Novel indazole derivatives and their applications

Abstract

This invention provides an indazole derivative with excellent TRIB2 or YAP inhibitory activity. [Solution] A novel indazole derivative, shown in the following chemical formula 1, is provided. The indazole derivative exhibits excellent TRIB2 or YAP inhibitory activity and can be usefully used in pharmaceutical compositions for the prevention or treatment of cancer, lethargy, and fasciitis. TIFF2026102832000091.tif45166

Description

[Technical Field]

[0001] The present invention relates to novel indazole derivatives and their uses, and more specifically to novel indazole derivatives having TRIB2 inhibitory activity or YAP inhibitory activity, and pharmaceutical compositions containing the same for the prevention or treatment of cancer, lethargy, and fasciitis. [Background technology]

[0002] TRIB2 (tribbles pseudokinases 2) is a protein that assists in molecular binding and is involved in various signaling pathways. In particular, TRIB2 is known to play an important role in carcinogenesis-related properties in various cancers, and various in vitro and in vivo experiments and tissue studies of cancer patients have reported its involvement in the proliferation / survival of androgen-independent prostate cancer, liver cancer, acute myeloid leukemia (AML), lung cancer, melanoma, and anticancer therapy-resistant cancers (Non-patent literature 1-8: Eyers, PA et al., Trends Cell Biol., 27(4), 284-298, 2017; Zhang, H Het al., Oncol Rep., 31(3), 1473-1479, 2014; Wang, P Y et al., FEBS Lett., 587(16), 2675-2681, 2013; Bisoffi, M. et al., J Urol., 172(3), 1145-1150, 2004; Wang, J. et al., Mol Cell.,51(2),211-225,2013;Keeshan,K.at al.,Cancer Cell.,10(5),401-411,2006;Keeshan,K.et al.,Blood Cells Mol Dis.,40(1),119-121,2008;Hill,R.et al., Carcinogenesis, 36(4), 469-477, 2015).

[0003] YAP (Yes-associated protein 1) is an important factor that mediates Hippo signaling. Hippo signaling is known to be involved in cell proliferation and tissue homeostasis, and to control cell proliferation and death through contact inhibition. However, it has been reported that abnormal changes in this regulatory mechanism can induce cancer, and it is considered an important mechanism in cancer treatment (Non-patent literature 9-12: Jung Hyowon et al., Study on the efficacy of inhibiting metastasis by suppressing YAP activity in cinnamon in prostate cancer cells, Kor. J. Herbol., 34(3), 55-61, 2019; Sudol, M., Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product, Oncogene, 9(8), 2145-2152, 1994; Pan, D., The hippo signaling pathway in development and cancer, Dev Cell., 19(4), 491-505, 2010; Zhao, B. et al., Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein, Cancer Res., 69(3), 1089-1098, 2009).

[0004] In particular, the Hippo tumor suppressor pathway, a downstream effector of YAP, is known to be involved in liver cancer formation along with CREB (cAMP response element-binding protein) (Non-patent Literature 13: Wang, J. et al., Mutual interaction between YAP and CREB promotes tumorigenesis in liver cancer, Hepatology, 58(3), 1011-1020, 2013).

[0005] On the other hand, prior art related to pharmaceutical compositions for the prevention or treatment of cancer, lethargy, and fasciitis containing indazole derivatives as active ingredients includes Patent Document 1: Korean Registered Patent No. 10-1796781, which discloses a novel indazole derivative, a method for producing the same, and a pharmaceutical composition for the prevention or treatment of cancer containing the same as an active ingredient, and Patent Document 2: Korean Registered Patent No. 10-1936851, which discloses a novel pyrazolopyridine derivative or indazole derivative that is a protein kinase inhibitor.

[0006] However, there are currently no reports mentioning indazole derivatives such as those of chemical formulas 1 and 2 of the present invention, their TRIB2 inhibitory activity or YAP inhibitory activity, or their potential for treating cancer, lethargy, and fasciitis.

[0007] Therefore, in the process of researching indazole derivatives, the present inventors confirmed excellent inhibitory activity against TRIB2 or YAP, and thus completed the present invention. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Korean Registered Patent No. 10-1796781 [Patent Document 2] Korean Registered Patent No. 10-1936851 [Non-patent literature]

[0009] [Non-Patent Document 1] Eyers, PAet al.,Trends Cell Biol.,27(4),284-298,2017 [Non-Patent Document 2] Zhang,HHet al.,Oncol Rep.,31(3),1473-1479,2014 [Non-Patent Document 3] Wang,PY et al.,FEBS Lett.,587(16),2675-2681,2013

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-Patent Document 13

Summary of the Invention

Problems to be Solved by the Invention

[0010] An object of the present invention relates to a novel indazole derivative and its use, and more specifically, to provide a novel indazole derivative having TRIB2 inhibitory activity or YAP inhibitory activity and a pharmaceutical composition for preventing or treating cancer, narcolepsy and myositis containing the same.

Means for Solving the Problems

[0011] The present invention relates to a compound represented by the following Chemical Formula 1, its optical isomers, or its pharmaceutically acceptable salts.

[0012]

Chemical Formula

[0013] In the above Chemical Formula 1,

[0014] R1 is a substituted or unsubstituted C4 - C 12 heterocycloalkyl, a C4 - C 12 heterocycloalkyl substituted with N, a substituted or unsubstituted C4 - C 12Cycloalkyl, substituted or unsubstituted C4-C 12 Heteroaryl, substituted or unsubstituted C1-C4 alkyl C4-C 12 Heterocycloalkyl, substituted or unsubstituted C1-C4 alkyl C4-C 12 One or more substituents selected from the group consisting of heteroaryl;

[0015] TIFF2026102832000003.tif45166

[0016] TIFF2026102832000004.tif26166

[0017] R3 is substituted or unsubstituted C4-C 12 Aryl, substituted or unsubstituted C4-C 12 Heteroaryl, substituted or unsubstituted C4-C 12 Heterocycloalkyl, and can form substituted or unsubstituted pyridine,

[0018] TIFF2026102832000005.tif45166

[0019] The present invention is a compound represented by Chemical Formula 1,

[0020] TIFF2026102832000006.tif45166

[0021] TIFF2026102832000007.tif32166

[0022] TIFF2026102832000008.tif20166

[0023] R3 is substituted or unsubstituted C4-C 12 Aryl, substituted or unsubstituted C4-C 12 Heteroaryl, substituted or unsubstituted C4-C 12 Heterocycloalkyl, and can form substituted or unsubstituted pyridine,

[0024] TIFF2026102832000009.tif45166

[0025] Furthermore, the present invention relates to a compound represented by the following chemical formula 2, its optical isomers, or a pharmaceutically acceptable salt thereof.

[0026] The compound represented by the following chemical formula 2, its optical isomers, or its pharmaceutically acceptable salts;

[0027] [ka]

[0028] In the aforementioned chemical formula 2,

[0029] TIFF2026102832000011.tif20166

[0030] R3 is the substituted or unsubstituted C4-C 12 Aryl, substituted, or unsubstituted C4-C 12 Heteroaryl, substituted or unsubstituted C4-C 12 Heterocycloalkyl, substituted or unsubstituted pyridine can be formed.

[0031] TIFF2026102832000012.tif45166

[0032] R4 is a substituent selected from the group consisting of hydrogen, C1-C6 alkyl, acetyl, or trihaloacetyl;

[0033] R5 is independently one or more substituents selected from the group consisting of hydrogen, hydroxyl, halogen, and C1-C6 alkyl;

[0034] R6 is independently one or more substituents selected from the group consisting of hydrogen, hydroxyl, nitro, amino, halogen, C1-C4 alkyl, and C1-C4 alkoxy;

[0035] n is an integer between 0, 1, and 2.

[0036] More specifically, the compounds of chemical formula 1 or 2 of the present invention are as follows:

[0037] tert-butyl-4-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide)piperidine-1-carboxylate (compound 1);

[0038] 5-(2-fluoropyridine-3-yl)-N-(piperidine-4-yl)-1H-indazole-3-carboxamide (compound 2);

[0039] tert-butyl 4-(5-(pyridine-3-yl)-1H-indazole-3-carboxamide)piperidine-1-carboxylate (compound 3);

[0040] N-(piperidine-4-yl)-5-(pyridine-3-yl)-1H-indazole-3-carboxamide (compound 4);

[0041] tert-butyl 4-(5-(2-fluorophenyl)-1H-indazole-3-carboxamide)piperidine-1-carboxylate (compound 5);

[0042] 5-(2-fluorophenyl)-N-(piperidine-4-yl)-1H-indazole-3-carboxamide (compound 6);

[0043] 5-(2-fluoropyridine-3-yl)-N-(piperidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (compound 7);

[0044] 5-(2-fluoropyridine-3-yl)-N-(piperidine-4-yl)-1H-indole-3-carboxamide (compound 8);

[0045] 5-(2-fluoropyridine-3-yl)-1-methyl-N-(piperidine-4-yl)-1H-indazole-3-carboxamide (compound 9);

[0046] 1-Benzoyl-N-(1-benzoylpiperidine-4-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 10);

[0047] 1-(cyclopropanecarbonyl)-N-(1-(cyclopropanecarbonyl)piperidine-4-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 11);

[0048] N-(1-benzoylpiperidine-4-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 12);

[0049] 5-(2-fluoropyridine-4-yl)-N-(piperidine-4-yl)-1H-indazole-3-carboxamide (compound 13);

[0050] N-cyclohexyl-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 14);

[0051] 1-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carbonyl)piperidine-4-carboxamide (compound 15);

[0052] 5-(2-fluoropyridine-3-yl)-N-((1r,4r)-4-hydroxycyclohexyl)-1H-indazole-3-carboxamide (compound 16);

[0053] 5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 17);

[0054] N-((1s,4s)-4-aminocyclohexyl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 18);

[0055] N-((1r,4r)-4-aminocyclohexyl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 19);

[0056] 5-(2-fluoropyridine-3-yl)-N-(pyrrolidine-3-yl)-1H-indazole-3-carboxamide (compound 20);

[0057] (3,4-Dihydroisoquinoline-2(1H)-yl)(5-(2-Fluoropyridine-3-yl)-1H-Indazole-3-yl)methanone (Compound 21);

[0058] 5-(2-fluoropyridine-3-yl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide (compound 22);

[0059] (5-(2-fluoropyridine-3-yl)-1H-indazole-3-yl)(4-methylpiperazine-1-yl)methanone (compound 23);

[0060] 5-(2-fluoropyridine-3-yl)-N-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide (compound 24);

[0061] 5-(3,4-difluorophenyl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 25);

[0062] 5-(1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 26);

[0063] N-(pyridine-4-yl)-5-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indazole-3-carboxamide (compound 27);

[0064] 5-(1-isopropyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 28);

[0065] 5-(1-methyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 29);

[0066] tert-butyl 5-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-yl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate (compound 30);

[0067] tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate (compound 31);

[0068] tert-butyl 5-(4-((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)phenyl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate (compound 32);

[0069] 5-(1-benzyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 33);

[0070] 5-(furan-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 34);

[0071] tert-butyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate (compound 35);

[0072] 5-(1-propyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 36);

[0073] 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 37);

[0074] tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)benzyl)piperazine-1-carboxylate (compound 38);

[0075] tert-butyl4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (compound 39);

[0076] tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)phenyl)piperazine-1-carboxylate (compound 40);

[0077] 5-(5-formylfuran-2-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 41);

[0078] N-(pyridine-4-yl)-5-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indazole-3-carboxamide (compound 42);

[0079] 5-(benzo[b]thiophen-2-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 43);

[0080] 5-(2-(dimethylamino)pyrimidine-5-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 44);

[0081] 5-(6-formylbenzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 45);

[0082] 5-(4-(piperazine-1-yl)phenyl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide hydrochloride (compound 46);

[0083] 5-(5-formylfuran-2-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 47);

[0084] 5-(benzo[b]thiophen-2-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 48);

[0085] 5-(2-fluoropyridine-3-yl)-N-(pyridine-4-ylmethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 49);

[0086] 5-(2-(dimethylamino)pyrimidine-5-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 50);

[0087] 5-(2-fluoropyridine-3-yl)-N-(pyridine-4-ylmethyl)-1H-indazole-3-carboxamide (compound 51);

[0088] 5-(6-formylbenzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 52);

[0089] 5-(2-fluoropyridine-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide (compound 53);

[0090] 5-(2-fluoropyridine-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide (compound 54);

[0091] 5-(2-fluoropyridine-3-yl)-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide hydrochloride (compound 55);

[0092] 5-(6-(piperidine-1-ylmethyl)benzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 56);

[0093] tert-butyl 4-((5-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)furan-2-yl)methyl)piperazine-1-carboxylate (compound 57);

[0094] N-(1,1-dimethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 58);

[0095] N-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 59);

[0096] 5-(2-fluoropyridine-3-yl)-N-(1-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 60);

[0097] tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)benzoyl)piperazine-1-carboxylate (compound 61);

[0098] tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)benzyl)piperazine-1-carboxylate (compound 62);

[0099] 5-(2-fluoropyridine-3-yl)-N-(1-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide (compound 63);

[0100] 5-(2-fluoropyridine-3-yl)-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-indazole-3-carboxamide (compound 64);

[0101] 5-(2-fluoropyridine-3-yl)-N-(1-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-1H-indazole-3-carboxamide (compound 65);

[0102] 5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 66);

[0103] 5-(4-(piperazine-1-carbonyl)phenyl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 67);

[0104] 5-(4-(piperazine-1-ylmethyl)phenyl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 68);

[0105] 5-(5-(piperazine-1-ylmethyl)furan-2-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 69);

[0106] 5-(5-(piperidine-1-ylmethyl)furan-2-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 70);

[0107] N-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 71);

[0108] 5-(5-(piperidine-1-ylmethyl)furan-2-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide hydrochloride (compound 72); and

[0109] Selected from the group consisting of 5-(1-(piperidine-4-yl)-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide hydrochloride (compound 73).

[0110] Furthermore, unless otherwise specified, the following terms in this invention have the meanings set forth below. Any undefined terms have the meanings understood in the art.

[0111] The aforementioned term "halogen" refers to fluoro(F), chlorine(Cl), bromine(Br), and iodine(I).

[0112] The term "alkyl" refers to a single-bonded, linear or branched hydrocarbon group. Examples include methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, and 1-methylpropyl.

[0113] The term "cycloalkyl" refers to a cyclic, single-bonded saturated hydrocarbon group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0114] The term "heterocycloalkyl" refers to a cyclic, single-bonded saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S. Depending on the number and type of heteroatoms in the ring and the number of carbon atoms, there are various types such as azilidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranil, tetrahydropyranil, and tetrahydroisoquinoline.

[0115] The term "aryl" refers to an aromatic substituted compound having at least one ring with a shared π-electron system, such as phenyl and benzyl.

[0116] The term "heteroaryl" refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S. Depending on the number and type of heteroatoms contained in the ring, and the number of carbon atoms, there are compounds such as pyrrolyl, furanyl, pyridinyl, pyrimidinyl, and pyranyl.

[0117] Furthermore, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and partial stereoisomers are included within the scope of the present invention.

[0118] In the present invention, the pharmaceutically acceptable salt means a salt or complex of chemical formula 1 or 2 that possesses desirable biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly including chlorides, bromides, iodides, -O-alkyls, toluenesulfonates, methylsulfonates, sulfonates, phosphates, or carboxylates (e.g., benzoates, succinates, acetates, glycoates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinnamoates, mandeloates, and diphenylacetates). In addition to pharmaceutically acceptable salts, the compounds of chemical formula 1 or 2 of the present invention may also include any salts, hydrates, solvates, and prodrugs that can be produced by conventional methods.

[0119] The acid addition salt according to the present invention can be produced by conventional methods. For example, it can be produced by dissolving a derivative of chemical formula 1 or 2 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, or acetonitrile, adding an organic or inorganic acid, filtering and drying the resulting precipitate, or by vacuum distillation of the solvent and excess acid, followed by drying and crystallization under an organic solvent.

[0120] Furthermore, pharmaceutically acceptable metal salts can be produced using bases. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the insoluble compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are suitable for pharmaceutical purposes as the metal salts produced. The corresponding salts can also be obtained by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0121] In other respects, the present invention relates to a pharmaceutical composition for the prevention or treatment of cancer, lethargy, and fasciitis, comprising a compound represented by chemical formula 1 or 2 as an active ingredient, wherein the compound represented by chemical formula 1 or 2 has activity to inhibit TRIB2 or YAP.

[0122] Furthermore, the aforementioned cancers may be selected from, but are not limited to, the group consisting of lung cancer, liver cancer, stomach cancer, colorectal cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, thyroid cancer, melanoma, hematological cancer, colon cancer, non-small cell lung cancer, pancreatic cancer, skin cancer, head and neck cancer, small intestine cancer, rectal cancer, endometrial cancer, vaginal cancer, testicular cancer, esophageal cancer, biliary tract cancer, lymphatic cancer, gallbladder cancer, endocrine adrenal cancer, adrenal cancer, lymphoma, multiple myeloma, thymoma, mesothelioma, kidney cancer, brain cancer, central nervous system tumors, brainstem glioma, and pituitary adenoma.

[0123] The pharmaceutical compositions according to the present invention may be formulated in a suitable dosage form with a commonly used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means a composition that is physiologically acceptable and does not typically cause allergic reactions or similar reactions such as gastrointestinal disorders or dizziness when administered to humans. Furthermore, each of the above compositions may be formulated by conventional methods into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, as well as topical preparations, suppositories, and sterile injection solutions.

