

The invention includes a method of treating a disease or disorder selected from cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological diseases, mediated by Pim kinase, comprising administering to a patient having a disease or disorder a therapeutically effective amount of a compound of formula I. The method further comprises administering an additional therapeutic agent selected from the group consisting of: chemotherapeutic agents, anti-inflammatory agents, immunomodulators, neurotrophic factors, agents for treating cardiovascular disease, agents for treating liver disease, antiviral agents, agents for treating hematologic diseases, agents for treating diabetes, and agents for treating immunodeficiency.

The present invention includes a kit for treating a condition mediated by Pim kinase, comprising: a) a first pharmaceutical composition comprising a compound of formula I; and b) instructions for use.

The invention includes compounds of formula I for use as medicaments and for the treatment of diseases or disorders selected from cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological diseases, and mediated by Pim kinases.

The invention includes the use of a compound of formula I in the manufacture of a medicament for the treatment of cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and wherein the medicament mediates Pim kinase.

The invention includes a process for preparing a compound of formula I.

Detailed Description

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulae. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that a variety of methods and materials similar or equivalent to those 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. The present application controls if one or more of the incorporated documents, patents, and similar materials differ or contradict the present application (including but not limited to defined terms, usage of terms, described techniques, and the like).

Definition of

The term "alkyl" as used herein refers to a compound having 1 to 12 carbon atoms (C)₁-C₁₂) Wherein the alkyl group may be optionally substituted independently with one or more substituents described below. In another embodiment, the alkyl group has 1 to 8 carbon atoms (C)₁-C₈) Or having 1 to 6 carbon atoms (C)₁-C₆). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) 1-propyl (n-Pr, n-propyl, -CH)₂CH₂CH₃) 2-propyl (i-Pr, isopropyl, -CH (CH)₃)₂) 1-butyl (n-Bu, n-butyl, -CH)₂CH₂CH₂CH₃) 2-methyl-1-propyl (i-Bu, isobutyl, -CH)₂CH(CH₃)₂) 2-butyl (s-Bu, sec-butyl, -CH (CH)₃)CH₂CH₃) 2-methyl-2-propyl (t-Bu, tert-butyl, -C (CH)₃)₃) 1-pentyl (n-pentyl, -CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) 1-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂)2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂)3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃1-heptyl, 1-octyl, and the like.

The term "alkylene" as used herein refers to a group having 1 to 12 carbon atoms (C)₁-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 (C)₁-C₈) Or having 1 to 6 carbon atoms (C)₁-C₆). Examples of alkylene groups include, but are not limited to, methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH₂-) and the like.

The term "alkenyl" refers to a group having 2 to 8 carbon atoms (C)₂-C₈) And has at least one site of unsaturation (i.e., carbon-carbon sp)²Double bond), wherein the alkenyl group may be optionally 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, vinyl (ethylene or vinyl) (-CH = CH)₂) Allyl (-CH)₂CH=CH₂) And the like.

The term "alkenylene" refers to a compound having 2-8 carbon atoms (C)₂-C₈) And has at least one site of unsaturation (i.e., a carbon-carbon sp)²Double bond), wherein the alkenylene group 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, vinylidene (-CH = CH-), allylidene (-CH-)₂CH = CH-), and the like.

The term "alkynyl" refers to a compound having 2-8 carbon atoms (C)₂-C₈) And a straight or branched monovalent hydrocarbon group having at least one site of unsaturation (i.e., a carbon-carbon sp triple bond), wherein the alkynyl group can be optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C ≡ CH), propynyl (propargyl, -CH)₂C.ident.CH) and the like.

The term "alkynylene" refers to a compound having 2-8 carbon atoms (C)₂-C₈) And a straight or branched chain divalent hydrocarbon radical having at least one site of unsaturation (i.e., a carbon-carbon sp triple bond), wherein the alkynylene radical may be optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, ethynylene (-C ≡ C-), propynyl (propargylene, -CH)₂C.ident.C-), and the like.

The terms "carbocycle", "carbocyclyl", "carbocycle", and cycloalkyl "refer to a compound having 3 to 12 carbon atoms (C)₃-C₁₂) A monovalent nonaromatic saturated or partially unsaturated ring which is monocyclic or which has 7 to 12 carbon atoms as the bicyclic ring. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as bicyclo [4, 5]]、[5,5]、[5,6]Or [6,6 ]]Systems, bicyclic carbocycles having 9 or 10 ring atoms may be arranged as a bicyclo [5,6 ]]Or [6,6 ]]Systems, or arrangements, of bridged systems, e.g. 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, and the like. Carbocyclyl is optionally independently substituted with one or more substituents described herein.

"aryl" means a group having from 6 to 20 carbon atoms (C) obtained by the removal of one hydrogen atom from a single carbon atom in a parent aromatic ring system₆-C₂₀) A monovalent aromatic hydrocarbon group of (2). Some aryl groups are represented as "Ar" in the exemplary structures. Aryl includes bicyclic radicals containing an aromatic ring fused to a saturated, partially unsaturated ring or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzenes, naphthalenes, anthracenes, biphenyls, indenyls, indanyls, 1, 2-dihydronaphthalenes, 1,2,3, 4-tetrahydronaphthylenes, and the like. Aryl is optionally substituted independently with one or more substituents described herein.

"arylene" means a compound having 6 to 20 carbon atoms (C) obtained by removing two hydrogen atoms from two carbon atoms in a parent aromatic ring system₆-C₂₀) A divalent aromatic hydrocarbon group of (1). Some arylene groups are represented as "Ar" in exemplary structures. Arylene includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring or aromatic carbocyclic ring. Typical arylene groups include, but are not limited to, those derived from benzene (phenylene), substituted benzenes, napthyl, anthracenyl, biphenylene, indenylene, indanylene, 1, 2-dihydronapthyl, 1,2,3, 4-tetrahydronapthyl, and the like. Arylene is optionally independently substituted with one or more substituents described herein.

The terms "heterocycle" (heterocyclic), "heterocyclyl" and "heterocyclic" 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 of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, wherein one or more ring atoms are optionally independently substituted with one or more substituents described below. The heterocyclic ring may be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or a bicyclic ring having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S), for example, a bicyclo [4, 5] ring]、[5,5]、[5,6]Or [6,6 ]]Provided is a system. Heterocycles are described in Paquette, Leo a.; "Principles of modern Heterocyclic Chemistry" (W.A. Benjamin, New York,1968) (especially items 1,3, 4,6, 7 andchapter 9); "The Chemistry of Heterocyclic Compounds, A series of monograms" (John Wiley)&Sons, New York,1950to 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, azetidin-1-yl, octahydropyrido [1,2-a ] base]Pyrazin-2-yl, [1,4 ]]Diazepan-1-yl, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thiexanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, and the likeRadical diazaRadical, sulfur nitrogen heteroYl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0 ] group]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 3H-indolyl, quinolizinyl and ureidopyridyl (N-pyridil urea). A spiro moiety is also included within the scope of this definition. Examples of heterocyclyl groups in which both ring atoms are partially substituted by oxo (= O) are oxopyrimidinyl (pyrimidinonyl) and 1, 1-dioxo-thiomorpholinyl. Heterocyclic radical of the present applicationThe groups are optionally independently substituted with one or more substituents described herein.

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

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

By way of example and not limitation, the nitrogen-linked heterocycle or heteroaryl is linked at the 1-position 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, the 2-position of isoindoline or isoindoline, the 4-position of morpholine, and the 9-position of carbazole or β -carboline.

The terms "treatment" and "treatment" refer to both therapeutic treatment and prophylactic measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e., not worsening) of the disease state, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "treatment" may also mean extended survival compared to the expected survival without treatment. Subjects in need of treatment include subjects already suffering from a condition or disorder as well as subjects susceptible to or to be prevented from the condition or disorder.

The phrase "therapeutically effective amount" means (i) an amount of a compound of the invention that treats or prevents a particular disease, condition, or disorder described herein, (ii) an amount of a compound of the invention that attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder described herein, or (iii) an amount of a compound of the invention that prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs (peripheral organ); inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or relieve to some extent one or more symptoms associated with cancer. The drug may be cytostatic and/or cytotoxic if it is of such a degree that it prevents the growth of and/or kills existing cancer cells. For cancer treatment, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR).

The term "cancer" refers to or describes a physiological condition in mammals that is characterized by, typically, unregulated cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma (carcinoma), lymphoma, blastoma, sarcoma, and leukemia (leukamia) or lymphoid malignancy (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 (adenocarcinomas of the lung), and squamous carcinoma of the lung (squamous carcinoma of the lung); peritoneal cancer; hepatocellular carcinoma; gastric cancer (gastric cancer), including gastrointestinal cancer; pancreatic cancer; a glioblastoma; cervical cancer; ovarian cancer; liver cancer (livercacer); bladder cancer; hepatoma (hepatoma); breast cancer (breast cancer); colon cancer; rectal cancer; colorectal cancer; endometrial or uterine cancer; salivary gland cancer; renal (kidney cancer) or renal (renal cancer); prostate cancer; vulvar cancer (vulval cancer); thyroid cancer; liver cancer (hepatic carcinoma); anal cancer; penile cancer; and head and neck cancer.

A "chemotherapeutic agent" is a compound useful in the treatment of cancer, regardless of its mechanism of action. Chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindly poison plant alkaloids (spindleleaf poison plant alkaloids), cytotoxic/antitumor antibiotics (cytoxic/antitumor or antineoplastic), topoisomerase inhibitors (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 (erlotinib) ((ii))Genentech/OSI Pharm.), docetaxel (docetaxel)Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No.51-21-8), gemcitabine (gemcitabine) (Lilly), PD-0325901(CAS No.391210-10-9, Pfizer), cisplatin (cisclinin) (cis-diamine, platinum (II) dichloride, CAS No.15663-27-1), carboplatin (CASNO.41575-94-4), paclitaxel (paclitaxel)Bristol-Myers Squibb Oncology, Princeton, N.J.), trastuzumab (trastuzumab) ((R)Genentech), temozolomide (temozolomide) (4-methyl-5-oxo-2, 3,4,6, 8-pentaazabicyclo [4.3.0 ]]Nonane-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 (doxorubicin) ((d))) Akti-1/2, HPPD and rapamycin (rapamycin).

Other examples of chemotherapeutic agents include: oxaliplatin (oxaliplatin) ((oxaliplatin))Sanofi), bortezomib (bortezomib), (b), (d), (Millennium Pharm.), sunitinib (sutent), (a mixture of them)SU11248, Pfizer), letrozole (letrozole), (L-Toxole)Novartis), imatinib mesylate (imatinib mesylate), (I) and (II) a pharmaceutically acceptable salt thereofNovartis), XL-518(MEK inhibitor, Exelixis, WO2007/044515), 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/ZK222584(Novartis), fulvestrant (fulvestrant) ((fulvestrant)AstraZeneca), leucovorin (leucovorin), rapamycin (sirolimus, and folic acid,Wyeth), everolimus (Novartis), lapatinib (lapatinib) (Novartis), lapatinibGSK572016,Glaxo Smith Kline)、lonafarnib(SARASAR^TMSCH66336, Schering Plough), Sorafenib (sorafenib) ((Schering Plough)BAY43-9006, Bayer Labs), gefitinib (gefitinib) ((B)AstraZeneca), irinotecan (irinotecan), (CPT-11,Pfizer)、tipifarnib(ZARNESTRA^TM,Johnson&Johnson)、ABRAXANE^TM(Cremophor-free), albumin engineered nanoparticle formulations of paclitaxel (albumin-engineered nanoparticles of paclitaxel) (American Pharmaceutical Patners, Schaumberg, Il.), vandetanib (rINN, ZD6474,AstraZeneca)、chloranmbucil、AG1478、AG1571(SU5271；Sugen)、temsirolimus(Wyeth)、pazopanib(GlaxoSmithKline)、canfosfamide(telik), Abiraterone (A), (B), (C), (Johnson&Johnson), thiotepa (thiotepa) and cyclophosphamide (cyclophosphamide) ((Johnson)) (ii) a Alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines (aziridines) such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine (ethyleneimine) and methylaminoacridine (methylaminoamine), including altretamine, triimine (triethyleneamine), triethylenephosphoramide (triethylenephosphoramide), triethylenephosphorothioateAmides (triethylhophosperamide) and trimethylomelamide; annonaceous acetogenin (especially bullatacin and bullatacin); camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin (adozelesin), carvelesin (carzelesin), and bizelesin (bizelesin) synthetic analogs); cryptophycins (especially cryptophycin1 and cryptophycin 8); dolastatin (dolastatin); duocarmycins (including the synthetic analogs KW-2189 and CB1-TM 1); eiscosahol (eleutherobin); pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlorophosphamide (chlorophosphamide), estramustine, ifosfamide, mechlorethamine (mechlorethamine), mechlorethamine hydrochloride (mechlorethamine oxydichloride), melphalan, neomustard (novembichin), benzene mustard cholesterol (phenylesterine), prednimustine (prednimustine), trofosfamide (trofosfamide), uracil mustard (uracil musard); nitroureas such as carmustine, chlorozotocin (chlorozotocin), fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne (enediyne) antibiotics (e.g., calicheamicin gamma 1I, calicheamicin omega I1(Angew chem. Intl. Ed. Engl. (1994)33:183-186), anthracyclines (dynemicin), dynemicin A, bisphosphonates (bisphosphates) such as clodronate, esperamicin (esperamicin), and neooncostatin chromophores (neocarzinostatin chromophoropterin) and related chromogenes enediyne (enediyne chromophoropterophore), acrinomycin, actinomycin (ubomycin), aureomycin, serazaserine (azacine), desmomycin, actinomycin C, actinomycin (5-carboxymycin), monocrotamycin (5-6-5), monocrotamycin (monocrotamycin-6), monocrotamycin (monocrotamycin), monocrotamycin-5-6-D), monocrotamycin (monocrotamycin-6-D), monocrotamycin (monocrotamycin-5-D, monocrotamycin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidino-doxorubicin and deoxydoxorubicin), epirubicin (epirubicin), esorubicin, idarubicinDabigatran, nemorubicin (nemorubicin), marijumycin (marcelomycin), mitomycins such as mitomycin C, mycophenolic acid (mycophenolic acid), norramycin (nogalamycin), olivomycin (olivomycin), pelomycin (pelomycin), pofiromycin (porfiromycin), puromycin (puromycin), triiron doxorubicin (quelamycin), rodobicin (rodorubicin), streptomycin (streptonigrin), streptozocin (streptozocin), tubercidin (tubidin), ubenimex (ubenimex), setastin (zinostatin), zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine (fludarabine), 6-mercaptopurine, thiamiprine (thiamiprine), thioguanine (thioguanine); pyrimidine analogs such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azaguanosine (6-azauridine), carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine (dideoxyuridine), doxifluridine (doxifluridine), enocitabine (enocitabine), floxuridine (floxuridine); androgens such as carposterone (calusterone), methyl androsterone propionate (dromostanolone propionate), epitioandrostanol (epitiostanol), mepiquane (mepiquitane), testolactone (testolactone); anti-adrenaline (anti-adrenaline) such as aminoglutethimide, mitotane, trilostane; folic acid replenisher (folic acid replenisher) such as folinic acid (frilic acid); acetoglucurolactone (acegultone); (ii) an aldophosphamide glycoside; aminolevulinic acid (aminolevulinic acid); eniluracil (eniluracil); amsacrine (amsacrine); bestrabuucil; bisantrene; idazot (edatraxate); desphosphamide (defofamine); colchicine (demecolcine); diazaquinone (diaziqutone); elfornitine; ammonium etitanium acetate; epothilone (epothilone); etoglut (etoglucid); gallium nitrate (gallium nitrate); hydroxyurea (hydroxyurea); lentinan (lentinan); lonidamine (lonidainine); maytansinol (maytansinoids) such as maytansinoids (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantroneQuinones (mitoxantrone); mopidanmol; rhizobia (nitrarine); pentostatin (pentostatin); methionine mustard (phenamett); pirarubicin (pirarubicin); losoxantrone (losoxantrone); podophyllinic acid (podophyllinic acid); 2-ethyl hydrazine; procarbazine (procarbazine);polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane (rizoxane); rhizomycin (rhizoxin); sizofuran (sizofiran); germanium spiroamines (spirogyranium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2,2' -trichlorotriethylamine; trichothecenes (trichothecene) (especially T-2 toxin, veracurin A, bacillocin A and anguidine); uratan; vindesine; dacarbazine (dacarbazine); mannomustine (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); a polycytidysine; cytarabine (arabine) ("Ara-C"); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (A)) (ii) a Norfloxacin (novantrone); teniposide (teniposide); idazocide (edatrexate); daunorubicin; aminopterin (aminopterin); capecitabine (capecitabine) (capecitabine)Roche); ibandronate (ibandronate); CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids (retinoids) such as retinoic acid (retinoic acid); and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Examples of chemotherapeutic agents also include: dexamethasone (dexamethasone), thiotepa, doxorubicin, vincristine, rituximab (rituximab), cyclophosphamide, prednisone (prednisone), melphalan, lenalidomide (lenalidomide), bortezomib (bortezomib), rapamycin, and cytarabine (cytarabine).

The following are also included in the definition of "chemotherapeutic agents": (i) anti-hormonal agents, such as anti-estrogen agents (anti-estrogens) and Selective Estrogen Receptor Modulators (SERMs), including for example tamoxifen (including tamoxifen) for modulating or inhibiting the effects of hormones on tumorsTamoxifen citrate), raloxifene, droloxifene, 4-hydroxy tamoxifen, trioxifene (trioxifene), raloxifene (keoxifene), LY117018, onapristone (onapristone), and(toremifene citrate); (ii) aromatase inhibitors which inhibit aromatase (which regulates estrogen production in the adrenal gland), e.g. 4(5) -imidazole, aminoglutethimide,(megestrol acetate)) (a salt of megestrol acetate),(exemestane; Pfizer), formestanie, fadrozole,(vorozole) and (C) a salt thereof,(letrozole; Novartis) and(anastrozole; AstraZeneca); (iii) antiandrogens (anti-androgens), such as flutamide, nilutamide, bicalutamide, leuprolide acetate and leuprolideGoserelin (goserelin) and troxacitabine (troxacitabine) (1, 3-dioxolane nucleoside cytosine analogues), (iv) protein kinase inhibitors, such as MEK inhibitors (WO2007/044515), (v) lipid kinase inhibitors, (vi) antisense oligonucleotides, in particular those that inhibit gene expression in signal transduction pathways involved in abnormal cell proliferation, such as PKC- α, Raf and H-Ras, e.g., oblimersen (R) ((R))Genta Inc.); (vii) ribozymes such as VEGF expression inhibitors (e.g.) And inhibitors of HER2 expression; (viii) vaccines, e.g. gene therapy vaccines, e.g.AndrIL-2; topoisomerase 1 inhibitors such asrmRH; (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 (Campath), bevacizumab (b)Genentech); cetuximab (Imclone); palizumab (panitumumab,amgen), rituximab (Genentech/Biogen Idec), pertuzumab (pertuzumab,2C4, Genentech), trastuzumab (Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate orituzumab (gemtuzumab ozogamicin,Wyeth)。

humanized monoclonal antibodies having therapeutic potential as chemotherapeutic agents in combination with the PI3K inhibitors of the invention include: alemtuzumab (alemtuzumab), aprezumab (apilizumab), aselizumab (aselizumab), atlizumab, bapineuzumab, bevacizumab (bevacizumab), mabuzumab (bivatuzumab mertansine), mocatuzumab (cantuzumab mertansine), sibuzumab (ceduzumab), certuzumab (cetuzumab), seduzumab (cetuzumab), ciduzumab (certuzumab), cidufuzumab, ciduzumab, daclizumab (daclizumab), eculizumab (efuzumab), epratuzumab (epatuzumab), epratuzumab (erbuzumab), panzeuzumab (feruzumab), aryltumumab (givintuzumab), aprezumab (epuzumab), epruzumab (epuzumab), rituzumab (erbuzumab), trastuzumab (rituzumab), rituzumab (zerumab), rituzumab (zerumab (rituzumab), or (rituzumab), or (rituzumab), or the like (rituzumab), or the like (rituzumab), or, Paclobutrazuzumab (paclobutrazumab), pecfuuzumab, petuuzumab, pertuzumab (pertuzumab), pexelizumab (pexelizumab), ralivizumab, ranibizumab (ranibizumab), rayleigh-zumab (relivizumab), rayleigh-mab (relilizumab), resyvizumab (rovelizumab), lullizumab (ruplizumab), sibrotuzumab (sibutrumab), sibutrumab (siplizumab), solozuzumab (solvumab), taclizumab (tracatuzumab), taduzumab (taluzumab), talocuzumab (taluzumab), taluzumab (talilizumab), terteubazumab (tebazumab), toluzumab (tollizumab), urotuzumab (tuzumab), urotuzumab (talluzumab), tuzumab (talluzumab), and tuzumab (tuzumab), tuzumab (tuzumab).

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

The term "package insert" refers to instructions typically included in commercial packages of therapeutic products that contain information regarding the indications, usage, dosage, administration, contraindications, and/or precautions relating to the use of the therapeutic products described above.

The term "chiral" refers to a molecule that has the property that its mirror partners (mirror image partner) are non-overlapping, while the term "achiral" refers to a molecule that can overlap its mirror partners.

The term "stereoisomers" refers to compounds having the same chemical composition but differing in the spatial arrangement of the orientation of the atoms or groups.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography.

"enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The stereochemical definitions and conventional terminology (convention) used herein generally follow the general definitions 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 invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are used to designate the sign of the rotation of plane polarized light by the compound, where (-) or l denotes that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. 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 commonly referred to as enantiomeric mixtures. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which are not optically active.

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

The phrase "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate (tanate), pantothenate (pantoate), bitartrate, ascorbate, succinate, maleate, gentisate (gentisate), fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate (mesylate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)). A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate, succinate or other counterion (inclusion). The counterion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, pharmaceutically acceptable salts may have more than one charged atom in their structure. The plurality of charged atoms can have a plurality of counterions where the plurality of charged atoms are part of a pharmaceutically acceptable salt. Thus, pharmaceutically acceptable salts can have one or more charged atoms and/or one or more counterions.

If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example by treating the free base with an inorganic acid (e.g. hydrochloric, hydrobromic, sulphuric, nitric, methanesulphonic, phosphoric and the like) or with an organic acid (e.g. acetic, trifluoroacetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, oxalic, glycolic, salicylic, a pyranosyl acid (glucuronic) acid such as glucuronic or galacturonic acid, α -hydroxy acid such as citric or tartaric acid, an amino acid such as aspartic or glutamic acid, an aromatic acid such as benzoic or cinnamic acid, a sulphonic acid such as p-toluenesulphonic or ethanesulphonic acid and the like).

If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from: amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine; and inorganic salts obtained from: sodium, calcium, potassium, magnesium, iron, copper, zinc, aluminum, and lithium.

The phrase "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith.

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

The terms "the compounds of the invention" and "the compounds of formula I" include the 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 compounds, or mixtures thereof.

Any formula or structure given herein, including compounds of formula I, is also intended to represent unlabeled forms and isotopically labeled forms of the compounds. Isotopically-labeled compounds have the structure depicted in the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to²H (deuterium D),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I. various isotopically-labelled compounds of the invention, for example those into which a radioactive isotope is incorporated, for example³H、¹³C and¹⁴those of C. The isotopically labeled compounds can be used in metabolic studies, reaction kinetics 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 the radioactive treatment of patients. Deuterium labeled or deuterium substituted compounds of the invention may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford some therapeutic benefit resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.¹⁸The F-labeled compounds are useful for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can be prepared by carrying out the procedures disclosed in the examples and the preparative methods described below in a manner that readily available isotopically labeled reagents are substituted for non-isotopically labeled reagents. In addition, the heavy isotopes, particularly deuterium (i.e.,²h or D) substitution may result in some therapeutic benefit due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements or improved therapeutic index. It is to be understood that deuterium in this context is considered as a substituent in the compound of formula (I). The concentration of the heavier isotopes, in particular deuterium, can be defined by the isotopic enrichment factor (isotopic enrichment factor). In the compounds of the present invention, an atom not specifically designated as a specific isotope is any stable isotope representing the atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is to be understood as hydrogen having a natural abundance isotopic composition. Thus, any atom designated specifically as deuterium (D) in the compounds of the present invention is intended to represent deuterium.

Pyrazolo [3,4-c ] pyridine compounds

The present invention provides pyrazolo [3,4-c ] pyridine compounds of formula I and pharmaceutical formulations thereof, which are useful for treating diseases, conditions, and/or disorders modulated by Pim kinase.

The compounds of formula I have the following structure:

and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

R¹selected from-CN, -CH₂CN、-CH₂CONH₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCONH₂、C₃-C₁₂Carbocyclyl, C₂-C₂₀Heterocyclic group, C₁-C₂₀Heteroaryl, - (C)₁-C₂₀Heteroaryl) - (C)₁-C₂₀Heteroaryl), - (C)₁-C₂₀Heteroaryl) - (C)₂-C₂₀Heterocyclyl), - (C)₁-C₂₀Heteroaryl) -O- (C₂-C₂₀Heterocyclyl), - (C)₁-C₂₀Heteroaryl) -O- (C₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl), - (C)₁-C₂₀Heteroaryl) -NR³-(C₂-C₂₀Heterocyclyl) and- (C)₁-C₂₀Heteroaryl) -NR³-(C₁-C₁₂Alkylene group) - (C₂-C₂₀A heterocyclic group);

R²is selected from C₁-C₁₂Alkyl radical, C₃-C₁₂Carbocyclyl, C₂-C₂₀Heterocyclic group, C₁-C₂₀Heteroaryl group, C₆-C₂₀Aryl, - (C)₆-C₂₀Aryl group) - (C₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene) -NR³(C₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene) -NR³-(C₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl), - (C)₁-C₂₀Heteroaryl) - (C)₁-C₂₀Heteroaryl), - (C)₁-C₂₀Heteroaryl) - (C)₂-C₂₀Heterocyclyl), - (C)₁-C₂₀Heteroaryl) - (C)₂-C₂₀Heterocyclyl) - (C)₂-C₂₀Heterocyclyl), - (C)₁-C₂₀Heteroaryl) -NR³-(C₂-C₂₀Heterocyclyl), - (C)₁-C₂₀Heteroaryl) - (C)₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl), - (C)₁-C₂₀Heteroaryl) -NR³-(C₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl) and- (C)₁-C₂₀Heteroaryl) -NR³-(C₁-C₁₂Alkylene group) - (C₁-C₂₀Heteroaryl);

R³independently selected from H and C₁-C₁₂Alkyl radical, said C₁-C₁₂Alkyl is optionally substituted with F, Cl, CN, -CO₂H、-COCH₃、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-N(CH₃)COCH₃、-NHS(O)₂CH₃、-NHCH₂CH₂NH₂、-NHCH₂CH₂CH₂NH₂、-NHCH₂CH₂CH₂CH₂NH₂、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCH₂CH₂OCH₃、-OCH₂CH₂NH₂、-S(O)₂N(CH₃)₂、-SCH₃and-S (O)₂CH₃；

Wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-CH₂CH(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-CH₂CH₂NH₂、-CH₂CHCH₂NH₂、-CH₂CHCH₂CH₂NH₂、-CH₂CH(CH₃)NH₂、-CH₂CONH₂、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH(OH)CH(CH₃)₂、-C(CH₃)₂CH₂OH、-CH₂C(CH₃)₂OH、-CH₂CH₂SO₂CH₃、-CN、-CF₃、-CO₂H、-COCH₃、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-N(CH₃)COCH₃、-NHS(O)₂CH₃、-NHCH₂CH₂NH₂、-NHCH₂CH₂CH₂NH₂、-NHCH₂CH₂CH₂CH₂NH₂、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCH₂CH₂OCH₃、-OCH₂CH₂NH₂、-S(O)₂N(CH₃)₂、-SCH₃、-CH₂OCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-ylethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino.

Exemplary embodiments of compounds of formula I include those wherein R¹Is C₁-C₂₀A heteroaryl group.

Exemplary embodiments of compounds of formula I include those wherein R¹Selected from the following structures:

wherein the wavy line indicates the site of attachment.

Exemplary embodiments of compounds of formula I include those wherein R¹Selected from-CN, -CH₂CN、-CH₂CONH₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂and-NHCONH₂。

Exemplary embodiments of compounds of formula I include those wherein R²Is C₁-C₂₀A heteroaryl group.

Exemplary embodiments of compounds of formula I include those wherein R²Is- (C)₁-C₂₀Heteroaryl) - (C)₂-C₂₀A heterocyclic group).

Exemplary embodiments of compounds of formula I include those wherein R²Selected from the following structures:

wherein the wavy line indicates the site of ligation; and is

R⁴Selected from F, Cl, Br, I, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-CH₂CH(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-CH₂CH₂NH₂、-CH₂CHCH₂NH₂、-CH₂CHCH₂CH₂NH₂、-CH₂CH(CH₃)NH₂、-CH₂CONH₂、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH(OH)CH(CH₃)₂、-C(CH₃)₂CH₂OH、-CH₂C(CH₃)₂OH、-CH₂CH₂SO₂CH₃、-CN、-CF₃、-CO₂H、-COCH₃、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-N(CH₃)COCH₃、-NHS(O)₂CH₃、-NHCH₂CH₂NH₂、-NHCH₂CH₂CH₂NH₂、-NHCH₂CH₂CH₂CH₂NH₂、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCH₂CH₂OCH₃、-OCH₂CH₂NH₂、-S(O)₂N(CH₃)₂、-SCH₃、-CH₂OCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-ylethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and is

_nIs 0, 1 or 2.

Exemplary embodiments of the compounds of formula I include compounds having the structure of formula Ia:

wherein R is⁴Selected from F, Cl, Br, I, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-CH₂CH(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-CH₂CH₂NH₂、-CH₂CHCH₂NH₂、-CH₂CHCH₂CH₂NH₂、-CH₂CH(CH₃)NH₂、-CH₂CONH₂、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH(OH)CH(CH₃)₂、-C(CH₃)₂CH₂OH、-CH₂C(CH₃)₂OH、-CH₂CH₂SO₂CH₃、-CN、-CF₃、-CO₂H、-COCH₃、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-N(CH₃)COCH₃、-NHS(O)₂CH₃、-NHCH₂CH₂NH₂、-NHCH₂CH₂CH₂NH₂、-NHCH₂CH₂CH₂CH₂NH₂、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCH₂CH₂OCH₃、-OCH₂CH₂NH₂、-S(O)₂N(CH₃)₂、-SCH₃、-CH₂OCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-ylethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and is

n is 0, 1 or 2.

Exemplary embodiments of the compounds of formula I include compounds having the structure of formula Ib:

wherein R is³Selected from H, C₃-C₁₂Carbocyclyl and C₁-C₁₂Alkyl radical, wherein carbonCyclyl and alkyl optionally substituted with F, Cl, CN, -CO₂H、-COCH₃、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-N(CH₃)COCH₃、-NHS(O)₂CH₃、-NHCH₂CH₂NH₂、-NHCH₂CH₂CH₂NH₂、-NHCH₂CH₂CH₂CH₂NH₂、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCH₂CH₂OCH₃、-OCH₂CH₂NH₂、-S(O)₂N(CH₃)₂、-SCH₃and-S (O)₂CH₃(ii) a And is

n is 0, 1 or 2.

Exemplary embodiments of the compounds of formula I include compounds having the structure of formula Ic:

n is 0, 1 or 2.

Biological evaluation

It is possible to determine the Pim kinase activity of the compounds of formula I by a number of direct and indirect assays. Certain exemplary compounds described herein were assayed for Pim kinase (Pim-1, Pim-2, and Pim-3 subtypes) binding activity (example 901) and in vitro activity on tumor cells (example 902). P of certain exemplary Compounds of the inventionim binding Activity IC₅₀The value is less than about 1 micromolar (μ M). Tumor cell-based Activity EC of certain Compounds of the invention₅₀The value is less than about 1 micromolar (μ M).

Exemplary compounds of formula I in table 1 were prepared, characterized, and tested for Pim kinase inhibition according to the methods of the present invention, and have the following structure and corresponding names (ChemBioDraw Ultra, version11.0, Cambridge soft corp., Cambridge MA).

TABLE 1.

Table 2.

The compounds of the invention were tested for their ability to inhibit Pim kinase activity and for their biological effect on growing cells as described below in examples 901 and 902. Ki/IC in the assays described in examples 901 and 902₅₀/EC₅₀Less than 1 μ M of a compound of formula I may be used therapeutically as a Pim kinase inhibitor (Pim-1, Pim-2 and/or Pim-3).

The present invention includes compositions (e.g., pharmaceutical compositions) comprising a compound of formula I and/or solvates, hydrates, and/or salts thereof, and a carrier (pharmaceutically acceptable carrier). The invention also includes compositions (e.g., pharmaceutical compositions) comprising a compound of formula I and/or solvates, hydrates, and/or salts thereof, and a carrier (pharmaceutically acceptable carrier), further comprising another chemotherapeutic agent (such as those described herein). The compositions of the invention are useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder (such as cancer) in a mammal (e.g., a human). For example, the compounds and compositions of the present invention are useful 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).

The present invention includes a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder, such as 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 solvates, hydrates, and/or salts thereof, or compositions thereof. For example, the present invention includes a method of 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 solvates, hydrates, and/or salts thereof or compositions thereof.

The present invention includes methods of inhibiting abnormal cell growth or treating a hyperproliferative disorder, such as 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 solvates, hydrates, and/or salts thereof, or compositions thereof, in combination with another chemotherapeutic agent, such as those described herein. For example, the present invention includes a method of 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 solvates, hydrates, and/or salts thereof or a composition thereof in combination with another chemotherapeutic agent (such as those described herein).

The present invention includes methods 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 solvates, hydrates, and/or salts thereof, or compositions thereof, alone or in combination with another chemotherapeutic agent, such as anti-B-cell antibody therapy (e.g., Rituxan and/or Dacetuzumab), gemcitabine, corticosteroids (e.g., prednisolone and/or dexamethasone), mixed chemotherapies (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and/or ICE (ifosfamide), cyclophosphamide (cytoxan), etoposide), a combination of biologicals and chemotherapies (e.g., Rituxan-ICE, dactuzumab-Rituxan, Rituxan-and/or dexamethasone), alone or in combination with another chemotherapeutic agent, or a combination thereof, R-Gem and/or D-R-Gem), Akt inhibitors, PI3K inhibitors (e.g., GDC-0941(Genentech) and/or GDC-0980(Genentech)), rapamycin, MEK inhibitors (GDC-0973), Bcl-2 inhibitors (ABT-263), and lymphoma-directed antibody drug conjugates (e.g., anti-CD 22 antibody drug conjugates, including but not limited to anti-CD 22-vcMAE, and/or anti-CD 79 b-antibody drug conjugates, including but not limited to anti-CD 79 b-vcMAE).

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 solvates, hydrates, and/or salts thereof, or compositions thereof, alone or in combination with another chemotherapeutic agent, such as melphalan, thalidomide (thalidomide), lenalidomide (lemidomide), pomalidomide (pomolidamide), corticosteroids, dexamethasone, 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 solvates, hydrates, and/or salts thereof, or compositions thereof, alone or in combination with another chemotherapeutic agent, such as cytarabine (araC), anthracyclines (e.g., daunorubicin and/or idarubicin), anti-myeloid antibody therapy (e.g., SGN-33), anti-myeloid antibody-drug conjugates (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 solvates, hydrates, and/or salts thereof, or compositions thereof, alone or in combination with another chemotherapeutic agent, such as fludarabine, cyclophosphamide, anti-B-cell antibody therapy (e.g., Rituxan and/or daclizumab).

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 solvates, hydrates and/or salts thereof or compositions thereof, alone or in combination with another chemotherapeutic agent, such as a BCR-abl inhibitor (e.g., imatinib (imatinib), nilotinib (nilotinib) and/or dasatinib).

The present invention includes methods of treating Myelodysplastic Diseases (MDS) and myeloproliferative diseases (which include Polycythemia Vera (PV), Essential Thrombocythemia (ET) or Myelofibrosis (MF)) in a mammal (e.g., a human) comprising administering to the mammal a therapeutically effective amount of a compound of formula I and/or solvates, hydrates and/or salts thereof or compositions thereof, alone or in combination.

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

Administration of the compounds of the present invention (hereinafter "active compounds") may be accomplished by any method capable of delivering the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (which includes intravenous, subcutaneous, intramuscular, intravascular or infusion), topical administration, inhalation administration and rectal administration.

The amount of active compound administered will depend on the subject to be treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound (dispersion), the judgment of the attending physician (dispersion). However, an effective dosage range for a single or divided dosage form is from about 0.001 to about 100mg/kg body weight/day, preferably from about 1 to about 35 mg/kg/day. For a 70kg person, this amount will correspond to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several small doses for administration throughout the 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 combination therapy may be achieved by administering the individual components of the therapy simultaneously, sequentially or separately.

The pharmaceutical compositions may be, for example, in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions for parenteral injection, suspensions, such as sterile solutions, suspensions, or emulsions for topical administration, such as ointments or creams, or for rectal administration, such as suppositories. The pharmaceutical compositions may be in unit dosage forms suitable for the individual administration of precise dosages. The pharmaceutical compositions will contain conventional pharmaceutical carriers or excipients and the compounds of the present invention as active ingredients. In addition, it may contain other medicinal or pharmaceutical agents, carriers, excipients and the like.

Exemplary parenteral administration forms include solutions or suspensions of the compounds of formula I in an inert aqueous solution, for example, an aqueous solution of propylene glycol or glucose. Such dosage forms may be suitably buffered if desired.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, and the like, if desired. For oral administration, therefore, tablets containing various excipients, such as citric acid, may be employed with various disintegrants such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used for tableting. Solid compositions of a similar type may also be used in the form of soft and hard filled gelatin capsules. Thus, preferred materials include lactose (lactose) or lactose (milk sugar) and high molecular weight polyethylene glycols. When an aqueous suspension or elixir is desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and emulsifying or suspending agents, if desired, together with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.

Methods for preparing various pharmaceutical compositions with such amounts of active compounds are known or will be apparent to those skilled in the art. See, for example, Remington's pharmaceutical Sciences, MackPubristing Company, Ester, Pa.,15.sup.th Edition (1975).

Administration of Compounds of formula I

The compounds of formula I of the present invention may be administered by any route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. For local immunosuppressive therapy, the compound may be administered by administration to the injury area (including perfusion or contacting the graft with the inhibitor prior to transplantation). It will be appreciated that the preferred route may vary with, for example, the conditions of the receptor. When the compound is administered orally, it can be formulated with pharmaceutically acceptable carriers or excipients into pills, capsules, tablets, and the like. When the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and in unit dose injectable form as described in detail below.

The dose for treating a human patient may be from about 10mg to about 1000 mg of a compound of formula I. A typical dose may be from about 100mg to about 300mg of the compound. The dose may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may affect the dosage and dosing regimen. When administered orally, the pills, capsules or tablets may be taken daily, or less frequently, over a specified period of time. The regimen may be repeated for a plurality of treatment cycles.

Methods of treatment using compounds of formula I

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

Cancers that may be treated according to the methods of the invention include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract (genitourinary tract) cancer, esophageal cancer, larynx (larynx) cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma (keratanchoma), lung cancer, epidermoid carcinoma (epitopic carcinoma), large cell carcinoma (large cell carcinoma), non-small cell lung cancer (NSCLC), small cell lung cancer, lung adenocarcinoma (lung adenocarinoma), bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma (adenocarinoma), thyroid cancer, follicular carcinoma (cystic carcinoma), undifferentiated carcinoma (undifferentiated carcinoma), papillary carcinoma (papillary carcinoma), seminoma (seminoma), melanoma, bladder carcinoma, liver carcinoma (renal carcinoma), renal carcinoma (renal carcinoma), lymphoid conditions (renal cancer), myeloid disorder), lymphoid conditions of the human tract (lymphoblastoid), and renal cancer (renal cancer), and cervical cancer, Hair cell carcinoma, oral and pharyngeal (oral) carcinoma, lip carcinoma, tongue carcinoma, mouth carcinoma (mouth), pharyngeal carcinoma, small intestine carcinoma, colorectal carcinoma, large intestine carcinoma, rectal carcinoma, brain carcinoma and central nervous system carcinoma and hodgkin's lymphoma and leukemia.

Another aspect of the invention provides a compound of the invention for use in treating a disease or condition described herein in a mammal, such as a human, suffering from such a disease or condition. The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of the diseases and conditions described herein in a warm-blooded animal such as man, suffering from such conditions.

Pharmaceutical preparation

For the use of the compounds of formula I for the therapeutic treatment (including prophylactic treatment) of mammals, including humans, they are generally formulated as pharmaceutical compositions in accordance with standard pharmaceutical practice. According to this aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention in association with a pharmaceutically acceptable diluent or carrier.

Typical formulations are prepared by mixing a compound of formula I with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the mode and purpose for which the compounds of the present invention are to be employed. Solvents are generally selected based on the solvents considered safe for administration to mammals by those skilled in the art (GRAS). Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulation may also include one or more of the following: buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers (opacifying agents), glidants, processing aids, colorants, sweeteners, fragrances, flavors, and other known additives that provide a superior appearance to a drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or aid in the manufacture of a pharmaceutical product (i.e., a drug).

The formulations may be prepared using conventional dissolution and mixing operations. For example, a bulk pharmaceutical product (i.e., a stabilized form of a compound of the invention or a compound of formula I (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-described excipients. The compounds of the present invention are typically formulated into pharmaceutical dosage forms that provide readily controllable dosages of the drug and enable patient compliance with a given regimen.

Depending on the method used to administer the drug, the pharmaceutical composition (or formulation) for administration may be packaged in a variety of ways. Generally, articles for dispensing include a container having a pharmaceutical formulation in a suitable form stored therein. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets (sachets), ampoules, plastic bags, metal cylinders and the like. The container may also include a tamper-proof device (tag-proof) to prevent inadvertent access to the contents of the package. Further, there is a label on the container that describes the contents of the container. The label may also include appropriate precautions.

Pharmaceutical formulations of the compounds of the present invention may be prepared for a variety of routes and types of administration. For example, a compound of formula I having a desired purity may be optionally mixed with a pharmaceutically acceptable diluent, carrier, excipient or stabilizer (Remington's pharmaceutical Sciences (1980)16th edition, Osol, a.ed.) in the form of a lyophilized formulation, a finely divided powder or an aqueous solution. The formulation can be carried out as follows: mixed at ambient temperature, at an appropriate pH, and in an appropriate purity, with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosages and concentrations employed. The pH of the formulation depends primarily on the particular use and concentration of the compound, but can range from about 3 to about 8. Formulations with a pH of 5 in acetate buffer are suitable embodiments.

The compounds of the invention used herein are preferably sterile. In particular, formulations for in vivo administration must be sterile. The sterilization is readily accomplished by filtration through sterile filtration membranes.

The compounds may generally be stored as solid compositions, lyophilized formulations or aqueous solutions.

The pharmaceutical compositions of the present invention comprising a compound of formula I will be formulated, dosed and administered in a manner consistent with good medical practice (i.e., amount, concentration, schedule, procedure, vehicle and route of administration). Factors considered in this context include the particular condition being treated, the particular 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. A "therapeutically effective amount" of a compound administered will be governed by such considerations and is the minimum amount necessary to prevent, ameliorate or treat a condition mediated by coagulation factors. The amount is preferably below an amount that is toxic to the host or that renders the host significantly more prone to bleeding.

As a general proposition, the initial pharmaceutically effective amount of a compound of formula I per dose administered parenterally is about 0.01-100 mg/kg daily, i.e. about 0.1 to 20 mg/kg body weight of the patient, with a typical initial range of compounds used being 0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients and stability are nontoxic to recipients at the dosages and concentrations employed, and include buffering agents such as phosphates, citrates and other organic acids; antioxidants, including ascorbic acid and methionine (methionine); preservatives (e.g. octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol 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, e.g. TWEEN^TM、PLURONICS^TMOr polyethylene glycol (PEG). The active pharmaceutical ingredient can also be embedded in the pass exampleSuch as coacervation techniques or microcapsules prepared by interfacial polymerization, for example hydroxymethylcellulose or gelatin microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules or in macroemulsions (macroemulsions). The technique is disclosed in Remington's Pharmaceutical Sciences16th edition, Osol, A.Ed. (1980).

Sustained release formulations of the compounds of formula I may be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I, which matrices are present in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactides (US3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT^TM(injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D- (-) -3-hydroxybutyric acid.

The formulations include those suitable for the routes of administration detailed herein. The formulations may suitably be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally described in Remington's pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The process comprises the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients (access ingredients). Typically the formulation is prepared as follows: the active ingredient is homogeneously and intimately associated with liquid carriers or finely divided solid carriers or both, and then, if necessary, the product is shaped.

Formulations of a compound of formula I suitable for oral administration may 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 may be prepared as follows: the active ingredient in free-flowing form (e.g., powder or granules) and, optionally, admixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant, is compacted in a suitable machine. Molded tablets may be prepared as follows: the mixture of powdered active ingredient moistened with an inert liquid diluent is moulded in a suitable machine. The tablets may optionally be coated or scored and optionally formulated to provide slow or controlled release of the active ingredient therefrom.

Tablets, troches (troche), 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. Formulations of compounds of formula I intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions which may contain one or more agents, including sweeteners, flavoring agents, colorants and preservatives, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic physiologically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents (granulating and disintegrating agents), such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a timing delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

For the treatment of the eye or other external tissues such as mouth and skin, the formulations are preferably applied as a topical ointment (ointment) or cream (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 either a paraffinic (parafinic) or a 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 polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol, and polyethylene glycols (including PEG400) and mixtures of such alcohols. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin permeation enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsions of the invention may be constituted by known ingredients in a known manner. While the phase may comprise emulsifiers alone, it is contemplated that it comprises a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier may be included as well as a lipophilic emulsifier as a stabilizer. It also preferably includes both oil and fat. At the same time, the emulsifiers, with or without stabilizers, constitute the so-called emulsifying waxes (emulsifying wax), which, together with oils and fats, constitute the so-called emulsifying ointment base which forms the oily dispersed phase of the ointment formulation. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include60、80. Stearyl/cetyl alcohol (cetostearyl alcohol), benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.

Aqueous suspensions of the compounds of formula I contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, as well as dispersing or wetting agents (dispersing or wetting agents) such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose or saccharin.

Pharmaceutical compositions of the compounds of formula I may be presented as sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspension formulations. This suspension may be formulated according to the methods known in the art using suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in1, 3-butanediol, or as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils (sterile fixed oils) are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time release formulation intended for oral administration to humans may contain from about 1 to 1000 milligrams of active substance in admixture with a suitable and convenient amount of a carrier material which may comprise from about 5 to about 95% of the total composition (weight: weight). The pharmaceutical composition can be prepared to provide an amount that is readily measured upon administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μ g of active ingredient per ml of solution, so that an appropriate volume of infusion occurs at a rate of about 30 ml/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 wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The concentration of active ingredient present in the formulation is preferably from about 0.5 to 20% w/w, for example from about 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges (lozenes) comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; lozenges (pastilles) comprising the active ingredient in an inert base (such as gelatin and glycerin, or sucrose and acacia); and mouthwashes comprising 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 a particle size, for example, of from 0.1 to 500 microns (including between 0.1 and 500 microns, in increments of particle size, for example, of 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nasal passage or by oral inhalation, in order to reach the alveolar sacs (alveolars sacs). Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds heretofore used in the treatment or prevention of the conditions described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons (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.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules or vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, immediately prior to use. Extemporaneous injection solutions (injections solutions and suspensions) and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit sub-dose as herein above described, or an appropriate fraction thereof, of the active ingredient.

The invention also provides a veterinary composition (veterinary composition) whereby it contains at least one active ingredient as defined above together with a veterinary carrier. Veterinary carriers are substances used for the purpose of administering the composition and may be solid, liquid or gaseous substances which are either inert or acceptable in the veterinary art and which are compatible with the active ingredient. These veterinary combinations may be administered parenterally, orally or by any other desired route.

Combination therapy

The compounds of formula I may be used alone or in combination with other therapeutic agents to treat diseases or disorders described herein, such as hyperproliferative disorders (e.g., cancer). In certain embodiments, a compound of formula I is used in combination therapy with a second compound having anti-hyperproliferative properties or for the treatment of a hyperproliferative disorder (e.g., cancer), in a pharmaceutical combination formulation or dosage regimen. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activity to the compound of formula I, such that they do not adversely affect each other. The amount of the compound present in the combination is suitably an amount effective for the intended purpose. In one embodiment, the compositions of the invention comprise a compound of formula I in combination with a chemotherapeutic agent as described herein.

The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the compositions may be administered in two or more administrations. Combination administration includes simultaneous administration using separate formulations or a single pharmaceutical formulation, and sequential administration in either order, wherein it is preferred that there be a period of time during which both (or all) active agents exert their biological activities simultaneously.

Suitable dosages for any of the above-mentioned co-administered drugs are those presently used and may be reduced due to the combined effect (synergy) of the newly identified drug and the other chemotherapeutic agent or treatment.

Combination therapy can provide "synergy" and "synergy", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects that would result from the separate use of these compounds. When the active ingredients are: (1) when formulated simultaneously and administered or delivered simultaneously in a combined unit dose formulation; (2) when delivered alternately or in parallel as separate formulations; or (3) when administered by some other regimen, a synergistic effect may be achieved. When delivered in alternation therapy, a synergistic effect may be achieved when the compounds are administered or delivered sequentially, e.g. by separate injections in separate syringes, by separate pills or capsules or by separate infusions. Generally, an effective dose of each active ingredient is administered sequentially (i.e., sequentially) during alternation therapy, while in combination therapy, an effective dose of two or more active ingredients are administered together.

In a particular embodiment of anticancer therapy, a compound of formula I, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, may be used in combination with other chemotherapeutic, hormonal, or antibody drugs (e.g., the drugs described herein), or in combination with surgical treatment and radiation therapy. The combination therapy according to the present invention thus comprises the administration of at least one compound of formula I or a stereoisomer, geometric isomer, tautomer, solvate, metabolite or pharmaceutically acceptable salt or prodrug thereof, as well as the use of at least one other cancer treatment method. The amounts of the compound of formula I and the other pharmaceutically active chemotherapeutic agent and the associated time period of administration will be selected so as to achieve the desired therapeutic effect in combination.

Metabolites of compounds of formula I

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

Metabolites are typically identified as follows: preparation of a radiolabelled compound of the invention (for example,¹⁴c or³H) Isotopes, which are administered parenterally to an animal, such as a rat, mouse, guinea pig, monkey, or to a human in detectable doses (e.g., greater than about 0.5 mg/kg), allowed sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and then their conversion products are separated from urine, blood samples, or other biological samples. These products are easy to isolate because they are labelled (others are isolated by using antibodies that are capable of binding to epitopes that survive in the metabolite). Metabolite structure is determined in a conventional manner, e.g. by MS, LC/MS or NMR analysis. In general, analysis of metabolites is accomplished in the same manner as in conventional drug metabolism studies well known to those skilled in the art. Said metabolites, as long as they are not otherwise present in the body, are useful in diagnostic assays for therapeutic dosages of the compounds of the present invention.

Article of manufacture

In another embodiment of the invention, there are provided articles of manufacture and "kits" containing materials useful for the treatment of the diseases and conditions described above. In one embodiment, the kit comprises a container comprising a compound of formula I. 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 packages of therapeutic products containing information regarding the indications, usage, dosage, administration, contraindications and/or precautions relating to the use of the therapeutic product. Suitable containers include, for example, bottles, vials, syringes, blister packs (etc.). The container may be formed from a variety of materials, such as glass or plastic. The container may contain a compound of formula I or II or a formulation thereof effective to treat the condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of formula I. The label or package insert indicates that the composition is for use in treating a selected condition, such as cancer. Further, the label or package insert may indicate that the patient to be treated is a patient suffering from a condition such as a hyperproliferative condition, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotrauma disease or event. In one embodiment, the label or package insert indicates that compositions comprising compounds of formula I are useful for treating conditions resulting from abnormal cell growth. The label or package insert may also indicate that the composition may be used to treat other conditions. Alternatively or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. The kit may also include other materials desirable from a commercial and user standpoint, 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 a kit comprises a first composition comprising 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 such formulation.

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 kits preferably comprise a plurality of unit doses. The kit may include a dosage card for the purpose of the intended use. One 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 dose forms. If desired, a memory aid (memory aid) may be provided, which may be in the form of, for example, numbers, letters or other indicia, or with a calendar insert, which specifies the number of days in a treatment schedule during which the dose may be administered.

According to one embodiment, a kit may comprise (a) a first container having a compound of formula I therein; and optionally (b) a second container having a second pharmaceutical formulation therein, wherein the second pharmaceutical formulation comprises a second compound having anti-hyperproliferative activity. Alternatively or additionally, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may also include other substances desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

In certain other embodiments of kits comprising a composition of formula I and a second therapeutic agent, the kit may comprise containers for holding separate compositions, such as separate bottles or separate foil packets, however, separate compositions may also be held in a single, undivided container. Typically, the kit contains instructions for administering the separate components. The kit form 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 desired by the attending physician.

Preparation of Compounds of formula I

The compounds of formula I can be synthesized by synthetic routes that include methods analogous to those well known in the chemical arts, particularly in light of the description contained herein, as well as methods directed to such other heterocycles: comparative Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier,1997, e.g. Volume3, 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. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., by Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-23, Wiley, N.Y. (1967. d. 2006.), or Bellsteins Handbuch der organischen Chemie,4, of autofl. ed. Springer-Verlag, Berlin, including the procedures generally described in the appendix (also available via the Beilstein Web database)).

Synthetic chemical transformations and protecting group methodologies (protection and deprotection) and necessary reagents and intermediates useful in the Synthesis of 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 P.G.M.Wuts, protective groups in Organic Synthesis,3^rdEd., John Wiley and Sons (1999); and L.Patatte, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent versions thereof.

The compounds of formula I may be prepared alone or as a library of compounds comprising at least 2, for example 5 to 1,000 or 10 to 100 compounds. Libraries of compounds of formula I can be prepared by procedures known to those skilled in the art, using solution-phase or solid-phase chemistry, by combinatorial "split and mix" routes, or by multiple parallel syntheses. Thus according to another method of the present invention there is provided a library of compounds comprising at least 2 compounds or pharmaceutically acceptable salts thereof.

General procedures 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 may be used to synthesize the compounds of formula I. Although specific starting materials and reagents are described and discussed in the figures, general procedures, and examples, other starting materials and reagents can be readily substituted 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 in light of this disclosure using conventional chemistry well known to those skilled in the art.

Protection of remote functional groups (e.g., primary or secondary amines) of intermediates may be necessary in the preparation of compounds of formula I. The need for such protection will vary with the nature of the remote functionality and the conditions of the preparation process. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting Groups and their use, see t.w. greene, Protective Groups in organic synthesis, John Wiley & Sons, New York, 1991.

Separation method

In the process for preparing the compounds of the formula I, it may be advantageous to separate the reaction products from one another and/or from the starting materials. The desired product in each step or steps is isolated and/or purified to the desired degree of homogeneity by techniques common in the art. Typically the separation involves heterogeneous extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography may involve any number of methods, including, for example: reverse phase and normal phase; size exclusion (size exclusion); ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated Moving Bed (SMB) and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques.

Another class of separation methods involves treating the mixture with selected reagents to combine with or separate the desired product, unreacted starting materials, reaction byproducts, etc. The reagent comprises an adsorbent (adsorbent) or absorbent (adsorbent), such as activated carbon, molecular sieves, ion exchange media, and the like. 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 exchange reagent (LIX), or the like. The choice of an appropriate separation method depends on the nature of the substances involved. For example, boiling point and molecular weight (in distillation and sublimation), presence or absence of polar functional groups (in chromatography), stability of the material in acidic and basic media (in heterogeneous extraction), and the like.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences, by methods well known to those skilled in the art (e.g., chromatography and/or fractional crystallization). Enantiomers can be separated by: the enantiomeric mixtures are converted into diastereomeric mixtures by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), the diastereomers are separated, and the individual diastereomers are then converted (e.g., hydrolyzed) into the corresponding pure enantiomers. In addition, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryl) and are considered part of the present invention. Enantiomers can also be separated by using a chiral HPLC column.

A single stereoisomer, e.g., an enantiomer substantially free of its stereoisomer, can be obtained by: the racemic mixture is resolved with an optically active resolving agent using methods such as diastereomer formation (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-. The racemic mixture of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) ionic diastereomeric salts with chiral compounds and subsequent separation by fractional crystallization or other means, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers and subsequent conversion to pure stereoisomers, and (3) direct separation of 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 the case of process (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases such as brucine (brucine), quinine, ephedrine, brucine (strychnine), α -methyl- β -phenylethylamine (amphetamine), etc. with asymmetric compounds with acidic functionalities such as carboxylic and sulfonic acids.

Alternatively, by process (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form diastereomeric pairs (Eliel, E.and Wilen, S. "Stereochemistry of organic Compounds", John Wiley&Sons, inc.,1994, p.322). diastereoisomeric compounds may be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing agent such as a menthyl derivative, followed by separation of the diastereomers, followed by hydrolysis to give the pure or enriched enantiomer¹H NMR spectrum (Jacob III.J.org.chem. (1982)47: 4165). The stable diastereoisomers of atropisomeric compounds can be separated and isolated by normal and reverse phase chromatography following the procedure for separating the atropisomeric naphthyl-isoquinoline (WO 1996/15111). By method (3), racemic mixtures of the two enantiomers can be separated by Chromatography using a Chiral stationary phase ("Chiral Liquid Chromatography" (1989) W.J.Lough, Ed., Chapman and Hall, New York; Okamoto, J.Chromatogr., 1990)513: 375-.Enriched or purified enantiomers can be distinguished by methods for distinguishing other chiral molecules with asymmetric carbon atoms, such as optical rotation or circular dichroism.

General preparation method

Scheme 1 shows a general synthesis of compound 13. 4-R can be prepared by 3-step synthesis starting from 2-bromo-4-methyl-5-nitropyridine 1¹Substituted 6-azaindazoles 5. Placement of R by Suzuki reaction¹Group, followed by reduction of the nitro group, then formation of an oxidized indazole ring, provides compound 5. Subsequent iodination and SEM protection gave a mixture of regioisomers 7a and 8 a. Other suitable protecting groups such as tetrahydropyranyl, Boc groups, etc. may be alternatives to SEM groups. R²The addition of groups can be achieved by the following methods: direct Suzuki, Buchwald or Goldberg reactions, or Stille reactions starting from tin reagents 7b and 8 b. R can be carried out by direct SnAr or Buchwald reaction²Further modification of the group. Compound 13 can be prepared from a mixture of 11 and 12 by using an acidic, basic or fluorinated reagent in a suitable solvent.

Scheme 1

Scheme 2 describes the general synthesis of compound 20. 5-bromo-6-azaindazole 15 can be prepared from 2-bromo-4-methyl-5-aminopyridine 14 by oxidative cyclization, as described in J.chem.Soc., Perkin Trans.1, (1980), 2398-. Compound 17 can be prepared by iodination of compound 15 followed by tetrahydropyran protection. Compound 18 can be synthesized regioselectively from compound 17 by Suzuki, Stille or Buchwald reactions. Compound 19 can be prepared from compound 18 by direct SnAr, Suzuki or Buchwald reactions. Compound 20 can be prepared from compound 19 by acid-mediated removal of the tetrahydropyran protecting group. Other optional protecting groups such as SEM, Boc, etc. may be used in place of tetrahydropyran.

Scheme 2

Examples

Intermediates

Example 14-methyl-5-nitro-2, 3' -bipyridine

To a solution of 2-bromo-4-methyl-5-nitropyridine (217g,1mol) in DMF (2000mL) was added Pd (dppf) Cl₂(5g)、Na₂CO₃And pyridin-3-ylboronic acid (147g,1.2 mol). The mixture was stirred at 100 ℃ for 6 hours under argon. After cooling down, the solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (mobile phase: EA: PE =1:1) to give 4-methyl-5-nitro-2, 3' -bipyridine (172g, 80%).

Example 24-methyl-2, 3' -bipyridin-5-amine

A mixture of 4-methyl-5-nitro-2, 3' -bipyridine (215g,1mol), Pd/C (10g,10%) and MeOH (1000mL) was stirred at room temperature under 10atm of hydrogen for 16 h. After the reaction, the mixture was filtered. The filtrate was evaporated under reduced pressure to give 4-methyl-2, 3' -bipyridin-5-amine as a yellow solid (152g, 82%).

Example 35- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine compound

To a solution of 4-methyl-2, 3' -bipyridin-5-amine (185g,1mol) in AcOH (27L) was added NaNO₂Aqueous solution (82g,1.2mol,100 mL). The mixture was stirred at room temperature for 16 hours. After the reaction, the solvent was removed, and then the residue was purified by silica gel column chromatography (mobile phase: EA: PE =1:1) to give 5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine as a yellow solid (98g, 50%).

Example 43-iodo-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine compound

Reacting 5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine (196g,1mol) was dissolved in 1000mL DMF. KOH (112g,2mol) was added. After stirring for 30 minutes, I is added₂(303g,1.2 mol). The mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was washed with saturated Na₂S₂O₅The aqueous solution was quenched, followed by addition of water (5L). The solid was filtered and washed with water to give 3-iodo-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine as a yellow solid (290g, 90%).

Example 53-iodo-5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine and 3-iodo-5- (pyridin-3-yl) -2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-pyrazolo [3,4-c]Pyridine.

To 3-iodo-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine (100g,0.31mol) in CH₂Cl₂(500mL) was added DIPEA (120g,0.93mol) and SEM-Cl (77g,0.46 mol). The mixture was stirred at room temperature for 1 hour. After removal of the solvent, the residue was purified by silica gel column chromatography (mobile phase: EA: PE =1:1) to give 3-iodo-5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine and 3-iodo-5- (pyridin-3-yl) -2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-pyrazolo [3,4-c]Mixture of pyridines as white solid (50g, 35%).

Example 65-bromo-1H-pyrazolo [3,4-c]Pyridine compound

To a solution of 6-bromo-4-methylpyridin-3-amine (7.76g,0.0415mol) in acetic acid (412.8mL,7.260mol) was added 4.0mL of an aqueous solution of sodium nitrite (2.87g,0.0416mol) (bioorg. Med. chem.15(2007) 2441-2452). The reaction mixture was stirred for 15 minutes and allowed to stand at room temperature (rt) for 2 days (d). The reaction mixture was concentrated and diluted with EtOAc, then NaHCO₃And a brine wash. Mixing the organic layer with Na₂SO₄Dried, filtered and concentrated. The crude product was purified by chromatography (DCM/MeOH, eluting with 5% MeOH) to give 5-bromo-1H-pyrazolo [3, 4-c)]Pyridine (79.1% yield).

Example 75-bromo-3-iodo-1H-pyrazolo [3,4-c]Pyridine compound

Will be in DMF (1.2)L) comprises 5-bromo-1H-pyrazolo [3,4-c]A solution of pyridine (168.0g,848.4mmol) and NIS (286.3g,1.27mol) was stirred at room temperature. The reaction mixture was poured into water and then filtered. The solid was washed with water and 5% Na₂S₂O₅And (6) washing. The crude product was dried under high vacuum overnight to give 5-bromo-3-iodo-1H-pyrazolo [3,4-c]Pyridine.

Example 85-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine compound

To a solution of bromo-iodo-azaindazole (50g,154.36mmol) in dichloromethane (500mL) was added dihydropyran (28.57g,339.59mmol) and TsOH (2.06g,10.81 mmol). The reaction mixture was stirred at 20 ℃ overnight. LCMS showed the reaction was complete, then the reaction mixture was taken up with saturated NaHCO₃And (4) quenching. The organic layer was dried and concentrated to give a crude product, which was purified by silica gel column chromatography to give 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine (40g,71%) as a light yellow solid.

Example 9Bromo-3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine compound

A mixture of 2.0g (4.90mmol) of 5-bromo-3-iodo-1H-pyrazolo [3,4-c ] pyridine, 2.0g (5.17mmol) of 2-fluoro-6-tributylstannyl-pyridine and 566.4mg (0.4902mmol) of tetrakis (triphenylphosphine) palladium (0) in 45ml of toluene is degassed and heated at 120 ℃ for 24 hours. The clear solution was concentrated in vacuo; the crystalline residue is mixed with 30ml of diethyl ether and stirred for 20 minutes. The yellow precipitate was filtered off, washed with diethyl ether and then dried in air to give bromo-3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine. Yield 1.356g (71%). ESIMS M/z =377.0,378.9 (bimodal, M +1)

Example 103- (6-Fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine compound

A mixture of 1.356g (3.60mmol) of 5-bromo-3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine, 3.445g (16.80mmol) of pinacol 3-pyridineboronic acid ester and 0.457g (0.560mmol) of 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) and 7.2ml of a 1.0M aqueous solution of cesium carbonate in 60ml of acetonitrile is degassed and heated in a sealed glass bottle at 95 ℃ for 2 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was redissolved in dichloromethane and the organic layer was washed with water, brine, dried over MgSO4 and concentrated. The crude residue was purified on an 80g silica gel column (eluting with 3-4% methanol in dichloromethane). The collected fractions were concentrated. The residue was triturated with 7ml of cold methanol and filtered to give 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine. Yield 1.147g (85%). ESI MS M/z =376.1(M +1)

Example 115- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine compound

To 5-bromo-1H-pyrazolo [3,4-c]To a solution of pyridine (100mg,0.5mmol) in DME: EtOH (5:1,5mL) was added Pd (dppf) Cl₂(20mg)、Na₂CO₃And 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (116mg,0.6 mmol). The mixture was stirred under microwave irradiation at 150 ℃ for 60 minutes under argon. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (mobile phase: EA: PE =1:1) to give 5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine (40mg, 43%).¹H NMR(500MHz,MeOD)δ9.17(s,1H),8.98(s,1H),8.17(m,3H),8.05(d,J=1.5,1H).ESI MS m/z=186.1(M+1).

Example 125- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine (P2-040)

To 5-bromo-1H-pyrazolo [3,4-c]To a solution of pyridine (100mg,0.5mmol) in DME: EtOH (5:1,5mL) was added Pd (dppf) Cl₂(20mg)、Na₂CO₃And 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (116mg,0.6 mmol). The mixture was stirred under microwave irradiation at 150 ℃ for 60 minutes under argon. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (mobile phase: EA: PE =1:1) to give 5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine (20mg, 22%).¹H NMR(500MHz,MeOD)δ9.05(s,1H),8.24(m,2H),7.75(s,1H),6.89(s,1H).ESI MS m/z=186.1(M+1)

TABLE 1 Compounds of formula I

Example 1013-methyl-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 101

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

To 5-bromo-1H-pyrazolo [3,4-c from example 6]To a solution of pyridine (100mg,0.5mmol) in DMF (5mL) was added Pd (dppf) Cl₂(20mg)、Na₂CO₃And pyridin-3-ylboronic acid (74mg,0.6 mmol). The mixture was stirred at 80 ℃ for 16 hours under argon. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (mobile phase: EA: PE =1:1) to give 5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine (59mg, 60%).¹H NMR(500MHz,MeOD)δ9.17(s,1H),9.09(s,1H),8.52(d,J=3.5,1H),8.44(q,J=7,2,1H),8.29(d,J=5,1H),8.23(s,1H),7.53(q,J=9.5,5.5,1H).ESI MS m/z=197.1(M+1).

Step 2 3-bromo-lH-pyrazolo [3,4-c ] pyridine

1H-pyrazolo [3,4-c ] pyridine (1g), bromine (1.33g) and water (40mL) were stirred for 1 hour. Basified with 20% sodium hydroxide solution and adjusted to pH7 by addition of acetic acid to give 3-bromo-lH-pyrazolo [3,4-c ] pyridine (1.1g, 67%). ESIMS M/z =275(M +1)

Step 3 to 90mg (0.6mmol) of 9-methoxy-9-bora-bicyclo [3.3.1]To a solution of nonane in 5mL of anhydrous tetrahydrofuran was added dropwise a solution of 0.37mL (0.6mmol) of 1N methyllithium in diethyl ether. After stirring for several minutes, 3-bromo-1H-pyrazolo [3, 4-c) is added]A mixture of pyridine (0.16g,0.6mmol) and 10mg (0.015mmol) of bis (triphenylphosphine) palladium (II) dichloride in 10mL of anhydrous tetrahydrofuran. The reaction mixture was stirred in a microwave oven at 150 ℃ for 15 minutes. After filtration through celite and concentration in vacuo, flash chromatography (SiO)₂PE/Ethyl acetate 1:1) the residue was purified to yield 47mg101 (37%).¹H NMR(500MHz,DMSO-d6)δ9.34(d,J=2,1H),9.09(s,1H),8.57(dd,J=4.5,1.5,1H),8.48(d,J=7.5,1H),8.44(s,1H),7.51(q,J=8,5,1H),2.60(s,3H).ESI MS m/z=211.1(M+1)

Example 1023-methyl-5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine 102

Step 1- (2-bromo-5-fluoropyridin-4-yl) ethanol

To a 1000mL 3-necked flask was added 2-bromo-5-fluoropyridine (8.80g,50mmol) and THF (200mL) at-78 deg.C, followed by LDA (20.0mL,50mmol,2.5M) dropwise. After stirring for 4 hours at-78 ℃, acetaldehyde (3.1mL,55mmol) was added dropwise via syringe. The contents were removed from the cold bath and stirred at room temperature overnight. The mixture was diluted with H2O (150mL) and stirred vigorously for 5 minutes. The contents were washed with diethyl ether (3X150mL), the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The crude product was passed through a short silica gel column (eluent: 3:1PE/EtOAc) to give 1- (2-bromo-5-fluoropyridin-4-yl) ethanol as a white solid (9.5g, 86%). ESI MS M/z =220(M +1)

Step 21- (2-bromo-5-fluoropyridin-4-yl) ethanone

To a 350mL closed flask, 1- (2-bromo-5-fluoro-4-pyridinyl) ethanol (9.4g,42.3mmol) was dissolved in 60mL anhydrous CHCl 3. Manganese (IV) oxide (14.7g,169mmol) was then added to the stirred solution. The vigorously stirred contents were sealed and heated at 95 ℃ for 2.5 hours. After cooling to room temperature, the black heterogeneous mixture was vacuum filtered through a plug of celite and the filter plug was washed with CH2Cl2(10 mL). The yellow filtrate was concentrated in vacuo to a yellow oil which was purified by silica gel column chromatography (eluent: 9:1PE/EtOAc) to give 1- (2-bromo-5-fluoropyridin-4-yl) ethanone as a pale yellow oil (8.2g, 88%). ESI MS M/z =218(M +1)

Step 3-5-bromo-3-methyl-1H-pyrazolo [3,4-c ] pyridine

To a 150mL closed flask containing 50mL of anhydrous ethylene glycol was dissolved 1- (2-bromo-5-fluoro-4-pyridinyl) ethanone (8.2g,37.6 mmol). Then anhydrous hydrazine (1.24mL,39.5mmol) was added dropwise via syringe. The stirred pale yellow mixture was sealed and heated at 165 ℃. After 3.5 hours, the orange-brown reaction mixture was removed from the heating. After cooling to room temperature, the contents were poured onto a stirred 300g ice/water (1:1) mixture, where a solid precipitate appeared. After stirring for 10 minutes, an off-white precipitate was collected. The solid was dried in vacuo and 5-bromo-3-methyl-1H-pyrazolo [3,4-c ] pyridine was collected as an off-white solid (7.9g, 99%). ESI MS M/z =212(M +1).