[0124] Examples of carriers, excipients, and diluents that may be included in the above composition include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl parahydroxybenzoate, propyl parahydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulation, the product is prepared using commonly used fillers, stabilizers, binders, disintegrants, surfactants, and other diluents or excipients. Solid formulations for oral administration include tablets, pills, powders, granules, and capsules, and such solid formulations are prepared by mixing the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose or lactose, low-substituted hydroxypropyl cellulose, or hypromellose. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, solution-resistant preparations, emulsions, and syrups, and may contain various excipients in addition to commonly used simple diluents such as water and liquid paraffin, such as humectants, sweeteners, fragrances, and preservatives. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspension solvents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, tween 61, cocoa butter, lauric acid butter, glycerol, and gelatin. To formulate a parenteral dosage form, the indazole derivative compound of chemical formula 1 or 2 or a pharmaceutically acceptable salt thereof may be sterilized, or mixed with water with an adjuvant such as a preservative, stabilizer, hydrated agent or emulsifier, a salt or buffer for adjusting osmotic pressure, and other therapeutically useful substances to produce a solution or suspension, which can then be dispensed in ampoule or vial units.

[0125] Pharmaceutical compositions containing the compound of chemical formula 1 or 2 disclosed in this invention as an active ingredient may be administered to mammals such as mice, livestock, and humans via various routes. All methods of administration are predictable, and may be administered, for example, orally, rectally or intravenously, intramuscularly, subcutaneously, intrauterine dura materally, or intravascularly. The dosage may vary depending on the age, sex, weight of the subject being treated, the specific disease or pathological condition being treated, the severity of the disease or pathological condition, the time of administration, the route of administration, the absorption, distribution, and excretion rate of the drug, the types of other drugs used concomitantly, and the prescriber's judgment. Dosage determination based on such factors can be performed by those skilled in the art, and generally, the dosage is in the range of 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferred dosage is 1 mg / kg / day to 500 mg / kg / day. Administration may be once a day or divided into several doses. The aforementioned dosages do not limit the scope of this invention in any way.

[0126] Furthermore, the pharmaceutical compositions of the present invention can be used alone or in combination with surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of cancer, lethargy, and fascial salts. [Effects of the Invention]

[0127] The present invention relates to novel indazole derivatives and their uses, wherein the indazole derivatives exhibit excellent TRIB2 or YAP inhibitory activity and can be usefully used in pharmaceutical compositions for the prevention or treatment of cancer, lethargy, and fasciitis. [Brief explanation of the drawing]

[0128] [Figure 1] This figure shows that compound 17 of the present invention reduced the phosphorylation of TRIB2 and YAP proteins in a concentration-dependent manner in the liver cancer cell line (HepG2), and that it also possesses YAP inhibitory activity in ovarian cancer cell line A2780, as confirmed by the detection of p-YAP. [Modes for carrying out the invention]

[0129] Preferred embodiments of the present invention will be described in detail below. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the content presented herein is provided to ensure thoroughness and completeness, and to fully convey the idea of ​​the present invention to those skilled in the art.

[0130] <Example 1. Synthesis of indazole derivatives and confirmation of physicochemical properties>

[0131] The synthesis process of compounds 1 to 73 of the present invention and their physicochemical properties are as follows.

[0132] Compound 1. tert-butyl-4-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide)piperidine-1-carboxylate

[0133] [ka]

[0134] 1) Synthesis of 5-bromo-1H-indazole-3-carboxylic acid

[0135] A suspension of indazole-3-carboxylic acid (500 mg, 3.08 mmol) was heated in AcOH (25 ml) at 120°C to dissolve the starting material. The reaction mixture was cooled to 90°C, and bromine (0.32 ml, 6.16 mmol) was added. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was diluted with water (20 ml) and stirred for 1 hour. The solid formed in the reaction mixture was filtered and dried by suction to obtain 15-246 (550 mg, 2.28 mmol, 74%) as a white solid.

[0136] 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.56 (dd, J=1.8 Hz, 8.8 Hz, 1H); LC / MS 243.2 [M + H+].

[0137] 2) Synthesis of 1-(tert-butoxycarbonyl)-5-bromo-1H-indazole-3-carboxylic acid

[0138] To a solution of 15-246 (400 mg, 1.66 mmol) dissolved in THF (25 ml), NaOH (1.0 M) (3 ml) was added, followed by the addition of DiBoc at 0°C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was rapidly cooled with 1.5 N HCl aqueous solution, extracted with ELISA (150 ml x 2), and the organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM (1:4) as the eluent to obtain 15-276 (480 mg, 1.41 mmol, 85%) as a white solid.

[0139] 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J=1.5 Hz, 1H), 8.10 (d, J=8.9 Hz, 1H), 7.82 (d, J=1.9 Hz, 8.9 Hz, 1H), 1.67 (s, 9H); LC / MS 338.9 [M - H+].

[0140] 3) Synthesis of tert-butyl 5-bromo-3-((1-(tert-butoxycarbonyl)piperidine-4-yl)carbamoyl)-1H-indazole-1-carboxylate

[0141] A suspension of 15-276 (470 mg, 1.38 mmol) dissolved in THF (20 ml) was mixed with DIPEA (0.48 ml, 2.75 mmol), followed by the addition of HATU (628 mg, 1.65 mmol) at 0°C. The reaction mixture was stirred for 15 minutes. Tert-butyl 4-aminopiperidine-1-carboxylate (304 mg, 1.52 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. TLC analysis showed complete disappearance of the starting material. The reaction mixture was quenched with water and extracted with RINKAN (2 × 35 ml). The organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using RINKAN / Hex (2:3) as the eluent to obtain 18-083 (500 mg, 0.95 mmol, 69%) as a white solid.

[0142] 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 4.22-4.08 (m, 3H), 2.93 (t, J=13.0 Hz, 2H), 2.07-2.03 (m, 2H), 1.76 (s, 9H), 1.58-1.54 (m, 2H), 1.49 (s, 9H); LC / MS 521.1 [M - H+].

[0143] 4) Synthesis of tert-butyl-4-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide)piperidine-1-carboxylate

[0144] (2-fluoropyridine-3-yl)boronic acid (32.2 mg, 0.229 mmol) and sodium carbonate (51.8 mg, 0.477 mmol) were added to a solution of 18-083 in dioxane (2 ml) and H2O (0.5 ml) at room temperature, and the reaction mixture was purged with nitrogen for 10 minutes. PdCl2(PPh3)2 (13.4 mg, 0.019 mmol) was added to this stirred solution, and the reaction mixture was irradiated with microwaves at 120°C for 20 minutes. After the reaction was complete, the solvent was removed using a rotary evaporator. The crude reaction mixture was diluted with 10 ml of water and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using siRNA / hexane to obtain compound 1 (60 mg, 0.136 mmol, 71%) as a white solid.

[0145] 1H NMR (300 MHz, CDCl3) δ 11.08 (s, br, 1H), 8.56 (s, 1H), 8.21 (d, J=4.6 Hz, 1H), 7.94 (t, J=7.4 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.28 (t, J=6.9 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 4.23-4.09 (m, 3H), 2.97 (t, J=11.7 Hz, 2H), 2.09-2.05 (m, 2H), 1.60-1.53 ​​(m, 2H), 1.48 (s, 9H); LC / MS 438.1 [M - H+].

[0146] Compound 2.5-(2-fluoropyridine-3-yl)-N-(piperidine-4-yl)-1H-indazole-3-carboxamide

[0147] [ka]

[0148] A solution of 18-084 (40 mg, 0.091 mmol) in DCM (15 ml) was mixed with 4.0 M HCl in dioxane (2.0 ml) at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was quenched with sodium bicarbonate solution (aq), extracted with DCM (25 ml x 2), and the organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM to obtain compound 2 (25 mg, 0.073 mmol, 81%) as a white solid.

[0149] 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), 8.22 (d, J=5.1 Hz, 1H), 8.20 - 8.11 (m, 1H), 7.77 - 7.66 (m, 2H), 7.50 - 7.44 (m, 1H), 4.33 - LC / MS 340.1 [M + H+].

[0150] Compound 3. tert-butyl 4-(5-(pyridine-3-yl)-1H-indazole-3-carboxamide)piperidine-1-carboxylate

[0151] [ka]

[0152] To a solution of 18-083 (100 mg, 0.191 mmol) in dioxane (2 ml) and H2O (0.5 ml), (piperidine-3-yl)boronic acid (28.1 mg, 0.229 mmol) and sodium carbonate (51.8 mg, 0.477 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen for 10 minutes. PdCl2(PPh3)2 (13.4 mg, 0.019 mmol) was added to this stirred solution, and the reaction mixture was irradiated with microwaves at 120°C for 20 minutes. After the reaction was complete, the solvent was removed using a rotary evaporator. The crude reaction mixture was diluted with 10 ml of water and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using siRNA / hexane to obtain compound 3 (60 mg, 0.142 mmol, 74%) as a white solid.

[0153] 1H NMR (300 MHz, CDCl3) δ 11.06 (s, 1H), 8.97 (dd, J=2.4, 0.9 Hz, 1H), 8.68 - 8.61 (m, 2H), 8.00 (dt, J=8.0, 2.0 Hz, 1H), 7.74 - 7.61 (m, 2H), 7.41 (ddd, J=8.0, 4.8, 0.9 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 4.34 - 4.02 (m, 3H), 2.99 (t, J=12.5 Hz, 2H), 2.10 (d, J=13.9 Hz, 2H), 1.59 (dd, J=12.0, 4.1 Hz, 2H), 1.51 (s, 9H); LC / MS 420.1 [M - H+].

[0154] Compound 4.N-(piperidine-4-yl)-5-(pyridine-3-yl)-1H-indazole-3-carboxamide

[0155] [ka]

[0156] A solution of 18-085 (40 mg, 0.095 mmol) in DCM (15 ml) was mixed with 4.0 M HCl in dioxane (2.0 ml) at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with DCM (25 ml x 2), and the organic layer was washed with saturated salt solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM to obtain compound 4 (25 mg, 0.077 mmol, 82%) as a white solid.

[0157] 1H NMR (300 MHz, CD3OD) δ 9.27 (s, 1H), 9.03 (d, J=8.1 Hz, 1H), 8.87 (d, J=5.8 Hz, 1H), 8.70 (s, 1H), 8.23 ​​(dd, J=8.3, 5.7 Hz, 1H), 7.95 LC / MS 322.1 [M + H+].

[0158] Compound 5. tert-butyl 4-(5-(2-fluorophenyl)-1H-indazole-3-carboxamide)piperidine-1-carboxylate

[0159] [ka]

[0160] To a solution of 18-083 (100 mg, 0.191 mmol) in dioxane (2 ml) and H2O (0.5 ml), (2-fluorophenyl)boronic acid (32.0 mg, 0.229 mmol) and sodium carbonate (51.8 mg, 0.477 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen for 10 minutes. PdCl2(PPh3)2 (13.4 mg, 0.019 mmol) was added to this stirred solution, and the reaction mixture was irradiated with microwaves at 120°C for 20 minutes. After the reaction was complete, the solvent was removed using a rotary evaporator. The crude reaction mixture was diluted with 10 ml of water and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using siRNA / hexane to obtain compound 5 (70 mg, 0.159 mmol, 83%) as a white solid.

[0161] 1H NMR (300 MHz, CDCl3) δ 10.65 (s, 1H), 8.58 (s, 1H), 7.69 (dt, J=8.8, 1.9 Hz, 1H), 7.59 (dd, J=8.8, 0.9 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.37 - 7.31 (m, 1H), 7.25 (dd, J=7.5, 1.3 Hz, 1H), 7.21 - 7.14 (m, 1H), 7.00 (d, J=8.1 Hz, 1H), 4.31 - 4.05 (m, 3H), 2.98 (t, J=12.6 Hz, 2H), 2.09 (d, J=11.2 Hz, 2H), 1.58 (d, J=11.8 Hz, 2H), 1.50 (s, 9H); LC / MS 437.1 [M - H+].

[0162] Compound 6.5-(2-fluorophenyl)-N-(piperidine-4-yl)-1H-indazole-3-carboxamide

[0163] [ka]

[0164] A solution of 18-086 (40 mg, 0.091 mmol) in DCM (15 ml) was mixed with 4.0 M HCl in dioxane (2.0 ml) at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with DCM (25 ml x 2). The organic layer was washed with saturated salt solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM to obtain compound 6 (26 mg, 0.077 mmol, 84%) as a white solid.

[0165] 1H NMR (300 MHz, CD3OD) δ 8.40 (s, 1H), 7.72 - 7.65 (m, 2H), 7.61 - 7.53 (m, 1H), 7.43 - 7.36 (m, 1H), 7.32 - 7.29 (m, 1H), 7.27 - 7.19 (m, 1H), 4.33 - 4.21 (m, 1H), 3.51 (d, J=13.2 Hz, 2H), 3.26 - 3.16 (m, 2H), 2.30 - 2.24 (m, 2H), 2.03 - 1.88 (m, 2H); LC / MS 339.1 [M + H+].

[0166] Compound 7.5-(2-fluoropyridine-3-yl)-N-(piperidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0167] [ka]

[0168] 1) Synthesis of 5-bromo-7H-pyrrolo[2,3-b]pyridine

[0169] 500 mg, 2.51 mmol of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine and manganese dioxide (873 mg, 10.0 mmol) dissolved in toluene (10 ml) were stirred at 110°C for 4 hours. The reaction mixture was cooled to room temperature and filtered. The solid was washed with DCM, and the filtrate and washing solution were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a brown solid, 18-097 (350 mg, 1.77 mmol, 70%).

[0170] 1H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.26 (d, J=2.2 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 7.55 (d, J=3.4 Hz, 1H), 6.45 (d, J=3.4 Hz, 1H); LC / MS 198.2 [M + H+].

[0171] 2) Synthesis of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-2,2,2-trichloroethane-1-one

[0172] AlCl3 (590 mg, 4.42 mmol) was added to a solution of 18-097 (350 mg, 1.77 mmol) in dry DCM (10 ml) at 0°C under a nitrogen atmosphere. After 10 minutes, trichloroacetyl chloride (387 mg, 2.13 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 12 hours. After monitoring by TLC, the reaction was quenched with cold water (20 ml), extracted with DCM (3 × 10 ml), the organic layer was dried (MgSO4), and concentrated under vacuum to obtain 18-098 (400 mg, 1.16 mmol, 66%) as a white solid.

[0173] 1H NMR (300 MHz, CDCl3) δ 11.46 (s, 1H), 8.94 (d, J=2.1 Hz, 1H), 8.55 (d, J=2.1 Hz, 1H), 8.53 (s, 1H); LC / MS 341.1 [M + H+].

[0174] 3) Synthesis of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

[0175] 18-098 (400 mg, 1.16 mmol) was treated with 15 ml of NaOH aqueous solution and stirred at room temperature for 12 hours. The resulting mixture was adjusted to pH 4-6 by adding concentrated hydrochloric acid dropwise at 0°C, the resulting precipitate was filtered, washed with water and hexane, vacuum dried, and purified by column chromatography to obtain 18-101 (250 mg, 1.03 mmol, 89%) as a white solid.

[0176] 1H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 12.42 (s, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.40 (d, J=2.3 Hz, 1H), 8.22 (s, 1H); LC / MS 241.2 [M + H+].

[0177] 4) Synthesis of tert-butyl 4-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxamide)piperidine-1-carboxylate

[0178] A suspension of 18-101 (100 mg, 0.414 mmol) dissolved in THF (20 ml) was mixed with DIPEA (107 mg, 0.828 mmol), followed by the addition of HATU (188 mg, 0.496 mmol) at 0°C. The reaction mixture was stirred for 15 minutes. Tert-butyl 4-aminopiperidine-1-carboxylate (91 mg, 0.456 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. TLC analysis showed complete disappearance of the starting material. The reaction mixture was quenched with water and extracted with SiO2 (2 × 35 ml). The organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using SiO2 / hexane (2:3) to obtain 18-103 (120 mg, 0.283 mmol, 68%) as a white solid.

[0179] 1H NMR (300 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.57 (d, J=2.3 Hz, 1H), 8.35 (d, J=2.3 Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=7.8 Hz, 1H), 3.97-3.92 (m, 3H), 2.87 (s, 2H), 1.82 (d, J=9.7 Hz, 2H), 1.42 (s, 11H); LC / MS 423.2 [M + H+].

[0180] 5) Synthesis of tert-butyl-4-(5-(2-fluoropyridine-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide)-piperidine-1-carboxylate

[0181] To a solution of 18-103 (100 mg, 0.236 mmol) in dioxane (2 ml) and H2O (0.5 ml), (2-fluoropyridine-3-yl)boronic acid (40 mg, 0.283 mmol) and sodium carbonate (64 mg, 0.590 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen for 10 minutes. PdCl2(PPh3)2 (16 mg, 0.023 mmol) was added to this stirred solution, and the reaction mixture was irradiated with microwaves at 120°C for 20 minutes. After the reaction was complete, the solvent was removed using a rotary evaporator. The crude reaction mixture was diluted with 10 ml of water and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by HPLC to obtain 18-104 (30 mg, 0.068 mmol, 29%) as a white solid.