Step 4, adding 5-bromo-3-methyl-1H-pyrazolo [3, 4-c)]To a solution of pyridine (106mg,0.5mmol) in DMF (5mL) was added Pd (dppf) Cl₂(20mg)、Na₂CO₃And 1H-pyrazol-4-ylboronic acid (67mg,0.6 mmol). The mixture was stirred under microwave irradiation at 150 ℃ for 1 hour under argon. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (mobile phase: EA: PE =1:1) to give 102(15mg, 15%).¹H NMR(500MHz,MeOD)δ8.88(s,1H),8.16(m,2H),8.00(s,1H),2.61(s,3H);ESI MS m/z=200.1(M+1)

Example 1033-methyl-5- (1H-pyrazol-5-yl) -1H-pyrazolo [3,4-c]Pyridine 103

To 5-bromo-3-methyl-1H-pyrazolo [3,4-c ] from example 102]To a solution of pyridine (106mg,0.5mmol) in DMF (5mL) was added Pd (dppf) Cl₂(20mg)、Na₂CO₃And 1H-pyrazol-3-ylboronic acid (67mg,0.6 mmol). The mixture was stirred at 80 ℃ for 16 hours under argon. After cooling down, the solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography (mobile phase: EA: PE =1:1)Purification yielded 103(15mg, 15%).¹H NMR(500MHz,MeOD)δ8.96(s,1H),8.23(s,1H),7.71(s,1H),6.90(d,J=1.5,1H),2.65(s,3H).ESIMS m/z=200.1(M+1)

Example 1153-methyl-5- (pyrimidin-5-yl) -1H-pyrazolo [3,4-c]Pyridine 115

Charging 5-bromo-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] into a microwave reaction bottle]Pyridine (296mg,1.0mmol), pyrimidine-5-boronic acid (185mg,1.5mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (81.7mg,0.1mmol), 1.00M aqueous potassium acetate (1.5mL,1.5mmol), 1.00M aqueous sodium carbonate (1.5mL,1.5mmol), and acetonitrile (10 mL). The reaction mixture was heated at 130 ℃ for 30 minutes under microwave. The mixture was concentrated and the residue was purified on silica gel (with a solution containing 1% NH)₄OH 0-5% MeOH in DCM) to give 3-methyl-5- (pyrimidin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridine (281.9mg, 95.45%).

A solution of 3-methyl-5- (pyrimidin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine (281.2mg,0.9521mmol) in 4.0M hydrogen chloride in1, 4-dioxane (5mL) and 1, 4-dioxane (5mL,60mmol) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC to give 115 as an off-white solid (73.30mg, 37%). 1H NMR (400MHz, DMSO). delta.13.39 (s,1H),9.50(s,2H),9.18(s,1H),9.11(d, J =1.1Hz,1H),8.56(d, J =1.2Hz,1H),2.60(s,3H), ESI MS M/z =212.1(M +1)

Example 1163-phenyl-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 116

To 3-iodo-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c from example 4]Pyridine (161mg,0.5mmol) in DME: EtOH (5:1,5mL)Adding Pd (dppf) Cl to the solution of (1)₂(20mg)、Na₂CO₃And phenylboronic acid (74mg,0.6 mmol). The mixture was heated under microwave irradiation at 135 ℃ for 60 minutes under argon. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (mobile phase: EA: PE =1:1) to give 116(82mg, 60%).¹H NMR(400MHz,DMSO)δ9.33(s,1H),9.21(s,1H),8.56(s,1H),8.53-8.51(m,2H),8.12-8.10(m,2H),7.57-7.44(m,4H).;ESI MS m/z=273.7(M+1)

Example 1173- (2-fluorophenyl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 117

Following the procedure described in example 116, 3-iodo-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c from example 4 was prepared]Pyridine and 2-fluorophenylboronic acid were converted to 117 as a yellow solid (86mg,56%) in two steps.¹H NMR(400MHz,DMSO)δ9.32(s,1H),9.25(s,1H),8.59-8.58(m,1H),8.48-8.47(m,1H),8.35(s,1H),7.94-7.91(m,1H),7.59-7.54(m,4H).;ESI MS m/z=291.7(M+1)

Example 1183-methyl-5- (pyrazin-2-yl) -1H-pyrazolo [3,4-c]Pyridine 118

Following the procedure described in example 115 and starting with 2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazine, 118 was obtained in two steps as an off-white solid (3.10mg, 13%). 1H NMR (400MHz, DMSO). delta.13.42 (s,1H),9.56(d, J =1.3Hz,1H),9.11(s,1H), 8.73-8.70 (M,2H),8.64(d, J =2.5Hz,1H),2.61(s,3H), ESI MS M/z =212.1(M +1)

Example 1225- (3-fluorophenyl) -3-methyl-1H-pyrazolo [3,4-c]Pyridine 122

To 6mL of dioxane was added 5-bromo-3-methyl-1H-pyrazolo [3,4-c ] from example 102 under nitrogen]Pyridine (0.21g,1mmol), 3-fluorophenylboronic acid (0.28g,2mmol), PdCl₂(dppf) (87mg,0.1mmol) and 2M Na₂CO₃(2mmol,1 mL). The suspension was heated at 130 ℃ for 1 hour under microwave irradiation. It was cooled to room temperature and the solvent was removed. The crude product was purified by SGC (EtOAc/petroleum ether: 1/1) to give 79mg (34%) of 122 as a white solid.¹HNMR(400MHz,CDCl3):9.12(s,1H),7.98(s,1H),7.75–7.82(m,2H),7.44–7.47(m,1H),7.08-7.09(m,1H),2.67(s,3H).ESI MS m/z=229(M+1)

Example 1235- (5-Fluoropyridin-3-yl) -3-methyl-1H-pyrazolo [3,4-c]Pyridine 123

To 5-bromo-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]To a mixture of pyridine (90.0mg,0.304mmol), 5-fluoropyridin-3-ylboronic acid (128.6mg,0.9124mmol) and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (37.2mg,0.0456mmol) in acetonitrile (2.86mL,54.7mmol) was added 1.0M aqueous potassium acetate (0.456mL) and 1.0M aqueous sodium carbonate (0.456 mL). The reaction mixture was irradiated in a microwave at 125 ℃ for 20 minutes. The reaction mixture was filtered through celite and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate/heptane to give 5- (5-fluoropyridin-3-yl) -3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine, which was dissolved in 12M HCl (1.30mL,15.6mmol) and methanol (13.0 mL). The reaction mixture was stirred at RT (RT) for 18 h. The reaction mixture was concentrated and then subjected to rlhplc to give 123(27.9mg,40.2% yield). ESI MSm/z =229.1(M +1).¹H NMR(400MHz,DMSO)δ9.25(s,1H),9.08(s,1H),8.62–8.49(m,2H),8.47–8.30(m,1H),2.60(s,3H)

Example 1265- (pyridin-3-yl) -3- (3- (trifluoromethyl) phenyl) -1H-pyrazolo [3,4-c]Pyridine 126

Following the Suzuki coupling procedure of example 159, 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and 3- (trifluoromethyl) phenylboronic acid were reacted followed by reaction of the product with 3-pyridineboronic acid pinacol ester under the Suzuki coupling procedure of example 10 and deprotection by the procedure of example 131. The mixture was obtained as base and purified by crystallization from ethyl acetate in three steps to yield 56mg (33%) of 126. ESI MS M/z341.1(M +1)

Example 1273-methyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine 127

Charging 5-bromo-3-methyl-1H-pyrazolo [3,4-c ] in a microwave bottle]Pyridine-1-carboxylic acid tert-butyl ester (53mg,0.17mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (70.6mg,0.34mmol), potassium acetate (205.5mg,2.09mmol), cesium carbonate (166.0mg,0.51mmol) and bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]Palladium (II) dichloride (13.9mg,0.017 mmol). DMF (2.6mL) and water (0.5mL) were added. Nitrogen was passed through the mixture for 15 minutes and the bottle was capped. The reaction mixture was irradiated with microwaves at 125 ℃ for 20 minutes. The reaction mixture was filtered through a plug of celite and diluted with water and EtOAc. The organic layer was washed with brine, washed with Na₂SO₄Dried, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (Si-PPC gradient elution, solvent: 50-100% ethyl acetate/heptane, followed by 0-30% methanol/ethyl acetate) to give 127 as a foam (26.0mg, 71.8%).¹H NMR (400MHz, DMSO). delta.13.08 (broad singlet, 1H),8.90(s,1H),8.19(s,1H),7.98(s,1H),7.94(s,1H),3.88(s,3H),2.53(s,3H). LC/MS: M/z214.1[ M + 1]]

Example 1293- (2-fluorophenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine 129

Step 1 3- (2-fluorophenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

Following the procedure in example 133, using 2-fluorobenzylboronic acid instead of phenylboronic acid, 3- (2-fluorophenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] was obtained]Pyridine as a foam (50.7% over two steps).¹H NMR(400MHz,CDCl₃)δ9.15(s,1H),7.97(d,J=5.6Hz,2H),7.90–7.81(m,2H),7.45(ddd,J=7.3,6.3,1.7Hz,1H),7.30(dd,J=9.2,5.9Hz,1H),7.25(d,J=6.6Hz,1H),5.90(dd,J=8.8,2.5Hz,1H),4.06(dd,J=11.8,4.1Hz,1H),3.97(s,3H),3.87–3.76(m,1H),2.63–2.51(m,1H),2.19(d,J=9.5Hz,2H),1.89–1.68(m,3H).LC/MS:m/z378.3[M+1]

Step 2 following the procedure described in example 133, 3- (2-fluorophenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine instead of 5- (1-methyl-1H-pyrazol-4-yl) -3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine, which was converted to 129 as a white solid (69.1%).¹H NMR (400MHz, DMSO). delta.13.95 (broad singlet, 1H),9.06(s,1H),8.26(s,1H),7.99(s,1H),7.91(d, J =1.8Hz,1H), 7.89-7.82 (M,1H),7.54(dd, J =13.2,6.2Hz,1H), 7.47-7.35 (M,2H),3.87(s,3H). LC/MS: M/z294.0[ M + 1H ]]

Example 1313- (6-Fluoropyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 131

To a mixture of 120mg (0.32mmol) of 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine from example 10 in 3ml of methanol was added 12ml of a 4N HCl solution in dioxane. The mixture was stirred for 8 hours and concentrated in vacuo. The residue was triturated with ether. The solid material was filtered off, washed with diethyl ether and dried. The solid was dispersed in 30ml of saturated aqueous sodium bicarbonate and the suspension was stirred for 1 hour. The solid base was collected, washed with water and dried under high vacuum for 24 hours to yield 95mg of 131 (90%). ESI MS M/z292.1(M +1).1H NMR (400MHz, DMSO). 9.32-9.21 (M,1H),8.81(s,1H),8.61(dd, J =4.7,1.4Hz,1H),8.42(d, J =8.0Hz,1H), 8.21-8.06 (M,1H),7.55(dd, J =7.9,4.7Hz,1H),7.18(d, J =7.7Hz,1H),6.53(s,1H),6.28(s,1H)

Example 1326- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2 (1H) -one 132

A mixture of 58.2mg (0.200mmol) of 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine in 15ml of 1N aqueous HCl is heated for 4 hours. The product crystallized upon cooling. The precipitate was collected, washed with water and dried in vacuo to afford 132. Yield 48mg (83%). ESI MS M/z290.0(M +1).1H NMR (400MHz, DMSO). 14.18(s,1H),9.54(s,1H),9.26(s,1H)9.15(s,1H),8.94(d, J =6.5Hz,1H),8.77(d, J =5.0Hz,1H),7.86(s,1H),7.74(t, J =7.7Hz,1H),7.52(s,1H),6.62(d, J =8.2Hz,1H)

Example 1335- (1-methyl-1H-pyrazol-4-yl) -3-phenyl-1H-pyrazolo [3,4-c]Pyridine 133

Step 1-5-bromo-3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

Placing 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] in an oven-dried flask]Pyridine (2.0g,4.90mmol), phenylboronic acid (627.5mg,5.15mmol) and bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]Palladium (II) dichloride (200.14mg,0.24 mmol). Degassed acetonitrile (53mL), 1.0M aqueous sodium carbonate (7.4mL), and 1.0M aqueous potassium acetate (7.4mL) were added sequentially. The reaction mixture is stirred under N₂The mixture was degassed for a further 5 minutes at 80 ℃ under N₂Stirred for 1 hour. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water, and the layers were separated. The organic layer was washed with water (3 ×) and brine, over Na₂SO₄Dried and concentrated to an oil. The crude product was purified by flash column chromatography (Si-PPC gradient elution, solvent: 0-60% ethyl acetate/heptane) to yield 5-bromo-3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridine as a solid (1.45g, 82.47%).¹H NMR(400MHz,CDCl₃) δ 8.95(d, J =0.9Hz,1H),8.08(d, J =0.9Hz,1H), 7.94-7.88 (M,2H), 7.55-7.48 (M,2H), 7.48-7.41 (M,1H),5.86(dd, J =8.6,2.6Hz,1H), 4.07-3.97 (M,1H),3.80(ddd, J =12.3,8.9,3.8Hz,1H),2.54(qd, J =9.0,5.5Hz,1H), 2.24-2.11 (M,2H), 1.89-1.67 (M,3H), LC/MS: M/z274.1 (des-THP) [ M + 1H ], 1H, and M + 1H]

Step 2-5- (1-methyl-1H-pyrazol-4-yl) -3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

Charging 5-bromo-3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] in a microwave bottle]Pyridine (500mg,1.39mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (435.6mg,2.09mmol), potassium acetate (205.5mg,2.09mmol), sodium carbonate (221.9mg,2.09mmol) and bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]Palladium (II) dichloride (108.3mg,0.13 mmol). Degassed acetonitrile (10.5mL) and water (2.6mL) were added. Nitrogen was passed through the mixture for 15 minutes and the bottle was capped. The reaction mixture was irradiated with microwaves at 125 ℃ for 25 minutes. The reaction mixture was filtered through a plug of celite and diluted with water and EtOAc. The organic layer was washed with brine, washed with Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (Si-PPC gradient elution: 60-100% ethyl acetate/heptane, followed by 0-30% methanol/ethyl acetate) to yield 5- (1-methyl-1H-pyrazol-4-yl) -3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridine as a foam (340.0mg, 67.8%).¹HNMR(400MHz,CDCl₃)δ9.15(s,1H),8.07–7.94(m,5H),7.54(t,J=7.6Hz,2H),7.45(t,J=7.4Hz,1H),5.88(dd,J=8.8,2.2Hz,1H),4.06(dd,J=11.8,4.0Hz,1H),3.98(s,3H),3.86–3.76(m,1H),2.66–2.52(m,1H),2.19(d,J=10.8Hz,2H),1.89–1.67(m,3H).LC/MS:m/z378.3[M+1]

Step 3 to the stirred 5- (1-methyl-1H-pyrazol-4-yl) -3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]To a solution of pyridine (54.5mg,0.152mmol) in MeOH (8mL) was added 6M aqueous HCl. In N₂The reaction mixture was then stirred at 60 ℃ for 16 hours. The reaction mixture was cooled to room temperature. The volatile solvent was removed under reduced pressure. The crude product was redissolved in EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, washed with Na₂SO₄Dried, filtered and dried in vacuo. Crystallization from DCM-heptane yielded 133 as a solid (40mg, 95.8%).¹HNMR (400MHz, DMSO). delta.13.71 (broad singlet, 1H),9.04(s,1H),8.32(s,1H),8.24(s,1H),8.09(d, J =7.3Hz,3H),7.55(t, J =7.5Hz,2H),7.44(t, J =7.4Hz,1H),3.90(s,3H). LC/MS: M/z276.1[ M + 1H ], [ M, H ], [ 2H ], [ 7.4Hz,1H ], [ L ], []

Example 1363- (2-fluorophenyl) -5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine 136

Charging 5-bromo-3- (2-fluorophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) under microwave]Pyridine (376mg,1mmol), 1H-pyrazol-4-ylboronic acid (224mg,2mmol), Pd (dppf) Cl₂(50mg,0.0625mmol)、Na₂CO₃And DME/EtOH (5mL/0.5mL) were irradiated at 140 ℃ for 1 hour. After cooling down, ethyl acetate a was added. The mixture was washed twice with water (2X 20mL) and dried over anhydrous Na₂SO₄Dried and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel eluting with 50% ethyl acetate/heptane to give 3- (2-fluorophenyl) -5- (1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine, as a white solid (300mg,82%, ESI MS M/z =364(M +1), which was treated with HCl/dioxane (4mL,3mol/L) and stirred overnight₃CN at 10mmol NH₄HCO₃The solution in the aqueous solution was eluted and further purified by preparative-HPLC,136 was obtained as a white solid (180mg, 72%).¹H NMR(400MHz,DMSO)δ9.02(s,1H),8.16(s,2H),8.02(m,1H),7.87(m,1H),7.54(m,1H),7.38(m,2H).ESI MS m/z=280(M+1)

Example 1373-phenyl-5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine 137

Following the procedure described in example 136, 1H-pyrazol-4-ylboronic acid and 5-bromo-3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine reaction, followed by deprotection of the product, yielded 137 as a yellow solid in two steps (26mg, 23%).¹H NMR(400MHz,DMSO)δ12.9(s,1H),9.05(s,1H),8.37-8.09(m,5H),7.56(m,1H),7.44(m,1H)

Example 1383- (2-fluorophenyl) -5- (pyrimidin-5-yl) -1H-pyrazolo [3,4-c]Pyridine 138

Following the procedure described in example 136, pyrimidin-5-ylboronic acid and 3- (2-fluorophenyl) -5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine reaction, followed by deprotection of the product gave 138 as a white solid in two steps (25mg, 25%).¹H NMR(400MHz,DMSO)δ14.2(s,1H),9.51(s,2H),9.28(s,1H),9.21(s,1H),8.50(s,1H),7.92(mt,2H),7.59(t,2H),7.41(t,1H).ESI MS m/z=292(M+1)

Example 1423-phenyl-5- (1H-1,2, 4-triazol-1-yl) -1H-pyrazolo [3,4-c]Pyridine 142

Following the procedures of examples 146 and 131, 5-bromo-3-phenyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and 1,2, 4-triazole were reacted in two steps to give 142 as a white solid (20mg, 27%). ESI MS M/z263.0(M +1).1H NMR (400MHz, DMSO). 14,32(s,1H),9.36(s,1H),9.09(d, J =1.0Hz,1H),8.38(d, J =1.0Hz,1H),8.30(s,1H), 8.07-8.00 (M,2H),7.60(t, J =7.6Hz,2H),7.48(t, J =7.4Hz,1H)

Example 143N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) ethane-1, 2-diamine 143

A mixture of 56.3mg (0.150mmol) of 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and 1.0ml (15.0mmol) of 1, 2-ethylenediamine is heated at 160 ℃ for 30 minutes. The mixture was mixed with water and extracted with ethyl acetate. The organic extracts were washed with water (3 times), brine, dried over MgSO4 and concentrated. The residue was heated at 60 ℃ for 18 hours in a mixture of 4M hydrogen chloride in 6ml dioxane and 2ml concentrated hydrochloric acid. The mixture was concentrated in high vacuum and triturated with ether. The solid material was filtered off and washed with diethyl ether to give 143. The yield over the two steps was 37.5mg (56%). ESI MS M/z332.1(M +1).1H NMR (400MHz, DMSO). 14.27(s,1H),9.57(s,1H),9.30(s,1H),9.19(d, J =8.0Hz,1H),9.11(s,1H),8.90(d, J =4.8Hz,1H),8.23(s,3H),8.11(dd, J =7.9,5.6Hz,1H),7.68(d, J =7.5Hz,1H),7.53(d, J =7.2Hz,1H),6.71(d, J =7.3Hz,1H),3.75(t, J =6.0Hz,2H),3.17(dd, J =11.4,5.7Hz,2H)

Example 1441- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-4-amine 144

A mixture of 56.3mg (0.150mmol) of 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and 211mg (0.90mmol) of benzyl piperidin-4-ylcarbamate in 1.0ml of dimethyl sulfoxide is heated at 100 ℃ for 24 hours. The mixture was mixed with water and extracted with ethyl acetate. The organic extracts were washed with water, 1% aqueous citric acid, water, brine, dried over MgSO4 and concentrated. The residue was heated at 60 ℃ for 18 hours in a mixture of 4M hydrogen chloride in 6ml dioxane and 2ml concentrated hydrochloric acid. The mixture was concentrated in high vacuum and triturated with ether. The solid material was filtered off and washed with diethyl ether to give 144. The yield over the two steps was 13.7mg (19%). ESI MSm/z372.1(M +1).1H NMR (400MHz, DMSO):14.17(s,1H),9.41(s,1H),9.29(s,1H),8.99(s,1H),8.93(d, J =7.9Hz,1H),8.87(d, J =5.0Hz,1H),8.14(s,3H), 8.07-7.99 (M,1H), 7.76-7.69 (M,1H),7.51(d, J =7.4Hz,1H),6.99(d, J =8.5Hz,1H),4.52(d, J =13.3Hz,3H),3.40(s,2H),3.12(t, J =11.9Hz,2H),2.08(d, J =10.1, 2H),1.66, 12H =12, 8.5Hz,2H)

Example 1465- (1H-imidazol-1-yl) -3-phenyl-1H-pyrazolo [3,4-c]Pyridine 146

A mixture of 100.0mg (0.2791mmol) of 5-bromo-3-phenyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine, 47.51mg (0.6979mmol) of 1H-imidazole, 53.16mg (0.2791mmol) of copper (I) iodide, 30.04uL (0.2791mmol) of N, N' -dimethylethylenediamine and 363.8mg (1.116mmol) of cesium carbonate in 3ml of N, N-dimethylformamide was heated at 120 ℃ for 48 hours. The mixture was filtered, the filtrate was concentrated in high vacuum and the residue was partitioned between ethyl acetate and water. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified on a 4g silica gel column (eluting with a gradient of ethyl acetate/heptane) to give 5- (1H-imidazol-1-yl) -3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine. Yield 67mg (69%). ESI MS M/z346.1(M +1).

Reacting 5- (1H-imidazol-1-yl) -3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Deprotection of pyridine (67mg,0.193mmol) gave 60mg of the crude hydrochloride salt product with a NH content of 0.1%₄The OH eluted with a MeOH/water gradient and was purified by reverse phase HPLC to give 25mg (49%) of 146 as a white solid. ESI MS M/z262.0(M +1).1HNMR (400MHz, DMSO). 13.89(s,1H),9.05(d, J =0.9Hz,1H),8.59(s,1H),8.34(d, J =1.1Hz,1H),8.16-8.11(M,2H),8.09(t, J =1.3Hz,1H),7.57(t, J =7.6Hz,2H),7.46(t, J =7.4Hz,1H),7.13(s,1H)

Example 149(R) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 149

Following the procedure of example 144, 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and benzyl (R) -piperidin-3-ylcarbamate were reacted to give 17mg of 149 (over two steps 15%). ESI MS M/z372.1(M +1).1H NMR (400MHz, DMSO). 14.24(s,1H),9.49(s,1H),9.30(s,1H),9.10(d, J =8.3Hz,1H),9.06(s,1H),8.36(s,3H), 8.21-8.12 (M,1H), 7.78-7.72 (M,1H),7.56(d, J =7.4Hz,1H),6.99(d, J =8.5Hz,1H),4.49(d, J =11.3Hz,2H), 3.53-3.44 (M,3H),3.35(M,1H),3.22(d, J =9.2Hz,1H),2.10(M,1H),1.95(M,1H)

Example 1503-phenyl-5- (pyrimidin-5-yl) -1H-pyrazolo [3,4-c]Pyridine 150

Following the procedure in example 136, pyrimidin-5-ylboronic acid and 5-bromo-3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine reaction, followed by deprotection of the product, gave 150 as a yellow solid in two steps (25mg, 25%).¹H NMR(400MHz,DMSO)δ9.59(s,1H),9.26(s,1H),9.21(s,1H),8.79(s,1H),8.40(s,1H),8.18(d,2H),7.57(t,2H),7.47(t,1H).ESI MS m/z=274(M+1)

Example 1563- (1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 156

Step 1 3- (1-benzyl-1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

Following the Suzuki coupling procedure of example 159, 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and 1-benzyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole were reacted followed by the Suzuki coupling procedure of example 10 to react the product with pinacol ester of 3-pyridineboronic acid. The product was purified by silica gel chromatography with a gradient of methanol/DCM to give 236mg (54%) of 3- (1-benzyl-1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine in two steps. ESI MS M/z437.1(M +1).

Step 23- (1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

A mixture of 234mg (0.54mmol) of 3- (1-benzyl-1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine, 3.0ml (32mmol) of 1, 4-cyclohexadiene and 400mg of 20% palladium hydroxide on charcoal is heated to reflux for 8 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give 106mg (31%) of 3- (1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine in two steps. ESI MS M/z347.1(M +1).

Step 3 deprotection of 3- (1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine following the procedure of example 229 purified the product by trituration with ether and collected via filtration to give 24mg (7%) of 156 in four steps. ESI MS M/z263.0(M +1).1H NMR (400MHz, DMSO). 9.70(s,1H),9.37(d, J =8.3Hz,1H),9.22(s,1H), 8.94-8.84 (M,2H),8.48(s,2H), 8.19-8.11 (M,1H)

Example 1581- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) piperidin-4-amine 158

Step 1 tert-butyl 1- (5-bromopyridin-3-yl) piperidin-4-ylcarbamate

A solution of 3, 5-dibromopyridine (0.400g,1.69mmol), 4- (N-Boc-amino) -piperidine (0.238g,1.19mmol), tris (dibenzylideneacetone) dipalladium (0) (54mg,0.059mmol), rac-2, 2 '-bis (diphenylphosphino) -1,1' -binaphthyl (73.9mg,0.119mmol) and sodium tert-butoxide (114mg,1.19mmol) in toluene (16.9mL) was heated at 85 ℃ for 18 hours. The reaction mixture was filtered through celite, then rinsed with EtOAc. The crude product was purified by Isco (eluting with 40% EtOAc/Hep) to give tert-butyl 1- (5-bromopyridin-3-yl) piperidin-4-ylcarbamate (320mg,75.6% yield). ESIMS M/z =357.1(M +1).

Step 2 tert-butyl 1- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) piperidin-4-ylcarbamate

A solution of tert-butyl 1- (5-bromopyridin-3-yl) piperidin-4-ylcarbamate (0.120g,0.337mmol), dipicolinate (Bispinacol ester boronate) (0.13g,0.50mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (13.75mg,0.01684mmol) and potassium acetate (99.17mg,1.010mmol) in1, 4-dioxane (5.00mL) was purged with N2 and then heated at 85 ℃ for 18 hours. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate was washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude tert-butyl 1- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) piperidin-4-ylcarbamate is taken to the next step. ESIMS M/z =404.1(M +1).

Step 3 tert-butyl 1- (5- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) piperidin-4-ylcarbamate

5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine (0.0736g,0.180mmol), tert-butyl 1- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) piperidin-4-ylcarbamate (0.080g,0.20mmol), and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (0.0221g,0.0270mmol) were dissolved in acetonitrile (3.00mL), followed by the addition of 1.0M aqueous potassium acetate (0.270mL) and 1.0M aqueous sodium carbonate (0.270 mL). The reaction mixture was stirred at 80 ℃ for 1 hour. After filtration, the crude product was evaporated and purified by silica gel column chromatography (eluting with EtOAc/Hep with 75% EtOAc) to give tert-butyl 1- (5- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) piperidin-4-ylcarbamate (45mg,45% yield). ESI MS M/z =558.1(M +1).

Step 4 tert-butyl 1- (5- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) piperidin-4-ylcarbamate

To a mixture of tert-butyl 1- (5- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) piperidin-4-ylcarbamate (45.0mg,0.0807mmol), 3-pyridylboronic acid (29.8mg,0.242mmol), and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (9.888mg,0.01211mmol) in acetonitrile (1.01mL,19.4mmol) was added 1.0M aqueous potassium acetate (0.121mL) and 1.0M aqueous sodium carbonate (0.121 mL). The reaction mixture was irradiated in a microwave for 20 minutes at 125 ℃. The reaction mixture was filtered through celite. The filtrate was washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give tert-butyl 1- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) piperidin-4-ylcarbamate.

Step 5, in1- (5- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) piperidin-4-ylcarbamic acid tert-butyl ester in dichloromethane (1.00mL,15.6mmol) was added trifluoroacetic acid (0.3109mL,4.036 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated and then subjected to rHPLC (reverse phase HPLC) purification to give 158(10mg,33% yield). ESI MS M/z =372.1(M +1).¹HNMR(400MHz,DMSO)δ9.39(s,1H),9.24(s,1H),8.72(s,1H),8.61–8.52(m,3H),8.42(s,1H),7.83(s,1H),7.55–7.48(m,1H),3.85(d,J=13.0Hz,2H),2.98–2.76(m,3H),1.91–1.81(m,2H),1.42(dd,J=20.7,10.2Hz,2H)

Example 159N1- (4- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) ethane-1, 2-diamine 159

Step 1 5- (3, 4-dihydro-2H-pyran-5-yl) -3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

Following the Suzuki coupling procedure of example 10, 5-bromo-3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and 2- (3, 4-dihydro-2H-pyran-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan were reacted and purified by silica gel column chromatography using a gradient of EtOAc/heptane to yield 68mg (45%) of 5- (3, 4-dihydro-2H-pyran-5-yl) -3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H- Pyrazolo [3,4-c ] pyridines. ESI MS M/z381.1(M +1).

Step 23- (6-Fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -5- (tetrahydro-2H-pyran-3-yl) -1H-pyrazolo [3,4-c ] pyridine

A mixture of 68mg (0.18mmol) of 5- (3, 4-dihydro-2H-pyran-5-yl) -3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine, 2.0ml (21mmol) of 1, 4-cyclohexadiene and 300mg of 10% palladium on charcoal in 8ml of ethanol is heated to reflux for 24H. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give 70mg (100%) of 3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -5- (tetrahydro-2H-pyran-3-yl) -1H-pyrazolo [3,4-c ] pyridine. ESI MS M/z383.1(M +1).

Step 3- (6- (piperazin-1-yl) pyridin-2-yl) -5- (tetrahydro-2H-pyran-3-yl) -1H-pyrazolo [3,4-c ] pyridine

Following the procedure of example 144, 3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -5- (tetrahydro-2H-pyran-3-yl) -1H-pyrazolo [3,4-c]Pyridine and piperazine reaction, followed by deprotection by the procedure of example 131 gave a racemic mixture containing 0.1% NH₄A gradient of OH in MeOH/water purified by reverse phase HPLC to give 30mg (20%) of 3- (6- (piperazin-1-yl) pyridin-2-yl) -5- (tetrahydro-2H-pyran-3-yl) -1H-pyrazolo [3,4-c]Pyridine. ESI MS M/z365.1(M +1).

Step 43- (2-Fluoropyridin-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

A mixture of 0.408g (1.00mmol) of 5-bromo-3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine, 0.162g (1.15mmol) of pinacol 3-pyridineboronic acid ester and 0.817g (0.10mmol) of 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) and 1.2ml of a 1.0M aqueous solution of cesium carbonate in 12ml of acetonitrile is degassed and heated in a sealed glass vial at 95 ℃ for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane and the organic layer was washed with water, brine, dried over MgSO4 and concentrated to give 3- (2-fluoropyridin-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine.

Step 5 following the procedure of example 143, 3- (2-fluoropyridin-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine is reacted with 1, 2-ethylenediamine, then with a catalyst containing 0.1% NH₄A gradient of OH in MeOH/water, purified by reverse phase HPLC, afforded 32mg (64%) of 159. ESI MS M/z332.1(M +1).1H NMR (400MHz, DMSO). 9.38(s,1H),9.23(s,1H),8.60(d, J =11.0Hz,2H),8.53(d, J =7.1Hz,1H),8.10(s,1H),7.54(s,1H),7.25(d, J =11.9Hz,2H),6.67(s,1H),2.78(s,2H)

Example 160(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 160

Following the procedure of example 144, 3- (2-fluoropyridin-4-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine was reacted with tert-butyl piperidin-4-ylcarbamate and subsequently deprotected by the procedure of example 229 using a solution containing 0.1% NH₄A gradient of OH in MeOH/water/purification by reverse phase HPLC provided 50mg (59%) of 160. ESI MS M/z372.1(M +1)

Example 161(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 161

Following the procedure of example 144, 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and benzyl (R) -piperidin-3-ylcarbamate. With a content of 0.1% NH₄A MeOH/water gradient of OH, the reaction mixture was purified by reverse phase HPLC to give 20.0mg (20%) of 161 in two steps. ESI MSm/z372.1(M +1).1H NMR (400MHz, DMSO). 9.30(s,1H),9.21(s,1H),9.00(s,1H),8.60(s,1H),8.48(M,1H),7.66(s,1H)7.53(M,1H),7.46(s,1H),6.87(d,J=8.5Hz,1H),4.37(m,1H),4.29(d,J=12.6Hz,1H),3.06-2.97(m,1H),2.79(d,J=7.6Hz,2H),1.94(m,1H),1.80(m,1H),1.61(d,J=9.5Hz,1H),1.34(m,1H)

Example 1623- (6- (piperazin-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 162

Following the procedure of example 143, 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and piperazine were reacted, then reacted with a catalyst containing 0.1% NH₄A gradient of OH in MeOH/water, purification by reverse phase HPLC, provided 42mg (78%) of 162. ESI MS M/z358.1(M +1).1H NMR (400MHz, DMSO). 9.24(d, J =8.1Hz,1H),8.90(s,1H),8.61(s,1H),8.42(d, J =7.2Hz,1H),7.74(d, J =7.9Hz,1H),7.56(d, J =6.7Hz,1H),6.96(d, J =8.1Hz,1H),3.82(s,2H),3.17(s,2H)

Example 1633, 5-bis (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine 163

3, 5-bis (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] in methanol]The pyridine was treated with 4M HCl in1, 4-dioxane at 50 ℃ for 3 hours. The volatile solvent was evaporated in vacuo. The resulting residue was purified by reverse phase HPLC to give 163 as a white solid (34.2%).¹H NMR(500MHz,DMSO)δ13.35(s,1H),8.96(s,1H),8.47(s,1H),8.29(s,1H),8.15(s,1H),8.10(d,J=5.6Hz,2H),3.96(s,3H),3.90(s,3H).LC/MS:m/z280.0[M+1]

Example 165(1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) piperidin-4-yl) methylamine 165

Following the procedure in example 158, (1- (5- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) piperidin-4-yl) methylcarbamic acid tert-butyl ester was converted to 165. ESI MS M/z =386.1(M +1).¹H NMR(400MHz,DMSO)δ9.37(s,1H),9.23(s,1H),8.59(d,J=4.6Hz,1H),8.55(s,1H),8.52(s,1H),8.06(d,J=2.4Hz,1H),7.56(s,1H),7.51(dd,J=8.0,4.7Hz,1H),6.13(d,J=5.3Hz,1H),3.15–3.00(m,4H),2.62(dd,J=25.8,13.5Hz,2H),1.90–1.76(m,3H),1.21(dd,J=10.6Hz,2H)

Example 168(R) - (1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyrrolidin-3-yl) methylamine 168

Following the procedure in example 158, ((3R) -1- (5- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyrrolidin-3-yl) methylcarbamic acid tert-butyl ester was converted to 168. ESI MSm/z =372.1(M +1).¹H NMR(400MHz,DMSO)δ9.39(d,J=1.7Hz,1H),9.24(s,1H),8.70–8.52(m,4H),8.03(d,J=2.6Hz,1H),7.51(dd,J=7.9,4.8Hz,1H),7.43(s,1H),3.59–3.45(m,4H),2.81(d,J=7.1Hz,2H),2.20–2.12(m,1H),1.87–1.74(m,1H)

Example 1691- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) azepan-4-amine 169

Following the procedure in example 158, 1- (5- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) azepan-4-ylcarbamic acid tert-butyl ester is converted to 169. ESI MS M/z =386.2(M +1).¹H NMR(400MHz,DMSO)δ9.38(s,1H),9.24(s,1H),8.64–8.49(m,4H),8.21(d,J=2.7Hz,1H),7.58(s,1H),7.51(dd,J=7.8,4.8Hz,1H),3.76–3.65(m,1H),3.66–3.57(m,1H),3.56–3.43(m,2H),3.04(dd,J=14.6,9.5Hz,1H),2.12–2.00(m,1H),2.01–1.90(m1H),1.83–1.59(m,2H),1.53–1.37(m,1H),1.25–1.15(m,1H)

Example 170N- (piperidin-4-yl) -5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridin-3-yl) pyridin-3-amine 170

Following the operation in example 158, the4- (5- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-3-ylamino) piperidine-1-carboxylic acid tert-butyl ester was converted to 170. ESI MS M/z =372.1(M +1).¹H NMR(400MHz,DMSO)δ9.37(d,J=2.0Hz,1H),9.23(s,1H),8.59(d,J=4.6Hz,1H),8.56–8.47(m,3H),8.05(d,J=2.4Hz,1H),7.57(s,1H),7.51(dd,J=7.9,4.7Hz,1H),5.90(d,J=8.0Hz,1H),2.99(d,J=12.5Hz,2H),2.60(t,J=11.0Hz,2H),1.95(d,J=10.6Hz,2H),1.30(dd,J=19.6,10.8Hz,2H)

Example 1723- (2-fluoro-5-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine 172

Step 1 3- (2-fluoro-5-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

Charging 3-chloro-5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) in a microwave bottle]Pyridine (29.4mg,0.093mmol), 2- (2-fluoro-5-methoxyphenyl) -4,4,5, 5-tetramethyl- [1,3, 2%]Dioxaborolane (35.0mg,0.139mmol), potassium acetate (13.6mg,0.14mmol), sodium carbonate (14.7mg,0.14mmol) and bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]Palladium (II) dichloride (7.5mg, 9.2E)^- ³mmol). Degassed acetonitrile (0.8mL) and water (0.3mL) were added. Nitrogen was passed through the mixture for 15 minutes and the bottle was capped. The reaction mixture was irradiated with microwaves at 125 ℃ for 25 minutes. The reaction mixture was filtered through a plug of celite and diluted with water and EtOAc. The organic layer was washed with brine, washed with Na₂SO₄Dried, filtered and then concentrated under reduced pressure. The crude product was purified by flash chromatography (Si-PPC gradient elution, solvent: 10-100% ethyl acetate/heptane) to yield 3- (2-fluoro-5-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridine as a foam (37.3mg, 98.9%).¹H NMR(400MHz,CDCl₃)δ9.12(s,1H),7.95(s,1H),7.90(s,1H),7.81(d,J=2.8Hz,1H),7.32(dd,J=5.5,3.2Hz,1H),7.15(t,J=9.4Hz,1H),6.97–6.89(m,1H),5.86(dd,J=8.7,2.1Hz,1H),4.07–3.98(m,1H),3.93(s,3H),3.86–3.74(m,4H),2.64–2.47(m,1H),2.16(d,J=9.7Hz,2H),1.83–1.66(m,3H).LC/MS:m/z408.2[M+1].

Step 2 to the stirred 3- (2-fluoro-5-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]To a mixture of pyridine (37.0mg,0.09mmol) in methanol (5.0mL) was added 6M aqueous HCl (0.66 mL). The reaction mixture was stirred at 60 ℃ for 3 days. The volatile solvent was evaporated in vacuo, and the crude product was diluted into ethyl acetate (about 30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, washed with Na₂SO₄Dried, filtered and then concentrated under reduced pressure. Trituration from ether-heptane yielded 172 as a solid (15.3mg, 52.1%).¹HNMR(400MHz,DMSO)δ13.88(s,1H),9.06(s,1H),8.25(s,1H),7.97(s,1H),7.88(s,1H),7.36(t,J=9.6Hz,1H),7.31(dd,J=5.7,3.2Hz,1H),7.09(s,1H),3.88(s,3H),3.83(s,3H).LC/MS:m/z324.0[M+1]

Example 173(S) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 173

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine was reacted with tert-butyl (S) -piperidin-3-ylcarbamate and the product was then deprotected to yield 173 as a white solid (71.7% over two steps).¹H NMR(400MHz,DMSO)δ1HNMR(400MHz,DMSO)δ9.03(d,J=1.2Hz,1H),8.59(d,J=1.2Hz,1H),8.34(s,1H),7.95(s,1H),7.67–7.60(m,1H),7.42(d,J=7.3Hz,1H),6.84(d,J=8.5Hz,1H),4.46(d,J=8.9Hz,1H),4.21(d,J=12.7Hz,1H),3.90(s,3H),3.02–2.93(m,1H),2.84–2.74(m,2H),2.00–1.92(m,2H),1.88–1.77(m,2H),1.67–1.52(m,2H),1.39–1.28(m,1H).LC/MS:m/z375.1[M+1]

Example 1741- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-4-amine 174

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine was reacted with tert-butyl piperidin-4-ylcarbamate and the product was then deprotected to afford 174 as a white solid (36.8% over two steps).¹H NMR(400MHz,DMSO)δ1H NMR(400MHz,DMSO)δ9.03(d,J=1.2Hz,1H),8.54(d,J=1.3Hz,1H),8.12(s,1H),7.82(s,1H),7.63(dd,J=8.4,7.5Hz,1H),7.41(d,J=7.3Hz,1H),6.86(d,J=8.5Hz,1H),4.37(d,J=13.1Hz,2H),3.91(s,3H),3.51–3.20(m,3H),3.14–3.04(m,2H),2.96–2.83(m,1H),1.87(d,J=9.9Hz,2H),1.45–1.27(m,2H).LC/MS:m/z375.1[M+1]

Example 1753- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 175

Step 1 tert-butyl 4- (4- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Following the Suzuki coupling procedure of example 159, 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and tert-butyl 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate were reacted followed by the Suzuki coupling procedure of example 10 to react the product with pinacol ester of 3-pyridineboronic acid. The product mixture was purified by chromatography on silica gel with a gradient of methanol/DCM to give 230mg (75%) of tert-butyl 4- (4- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate in two steps. ESI MS M/z530.2(M +1).

Step 2 following the procedure of example 229, 4- (4- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Deprotection of pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester followed by a solution containing 0.1% NH₄A gradient of OH in MeOH/water, purified by reverse phase HPLC, afforded 42mg (21%) of 175. ESI MS M/z346.1(M +1).1H NMR (400MHz, DMSO). 13.75(s,1H),9.44(d, J =1.7Hz,1H),9.15(d, J =1.2Hz,1H),8.64(s,1H), 8.61-8.56 (M,3H), 4.36-4.26 (M,1H),3.09(d, J =12.3Hz,2H), 2.68-2.57 (M,2H), 2.05-1.87 (M,4H)

Example 1763, 5-bis (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 176

Adding 5-bromo-3-iodo-1H-pyrazolo [3,4-c ] to a microwave bottle]Pyridine (100mg,0.31mmol), pyridin-3-ylboronic acid (343mg,2.79mmol), Pd (dppf) Cl₂(24mg,0.03mmol), sodium carbonate (131mg,1.24mmol), 1, 2-dimethoxyethane (2mL), ethanol (0.5mL), and water (0.5 mL). The tube was purged with nitrogen for 2 minutes and then heated in a Biotage microwave for 1 hour at 160 ℃. The solvent was distilled off and then 15% CH₃CN/10mmol NH₄HCO₃The crude product was purified by reverse phase HPLC eluting with aqueous solution to give 176 as a pale yellow solid (30mg, 28%).¹H NMR(500MHz,DMSO)¹H NMR(500MHz,DMSO)δ14.1(s,1H),9.44(s,1H),9.37(s,3H),9.26(s,1H),8.71(s,1H),8.67–8.66(m,1H),8.60–8.59(m,2H),8.56-8.54(m,1H),7.60–7.58(m,1H),7.52–7.51(m,1H).ESI MS m/z=274(M+1)

Example 177(R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 177

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine was reacted with (R) -piperidin-3-ylcarbamic acid tert-butyl ester and the product was deprotected to give 177 as a white solid(in two steps 59.5%).¹H NMR(400MHz,DMSO)δ9.03(d,J=1.1Hz,1H),8.60(s,1H),8.34(s,1H),7.95(s,1H),7.69–7.56(m,1H),7.42(d,J=7.3Hz,1H),6.83(d,J=8.6Hz,1H),4.47(d,J=9.0Hz,1H),4.22(d,J=12.8Hz,1H),3.89(s,3H),3.04–2.90(m,1H),2.81–2.66(m,2H),2.01–1.92(m,2H),1.88–1.74(m,2H),1.56–1.52(m,2H),1.37–1.27(m,1H).LC/MS:m/z375.1[M+1].

Example 1782- (4- (3- (6-fluoropyridin-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-5-yl) -1H-pyrazol-1-yl) acetamide 178

Step 1 Ethyl 2- (4- (3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetate

Following the Suzuki coupling procedure of example 10, 5-bromo-3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and ethyl 2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) acetate were reacted and then purified by silica gel column chromatography with a gradient of EtOAc/heptane to give 100mg (56%) of 2- (4- (3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetic acid ethyl ester. ESI MS M/z451.1(M +1).

Step 2- (4- (3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetic acid

A mixture of 100mg (0.22mmol) of ethyl 2- (4- (3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetate and 1ml of 1M aqueous lithium hydroxide in 6ml of methanol and 2ml of tetrahydrofuran is stirred for 2 hours. The mixture was concentrated in vacuo and neutralized to pH5 by careful addition of 1N aqueous HCl. The product was collected via filtration, washed with water, and then dried under high vacuum to give 82mg (85%) of 2- (4- (3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetic acid. ESI MS M/z423.0(M +1).

Step 3 2- (4- (3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetamide

Following the procedure of example 144, 2- (4- (3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetic acid and ammonium chloride were reacted to give 60mg (75%) of 2- (4- (3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetamide. ESI MS M/z422.2(M +1).

Step 4A mixture of 60mg (0.142mmol) of 2- (4- (3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetamide and 2ml of trifluoroacetic acid is stirred for 18 hours. The mixture was concentrated in vacuo and the residue was stirred with 5ml of saturated aqueous sodium bicarbonate solution for 30 minutes. The precipitate was collected via filtration, washed with water, and then recrystallized from methanol in 4 steps to yield 35mg (26%) of 178. ESI MS M/z338.0(M +1).1H NMR (400MHz, DMSO). 14.02(s,1H),9.10(s,1H),8.46(s,1H),8.28(s,1H), 8.17-8.09 (M,2H),7.99(s,1H),7.51(s,1H),7.28(s,1H),7.20(dt, J =5.4,2.7Hz,1H),4.84(s,2H)

Example 182(1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-4-yl) methylamine 182

Following examples189 by the procedure described in (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridine was reacted with tert-butyl piperidin-4-ylmethyl carbamate and the product was then deprotected to afford 182 as a white solid (63% over two steps).¹H NMR(400MHz,DMSO)δ9.03(s,1H),8.54(s,1H),8.11(s,1H),7.82(s,1H),7.63(t,J=8.0Hz,1H),7.41(d,J=7.4Hz,1H),6.84(d,J=8.5Hz,1H),4.50(d,J=12.1Hz,2H),3.91(s,3H),2.99(t,J=12.5Hz,2H),2.53–2.44(m,4H),1.92–1.74(m,3H),1.58(s,1H),1.31–1.18(m,2H).LC/MS:m/z389.2[M+1]

Example 1836- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) -N- (piperidin-4-ylmethyl) pyridin-2-amine 183

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine was reacted with tert-butyl 4- (aminomethyl) piperidine-1-carboxylate and the product was then deprotected to give 183 as a white solid (55% over two steps).¹H NMR(400MHz,DMSO)δ9.01(s,1H),8.66(s,1H),8.16(s,1H),7.92(s,1H),7.47(t,J=7.8Hz,1H),7.30(d,J=7.3Hz,1H),6.76–6.70(m,1H),6.50(d,J=8.3Hz,1H),3.90(s,3H),3.44–3.34(m,4H),2.99(d,J=12.2Hz,2H),2.55–2.44(m,2H),1.85–1.71(m,3H),1.27–1.09(m,2H).LC/MS:m/z389.2[M+1]

Example 1845- (1-methyl-1H-pyrazol-4-yl) -3- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c]Pyridine 184

Following the procedure in example 189, 5- (1-methyl-1H-pyrazol-4-yl) -3- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Deprotection of pyridine afforded 184 as a solid (52.1%).¹H NMR(400MHz,DMSO)δ13.85(s,1H),9.08(s,1H),8.66(s,1H),8.43(s,1H),8.25(s,1H),8.16(s,1H),7.98(d,J=7.5Hz,2H),7.90(t,J=7.8Hz,1H),7.65(d,J=7.7Hz,1H),3.98(s,3H),3.93(s,3H).LC/MS:m/z357.1[M+1]

Example 1855- (furan-3-yl) -3-phenyl-1H-pyrazolo [3,4-c]Pyridine 185

Following the procedure described in example 176, pyrimidin-5-ylboronic acid and 5-bromo-3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine reaction, followed by deprotection of the product, yielded 185 as a white solid in two steps (25mg, 28%).¹H NMR(400MHz,DMSO)δ9.00(s,1H),8.17(t,1H),8.14(t,1H),8.03(t,2H),7.06-7.60(m,3H),7.45(t,1H),7.05(s,1H).ESI MS m/z=262(M+1)

Example 1863- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridine 186

Step 1 tert-butyl 4- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate

A solution of 630.8mg (2.5mmol) of 1,1' - (azodicarbonyl) -dipiperidine in 5ml of THF is added dropwise at 0 ℃ to a mixture of 388mg (2.0mmol) of 4,4,5, 5-tetramethyl-2- (1H-pyrazol-4-yl) -1,3, 2-dioxaborolane, 538mg (2.5mmol) of tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate and 0.62ml (2.5mmol) of tributylphosphine in 6ml of tetrahydrofuran. The mixture was stirred for 18 hours. The precipitate is filtered off and washed with diethyl ether. The filtrate was mixed with 50ml of water and extracted with diethyl ether. The organic layer was washed with water, brine, dried over MgSO4, and then concentrated. The residue was purified on a 24g silica gel column eluting with a gradient of 0-4% MeOH/DCM to give 0.43g (55%) of tert-butyl 4- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate. ESI MSm/z392.1

Step 2 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] following the Suzuki coupling procedure of example 159]Pyridine and 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester. The product was then reacted with 3-pyridineboronic acid pinacol ester by the Suzuki coupling procedure of example 10, followed by deprotection by the procedure of example 229. With a content of 0.1% NH₄A MeOH/water gradient of OH and reverse phase HPLC purified the mixture, which yielded 25mg (14%) of 186 in three steps. ESI MS M/z360.1(M +1).1HNMR (400MHz, DMSO)9.44(d, J =2.1Hz,1H),9.15(d, J =1.0Hz,1H), 8.64-8.54 (M,4H),8.17(s,1H),7.53(dd, J =8.0,4.8Hz,1H),4.08(d, J =7.2Hz,2H),2.91(d, J =12.0Hz,2H),2.41(t, J =10.9Hz,2H),1.98(s,1H),1.45(d, J =11.2Hz,2H), 1.18-1.05 (M,2H)

Example 1873- (6- (1, 4-diazepan-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridine 187

Following the procedure of example 143 and starting with 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and homopiperazine, 187 was obtained, which was then lyophilized from water to yield 42mg (78%). ESI MS M/z372.1(M +1).1H NMR (400MHz, DMSO) · 9.58(s,1H),9.44(s,1H),9.36(s,2H),9.31(s,1H),9.11(d, J =8.3Hz,1H),8.99(s,1H),8.94(d, J =5.4Hz,1H), 8.23-8.15 (M,1H),7.73(t, J =8.0Hz,1H),7.52(d, J =7.4Hz,1H),6.83(d, J =8.5Hz,1H),4.12(s,2H),3.89(t, J =6.0Hz,2H),3.43(d, J =21.5Hz,2H), 3.27-3.17 (M,2H),2.24(s,2H)

Example 1881- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 188

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and azepan-4-ylcarbamic acid tert-butyl esterAnd (4) reacting. The product was deprotected to afford 188 as a white solid (47.1% over two steps).¹H NMR (400MHz, DMSO) δ 9.02(s,1H),8.55(s,1H),8.11(s,1H),7.83(s,1H),7.60(t, J =8.0Hz,1H),7.37(d, J =7.3Hz,1H),6.61(d, J =8.5Hz,1H), 4.02-3.86 (m,4H), 3.85-3.75(m,1H), 3.75-3.55 (m,3H), 2.93-2.85 (s,1H), 2.10-1.93 (m,2H), 1.89-1.56 (m,3H), 1.45-1.31 (m,1H),2 protons are not seen. LC/MS M/z389.2[ M +1]]

Example 189(R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine 189

Step 1 (3R) -tert-butyl 1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ylcarbamate

In N₂3- (6-Fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] in a sealed tube]A mixture of pyridine (50.0mg,0.13mmol) and (R) -3- (Boc-amino) pyrrolidine (246.1mg,1.32mmol) in DMSO (2.6mL) was stirred at 95 ℃ for 3 days. The cooled reaction mixture was diluted into 1:1 diethyl ether-ethyl acetate. The organic layer was washed with 10% aqueous citric acid until the pH was about 4-5, water and brine, and Na₂SO₄Dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (Si-PPC gradient elution, solvent: 0-20% methanol/ethyl acetate) to give (3R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ylcarbamic acid tert-butyl ester as a foam (61.4mg, 85.3%).¹H NMR(400MHz,CDCl₃)δ1H NMR(400MHz,CDCl₃) δ 9.11(s,1H),8.79(s,1H),8.05 (broad singlet, 1H),7.97(s,1H), 7.62-7.50 (m,2H),6.37(d, J =7.9Hz,1H),5.86(dd, J =8.5,2.2Hz,1H),4.79(s,1H),4.44(s,1H),4.07–3.95(m,4H),3.92–3.84(m,1H),3.84–3.69(m,3H),3.63–3.51(m,1H),2.64–2.49(m,1H),2.37(td,J=13.6,7.7Hz,1H),2.17(d,J=9.8Hz,2H),2.11–2.01(m,1H),1.89–1.68(m,3H),1.46(s,9H).LC/MS:m/z545.3[M+1].

step 2 to the stirred (3R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ylcarbamic acid tert-butyl ester (60.0mg,0.12mmol) in anhydrous DCM (5.0mL) and methanol (2.5mL) was added 4M HCl in 1, 4-dioxane (4.0 mL). In N₂The reaction mixture was then stirred at 60 ℃ for 18 hours. The volatile solvent was evaporated in vacuo. The crude was redissolved in DMSO (1mL) and purified by reverse phase HPLC to give 189 as a white solid (25.5mg, 58.4%).¹H NMR(400MHz,DMSO)δ9.02(s,1H),8.71(s,1H),8.13(s,1H),7.87(s,1H),7.59(t,J=7.9Hz,1H),7.36(d,J=7.4Hz,1H),6.41(d,J=8.4Hz,1H),3.91(s,3H),3.81–3.64(m,4H),3.63–3.52(m,2H),2.17(dt,J=12.3,6.5Hz,2H),1.88–1.75(m,2H).LC/MS:m/z361.1[M+1]

Example 191(R) -1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 191

Mixing the mixture containing 3- (6-fluoropyridin-3-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]A solution of pyridine (0.070g,0.00019mol) and tert-butyl (R) -piperidin-3-ylcarbamate (0.224g,0.00112mol) in dimethyl sulfoxide (1.40mL,0.0197mol) was heated at 95 ℃ for 18 hours. The reaction mixture was quenched with water, then filtered and washed with water. The crude product was dried under high vacuum overnight to give (3R) -1- (5- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ylcarbamic acid tert-butyl ester was dissolved in dichloromethane (1.4mL,0.022mol) and then treated with trifluoroacetic acid (0.72mL,0.0093 mol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated and then subjected to rlhplc to give 191(50.6mg,73% yield). ESI MS M/z =372.1(M +1).¹H NMR(400MHz,DMSO)δ9.40(d,J=1.7Hz,1H),9.18(s,1H),8.88(d,J=2.3Hz,1H),8.60–8.53(m,3H),8.21(dd,J=8.9,2.4Hz,1H),7.50(dd,J=7.7,5.1Hz,1H),6.97(d,J=9.0Hz,1H),4.27(dd,J=23.6,12.1Hz,2H),2.88(dd,J=17.5,7.2Hz,2H),2.73–2.56(m,2H),1.89(d,J=12.0Hz,1H),1.73(d,J=13.5Hz,1H),1.47(dd,J=24.5,12.1Hz,1H),1.25(ddd,J=16.2,12.6,4.0Hz,1H)

Example 1933- (1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 193

A mixture of 3- (1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine (29.36mg,0.08476mmol) in 4.0M hydrogen chloride in 1, 4-dioxane (5mL) and 1, 4-dioxane (5mL) was stirred at room temperature overnight. The reaction mixture was concentrated, then the residue was purified by reverse phase HPLC to give 193 as an off-white solid (10.2mg, 45.9%). 1H NMR (400MHz, DMSO). delta.13.71 (s,1H),13.14(s,1H),9.23(d, J =31.1Hz,2H), 8.72-8.55 (M,2H),8.43(s,1H),7.91(s,1H),7.53(dd, J =8.0,4.8Hz,1H),6.84(s,1H), ESI MS M/z =263.0(M +1)

Example 1945- (pyridin-3-yl) -3- (pyridin-4-yl) -1H-pyrazolo [3,4-c]Pyridine 194

3-iodo-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c from example 4 was added to a microwave vial]Pyridine (100mg,0.31mmol), pyridin-4-ylboronic acid (190mg,1.55mmol), Pd (dppf) Cl₂(50mg,0.06mmol), sodium carbonate (131mg,1.24mmol), 1, 2-dimethoxyethane (2mL), ethanol (0.3mL), and water (0.3 mL). The tube was purged with nitrogen for 2 minutes and then heated in a Biotage microwave for 1 hour at 160 ℃. The solvent was distilled off and then 15% CH₃CN/10mmol NH₄HCO₃The crude product was purified by reverse phase HPLC eluting with aqueous solution to give 194 as a white solid (18mg, 21%).¹H NMR(400MHz,DMSO)¹H NMR(500MHz,DMSO)δ9.44(s,1H),9.28(s,1H),8.76–8.73(m,3H),8.62–8.59(m,2H),8.19(d,J=6.0Hz,2H),7.55–7.53(m,1H).ESI MS m/z=274(M+1)

Example 196(S) -1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 196

Following the procedure in example 191, 3- (6-fluoropyridin-3-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine is converted to 196. ESI MS M/z =372.1(M +1).¹H NMR(400MHz,DMSO)δ9.40(d,J=1.6Hz,1H),9.18(s,1H),8.87(d,J=2.4Hz,1H),8.62–8.50(m,3H),8.21(dd,J=8.9,2.4Hz,1H),7.50(dd,J=8.0,4.7Hz,1H),6.97(d,J=9.0Hz,1H),4.27(dd,J=23.4,12.0Hz,2H),2.94–2.82(m,1H),2.65(m,2H),1.90(d,J=9.1Hz,1H),1.78–1.64(m,2H),1.55–1.37(m,1H),1.33–1.17(m,1H)

Example 1971- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 197

Following the procedure in example 191, 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine is converted to 197. ESI MS M/z =386.1(M +1).¹H NMR(400MHz,DMSO)δ9.25–9.17(m,1H),8.97(s,1H),8.60(d,J=4.7Hz,1H),8.38(d,J=7.9Hz,1H),7.66–7.59(m,1H),7.55(dd,J=7.9,4.7Hz,1H),7.42(d,J=7.3Hz,1H),6.64(d,J=8.6Hz,1H),3.99–3.89(m,1H),3.86–1.77(m,1H),3.74–3.56(m,1H),2.98–2.83(m,1H),2.08–1.96(m,2H),1.92–1.54(m,3H),1.47–1.34(m,1H)

Example 2006- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) -N- (piperidin-4-yl) pyridin-2-amine 200

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and 4-aminopiperidine-1-carboxylic acid tert-butyl ester, followed by deprotection of the product to give 200 as a white solid(5.4% over two steps).¹H NMR(400MHz,MeOD)δ8.97(s,1H),8.61(s,1H),8.47(s,2H),8.12(s,1H),8.01(s,1H),7.55(t,J=7.8Hz,1H),7.44(d,J=7.3Hz,1H),6.57(d,J=8.2Hz,1H),4.69(m,1H),4.41-4.32(m,1H),3.99(s,3H),3.52-3.43(m,2H),3.12(dd,J=16.9,6.7Hz,2H),2.44-2.33(m,2H),1.97-1.85(m,2H).LC/MS:m/z375.1[M+1]

Example 202(S) -1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine 202

Following the procedure in example 191, 3- (6-fluoropyridin-3-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine is converted to 202. ESI MS M/z =358.1(M +1).¹H NMR(400MHz,DMSO)δ9.41(s,1H),9.17(s,1H),8.89(d,J=2.2Hz,1H),8.62–8.54(m,3H),8.20(dd,J=8.8,2.3Hz,1H),7.54–7.46(m,1H),6.58(d,J=8.8Hz,1H),3.66–3.56(m,3H),3.52–3.44(m,1H),3.19–3.11(m,1H),2.15–2.03(m,1H),1.80–1.70(m,1H)

Example 203(R) -1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine 203

Following the procedure in example 191, 3- (6-fluoropyridin-3-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine is converted to 203. ESI MS M/z =358.1(M +1).¹H NMR(400MHz,DMSO)δ9.41(s,1H),9.17(s,1H),8.89(d,J=2.2Hz,1H),8.62–8.52(m,3H),8.20(dd,J=8.8,2.3Hz,1H),7.50(dd,J=7.5,5.1Hz,1H),6.58(d,J=8.8Hz,1H),3.67–3.56(m,3H),3.52–3.40(m,1H),3.22–3.10(m,1H),2.16–2.00(m,1H),1.81–1.68(m,1H)

Example 2043- (pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 204

3-iodo-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c from example 4 was added to a microwave vial]Pyridine (120mg,0.37mmol), 2- (butyldipentylstannyl) pyridine (168mg,0.45mmol), Pd (PPh)₃(12mg,0.015mmol), LiCl (48mg,1.14mmol), CuI (12mg,0.06mmol), and 1, 4-dioxane (0.3 mL). The tube was purged with nitrogen for 2 minutes and then heated in a Biotage microwave at 140 ℃ for 15 minutes. Distilling off the solvent, then adding 10% -80% CH₃CN/0.5%NH₄The crude product was purified by reverse phase combiflash eluting with aqueous OH to give 204 as a pale red solid (11mg, 11%).¹H NMR(400MHz,DMSO)¹H NMR(500MHz,DMSO)δ14.0(s,1H),9.30(s,1H),9.25(s,1H),8.97(s,1H),8.81(d,J=4.0Hz,1H),8.62–8.61(m,1H),8.45(d,J=8.5Hz,1H),8.22(d,J=7.5Hz,1H),7.97–7.94(m,1H),7.55-7.53(m,1H),7.45–7.43(m,1H).ESI MS m/z=274(M+1)

Example 2053- (2-fluoro-5-methylphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine 205

Following the procedure in example 172, 2-fluoro-5-methylphenylboronic acid and 3-chloro-5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine reaction, followed by deprotection gave 205 as a white solid (21.3% over two steps).¹H NMR(400MHz,DMSO)δ(400MHz,DMSO)δ13.86(s,1H),9.05(s,1H),8.25(s,1H),7.98(s,1H),7.88(d,J=2.7Hz,1H),7.63(d,J=6.3Hz,1H),7.36–7.27(m,2H),3.88(s,3H),2.40(s,3H).LC/MS:m/z308.0[M+1]

Example 206(S) -1- (6- (5- (5-fluoropyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 206

Mixing the mixture containing 3- (6-fluoropyridin-2-yl) -5- (5-fluoropyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]A solution of pyridine (0.055g,0.14mmol) and tert-butyl (S) -piperidin-3-ylcarbamate (0.196g,0.979mmol) in dimethyl sulfoxide (0.840mL,11.8mmol) was stirred at 95 ℃ for 18 hours. The reaction mixture was quenched with water and then extracted 2 times with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was dried under high vacuum overnight to give (3S) -1- (6- (5- (5-fluoropyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ylcarbamic acid tert-butyl ester was dissolved in 1, 4-dioxane (1.50mL,19.2mmol) and treated with a 4.0M solution of hydrogen chloride in 1, 4-dioxane (2.50 mL). The reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated and then subjected to rlhplc to give 206(37.8mg,69% yield). ESI MS M/z =390.1(M +1).¹H NMR(400MHz,DMSO)δ9.22(s,1H),9.18(s,1H),9.03(s,1H),8.60(d,J=2.7Hz,1H),8.32(d,J=10.3Hz,1H),7.66(t,J=8.0Hz,1H),7.45(d,J=7.4Hz,1H),6.87(d,J=8.5Hz,1H),4.37–4.25(m,2H),3.08–2.96(m,1H),2.85–2.75(m,2H),2.00–1.88(m,1H),1.85–1.75(m,1H),1.68–1.56(m,1H),1.42–1.25(m,1H)

Example 2085- (5-Fluoropyridin-3-Yl) -3- (6- (piperazin-1-Yl) pyridin-2-Yl) -1H-pyrazolo [3,4-c]Pyridine 208

Following the procedure in example 206, 3- (6-fluoropyridin-2-yl) -5- (5-fluoropyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine is converted to 208. ESI MS M/z =376.1(M +1).¹H NMR(400MHz,DMSO)δ9.23(s,1H),9.12(s,1H),9.02(s,1H),8.61(d,J=2.7Hz,1H),8.23(d,J=10.4Hz,1H),7.69(t,J=7.9Hz,1H),7.49(d,J=7.4Hz,1H),6.88(d,J=8.5Hz,1H),3.67–3.60(m,4H),2.94–2.86(m,4H

Example 210(R) -1- (6- (5- (5-fluoropyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 210

Following the procedure in example 206, 3- (6-fluoropyridin-2-yl) -5- (5-fluoropyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]The pyridine is converted to 210. ESI MS M/z =390.1(M +1).¹H NMR(400MHz,DMSO)δ9.23(s,1H),9.18(s,1H),9.02(s,1H),8.60(d,J=2.7Hz,1H),8.32(d,J=10.4Hz,1H),7.66(t,J=8.0Hz,1H),7.45(d,J=7.4Hz,1H),6.87(d,J=8.5Hz,1H),4.39–4.23(m,2H),3.08–2.98(m,1H),2.86–2.74(m,2H),1.99–1.88(m,1H),1.71–1.65(m,1H),1.62–1.58(m,1H),1.38–1.30(m,1H)

Example 2123- (6- (piperazin-1-yl) pyridin-2-yl) -5- (tetrahydrofuran-3-yl) -1H-pyrazolo [3,4-c]Pyridine 212

Following the procedure in example 206, 3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -5- (tetrahydrofuran-3-yl) -1H-pyrazolo [3,4-c]Pyridine is converted to 212. ESI MS M/z =351.1(M +1).¹H NMR(400MHz,DMSO)δ9.02(s,1H),8.29(s,1H),7.66(t,J=7.9Hz,1H),7.46(d,J=7.4Hz,1H),6.84(d,J=8.5Hz,1H),4.13(t,J=7.6Hz,1H),3.99–3.83(m,2H),3.80–3.60(m,2H),3.65–3.60(m,4H),3.00–2.92(m,4H),2.45–2.35(m,1H),2.25–2.15(m,1H)

Example 2135- (1H-imidazol-5-yl) -3-phenyl-1H-pyrazolo [3,4-c]Pyridine 213

Following the procedure in example 204, 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-imidazole and 5-bromo-3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine reaction, followed by deprotection of the product, gave 213 as a yellow solid in two steps (30mg, 25%).¹H NMR(400MHz,DMSO)δ8.23(s,1H),7.75(s,1H),7.43(m,1H),7.34(m,1H),7.27(m,2H),6.77(m,2H),6.66(m,1H).ESI MSm/z=262(M+1)

Example 2143-phenyl-5- (pyrazin-2-yl) -1H-pyrazolo [3,4-c]Pyridine 214

Following the procedure in example 204, 2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazine and 5-bromo-3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine reaction, followed by deprotection of the product, gave 214 as a yellow solid in two steps (22mg, 28%).¹H NMR(400MHz,DMSO)δ9.61(s,1H),9.26(s,1H),8.97(s,1H),8.76(s,1H),8.67(d,1H),8.05(t,2H),7.61(t,2H),7.48(t,1H).ESIMS m/z=274(M+1)

Example 2153- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 215

Step 1 5-bromo-3- (1H-pyrazol-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine (408.03mg,1.0mmol), 1H-pyrazol-3-ylboronic acid (117.49mg,1.05mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (81.66mg,0.1mmol), 1.00M aqueous potassium acetate (1.5mL,1.5mmol), 1.00M aqueous sodium carbonate (1.5mL,1.5mmol), and acetonitrile (3mL) were charged to a microwave reaction flask. The reaction mixture was heated at 100 ℃ for 20 minutes under microwave. An additional 2 equivalents of 1H-pyrazol-3-ylboronic acid were added, followed by continued heating at 100 ℃ for 20 minutes under microwave. The same operation was repeated 2 more times. The mixture was concentrated and the residue was purified on silica gel eluting with 0-100% ethyl acetate/heptane to give 5-bromo-3- (1H-pyrazol-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine as an off-white solid (153.7mg, 44%).

Step 2 3- (1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

Reacting 5-bromo-3- (1H-pyrazol-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridine (as an off-white solid) (153.7mg0.44mmol), 3-pyridylboronic acid (81.62mg,0.66mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (36.15mg,0.044mmol), 1.00M potassium acetate in waterThe solution (0.66mL,0.66mmol), 1.00M aqueous sodium carbonate (0.66mL,0.66mmol) and acetonitrile (3mL) were charged to a microwave reaction flask. The reaction mixture was heated at 130 ℃ for 20 minutes under microwave. The mixture was concentrated and then concentrated to contain 1% NH₄OH 0-7% MeOH/DCM and the residue was purified on silica gel to give 3- (1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine (73.4mg, 48%).

Step 3 tert-butyl 4- (3- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

A mixture of 3- (1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine (44.0mg,0.13mmol), 1-N-BOC-4-bromopiperidine (100.8mg,0.38mmol), and cesium carbonate (124.3mg,0.38mmol) in N, N-dimethylformamide (5mL) was heated at 100 ℃ for 7 days. The mixture was concentrated to give tert-butyl 4- (3- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate, which was used without purification.

Step 4 a solution of tert-butyl 4- (3- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (17.0mg,0.032mmol) in dioxane (5mL) was treated with 4.0M hydrogen chloride in 1, 4-dioxane (5mL) at room temperature overnight. The reaction mixture was concentrated, then the residue was purified by reverse phase HPLC to give 215 as an off-white solid (1.2mg, 18%). 1H NMR (400MHz, DMSO) δ 9.28(s,1H),9.19(s,1H), 8.70-8.57 (M,2H),8.44(d, J =7.6Hz,1H),8.30(s,1H),7.94(s,1H), 7.59-7.51 (M,1H),6.84(s,1H),4.47(s,1H),3.22(d, J =12.7Hz,2H),2.82(t, J =12.0Hz,2H),2.15(d, J =11.5Hz,2H),2.04(d, J =9.0Hz,2H) ESI MS M/z =346.1(M +1)

Example 2163- (6- ((1S,4S) -2, 5-diazabicyclo [ 2.2.1)]Hept-2-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c]Pyridine 216

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and 2- (1-trityl-1H-imidazol-4-yl) -ethylamine. The product was deprotected to give 216 as a white solid (69.7% over two steps).¹H NMR (400MHz, DMSO) δ 9.02(s,1H),8.59(s,1H),8.11(s,1H),7.84(s,1H),7.59(t, J =7.9Hz,1H),7.36(d, J =7.4Hz,1H),6.64 (broad singlet, 1H),6.50(d, J =8.2Hz,1H),4.76(s,1H),3.91(s,3H),3.75(s,1H),3.69(d, J =8.5Hz,1H), 3.49-3.32 (M,2H),3.00(s,2H),1.89(d, J =8.5Hz,1H),1.78(d, J =9.1Hz,1H), LC/MS: M +1 z373.1[ M + 1H ]/]]

Example 217N- (2- (1H-imidazol-4-yl) ethyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-amine 217

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and 2- (1-trityl-1H-imidazol-4-yl) -ethylamine. The product was deprotected to afford 217 as a white solid (37.6% over two steps).¹H NMR(400MHz,DMSO)δ9.01(s,1H),8.62(s,1H),8.26(s,1H),8.03(s,1H),7.88(s,1H),7.56(s,1H),7.49(d,J=8.1Hz,1H),7.34(d,J=7.4Hz,1H),6.86(s,1H),6.80(s,1H),6.49(d,J=8.3Hz,1H),3.88(s,3H),3.78–3.70(m,2H),2.92(t,J=7.5Hz,2H),2.54(s,1H).LC/MS:m/z386.1[M+1]

Example 2183- (2-fluorophenyl) -5- (1H-imidazol-5-yl) -1H-pyrazolo [3,4-c]Pyridine 218

Step 1-5-bromo-3- (2-fluorophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

Adding 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) to a microwave tube]Pyridine (300mg,0.74mmol), 2-fluorophenylboronic acid (134mg,0.96mmol), Pd (dppf) Cl₂(60mg,0.07mmol), sodium carbonate (314mg,2.96mmol), 1, 2-dimethoxyethane (3mL), ethanol (0.3mL), and water (0.3 mL). The tube was purged with nitrogen for 2 minutes and then heated in a Biotage microwave at 145 ℃ for 1 hour. Distilling off the solvent, eluting with 20% -95% ethyl acetate/petroleum ether, and purifying the crude product by flash chromatography to obtain 5-bromo-3- (2-fluorophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine as a yellow oil (105mg, 38%). ESI MS M/z =377(M +1).