[0182] 1H NMR (300 MHz, CDCl3) δ 10.99 (s, 1H), 8.66 (s, 1H), 8.61 (t, J=2.0 Hz, 1H), 8.27 (d, J=4.7 Hz, 1H), 8.07 - 7.94 (m, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.40 - 7.32 (m, 1H), 5.92 (d, J=7.9 Hz, 1H), 4.30 - 4.02 (m, 3H), 2.95 (t, J=12.3 Hz, 2H), 2.09 (d, J=12.5 Hz, 2H), 1.49 (s, 9H), 1.48-1.46 (m, 2H); LC / MS 440.2 [M + H+].

[0183] 6) Synthesis of 5-(2-fluoropyridine-3-yl)-N-(piperidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0184] A solution of 18-104 (30 mg, 0.068 mmol) in DCM (15 ml) was mixed with 4.0 M HCl in dioxane (2.0 ml) at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was quenched with aqueous sodium bicarbonate solution, extracted with DCM (25 ml x 2), and the organic layer was washed with saturated salt solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM to obtain compound 7 (20 mg, 0.058 mmol, 86%) as a white solid.

[0185] 1H NMR (300 MHz, CD3OD) δ 9.32 (s, 1H), 8.82 (s, 1H), 8.52 (s, 1H), 8.36 (d, J=4.9 Hz, 1H), 8.29 (ddd, J=9.6, 7.5, 1.8 Hz, 1H), 7.56 (ddd, J=6.8, 4.9, 1.7 Hz, 1H), 4.31 - 4.18 (m, 1H), 3.53 (d, J=13.0 Hz, 2H), 3.26 - 3.12 (m, 2H), 2.26 (d, J=11.8 Hz, 2H), 2.06 - 1.86 (m, 2H); LC / MS 340.1 [M + H+].

[0186] Compound 8.5-(2-fluoropyridine-3-yl)-N-(piperidine-4-yl)-1H-indole-3-carboxamide

[0187] [ka]

[0188] 1) Synthesis of 1-(5-bromo-1H-indole-3-yl)-2,2,2-trifluoroethane-1-one

[0189] 5-bromoindole (500 mg, 2.55 mmol) was dissolved in dry DMF (5.0 ml) in a dry flask under argon. This solution was cooled to 0°C, and anhydrous trifluoroacetic acid (0.5 ml, 3.82 mmol) was added dropwise. The mixture was stirred at 0°C for 3 hours, and then quenched with water. The crude mixture was filtered to obtain a solid. This solid was washed twice with water and dissolved in ethyl acetate. The organic layer was washed with aqueous NaHCO3 solution and brine, dried over anhydrous MgSO4, and evaporated under vacuum. The desired product was 18-106 (600 mg, 2.05 mmol, 80%) as a white solid.

[0190] 1H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 8.61 (s, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.51 (dd, J=8.7, 1.9 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H); LC / MS 293.2 [M + H+].

[0191] 2) Synthesis of 5-bromo-1H-indole-3-carboxylic acid

[0192] 18-106 (600 mg, 2.05 mmol) was treated with 15 ml of 20% NaOH aqueous solution and heated at 90°C for 2 hours. The resulting mixture was adjusted to pH 4-6 by adding concentrated hydrochloric acid (con.HCl) dropwise at 0°C. The resulting precipitate was filtered, washed with water and hexane, and then vacuum-dried and purified by column chromatography to obtain 18-107 (420 mg, 1.75 mmol, 85%), a pale yellow solid.

[0193] 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 12.01 (s, 1H), 8.13 (d, J=1.8 Hz, 1H), 8.05 (s, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.32 (dd, J=8.6, 2.0 Hz, 1H); LC / MS 240.2 [M + H+].

[0194] 3) Synthesis of 1-(tert-butoxycarbonyl)-5-bromo-1H-indazole-3-carboxylic acid

[0195] To a solution of 18-107 (400 mg, 1.66 mmol) dissolved in THF (25 ml), 5 ml of NaOH (1.0 M) was added, followed by the addition of (Boc)2O (400 mg, 1.83 mmol) at 0°C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was rapidly cooled with 1.5 N HCl solution (aqueous solution), extracted with SiO2 (150 ml x 2), and the organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM (1:4) to obtain 18-108 (500 mg, 1.46 mmol, 88%) as a white solid.

[0196] 1H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.20 (d, J=1.9 Hz, 2H), 8.05 (d, J=8.9 Hz, 1H), 7.56 (dd, J=8.9, 2.0 Hz, 1H), 1.65 (s, 9H); LC / MS 338.9 [M - H+].

[0197] 4) Synthesis of tert-butyl 5-bromo-3-((1-(tert-butoxycarbonyl)piperidine-4-yl)carbamoyl)-1H-indole-1-carboxylate

[0198] To a suspension of 18-108 (200 mg, 0.587 mmol) dissolved in THF (20 ml), DIPEA (151 mg, 1.17 mmol) was added, followed by the addition of HATU (267 mg, 0.704 mmol) at 0°C. The reaction mixture was stirred for 15 minutes. Tert-butyl 4-aminopiperidine-1-carboxylate (129 mg, 0.646 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. TLC analysis showed complete disappearance of the starting material. The reaction mixture was quenched with water and extracted with siRNA (2 × 35 ml). The organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using siRNA / hexane (2:3) to obtain 18-109 (266 mg, 0.509 mmol, 87%) as a white solid.

[0199] 1H NMR (300 MHz, CDCl3) δ 8.23 ​​(d, J=1.8 Hz, 1H), 8.04 (d, J=8.9 Hz, 1H), 8.00 (s, 1H), 7.48 (dd, J=8.9, 1.9 Hz, 1H), 5.82 (d, J=6.2 Hz, LC / MS 520.2 [M - H+].

[0200] 5) tert-butyl-4-(5-(2-fluoropyridine-3-yl)-1H-indole-3-carboxamide)piperidine-1-carboxylate synthesis

[0201] To a solution of 18-109 (100 mg, 0.191 mmol) in dioxane (2 ml) and H2O (0.5 ml), (2-fluoropyridine-3-yl)boronic acid (32 mg, 0.229 mmol) and sodium carbonate (52 mg, 0.477 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen for 10 minutes. PdCl2(PPh3)2 (13 mg, 0.019 mmol) was added to this stirred solution, and the reaction mixture was irradiated with microwaves at 110°C for 20 minutes. After the reaction was complete, the solvent was removed using a rotary evaporator. The crude reaction mixture was diluted with 10 ml of water and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by HPLC to obtain 18-111 (60 mg, 0.136 mmol, 71%) as a white solid.

[0202] 1H NMR (300 MHz, CDCl3) δ 9.51 (s, 1H), 8.23 ​​(s, 1H), 8.19 (d, J=4.5 Hz, 1H), 7.94 (t, J=8.7 Hz, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.27 (s, 1H), 5.97 (d, J=7.6 Hz, 1H), 4.33 - 4.04 (m, 3H), 2.94 (t, J=12.0 Hz, 2H), 2.07 (s, 2H), 1.49 (s, 11H); LC / MS 439.2 [M + H+].

[0203] 6) Synthesis of 5-(2-fluoropyridine-3-yl)-N-(piperidine-4-yl)-1H-indole-3-carboxamide

[0204] A solution of 18-111 (60 mg, 0.136 mmol) in DCM (15 ml) was mixed with 4.0 M HCl in dioxane (2.0 ml) at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was quenched with sodium bicarbonate solution (aq), extracted with DCM (25 ml x 2), and the organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM to obtain compound 8 (40 mg, 0.118 mmol, 86%) as a white solid.

[0205] 1H NMR (300 MHz, CD3OD) δ 8.26 (s, 1H), 8.03 (dd, J=5.6, 4.0 Hz, 1H), 7.99 (s, 1H), 7.53 (dd, J=12.2, 7.2 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.37-7.25 (m, 2H), 4.16 - 4.03 (m, 1H), 3.39 (d, J=13.0 Hz, 2H), 3.12 - 2.97 (m, 2H), 2.12 (d, J=11.6 Hz, 2H), 1.93 - 1.73 (m, 2H); LC / MS 339.1 [M + H+].

[0206] Compound 9.5-(2-fluoropyridine-3-yl)-1-methyl-N-(piperidine-4-yl)-1H-indazole-3-carboxamide

[0207] [ka]

[0208] 1) Synthesis of 5-bromo-1H-indazole-3-carboxylic acid

[0209] A solution of 15-330 (250 mg, 0.732 mmol) in DCM (15 ml) was mixed with 4.0 M HCl in dioxane (2.0 ml) at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was concentrated under reduced pressure to obtain 18-102 (160 mg, 0.66 mmol, 90%) as a white solid.

[0210] 1H NMR (300 MHz, DMSO-d6) δ 14.01 (s, 1H), 13.14 (s, 1H), 8.22 (s, 1H), 7.66 (d, J=8.9 Hz, 1H), 7.57 (dd, J=8.8, 1.8 Hz, 1H); LC / MS 240.2 [M + H+].

[0211] 2) Synthesis of methyl 5-bromo-1-methyl-1H-indazole-3-carboxylate

[0212] 18-102 (160 mg, 0.663 mmol) was dissolved in acetonitrile (20 ml) at 20°C, to which potassium carbonate (458 mg, 3.31 mmol) and methyl iodide (0.2 ml, 3.31 mmol) were added. The mixture was stirred under a nitrogen atmosphere at 20°C for 10 hours. The mixture was concentrated under vacuum. The unpurified residue was purified by silica gel chromatography (Hex / Â=10 / 1~5 / 1) to obtain 18-105-1 (100 mg, 0.371 mmol, 56%) as a white solid and 18-105-2 (100 mg) as a white solid.

[0213] 18-105-1: 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=1.6 Hz, 0.2H), 8.20 (d, J=1.2 Hz, 1H), 7.75 (d, J=1.6 Hz, 0.2H), 7.67 (d, J=9.1 Hz, 1H), 7.44 (dd, J=9.1, 1.8 Hz, 1H), 4.55 - 4.50 (m, 4H), 4.07 (s, 3H); LC / MS 270.9 [M + H+].

[0214] 18-105-2: 1H NMR (300 MHz, CDCl3) δ 8.41 (d, J=1.2 Hz, 1H), 7.56 (dd, J=8.9, 1.8 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 4.18 (s, 3H), 4.06 (s, 3H); LC / MS 270.9 [M+H+].

[0215] 3) Synthesis of 5-bromo-1-methyl-1H-indazole-3-carboxylic acid

[0216] Lithium hydroxide monohydrate (31 mg, 0.743 mmol) was added at room temperature to a solution of 18-105-1 (100 mg, 0.371 mmol) dissolved in THF (4 ml), MeOH (2 ml), and H2O (1 ml), and the reaction mixture was stirred at room temperature for 2 hours. TLC analysis showed complete disappearance of the starting material. The reaction mixture was then concentrated to remove THF, methanol, and water, and 18-113 (80 mg, 0.313 mmol, 84%) was obtained as a white solid.

[0217] 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J=1.9 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.25 (dd, J=9.0, 2.0 Hz, 1H), 4.41 (s, 3H); LC / MS 255.2 [M + H+].

[0218] 4) Synthesis of tert-butyl 4-(5-bromo-1-methyl-1H-indazole-3-carboxamide)piperidine-1-carboxylate

[0219] To a suspension of 18-113 (80 mg, 0.313 mmol) dissolved in DMF (10 ml), DIPEA (0.11 ml, 0.626 mmol) was added, followed by HATU (142 mg, 0.375 mmol) at 0°C. The reaction mixture was stirred for 15 minutes, and tert-butyl 4-aminopiperidine-1-carboxylate (69 mg, 0.345 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours. TLC analysis showed complete disappearance of the starting material. The reaction mixture was quenched with water and extracted with ethyl acetate (2 × 35 ml). The organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using ethyl acetate / hexane (2:3) to obtain 18-115 (90 mg, 0.205 mmol, 65%) as a white solid.

[0220] 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=1.3 Hz, 1H), 7.65 (d, J=9.1 Hz, 1H), 7.40 (dd, J=9.1, 1.5 Hz, 1H), 6.12 (d, J=7.7 Hz, 1H), 4.44 (s, LC / MS 435.2 [M - H+].

[0221] 5) tert-butyl 4-(5-(2-fluoropyridine-3-yl)-1-methyl-1H-indazole-3-carboxamide)piperidine-1-carboxylate synthesis

[0222] To a solution of 18-115 (80 mg, 0.182 mmol) in dioxane (2 ml) and H2O (0.5 ml), (2-fluoropyridine-3-yl)boronic acid (31 mg, 0.219 mmol) and sodium carbonate (49 mg, 0.455 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen for 10 minutes. PdCl2(PPh3)2 (12 mg, 0.018 mmol) was added to this stirred solution, and the reaction mixture was irradiated with microwaves at 110°C for 20 minutes. After the reaction was complete, the solvent was removed using a rotary evaporator. The crude reaction mixture was diluted with 10 ml of water and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using siRNA / hexane (2:3) to obtain 18-119 (40 mg, 0.088 mmol, 48%) as a white solid.

[0223] 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J=4.8 Hz, 1H), 8.01 - 7.91 (m, 1H), 7.87 (s, 1H), 7.73 - 7.66 (m, 1H), 7.57 - 7.49 (m, 2H), 7.41 - 7.32 (m, 1H), 6.12 (d, J=7.9 Hz, 1H), 4.51 (s, 3H), 4.30-4.11 (m, 3H), 2.98 (t, J=12.1 Hz, 2H), 2.14 (d, J=9.7 Hz, 2H), 1.61 - 1.52 (m, 2H), 1.49 (s, 9H); LC / MS 454.2 [M + H+].

[0224] 6) Synthesis of 5-(2-fluoropyridine-3-yl)-1-methyl-N-(piperidine-4-yl)-1H-indazole-3-carboxamide

[0225] A solution of 18-119 (40 mg, 0.088 mmol) in DCM (15 ml) was mixed with 4.0 M HCl in dioxane (2.0 ml) at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was quenched with sodium bicarbonate solution (aq), extracted with DCM (25 ml x 2), and the organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM to obtain compound 9 (28 mg, 0.079 mmol, 90%) as a white solid.

[0226] 1H NMR (300 MHz, CD3OD) δ 8.25 - 8.14 (m, 2H), 8.02 (s, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.52 - 7.43 (m, 1H), 4.40 (s, LC / MS 354.2 [M +H+].

[0227] Compound 10. 1-Benzoyl-N-(1-benzoylpiperidine-4-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0228] [ka]

[0229] A suspension of 18-138 (10 mg, 0.029 mmol) dissolved in DCM (2.0 ml) was mixed with DIPEA (7.5 mg, 0.058 mmol), followed by the addition of benzoin chloride (4.5 mg, 0.032 mmol) at 0°C. The reaction mixture was stirred for 1 hour. TLC analysis showed complete disappearance of the starting material. The reaction mixture was rapidly cooled with water and extracted with ethyl acetate (2 × 35 ml). The organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using ethyl acetate / hexane (2:3) to obtain compound 10 (8.0 mg, 0.014 mmol, 50%) as a white solid.

[0230] 1H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 8.62 (d, J=8.8 Hz, 1H), 8.28 (d, J=4.9 Hz, 1H), 8.11 - 7.98 (m, 3H), 7.91 (dd, J=8.8, 1.8 Hz, 1H), 7.72 (t, J=7.4 Hz, 1H), 7.61 (t, J=7.5 Hz, 2H), 7.43 (s, 5H), 7.35 (ddd, J=6.8, 4.8, 1.6 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 4.81-4.64 (m, 1H), 4.37 - 4.25 LC / MS 548.2 [M + H+].

[0231] Compound 11.1-(cyclopropanecarbonyl)-N-(1-(cyclopropanecarbonyl)piperidine-4-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0232] [ka]

[0233] A suspension of 18-138 (10 mg, 0.029 mmol) dissolved in DCM (2.0 ml) was mixed with DIPEA (7.5 mg, 0.058 mmol), followed by the addition of cyclopropyl carbonyl chloride (3.3 mg, 0.032 mmol) at 0°C. The reaction mixture was stirred for 1 hour. TLC analysis showed complete disappearance of the starting material. The reaction mixture was rapidly cooled with water and extracted with RINKAN (2 × 35 ml). The organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using RINKAN / hexane (2:3) to obtain compound 11 (8.0 mg, 0.013 mmol, 43%) as a white solid.

[0234] 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.26 (d, J=4.8 Hz, 1H), 8.00 (ddd, J=9.6, 7.5, 1.9 Hz, 1H), 7.84 (dt, J=8.8, 1.8 Hz, 1H), 7.34 (ddd, J=6.8, 4.9, 1.7 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.72-4.57 (m, 1H), 4.42 - 4.24 (m, 2H), 3.41-3.28 (m, 1H), 3.27-3.18 (m, 1H), 2.96-2.79 (m, 1H), 2.25-2.08 (m, 2H), 1.85-1.72 (m, 1H), 1.61-1.54 (m, 2H) 1.46-1.39 (m, 2H), 1.29 - 1.22 (m, 2H), 1.05-0.98 (m, 2H), 0.83-0.78 (m, 2H); LC / MS 476.2 [M + H+].