Step 2 3- (2-fluorophenyl) -1- (tetrahydro-2H-pyran-2-yl) -5- (1- (tetrahydro-2H-pyran-2-yl) -1H-imidazol-5-yl) -1H-pyrazolo [3,4-c ] pyridine

To a 100mL round bottom flask was added 5-bromo-3- (2-fluorophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine (150mg,0.40mmol), 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-imidazole (222mg,0.80mmol), Pd (PPh)₃)₄(33mg,0.04mmol), CsF (152mg,1mmol), CuI (8mg,0.04mmol) and DMF (6 mL). The reaction mixture was heated at 90 ℃ overnight under nitrogen. The resulting mixture was poured into 50mL of water and then extracted with ethyl acetate (50mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried, filtered and then concentrated. With 5% -10% CH₃OH/CH₂Cl₂Eluting, and purifying the residue by flash chromatography to obtain 3- (2-fluorophenyl) -1- (tetrahydro-2H-pyran-2-yl) -5- (1- (tetrahydro-2H-pyran-2-yl) -1H-imidazol-5-yl) -1H-pyrazolo [3,4-c]Pyridine as a brown oil (100mg, 84%). ESI MS M/z =448(M +1).

Step 3 Add 3- (2-fluorophenyl) -1- (tetrahydro-2H-pyran-2-yl) -5- (1- (tetrahydro-2H-pyran-2-yl) -1H-imidazol-5-yl) -1H-pyrazolo [3,4-c ] to a 50mL round-bottom flask]Pyridine (150mg,0.33mmol) and 4N HCl-dioxane (5 mL). The mixture was stirred at 25 ℃ for 2 hours. The solvent was distilled off. With 35% CH₃CN/10mmol NH₄HCO₃The crude product was purified by reverse phase HPLC eluting with aqueous solution to give 218 as a white solid (20mg, 21%).¹H NMR(500MHz,DMSO)δ13.93(s,1H),12.21(s,1H),9.05(s,1H),8.20(s,1H),7.86(t,J=7.0,1H),7.71(s,1H),7.62(s,1H),7.56–7.54(m,1H),7.46(t,J=10.0,1H),7.41(t,J=7.5,1H).ESI MS m/z=280(M+1)

Example 2193- (2-fluorophenyl) -5- (pyrazin-2-yl) -1H-pyrazolo [3,4-c]Pyridine 219

The procedure described in example 218 was followed and repeated using 3- (2-fluorophenyl) -5- (pyrazin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine started to give 219 in two steps as a pale red solid (16mg, 20%).¹H NMR(500MHz,DMSO)δ9.60(s,1H),9.27(s,1H),8.77(s,1H),8.73(s,1H),8.67(s,1H),7.93–7.90(m,1H),7.60–7.56(m,1H),7.49(t,J=8.0,1H),7.43(t,J=8.0,1H).ESI MS m/z=292(M+1)

Example 222(R) -1- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) phenyl) piperidin-3-amine 222

Step 1 (3R) -1- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) phenyl) piperidin-3-ylcarbamic acid tert-butyl ester

(R) -1- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperidin-3-ylamino following the Suzuki coupling procedure in example 172Tert-butyl formate and 3-chloro-5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine reaction to obtain (3R) -1- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) phenyl) piperidin-3-ylcarbamic acid tert-butyl ester as a solid (60%).¹H NMR(400MHz,CDCl₃)δ9.12(s,1H),7.97(s,1H),7.95(s,1H),7.93(s,1H),7.34(t,J=7.8Hz,1H),7.26(s,1H),7.19(s,1H),6.73(d,J=8.4Hz,1H),5.90–5.83(m,1H),4.09–4.00(m,2H),3.97(s,3H),3.88–3.76(m,2H),3.67(s,1H),3.52(s,1H),3.17(s,1H),3.03(s,1H),2.64–2.52(m,1H),2.17(d,J=10.1Hz,2H),2.09–1.99(m,1H),1.84–1.70(m,5H),1.65–1.54(m,1H),1.41(s,9H).LC/MS:m/z558.2[M+1].

Step 2 (3R) -1- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) following the procedure in example 189]Pyridin-3-yl) phenyl) piperidin-3-ylcarbamic acid tert-butyl ester deprotected to give 222 as a solid (55.4%).¹H NMR (400MHz, DMSO) δ 9.02(s,1H),8.31(s,1H),8.28(s,1H),8.13(s,1H),8.05(s,1H),7.34-7.21(m,3H),6.70-6.65(m,1H),5.74(d, J =7.7Hz,1H),3.90(s,3H),3.24(d, J =11.4Hz,1H),2.96(d, J =12.3Hz,1H),2.62(t, J =11.4Hz,1H),2.45(d, J =10.7Hz,1H),2.05-1.96(m,1H),1.82-1.73(m,1H), 1.63-1.39 (m,2H),2 protons. LC/MS M/z374.1[ M +1]]

Example 2231-methyl-4- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c]Pyridin-5-yl) piperazin-2-one 223

Following the procedure of example 224, (3S) -1- (6- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ylcarbamic acid tert-butyl ester and 1-methylpiperazin-2-one were reacted and then deprotected by the procedure of example 229. The mixture was purified by lyophilization from water followed by trituration of the crude product with cold methanol. The solid material was collected via filtration, yielding 52mg (28%) of 223 in two steps. ESI MS M/z393.2(M +1).¹H NMR(400MHz,DMSO)δ13.55(s,1H),9.07(s,2H),8.81(s,1H),7.73(t,J=8.0Hz,1H),7.60(s,1H),7.52(d,J=7.5Hz,1H),6.92(d,J=8.5Hz,1H),3.95(s,2H),3.88(m,6H),3.48–3.44(m,2H),3.31(s,4H),2.91(s,3H)

Example 2241- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-5-yl) urea 224

Step 1 tert-butyl 4- (6- (5- (3-tert-butylureido) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate

A mixture of 109mg (0.2mmol) of tert-butyl 4- (6- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate, 46.5mg (0.40mmol) of (1, 1-dimethylethyl) urea, 23mg (0.040mmol) of 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene and 130mg (0.40mmol) of cesium carbonate in 1ml of dioxane was degassed and then heated at 95 ℃ for 30 minutes. The mixture was diluted with 10ml of dichloromethane and then filtered through celite. The filtrate was concentrated and the title compound was purified by silica gel chromatography using a gradient of ethyl acetate/heptane to yield 86mg (74%) of tert-butyl 4- (6- (5- (3-tert-butylureido) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate. ESI MS M/z579.2(M +1).

Step 24- (6- (5- (3-tert-butylureido) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) by the procedure of example 229]Pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester deprotection followed by a reaction with a solution containing 0.1% NH₄A gradient of OH in MeOH/water, purified by reverse phase HPLC, provided 17mg (25%) of 224 in two steps. ESI MS M/z339.1(M +1).1H NMR (400MHz, DMSO). 13.71-13.30 (s,1H),8.93(s,1H),8.74(d, J =10.4Hz,2H),7.52(M,1H),7.41(d, J =7.4Hz,1H),6.76(d, J =8.4Hz,1H),6.34(s,2H),3.57(s,2H),2.87(d, J =4.7Hz,2H)

Example 2253-cyclopentenyl-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 225

Step 1 3-cyclopentenyl-5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

The Suzuki coupling procedure of example 159 was followed to react 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and 2-cyclopentenyl-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane. The product was reacted with 3-pyridineboronic acid pinacol ester by the Suzuki coupling procedure of example 10, and the mixture was then purified by silica gel chromatography with a gradient of ethyl acetate/heptane to yield 106mg (61%) of 3-cyclopentenyl-5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine in two steps. ESI MS M/z347.3(M +1).

Step 2. mu.g (0.10mmol) of 3-cyclopentenyl-5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]A mixture of pyridine in 4ml of trifluoroacetic acid was stirred for 6 hours. The mixture was concentrated in vacuo and the residue partitioned between saturated aqueous NaHCO3 and ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4, and then concentrated. With a content of 0.1% NH₄A MeOH/water gradient of OH and the residue was purified by reverse phase HPLC to give 10mg (38%) of 225. ESI MS M/z263.0(M +1).1H NMR (400MHz, DMSO). 13.59(s,1H),9.39(s,1H),9.14(s,1H), 8.53-8.600 (M,3H),7.50(dd, J =7.9,4.8Hz,1H),6.88(s,1H),2.91(t, J =6.6Hz,2H),2.64(s,2H), 2.04-1.94 (M,2H)

Example 2261- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-3-amine 226

Following the procedure described in example 189, 3- (6-fluoro)Pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine is reacted with t-butyl azepan-3-ylcarbamate. The product was deprotected to give 226 as a white solid (58.6% over two steps).¹H NMR (400MHz, DMSO) δ 9.04(s,1H),8.52(s,1H),8.32(s,1H),8.28(s,1H),7.94(s,1H),7.64(t, J =7.9Hz,1H),7.43(d, J =7.4Hz,1H),6.75(d, J =8.5Hz,1H),4.18(d, J =12Hz,1H), 4.13-4.06 (m,1H),3.90(s,3H),3.54(m,1H),3.36(d, J =8.8Hz,1H),3.32(s,1H),2.05-1.95(m,1H),1.84-1.69(m,3H),1.53-1.41(m,1H),1.40-1.27(m, 2H), see no protons. LC/MS M/z389.2[ M +1]]

Example 227(S) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 227

Step 1 (4S) -benzyl 1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamate

Following the procedure of example 189, benzyl (S) -azepan-4-ylcarbamate and 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine were reacted to give benzyl (4S) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamate, as a solid (73.4%). LC/MS: M/z607.3[ M +1].

Step 2 reaction of (4S) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) at-10 deg.C]Pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamic acid benzyl ester (70.0mg,0.13mmol) in DCM (5.0mL) was added dropwise with a solution of 1M boron tribromide in DCM (0.33mL,0.33mmol), and the reaction mixture was slowly warmed to Room Temperature (RT) and at RT N₂Stirred for 16 hours. The reaction mixture was diluted into ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, washed with Na₂SO₄DryingFiltered and then concentrated under reduced pressure. The crude product was redissolved in DMSO (1mL) and then purified by reverse phase HPLC to give 227 as a white solid (4.3mg, 8.3%).¹H NMR (400MHz, DMSO) δ 9.03(s,1H),8.55(s,1H),8.11(s,1H),7.83(s,1H),7.60(t.J =7.8Hz,1H),7.37(d, J =7.1Hz,1H),6.61(d, J =8.4Hz,1H),3.91(s,3H),3.85-3.75(m,1H),3.74-3.58(m,2H),3.33-3.40(m,1H),2.95-2.85(m,1H),2.12-1.93(m,2H), 1.86-1.58 (m,3H), 1.56-1.33 (m,2H);2 protons are not seen. LC/MS M/z389.4[ M +1]]

Example 2283-cyclopentyl-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 228

Step 1 3-cyclopentyl-5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine

A mixture of 42mg (0.12mmol) of 3-cyclopentenyl-5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine, 2.0ml (21mmol) of 1, 4-cyclohexadiene and 100mg of 10% palladium on charcoal in 10ml of ethanol is heated to reflux for 48 hours, during which 1, 4-cyclohexadiene is added incrementally. The mixture was filtered through celite, and the filtrate was concentrated to give 31mg (76%) of 3-cyclopentyl-5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine. ESIMS M/z349.2(M +1).

Step 2-deprotection of 3-cyclopentyl-5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine by the procedure of example 229 followed by purification by trituration with ether. The product was collected via filtration to yield 9mg (30%) of 228. ESI MS M/z265.0(M +1).1H NMR (400MHz, DMSO). 13.24(s,1H),9.33(s,1H),9.08(s,1H),8.56(d, J =4.2Hz,1H),8.48(d, J =8.0Hz,1H),8.40(s,1H),7.50(M,1H),3.54(dd, J =16.4,8.2Hz,1H),2.16(M,2H), 2.00-1.63 (M,6H)

Example 2294-amino-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxamide 229

Step 1 methyl 4- (tert-Butoxycarbonylamino) -1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxylate

Following the procedure of example 144, 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and methyl 4- (tert-butoxycarbonylamino) piperidine-4-carboxylate were reacted and then purified by silica gel chromatography using a gradient of EtOAc/heptane to give 241mg (67%) of methyl 4- (tert-butoxycarbonylamino) -1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxylate And (3) an ester. ESI MS M/z614.2(M +1).

Step 2- (tert-Butoxycarbonylamino) -1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxylic acid

A mixture of 240mg (0.39mmol) of methyl 4- (tert-butoxycarbonylamino) -1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxylate and 3ml of a 1M aqueous solution of lithium hydroxide in 20ml of methanol and 10ml of tetrahydrofuran is stirred at room temperature for 18 hours and at 60 ℃ for 2 hours. The mixture was concentrated in vacuo, neutralized to pH5 by careful addition of 1N aqueous HCl, then extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated to give 150mg (43%) of 4- (tert-butoxycarbonylamino) -1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxylic acid over two steps. ESI MS M/z600.2(M +1).

Step 3 tert-butyl 4-carbamoyl-1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ylcarbamate

N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluoroborate (45.6mg,0.120mmol) was added to a mixture of 4- (tert-butoxycarbonylamino) -1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxylic acid (60.0mg,0.100mmol), ammonium chloride (21mg,0.40mmol) and N, N-diisopropylethylamine (0.087ml,0.50mmol) in 2ml of N, N-dimethylformamide. The mixture was stirred for 18 hours and then concentrated. The residue was partitioned between ethyl acetate and 1% aqueous citric acid. The organic extracts were washed with water, 5% aqueous NaHCO3, brine, dried over MgSO4, and concentrated to give tert-butyl 4-carbamoyl-1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ylcarbamate. Yield 47mg (78%). ESI MS M/z599.2(M +1).

Step 4 a mixture of 45mg (0.08mmol) of tert-butyl 4-carbamoyl-1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ylcarbamate in 3ml of methanol and 12ml of 4N HCl dioxane was stirred for 18 hours. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC using a MeCN/water gradient containing 0.1% HCOOH to give 20mg (43%) of 229. ESI MS M/z415.2(M +1).1H NMR (400MHz, DMSO):9.22(d, J =5.7Hz,2H),8.94(s,1H),8.60(d, J =4.6Hz,1H), 8.40-8.32 (M,4H),7.67(t, J =7.9Hz,1H),7.54(dd, J =8.0,4.8Hz,1H),7.46(d, J =7.4Hz,1H),6.95(s,1H),6.90(d, J =8.5Hz,1H),4.20(d, J =13.2Hz,1H),3.50(t, J =11.4Hz,1H),2.06(td, J =13.0,4.2, 1H),1.48(d, J =13.2, 1H).

Example 2323- (1-methyl-1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 232

Step 1 3- (1-methyl-1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine

A microwave reaction vial was charged with 3-iodo-5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (49.10mg,0.11mmol), 1-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (33.19mg,0.16mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (8.68mg,0.011mmol), 1.00M aqueous potassium acetate (0.16mL,0.16mmol), 1.00M aqueous sodium carbonate (0.16mL,0.16mmol), and acetonitrile (3 mL). The reaction mixture was heated at 150 ℃ for 5 minutes under microwave. The mixture was concentrated to give 3- (1-methyl-1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine, which was used without purification.

Step 2 a solution of 3- (1-methyl-1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (43.22mg,0.1063mmol) in dioxane (5mL) was treated with a 4.0M solution of hydrogen chloride in 1, 4-dioxane (5mL) at room temperature overnight. The reaction mixture was concentrated, then the residue was purified by reverse phase HPLC to give 232 as an off-white solid (23.7mg, 81%). 1H NMR (400MHz, DMSO) δ 13.74(s,1H),9.33(s,1H),9.19(s,1H),8.67(d, J =11.2Hz,2H),8.56(d, J =7.9Hz,1H),7.85(s,1H),7.63(s,1H),6.82(s,1H),4.01(s,3H). ESI MS M/z =277.0(M +1)

Practice ofExample 2345- (1-methyl-1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c]Pyridine 234

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and 1-piperazine carboxylic acid tert-butyl ester. The product was deprotected to afford The234 as a white solid (61% over two steps).¹H NMR (400MHz, DMSO) δ 9.03(s,1H),8.53(s,1H),8.11(s,1H),7.82(s,1H),7.65(t, J =7.9Hz,1H),7.45(d, J =7.2Hz,1H),6.83(d, J =8.5Hz,1H),3.91(s,3H),3.63(s,4H),2.94(s,4H), 2 protons not seen. LC/MS M/z361.1[ M +1]]

Example 2352- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-5-yl) acetonitrile 235

Step 1 tert-butyl 4- (6- (5- (cyanomethyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate

0.940mL of a 1.6M solution of n-butyllithium in hexane was added dropwise to a solution of 0.102mL (1.95mmol) of acetonitrile in tetrahydrofuran at-78 ℃. The mixture was stirred for 30 minutes, then 272mg (0.500mmol) of a solution of 4- {6- [ 5-bromo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl ] -pyridin-2-yl } -piperazine-1-carboxylic acid tert-butyl ester was added. The brown mixture was stirred at-50 ℃ for 30 minutes, then 2ml of saturated aqueous NH4Cl solution were added. The mixture was warmed to room temperature and then extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4, and then concentrated. The residue was purified by silica gel chromatography with a gradient of ethyl acetate/heptane to yield 44mg (17%) of tert-butyl 4- (6- (5- (cyanomethyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate. ESI MS M/z504.2(M +1).

Step 2 following the procedure of example 225, 4- (6- (5- (cyanomethyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester deprotection followed by a reaction with a solution containing 0.1% NH₄A gradient of OH in MeOH/water, purified by reverse phase HPLC, provided 10.4mg (6.5%) of 235 over two steps. ESI MS M/z320.1(M +1).¹H NMR(400MHz,DMSO)δ13.34(s,1H),7.62(dd,J=8.4,4.1Hz,1H),7.04(d,J=7.2Hz,1H),6.98(d,J=9.1Hz,1H),6.79(d,J=8.6Hz,1H),5.98(s,1H),3.63(s,2H),2.92(s,2H)

Example 2364-amino-N-methyl-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxamide 236

Following the procedure of example 229, the reaction was carried out starting with 4- (tert-butoxycarbonylamino) -1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxylic acid and methylamine, followed by purification by reverse phase HPLC using a MeCN/water gradient containing 0.1% HCOOH to give 19mg (24%) of 236 over two steps. ESI MS M/z429.2(M +1).1H NMR (400MHz, DMSO). 13.95(s,1H),9.22(d, J =8.4Hz,2H),8.92(s,1H),8.61(s,1H),8.41(d, J =7.6Hz,1H),8.28(s,1H),8.13(s,1H),7.72(t, J =7.9Hz,1H),7.52(d, J =7.6Hz,2H),6.96(d, J =8.3Hz,1H),6.49(s,1H),4.27(d, J =13.0Hz,2H),3.53(t, J =12.5Hz,2H),2.67(s,3H),2.29(M,2H), 1.87-1.73 (M,2H).

Example 237(R) -2- (1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-yl) ethylamine 237 andexample 242(S) -2- (1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-yl) ethylamine 242

Following the procedure of example 149, and substituting 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and racemic tert-butyl 2- (piperidin-3-yl) ethylcarbamate to give 237 and 242, which were then washed with a solution containing 0.1% NH₄A MeOH/water gradient of OH, purification by reverse phase HPLC, followed by separation of the enantiomers by SFC, yielded 27mg (14%) and 23mg (12%).

ESI MS m/z400.2(M+1).1H NMR(400MHz,DMSO):9.24(d,J=8.8Hz,2H),8.96(s,1H),8.61(s,1H),8.42(d,J=8.2Hz,1H),7.67(t,J=7.9Hz,1H),7.60–7.52(m,1H),7.47(d,J=7.1Hz,1H),6.90(d,J=8.5Hz,1H),4.34(t,J=11.3Hz,2H),3.00(m,2H),2.83–2.76(m,2H),1.91-1.19(m,5H).

ESI MS m/z400.2(M+1).1H NMR(400MHz,DMSO):9.23(d,J=9.3Hz,2H),8.95(s,1H),8.60(s,1H),8.41(d,J=7.9Hz,1H),7.66(t,J=7.6Hz,1H),7.56(s,1H),7.46(d,J=6.3Hz,1H),6.88(d,J=7.9Hz,1H),4.30(t,J=10.7Hz,2H),3.02(m,2H),2.75-2.68(m,2H),1.88-1.17(m,5H)

Example 2383- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-5-yl) pyridin-2-amine 238

Step 1 tert-butyl 4- (6- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate

Following the procedure of example 144, 5-bromo-3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and tert-butyl piperazine-1-carboxylate were reacted, triturated with ether, and then collected via filtration to give 910mg (80%) of tert-butyl 4- (6- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate. ESI MS M/z543.2(M +1).

Step 2 5-bromo-3- (6-fluoropyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine were reacted following the Suzuki coupling procedure of example 10 and then deprotected by the procedure of example 229. The crude compound was triturated with ether then collected via filtration to give 117mg (81%) of 238. ESIMS M/z373.1(M +1).1H NMR (400MHz, DMSO). 14.25(s,1H),9.39(s,2H),9.25(s,1H),8.85(s,1H),8.77(s,2H),8.45(d, J =7.4Hz,1H),8.13(d, J =5.4Hz,1H),7.79(t, J =7.9Hz,1H),7.60(d, J =7.2Hz,1H),7.11(t,1H),7.01(d, J =8.3Hz,1H),3.91(s,2H),3.28(s,2H)

Example 239(1S,3R) -N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) cyclohexa-1, 3-diamine 239 andexample 245(1S,3S) -N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) cyclohexa-1, 3-diamine 245

Following the procedure of example 143 and substituting 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and cis-and trans-cyclohexanediamine to give 239 and 245, followed by a catalyst containing 0.1% NH₄A gradient of OH in MeOH/water followed by reverse phase HPLC followed by SFC separation of the enantiomers gave 35mg (29%) of ESI MS M/z386.1(M +1), and 10mg (8%). ESI MS M/z386.1(M +1).

Example 2403- (piperazin-1-yl) -5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridin-3-yl) benzonitrile 240

Following the Suzuki coupling procedure of example 159, 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and 4- (3-cyano-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester. The compound was reacted with 3-pyridineboronic acid pinacol ester by the Suzuki coupling procedure of example 10, followed by deprotection by the procedure of example 225. With a content of 0.1% NH₄A MeOH/water gradient of OH and reverse phase HPLC purified the mixture, yielding 37mg (19%) of 240 in three steps. ESI MS M/z382.2(M +1).1H NMR (400MHz, DMSO). 9.41(s,1H),9.23(s,1H), 8.68-8.59 (M,2H),8.55(d, J =7.8Hz,1H),7.87(s,1H),7.80(s,1H), 7.56-7.50 (M,1H),7.43(s,1H), 3.26-3.23 (M,4H),2.87-2.81(M,4H)

Example 2411- (3-chloro-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-4-amine 241

Step 1 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannanyl) -1H-pyrazolo [3,4-c ] pyridine

To a mixture of 3-iodo-5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (3.3435g,7.3912mmol) in tetrahydrofuran (50mL,600mmol) was added trans-dichlorobis (triphenylphosphine) palladium (II) (259.39mg,0.36956mmol), hexamethylditin (1.6859mL,8.1303mmol), and lithium chloride (1.8800g,44.347mmol) under argon. The resulting mixture was refluxed at 65 ℃ for 2 hours. The mixture was cooled to room temperature, filtered through celite and washed with ethyl acetate. The filtrate was concentrated and the residue was purified on silica gel eluting with 0-6% methanol/dichloromethane to give 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannanyl) -1H-pyrazolo [3,4-c ] pyridine as a yellow oil (2.2541g, 62.33%).

Step 2 3- (5-chloro-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine

To a solution of 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannanyl) -1H-pyrazolo [3,4-c ] pyridine (1.3490g,2.7571mmol) and 6-bromo-3-chloro-2-fluoropyridine (696.23mg,3.3086mmol) in tetrahydrofuran (10mL,100mmol) under argon at room temperature was added cesium chloride (837.64mg,5.5143mmol), palladium (II) dichloride (24.446mg,0.13786mmol), copper (I) iodide (52.510mg,0.27571mmol) and a 1.000M toluene solution of tri-tert-butylphosphine (275.71 uL). The tube was sealed and the mixture was then heated at 45 ℃ overnight. The reaction mixture was cooled to room temperature and then filtered through celite. The filter cake was washed with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with 0-100% EtOAc/heptane to give 3- (5-chloro-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine as a yellow oil which solidified upon standing.

Step 3A pressure tube was charged with 3- (5-chloro-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (103.4mg,0.2268mmol), 4- (N-Boc-amino) -piperidine (136.24mg,0.6803mmol), 4-methylmorpholine (249.30uL,10mmol) and N-methylpyrrolidinone (3 mL). The mixture was stirred at 120 ℃ overnight. The reaction mixture was cooled to rt, diluted with EtOAc and washed 3 times with water. The organic layer was dried over MgSO4 and then concentrated. The residue was purified on silica gel eluting with 0-100% EtOAc/DCM to give tert-butyl 1- (3-chloro-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ylcarbamate. It was dissolved in 1, 4-dioxane (5mL) and treated overnight with 4.0M hydrogen chloride in 1, 4-dioxane (5 mL). The mixture was concentrated, then the residue was purified by reverse phase HPLC to give 241 as an off-white solid (8.7mg, 19%). 1H NMR (400MHz, DMSO) δ 9.24(d, J =10.3Hz,2H),8.99(s,1H),8.61(s,1H),8.42(d, J =7.5Hz,1H),7.89(d, J =8.1Hz,1H),7.77(d, J =8.1Hz,1H),7.56(d, J =4.4Hz,1H),3.99(d, J =12.0Hz,2H),3.09(d, J =12.4Hz,3H),1.94(d, J =11.6Hz,2H),1.56(d, J =11.1Hz,2H), ESI MS M/z =406.1(M +1)

Example 2431- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-4-amine 243

A microwave reaction vial was charged with tert-butyl 1- (3-chloro-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ylcarbamate (72.1mg,0.113mmol), methylboronic acid (34.0mg,0.567mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (9.25mg,0.0113mmol), 1.00M aqueous potassium acetate (0.17mL,0.17mmol), 1.00M aqueous sodium carbonate (0.17mL,0.17mmol), and acetonitrile (3mL) from example 241. The reaction mixture was heated at 150 ℃ for 3 minutes under microwave. An additional 5 equivalents of methylboronic acid were added and heating at 150 ℃ continued for 3 minutes under microwave. The same operation was repeated 2 more times. The mixture was concentrated to give crude tert-butyl 1- (3-methyl-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ylcarbamate, which was dissolved in 1, 4-dioxane (5mL) and treated with a 4.0M solution of hydrogen chloride in 1, 4-dioxane (5mL) at room temperature. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 243 as an off-white solid (14.0mg, 32%). 1H NMR (400MHz, DMSO) δ 9.24(d, J =17.9Hz,2H),9.07(s,1H),8.61(s,1H),8.43(d, J =7.8Hz,1H),8.38(s,1H),7.76(d, J =7.6Hz,1H),7.65(d, J =7.6Hz,1H),7.56(d, J =4.6Hz,1H),3.73(d, J =11.9Hz,2H),3.13(s,1H),3.01(d, J =11.6Hz,2H),2.32(s,3H),2.02(d, J =12.0Hz,2H),1.68(d, J =11.1Hz,2H), ESI MS M/z =386.2(M + 1H)

Example 246(R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 246

Step 1 (4R) -benzyl 1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-yl carbamate

Following the procedure of example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and benzyl (R) -azepan-4-ylcarbamate were reacted to give benzyl (4R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamate, as a solid (90.5%). LC/MS: M/z607.3[ M +1].

Step 2 (4R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

Placing (4R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) in a 5-mL bomb]Pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamic acid benzyl ester (110.0mg,0.18mmol), 1, 4-cyclohexadiene (102 μ L,1.09mmol) in ethanol (8.3). 10% Pd/C (11.0mg) was added, and N was used₂The reaction mixture was vacuum purged 3 times. The vial was sealed and the reaction mixture was stirred at 100 ℃. After 2 hours, another 10% Pd/C (11.0mg) and 1, 4-cyclohexadiene (102. mu.L) were added. The vial was resealed and the reaction mixture was stirred at 100 ℃ for 14 hours. The cooled reaction mixture was filtered through a plug of celite, and the plug was rinsed with EtOAc (3x5mL), MeOH (3x5mL), DCM (3x5mL), and finally EtOAc rinse (3x5 mL). The filtrate was concentrated under reduced pressure and then flash chromatographed (Si-PPC gradient elution, solvent: 0-80% MeOH/EtOAc +1% Et)₃N) the crude product was purified to give (4R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine as a solid (61.1mg, 71.3%). LC/MS M/z473.3[ M +1]].

Step 3 (4R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) following the procedure of example 189]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine deprotected to give 246 as a white solid (52.1%).¹H NMR(400MHz,DMSO)δ9.03(d,J=1.1Hz,1H),8.55(d,J=1.1Hz,1H),8.11(s,1H),7.84(s,1H),7.66–7.56(m,1H),7.38(d,J=7.3Hz,1H),6.62(d,J=8.5Hz,1H),3.97(m,1H),3.91(s,3H),386-3.76 (m,1H), 3.76-3.58 (m,3H),2.93(t,1H), 2.14-1.95 (m,2H), 1.86-1.60 (m,3H),1.42(m,1H), 2 protons not seen. LC/MS M/z389.2[ M +1]]

Example 2475- (1-methyl-1H-pyrazol-4-yl) -3- (6- (piperidin-4-yl) pyridin-2-yl) -1H-pyrazolo [3, 4-c)]Pyridine 247

Step 1 tert-butyl 4- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate

Placing 3- (6-chloropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] in a bomb]Pyridine ((84.1mg,0.21mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (197.5mg,0.64mmol), cesium carbonate (346.979mg,1.06494mmol), and [1,1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (1:1)]Palladium (II) dichloride (17.4mg,0.021mmol) and N, N-dimethylformamide (2.5 mL). Nitrogen was passed through the mixture for 15 minutes, and then the vessel was sealed. In N₂The reaction mixture was stirred at 90 ℃ for 4 days, cooled to RT and then diluted with EtOAc. The reaction mixture was filtered through a celite plug. The organic layer was washed with water and brine, washed with Na₂SO₄Dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (Si-PPC gradient elution, solvent: 0-20% methanol/ethyl acetate) and reverse phase HPLC to afford 4- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester as an oil (40.4mg, 35.0%).¹H NMR(400MHz,CDCl₃)δ9.12(s,1H),8.72(s,1H),8.08(d,J=7.8Hz,1H),7.98(s,1H),7.93(s,1H),7.75(t,J=7.8Hz,1H),7.39(d,J=7.7Hz,1H),6.79(s,1H),5.87(dd,J=8.5,2.0Hz,1H),4.23(d,J=2.6Hz,2H),4.07–3.96(m,1H),3.98(s,3H),3.85–3.72(m,3H),2.87(s,2H),2.66–2.52(m,1H),2.17(d,J=9.2Hz,2H),1.90–1.67(m,3H),1.52(s,9H).LC/MS:m/z542.4[M+1].

Step 2 tert-butyl 4- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-1-carboxylate

Placing 4- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) in a microwave bottle]Pyridin-3-yl) pyridin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (40.0mg,0.074mmol), 1, 4-cyclohexadiene (69. mu.L, 0.74mmol) and ethanol (3.000 mL). Palladium (4.0mg,0.04mmol;10% Pd/C) is added, followed by N₂The reaction mixture was vacuum purged 3 times with N₂And (6) ending. The vial was capped and the reaction mixture was then subjected to microwave irradiation at 120 ℃ for 60 minutes. An additional 10% palladium on C (4.0mg) and cyclohexadiene (69. mu.L) were added and the reaction mixture was then irradiated with microwaves at 120 ℃ for an additional 60 minutes. This procedure (2x) was repeated until no starting material was detected by LC/MS. The reaction mixture was filtered through a celite plug. The packing was rinsed with ethyl acetate (3x5mL), MeOH (3x5mL), DCM (3x5mL), and finally EtOAc rinse (3x5 mL). The combined filtrates were concentrated under reduced pressure and then dried under high vacuum to give 4- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (27.7mg, 69.0%). LC/MS M/z544.4[ M +1]].

Step 3 following the procedure of example 189, 4- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Deprotection of tert-butyl pyridin-3-yl) pyridin-2-yl) piperidine-1-carboxylate gave 247 as a solid (45.3%).¹H NMR(400MHz,DMSO)δ9.06(d,J=1.2Hz,1H),8.65(s,1H),8.37(s,2H),8.22(s,1H),8.02(d,J=7.8Hz,1H),7.96(s,1H),7.87(t,J=7.8Hz,1H),7.31(d,J=7.6Hz,1H),3.92(s,3H),3.36 (broad singlet, 1H),3.33 (broad singlet, 1H),3.10(t,1H),2.97(t,2H),2.11(d,2H),2.03(M,2H). LC/MS: M/z360.1[ M + 1H ]]

Example 248(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 248

To (4S) -1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamic acid benzyl ester (0.100g,0.166mmol) was added 2.0M aqueous hydrogen chloride (10.0 mL). The reaction mixture was stirred at 100 ℃ for 18 hours. The reaction mixture was concentrated and then purified by HPLC to give 248(6.9mg,11% yield). ESI MS M/z =386.1(M +1).¹H NMR(500MHz,DMSO)δ9.22(s,1H),9.19(s,1H),8.95(s,1H),8.59(d,J=4.3Hz,1H),8.38(d,J=7.6Hz,1H),7.61(t,J=7.7Hz,1H),7.57–7.51(m,1H),7.42(d,J=7.3Hz,1H),6.61(d,J=8.3Hz,1H),3.80-3.70(m,2H),3.60-3.55(m,2H),2.95-2.85(m,1H),2.10-1.96(m,2H),1.86-1.56(m,3H),1.40(m,1H)

Example 249(R) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 249

Mixing the mixture containing 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]A solution of pyridine (0.075g,0.20mmol) and benzyl (R) -azepan-4-ylcarbamate (0.298g,1.20mmol) in dimethyl sulfoxide (1.20mL) was heated at 95 ℃ for 18 h. The reaction mixture was quenched with water and then extracted 2 times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was dried under high vacuum overnight to give (4R) -1- (6- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamic acid benzyl ester was dissolved in dichloromethane (2.56mL) at-10 deg.C and then slowly treated with a 1.00M solution of boron tribromide in dichloromethane (0.600 mL). The reaction mixture was stirred at RT for 7 hours. Mixing the reactionThe compound was concentrated. The crude product was diluted into water and washed with EtOAc. The aqueous layer was basified to pH11 and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was subjected to rHPLC to give 249(21mg,27% yield). ESI MS M/z =386.1(M +1).¹H NMR(500MHz,DMSO)δ9.21(d,J=12.7Hz,2H),8.96(s,1H),8.59(d,J=3.8Hz,1H),8.38(d,J=7.6Hz,1H),7.61(t,J=7.6Hz,1H),7.58–7.51(m,1H),7.42(d,J=7.3Hz,1H),6.62(d,J=8.2Hz,1H),4.00-3.78(m,2H),3.76–3.57(m,2H),2.89(s,1H),2.00(d,J=30.7Hz,2H),1.85–1.55(m,3H),1.44–1.31(m,1H)

Example 2502-methyl-1- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) -1H-pyrazol-1-yl) propan-2-ol 250

Following the procedure in example 172, 2-methyl-1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol and 3-chloro-5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine reaction, followed by deprotection gave 250 as a white solid (40.7% over two steps).¹H NMR(500MHz,DMSO)δ13.39(s,1H),8.97(s,1H),8.39(s,1H),8.30(s,1H),8.16(d,J=10.2Hz,2H),8.10(s,1H),4.78(s,1H),4.13(s,2H),3.90(s,3H),1.13(s,6H).LC/MS:m/z338.1[M+1]

Example 251(1s,4s) -N1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) cyclohexa-1, 4-diamine 251

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine is reacted with tert-butyl (1s,4s) -4-aminocyclohexylcarbamate. The product was deprotected and then purified to give 251 as a white solid (41.4% over two steps).¹H NMR(500MHz,DMSO)δ9.01(s,1H),8.59(s,1H),8.13(s,1H),7.87(s,1H),7.46(t,J=7.5Hz,1H),7.29(d,J=7.0Hz,1H),6.55(dd,J=14.4,7.8Hz,2H),4.12(s,1H) 3.90(s,3H),3.42(s,1H),2.87(s,1H), 1.99-1.39 (m,9H);1 proton not seen. LC/MS M/z389.2[ M +1]]

Example 2525- (pyridin-3-yl) -3- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-c]Pyridine 252

To 5- (pyridin-3-yl) -3- (pyrrolidin-1-yl) -1-trityl-1H-pyrazolo [3,4-c]To a solution of pyridine (0.120g,0.236mmol) in dichloromethane (3.030mL,47.28mmol) was added triethylsilane (0.151mL,0.946mmol) and trifluoroacetic acid (3.642mL,47.28 mmol). The mixture was stirred at RT for 3 hours. The reaction mixture was concentrated. The crude product in DMF was purified by HPLC to give 252(22.4mg,35.7% yield). ESI MS M/z =266.1(M +1).¹H NMR(400MHz,DMSO)δ12.34(s,1H),9.30(d,J=1.8Hz,1H),8.90(d,J=0.9Hz,1H),8.53(dd,J=4.7,1.5Hz,1H),8.50–8.42(m,1H),8.32(s,1H),7.47(dd,J=7.9,4.7Hz,1H),3.63(t,J=6.5Hz,4H),1.99(t,J=6.5Hz,4H)

Example 2532- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-5-yl) acetamide 253

Step 1 diethyl 2- (3- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) malonate

A mixture of 218mg (0.40mmol) of 4- {6- [ 5-bromo-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl ] -pyridin-2-yl } -piperazine-1-carboxylic acid tert-butyl ester, 1.22mL (8.02mmol) of diethyl malonate, 76mg (0.40mmol) of copper (I) iodide, 654mg (2.006mmol) of cesium carbonate and 99mg (0.80mmol) of pyridine-2-carboxylic acid in 4.0mL of 1, 4-dioxane was degassed and then heated at 100 ℃ for 24 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic extracts were washed with saturated aqueous NaHCO3, 5% aqueous citric acid, water, brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography with a gradient of ethyl acetate/heptane to yield 117mg (47%) of diethyl 2- (3- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) malonate. ESI MS M/z623.3(M +1).