[0235] Compound 12. N-(1-benzoylpiperidine-4-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0236] [ka]

[0237] A suspension of 18-138 (20 mg, 0.058 mmol) dissolved in THF (2.0 ml) was mixed with DIPEA (15 mg, 0.116 mmol), followed by the addition of HATU (24 mg, 0.064 mmol) at 0°C. The reaction mixture was stirred for 15 minutes. Benzoic acid (7.9 mg, 0.064 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. TLC analysis showed complete disappearance of the starting material. The reaction mixture was quenched with water and extracted with SiO2 (2 × 35 ml). The organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using SiO2 / hexane (2:3) to obtain compound 12 (12 mg, 0.027 mmol, 46%) as a white solid.

[0238] 1H NMR (300 MHz, CDCl3) δ 11.25 (s, 1H), 8.57 (s, 1H), 8.23 ​​(d, J=4.8 Hz, 1H), 7.98 (ddd, J=9.5, 7.5, 1.9 Hz, 1H), 7.69 (dt, J=8.8, 1.9 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (s, 5H), 7.36 - 7.30 (m, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.88 - 4.68 (m, 1H), 4.45 - 4.27 (m, 1H), 4.01 - 3.79 (m, 1H), 3.29 - 3.06 (m, 2H), 2.30 - 2.10 (m, 2H), 1.83 - 1.69 (m, 1H), 1.64 - 1.49 (m, 1H); LC / MS 444.2 [M + H+].

[0239] Compound 13.5-(2-fluoropyridine-4-yl)-N-(piperidine-4-yl)-1H-indazole-3-carboxamide

[0240] [ka]

[0241] 1) Synthesis of tert-butyl-4-(5-(2-fluoropyridine-4-yl)-1H-indazole-3-carboxamide)piperidine-1-carboxylate

[0242] To a solution of 18-120 (100 mg, 0.191 mmol) in dioxane (2 ml) and H2O (0.5 ml), (2-fluoropyridine-4-yl)boronic acid (32.2 mg, 0.229 mmol) and sodium carbonate (51.8 mg, 0.477 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen for 10 minutes. PdCl2(PPh3)2 (13.4 mg, 0.019 mmol) was added to this stirred solution, and the reaction mixture was irradiated with microwaves at 120°C for 20 minutes. After the reaction was complete, the solvent was removed using a rotary evaporator. The crude reaction mixture was diluted with 10 ml of water and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using siRNA / hexane to obtain 18-160 (60 mg, 0.136 mmol, 71%) as a white solid.

[0243] 1H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 8.75 (s, 1H), 8.30 (d, J=4.8 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.53 (s, 1H), 7.25 (s, 1H), 7.00 (d, J=8.2 Hz, 1H), 4.16 (s, 3H), 3.07 - 2.91 (m, 2H), 2.10 (d, J=14.7 Hz, 2H), 1.58-1.52 (m, 2H), 1.51 (s, 9H); LC / MS 438.1 [M - H+].

[0244] 2) Synthesis of 5-(2-fluoropyridine-4-yl)-N-(piperidine-4-yl)-1H-indazole-3-carboxamide

[0245] To a solution of 18-160 (60 mg, 0.136 mmol) dissolved in DCM (15 ml), 4.0 M HCl dissolved in dioxane (2.0 ml) was added at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was quenched with sodium bicarbonate solution (aq), extracted with DCM (25 ml x 2), and the organic layer was washed with saturated salt aqueous solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM to obtain compound 13 (39 mg, 0.115 mmol, 85%) as a white solid.

[0246] 1H NMR (300 MHz, CD3OD) δ 8.66 (s, 1H), 8.29 (d, J=5.5 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.71 (d, J=4.6 Hz, 1H), 7.46 (s, 1H), 4.35 - 4.22 (m, 1H), 3.52 (d, J=13.0 Hz, 2H), 3.22 (t, J=12.3 Hz, 2H), 2.28 (d, J=13.7 Hz, 2H), 2.05 - 1.88 (m, 2H); LC / MS 340.1 [M + H+].

[0247] Compound 14. N-cyclohexyl-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0248] [ka]

[0249] 1) Synthesis of tert-butyl 5-bromo-3-(cyclohexylcarbamoyl)-1H-indazole-1-carboxylate

[0250] A solution of 18-006 (50 mg, 0.147 mmol) in DMF (2 ml) was added with DIPEA (0.05 ml, 0.294 mmol) and HATU (67 mg, 0.176 mmol). Cyclohexylamine (0.018 ml, 0.162 mmol) was added thereto and stirred at room temperature for 3 hours. TLC analysis indicated the completion of the starting material. The reaction mixture was quenched with water and extracted with EtOAc (2 × 15 ml), and the organic layer was washed with saturated brine. The organic layer was evaporated under vacuum to obtain the crude product. Then, it was purified by silica gel chromatography using EtOAc / Hx 3:7 to obtain 18-008 (44 mg, 0.104 mmol, 71%) in the form of a white solid.

[0251] 1H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 4.03 - 4.00 (m, 1H), 2.09 - 2.05 (m, 2H), 1.88 - 1.79 (m, 2H), 1.77 (s, 9H), 1.55 - 1.19 (m, 6H).

[0252] 2) Synthesis of N-cyclohexyl-5-(2-fluoropyridin-3-yl)-1H-indazole-3-carboxamide

[0253] A mixture of Na2CO3 (26 mg, 0.237 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (16 mg, 0.114 mmol) dissolved in 18-008 (50 mg, 0.095 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (7 mg, 0.009 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 115°C for 30 minutes. TLC analysis and LC / MS showed that the starting materials were present in the reaction mixture. Water was added to the reaction mixture and extracted with ethyl acetate (2 × 15 ml). The organic layer was dried on sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using siRNA / Hx 3:7 to obtain compound 14 (5 mg, 0.015 mmol, 16%) as a white solid.

[0254] 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.21 (d, J=4.6 Hz, 1H), 8.01 - 7.94 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.30 (d, J=5.3 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 4.10 - 3.99 (m, 1H), 2.07 (d, J=8.9 Hz, 2H), 1.83 - 1.75 (m, 2H), 1.48 - 1.28 (m, 6H).

[0255] Compound 15.1-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carbonyl)piperidine-4-carboxamide

[0256] [ka]

[0257] 1) Synthesis of tert-butyl 5-bromo-3-(4-carbamoylpiperidine-1-carbonyl)-1H-indazole-1-carboxylate

[0258] A solution of 18-015 (150 mg, 0.147 mmol) was dissolved in DMF (6 ml), to which DIPEA (0.15 ml, 0.879 mmol) was added, followed by HATU (201 mg, 0.528 mmol). Piperidine-4-carboxamide (63 mg, 0.484 mmol) was added and the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the completion of the starting material. The reaction mixture was quenched with water and extracted with siRNA (2 × 45 ml). The organic layer was washed with saturated salt aqueous solution. The organic layer was evaporated under vacuum to obtain the crude product. Subsequently, the product was purified by silica gel chromatography using MeOH / DCM 1:9 to obtain 18-021 (178 mg, 0.394 mmol, 90%) in the form of a white solid.

[0259] 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J=1.4 Hz, 1H), 8.05 (d, J=8.9 Hz, 1H), 7.81 (dd, J=9.0, 1.9 Hz, 1H), 7.31 (s, 1H), 6.82 (s, 1H), 4.51 (d, J=12.6 Hz, 1H), 4.23 (d, J=13.7 Hz, 1H), 3.21 (t, J=11.6 Hz, 1H), 2.95 (t, J=11.3 Hz, 1H), 2.48 - 2.36 (m, 1H), 1.90 - 1.80 (m, 1H), 1.73 (d, J=11.1 Hz, 1H), 1.66 (s, 9H), 1.60 - 1.47 (m, 2H).

[0260] LC / MS 453.0 [M + H+].

[0261] 2) Synthesis of 1-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carbonyl)piperidine-4-carboxamide

[0262] A mixture of Na2CO3 (60 mg, 0.555 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (37 mg, 0.266 mmol) dissolved in 18-021 (100 mg, 0.222 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (16 mg, 0.022 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 110°C for 30 minutes. LC / MS and TLC analysis showed completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried on sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using MeOH / DCM 1:9 to obtain compound 15 (30 mg, 0.082 mmol, 37%) as a white solid.

[0263] 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=4.7 Hz, 1H), 8.19 - 8.13 (m, 2H), 7.74 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.48 (ddd, J=7.0, 4.8, 1.8 Hz, 1H), 7.31 (s, 1H), 6.81 (s, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 3.27 - 3.19 (m, 1H), 2.94 - 2.83 (m, 1H), 2.48 - 2.40 (m, 1H), 1.88 -1.73 (m, 2H), 1.61 - 1.50 (s, 2H).

[0264] LC / MS 368.1 [M + H+]

[0265] Compound 16.5-(2-fluoropyridine-3-yl)-N-((1r,4r)-4-hydroxycyclohexyl)-1H-indazole-3-carboxamide

[0266] [ka]

[0267] 1) Synthesis of tert-butyl 5-bromo-3-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)-1H-indazole-1-carboxylate

[0268] DIPEA (0.15 ml, 0.879 mmol) was added to a solution of 18-015 (150 mg, 0.147 mmol) dissolved in DMF (6 ml), and HATU (201 mg, 0.528 mmol) was added. 4-Aminocyclohexan-1-ol (56 mg, 0.484 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC analysis indicated the completion of the starting material. The reaction mixture was quenched with water and extracted with EtOAc (2 × 45 ml), and the organic layer was washed with saturated brine. The organic layer was evaporated under vacuum to obtain the crude product. Then, it was purified by silica gel chromatography using EtOAc / Hx 1:1 to obtain 18-018 (115 mg, 0.262 mmol, 60%) in the form of a white solid.

[0269] 1H NMR (400 MHz, CD3OD) δ 8.46 (d, J = 1.4 Hz, 1H), 8.06 (d, 1H), 7.74 (dd, J = 9.0, 1.9 Hz, 1H), 3.96 - 3.86 (m, 1H), 3.65 - 3.54 (m, 1H), 2.10 - 1.98 (m, 4H), 1.74 (s, 9H), 1.54 - 1.39 (m, 4H).

[0270] LC / MS 338.1 [M - 100] +.

[0271] 2) Synthesis of 5-(2-fluoropyridin-3-yl)-N-((1r,4r)-4-hydroxycyclohexyl)-1H-indazole-3-carboxamide

[0272] A mixture of Na2CO3 (49 mg, 0.456 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (39 mg, 0.274 mmol) dissolved in 18-018 (100 mg, 0.228 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (16 mg, 0.023 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 110°C for 30 minutes. TLC analysis and LC / MS showed completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried on sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using siRNA / Hx 1:1 to obtain compound 16 (22 mg, 0.062 mmol, 27%) as a white solid.

[0273] 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.26 (d, J=4.8 Hz, 1H), 8.20 - 8.10 (m, 2H), 7.74 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.50 (ddd, J=7.0, 4.8, 1.8 Hz, 1H), 4.56 (s, 1H), 3.87 - 3.73 (m, 1H), 3.44 - 3.38 (m, 1H). 1.85 (t, J=12.9 Hz, 4H), 1.57 - 1.43 (m, 2H), 1.32 - 1.19 (m, 2H).

[0274] LC / MS 353.1 [M - H+]

[0275] Compound 17.5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0276] [ka]

[0277] 1) Synthesis of tert-butyl 5-bromo-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate

[0278] A solution of 18-015 (150 mg, 0.147 mmol) was dissolved in DMF (6 ml), to which DIPEA (0.15 ml, 0.879 mmol) was added, followed by HATU (201 mg, 0.528 mmol). Pyridine-4-amine (46 mg, 0.484 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the completion of the starting material. The reaction mixture was quenched with water and extracted with siRNA (2 × 45 ml). The organic layer was washed with saturated salt aqueous solution. The organic layer was evaporated under vacuum to obtain the crude product. Subsequently, the product was purified by silica gel chromatography using siRNA / Hx 3:7 to obtain 18-020 (122 mg, 0.268 mmol, 61%) in the form of a white solid.

[0279] 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.66 (d, J=1.4 Hz, 1H), 8.59 (dd, J=4.8, 1.5 Hz, 2H), 8.00 (s, 1H), 7.76 - 7.66 (m, 3H), 1.78 (s, 9H).

[0280] LC / MS 416.1 [M - H +.]

[0281] 2) Synthesis of 5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0282] A mixture of Na2CO3 (52 mg, 0.237 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (41 mg, 0.288 mmol) dissolved in 18-020 (100 mg, 0.240 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (17 mg, 0.024 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 110°C for 30 minutes. TLC analysis and LC / MS showed completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried on sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using HCl / Hx 1:1 to obtain compound 17 (14 mg, 0.042 mmol, 18%) as a white solid.

[0283] 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.48 (dd, J=4.9, 1.4 Hz, 1H), 8.44 (s, 1H). 8.28 (d, J=4.8 Hz, 1H), 8.25 - 8.18 (m, 1H), 7.94 (dd, J=4.9, 1.5 Hz, 2H), 7.83 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.54 - 7.49 (m, 1H).

[0284] LC / MS 334.1 [M + H+]

[0285] Compound 18. N-((1s,4s)-4-aminocyclohexyl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0286] [ka]

[0287] 1) Synthesis of tert-butyl 5-bromo-3-(((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-1H-indazole-1-carboxylate

[0288] A solution of 18-015 (150 mg, 0.147 mmol) was dissolved in DMF (6 ml), to which DIPEA (0.15 ml, 0.879 mmol) was added, followed by HATU (201 mg, 0.528 mmol). Tert-butyl ((1s,4s)-4-aminocyclohexyl)carbamate (104 mg, 0.484 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the completion of the starting material. The reaction mixture was quenched with water and extracted with SiO2 (2 × 45 ml), and the organic layer was washed with saturated salt aqueous solution. The organic layer was evaporated under vacuum to obtain the crude product. Subsequently, the product was purified by silica gel chromatography using SiO2 / Hx 3:7 to obtain 18-016 (186 mg, 0.346 mmol, 79%) in the form of a white solid.

[0289] 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=1.5 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.64 (dd, J=9.0, 1.9 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 4.61 (s, 1H), 4.18 - 4.07 (m, 1H), 3.70 (s, 1H), 1.92 - 1.77 (m, 4H), 1.75 (s, 9H), 1.73 - 1.66 (m, 4H), 1.46 (s, 9H).

[0290] LC / MS 438.0 [M - 100] +.

[0291] 2) Synthesis of tert-butyl-((1s,4s)-4-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide)cyclohexyl)carbamate

[0292] A mixture of Na2CO3 (40 mg, 0.372 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (31 mg, 0.223 mmol) dissolved in 18-016 (100 mg, 0.186 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (13 mg, 0.019 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 110°C for 30 minutes. TLC analysis and LC / MS showed completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried on sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using HCl / Hx 1:1 to obtain 18-022 (38 mg, 0.084 mmol, 45%) as a white solid.

[0293] 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.21 (d, J=4.8 Hz, 1H), 7.97 (ddd, J=9.6, 7.4, 1.8 Hz, 1H), 7.72 - 7.67 (m, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.10 (d, J=7.4 Hz, 1H), 4.62 (s, 1H), 4.24 - 4.14 (m, 1H), 3.68 (s, 1H), 1.93 - 1.80 (m, 4H), 1.80 - 1.63 (m, 4H), 1.46 (s, 9H).

[0294] LC / MS 452.1 [M - H+]

[0295] 3) Synthesis of N-((1s,4s)-4-aminocyclohexyl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0296] To a solution of 18-022 (30 mg, 0.066 mmol) in DCM (15 ml), 4.0 M HCl in dioxane (2.0 ml) was added at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was concentrated under reduced pressure to obtain compound 18 (20 mg, 0.056 mmol, 85%) as a white solid.

[0297] 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 8.22 (d, J=4.4 Hz, 1H), 8.18 - 8.11 (m, 1H), 7.76 - 7.68 (m, 2H), 7.49 - 7.45 (m, 1H), 4.22 (s, 1H), 3.32 (s, 1H), 2.09 - 1.95 (m, 4H), 1.94 - 1.79 (m, 4H).

[0298] LC / MS 354.1 [M + H+].

[0299] Compound 19. N-((1r,4r)-4-aminocyclohexyl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0300] [ka]

[0301] 1) Synthesis of tert-butyl 5-bromo-3-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-1H-indazole-1-carboxylate

[0302] A solution of 18-015 (150 mg, 0.147 mmol) was dissolved in DMF (6 ml), to which DIPEA (0.15 ml, 0.879 mmol) was added, followed by HATU (201 mg, 0.528 mmol). Tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (104 mg, 0.484 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the completion of the starting material. The reaction mixture was rapidly cooled with water and extracted with SiO2 (2 × 45 ml), and the organic layer was washed with saturated salt aqueous solution. The organic layer was evaporated under vacuum to obtain the crude product. Subsequently, the product was purified by silica gel chromatography using SiO2 / Hx 3:7 to obtain 18-017 (172 mg, 0.320 mmol, 73%) as a yellow solid.

[0303] 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=1.4 Hz, 1H), 7.95 (d, J=8.9 Hz, 1H), 7.64 (dd, J=9.0, 1.9 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 4.42 (s, 1H), 4.02 - 3.91 (m, J=8.1 Hz, 1H), 3.47 (s, 1H), 2.11 (t, J=11.2 Hz, 4H), 1.74 (s, 9H), 1.45 (s, 9H), 1.36 - 1.23 (m, 4H).

[0304] LC / MS 438.0 [M - 100] +.