Step 2- (3- (6- (4- (tert-butyloxycarbonyl) piperazin-1-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) acetic acid

A mixture of diethyl 2- (3- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) malonate (117mg (0.188mmol) and 0.5ml of 1M aqueous LiOH in 6ml of a methanol/THF mixture (2:1) was heated at 60 ℃ for 1 hour, the mixture was acidified to pH <1 with 1N aqueous HCl then stirred for 20 minutes, the mixture was concentrated, the residue was partitioned between ethyl acetate and water, the pH of the mixture was adjusted to 4 by the careful addition of saturated aqueous sodium bicarbonate solution, the organic extract was washed with brine, dried over MgSO4, then concentrated to give 2- (3- (6- (4- (tert-butyloxycarbonyl) piperazin-1-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) acetic acid (68mg,32%) in two steps. ESI MS M/z523.4(M +1).

Step 3 following the procedure of example 229, 2- (3- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-5-yl) acetic acid was converted to the amide, which was deprotected as in example 225. With a content of 0.1% NH₄A MeOH/water gradient of OH, and purification of the product by reverse phase HPLC, yielded 7.3mg (5.4%) of 253 in two steps. ESI MS M/z338.1(M +1).1H NMR (500MHz, DMSO). 13.70(s,1H),8.97(s,1H),8.33(s,1H),7.64(t, J =7.8Hz,1H),7.52(s,1H),7.44 (M + 1H) ((M + 1))d,J=7.2Hz,1H),6.96(s,1H),6.80(d,J=8.3Hz,1H),3.70(s,2H),3.54(s,4H),2.87(s,4H)

Example 2541-methyl-3- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) imidazolidin-2-one 254

1-methyl-3- (5- (pyridine-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]A solution of pyridin-3-yl) imidazolidin-2-one (0.140g,0.371mmol) in 4.00M hydrogen chloride in 1, 4-dioxane (3.00mL) and 1, 4-dioxane (3.00mL,38.4mmol) was stirred at RT for 18 hours. The reaction mixture was concentrated. The crude product was subjected to HPLC to give 254(16.9mg,15.4% yield). ESIMS M/z =295.1(M +1).¹H NMR(400MHz,DMSO)δ9.18(s,1H),9.04(s,1H),8.82(s,1H),8.56(d,J=4.3Hz,1H),8.32(d,J=8.0Hz,1H),7.50(dd,J=7.9,4.7Hz,1H),4.01–3.93(m,2H),3.64–3.53(m,2H),2.86(s,3H)

Example 2553- (5-chloro-6- (4-methylpiperazin-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 255

Following the procedure described in example 241 and starting with 1-methylpiperazine, 255 was obtained in two steps as an off-white solid (11.0mg, 29%). 1H NMR (400MHz, DMSO). delta.9.30-9.20 (M,2H),8.97(s,1H),8.61(d, J =4.7Hz,1H),8.41(d, J =8.0Hz,1H),7.91(d, J =8.1Hz,1H),7.79(d, J =8.1Hz,1H),7.56(dd, J =8.0,4.7Hz,1H),3.54(s,4H),2.58(s,4H),2.29(s,3H); ESI MS M/z =406.1(M +1)

Example 2563, 5-bis (pyridin-2-yl) -1H-pyrazolo [3,4-c]Pyridine 256

3- (pyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine (67.6mg,0.189mmol) in 4.0M hydrogen chloride in 1, 4-dioxane (5mL) and methanol (5mL,100mmol) was stirred at room temperature overnight. The reaction mixture was then concentrated and the residue was purified by reverse phase HPLC to give 256 as an off-white solid (20.8mg, 40%). 1H NMR (400MHz, DMSO). delta.14.04 (s,1H),9.50(s,1H),9.19(d, J =0.9Hz,1H),8.84(d, J =4.4Hz,1H),8.72(d, J =4.0Hz,1H),8.45(d, J =8.0Hz,1H),8.23(d, J =8.0Hz,1H),7.95(qd, J =7.6,1.7Hz,2H), 7.46-7.38 (M,2H); ESI MS M/z =274.1(M +1)

Example 2573- (5-methyl-6- (4-methylpiperazin-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 257

Following the procedure described in example 241 and starting with 1-methylpiperazine, 257 was obtained in two steps as an off-white solid (6.8mg, 19%). 1H NMR (400MHz, DMSO). delta.9.25 (s,1H),9.21(s,1H),9.07(s,1H),8.61(d, J =4.6Hz,1H),8.41(d, J =8.0Hz,1H),8.16(s,1H),7.76(d, J =7.6Hz,1H),7.65(d, J =7.7Hz,1H),7.56(dd, J =7.9,4.8Hz,1H),2.60(s,4H),2.31(d, J =3.7Hz,6H), ESI MS M/z =386.2(M +1)

Example 2581- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyrrolidin-2-one 258

Following the procedure of example 254, 1- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyrrolidin-2-one is converted to 258. ESI MS M/z =280.1(M +1).¹H NMR(400MHz,DMSO)δ9.20(d,J=1.9Hz,1H),9.09(d,J=1.0Hz,1H),8.66(d,J=1.0Hz,1H),8.57(dd,J=4.7,1.5Hz,1H),8.37–8.31(m,1H),7.51(dd,J=7.9,4.8Hz,1H),4.02(t,J=7.1Hz,2H),2.60(t,J=8.0Hz,2H),2.27–2.15(m,2H)

Example 2591-methyl-4- (3-phenyl-1H-pyrazolo [3, 4-c)]Pyridin-5-yl) -1H-pyrrol-2 (5H) -one 259

Step 1 4- (3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) furan-2 (5H) -one

Reacting 5-bromo-3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine (400.0mg,1.12mmol), bis (triphenylphosphine) palladium (II) dichloride (79.0mg,0.11mmol) and dry toluene (8.0mL) were charged to a high pressure reaction vessel. Tributylstannyl-5H-furan-2-one (437.5mg,1.17mmol) was added, then the reaction mixture was vacuum purged and backfilled with nitrogen (3X). The vessel was sealed and the reaction mixture was then stirred at 110 ℃ for 3 days. The reaction mixture was cooled to RT and then slowly poured into saturated aqueous sodium bicarbonate (30 mL). The resulting mixture was extracted with ethyl acetate (3 × 75 mL). The combined organic layers were washed with Na₂SO₄Dried, filtered and then concentrated under reduced pressure. The crude product was purified by flash column chromatography (Si-PPC gradient elution, solvent: 0-100% ethyl acetate/heptane) to give 4- (3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-5-yl) furan-2 (5H) -one as a white solid (130.0mg, 32.2%). LC/MS M/z362.3[ M +1]].

Step 2-1-methyl-5- (methylamino) -4- (3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrrolidin-2-one

Reacting 4- (3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-5-yl) furan-2 (5H) -one (120.0mg,0.33mmol) and a 2M solution of methylamine in methanol (10mL) were charged to a high pressure reaction vessel. The vessel was sealed and the heterogeneous reaction mixture was then stirred at 90 ℃ for 17 hours. The reaction mixture was cooled to RT. The volatile solvent was evaporated in vacuo to give an oil. The oil was taken up in 1:1v/v DCM-ether (ca. 10 mL). Heptane was slowly added until an orange solid precipitated, then the precipitate was filtered off. The filtrate was evaporated in vacuo and then dried on a high vacuum pump to give 1-methyl-5- (methylamino) -4- (3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridin-5-yl) pyrrolidin-2-one (104.8mg,77.8%) as a foamA compound (I) is provided.¹H NMR1H NMR(400MHz,CDCl₃)δ9.16(d,J=8.2Hz,1H),7.94(d,J=7.6Hz,2H),7.75(s,1H),7.52(t,J=7.5Hz,2H),7.43(t,J=7.3Hz,1H),5.90–5.83(m,1H),4.66(dd,J=5.4,2.0Hz,1H),4.09–4.01(m,1H),3.87–3.76(m,1H),3.59–3.52(m,1H),2.88(s,3H),2.64–2.52(m,1H),2.40(s,3H),2.20(d,J=14.8Hz,2H),1.91–1.68(m,6H).LC/MS:m/z406.3[M+1].

Step 3-reacting 1-methyl-5- (methylamino) -4- (3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] in a sealed high-pressure tube]A mixture of pyridin-5-yl) pyrrolidin-2-one (34.3mg,0.084mmol) and trifluoroacetic acid (3mL) was stirred at 105 ℃ for 3 days. The reaction mixture was cooled to RT and then trifluoroacetic acid was removed via rotary evaporator. The resulting oil was diluted with ethyl acetate (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (2 ×), water and brine, over Na₂SO₄Dried, filtered and evaporated in vacuo. The crude product was purified by reverse phase HPLC to give 259 as a white solid (4.0mg, 16.3%).¹H NMR(400MHz,DMSO)δ9.13(s,1H),8.43(s,1H),8.11(d,J=7.5Hz,2H),7.56(t,J=7.6Hz,2H),7.47(d,J=7.3Hz,1H),6.82(s,1H),6.68(s,1H),4.61(s,2H),2.99(s,3H).LC/MS:m/z291.0[M+1]

Example 2601- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) piperidin-2-one 260

Following the procedure of example 254, 1- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) piperidin-2-one is converted to 260. ESI MS M/z =294.1(M +1)

Example 2613- (6- (piperidin-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 261

The procedure of example 271 was followed with 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3, 4-c) from example 279]Pyridine starting in two steps to obtain 261As a yellow solid (20mg, 32%).¹H NMR(400MHz,DMSO)δ9.22(s,2H),8.97(s,1H),8.60(s,1H),8.38(d,1H,J=6,4Hz),7.67-7.64(t,1H,J=6,4Hz),7.57-7.54(m,1H),7.45(d,1H,J=6,4Hz),6.87(d,1H,J=6,8Hz),3.73(s,4H),1.69(s,6H).ESI MS m/z=356.4(M+1)

Example 2621- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ol 262

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and piperidine-3-ol. The product was deprotected and then purified to yield 262 as a white solid (62.8% over two steps).¹H NMR δ 13.68 (broad singlet, 1H),9.03(s,1H),8.60(s,1H),8.24(s,1H),7.96(s,1H), 7.67-7.58 (M,1H),7.42(d, J =7.4Hz,1H),6.83(d, J =8.5Hz,1H),5.04(d, J =5.1Hz,1H), 4.59-4.49 (M,1H),4.08(d, J =13.1Hz,1H),3.89(s,3H),3.65(dt, J =14.0,4.8Hz,1 ddh), 3.05 (J =17.1,6.8Hz,1H),2.91(dd, J =12.4,9.4, 1H), 2.07-1.97 (M,1H), 1.78(M,1H, 1M + 1H), 1M: [ LC: [ 1H ] + 78/M ] (+ 1H), 1H, 1M, 1H, 1M, 1H]

Example 2631-methyl-4- (3-phenyl-1H-pyrazolo [3, 4-c)]Pyridin-5-yl) pyrrolidin-2-one 263

Placing 1-methyl-5- (methylamino) -4- (3-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) in a high-pressure vessel]Pyridin-5-yl) pyrrolidin-2-one 259(70.0mg,0.17mmol) and trifluoroacetic acid (5 mL). The vessel was sealed and the reaction mixture was then stirred at 105 ℃ for 20 hours. The reaction mixture was cooled to RT and triethylsilane (0.50mL) was added. The vessel was sealed again and the reaction mixture was then stirred at 75 ℃. After 2 hours, triethylsilane (0.5mL) was added further at RT and the reaction mixture was stirred in a sealed vessel at 95 ℃ for 17 hours. The volatile solvent was evaporated in vacuo. The resulting crude oil was dissolved in DMF (2 mL). Filtering the black insoluble material and applying on the nailThe alcohol (2 × 2mL) was rinsed well. The combined filtrates were evaporated in vacuo and the crude product was purified by reverse phase HPLC to give 263 as a white solid (12.7mg, 25.2%).¹H NMR (400MHz, DMSO) δ 13.37 (broad singlet, 1H),9.08(s,1H),8.04(d, J =7.4Hz,2H),7.98(s,1H),7.54(t, J =7.6Hz,2H),7.44(d, J =7.4Hz,1H), 3.98-3.85 (M,1H),3.75(t, J =9.0Hz,1H),3.53(dd, J =9.3,7.2Hz,1H),2.78(s,3H),2.66(dd, J =8.8,2.9Hz,2H), LC/MS: M/z293.1[ M + 1H, 1H ], M/z293.1[ M,1H ], n-J =8.8,2.9Hz,2H ], n-J = 3H, M/z293.1[ M + 1H ], (M]

Example 264(R) -5- (1-methyl-1H-pyrazol-4-yl) -3- (6- (piperidin-3-yloxy) pyridin-2-yl) -1H-pyrazolo [3,4-c]Pyridine 264

Step 1 (3R) -tert-butyl 3- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yloxy) piperidine-1-carboxylate

To a solution of tert-butyl (R) -3-hydroxypiperidine-1-carboxylate (61.2mg,0.30mmol) in anhydrous DMF (3mL) was added sodium hydride (40.5mg,1.01mmol,60% in mineral oil) followed by N₂The reaction mixture was stirred at 60 ℃ for 1 hour. Then 3- (6-chloropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] was added]Pyridine (40.0mg,0.10mmol) in anhydrous DMF (about 1.0mL) and in N₂The reaction mixture was then stirred at 90 ℃ for 16 hours. The reaction mixture was washed with saturated NH₄Aqueous Cl was quenched and then extracted with ethyl acetate (3 ×). The combined organic layers were washed with Na₂SO₄Dried, filtered and then dried in vacuo. The crude product was purified by flash chromatography (Si-PPC gradient elution, solvent: 0-60% MeOH/EA) to give (3R) -3- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yloxy) piperidine-1-carboxylic acid tert-butyl ester as a foam (15.8mg, 27.9%). LC/MS M/z560.4[ M +1]].

Step 2 (3R) -3- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) following the procedure in example 189]Pyridin-3-yl) pyridin-2-yloxy) piperidine-1-carboxylic acid tert-butyl ester deprotected to give 264 as a solid (19.1%).¹H NMR (400MHz, MeOD) delta 8.98(s,1H),8.55(s,1H),8.50(s,1H),8.12(s,1H),7.98(s,1H), 7.90-7.80 (m,2H),6.90(d, J =7.6Hz,1H),5.68(s,1H),3.99(s,3H),3.54(dd, J =13.0,3.9Hz,1H),3.48-3.42(m,1H),3.29-3.22(m,1H), 3.20-3.09 (m,1H),2.33-2.23(m,1H), 2.19-2.06 (m,2H), 1.89-1.77 (m,1H),1 proton not seen. LC/MS M/z376.1[ M +1]]

Example 265(S) -1- (3-chloro-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 265

Following the procedure described in example 241 and starting with tert-butyl (S) -piperidin-3-ylcarbamate, 265 was obtained in two steps as an off-white solid (8.4mg, 25%). 1H NMR (400MHz, DMSO). delta.9.31 (s,1H),9.23(s,1H),9.03(s,1H),8.60(d, J =4.4Hz,1H), 8.49-8.42 (M,1H),7.90(d, J =8.1Hz,1H),7.78(d, J =8.1Hz,1H),7.53(dd, J =7.9,4.8Hz,1H),6.62(s,1H),3.90(dd, J =33.6,11.5Hz,2H),2.91(dd, J =13.2,7.5Hz,2H), 2.85-2.75 (M,1H),1.96(d, J =12.4Hz,1H),1.83(s,1H),1.74(d, J =9.8, 2H), 1.85-2.75 (M,1H),1.96(d, J = 12.406 Hz,1H),1.83(s,1H),1.74(d =9.8, 24H), 1M + z/M)

Example 266(R) -1- (3-chloro-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 266

Following the procedure described in example 241 and starting with tert-butyl (R) -piperidin-3-ylcarbamate, 266 was obtained in two steps as an off-white solid (55.1mg, 58%). 1H NMR (400MHz, DMSO) δ 9.31(d, J =2.1Hz,1H),9.22(s,1H),9.03(s,1H),8.59(dd, J =4.7,1.4Hz,1H), 8.48-8.43 (M,1H),7.89(d, J =8.1Hz,1H),7.77(d, J =8.1Hz,1H),7.52(dd, J =8.0,4.8Hz,1H),3.94(d, J =9.1Hz,1H),3.87(d, J =12.1Hz,1H),2.88(dd, J =17.0,6.1Hz,2H), 2.82-2.73 (M, 406H), 1.95(d, J =12.7Hz,1H), 1.89-1.72 (ESI, 1.72M, 1H), 1.31.31M + 2H (M,1H)

Example 2674- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) morpholine 267

The procedure as in example 271 was followed and repeated except for using 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine was started to give 267 in two steps as a yellow solid (20mg, 32%).¹H NMR(400MHz,DMSO)δ9.25(s,1H),9.22(s,1H),8.93(s,1H),8.60-9.59(m,1H),8.39-8.37(m,1H),7.74-7.71(t,1H),7.57-7.54(m,2H),6.91(d,1H,J=6,8Hz),3.83-3.80(m,4H),3.67-3.65(m,4H).ESI MS m/z=358.4(M+1)

Example 268(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine 268

The procedure of example 271 was followed and repeated using 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine was started to give 268 as a yellow solid in two steps (58mg, 46%).¹H NMR(400MHz,DMSO)δ9.29(s,1H),9.23(s,1H),9.06(s,1H),8.62(s,1H),8.44(d,J=6.0,1H),7.69(t,J=6.4,1H),7.59-7.57(m,1H),7.49(d,J=5.6,1H),6.54(d,J=6.4,1H)，3.98(s,1H),3.88-3.68(m,4H),2.40-2.35(m,1H),2.17-2.13(m,1H).ESI MS m/z=358.1(M+1)

Example 269(S) - (1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-yl) methylamine 269

Following the procedure of example 271 and starting with (S) -pyrrolidin-3-ylmethylamine, 269 was obtained in three steps as a yellow solid (30mg, 35%).¹H NMR(400MHz,DMSO)δ9.27(s,1H),9.20(s,1H),9.13(s,1H),8.59(s,1H),8.43-8.41(m,1H),7.64-7.61(s,1H),7.54-7.52(m,1H),7.42-7.40(m,1H),6.46-6.45(d,j=6.4,1H),3.81-3.80(m,2H),3.65-3.64(m,2H),3.14-3.13(m,2H),2.18-2.13(m,2H),1.83-1.81(m,2H),1.22(s,1H).ESI MS m/z=374(M+1)

Example 270(R) - (1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-yl) methylamine 270

Following the procedure of example 271 and starting with (R) -pyrrolidin-3-ylmethylamine, 270 was obtained in three steps as a yellow solid (34mg, 36%).¹H NMR(400MHz,DMSO)δ9.28(s,1H),9.21(s,1H),9.15(s,1H),8.60(s,1H),8.42-8.41(m,1H),7.63-7.60(s,1H),7.54-7.52(m,1H),7.42-7.40(m,1H),6.46-6.45(d,j=6.4,1H),3.81-3.80(m,2H),3.65-3.64(m,2H),3.14-3.13(m,2H),2.19-2.17(m,2H),1.82-1.78(m,2H),1.24(s,1H).ESI MS m/z=374(M+1)

Example 271(R) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ol 271

Step 1 3- (6-Fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine

To 3-iodo-5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine (GCP-P3-205-1) (200mg,0.44mmol) and 2-fluoro-6- (tributylstannyl) pyridine (206mg,0.53mmol) in a mixture of 3mL DMF was added TEA (1mL), LiCl (56mg,1.32mmol) and CuI (84mg,0.44mmol) and Pd (PPh)₃)₄(254mg,0.22 mmol). The reaction mixture was heated at 120 ℃ for 1 hour under microwave irradiation and the reaction was monitored by LCMS. Once complete, the reaction mixture was extracted with 100mL EtOAc, washed with 50mL brine, and then dried. Distilling off the solvent, eluting with 5% -30% ethyl acetate/heptane, passing throughFlash chromatography of the crude material afforded 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine as a yellow solid (148mg, 80%). ESI MS M/z =421.1(M +1).

Step 2 (R) -1- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

To a mixture of 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (200mg,0.5mmol) and (R) -piperidin-3-ol (100mg,1.0mmol) in EtOH (5mL) was added DIPEA5 mL. The reaction mixture was heated at 120 ℃ for 15 hours and the reaction was monitored by LCMS. Once the reaction was complete, the solvent was distilled off, then eluted with 5% -30% heptane/ethyl acetate and the crude material was purified by flash chromatography to give (R) -1- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol as a yellow oil (163mg, 65%). ESI MS M/z =502.2(M +1).

Step 3 to (R) -1- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ol (60mg,0.12mmol) was added to a solution of 5mL dioxane with 10% HCl (1 mL). The reaction mixture was heated at 70 ℃ for 2 hours and the reaction was monitored by LCMS. Once the reaction was complete, the solvent was distilled off, then replaced with 40% -80% MeOH/0.1% NH₄The crude material was purified by reverse phase prep-HPLC eluting with aqueous OH to give 271 as a yellow solid (20mg, 45%).¹H NMR(400MHz,DMSO)δ9.34-9.28(m,1H),9.21(s,1H),8.62-8.58(m,1H),8.45(d,J=6,1H),7.67–7.64(m,1H),7.54-7.50(m,1H),7.45-7.44(m,1H),6.87-6.85(m,1H),4.96(s,1H),4.36-4.34(m,1H),4.15-4.12(m,1H),3.63(s,1H),3.16-3.12(m,1H),3.01-2.97(m,1H),1.99-1.97(m,1H),1.85-1.83(m,1H),1.60-1.56(m,1H),1.52-1.45(m,1H).ESI MS m/z=373.7(M+1)

Example 2721- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-4-ol 272

The procedure of example 271 was followed and repeated using 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine was started to give 272 in two steps as a yellow solid (20mg, 30%).¹H NMR(400MHz,DMSO)δ9.22-9.20(m,2H),8.94(s,1H),8.60-8.59(m,1H),8.39-8.38(m,1H),7.67–7.64(m,1H),7.56-7.53(m,1H),7.47-7.44(m,1H),6.90-6.89(m,1H),4.77-4.76(m,1H),4.22-4.19(m,2H),3.80-3.79(m,1H),3.42-3.39(m,1H),1.91-1.89(m,2H),1.51-1.49(m,2H).ESI MS m/z=373.7(M+1)

Example 2733- (6- (4,4' -bipiperidin-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridine 273

Following the procedure of example 143 and starting with 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine and 4,4' -bipiperidine, 273 was obtained in two steps and then purified by reverse phase HPLC using a MeCN/water gradient containing 0.1% HCOOH to obtain 25mg (20%) in two steps. ESI MS M/z440.2(M +1).1H NMR (400MHz, DMSO). 9.23(s,1H),8.97(s,1H),8.61(s,1H),8.39(s,1H),7.67(t, J =7.9Hz,1H),7.55(s,1H),7.46(d, J =7.3Hz,1H),6.89(d, J =8.2Hz,1H),4.54(d, J =11.1Hz,2H),2.97(s,2H),2.66(s,2H), 1.88-1.71 (M,4H),1.46(s,1H),1.31(s,5H)

Example 2743- (6-fluoro-5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 274

3- (5-chloro-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (387.1mg,0.8489mmol), methylboronic acid (254.1mg,4.245mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (69.3mg,0.085mmol), 1.00M aqueous potassium acetate (1.27mL,1.27mmol), 1.00M aqueous sodium carbonate (1.27mL,1.27mmol), and acetonitrile (10mL) were charged to a microwave reaction flask. The reaction mixture was heated at 150 ℃ for 5 minutes under microwave. An additional 5 equivalents of methylboronic acid were added and heating at 150 ℃ was continued for 3 minutes under microwave. The same operation is repeated once more. The mixture was concentrated and the residue was purified on silica gel eluting with 0-100% EtOAc/heptane to give 3- (6-fluoro-5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (311.7mg, 84%).

3- (6-fluoro-5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine was dissolved in trifluoroacetic acid (5mL) and dichloromethane (5 mL). To the solution was added trifluoromethanesulfonic acid (104.2uL,1.18mmol) and triethylsilane (18.1uL,1.18 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 274 as an off white solid (7.8mg, 11%). 1H NMR (400MHz, DMSO). delta.9.29-9.21 (M,2H),8.81(s,1H),8.62(dd, J =4.7,1.4Hz,1H),8.42(dt, J =8.0,1.9Hz,1H),8.06(dd, J =7.6,1.6Hz,1H), 8.01-7.95 (M,1H),7.55(dd, J =8.0,4.8Hz,1H),2.34(s,3H); ESI MS M/z =306.1(M +1)

Example 2753- (5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 275

To 3-iodo-5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine (200mg,0.44mmol)) And 1,1,1,2,2, 2-hexamethyldisiloxane (159mg,0.48mmol) in 10mL THF were added LiCl (112mg,2.64mmol) and Pd (PPh)₃)Cl₂(16mg,0.02 mmol). The reaction mixture was heated at 80 ℃ for 1 hour under argon and the reaction was monitored by LCMS. Once the reaction was complete, the mixture was evaporated to dryness. With CH₂Cl₂/CH₃OH (9:1) and the residue was purified by flash chromatography to give 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannanyl) -1H-pyrazolo [3,4-c]Pyridine as a clear oil (188mg, 87%). ESI MS M/z =490.1(M +1).

Step 2 3- (5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine

To 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannanyl) -1H-pyrazolo [3,4-c]Pyridine (250mg,0.51mmol) and 2-bromo-5-methylpyridine (87mg,0.51mmol) to a mixture of DMF10mL was added TEA (10mL), LiCl (64mg,1.53mmol), CuI (97mg,0.51mmol) and Pd (PPh)₃)₄(294mg,0.25 mmol). The reaction mixture was heated at 120 ℃ for 1 hour under microwave irradiation and the reaction was monitored by LCMS. Once the reaction was complete, the mixture was extracted with 100mL EtOAc, washed with 50mL brine, and then dried. The solvent was distilled off, then eluted with 33% -66% ethyl acetate/heptane and the crude material was purified by flash chromatography to give 3- (5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine as a clear oil (115mg, 54%). ESI MS M/z =417.2(M +1).

Step 3 to 3- (5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]To a solution of pyridine (110mg,0.26mmol) in dioxane (5mL) was added 10% HCl (2 mL). The reaction mixture was heated at 80 ℃ for 2 hours and the reaction was monitored by LCMS. Once the cover is closedAfter the reaction is completed, the solvent is distilled off and then the solvent is added with 40-80% of CH₃CN/0.1%NH₄The crude material was purified by reverse phase prep-HPLC eluting with aqueous OH to give 275 as a pink solid (32 m)_g,42%)。¹H NMR(400MHz,DMSO)δ9.28(s,1H),9.23(s,1H),9.21(s,1H),8.93(s,1H),8.65-8.60(m,2H),8.44–8.43(m,1H),8.11(d,1H,J=6,4Hz),7.77(d,1H,J=6,8Hz),7.55-7.53(m,1H),3.32(s,3H).ESI MS m/z=287.3(M+1)

Example 276(R) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine 276

Following the procedure in example 271, 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c was prepared in two steps]Pyridine was converted to 276 as a yellow solid (24mg, 25%).¹H NMR(400MHz,DMSO&H₂O)δ9.13(d,J=8.0,1H),9.01(s,1H),8.55(s,1H),8.36(d,J=6.0,1H),7.60-7.54(m,2H),7.35(d,J=5.6,1H),6.42(d,J=6.8,1H),3.72-3.53(m,4H),3.27(s,1H),2.19(s,1H),1.83(s,1H).ESI MS m/z=358.1(M+1)

Example 277(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ol 277

The procedure as in example 271 was followed and repeated except for using 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine (GCP-P3-205-3) was started to give 277 as a yellow solid (20mg,25%) in two steps.¹H NMR(400MHz,DMSO)δ9.34-9.28(m,1H),9.21(s,1H),8.62-8.58(m,1H),8.45(d,J=6,1H),7.67–7.64(m,1H),7.54-7.50(m,1H),7.45-7.44(m,1H),6.87-6.85(m,1H),4.96(s,1H),4.36-4.34(m,1H),4.15-4.12(m,1H),3.63(s,1H),3.16-3.12(m,1H),3.01-2.97(m,1H),1.99-1.97(m,1H),1.85-1.83(m,1H),1.60-1.56(m,1H),1.52-1.45(m,1H).ESI MS m/z=373.7(M+1)

Example 278(1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-4-yl) methylamine 278

Step 1 (1- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-yl) methylcarbamic acid tert-butyl ester

To a mixture of 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (211mg,0.5mmol) and tert-butyl methyl (piperidin-4-yl) carbamate (213mg,1.0mmol) from example 271 in DMF (5mL) was added potassium carbonate (138mg,1.0 mmol). The reaction mixture was heated at 120 ℃ for 15 hours and the reaction was monitored by LCMS. Once the reaction was complete, the solvent was distilled off, then eluted with 5% -30% ethyl acetate/heptane and the crude material was purified by flash chromatography to give tert-butyl (1- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-yl) methylcarbamate as a yellow oil (193mg, 63%). ESI MS M/z =615.34(M +1).

Step 2 to (1- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3, 4-c)]A solution of pyridin-3-yl) pyridin-2-yl) piperidin-4-yl) methylcarbamic acid tert-butyl ester (190mg,0.31mmol) in dioxane (5mL) was added 10% HCl (1 mL). The reaction mixture was heated at 70 ℃ for 2 hours and the reaction was monitored by LCMS. Once the reaction was complete, the solvent was distilled off, then replaced with 40% -80% MeOH/0.1% NH₄The crude material was purified by reverse phase prep-HPLC eluting with aqueous OH to give 278 as a yellow solid (60mg, 50%).¹H NMR(400MHz,DMSO)9.23(s,2H),8.95(s,1H),8.61-8.60(d,J=2.8,1H),8.40-8.38(m,1H),7.68-7.65(m,1H),7.58-7.55(m,1H),7.48-7.46(m,1H),4.96(s,1H),4.53-4.50(d,J=10.4,1H),3.38-3.36(m,3H),2.69-2.68(d,J=4,2H),188-1.86(d,J=8,3H),1.32-1.30(m,3H).ESI MS m/z=385.2(M+1)

Example 2794- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperazin-2-one 279

Step 1 4- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazin-2-one

A mixture of 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (211mg,0.5mmol) and piperazin-2-one (100mg,1.0mmol) from example 271 in pyridine (5mL) was heated at 130 ℃ for 16 hours and the reaction monitored by LCMS. Once the reaction was complete, the solvent was distilled off, then eluted with 5% -30% ethyl acetate/heptane and the crude material was purified by flash chromatography to give 4- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazin-2-one as a yellow oil (76mg, 30%). ESI MS M/z =501.23(M +1).