[0305] 2) Synthesis of tert-butyl((1r,4r)-4-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide)cyclohexyl)carbamate

[0306] A mixture of Na2CO3 (40 mg, 0.372 mmol) in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (31 mg, 0.223 mmol) dissolved in 18-017 (100 mg, 0.186 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (13 mg, 0.019 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 110°C for 30 minutes. TLC analysis and LC / MS showed completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried over sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using Âx 1:1 to obtain 18-023 (28 mg, 0.062 mmol, 33%) as a white solid.

[0307] 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.20 (d, J=4.7 Hz, 1H), 8.02 - 7.94 (m, 1H), 7.69 - 7.63 (m, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.32 - 7.29 (m, 1H), 6.95 (d, J=8.3 Hz, 1H), 4.50 (s, 1H), 4.05 - 3.94 (m, 1H), 3.51 (s, 1H), 2.13 (dd, J=28.0, 11.0 Hz, 4H), 1.47 (s, 9H), 1.44 - 1.29 (m, 4H).

[0308] LC / MS 452.1 [M - H+]

[0309] 3) Synthesis of N-((1r,4r)-4-aminocyclohexyl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0310] To a solution of 18-023 (20 mg, 0.044 mmol) in DCM (15 ml), 4.0 M HCl in dioxane (2.0 ml) was added at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was concentrated under reduced pressure to obtain compound 19 (13 mg, 0.037 mmol, 85%) as a white solid.

[0311] 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 8.22 (d, J=4.7 Hz, 1H), 8.14 (ddd, J=9.7, 7.5, 1.8 Hz, 1H), 7.71 (q, J=8.4 Hz, 2H), 7.46 (ddd, J=7.1, 4.9, 1.7 Hz, 1H), 4.02 - 3.95 (m, 1H), 3.23 - 3.13 (m, 1H), 2.17 (s, 4H), 1.67 - 1.54 (m, 4H).

[0312] LC / MS 352.1 [M - H+]

[0313] Compound 20.5-(2-fluoropyridine-3-yl)-N-(pyrrolidine-3-yl)-1H-indazole-3-carboxamide

[0314] [ka]

[0315] 1) Synthesis of tert-butyl-5-bromo-3-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)carbamoyl)-1H-indazole-1-carboxylate

[0316] A solution of 18-015 (150 mg, 0.147 mmol) was dissolved in DMF (6 ml), to which DIPEA (0.15 ml, 0.879 mmol) was added, followed by HATU (201 mg, 0.528 mmol). Tert-butyl 3-aminopyrrolidine-1-carboxylate (90 mg, 0.484 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the completion of the starting material. The reaction mixture was quenched with water and extracted with siRNA (2 × 45 ml), and the organic layer was washed with saturated salt aqueous solution. The organic layer was evaporated under vacuum to obtain the crude product. Subsequently, the product was purified by silica gel chromatography using siRNA / Hx 3:7 to obtain 18-019 (136 mg, 0.267 mmol, 61%) in the form of a white solid.

[0317] 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=1.4 Hz, 1H), 7.97 (d, J=8.9 Hz, 1H), 7.65 (dd, J=9.0, 1.9 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 4.74 - 4.65 (m, 1H), 3.75 (dd, J=11.3, 6.6 Hz, 1H), 3.56 - 3.30 (m, 3H), 2.34 - 2.20 (m, 1H), 2.09 - 1.96 (m, 1H), 1.75 (s, 9H), 1.48 (s, 9H).

[0318] LC / MS 410.0 [M - 100] +.

[0319] 2) Synthesis of tert-butyl-3-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide)pyrrolidine-1-carboxylate

[0320] A mixture of Na2CO3 (42 mg, 0.392 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (33 mg, 0.236 mmol) dissolved in 18-019 (100 mg, 0.196 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (14 mg, 0.020 mmol) was added to the reaction mixture, and the mixture was irradiated in a microwave reactor at 110°C for 30 minutes. TLC analysis and LC / MS confirmed the completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried over sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using siRNA / Hx 1:1 to obtain 18-026 (38 mg, 0.089 mmol, 45%) as a white solid.

[0321] 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.21 (d, J=4.5 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 7.19 (d, J=7.3 Hz, 1H), 4.79 - 4.68 (m, 1H), 3.84 - 3.69 (m, 1H), 3.62 - 3.35 (m, 4H), 2.05 - 2.97 (m, 1H), 1.49 (s, 9H).

[0322] LC / MS 424.1 [M - H+]

[0323] 3) Synthesis of 5-(2-fluoropyridine-3-yl)-N-(pyrrolidine-3-yl)-1H-indazole-3-carboxamide

[0324] To a solution of 18-026 (30 mg, 0.071 mmol) in DCM (15 ml), 4.0 M HCl in dioxane (2.0 ml) was added at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC analysis showed that the starting material had completely disappeared. The reaction mixture was concentrated under reduced pressure to obtain compound 20 (20 mg, 0.060 mmol, 85%) as a white solid.

[0325] 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 8.22 (d, J=4.6 Hz, 1H), 8.18 - 8.11 (m, 1H), 7.76 - 7.66 (m, 2H), 7.49 - 7.44 (m, 1H), 4.77 - 4.70 (m, 1H), 3.71 - 3.66 (m, 1H), 3.65 - 3.59 (m, 2H), 3.52 - 3.39 (m, 2H), 2.54 - 2.43 (m, 1H), 2.34 - 2.22 (m, 1H).

[0326] LC / MS 326.0 [M + H+].

[0327] Compound 21. (3,4-dihydroisoquinoline-2(1H)-yl)(5-(2-fluoropyridine-3-yl)-1H-indazole-3-yl)methanone

[0328] [ka]

[0329] 1) Synthesis of tert-butyl-5-bromo-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-indazole-1-carboxylate

[0330] A solution of 18-015 (150 mg, 0.147 mmol) was dissolved in DMF (6 ml), to which DIPEA (0.15 ml, 0.879 mmol) was added, followed by HATU (201 mg, 0.528 mmol). 1,2,3,4-tetrahydroisoquinoline (64 mg, 0.484 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the completion of the starting material. The reaction mixture was rapidly cooled with water, extracted with siRNA (50 ml), and the organic layer was washed with saturated salt aqueous solution. The organic layer was evaporated under vacuum to obtain the crude product. Subsequently, the product was purified by silica gel chromatography using siRNA / Hx 3:7 to obtain 18-031 (126 mg, 0.276 mmol, 63%) in the form of a white solid.

[0331] 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.04 (d, J=8.9 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.25 - 7.14 (m, 4H), 5.22 (s, 1H), 4.97 (s, 1H), 4.21 (t, J=5.9 Hz, 1H), 4.06 (t, J=6.1 Hz, 1H), 3.03 (t, J=5.9 Hz, 2H), 1.74 (d, J=5.5 Hz, 9H).

[0332] LC / MS 357.0 [M - 100] +.

[0333] 2) Synthesis of (3,4-dihydroisoquinoline-2(1H)-yl)(5-(2-fluoropyridine-3-yl)-1H-indazole-3-yl)methanone

[0334] A mixture of Na2CO3 (47 mg, 0.438 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (37 mg, 0.263 mmol) dissolved in 18-031 (100 mg, 0.219 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (15 mg, 0.022 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 110°C for 30 minutes. TLC analysis and LC / MS showed completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried over sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using RINKAN HCl / Hx 3:2 to obtain compound 21 (31 mg, 0.083 mmol, 38%) as a white solid.

[0335] 1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.36 (m, 1H), 8.20 (m, 1H), 7.95 (m, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.51-7.42 (m, 4H), 5.30 (s, 1H), 5.01 (s, 1H), 4.28 (m, 1H), 4.10 (m, 1H), 3.04 (m, 2H).

[0336] LC / MS 373.1 [M + H+]

[0337] Compound 22.5-(2-fluoropyridine-3-yl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide

[0338] [ka]

[0339] 1) Synthesis of tert-butyl 5-bromo-3-((2-morpholinoethyl)carbamoyl)-1H-indazole-1-carboxylate

[0340] A solution of 18-015 (150 mg, 0.147 mmol) was dissolved in DMF (6 ml), to which DIPEA (0.15 ml, 0.879 mmol) was added, followed by HATU (201 mg, 0.528 mmol). 2-Morpholinoethane-1-amine (63 mg, 0.484 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the completion of the starting material. The reaction mixture was quenched with water and extracted with siRNA (2 × 45 ml), and the organic layer was washed with saturated salt aqueous solution. The organic layer was evaporated under vacuum to obtain the crude product. Subsequently, the product was purified by silica gel chromatography using siRNA / Hx 6:4 to obtain 18-032 (129 mg, 0.285 mmol, 65%) in the form of a white solid.

[0341] 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=1.4 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.64 (dd, J=9.0, 1.9 Hz, 1H), 3.80 - 3.76 (m, 4H), 3.67 - 3.62 (m, 2H), 2.72 (t, J=6.2 Hz, 2H), 2.67 - 2.60 (m, 4H), 1.74 (s, 9H).

[0342] LC / MS [M - 100] +.

[0343] 2) Synthesis of 5-(2-fluoropyridine-3-yl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide

[0344] A mixture of Na2CO3 (48 mg, 0.442 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (37 mg, 0.265 mmol) dissolved in 18-032 (100 mg, 0.221 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (15 mg, 0.022 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 110°C for 30 minutes. TLC analysis and LC / MS showed completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried over sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using MeOH / DCM 1:9 to obtain compound 22 (45 mg, 0.122 mmol, 55%) as a white solid.

[0345] 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.21 (d, J=4.5 Hz, 1H), 7.95 (ddd, J=9.6, 7.4, 1.9 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.61 - 7.56 (m, 1H), 7.31 - 7.28 (m, 1H), 3.81 - 3.75 (m, 4H), 3.70 - 3.63 (m, 2H), 2.69 (t, J=6.1 Hz, 1H)., 2.63 - 2.54 (m, 4H).

[0346] LC / MS 373.1 [M + H+]

[0347] Compound 23. (5-(2-fluoropyridine-3-yl)-1H-indazole-3-yl)(4-methylpiperazine-1-yl)methanone

[0348] [ka]

[0349] 1) Synthesis of tert-butyl 5-bromo-3-(4-methylpiperazine-1-carbonyl)-1H-indazole-1-carboxylate

[0350] A solution of 18-015 (150 mg, 0.147 mmol) was dissolved in DMF (6 ml), to which DIPEA (0.15 ml, 0.879 mmol) was added, followed by HATU (201 mg, 0.528 mmol). 1-Methylpiperazine (0.053 ml, 0.484 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the completion of the starting material. The reaction mixture was quenched with water, extracted with siRNA (50 ml), and the organic layer was washed with saturated salt aqueous solution. The organic layer was evaporated under vacuum to obtain the crude product. Subsequently, the product was purified by silica gel chromatography using MeOH / DCM 1:9 to obtain yellow solid in 18-038 (144 mg, 0.340 mmol, 77%).

[0351] 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=1.4 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.64 (dd, J=8.9, 1.9 Hz, 1H), 4.12 - 4.02 (m, 2H), 3.96 - 3.87 (m, 2H), 2.57 (dt, J=20.5, 5.0 Hz, 4H), 2.37 (s, 2H), 1.72 (s, 9H).

[0352] LC / MS 425.0 [M +H +].

[0353] 2) Synthesis of (5-(2-fluoropyridine-3-yl)-1H-indazole-3-yl)(4-methylpiperazine-1-yl)methanone

[0354] A mixture of Na2CO3 (51 mg, 0.472 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (40 mg, 0.284 mmol) dissolved in 18-038 (100 mg, 0.236 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (17 mg, 0.024 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 110°C for 30 minutes. TLC analysis and LC / MS showed completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried over sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using MeOH / DCM 1:9 to obtain compound 23 (35 mg, 0.103 mmol, 44%) as a white solid.

[0355] 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=4.7 Hz, 1H), 8.20 - 8.13 (m, 2H), 7.74 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.51 - 7.46 (m, 1H), 4.02 (s, 1H), 3.72 (s, 1H), 2.39 (s, 1H), 2.22 (s, 3H).

[0356] LC / MS 340.1 [M + H+]

[0357] Compound 24.5-(2-fluoropyridine-3-yl)-N-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide

[0358] [ka]

[0359] 1) tert-butyl-5-bromo-3-((2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)carbamoyl)-1H-indazole-1-carboxylate synthesis

[0360] A solution of 18-015 (150 mg, 0.147 mmol) was dissolved in DMF (6 ml), to which DIPEA (0.15 ml, 0.879 mmol) was added, followed by HATU (201 mg, 0.528 mmol). 1-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (118 mg, 0.484 mmol) was added and the mixture was stirred at room temperature for 3 hours. TLC analysis confirmed the completion of the starting material. The reaction mixture was quenched with water and extracted with siRNA (50 ml), and the organic layer was washed with saturated salt aqueous solution. The organic layer was evaporated under vacuum to obtain the crude product. Subsequently, the product was purified by silica gel chromatography using siRNA / Hx 3:7 to obtain 18-039 (149 mg, 0.263 mmol, 60%) as a yellow solid.

[0361] 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.40 (s, 1H), 8.08 (d, J=8.9 Hz, 1H), 7.86 (dd, J=9.0, 2.0 Hz, 1H), 7.77 (d, J=20.6 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.26 - 7.22 (m, 1H), 4.77 (d, J=6.1 Hz, 2H), 3.84 (d, J=5.4 Hz, 2H), 2.94 - 2.88 (m, 2H), 1.71 (s, 9H).

[0362] LC / MS 566.8 [M - H +].

[0363] 2) Synthesis of 5-(2-fluoropyridine-3-yl)-N-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide

[0364] A mixture of Na2CO3 (38 mg, 0.352 mmol) dissolved in water (0.5 ml) was introduced into a suspension of (2-fluoropyridine-3-yl)boronic acid (30 mg, 0.212 mmol) dissolved in 18-039 (100 mg, 0.221 mmol) and dioxane (2 ml). After purging with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (12 mg, 0.018 mmol) was added to the reaction mixture and irradiated in a microwave reactor at 110°C for 30 minutes. TLC analysis and LC / MS showed completion of the starting materials. Water was added to the reaction mixture and extracted with ethyl acetate (15 ml). The organic layer was dried over sodium sulfate and evaporated under vacuum to obtain a crude mixture, which was purified by silica gel chromatography using HCl / Hx 1:1 to obtain compound 24 (26 mg, 0.054 mmol, 31%) as a white solid.

[0365] 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.45 (s, 1H), 8.27 (d, J=4.7 Hz, 1H), 8.23 ​​- 8.17 (m, 1H), 7.84 - 7.78 (m, 2H), 7.74 - 7.66 (m, 2H), 7.52 (dt, J=4.4, 2.0 Hz, 1H), 7.20 (dd, J=8.3, 4.2 Hz, 1H), 4.76 (d, J=6.5 Hz, 2H), 3.88 - 3.79 (m, 2H), 2.96 - 2.86 (m, 2H).

[0366] LC / MS 484.0 [M + H+]

[0367] Compound 25.5-(3,4-difluorophenyl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0368] [ka]

[0369] A mixture of Na2CO3 (15.3 mg, 0.144 mmol) in water was introduced into a suspension of 20-083 (20.0 mg, 0.0479 mmol), palladium catalyst (3.36 mg, 0.00479 mmol), and (3,4-difluorophenyl)boronic acid (9.08 mg, 0.0575 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 25 (10.3 mg, 0.0310 mmol, 65%) as a white solid.

[0370] 1 H NMR (300 MHz, DMSO- d6) δ14.12 (s,1H), 10.85(s,1H), 8.48(d, J=5.7Hz,2H), 8.45-8.33(m,2H), 7.98-7.90(m,2H), 7.80(s,1H), 7.73-7.67(m,1H), 7.64-7.54(m,2H).

[0371] Compound 26.5-(1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0372] [ka]

[0373] A aqueous mixture of Na2CO3 (22.9 mg, 0.216 mmol) was introduced into a suspension of 20-086 (30.0 mg, 0.0719 mmol), palladium catalyst (5.04 mg, 0.00719 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.4 mg, 0.0863 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 10% DCM / MeOH to obtain compound 26 (7.9 mg, 0.0260 mmol, 35%) as a white solid.

[0374] LC / MS 305.3[M + H] +

[0375] 1 H NMR (400 MHz, DMSO- d6) δ 13.90(s,1H), 12.99(s,1H), 10.93-10.70 (m,1H), 8.52-8.42(m,2H), 8.32-8.22(m,1H), 8.02-7.89(m,3H), 7.86-7.73(m,2H), 7.70-7.58(m,1H).

[0376] Compound 27. N-(pyridine-4-yl)-5-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indazole-3-carboxamide

[0377] [ka]

[0378] A aqueous mixture of Na2CO3 (22.9 mg, 0.216 mmol) was introduced into a suspension of 20-086 (30.0 mg, 0.0719 mmol), palladium catalyst (5.04 mg, 0.00719 mmol), and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.4 mg, 0.0863 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 10% to obtain compound 27 (6.60 mg, 0.0191 mmol, 27%) as a yellow solid.

[0379] 1 H NMR (300 MHz, DMSO- d6) δ 13.95(s,1H), 10.78(s,1H), 8.47(d, J=5.5Hz,2H), 8.05(s,1H), 7.94(d, J=6.0Hz,2H), 7.73(d, J=8.6Hz,1H), 7.39(d, J=8.7Hz,1H), 3.74(s,3H), 2.25(s,3H), 2.16(s,3H).

[0380] Compound 28.5-(1-isopropyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0381] [ka]

[0382] A aqueous mixture of Na2CO3 (19.0 mg, 0.180 mmol) was introduced into a suspension of 20-094 (30.0 mg, 0.0719 mmol), palladium catalyst (5.05 mg, 0.00719 mmol), and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.4 mg, 0.0863 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 28 (6.70 mg, 0.0193 mmol, 27%) as a white solid.

[0383] 1 H NMR (300 MHz, DMSO- d6) δ 13.89(s,1H), 10.76(s,1H), 8.48(d, J=5.9Hz,2H), 8.35(s,1H), 8.31(s,1H), 7.97-7.92(m,2H), 7.90(s,1H), 7.73(d, J=1.6Hz,1H), 7.67(d, J=8.7Hz,1H), 4.59-4.51(m,1H), 1.48(d, J=6.7Hz,6H).

[0384] Compound 29.5-(1-methyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0385] [ka]

[0386] A aqueous mixture of Na2CO3 (22.9 mg, 0.216 mmol) was introduced into a suspension of 20-097 (30.0 mg, 0.0719 mmol), palladium catalyst (5.04 mg, 0.00719 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.0 mg, 0.0863 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 10% DCM / MeOH to obtain compound 29 (8.70 mg, 0.0273 mmol, 38%) as a yellow solid.

[0387] 1 H NMR (300 MHz, DMSO- d6) δ 13.89(s,1H), 10.76(s,1H), 8.47(d, J=6.1Hz,2H), 8.32(s,1H), 8.22(s,1H), 7.96-7.91(m,2H), 7.89(d, J=0.9Hz,1H), 7.73-7.65(m,2H), 3.89(s,3H).

[0388] Compound 30. tert-butyl 5-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-yl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate

[0389] [ka]

[0390] 1) Synthesis of tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1H-indazole-5-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate

[0391] A mixture of Na2CO3 (31.8 mg, 0.300 mmol) and water was introduced into a suspension of 20-086 (50.0 mg, 0.120 mmol), palladium catalyst (8.42 mg, 0.0120 mmol), and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (54.3 mg, 0.144 mmol) in dioxane, and the mixture was purged with nitrogen for 15 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL (2 × 15 mL) of ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture. This was purified by column chromatography using 5% MeOH / MC to obtain 20-091 (15 mg of mixture compound) as a white solid.

[0392] *A mixture (the desired product and the deprotected starting material) was obtained.

[0393] 1 H NMR (400 MHz, DMSO- d6) δ 14.01(d, J=98.6Hz,1H), 10.80(d, J=34.9Hz,1H), 8.47(d, J=4.7Hz,2H), 8.39-8.34(m,1H), 7.99-7.89(m,3H), 7.86-7.58(m,4H), 4.46-4.32(m,1H), 4.19-3.97(m,2H), 3.10-2.82(m,2H), 2.16-2.00(m,2H), 1.92-1.75(m,2H).

[0394] 2) Synthesis of tert-butyl 5-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-yl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate

[0395] To a solution of the 20-091 mixture (10.0 mg) in THF (1 mL), Boc2O (8.95 mg, 0.0410 mmol) and TEA (7.15 μL, 0.0513 mmol) were added at 0°C from room temperature for 2 hours. After TLC results indicated completion of the reaction, the reaction mixture was evaporated, Â (20 mL) was added, and the organic layer was washed with water. The combined organic layer was concentrated under reduced pressure to obtain an unpurified mixture, which was purified by column chromatography using MeOH / MC 7% as the eluent to obtain compound 30 (5.1 mg, 0.0087 mmol, 84%) as a white solid.

[0396] *According to previous NMR data, the product yield is considered to be a 1:1 mixture with the starting material.

[0397] 1 H NMR (400 MHz, DMSO- d6) δ 11.04(s,1H), 8.53(d, J=5.4Hz,2H), 8.45(s,1H), 8.36(d,1H), 8.11(d, J=8.8,0.8Hz,1H), 8.00-7.95(m,2H), 7.91(d,2H), 4.51-4.30(m,1H), 4.07(d, J=12.5Hz,2H), 3.04-2.81(m,2H), 2.14-2.02(m,2H), 1.91-1.78(m,2H), 1.72(s,9H), 1.43(s,9H).

[0398] Compound 31. tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate

[0399] [ka]

[0400] 1) Synthesis of tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1H-indazole-5-yl)benzoyl)piperazine-1-carboxylate

[0401] A mixture of Na2CO3 (31.8 mg, 0.300 mmol) and water was introduced into a suspension of 20-086 (50.0 mg, 0.120 mmol), palladium catalyst (8.42 mg, 0.0120 mmol), and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (40.9 mg, 0.144 mmol) in dioxane, and the mixture was purged with nitrogen for 15 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL (2 × 15 mL) of ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 5% MeOH / MC to obtain 20-104 (10 mg, 0.0190 mmol, 16%) as a yellow solid.

[0402] According to LC-MS data, a mixture of the Boc-deprotected starting material and the desired product was observed.

[0403] 2) Synthesis of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate

[0404] To a solution of the 20-104 mixture (10.0 mg) in THF (1 mL), Boc2O (16.6 mg, 0.0760 mmol) and TEA (13.3 μL, 0.0950 mmol) were added from 0°C to room temperature for 2 hours. After TLC results indicated completion of the reaction, the reaction mixture was evaporated, siRNA (20 mL) was added, and the organic layer was washed with water. The combined organic layers were concentrated under reduced pressure to obtain an unpurified mixture, which was purified by column chromatography using MeOH / MC 7% as the eluent to obtain compound 31 (7.7 mg, 0.012 mmol, 65%) as a white solid.

[0405] *According to previous NMR data, the product yield is assumed to be based on a 1:1 mixture of starting materials.

[0406] 1 H NMR (400 MHz, DMSO- d6) δ 11.09(s,1H), 8.53(d,2H), 8.51(s,1H), 8.24(d, J=8.8,0.8Hz,1H), 8.08(dd, J=8.9,1.8Hz,1H), 7.92(d,2H), 7.84(d,2H), 7.57(d, J=8.3Hz,2H), 3.73-3.37(m,8H), 1.74(s,9H), 1.42(s,9H).

[0407] Compound 32. tert-butyl 5-(4-((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)phenyl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate

[0408] [ka]

[0409] 1) Synthesis of tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1H-indazole-5-yl)benzyl)piperazine-1-carboxylate

[0410] A mixture of Na2CO3 (31.8 mg, 0.300 mmol) and water was introduced into a suspension of 20-097 (50.0 mg, 0.120 mmol), palladium catalyst (8.42 mg, 0.0120 mmol), and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate (57.9 mg, 0.0863 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture. This was purified by recrystallization using CHCl3, HEX, and 20-010 (24.3 mg, 0.0474 mmol, 40%) was obtained as a white solid.

[0411] LC / MS 317.3, 513.6[M + H] + , mixture with De-Boc

[0412] 1 H NMR (300 MHz, DMSO- d6) δ 14.13(s,1H), 10.83(d, J=9.9Hz,1H), 8.48(d, J=6.2Hz,2H), 8.37(d, J=1.7Hz,1H), 7.92(d, J=6.5Hz,2H), 7.79(s,1H), 7.70(d, J=8.9Hz,1H), 7.64-7.57(m,1H), 7.43(d, J=7.9Hz,1H), 3.54(s,1H), 1.39(s,4H), 1.24(s,3H).

[0413] 2) Synthesis of tert-butyl 5-(4-((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)phenyl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate

[0414] Di-tert-butyl dicarbonate (17.0 mg, 0.0780 mmol) and TEA (9.87 mg, 0.0975 mmol) were added to 20-010 (20.0 mg, 0.0390 mmol) in 1 mL of THF at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The crude reaction mixture was diluted with 5 mL of water and extracted with 10 mL of ethyl acetate. The bound organic layer was concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 5% DCM / MeOH to obtain compound 32 (8.2 mg, 0.0134 mmol, 31%) as a white solid.

[0415] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.55-8.49 (m, 2H), 8.45 (dd, J=1.9, 0.8 Hz, 1H), 8.22-8.18 (m, 1H), 8.03 (dd, J=8.9, 1.8 Hz, 1H), 7.93-7.89 (m, 2H), 7.74-7.69 (m, 2H), 7.48 - 7.42 (m, 2H), 3.55 (s, 2H), 3.33 (s, 4H), 2.35 (t, J=5.0 Hz, 4H), 1.73 (s, 9H), 1.39 (s, 9H).

[0416] Compound 33.5-(1-benzyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0417] [ka]

[0418] A aqueous mixture of Na2CO3 (22.9 mg, 0.216 mmol) was introduced into a suspension of 20-107 (30.0 mg, 0.0719 mmol), palladium catalyst (5.04 mg, 0.00719 mmol), and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.5 mg, 0.0863 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 10% DCM / MeOH to obtain compound 33 (12.6 mg, 0.0319 mmol, 44%) as a white solid.

[0419] LC / MS 395.4[M + H]+

[0420] 1H NMR (300 MHz, DMSO-d6) δ 13.90 (s, 1H), 10.77 (s, 1H), 8.48 (d, J=5.3 Hz, 2H), 8.40 (s, 1H), 8.35 (s, 1H), 8.00-7.90 (m, 3H), 7.77-7.62 (m, 2H), 7.42-7.25 (m, 5H), 5.38 (s, 2H).

[0421] Compound 34.5-(furan-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0422] [ka]

[0423] A aqueous mixture of Na2CO3 (19.0 mg, 0.180 mmol) was introduced into a suspension of 20-107 (30.0 mg, 0.0719 mmol), palladium catalyst (5.05 mg, 0.00719 mmol), and furan-3-ylboronic acid (9.66 mg, 0.0863 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture. This was purified by recrystallization using CHCl3, HEX, and compound 34 (9.3 mg, 0.0306 mmol, 43%) was obtained as a brown solid.

[0424] LC / MS 305.4[M + H]+

[0425] 1H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 10.78 (s, 1H), 8.48 (d, J=5.5 Hz, 2H), 8.36 (s, 1H), 8.26 (d, J=1.3 Hz, 1H), 7.97-7.92 (m, 2H), 7.79 (t, J=1.7 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.72 (s, 1H), 7.02 (d, J=1.7 Hz, 1H).

[0426] Compound 35. tert-butyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate

[0427] [ka]

[0428] 1) Synthesis of tert-butyl 4-(3-(pyridine-4-ylcarbamoyl)-1H-indazole-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0429] A water mixture of Na2CO3 (12.7 mg, 0.120 mmol) was introduced into a suspension of 20-097 (20.0 mg, 0.0479 mmol), palladium catalyst (3.36 mg, 0.00479 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (17.8 mg, 0.0575 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture. This was purified by column chromatography using 10% DCM / MeOH to obtain 20-013 (9.5 mg, 0.0226 mmol, 47%) as a white solid.

[0430] LC / MS 319.2, 420.5[M + H]+, Mixture with De-Boc.

[0431] 1H NMR (400 MHz, DMSO-d6) δ 13.91 (s, 0H), 10.76 (s, 0H), 8.50-8.44 (m, 1H), 7.93 (td, J=4.4, 1.6 Hz, 1H), 7.73-7.58 (m, 1H), 6.23 (s, 0H), 4.05 (s, 1H), 3.60 (t, J=5.6 Hz, 1H), 2.57 (s, 1H), 1.45 (s, 4H).

[0432] 2) Synthesis of tert-butyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridine-4-ylcarbamoyl)-1H-indazole-1-carboxylate

[0433] Di-tert-butyl dicarbonate (8.64 mg, 0.0396 mmol) and TEA (5.01 mg, 0.0495 mmol) were added to 20-013 (8.30 mg, 0.0198 mmol) in 1 mL of THF at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The crude reaction mixture was diluted with 5 mL of water and extracted with 10 mL of ethyl acetate. The bound organic layer was concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 10% DCM / MeOH to obtain compound 35 (5.8 mg, 0.0112 mmol, 56%) as a white solid.

[0434] LC / MS 520.6[M + H]+

[0435] 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.55-8.49 (m, 2H), 8.20 (d, J=1.8 Hz, 1H), 8.09 (d, J=8.9 Hz, 1H), 7.92-7.88 (m, 2H), 7.87-7.83 (m, 1H), 6.29 (s, 1H), 4.05 (s, 2H), 3.59 (t, J=5.5 Hz, 2H), 2.56 (s, 2H), 1.71 (s, 9H), 1.44 (s, 9H).

[0436] Compound 36.5-(1-propyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0437] [ka]

[0438] A aqueous mixture of Na2CO3 (17.2 mg, 0.162 mmol) was introduced into a suspension of 20-107 (27.0 mg, 0.0647 mmol), palladium catalyst (5.04 mg, 0.00719 mmol), and 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.5 mg, 0.0863 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 15 mL of water and extracted with 3 × 15 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 36 (5.90 mg, 0.0170 mmol, 28%) as a white solid.

[0439] LC / MS 347.5[M + H]+

[0440] 1H NMR (300 MHz, DMSO-d6) δ 13.90 (s, 1H), 10.77 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H), 8.27 (s, 0H), 8.00-7.92 (m, 1H), 7.91 (s, 0H), 7.76-7.65 (m, 1H), 4.11 (t, J=6.9 Hz, 1H), 1.85 (q, J=7.2 Hz, 1H), 0.87 (t, J=7.3 Hz, 2H).

[0441] Compound 37.5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0442] [ka]

[0443] 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0444] A water mixture of Na2CO3 (19.8 mg, 0.187 mmol) was introduced into a suspension of 20-117 (30.0 mg, 0.0748 mmol), palladium catalyst (5.25 mg, 0.00748 mmol), and (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (16.1 mg, 0.0897 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 37 (11.9 mg, 0.0261 mmol, 35%) as a yellow solid.

[0445] LC / MS 457.5[M + H]+

[0446] 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.54-8.47 (m, 2H), 8.34 (dd, J=1.8, 0.8 Hz, 1H), 7.98- 7.90 (m, 3H), 7.79 (dd, J=8.9, 1.8 Hz, 1H), 7.22-7.17 (m, 2H), 7.01-6.97 (m, 1H), 6.04 (dd, J=10.1, 2.3 Hz, 1H), 4.31 (s, 4H), 4.00 (d, J=11.4 Hz, 1H), 3.84 (td, J=11.0, 10.5, 3.9 Hz, 1H), 2.60 (d, J=12.5 Hz, 1H), 2.08 (s, 2H), 1.65 (s, 2H), 1.24 (s, 1H).

[0447] Compound 38. tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)benzyl)piperazine-1-carboxylate

[0448] [ka]

[0449] A water mixture of Na2CO3 (19.8 mg, 0.187 mmol) was introduced into a suspension of 20-117 (30.0 mg, 0.0748 mmol), palladium catalyst (5.25 mg, 0.00748 mmol), and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate (36.1 mg, 0.0897 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 38 (23.1 mg, 0.0387 mmol, 52%) as a brown solid.

[0450] LC / MS 597.7[M + H]+

[0451] 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.53-8.48 (m, 2H), 8.44 (d, J=1.5 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.95-7.91 (m, 2H), 7.86 (dd, J=8.9, 1.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.08-6.03 (m, 1H), δ 4.01 (d, J=11.8 Hz, 1H), 3.89-3.80 (m, 1H), 3.55 (s, 2H), 3.41-3.34 (m, 4H), 2.63-2.56 (m, 1H), 2.41-2.26 (m, 4H), 2.13-2.03 (m, 2H), 1.87-1.77 (m, 1H), 1.70-1.60 (m, 2H), 1.40 (s, 9H).

[0452] Compound 39. tert-butyl 4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0453] [ka]

[0454] A mixture of Na2CO3 (19.8 mg, 0.187 mmol) and water was introduced into a suspension of 20-117 (30.0 mg, 0.0748 mmol), palladium catalyst (5.25 mg, 0.00748 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (27.7 mg, 0.0897 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 39 (26.6 mg, 0.0528 mmol, 71%) as a yellow solid.

[0455] LC / MS 504.4[M + H]+

[0456] 1H NMR (300 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.51 (d, J=6.1 Hz, 2H), 8.20 (s, 1H), 7.94 (d, J=6.3 Hz, 2H), 7.88 (d, J=9.0 Hz, 1H), 7.75-7.68 (m, 1H), 6.25 (s, 1H), 6.00 (s, 0H), 4.03 (d, J=13.0 Hz, 2H), 3.92 (s, 1H), 3.83 (s, 1H), 3.60 (t, J=5.6 Hz, 2H), 2.57 (s, 5H), 2.04 (d, J=14.5 Hz, 3H), 1.65 (s, 2H), 1.45 (s, 9H).

[0457] Compound 40. tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)phenyl)piperazine-1-carboxylate

[0458] [ka]

[0459] A water mixture of Na2CO3 (19.8 mg, 0.187 mmol) was introduced into a suspension of 20-117 (30.0 mg, 0.0748 mmol), palladium catalyst (5.25 mg, 0.00748 mmol), and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (34.8 mg, 0.0897 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 40 (20.5 mg, 0.0403 mmol, 54%) as a yellow solid.