Step 2 to 4- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperazin-2-one (70mg,0.14mmol) in dioxane (5mL) was added 10% HCl1 mL. The reaction mixture was stirred at 25 ℃ for 16 h and the reaction was monitored by LCMS. Once the reaction was complete, the solvent was distilled off, then replaced with 40% -80% MeOH/0.1% NH₄The crude material was purified by reverse phase prep-HPLC eluting with aqueous OH to give 279 as a yellow solid (13mg, 25%).¹H NMR(400MHz,DMSO)δ9.28(s,1H),9.13(s,1H),9.02(s,1H),8.58-8.53(m,2H),7.76-7.73(t,1H),7.64-7.60(m,2H),6.88-6.87(d,J=6.4,1H),4.39(s,2H),3.99-3.98(t,J=4,2H).ESI MS m/z=371.15(M+1)

Example 280N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) propane-1, 3-diamine 280

Following the procedure in example 271, 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine was reacted with propane-1, 3-diamine, and the product was then deprotected to give 280 as a yellow solid in two steps (20mg, 31%).¹H NMR(400MHz,DMSO)δ9.30(s,1H),9.22(s,1H),9.03(s,1H),8.60(s,1H)8.43–8.44(m,1H),7.53–7.57(m,2H),7.38–7.40(m,1H),7.03(s,1H),6.53(d,J=6.4Hz,1H),4.01(t,J=1.2Hz,2H),2.92(m,2H),2.50(t,J=1.2Hz,2).ESI MSm/z=346(M+1)

Example 2813- (3, 4-dihydro-2H-pyran-5-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 281

3-iodo-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c from example 4 was added to a microwave tube]Pyridine (0.32g,1mmol), 2- (5, 6-dihydro-4H-pyran-3-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.31g,1.5mmol), 2M Na₂CO₃(2mmol,1mL)、PdCl₂(dppf) (87mg,0.1mmol) and dioxane (8 mL). The suspension is mixed with N₂Cleaned and then heated at 130 ℃ for 1 hour under microwave irradiation. It was then cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified by SGC (Petrol/EtOAc:5/1-1/1) to give 281 as a yellow solid (97mg, 35%). 1HNMR (400MHz, DMSO) δ 9.19(d, J =1.2Hz,1H),9.07(d, J =0.8Hz,1H), 8.53-856 (M,2H),8.45(d, J =0.8Hz,1H),7.71(s,1H), 7.47-7.49 (M,1H), 4.08-4.10 (M,2H), 2.59-2.61 (M,2H),. 1.98-2.0 (M,2H). ESI MS M/z =279(M +1)

Example 2822- (4- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperazin-1-yl) ethanol 282

Following implementationExample 271 procedure 3- (6-Fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine and (piperazin-1-yl) ethanol were reacted, and the product was then deprotected to give 282 as a yellow solid (20mg,32%) in two steps.¹H NMR(400MHz,DMSO)δ9.22(s,1H),8.94(s,1H),8.61(s,1H),8.40-8.38(m,1H),7.70–7.67(m,1H),7.57-7.55(m,1H),7.51-7.49(m,1H),6.90-6.88(m,1H),4.50(s,1H),3.69(s,4H),3.60-3.57(m,2H),2.62(s,1H),2.51-2.48(m,2H).ESI MSm/z=402.7(M+1)

Example 283N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) butane-1, 4-diamine 283

Following the procedure of example 271, 3- (6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine was reacted with butane-1, 4-diamine and the product was then deprotected to give 283 in two steps as a yellow solid (20mg, 28%).¹H NMR(400MHz,DMSO)δ9.19–9.21(m,1H),9.12–9.13(m,2H),8.53–8.60(m,2H),7.60–7.63(m,1H)7.51–7.54(m,1H),7.44–7.46(m,1H),6.53(d,J=6.4Hz,1H),3.65(t,J=1.2Hz,2H),2.93(t,J=1.2Hz,2H),1.80–1.85(m,4H).ESIMS m/z=360(M+1)

Example 2843- (4, 5-dihydrofuran-3-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c]Pyridine 284

Following the procedure of example 281, 3-iodo-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine from example 4 and 2- (4, 5-dihydrofuran-3-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan were reacted to give 284 as a white solid (0.1g, 40%). 1H NMR (400MHz, DMSO): δ 9.42(s,1H),9.09(s,1H), 8.56-8.57 (M,2H),8.51(s,1H),7.86(s,1H), 7.47-7.49 (M,1H), 4.46-4.50 (M,2H), 3.12-3.14 (M,2H). ESI MS M/z =265(M +1)

Example 285(R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 285

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-ethyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and (R) -piperidin-3-ylcarbamic acid tert-butyl ester. The product was deprotected and then purified to give 285 as a white solid (41.6% over two steps).¹H NMR (400MHz, DMSO) δ 9.02(s,1H),8.60(s,1H),8.34(s,1H),7.97(s,1H),7.62(t, J =8.0Hz,1H),7.42(d, J =7.4Hz,1H),6.83(d, J =8.5Hz,1H),4.45(d, J =8.7Hz,1H), 4.28-4.12 (m,3H),2.98(t, J =10.9Hz,1H), 2.82-2.72 (m,2H),2.03-1.93(m,1H),1.86-1.77(m,1H),1.67-1.51(m,1H),1.42(t, J =7.3Hz,3H), 1.38-1.26 (m,1H),3 protons. LC/MS M/z389.2[ M +1]]

Example 2861- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) -3- (trifluoromethyl) pyrrolidin-3-amine 286

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine is reacted with tert-butyl 3- (trifluoromethyl) pyrrolidin-3-ylcarbamate. The product was deprotected and then purified to give 286 as a white solid (47.3% over two steps).¹H NMR (400MHz, DMSO) δ 9.02(s,1H),8.65(s,1H),8.09(s,1H),7.86(s,1H),7.65(t, J =7.9Hz,1H),7.44(d, J =7.4Hz,1H),6.51(d, J =8.3Hz,1H),3.91-3.86(m,4H), 3.84-3.65 (m,3H),2.47(s,2H),2.38-2.27(m,1H),2.05(dd, J =12.3,6.1Hz,1H), 1 proton not seen. LC/MS M/z429.2[ M +1]]

Example 287(R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine 287

Step 1: 3-bromo-2-fluoro-6-iodopyridine

To a solution of 2-fluoropyridin-3-amine (5.00g,44.60mmol) in DMF (100mL) was added N-iodosuccinimide (11.04g,49.06 mmol). The resulting mixture was stirred overnight. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried over MgSO4 and then concentrated. The residue was purified on silica gel eluting with 0-50% EtOAc in heptane. 2-fluoro-6-iodopyridin-3-amine was obtained as a dark tan solid (8.8674g, 83%). To an ice-cooled mixture of tert-butyl nitrite (356.8uL,3.000mmol) and copper (II) bromide (536.0mg,2.400mmol) in acetonitrile (5mL) was added 2-fluoro-6-iodopyridin-3-amine (to give a dark tan solid) (476.0mg,2.000 mmol). The resulting mixture was stirred overnight and allowed to warm to room temperature. The mixture was filtered through celite. The filtrate was concentrated. The residue was partitioned between Et2O and saturated NH4 Cl. The organic layer was dried over MgSO4 and then concentrated. The residue was purified on silica gel eluting with 0-20% EtOAc in heptane. 3-bromo-2-fluoro-6-iodopyridine was obtained as a yellow solid (407.1mg, 57%).

Step 2 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine

To a mixture of argon-protected 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannyl) -1H-pyrazolo [3,4-c ] pyridine (239mg,0.489mmol) and 3-bromo-2-fluoro-6-iodopyridine (162.3mg,0.538mmol) in N, N-dimethylformamide (5mL,60mmol) was added cesium fluoride (148mg,0.98 mmol). Tetrakis (triphenylphosphine) palladium (0) (56.482mg,0.048878mmol) and copper (I) iodide (18.618mg,0.097757mmol) were then added and the resulting mixture was stirred at 40 ℃ for 2 h. The mixture was cooled to room temperature and filtered through celite. The filter cake was washed with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated. The residue was purified on silica gel eluting with 0-100% EtOAc/heptane to give 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine as a pale yellow oil which solidified upon standing (208.1mg, 85%).

Step 3 following the procedure described in example 241 and starting with 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and tert-butyl (R) -pyrrolidin-3-ylcarbamate gave 287 as an off-white solid in two steps (12.2mg, 34%). 1H NMR (400MHz, DMSO). delta.9.27 (s,1H),9.22(s,1H),9.02(s,1H),8.60(d, J =4.6Hz,1H),8.41(d, J =8.0Hz,1H),7.92(d, J =8.0Hz,1H),7.62(dd, J =11.8,7.2Hz,3H), 7.58-7.49 (M,3H),7.45(d, J =8.0Hz,1H), 4.01-3.92 (M,2H), 3.64-3.51 (M,3H),2.10(dt, J =12.0,5.9Hz,1H), 1.82-1.72 (M,1H); ESI M/z =358.2(M + 1H)

Example 2881- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-4-ol 288

Following the procedure described in examples 241, 243 and 287 and starting with 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and piperidin-4-ol, 288 was obtained in three steps as an off-white solid (20.4mg, 29%). 1H NMR (400MHz, DMSO) δ 13.85(s,1H),9.25(d, J =1.5Hz,1H),9.20(s,1H),9.09(s,1H),8.61(d, J =3.7Hz,1H),8.41(d, J =8.0Hz,1H),7.74(d, J =7.6Hz,1H),7.63(d, J =7.7Hz,1H),7.55(dd, J =7.9,4.8Hz,1H),4.73(d, J =4.0Hz,1H),3.74(dd, J =8.7,4.3Hz,1H),3.61(d, J =12.7Hz,2H),3.06(t, J =10.3Hz,2H),2.31(s,3H),1.95 (J = 10.95), 1.65(d, J =10.7Hz, 2H), 2H = 10.06 (M/1H), 2.25H, 1H

Example 289(S) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 289

Following the procedure described in example 241 and starting from 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and tert-butyl (S) -piperidin-3-ylcarbamate, over two steps gives 289 as an off-white solid (17.8mg, 22.32%). 1H NMR (400MHz, DMSO) δ 9.31(d, J =1.8Hz,1H),9.23(s,1H),9.03(s,1H),8.60(d, J =4.7Hz,1H),8.46(d, J =7.9Hz,1H),8.06(d, J =8.1Hz,1H),7.71(d, J =8.1Hz,1H),7.62(dd, J =11.8,7.1Hz,1H),7.52(dd, J =8.0,4.8Hz,1H),3.92(d, J =10.0Hz,1H),3.84(d, J =11.7Hz,1H),2.89(dt, J =16.9,10.7Hz,2H), 2.82-2.75 (M,1H),1.96 = 96, 1.6H, 1H = 6.7Hz, 1H),2.89(dd, 16.9, 1H =16, 1H, 1M, 1H = 6H, 1H

Example 290(R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 290

Following the procedure described in example 241 and starting from 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and tert-butyl (R) -piperidin-3-ylcarbamate, 290 was obtained in two steps as an off-white solid (19.7mg, 35.9%). 1H NMR (400MHz, DMSO) δ 9.31(s,1H),9.22(s,1H),9.03(s,1H),8.59(d, J =4.7Hz,1H),8.46(d, J =8.0Hz,1H),8.05(d, J =8.1Hz,1H),7.70(d, J =8.1Hz,1H),7.62(dd, J =11.8,7.1Hz,1H),7.54(ddd, J =12.7,7.2,4.0Hz,2H),3.92(d, J =9.3Hz,1H),3.84(d, J =12.1Hz,1H),2.88(d, J =12.9Hz,2H), 2.81-2.69 (M,1H),1.95(d, J = 12.90H), 1H = 69(M,1H),1.95(d, J =6, 1H = 12H), 1H = 26.1H, 1M +1 z (M,1H)

Example 291(R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ol 291

Following the procedure described in example 241 and starting from 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and (R) -piperidin-3-ol hydrochloride, 291 was obtained in two steps as an off-white solid (11.0mg, 29.9%). 1H NMR (400MHz, DMSO) δ 9.31(d, J =1.8Hz,1H),9.24(s,1H),9.01(s,1H),8.60(d, J =4.0Hz,1H),8.44(d, J =8.1Hz,1H),8.06(d, J =8.1Hz,1H),7.70(d, J =8.1Hz,1H),7.51(dd, J =8.0,4.8Hz,1H),4.93(d, J =4.4Hz,1H),3.97(d, J =11.6Hz,1H),3.83(d, J =12.2Hz,1H),3.74(dd, J =9.2,4.8Hz,1H), 2.99-2.81 (M,2H),2.02(d, J = 9.88H), 1H, 5(dd, 1H, 9.8H), 5H, 5(dd, 1H), 2H, 1

Example 2921- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-4-ol 292

Following the procedure described in example 241 and starting with 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and piperidin-4-ol, 292 was obtained as an off-white solid in two steps (9.50mg, 26.8%). 1H NMR (400MHz, DMSO). delta.9.26-9.20 (M,2H),8.99(s,1H),8.61(d, J =3.7Hz,1H),8.41(d, J =7.9Hz,1H),8.06(d, J =8.1Hz,1H),7.70(d, J =8.1Hz,1H),7.55(dd, J =8.0,4.8Hz,1H),4.75(d, J =3.7Hz,1H), 3.91-3.71 (M,3H),3.18(d, J =10.1Hz,2H),1.96(d, J =11.1Hz,2H),1.65(dd, J =18.8,9.2Hz,2H), ESI MS M/z =.2 (M +1 451)

Example 293(R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ol 293

Following the procedure described in example 241 and starting with 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and (R) -pyrrolidin-3-ol hydrochloride, 293 was obtained as an off-white solid in two steps (3.50mg, 9.60%). ESI MSm/z =437.1(M +1)

Example 2941- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidines-4-alcohols 294

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and piperidine-4-ol. The product was deprotected and then purified to afford 294 as a white solid (56.1% over two steps).¹H NMR (400MHz, DMSO) δ 13.69 (broad singlet, 1H),9.03(s,1H),8.53(s,1H),8.11(s,1H),7.82(s,1H),7.64(t, J =7.9Hz,1H),7.42(d, J =7.4Hz,1H),6.87(d, J =8.5Hz,1H),4.73(d, J =3.2Hz,1H),4.24-4.15(M,2H),3.91(s,3H),3.6-3.76(M,1H),3.37-3.29(M,2H),1.97-1.86(M,2H),1.58-1.44(M,2H). LC/MS M/z376.2[ M + 1H ], [ M]

Example 2952- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) -2, 8-diazaspiro [4.5]Decan-1-ones 295

Step 1 benzyl 1-oxo-2- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -2, 8-diazaspiro [4.5] decane-8-carboxylate

A solution of 3-iodo-5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine (0.196g,0.434mmol), benzyl 1-oxo-2, 8-diazaspiro [4.5] decane-8-carboxylate (0.250g,0.867mmol), N' -dimethylethylenediamine (0.103mL,0.954mmol), copper (I) iodide (0.0908g,0.477mmol), and cesium carbonate (0.311g,0.954mmol) in 1, 4-dioxane (7.08mL,90.7mmol) was stirred at 75 ℃ for 2 hours. The reaction mixture was filtered through celite and then concentrated. The crude product was purified by Isco column (EtOAc/Hep eluting with 50% EtOAc) to give benzyl 1-oxo-2- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -2, 8-diazaspiro [4.5] decane-8-carboxylate (140mg,52.7% yield). ESI MS M/z =613.1(M +1).

Step 2 Synthesis of 1-oxo-2- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) -2, 8-diazaspiro [4.5]A solution of benzyl decane-8-carboxylate (0.140g,0.229mmol) in 2.00M aqueous hydrogen chloride (16.2mL) was stirred at 100 ℃ for 18 hours. The reaction mixture was concentrated and then subjected to rlhplc to give 295(21.2mg,26.5% yield). ESI MS M/z =349.2(M +1).¹H NMR(400MHz,DMSO)δ9.19(d,J=1.8Hz,1H),9.07(s,1H),8.67(s,1H),8.57(d,J=4.6Hz,1H),8.33(d,J=8.0Hz,1H),7.51(dd,J=7.9,4.7Hz,1H),3.97(t,J=7.0Hz,2H),2.92(d,J=12.6Hz,2H),2.63(dd,J=21.4,9.3Hz,2H),2.20(t,J=7.0Hz,2H),1.74(td,J=12.5,4.1Hz,2H),1.48(d,J=13.0Hz,2H)

Example 2961- (piperidin-4-ylmethyl) -3- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) imidazolidin-2-one 296

Step 1-1-acetyl-3- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) imidazolidin-2-one

A solution of 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridine (1.00g,2.45mmol), 1-acetylimidazolidin-2-one (0.3768g,2.941mmol), N' -dimethylethylenediamine (0.528mL,4.90mmol), copper (I) iodide (0.467g,2.45mmol), and potassium carbonate (0.4064g,2.941mmol) in 1, 4-dioxane (40.0mL,512mmol) was stirred at 75 ℃ for 2 hours. The reaction mixture was filtered through celite and then concentrated. The crude product was purified by Isco column (1% MeOH/EtOAc/Hep eluting with 55% EtOAc) to give 1-acetyl-3- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) imidazolidin-2-one (620mg,62% yield). ESI MSm/z =408.1(M +1).

Step 2 1- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) imidazolidin-2-one

To a solution of 1-acetyl-3- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) imidazolidin-2-one (0.295g,0.722mmol), pinacol 3-pyridineboronic acid ester (0.444g,2.17mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (0.0472g,0.0578mmol) in acetonitrile (5.47mL,105mmol) was added 1.00M aqueous potassium acetate (1.44mL) and 1.00M aqueous sodium carbonate (1.44 mL). The reaction mixture was stirred at 100 ℃ for 3 hours. The reaction mixture was filtered through celite. The crude product was diluted in EtOAc, then washed with water and saturated NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to give 1- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) imidazolidin-2-one. ESI MS M/z =365.2(M +1).

Step 3 to 1- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c), dissolved in N, N-dimethylformamide (3.43mL) and cooled to 0 ℃]Pyridin-3-yl) imidazolidin-2-one (0.120g,0.329mmol) was dissolved in NaH (6:4, sodium hydride: mineral oil, 26.3mg) in oil. The reaction mixture was stirred at RT for 30 minutes and then cooled to 0 ℃. 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.183g,0.659mmol) was added. The reaction mixture was stirred at RT for 18 h. The mixture was quenched with H2O and then extracted with EtOAc. The organic layer was dried, filtered, and concentrated to give 4- ((2-oxo-3- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) imidazolidin-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester was dissolved in 4.0M hydrogen chloride in 1, 4-dioxane (6.00mL) and 1, 4-dioxane (3.00mL,38.4mmol) and stirred at RT for 18 h. The reaction mixture was concentrated and then subjected to rHPLC purification to give 296(11.6mg,9.3% yield). ESI MS M/z =378.2(M +1).¹H NMR(400MHz,DMSO)δ9.17(s,1H),9.03(s,1H),8.78(s,1H),8.55(d,J=4.7Hz,1H),8.30(d,J=8.0Hz,1H),7.50(dd,J=8.0,4.7Hz,1H),4.03–3.93(m,2H),3.65–3.56(m,2H),3.11(d,J=7.2Hz,2H),2.92(d,J=12.0Hz,2H),2.42(d,J=10.9Hz,1H),1.79-1.67(m,1H),1.59(d,J=11.8Hz,2H),1.05(dd,J=21.5,9.9Hz,2H)

Example 2972-methyl-1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-ylamino) propan-2-ol 297

Following the procedure described in example 189, 3- (6-fluoropyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-c]Pyridine and 1-amino-2-methyl-propan-2-ol. The product was deprotected and then purified to give 297 as a white solid (87% over two steps).¹H NMR (400MHz, DMSO) δ 13.62 (broad singlet, 1H),9.01(s,1H),8.72(s,1H),8.25(s,1H),7.98(s,1H),7.47(t, J =7.8Hz,1H),7.31(d, J =7.3Hz,1H),6.63-6.56(M,2H),4.73(s,1H),3.89(s,3H),3.56(d, J =5.8Hz,2H),1.25(s,6H) LC/MS: M/z.2 [ M +1 364H ], 3.1.2]

Example 298(S) -1- (3- (6- (3-aminopiperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-5-yl) urea 298

(3S) -1- (6- (5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c) was prepared following the Buchwald-Hartwig procedure of example 224]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ylcarbamic acid tert-butyl ester and (1, 1-dimethylethyl) urea were reacted and then deprotected by the procedure of example 229. With a content of 0.1% NH₄A MeOH/water gradient of OH and reverse phase HPLC purified the mixture, which yielded 20mg (23%) of 298 in three steps. ESI MS M/z353.2(M +1).1H NMR (400MHz, DMSO). 9.14(s,1H),8.96(s,1H),8.75(s,1H),8.40(s,2H),7.63(t, J =8.0Hz,1H),7.45(d, J =7.4Hz,1H),6.80(d, J =8.5Hz,1H),6.48(s,2H),4.92(d, J =11.4Hz,1H),4.05(d, J =12.9Hz,1H),3.09(M,1H), 2.94-2.77 (M,2H),2.54(s,2H),2.05(d, J =9.7Hz,1H),1.84(d, J =13.1Hz,1H), 1.64-1H (M,2H)

Example 299(1S,3R) -3- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yloxy) Cyclohexylamine 299

Step 1 (1S,3S) -3-Hydroxycyclohexylcarbamic acid tert-butyl ester

A solution of 0.5238g (2.4mmol) of di-tert-butyl dicarbonate in 5ml of THF and 0.6ml of 4.0M aqueous sodium hydroxide solution is added dropwise at 0 ℃ to a solution of 230.3mg (2.0mmol) of (1S,3S) -3-aminocyclohexanol in 6ml of tetrahydrofuran and 4ml of water. The mixture was stirred for 18 hours, diluted with water and then extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4, and then concentrated to give 434mg (100%) of tert-butyl (1S,3S) -3-hydroxycyclohexylcarbamate as a crystalline residue.

Step 2 (1S,3R) -3- (6-bromopyridin-2-yloxy) cyclohexylcarbamic acid tert-butyl ester

0.473mL (2.4mmol) of a solution of diisopropyl azodicarboxylate in 2mL of tetrahydrofuran are added dropwise at 0-5 ℃ to a mixture of 454mg (2.0mmol) of tert-butyl (1S,3S) -3-hydroxycyclohexylcarbamate, 418mg (2.40mmol) of 2-bromo-6-hydroxypyridine and 629.5mg (2.4mmol) of triphenylphosphine in 5mL of tetrahydrofuran. The mixture was stirred for 18 hours. The mixture is concentrated and the residue is purified by chromatography on silica gel with a gradient of ethyl acetate/heptane to yield 222mg (30%) of tert-butyl (1S,3R) -3- (6-bromopyridin-2-yloxy) cyclohexylcarbamate. ESI MS M/z370.9(M +1).

Step 3 (1S,3R) -3- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yloxy) cyclohexylcarbamic acid tert-butyl ester

In a Stille coupling, a mixture of 147mg (0.3mmol) of 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannanyl) -1H-pyrazolo [3,4-c ] pyridine, 123mg (0.33mmol) of tert-butyl (1S,3R) -3- (6-bromopyridin-2-yloxy) cyclohexylcarbamate, 109mg (0.72mmol) of cesium fluoride, 35mg (0.03mmol) of tetrakis (triphenylphosphine) palladium (0) and 11.4mg (0.06mmol) of copper (I) iodide in 2ml of N, N-dimethylformamide is heated at 50 ℃ for 2 hours. The mixture was diluted with water and then extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4, and then concentrated. The residue was purified by silica gel chromatography with a gradient of ethyl acetate/heptane to yield 98mg (53%) of tert-butyl (1S,3R) -3- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yloxy) cyclohexylcarbamate. ESI MSm/z617.5(M +1).

Step 4 (1S,3R) -3- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3, 4-c) by the procedure of example 225]Pyridin-3-yl) pyridin-2-yloxy) cyclohexyl carbamic acid tert-butyl ester deprotection with a solution containing 0.1% NH₄A gradient of OH in MeOH/water, purified by reverse phase HPLC, afforded 32mg (61%) of 299. ESI MS M/z387.2(M +1).1H NMR (400MHz, DMSO). 9.26(d, J =1.7Hz,1H),9.23(s,1H),8.86(s,1H),8.61(d, J =4.7Hz,1H),8.42(d, J =8.0Hz,1H), 7.86-7.78 (M,2H),7.52(dd, J =7.9,4.8Hz,1H), 6.81-6.73 (M,1H),5.35(M,1H), 2.79-2.69 (M,1H),2.33(M,1H),2.22(s,1H),1.71(M,2H), 1.36-1.19 (M,3H), 1.06-0.93 (M,1H)

Example 300(R) -1- (4- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyrimidin-2-yl) piperidin-3-amine 300

Step 1 3- (2-Chloropyrimidin-4-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine

Following the Stille coupling procedure of example 299, 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannanyl) -1H-pyrazolo [3,4-c ] pyridine and 2, 4-dichloropyrimidine were reacted. The product was purified by silica gel chromatography with a gradient of ethyl acetate/heptane to yield 60mg (50%) of 3- (2-chloropyrimidin-4-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine. ESI MS M/z439.2(M +1).

Step 2 following the procedure of example 144, 3- (2-Chloropyrimidin-4-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine and (R) -piperidin-3-ylcarbamic acid tert-butyl ester. The product was deprotected by the procedure of example 225 and then washed with a solution containing 0.1% NH₄A gradient of OH in MeOH/water, purified by reverse phase HPLC, gave 32mg (63%) of 300. ESI MS M/z373.2(M +1).1H NMR (400MHz, DMSO). 9.30(s,1H),9.25(s,1H),8.91(s,1H),8.59(dd, J =4.7,1.2Hz,1H),8.45(t, J =8.1Hz,2H),7.53(dd, J =7.9,4.7Hz,1H),7.32(d, J =5.0Hz,1H),4.71(d, J =10.8Hz,1H),4.61(d, J =12.5Hz,1H), 3.15-3.06 (M,1H), 2.91-2.83 (M,1H), 2.82-2.73 (M,1H),1.96(d, J =11, 1H),1.81(d, J = 13.13, 1H),1.55 Hz,1H, 12.13, 1H), td, 1H, 13H, 1H, 13 Hz,1H)

Example 3011- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperazin-2-one 301

Step 1 3- (6-Bromopyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine

Following the Stille coupling procedure of example 299, 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannanyl) -1H-pyrazolo [3,4-c ] pyridine and 2, 6-dibromopyridine were reacted. The mixture was purified by silica gel chromatography with a gradient of ethyl acetate/heptane to yield 81mg (67%) of 3- (6-bromopyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine. ESI MS M/z482.2(M +1).

Step 2 following the procedure of example 224, 3- (6-bromopyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c]Pyridine and 3-oxopiperazine-1-carboxylic acid tert-butyl ester. The product was deprotected by the procedure of example 225 and then washed with a solution containing 0.1% NH₄A gradient of OH in MeOH/water, purified by reverse phase HPLC, provided 8.0mg (20%) of 301 in two steps. ESI MS M/z372.1(M +1).1H NMR (400MHz, DMSO). 14.08(s,1H),9.29(d, J =2.0Hz,1H),9.25(s,1H),8.94(s,1H),8.61(dd, J =4.7,1.3Hz,1H), 8.47-8.40 (M,1H), 8.07-7.92 (M,3H),7.56(dd, J =7.9,4.8Hz,1H),6.48(s,1H),4.22(t, J =5.4Hz,2H),3.56(s,2H),3.18(t, J =5.4Hz,2H). M/z372.1(M +1)

Example 3022- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) isonicotinamide 302

Following the Stille coupling procedure of example 299, 5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -3- (trimethylstannanyl) -1H-pyrazolo [3,4-c ] pyridine and 2-bromoisonicotinamide were reacted. The product was deprotected by the procedure of example 225 and then purified by silica gel chromatography using a gradient of methanol/dichloromethane to give 10mg (21%) of 302 in two steps. ESI MS M/z317.1(M +1).1H NMR (400MHz, DMSO). 14.16(s,1H),9.28(d, J =12.0Hz,2H),8.96(s,1H),8.94(d, J =5.1Hz,1H),8.62(d, J =5.3Hz,2H),8.45(d, J =8.0Hz,1H),8.40(s,1H),7.80(d, J =5.1Hz,1H),7.76(s,1H),7.55(dd, J =8.0,4.7Hz,1H)

Example 3031- (5- (pyridin-3-yl) -1H-pyrazolesAnd [3,4-c ]]Pyridin-3-yl) -3- (pyrrolidin-3-ylmethyl) imidazolidin-2-one 303

Following the procedure of example 296, 1- (5- (pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) imidazolidin-2-one is converted to 303. ESI MS M/z =364.2(M +1).¹H NMR(400MHz,DMSO)δ9.17(d,J=2.1Hz,1H),9.05(s,1H),8.81(s,1H),8.57(dd,J=4.7,1.3Hz,1H),8.31(d,J=8.0Hz,1H),7.51(dd,J=8.0,4.7Hz,1H),4.06–3.96(m,2H),3.69–3.60(m,2H),3.30(dd,J=7.4,3.5Hz,2H),3.22–3.07(m,2H),3.00(dd,J=17.3,9.1Hz,1H),2.77(dd,J=11.0,7.1Hz,1H),1.98(dt,J=12.7,7.6Hz,1H),1.57(dt,J=20.3,7.6Hz,1H)

Example 305(S) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ol 305

Following the procedure described in example 241 and starting from 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and (S) -pyrrolidin-3-ol, 305 was obtained in three steps as an off-white solid (17mg, 20%). 1H NMR (400MHz, DMSO) δ 9.25(s,1H),9.18(s,1H),9.09(s,1H),8.59(d, J =4.6Hz,1H),8.40(d, J =8.0Hz,1H),7.53(dd, J =7.9,4.7Hz,1H),7.47(q, J =7.6Hz,2H),4.96(s,1H),4.43(s,1H), 4.00-3.87 (M,2H),3.75(td, J =8.8,3.9Hz,1H),3.51(d, J =11.0Hz,1H),2.37(s,3H), 2.12-2.04 (M,1H), 1.97-1.88 (M,1H), ESI M/z = 891M + 373.2M)

Example 306(R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ol 306

Following the procedure described in examples 241, 243, 287 and starting with 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and (R) -pyrrolidin-3-ol hydrochloride, 306 was obtained in three steps as an off-white solid (25.5mg, 35%). 1H NMR (400MHz, DMSO). delta.9.25 (s,1H),9.18(s,1H),9.09(s,1H),8.60(d, J =4.6Hz,1H),8.40(d, J =7.9Hz,1H),7.54(dd, J =7.9,4.8Hz,1H), 7.51-7.44 (M,2H),4.96(s,1H),4.43(s,1H), 4.00-3.88 (M,2H), 3.80-3.70 (M,1H),3.51(d, J =10.2Hz,1H),2.38(s,3H), 2.10-2.03 (M,1H),1.93(s,1H); ESIm/z =373.2(M + 1H)

Example 307(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) -3-vinylpyridin-2-yl) piperidin-3-amine 307

Tert-butyl (S) -1- (3-bromo-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ylcarbamate (128.3mg,0.189mmol), 4,5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolane (320uL,1.9mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (15.4mg,0.0189mmol), a microwave reaction flask was charged with 1.00M aqueous potassium acetate (0.28mL,0.28mmol), 1.00M aqueous sodium carbonate (0.28mL,0.28mmol), and acetonitrile (10 mL). The reaction mixture was heated at 150 ℃ for 5 minutes under microwave. The mixture was concentrated and then purified on silica gel eluting with 0-100% EtOAc/heptane to give tert-butyl (S) -1- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-vinylpyridin-2-yl) piperidin-3-ylcarbamate (107mg, 91%).

Tert-butyl (S) -1- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-vinylpyridin-2-yl) piperidin-3-ylcarbamate (23.7mg,0.038mmol) above was dissolved in trifluoroacetic acid (2mL) and dichloromethane (2 mL). To the solution was added trifluoromethanesulfonic acid (50uL,0.6mmol) and triethylsilane (30uL,0.19 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 307 as an off white solid (5.1mg, 34%). 1H NMR (400MHz, DMSO) δ 9.32(d, J =1.9Hz,1H),9.20(s,1H),9.11(s,1H),8.59(d, J =3.8Hz,1H),8.46(d, J =8.0Hz,1H),7.96(d, J =7.9Hz,1H),7.82(d, J =7.9Hz,1H),7.52(dd, J =8.0,4.7Hz,1H),6.80(dd, J =17.7,11.0Hz,1H),5.88(d, J =17.6Hz,1H),5.38(d, J =11.3Hz,1H),3.77(d, J =9.7Hz,1H),3.58(d, J =12.1Hz,1H), 2.92-2.398 (d, J = 2.2H = 2H, 1H = 19H, 1H), 1H, 5.7H, 1H =9.7H, 1H, ESI, 2.95H, 1H, 2H, 1H

Example 308(S) -1- (3- (prop-1-en-2-yl) -6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 308

Following the procedure described in example 307 and starting with 4,4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan, 308 was obtained in two steps as an off-white solid (6.7mg, 43%). 1H NMR (400MHz, DMSO) δ 9.33(d, J =1.8Hz,1H),9.21(s,1H),9.11(s,1H),8.59(d, J =3.6Hz,1H),8.48(d, J =8.0Hz,1H),7.73(d, J =7.7Hz,1H),7.58(d, J =7.7Hz,1H),7.51(dd, J =8.0,4.7Hz,1H),5.23(d, J =27.4Hz,2H),4.00(d, J =10.2Hz,1H),3.83(d, J =12.2Hz,1H),2.76(ddd, J =30.9,18.3,10.1, 3H),2.13(s,3H),1.93(d, J =8.2Hz,1H), 1.82H, 22.22H, ESI, 1H, 22M, 25H, 1H, 4

Example 309(R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-ol 309

Following the procedure described in examples 241, 243, 287 and starting with 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and (R) -piperidin-3-ol hydrochloride, 309 was obtained in three steps as an off-white solid (18mg, 34%). 1H NMR (400MHz, DMSO) δ 13.87(s,1H),9.31(d, J =1.7Hz,1H),9.21(s,1H),9.11(s,1H),8.60(d, J =3.6Hz,1H),8.45(d, J =8.0Hz,1H),7.74(d, J =7.6Hz,1H),7.63(d, J =7.7Hz,1H),7.51(dd, J =8.0,4.7Hz,1H),4.88(d, J =4.4Hz,1H), 3.80-3.65 (M,2H),3.53(d, J =12.2Hz,1H),2.84(dt, J =20.1,9.9, 2H),2.31(s,3H),2.00(d = 11.00, J = 11.86, J =1.2Hz,1H), 1H, 2.84(dt, J = 20.1H, 9.9, 2H),2.31(s,3H),2.00(d = 11.00, J = 11.7H), 1H, 1

Example 310(R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 310

Following the procedure described in examples 241, 243, 287 and starting from 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and tert-butyl (R) -piperidin-3-ylcarbamate, 310 was obtained in three steps as an off-white solid (46mg, 42%). 1H NMR (400MHz, DMSO). delta.9.30 (s,1H),9.22(s,1H),9.08(s,1H),8.61(d, J =4.6Hz,1H),8.45(d, J =7.9Hz,1H),8.32(s,2H),7.77(d, J =7.7Hz,1H),7.66(d, J =7.7Hz,1H),7.54(dd, J =7.9,4.7Hz,1H),3.70(s,2H),2.90(s,2H),1.98(s,1H),1.88(s,1H),1.77(s,1H),1.43(s,1H), ESI MS M/z =386.3(M +1)

Example 311(R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 311

Following the procedure described in examples 241, 243, 287, 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and benzyl (R) -azepan-4-ylcarbamate hydrochloride were reacted to give benzyl (R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamate, it was dissolved in trifluoroacetic acid (5mL) and dichloromethane (5mL) and then treated with trifluoromethanesulfonic acid (5 equiv.) and triethylsilane (5 equiv.). The resulting mixture was stirred at room temperature for 2 days. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 311 as an off white solid in three steps (31mg, 28%). 1H NMR (400MHz, DMSO) δ 9.23(d, J =14.6Hz,2H),8.99(s,1H),8.61(d, J =4.6Hz,1H),8.42(d, J =8.0Hz,1H),8.29(s,1H),7.59(ddd, J =14.0,12.7,6.2Hz,3H),3.82(dd, J =10.5,5.8Hz,1H),3.72(t, J =9.3Hz,1H), 3.66-3.61 (M,1H), 3.55-3.50 (M,2H),2.34(s,3H),2.17(d, J =9.2Hz,1H), 2.06-1.80 (M,4H),1.72(q, J = 10.4H); ESI 1.400M/z (M,1H); 1H =1 z + 1H)

Example 312(S) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 312

Following the procedures of examples 241 and 287, 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and benzyl (S) -azepan-4-ylcarbamate were reacted to give benzyl (S) -1- (3-bromo-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamate, it was dissolved in trifluoroacetic acid (5mL) and dichloromethane (5mL) and then treated with trifluoromethanesulfonic acid (5 equiv.) and triethylsilane (5 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 312 as an off white solid in two steps (21mg, 37%). 1H NMR (400MHz, DMSO). delta.9.25 (s,2H),8.91(s,1H),8.62(d, J =3.7Hz,1H),8.42(d, J =8.0Hz,1H),8.04(d, J =8.1Hz,1H),7.60(d, J =8.0Hz,1H),7.56(dd, J =7.8,4.7Hz,1H),4.02(d, J =15.1Hz,1H), 3.91-3.83 (M,1H),3.78(dd, J =11.6,6.8Hz,1H), 3.69-3.58 (M,1H),2.19 (MSs, 1H),1.99(d, J =38.8Hz,4H),1.71(dd, 21.2, ESI = 1.2), 1H = 464.01M + Z)

Example 313(R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 313

Following the procedures of examples 241 and 287, 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and benzyl (R) -azepan-4-ylcarbamate hydrochloride were reacted to give benzyl (R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamate, it was dissolved in trifluoroacetic acid (5mL) and dichloromethane (5mL) and then treated with trifluoromethanesulfonic acid (5 equiv.) and triethylsilane (5 equiv.). The resulting mixture was stirred at room temperature for 2 days. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 313 in two steps as an off white solid (14.2mg, 25.5%). 1H NMR (400MHz, DMSO). delta.9.24 (s,2H),8.91(s,1H),8.61(d, J =3.6Hz,1H),8.42(d, J =8.0Hz,1H),8.35(s,1H),8.03(d, J =8.0Hz,1H), 7.62-7.51 (M,2H),4.00(d, J =14.6Hz,2H), 3.90-3.81 (M,2H),3.77(dd, J =11.4,6.7Hz,2H), 3.67-3.59 (M,3H),2.18(s,1H),1.98(dd, J =31.3,18.3Hz,4H), 1.75-1.59 (M,1H), ESI MS M/z =464.01(M + 1H)

Example 314(S) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) azepan-4-amine 314

Following the procedure of example 241, 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and benzyl (S) -azepan-4-ylcarbamate were reacted to give benzyl (S) -1- (3-methyl-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-ylcarbamate, it was dissolved in trifluoroacetic acid (5mL) and dichloromethane (5mL) and then treated with trifluoromethanesulfonic acid (5 equiv.) and triethylsilane (5 equiv.). The resulting mixture was stirred at room temperature for 2 days. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 314 as an off-white solid in three steps (34.1mg, 30.5%). 1H NMR (400MHz, DMSO). delta.9.25 (d, J =1.9Hz,1H),9.21(s,1H),8.99(s,1H),8.61(d, J =4.7Hz,1H),8.41(d, J =7.9Hz,1H),8.34(s,1H),7.63(t, J =10.2Hz,1H), 7.59-7.53 (M,1H),2.34(s,3H),2.15(s,1H),1.95(dd, J =29.7,7.9Hz,4H), 1.77-1.64 (M,1H); ESI MS M/z =400.12(M +1)

Example 315(S) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 315

Following the procedures in examples 241, 243, 287 and starting with 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and tert-butyl (S) -piperidin-3-ylcarbamate, 315 was obtained in three steps as an off-white solid (37mg, 29%). 1H NMR (400MHz, DMSO) δ 9.31(d, J =2.0Hz,1H),9.20(s,1H),9.13(s,1H),8.59(dd, J =4.7,1.3Hz,1H),8.46(d, J =8.0Hz,1H),7.74(d, J =7.6Hz,1H),7.62(d, J =7.7Hz,1H),7.52(dd, J =8.0,4.7Hz,1H),3.67(d, J =9.6Hz,1H),3.53(d, J =11.9Hz,1H),2.89(dd, J =11.6,7.5Hz,1H),2.81(t, J =10.3, 1H), 2.75-2.65 (M,1H), 2.89(d, J =3.6, 7.5Hz,1H),2.81(t, J =10.3, 1H), 2.75-2.65 (M,1H),2.31, 3.31 (s = 1H), 1H, 13H, 1H

Example 316(R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine 316

Tert-butyl (R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ylcarbamate (124.5mg,0.1867mmol), methylboronic acid (111.76mg,1.867mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (15.2mg,0.01876mmol), 1.00M aqueous potassium acetate (0.28mL,0.28mmol), 1.00M aqueous sodium carbonate (0.28mL,0.28mmol), and acetonitrile (10mL) were charged to a microwave reaction flask. The reaction mixture was heated at 150 ℃ for 5 minutes under microwave. The mixture was concentrated and the residue was purified on silica gel eluting with 0-100% EtOAc/heptane to give tert-butyl (R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ylcarbamate (43.8mg, 39%).