[0460] LC / MS 583.7[M + H]+

[0461] 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.56-8.51 (m, 2H), 8.40 (dd, J=1.8, 0.8 Hz, 1H), 8.01-7.98 (m, 3H), 7.99-7.96 (m, 1H), 7.85 (dd, J=8.9, 1.8 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.23 (t, J=2.1 Hz, 1H), 7.15 (dd, J=7.7, 1.5 Hz, 1H), 6.08 (d, J=2.5 Hz, 1H), 3.99 (d, 1H), 3.86 (d, J=8.4 Hz, 1H), 3.51 (t, J=5.1 Hz, 4H), 3.21 (t, J=5.2 Hz, 4H), 2.62 (d, J=12.3 Hz, 1H), 2.09 (m, 2H), 1.82 (q, J=4.9, 4.4 Hz, 1H), 1.66 (d, J=5.2 Hz, 2H), 1.44 (s, 9H).

[0462] Compound 41.5-(5-formylfuran-2-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0463] [ka]

[0464] A aqueous mixture of Na2CO3 (19.8 mg, 0.187 mmol) was introduced into a suspension of 20-117 (30.0 mg, 0.0748 mmol), palladium catalyst (5.25 mg, 0.00748 mmol), and (5-formylfuran-2-yl)boronic acid (27.7 mg, 0.0897 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 41 (15.8 mg, 0.0379 mmol, 51%) as a brown solid.

[0465] LC / MS 417.5[M + H]+

[0466] 1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.65 (s, 1H), 8.71 (t, J=1.2 Hz, 1H), 8.52 (s, 2H), 8.07 (d, J=1.5 Hz, 1H), 7.96 (d, J=5.3 Hz, 2H), 7.71 (d, J=3.8 Hz, 1H), 7.42 (d, J=3.7 Hz, 1H), 6.08 (d, J=9.6 Hz, 1H), 4.03 m, 1H), 3.87 (m, J=12.2 Hz, 1H), 2.61 (d, J=13.2 Hz, 1H), 2.09 (m, 2H), 1.82 (m, 1H), 1.66 (m, 2H).

[0467] Compound 42. N-(pyridine-4-yl)-5-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indazole-3-carboxamide

[0468] [ka]

[0469] To a solution of 20-023 (22.0 mg, 0.0511 mmol) in DCM (0.5 ml), 4N HCl in dioxane (0.25 ml) was added, and the reaction mixture was stirred overnight at room temperature. The crude reaction mixture was diluted with 10 mL of water and extracted with 10 mL of ethyl acetate. NaHCO3 was added to the bound organic layer, and the mixture was purified by filtration using water to obtain compound 42 (3.6 mg, 0.0113 mmol, 40%) as a brown solid.

[0470] LC / MS 320.4[M + H]+

[0471] 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.57-8.39 (m, 3H), 8.18 (s, 1H), 7.99-7.84 (m, 3H), 7.64 (s, 2H), 6.28 (s, 1H), 3.47-3.41 (m, 2H), 3.04-2.94 (m, 2H), 2.47-2.41 (m, 2H).

[0472] Compound 43.5-(benzo[b]thiophen-2-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0473] [ka]

[0474] A water mixture of Na2CO3 (33.1 mg, 0.312 mmol) was introduced into a suspension of 20-117 (50.0 mg, 0.125 mmol), palladium catalyst (8.77 mg, 0.0125 mmol), and benzo[b]thiophene-2-ylboronic acid (23.4 mg, 0.131 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 43 (38.8 mg, 0.0854 mmol, 68%) as a yellow solid.

[0475] LC / MS 455.5[M + H]+

[0476] 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.62-8.56 (m, 2H), 8.55-8.53 (m, 1H), 8.12-8.08 (m, 2H), 8.07-8.05 (m, 2H), 8.03-7.99 (m, 1H), 7.98 (s, 1H), 7.92-7.87 (m, 1H), 7.45-7.34 (m, 2H), 6.08 (dd, J=10.1, 2.4 Hz, 1H), 4.08-3.95 (m, 1H), 3.90-3.71 (m, 1H), 2.70-2.53 (m, 1H), 2.20-2.01 (m, 2H), 1.88-1.77 (m, 1H), 1.72-1.61 (m, 2H).

[0477] Compound 44.5-(2-(dimethylamino)pyrimidine-5-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0478] [ka]

[0479] A water mixture of Na2CO3 (33.1 mg, 0.312 mmol) was introduced into a suspension of 20-117 (50.0 mg, 0.125 mmol), palladium catalyst (8.77 mg, 0.0125 mmol), and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-amine (37.4 mg, 0.150 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 44 (32.5 mg, 0.0733 mmol, 59%) as a yellow solid.

[0480] LC / MS 444.5[M + H]+

[0481] 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.73 (s, 2H), 8.54-8.46 (m, 2H), 8.33 (dd, J=1.8, 0.8 Hz, 1H), 7.98 (dd, J=8.8, 0.9 Hz, 1H), 7.95-7.90 (m, 2H), 7.81 (d, J=1.8 Hz, 1H), 6.04 (dd, J=10.0, 2.3 Hz, 1H), 3.97 (m, 1H), 3.83 (m, J=12.5 Hz, 1H), 3.19 (s, 6H), 2.58 (m, J=10.8 Hz, 1H), 2.08 (m, J=3.4 Hz, 2H), 1.82 (m, 1H), 1.64 (m, 2H).

[0482] Compound 45.5-(6-formylbenzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0483] [ka]

[0484] A aqueous mixture of Na2CO3 (33.1 mg, 0.312 mmol) was introduced into a suspension of 20-117 (50.0 mg, 0.125 mmol), palladium catalyst (8.77 mg, 0.0125 mmol), and (6-formylbenzo[d][1,3]dioxol-5-yl)boronic acid (29.1 mg, 0.150 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 10% to obtain compound 45 (48.1 mg, 0.102 mmol, 82%) as a brown solid.

[0485] LC / MS 471.5[M + H]+

[0486] 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.67 (s, 1H), 8.53-8.46 (m, 2H), 8.17 (dd, J=1.8, 0.8 Hz, 1H), 8.02 (dd, J=8.8, 0.8 Hz, 1H), 7.94-7.90 (m, 2H), 7.64-7.60 (m, 1H), 7.39 (s, 1H), 7.16 (s, 1H), 6.24 (s, 2H), 6.09 (dd, J=10.1, 2.3 Hz, 1H), 4.05-3.97 (m, 1H), 3.90-3.81 (m, 1H), 2.65-2.57 (m, 1H), 2.15-2.04 (m, 2H), 1.88-1.77 (m, 1H), 1.71-1.60 (m, 2H).

[0487] Compound 46.5-(4-(piperazine-1-yl)phenyl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide hydrochloride

[0488] [ka]

[0489] To a solution of 20-025 (13.1 mg, 0.0225 mmol) in DCM (0.5 ml), 4N HCl in dioxane (0.25 ml) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to obtain compound 46 (10.3 mg, 0.0219 mmol, 97%) as a light brown solid.

[0490] LC / MS 399.5[M + H]+

[0491] 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 11.86 (s, 1H), 9.18 (s, 2H), 8.79 (d, J=7.3 Hz, 2H), 8.59-8.48 (m, 2H), 8.41 (d, J=1.3 Hz, 1H), 7.83 (d, J=1.2 Hz, 2H), 7.43-7.36 (m, 1H), 7.28 (s, 1H), 7.21 (d, 1H), 7.05 (dd, J=8.1, 2.5 Hz, 1H), 3.56-3.42 (m, 4H), 3.26 (s, 4H).

[0492] Compound 47.5-(5-formylfuran-2-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0493] [ka]

[0494] To a solution of 20-026 (10.9 mg, 0.0262 mmol) in DCM (0.5 ml), 4N HCl in dioxane (0.25 ml) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to obtain compound 47 (8.20 mg, 0.0247 mmol, 94%) as a blue solid.

[0495] 1H NMR (400 MHz, DMSO-d6) δ 14.50 (s, 1H), 11.86 (s, 1H), 9.65 (s, 1H), 8.78 (d, J=7.0 Hz, 2H), 8.71 (d, J=1.6 Hz, 1H), 8.49 (d, 2H), 8.06 (dd, J=8.8, 1.7 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.71 (d, J=3.7 Hz, 1H), 7.40 (d, J=3.7 Hz, 1H).

[0496] Compound 48.5-(benzo[b]thiophen-2-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0497] [ka]

[0498] To a solution of 20-032 (24.3 mg, 0.0535 mmol) in DCM (0.5 ml), 4N HCl in dioxane (0.25 ml) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to obtain compound 48 (16.7 mg, 0.0451 mmol, 84%) as a yellow solid.

[0499] LC / MS 371.4[M + H]+

[0500] 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 11.87 (s, 1H), 8.79 (d, J=7.1 Hz, 2H), 8.55 (d, J=1.7 Hz, 1H), 8.53-8.48 (m, 2H), 8.02 (ddd, J=9.6, 8.4, 1.6 Hz, 2H), 7.97 (s, 1H), 7.91-7.85 (m, 2H), 7.46-7.36 (m, 2H).

[0501] Compound 49.5-(2-fluoropyridine-3-yl)-N-(pyridine-4-ylmethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0502] [ka]

[0503] DIPEA (56.7 mg, 0.438 mmol) was added to a suspension of 20-028 (50.0 mg, 0.146 mmol) in THF (1 mL), followed by HATU (66.5 mg, 0.175 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Piperidine-4-ylmethaneamine (17.4 mg, 0.161 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The residual solvent was evaporated under vacuum. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using MeOH / DCM 8% to obtain compound 49 (31.2 mg, 0.0723 mmol, 50%) as a light brown solid.

[0504] LC / MS 432.6[M + H]+

[0505] 1H NMR (400 MHz, DMSO-d6) δ 9.16 (t, J=6.3 Hz, 1H), 8.53-8.49 (m, 2H), 8.40-8.38 (m, 1H), 8.26 (dt, J=4.8, 1.5 Hz, 1H), 8.21-8.15 (m, 1H), 7.99 (dd, J=8.9, 0.9 Hz, 1H), 7.74 (dt, J=8.8, 1.7 Hz, 1H), 7.50 (ddd, J=7.0, 4.8, 1.9 Hz, 1H), 7.37-7.33 (m, 2H), 6.04 (dd, J=9.7, 2.4 Hz, 1H), 4.54 (d, J=6.3 Hz, 2H), 3.98-3.91 (m, 1H), 3.86-3.76 (m, 1H), 2.58-2.52 (m, 1H), 2.13-2.02 (m, 2H), 1.85-1.75 (m, 1H), 1.67-1.58 (m, 2H).

[0506] Compound 50.5-(2-(dimethylamino)pyrimidine-5-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0507] [ka]

[0508] To a solution of 20-033 (17.9 mg, 0.0511 mmol) in DCM (0.5 ml), 4N HCl in dioxane (0.25 ml) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to obtain compound 50 (16.7 mg, 0.0465 mmol, 84%) as a yellow solid.

[0509] LC / MS 360.5[M + H]+

[0510] 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 11.85 (s, 1H), 8.78 (d, J=6.8 Hz, 2H), 8.75 (s, 2H), 8.50 (d, J=6.8 Hz, 2H), 8.34 (d, J=1.5 Hz, 1H), 7.86-7.76 (m, 2H), 3.21 (s, 6H).

[0511] Compound 51.5-(2-fluoropyridine-3-yl)-N-(pyridine-4-ylmethyl)-1H-indazole-3-carboxamide

[0512] [ka]

[0513] To a solution of 20-040 (23.9 mg, 0.0688 mmol) in DCM (0.5 ml), 4N HCl in dioxane (0.25 ml) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to obtain compound 51 (18.6 mg, 0.0535 mmol, 78%) as a white solid.

[0514] LC / MS 348.4[M + H]+

[0515] 1H NMR (400 MHz, DMSO-d6) δ 13.98 (s, 1H), 9.39 (t, J=6.1 Hz, 1H), 8.83 (d, 2H), 8.36 (s, 1H), 8.26 (dt, J=4.8, 1.6 Hz, 1H), 8.16 (ddd, J=10.4, 7.5, 1.9 Hz, 1H), 7.96 (d, 2H), 7.80 (dd, J=8.8, 0.9 Hz, 1H), 7.68 (dt, J=8.8, 1.7 Hz, 1H), 7.49 (ddd, J=7.0, 4.8, 1.9 Hz, 1H), 4.76 (d, J=6.1 Hz, 2H).

[0516] Compound 52.5-(6-formylbenzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0517] [ka]

[0518] 1) Synthesis of 5-(6-formylbenzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0519] A aqueous mixture of Na2CO3 (33.1 mg, 0.312 mmol) was introduced into a suspension of 20-117 (50.0 mg, 0.125 mmol), palladium catalyst (8.77 mg, 0.0125 mmol), and (6-formylbenzo[d][1,3]dioxol-5-yl)boronic acid (29.1 mg, 0.150 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using DCM / MeOH 10% to obtain 20-035 (48.1 mg, 0.102 mmol, 82%) as a brown solid.

[0520] LC / MS 471.5[M + H]+

[0521] 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.67 (s, 1H), 8.53-8.46 (m, 2H), 8.17 (dd, J=1.8, 0.8 Hz, 1H), 8.02 (dd, J=8.8, 0.8 Hz, 1H), 7.94-7.90 (m, 2H), 7.64-7.60 (m, 1H), 7.39 (s, 1H), 7.16 (s, 1H), 6.24 (s, 2H), 6.09 (dd, J=10.1, 2.3 Hz, 1H), 4.05-3.97 (m, 1H), 3.90-3.81 (m, 1H), 2.65-2.57 (m, 1H), 2.15-2.04 (m, 2H), 1.88-1.77 (m, 1H), 1.71-1.60 (m, 2H).

[0522] 2) Synthesis of 5-(6-formylbenzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0523] To a solution of 20-035 (36.8 mg, 0.0782 mmol) in DCM (0.5 ml), 4N HCl in dioxane (0.25 ml) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to obtain compound 52 (11.8 mg, 0.0305 mmol, 39%) as a green solid.

[0524] LC / MS 401.5[M + H]+

[0525] 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 11.93 (s, 1H), 8.79 (d, J=6.6 Hz, 2H), 8.46 (d, J=6.7 Hz, 2H), 7.97 (d, J=8.7 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.57 (s, 1H), 7.29 (s, 1H), 6.42 (s, 1H), 6.12 (s, 2H).

[0526] Compound 53.5-(2-fluoropyridine-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide

[0527] [ka]

[0528] To a suspension of 20-028 (40.0 mg, 0.117 mmol) in THF (1 mL), DIPEA (45.5 mg, 0.351 mmol) was added, followed by HATU (53.2 mg, 0.140 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. 1-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (31.5 mg, 0.129 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The residual solvent was evaporated under vacuum. The crude reaction mixture was diluted with 15 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to obtain a crude mixture, which was purified twice by column chromatography using 8% MeOH / DCM to obtain compound 53 (33.0 mg, 0.0581 mmol, 50%) as a brown solid.

[0529] Impurities observed (δ 7.68-7.90)

[0530] 1H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 10.78 (s, 1H), 8.48 (d, J=5.5 Hz, 2H), 8.36 (s, 1H), 8.26 (d, J=1.3 Hz, 1H), 7.97-7.92 (m, 2H), 7.79 (t, J=1.7 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.72 (s, 1H), 7.02 (d, J=1.7 Hz, 1H).

[0531] Compound 54.5-(2-fluoropyridine-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide

[0532] [ka]

[0533] Lithium hydroxide monohydrate (3.96 mg, 0.106 mmol) was added at room temperature to a solution of 20-041 (26.8 mg, 0.0529 mmol) in THF (4 mL), MeOH (2 mL), and H2O (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. The crude reaction mixture was concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 10% to obtain compound 54 (17.5 mg, 0.0371 mmol, 70%) in the form of a white solid.

[0534] LC / MS 472.5[M + H]+

[0535] 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.44 (d, J=1.9 Hz, 1H), 8.28 (dt, J=4.8, 1.5 Hz, 1H), 8.20 (ddd, J=10.4, 7.4, 1.9 Hz, 1H), 8.04-8.00 (m, 1H), 7.77 (dt, J=8.7, 1.7 Hz, 2H), 7.65 (dd, J=8.3, 2.3 Hz, 1H), 7.52 (ddd, J=7.0, 4.8, 1.8 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.05 (dd, J=9.9, 2.4 Hz, 1H), 4.13 (s, 2H), 4.01-3.95 (m, 1H), 3.87-3.80 (m, 1H), 3.23 (t, J=6.1 Hz, 2H), 2.85 (t, J=6.1 Hz, 2H), 2.68-2.56 (m, 1H), 2.13-2.03 (m, 2H), 1.86-1.76 (m, 1H), 1.69-1.60 (m, 2H).

[0536] Compound 55.5-(2-fluoropyridine-3-yl)-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide hydrochloride

[0537] [ka]

[0538] To a solution of 20-049 (7.50 mg, 0.0159 mmol) in MeOH (0.5 ml), 4N HCl in dioxane (0.3 ml) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to obtain compound 55 (4.80 mg, 0.0113 mmol, 71%) as a white solid.

[0539] LC / MS 388.4[M + H]+

[0540] 1H NMR (400 MHz, DMSO-d6) δ 14.06-13.88 (m, 1H), 10.49-10.40 (m, 1H), 9.16 (s, 2H), 8.49-8.33 (m, 1H), 8.28 (dt, J=4.8, 1.5 Hz, 1H), 8.23-8.16 (m, 1H), 7.92-7.86 (m, 1H), 7.85-7.77 (m, 1H), 7.75-7.62 (m, 2H), 7.52 (ddd, J=7.0, 4.8, 1.8 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 4.33-4.21 (m, 2H), 3.95-3.85 (m, 2H), 3.02-2.93 (m, 2H).