To a solution of tert-butyl (R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-yl carbamate in MeOH (4mL) was added a 4.0M solution of hydrogen chloride in 1, 4-dioxane (6 mL). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 316 as an off-white solid (15.4mg, 56.9%). 1H NMR (400MHz, DMSO). delta.9.27 (d, J =1.7Hz,1H),9.19(s,1H),9.12(s,1H),8.59(d, J =3.8Hz,1H),8.41(d, J =8.0Hz,1H),7.53(dd, J =7.9,4.8Hz,1H), 7.51-7.43 (M,2H),3.85(dd, J =9.5,5.6Hz,2H),3.77(dd, J =16.6,7.1Hz,1H), 3.63-3.57 (M,1H),3.43(dd, J =9.6,5.6Hz,1H),2.37(s,3H),2.11 (ESI, J =12.2,5.9, 1H),1.74 = 1.74 Hz,1H, 1g = 13.6 Hz,1H), 2.11 (ESI, J =12.2,5.9, 1H),1 dZ, 13.13, 1Hz,1H)

Example 317(S) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine 317

Following the procedure described in examples 241, 243, 287 and starting from 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and tert-butyl (S) -piperidin-3-ylcarbamate, 317 was obtained in three steps as an off-white solid (11mg, 38%). 1H NMR (400MHz, DMSO) δ 9.27(d, J =2.1Hz,1H),9.18(s,1H),9.12(s,1H),8.59(dd, J =4.7,1.3Hz,1H),8.41(d, J =8.0Hz,1H),7.53(dd, J =7.9,4.7Hz,1H), 7.49-7.43 (M,2H), 3.89-3.81 (M,2H), 3.81-3.73 (M,1H), 3.63-3.55 (M,1H), 3.45-3.41 (M,1H),2.37(s,3H),2.10(td, J =12.3,5.9Hz,1H),1.74(dq, J =14.0,7.1 ESI, 1H = 2.372 Hz/M +1 z)

Example 318(S) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ol 318

Following the procedure described in example 241 and starting with 3- (5-bromo-6-fluoropyridin-2-yl) -5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridine and (S) -pyrrolidin-3-ol, 318 was obtained in two steps as an off-white solid (1.8mg, 3.0%). 1H NMR (400MHz, DMSO). delta.9.29-9.18 (M,2H),9.00(s,1H),8.60(d, J =4.6Hz,1H),8.40(d, J =8.0Hz,1H),7.93(d, J =8.0Hz,1H),7.54(dd, J =8.0,4.7Hz,1H),7.46(d, J =8.0Hz,1H),5.75(s,1H),5.01(d, J =3.5Hz,1H),4.45(s,1H), 4.11-4.00 (M,2H), 3.90-3.81 (M,1H),3.63(d, J =10.7Hz,1H),2.06(dd, J =8.4,4.2Hz,1H), 1H = 1.95(s,1H) (+ 437.1M/z)

Example 327(S) -1- (3-Ethyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3, 4-c)]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 327

In a round-bottom flask, (S) -tert-butyl 1- (6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-vinylpyridin-2-yl) piperidin-3-ylcarbamate (59.18mg,0.09426mmol) and palladium hydroxide/charcoal 20% (0.2:0.8, palladium hydroxide: carbon black, 6.619mg) in ethanol (30mL) were evacuated and then a hydrogen balloon was attached. The mixture was stirred at room temperature over the weekend. The reaction mixture was filtered through celite. The filtrate was concentrated to give tert-butyl (S) -1- (3-ethyl-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ylcarbamate, which was dissolved in trifluoroacetic acid (3mL) and dichloromethane (3mL) and then treated with trifluoromethanesulfonic acid (83.4uL,0.943mmol) and triethylsilane (150.6uL,0.943 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 327 as an off white solid in two steps (5.8mg, 15%). 1H NMR (400MHz, DMSO) δ 9.31(s,1H),9.20(s,1H),9.13(s,1H),8.59(d, J =4.5Hz,1H),8.46(d, J =8.0Hz,1H),7.81(d, J =7.8Hz,1H),7.71(d, J =7.8Hz,1H),7.53(dd, J =8.0,4.8Hz,1H),3.60(d, J =11.4Hz,2H),2.86(dt, J =20.8,9.5Hz,2H),2.70(dd, J =18.0,10.0Hz,2H),1.95(d, J =12.5Hz,1H),1.84(d, J =13.1H, 1H), 1.80-1.69 (J = 1H), 1.26H, 1M (M = 26H), 1H = 1M (M + 2H)

Example 328(S) -1- (3-isopropyl-6- (5- (pyridin-3-yl) -1H-pyrazolo[3,4-c]Pyridin-3-yl) pyridin-2-yl) piperidin-3-amine 328

In a round-bottom flask, (S) -tert-butyl 1- (3- (prop-1-en-2-yl) -6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-yl carbamate (60.50mg,0.09426mmol) and palladium hydroxide/charcoal 20% (0.2:0.8, palladium hydroxide: carbon black, 6.619mg) in ethanol (30mL) were evacuated and then a hydrogen balloon was attached. The mixture was stirred at room temperature over the weekend. The reaction mixture was filtered through celite. The filtrate was concentrated to give tert-butyl (S) -1- (3-isopropyl-6- (5- (pyridin-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ylcarbamate, which was dissolved in trifluoroacetic acid (3mL) and dichloromethane (3mL) and then treated with trifluoromethanesulfonic acid (83.4uL,0.943mmol) and triethylsilane (150.6uL, 0.943). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was purified by reverse phase HPLC to give 328 as an off-white solid (8.2mg,21%) over two steps. 1H NMR (400MHz, DMSO) δ 9.31(d, J =2.1Hz,1H),9.22(s,1H),9.06(s,1H),8.61(dd, J =4.7,1.3Hz,1H),8.45(d, J =8.0Hz,1H),8.32(s,1H),7.88(d, J =7.9Hz,1H),7.82(d, J =7.9Hz,1H),7.54(dd, J =8.0,4.8Hz,1H),2.90(d, J =9.1Hz,2H),2.00(d, J =12.6Hz,1H),1.90(d, J =13.4Hz,1H),1.76(dd, J =24.1,11.0Hz,1H), 1.46-1.34H, 1H = 1H), 1.6H (J = 24.1H, 1H), 1.5.5H = 1.6H, 1H = 24.1H, 1H = 1H, 1H

Example 901Pim kinase binding Activity

PIM-1, PIM-2 and PIM-3 enzymes were produced 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-. Fluorescently labeled Pim-specific Peptide substrates were custom synthesized by the American Peptide Company (Sunnyvale, Calif.). The reaction buffer contained 10mM HEPES, pH7.2, 10mM MgCl₂0.01% Tween20, 2mM DTT. The stop buffer contained 190mM HEPES, pH7.2, 0.015% Brij-35, 0.2% coating reagent 3(Caliper Life Sciences, Hopkinton, Mass.), 20mM EDTA. Separation ofThe buffer contained 100mM HEPES, pH7.2, 0.015% Brij-35, 0.1% coating reagent 3, 1:200 coating reagent 8(Caliper Life Sciences, Hopkinton, Mass.), 10mM EDTA and 5% DMSO.

The PIM reaction was performed in 384 well plates at a final volume of 10. mu.L/well. A standard enzymatic reaction was initiated by adding 5. mu.L of 2 Xenzyme and FAM-peptide to 5. mu.L of 2X ATP and test compound, containing 20pM PIM-1, 50pMPIM-2 or 55pM PIM-3, 1. mu.M FAM-peptide, and 10. mu.M ATP in reaction buffer. After incubation at room temperature for 90 minutes, the phosphorylation reaction was stopped by adding 10. mu.L of stop buffer. In operation at the CaliperThe product and substrate in each independent reaction were separated on a 12-Sipper microfluidic chip (Caliper Life Sciences, Hopkinton, MA). The separation of product and substrate was optimized by selection of voltage and pressure using a Caliper's Optimizer software (Hopkinton, MA). The downstream voltage used for the separation conditions was-500V, the upstream voltage was-2150V, and the sweep pressure was-1.2 psi. The product and substrate fluorophores are excited at 488nm and detected at 530 nm. Substrate conversion was calculated from the electropherograms using HTSWell Analyzer software (Caliper Life Sciences, Hopkinton, MA). The Ki values of the test compounds were calculated.

Example 902In vitro cell proliferation potency assay

The BaF3 parental line was obtained from the DSMZ depository. A strain of BaF3 transfected with PIM-1 or PIM-2 was generated. Mouse IL-3 was purchased from R & D Systems. G418 was purchased from Clontech. The medium used for the BaF3 parental line contained RPMI, 10% FBS, 2 mML-glutamine, 2ng/mL mIL-3. The medium for the BaF3PIM1&2 line contained RPMI, 10% FBS, 2mM L-glutamine, 250. mu.g/mL. The medium used for the mm1.s (multiple myeloma cell) line contains RPMI, 10% FBS, 2mM L-glutamine.

At 45. mu.L/well, murine interleukin-3 dependent pro-B cell line BaF3 parental cells, BaF3PIM1 cells, BaF3PIM-2 cells and mm1.s (multiple myeloma) cells were seeded at 2 k/well, 5 k/well and 10 k/well, respectively, in 384-well plates. Test compounds were added at 5 μ L/well. BaF3 cells (parental and transfected) were incubated overnight while MM1.S cells were incubated at 37 ℃ with 5% CO₂Incubate for 72 hours. Cell Titer Glo Reagent (Promega) was added at 50 μ L/well, the plates were incubated for 30 minutes, and their luminescence was read on HT analysts. Calculating IC of test Compound₅₀/EC₅₀The value is obtained.

Representative compounds of the invention were tested as described above and found to exhibit Ki/IC as shown below in an in vitro cell proliferation potency assay₅₀/EC₅₀。

Claims

1. A compound selected from compounds of formula I:

R¹selected from the following structures:

wherein the wavy line indicates the site of ligation;

R²selected from the following structures:

wherein the wavy line indicates the site of ligation; and is

R⁴Selected from F, Cl, Br, I, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-CH₂CH(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-CH₂CH₂NH₂、-CH₂CHCH₂NH₂、-CH₂CHCH₂CH₂NH₂、-CH₂CH(CH₃)NH₂、-CH₂CONH₂、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH(OH)CH(CH₃)₂、-C(CH₃)₂CH₂OH、-CH₂C(CH₃)₂OH、-CH₂CH₂SO₂CH₃、-CN、-CF₃、-CO₂H、-COCH₃、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-N(CH₃)COCH₃、-NHS(O)₂CH₃、-NHCH₂CH₂NH₂、-NHCH₂CH₂CH₂NH₂、-NHCH₂CH₂CH₂CH₂NH₂、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、＝O、-OH、-OCH₃、-OCH₂CH₂OCH₃、-OCH₂CH₂NH₂、-S(O)₂N(CH₃)₂、-SCH₃、-CH₂OCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-ylethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and is

n is 0, 1 or 2;

R³independently selected from H.

2. The compound of claim 1, having the structure of formula Ic:

wherein R is⁴Selected from F, Cl, Br, I, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-CH₂CH(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-CH₂CH₂NH₂、-CH₂CHCH₂NH₂、-CH₂CHCH₂CH₂NH₂、-CH₂CH(CH₃)NH₂、-CH₂CONH₂、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH(OH)CH(CH₃)₂、-C(CH₃)₂CH₂OH、-CH₂C(CH₃)₂OH、-CH₂CH₂SO₂CH₃、-CN、-CF₃、-CO₂H、-COCH₃、-CO₂CH₃、-CO₂C(CH₃)₃、-COCH(OH)CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-N(CH₃)COCH₃、-NHS(O)₂CH₃、-NHCH₂CH₂NH₂、-NHCH₂CH₂CH₂NH₂、-NHCH₂CH₂CH₂CH₂NH₂、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、＝O、-OH、-OCH₃、-OCH₂CH₂OCH₃、-OCH₂CH₂NH₂、-S(O)₂N(CH₃)₂、-SCH₃、-CH₂OCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-ylethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and is

n is 0, 1 or 2.

3. A compound selected from:

3-methyl-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

3-methyl-5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

3-methyl-5- (1H-pyrazol-5-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- ((5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) methyl) piperidin-3-amine

(R) -1- ((5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) methyl) piperidin-3-amine

1- ((5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) methyl) piperidin-4-amine

(S) -1- ((5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) methyl) piperidin-3-amine

1- ((5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) methyl) piperidin-4-amine

N- ((5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) methyl) piperidin-4-amine

1- (6- (3-methyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-4-amine

(S) -1- (3- (3-methyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-4-yl) piperidin-3-amine

1- (piperidin-4-yl) -N- ((5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) methyl) methylamine

3-methyl-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

3-methyl-5- (pyrimidin-5-yl) -1H-pyrazolo [3,4-c ] pyridine

3-phenyl-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridines

3- (2-fluorophenyl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

3-methyl-5- (pyrazin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(R) -1- (3- (3-methyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-4-yl) piperidin-3-amine

(S) -1- (6- (3-methyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-3-amine

(R) -1- (6- (3-methyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-3-amine

5- (3-fluorophenyl) -3-methyl-1H-pyrazolo [3,4-c ] pyridine

5- (5-Fluoropyridin-3-yl) -3-methyl-1H-pyrazolo [3,4-c ] pyridines

(S) -1- (3- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-4-yl) piperidin-3-amine

3- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) benzamide

5- (pyridin-3-yl) -3- (3- (trifluoromethyl) phenyl) -1H-pyrazolo [3,4-c ] pyridine

3-methyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (3- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-4-yl) piperidin-4-amine

3- (2-fluorophenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) - (1- (3- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-4-yl) pyrrolidin-3-yl) methylamine

3- (6-Fluoropyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2 (1H) -one

5- (1-methyl-1H-pyrazol-4-yl) -3-phenyl-1H-pyrazolo [3,4-c ] pyridine

2- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) acetonitrile

2- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) acetonitrile

3- (2-fluorophenyl) -5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

3-phenyl-5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (2-fluorophenyl) -5- (pyrimidin-5-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (3- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-4-yl) azepan-4-amine

(S) - (1- (3- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-4-yl) piperidin-3-yl) methylamine

(R) -1- (3- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-4-yl) piperidin-3-amine

3-phenyl-5- (1H-1,2, 4-triazol-1-yl) -1H-pyrazolo [3,4-c ] pyridine

N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) ethane-1, 2-diamine

1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-amine

2- (5- (1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) acetonitrile

5- (1H-imidazol-1-yl) -3-phenyl-1H-pyrazolo [3,4-c ] pyridine

1- (6- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-4-amine

(S) -3- (2-fluorophenyl) -5- (4- (piperidin-3-yloxy) pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

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

3-phenyl-5- (pyrimidin-5-yl) -1H-pyrazolo [3,4-c ] pyridines

(S) -1- (6- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) pyrrolidin-3-amine

(S) -1- (6- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-3-amine

(R) -1- (6- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-3-amine

(R) -1- (6- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) pyrrolidin-3-amine

3- (2-fluorophenyl) -5- (4- (piperidin-4-ylmethoxy) pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (5- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-3-yl) piperidin-4-amine

1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) piperidin-4-amine

N1- (4- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) ethane-1, 2-diamine

1- (4- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-amine

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

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

3, 5-bis (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(R) - (1- (5- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-3-yl) pyrrolidin-3-yl) methylamine

(1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) piperidin-4-yl) methylamine

1- (5- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-3-yl) azepan-4-amine

(1- (5- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-3-yl) piperidin-4-yl) methylamine

(R) - (1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyrrolidin-3-yl) methylamine

1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) azepan-4-amine

N- (piperidin-4-yl) -5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-3-amine

5- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -N- (piperidin-4-yl) pyridin-3-amine

3- (2-fluoro-5-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-amine

3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

3, 5-bis (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridines

(R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

2- (4- (3- (6-fluoropyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetamide

(S) -1- (6- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) azepan-4-amine

(S) -1- (5- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-3-yl) piperidin-3-amine

3- (6- (piperazin-1-yl) pyridin-2-yl) -5- (tetrahydro-2H-pyran-3-yl) -1H-pyrazolo [3,4-c ] pyridine

(1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-yl) methylamine

6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -N- (piperidin-4-ylmethyl) pyridin-2-amine

5- (1-methyl-1H-pyrazol-4-yl) -3- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (furan-3-yl) -3-phenyl-1H-pyrazolo [3,4-c ] pyridine

3- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

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

1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

(R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine

(S) -1- (5- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-3-yl) pyrrolidin-3-amine

(R) -1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(R) -1- (5- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-3-yl) pyrrolidin-3-amine

3- (1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (pyridin-3-yl) -3- (pyridin-4-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (2-fluorophenyl) -5- (4- (piperidin-4-yloxy) pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

5- (4- (azetidin-3-yloxy) pyridin-3-yl) -3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridine

(R) -3- (2-fluorophenyl) -5- (4- (piperidin-3-ylmethoxy) pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -N- (piperidin-4-yl) pyridin-2-amine

(S) -3- (2-fluorophenyl) -5- (4- (piperidin-3-ylmethoxy) pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine

(R) -1- (5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine

3- (pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (2-fluoro-5-methylphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (6- (5- (5-fluoropyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

3- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -N- (piperidin-4-ylmethyl) pyridin-4-amine

5- (5-Fluoropyridin-3-Yl) -3- (6- (piperazin-1-Yl) pyridin-2-Yl) -1H-pyrazolo [3,4-C ] pyridines

(R) -3- (2-fluorophenyl) -5- (4- (pyrrolidin-3-ylmethoxy) pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

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

(S) -3- (2-fluorophenyl) -5- (4- (pyrrolidin-3-ylmethoxy) pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

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

5- (1H-imidazol-5-yl) -3-phenyl-1H-pyrazolo [3,4-c ] pyridine

3-phenyl-5- (pyrazin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (6- ((1S,4S) -2, 5-diazabicyclo [2.2.1] hept-2-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

N- (2- (1H-imidazol-4-yl) ethyl) -6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-amine

3- (2-fluorophenyl) -5- (1H-imidazol-5-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (2-fluorophenyl) -5- (pyrazin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (2-fluorophenyl) -5- (4- (2- (piperidin-4-yl) ethoxy) pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (6- (3- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-4-amine

(R) -1- (3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) phenyl) piperidin-3-amine

1-methyl-4- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) piperazin-2-one

1- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) urea 3-cyclopentenyl-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-3-amine

(S) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

3-cyclopentyl-5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

4-amino-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxamide

1- (6- (3- (2, 6-difluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-4-amine

1- (6- (3-phenyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-4-amine

3- (1-methyl-1H-pyrazol-3-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (6- (3- (1-methyl-1H-pyrazol-3-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) piperidin-4-amine

5- (1-methyl-1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

2- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) acetonitrile

4-amino-N-methyl-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidine-4-carboxamide

(R) -2- (1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-yl) ethylamine

3- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-2-amine

(1S,3R) -N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) cyclohexan-1, 3-diamine

3- (piperazin-1-yl) -5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) benzonitrile

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

(S) -2- (1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-yl) ethylamine

1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-amine

(R) -1- (6- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrazin-2-yl) azepan-4-amine

(1R,3S) -N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) cyclohexane-1, 3-diamine

(R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

5- (1-methyl-1H-pyrazol-4-yl) -3- (6- (piperidin-4-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

(R) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

2-methyl-1- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -1H-pyrazol-1-yl) propan-2-ol

(1s,4s) -N1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) cyclohexane-1, 4-diamine

5- (pyridin-3-yl) -3- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-c ] pyridine

2- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) acetamide

1-methyl-3- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) imidazolidin-2-one

3- (5-chloro-6- (4-methylpiperazin-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

3, 5-bis (pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridines

3- (5-methyl-6- (4-methylpiperazin-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyrrolidin-2-one

1-methyl-4- (3-phenyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrrol-2 (5H) -one

1- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) piperidin-2-one

3- (6- (piperidin-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

1-methyl-4- (3-phenyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrrolidin-2-one

(R) -5- (1-methyl-1H-pyrazol-4-yl) -3- (6- (piperidin-3-yloxy) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

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

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

4- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) morpholine

(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine

(S) - (1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-yl) methylamine

(R) - (1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-yl) methylamine

(R) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ol

3- (6- (4,4' -bipiperidin-1-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (6-fluoro-5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

(R) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine

(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

(1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-yl) methylamine

4- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazin-2-one

N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) propane-1, 3-diamine

3- (3, 4-dihydro-2H-pyran-5-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridines

2- (4- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazin-1-yl) ethanol

N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) butane-1, 4-diamine

3- (4, 5-dihydrofuran-3-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

(R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -3- (trifluoromethyl) pyrrolidin-3-amine

(R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine

1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ol

(S) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

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

(R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ol

(R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ol

1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ol

2- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -2, 8-diazaspiro [4.5] decan-1-one

1- (piperidin-4-ylmethyl) -3- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) imidazolidin-2-one

2-methyl-1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-ylamino) propan-2-ol

(S) -1- (3- (6- (3-aminopiperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) urea (1S,3R) -3- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yloxy) cyclohexylamine

(R) -1- (4- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyrimidin-2-yl) piperidin-3-amine

1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazin-2-one

2- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) isonicotinamide

1- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3- (pyrrolidin-3-ylmethyl) imidazolidin-2-one

(S) -3-amino-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-2-one

(S) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ol

(R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ol

(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-vinylpyridin-2-yl) piperidin-3-amine

(S) -1- (3- (prop-1-en-2-yl) -6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

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

(R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

(S) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

(R) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

(S) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

(S) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(R) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine

(S) -1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-amine

(S) -1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-ol

(1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-yl) methylamine

3- (3- (piperazin-1-yl) pyrrolidin-1-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

(3S,5R) -5-fluoro-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

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

5- (3-phenyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) thiazole

(1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-2-yl) methylamine

3- (4-aminopiperidine-1-carbonyl) -1- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyrrolidin-2-one

N- (2-aminoethyl) -6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridine-2-carboxamide

(S) -1- (3-Ethyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

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

N- (azetidin-3-yl) -6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridine-2-carboxamide

1-methyl-4- (3-phenyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) piperazin-2-one

1-methyl-4- (3- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) piperazin-2-one

5- (1-methyl-1H-pyrazol-4-yl) -3- (pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

2- (1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) pyrrolidin-3-yl) ethylamine

(S) -3-amino-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyrrolidin-2-one

4- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) piperazin-2-one

(4-Aminopiperidin-1-yl) (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) methanone

N- (piperidin-4-yl) -6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridine-2-carboxamide

5- (3- (pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) thiazole

4- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1-methylpiperazin-2-one

(S) -1- (3-ethynyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(S) -3-methyl-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyrrolidine-2-carboxamide

(S) -4- (3- (6- (3-aminopiperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) piperazin-2-one

1- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) piperazin-2-one

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

5- (3- (2-fluorophenyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) thiazole

(S) -1- (6- (5- (thiazol-5-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

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

1-methyl-4- (3- (pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) piperazin-2-one

(1R,3R) -N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) cyclohexan-1, 3-diamine

(1S,3S) -N1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) cyclohexan-1, 3-diamine

2- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -5- (trifluoromethyl) pyridine 1-oxide

3-methyl-1- (3-phenyl-1H-pyrazolo [3,4-c ] pyridin-5-yl) imidazolidine-2, 4-dione

5- (1-ethyl-1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

2- (4- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -1, 4-diazepan-1-yl) ethanol

5- (3- (6- (piperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) thiazole

5- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) thiazole

5- (1-methyl-1H-pyrazol-4-yl) -3- (2- (piperidin-1-yl) pyrimidin-4-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1-methyl-1H-pyrazol-4-yl) -3- (2- (piperazin-1-yl) pyrimidin-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (3-butyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

5- (1H-imidazol-1-yl) -3- (6- (piperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(R) -1- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyrimidin-2-yl) piperidin-3-amine

(S) -1- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyrimidin-2-yl) piperidin-3-amine

1-methyl-4- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-2 (1H) -one

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

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

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

(R) -3- (3- (6- (3-aminopiperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) oxazolidin-2-one

3-methyl-1- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) imidazolidine-2, 4-dione

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (6- (4-methylpiperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (3- (6- (piperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) oxazolidin-2-one

(S) -3- (3- (6- (3-aminopiperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) oxazolidin-2-one

3- (6- (piperazin-1-yl) pyridin-2-yl) -5- (1-propyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (3-bromo-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -N-methylpiperidin-3-amine

5- (6-Fluoropyridin-3-Yl) -3- (6- (piperazin-1-Yl) pyridin-2-Yl) -1H-pyrazolo [3,4-C ] pyridines

1- (3-amino-2, 2-dimethylpropyl) -5- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2 (1H) -one

(S) -1- (6- (5- (1H-imidazol-1-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

5- (1-isobutyl-1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

3-methyl-1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

5- (5-methylpyridin-3-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine (3S,5R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -5-fluoropiperidin-3-amine

(S) -1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3- (trifluoromethyl) pyridin-2-yl) piperidin-3-amine

4- (1- (3-bromo-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azetidin-3-yl) -1, 1-dioxothiomorpholine

2-methyl-1- (4- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) propan-2-ol

5- (1-isopropyl-1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1-cyclobutyl-1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (3-bromo-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-amine

(S) -1- (3-bromo-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

(R) -1- (3-bromo-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (6- ((3aR,6aS) -hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -5- (1-ethyl-1H-pyrazol-4-yl) -3- (6- (3-methylpiperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(R) -5- (1-ethyl-1H-pyrazol-4-yl) -3- (6- (3-methylpiperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(R) -3- (6- (3-aminopiperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine-5-carbonitrile

(S) -3- (6- (3-aminopiperidin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine-5-carbonitrile

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

4- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) morpholine

3- (5-bromo-6- (4-methylpiperazin-1-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (3-bromo-6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

3- (5-bromo-6- (piperazin-1-yl) pyridin-2-yl) -5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

4- (1- (3-bromo-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azetidin-3-yl) piperazin-2-one

3- (5-bromo-6- (3, 3-dimethyl-4- (2- (methylsulfonyl) ethyl) piperazin-1-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(R) -1- (3-bromo-6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

4- (1- (3-bromo-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azetidin-3-yl) piperazin-2-one

3- (6- (1, 4-diazepan-1-yl) pyridin-2-yl) -5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -1, 4-diazepan-6-ol

(R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -1, 4-diazepan-6-ol

(S) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-vinylpyridin-2-yl) piperidin-3-amine

4- (1- (3-methyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azetidin-3-yl) -1, 1-dioxothiomorpholine

(S) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3- (prop-1-en-2-yl) pyridin-2-yl) piperidin-3-amine

3- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) oxazolidin-2-one

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

1- (3-methyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-amine

(R) -1- (3-methyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

4- (3-methyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) morpholine

4- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) morpholine

3- (6- (4-fluoropiperidin-4-yl) pyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridine

4- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-4-ol

(S) -3-methyl-1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

(R) -3-methyl-1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

4- (1- (3-methyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azetidin-3-yl) piperazin-2-one

4- (1- (3-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azetidin-3-yl) piperazin-2-one

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3- (prop-1-en-2-yl) pyridin-2-yl) piperidin-3-amine

3- (6- (3, 3-dimethyl-4- (2- (methylsulfonyl) ethyl) piperazin-1-yl) -5-methylpyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (3-ethyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-methylpyridin-2-yl) piperidin-3-amine

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-vinylpyridin-2-yl) piperidin-3-amine

5- (1-ethyl-1H-pyrazol-4-yl) -3- (5-methyl-6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (3-methyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(S) -1- (3-isopropyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

4-fluoro-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

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

N-methyl-6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-amine 5- (5-ethylpyridin-3-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine 5- (1-methyl-1H-pyrazol-4-yl) -3- (2- (piperidin-4-yl) pyrimidin-4-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1-methyl-1H-pyrazol-4-yl) -3- (5-methyl-6- (4-methylpiperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (3-methyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

(S) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

(R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-methylpyridin-2-yl) piperidin-3-amine

3- (6- ((3S,5R) -3, 5-dimethylpiperazin-1-yl) pyridin-2-yl) -5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

3- (6- (3, 3-dimethylpiperazin-1-yl) pyridin-2-yl) -5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (6- (6, 6-difluoro-1, 4-diazepan-1-yl) pyridin-2-yl) -5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1-tert-butyl-1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

4- (3-bromo-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) morpholine

4- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) morpholine

(R) -1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-ol

Cis-4-fluoro-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

Trans-4-fluoro-1- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(3S,5R) -1- (3-bromo-6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -5-fluoropiperidine-3-amine

(3R,5R) -1- (3-bromo-6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -5-fluoropiperidine-3-amine

(3S,5R) -1- (3-bromo-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -5-fluoropiperidine-3-amine

3- (6- (1, 4-diazepan-1-yl) -4-methylpyridin-2-yl) -5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

(1R) -3- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) cyclohexylamine

(1S) -3- (6- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) cyclohexylamine

(R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -3-methylpiperidin-3-ol

N1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) cyclohexane-1, 3-diamine

Trans-1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -4-fluoropiperidin-3-amine

(4- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazin-2-yl) methanol

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -3-methylpiperidin-3-ol

Cis-1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -4-fluoropiperidin-3-amine

(S) -1- (5-chloro-6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

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

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (6- (3- (trifluoromethyl) piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (4- (trifluoromethyl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

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

(R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

1- (4- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperazin-1-yl) ethanone

2- (4- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) acetonitrile

1- ((5- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -2-oxopyridin-1 (2H) -yl) methyl) cyclopropylcarboxamide

1- ((5- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -2-oxopyridin-1 (2H) -yl) methyl) cyclobutylcarboxamide

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (4-methoxypyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine (S) -1- (3-ethyl-6- (5- (1-Ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-isopropylpyridin-2-yl) piperidin-3-amine

5- (1-ethyl-1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyrazin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

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

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-4-amine

(R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -N-methylpiperidin-3-amine

1- (5- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyridin-3-yl) ethanol

3- (4-Cyclopropylpyridin-2-yl) -5- (1-Ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

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

(S) -1- (3-cyclopropyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

5- (1-cyclopropyl-1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (6- (piperazin-1-yl) pyridin-2-yl) -5- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

3- (6- (1, 4-diazepan-1-yl) pyridin-2-yl) -5- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridine

2- (1, 4-diazepan-1-yl) -6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridine-4-carbonitrile

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (6- (5- (trifluoromethyl) -1, 4-diazepan-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (4-methylpyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (4-ethylpyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-3-ol

(3S,5R) -5-fluoro-1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

2- (4- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) -1H-pyrazol-1-yl) ethanol

5- (1- (cyclopropylmethyl) -1H-pyrazol-4-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(2- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-4-yl) methanol

1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -1, 4-diazepan-6-carbonitrile

5- (1-ethyl-1H-pyrazol-4-yl) -3- (4- (prop-1-en-2-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(S) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-3-ol

(R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-3-ol

(S) -5- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -3- (6- (3-methylpiperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (6- (6-fluoro-1, 4-diazepan-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

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

(S) -1- (3-cyclopropyl-6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl)

Pyridin-2-yl) piperidin-3-amines

5- (1-Ethyl-1H-pyrazol-4-yl) -3- (4-isopropylpyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

5- (1-ethyl-1H-pyrazol-4-yl) -3- (pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(3S,5R) -5-fluoro-1- (3-methyl-6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) piperidin-3-amine

(3S,5R) -1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) -3-methylpyridin-2-yl) -5-fluoropiperidine-3-amine

(1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) -1, 4-diazepan-6-yl) methanol

N- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-3-amine

1- (6- (5- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-3-amine

3-ethyl-5- (3- (6- (piperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridin-5-yl) pyrimidine

-4(3H) -one

5- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -3- (6- (3-methylpiperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine

(3R,5R) -5-fluoro-1- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl)

Pyridin-2-yl) piperidin-3-amines

1- (6- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-3-amine

(S) -1- (6- (5- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-3-amine

(R) -1- (6- (5- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -1H-pyrazolo [3,4-c ] pyridin-3-yl) pyridin-2-yl) azepan-3-amine

(R) -5- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -3- (6- (3-methylpiperazin-1-yl) pyridin-2-yl) -1H-pyrazolo [3,4-c ] pyridine.

4. A pharmaceutical composition comprising a compound according to any one of claims 1-3 and a pharmaceutically acceptable carrier, excipient.

5. A pharmaceutical composition comprising a compound of any one of claims 1-3 and a pharmaceutically acceptable carrier, glidant, or diluent.

6. The pharmaceutical composition of claim 4 or 5, further comprising another chemotherapeutic agent.

7. A process for preparing a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of a disease or disorder selected from cancer, immune, cardiovascular, viral infection, inflammation, metabolism/endocrine function disorders and neurological diseases, and mediated by Pim kinase, wherein a therapeutically effective amount of a compound according to any one of claims 1 to 3 is administered to a patient suffering from the disease or disorder.

9. The use of claim 8, wherein the disease or disorder is a cancer selected from the group consisting of: multiple myeloma, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, 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, lymphoma, hairy cell carcinoma, oral cavity cancer, nasopharyngeal cancer, pharyngeal cancer, small intestine cancer, colon-rectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, hodgkin's cancer, leukemia, bronchial cancer, intrahepatic bile duct cancer, hepatocellular carcinoma, glioma, endometrial cancer, renal carcinoma, bladder cancer, pyelocarcinoma, hairy cell carcinoma, thyroid carcinoma, bladder carcinoma, Uterine corpus carcinoma, non-hodgkin lymphoma and villous colon adenoma.

10. The use of claim 8, wherein the disease or disorder is a cancer selected from the group consisting of: non-small cell lung cancer (NSCLC), acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, lip cancer, tongue cancer, and oropharyngeal cancer.

11. The use of claim 9 or 10, further comprising administering an additional therapeutic agent selected from the group consisting of: chemotherapeutic agents, anti-inflammatory agents, immunomodulators, neurotrophic factors, agents for treating cardiovascular disease, agents for treating liver disease, antiviral agents, agents for treating hematologic diseases, agents for treating diabetes, and agents for treating immunodeficiency.

12. The use of claim 11, wherein the additional therapeutic agent is selected from the group consisting of dexamethasone, thiotepa, doxorubicin, vincristine, rituximab, cyclophosphamide, prednisone, melphalan, lenalidomide, bortezomib, rapamycin, and cytarabine.

13. A kit for treating a condition mediated by Pim kinase, comprising:

a) a first pharmaceutical composition comprising a compound of any one of claims 1-3; and

b) instructions for use.