[0541] Compound 56.5-(6-(piperidine-1-ylmethyl)benzo[d][1,3]dioxol-5-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0542] [ka]

[0543] At 0°C, piperidine (2.57 mg, 0.0302 mmol) was added to a solution of 20-043 (10.6 mg, 0.0274 mmol) in MeOH (1 mL), and the reaction was carried out at room temperature for 1 hour with stirring, using AcOH (0.1 mL) as a catalyst. Sodium cyanoborohydride (8.9 mg, 0.14 mmol) was added, and the reaction was stirred at room temperature until complete. After the reaction was complete, the compound was quenched with 2 mL of water, and the MeOH was evaporated. The aqueous layer was extracted with ethyl acetate (2 × 15 mL). The crude reaction mixture was concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using DCM / MeOH 5% to obtain compound 56 (10.1 mg, 0.0222 mmol, 81%) as a yellow solid.

[0544] LC / MS 456.6[M + H]+

[0545] 1H NMR (400 MHz, DMSO-d6) δ 14.00 (d, J=29.6 Hz, 1H), 10.95 (s, 1H), 8.52 (d, 2H), 7.95 (dd, 2H), 7.87 (d, J=8.6 Hz, 1H), 7.73-7.68 (m, 1H), 7.49 (d, J=5.0 Hz, 1H), 7.28 (d, J=4.0 Hz, 1H), 6.07 (d, J=8.8 Hz, 2H), 5.84 (s, 1H), 3.04-2.97 (m, 4H), 1.69-1.67 (m, 4H), 1.60-1.52 (m, 2H).

[0546] Compound 57. tert-butyl 4-((5-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)furan-2-yl)methyl)piperazine-1-carboxylate

[0547] [ka]

[0548] 1) Synthesis of 5-(5-formylfuran-2-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0549] A water mixture of Na2CO3 (198 mg, 1.87 mmol) was introduced into a suspension of 20-117 (300 mg, 0.748 mmol), palladium catalyst (52.5 mg, 0.0748 mmol), and (5-formylfuran-2-yl)boronic acid (125 mg, 0.897 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using DCM / MeOH 7% to obtain 20-092 (136 mg, 0.326 mmol, 44%) as an orange solid.

[0550] 1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.65 (s, 1H), 8.71 (t, J=1.2 Hz, 1H), 8.52 (d, J=5.5 Hz, 2H), 8.11-8.02 (m, 2H), 7.99-7.93 (m, 2H), 7.70 (d, J=3.8 Hz, 1H), 7.40 (d, J=3.8 Hz, 1H), 6.07 (dd, J=10.1, 2.3 Hz, 1H), 4.06-3.95 (m, 1H), 3.91-3.79 (m, 1H), 2.67-2.55 (m, 1H), 2.16-1.98 (m, 2H), 1.90-1.76 (m, 1H), 1.70-1.58 (m, 2H).

[0551] 2) Synthesis of tert-butyl 4-((5-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)furan-2-yl)methyl)piperazine-1-carboxylate

[0552] To a solution of 20-092 (30.0 mg, 0.0720 mmol) in DMF (1 mL), tert-butylpiperazine-1-carboxylate (14.8 mg, 0.0792 mmol) was added, and the reaction was carried out at room temperature for 1 hour with stirring using AcOH (0.1 ml) as a catalyst. Sodium borohydride cyanohydride (6.79 mg, 0.108 mmol) was added, and the reaction was carried out at room temperature with stirring until completion. After the reaction was complete, the compound was quenched with 2 ml of water and extracted with ethyl acetate (2 × 15 ml). The organic layer was washed with water and salt solution, dried on sodium sulfate, and the solvent was evaporated under vacuum. The crude mixture was purified by column chromatography using DCM / MeOH 7%, and compound 57 (19.3 mg, 0.0329 mmol, 46%) was obtained as a white solid.

[0553] LC / MS 587.5[M + H]+

[0554] 1H NMR (300 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.59 (dd, J=1.6, 0.8 Hz, 1H), 8.49-8.40 (m, 2H), 8.06-7.98 (m, 2H), 7.84 (dd, J=8.9, 1.6 Hz, 1H), 7.72-7.66 (m, 1H), 6.72 (d, J=3.3 Hz, 1H), 6.35 (d, J=3.3 Hz, 1H), 5.82 (dd, J=9.7, 2.5 Hz, 1H), 4.19-4.08 (m, 1H), 3.89-3.80 (m, 1H), 3.48 (q, J=8.4, 6.7 Hz, 4H), 2.53 (t, J=5.1 Hz, 4H), 2.21-2.11 (m, 3H), 1.88-1.74 (m, 3H), 1.46 (s, 9H).

[0555] Compound 58. N-(1,1-dimethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0556] [ka]

[0557] 1) Synthesis of 5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxylic acid

[0558] A solution of 20-046 (100 mg, 0.293 mmol) in DCM (2.0 mL) was mixed with 4N HCl in dioxane (0.70 mL, excess) and reacted by stirring at 30°C for 4 hours. No starting material was observed from the TLC results, so the solvent was evaporated under vacuum. After washing with MC and filtering, compound 20-228 (64 mg, 0.249 mmol, 85%) was obtained as a grayish-white solid.

[0559] *Blue fluorescent spots were observed from TLC analysis.

[0560] 1H NMR (400 MHz, DMSO-d6) δ 14.02 (s, 1H), 13.05 (s, 1H), 8.33-8.24 (m, 2H), 8.18 (ddd, J=9.6, 7.4, 1.9 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.67 (dt, J=8.7, 1.8 Hz, 1H), 7.50 (ddd, J=7.1, 4.8, 1.9 Hz, 1H).

[0561] 2) Synthesis of N-(1,1-dimethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0562] A suspension of 18-036 (23.3 mg, 0.0855 mmol) dissolved in DMF (1 mL) was mixed with DIPEA (30.2 mg, 0.0934 mmol), followed by HATU (35.5 mg, 0.0934 mmol), and then 20-228 (20.0 mg, 0.0778 mmol). The reaction mixture was stirred overnight at room temperature. TLC analysis showed complete disappearance of the starting materials. The reaction mixture was evaporated, Â (20 mL) was added, and the organic layer was washed with water. The organic layer was dried over sodium sulfate and concentrated under vacuum. The reaction mixture was recrystallized in EA / Hex to obtain compound 58 (15 mg, 0.0293 mmol, 38%) in the form of a grayish-white solid.

[0563] LCMS:[M+H] 512.2

[0564] 1H NMR (400 MHz, DMSO-d6) δ 13.97 (s, 1H), 10.38 (s, 1H), 8.46 (d, J=1.6 Hz, 1H), 8.28 (dt, J=4.7, 1.6 Hz, 1H), 8.21 (ddd, J=10.4, 7.5, 1.9 Hz, 1H), 7.98 (d, J=2.1 Hz, 1H), 7.84-7.77 (m, 2H), 7.71 (dt, J=8.8, 1.8 Hz, 1H), 7.52 (ddd, J=7.1, 4.8, 1.9 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 3.64 (m, 2H), 2.89-2.84 (m, 2H), 1.80 (s, 6H).

[0565] Compound 59. N-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0566] [ka]

[0567] A solution of 20-232 (10.0 mg, 0.0196 mmol) dissolved in THF (1 ml), MeOH (0.5 ml), and H2O (0.25 ml) was prepared. Lithium hydroxide monohydrate (1.64 mg, 0.0391 mmol) was added at room temperature, and the reaction mixture was stirred overnight at room temperature to 50°C. TLC analysis showed complete disappearance of the starting material. The mixture was evaporated under vacuum, and H2O was added. After the addition of water, a solid was formed and filtered to obtain compound 59 (1.8 mg, 0.00433 mmol, 22%) in the form of a grayish-white solid.

[0568] LCMS:[M+H] 416.2

[0569] 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H), 10.20 (s, 1H), 8.45 (s, 1H), 8.27 (d, J=4.6 Hz, 1H), 8.21 (ddd, J=9.9, 7.4, 2.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.70 (dt, J=8.8, 1.8 Hz, 1H), 7.65 (dd, J=8.3, 2.2 Hz, 1H), 7.51 (ddd, J=7.0, 4.8, 1.8 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 2.96 (t, J=5.8 Hz, 2H), 2.65 (t, J=5.7 Hz, 2H), 1.37 (s, 6H).

[0570] Compound 60.5-(2-fluoropyridine-3-yl)-N-(1-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0571] [ka]

[0572] A suspension of 1-methyl-1H-pyrazolo[3,4-b]pyridine-5-amine (9.50 mg, 0.0645 mmol) in DMF (1 mL) was mixed with DIPEA (22.8 mg, 0.176 mmol) followed by HATU (26.7 mg, 0.0703 mmol). Subsequently, 20-081 (20.0 mg, 0.0778 mmol) was added, and the reaction mixture was stirred overnight at room temperature. TLC analysis showed complete disappearance of the starting materials. The reaction mixture was evaporated, siRNA (20 mL) was added, and the organic layer was washed with water. The organic layer was dried over sodium sulfate and concentrated under vacuum. The reaction mixture was recrystallized in EA / Hex to obtain compound 60 (46.1 mg, 0.0978 mmol, 67%) in the form of a brown solid.

[0573] LCMS:[M+H] 472 .2

[0574] 1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.47 (s, 1H), 8.28 (dt, J=4.8, 1.5 Hz, 1H), 8.21 (ddd, J=10.3, 7.5, 1.9 Hz, 1H), 8.16 (s, 1H), 8.04 (dd, J=8.9, 0.8 Hz, 1H), 7.78 (dt, J=8.8, 1.7 Hz, 1H), 7.54-7.47 (m, 1H), 6.08 (dd, J=10.0, 2.3 Hz, 1H), 4.08 (s, 3H), 4.03-3.96 (m, 1H), 3.90-3.78 (m, 1H), 2.64 (d, J=11.6 Hz, 1H), 2.23-1.77 (m, 3H), 1.71-1.56 (m, 2H).

[0575] Compound 61. tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)benzoyl)piperazine-1-carboxylate

[0576] [ka]

[0577] A aqueous mixture of Na2CO3 (33.2 mg, 0.313 mmol) was introduced into a suspension of 20-130 (50 mg, 0.125 mmol), a palladium catalyst (8.80 mg, 0.0125 mmol), and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (62.3 mg, 0.150 mmol) in dioxane, and the mixture was purged with nitrogen for 15 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The bound organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using MeOH / MC 10% to obtain compound 61 (47.3 mg, 0.0774 mmol, 62%) as a grayish-white solid.

[0578] LCMS:[M+H] 611.3

[0579] 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.55-8.44 (m, 3H), 8.03 (dd, J=9.0, 0.8 Hz, 1H), 7.96-7.93 (m, 2H), 7.91 (dd, J=8.9, 1.8 Hz, 1H), 7.84-7.80 (m, 2H), 7.58-7.53 (m, 2H), 6.07 (dd, J=10.0, 2.4 Hz, 1H), 4.06-3.96 (m, 1H), 3.92-3.81 (m, 1H), 3.66-3.37 (m, 8H), 2.68-2.57 (m, 1H), 2.08 (d, J=12.5 Hz, 2H), 1.83 (s, 1H), 1.72-1.60 (m, 2H), 1.42 (s, 9H).

[0580] Compound 62. tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)benzyl)piperazine-1-carboxylate

[0581] [ka]

[0582] A water mixture of Na2CO3 (33.2 mg, 0.313 mmol) was introduced into a suspension of 20-130 (50 mg, 0.125 mmol), palladium catalyst (8.80 mg, 0.0125 mmol), and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (60.4 mg, 0.150 mmol) in dioxane, and the mixture was purged with nitrogen for 15 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using MeOH / MC 10% to obtain compound 62 (35.6 mg, 0.0596 mmol, 51%) as a grayish-white solid.

[0583] LCMS:[M+H] 597.3

[0584] 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.55-8.48 (m, 2H), 8.44 (dd, J=1.8, 0.8 Hz, 1H), 8.03-7.96 (m, 1H), 7.95-7.92 (m, 2H), 7.86 (dd, J=8.9, 1.7 Hz, 1H), 7.73-7.63 (m, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.06 (dd, J=10.1, 2.3 Hz, 1H), 4.05-3.96 (m, 1H), 3.89-3.80 (m, 1H), 3.55 (s, 2H), 3.36-3.34 (m, 4H), 2.74-2.57 (m, 1H), 2.41-2.32 (m, 4H), 2.15-2.02 (m, 2H), 1.91-1.73 (m, 1H), 1.71-1.59 (m, 2H), 1.39 (s, 9H).

[0585] Compound 63.5-(2-fluoropyridine-3-yl)-N-(1-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide

[0586] [ka]

[0587] Lithium hydroxide monohydrate (3.40 mg, 0.0804 mmol) was added at room temperature to a solution of 20-244 (10.0 mg, 0.0201 mmol) dissolved in THF (1 ml), MeOH (0.5 ml), and H2O (0.25 ml). The reaction mixture was stirred overnight at room temperature to 50°C. TLC analysis showed complete disappearance of the starting material. The mixture was evaporated under vacuum, and H2O was added. After the addition of water, the solid formed was filtered to obtain compound 63 (2.4 mg, 0.00598 mmol, 30%) in the form of a yellow solid.

[0588] LCMS:[M+H] 402.2

[0589] 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.45 (s, 1H), 8.27 (dt, J=4.9, 1.5 Hz, 1H), 8.20 (ddd, J=9.8, 7.4, 1.9 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.69 (dt, J=8.7, 1.8 Hz, 1H), 7.63 (dd, J=8.2, 2.2 Hz, 1H), 7.51 (ddd, J=7.1, 4.8, 1.9 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 3.99-3.87 (m, 1H), 3.13-3.04 (m, 1H), 2.87-2.77 (m, 1H), 2.75-2.67 (m, 1H), 2.65-2.56 (m, 1H), 1.36 (d, J=6.6 Hz, 3H), 1.26 (dd, J=14.3, 7.7 Hz, 1H).

[0590] Compound 64.5-(2-fluoropyridine-3-yl)-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-indazole-3-carboxamide

[0591] [ka]

[0592] A solution of 20-245 (10.0 mg, 0.0207 mmol) dissolved in THF (1 ml), MeOH (0.5 ml), and H2O (0.25 ml) was prepared. Lithium hydroxide monohydrate (3.50 mg, 0.0827 mmol) was added at room temperature, and the reaction mixture was stirred overnight at room temperature to 50°C. TLC analysis showed complete disappearance of the starting material. The mixture was evaporated under vacuum, and H2O was added. After the addition of water, the resulting solid was filtered to obtain compound 64 (4.9 mg, 0.0126 mmol, 61%) in the form of a yellow solid.

[0593] LCMS:[M+H] 388.2

[0594] 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.45 (s, 1H), 8.27 (dt, J=4.8, 1.5 Hz, 1H), 8.20 (ddd, J=10.5, 7.4, 1.9 Hz, 1H), 7.80 (dd, J=8.7, 0.9 Hz, 1H), 7.75-7.65 (m, 2H), 7.57 (dd, J=8.3, 2.2 Hz, 1H), 7.51 (ddd, J=7.1, 4.8, 1.9 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 3.81 (s, 2H), 2.95 (t, J=5.9 Hz, 2H), 2.69 (t, J=7.6, 4.6 Hz, 2H), 1.24 (s, 1H).

[0595] Compound 65.5-(2-fluoropyridine-3-yl)-N-(1-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-1H-indazole-3-carboxamide

[0596] [ka]

[0597] To a solution of 20-239 (10.0 mg, 0.0212 mmol) dissolved in DCM (1.0 mL), 4N HCl (0.50 ml, excess) dissolved in dioxane was added. The mixture was stirred and reacted overnight at 30°C. No starting material was observed from the TLC results. The solvent was evaporated under vacuum, and MC was added for filtration to obtain compound 65 (1.7 mg, 0.00439 mmol, 21%) in the form of a yellow solid.

[0598] LCMS:[M+H] 388.2

[0599] 1H NMR (400 MHz, DMSO-d6) δ 14.05 (s, 1H), 10.78 (s, 1H), 9.00-8.90 (m, 1H), 8.76-8.70 (m, 1H), 8.47 (s, 1H), 8.30-8.26 (m, 1H), 8.21 (ddd, J=9.8, 7.3, 2.0 Hz, 1H), 8.15 (d, J=4.1 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.72 (dt, J=8.7, 1.8 Hz, 1H), 7.52 (ddt, J=7.0, 4.8, 2.1 Hz, 1H), 4.08 (s, 3H).

[0600] Compound 66.5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0601] [ka]

[0602] A water mixture of Na2CO3 (198 mg, 1.87 mmol) was introduced into a suspension of 20-130 (300 mg, 0.748 mmol), palladium catalyst (52.5 mg, 0.0748 mmol), and (2-fluoropyridine-3-yl)boronic acid (127 mg, 0.897 mmol) in dioxane, and the mixture was purged with nitrogen for 15 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using MeOH / MC 10% to obtain compound 66 (260 mg, 0.623 mmol, 83%) as a brown solid.

[0603] *Sigma boronic acid was used.

[0604] 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.46 (d, 2H), 8.23 ​​(ddd, J=5.0, 1.9, 1.1 Hz, 1H), 8.15 (ddd, J=9.6, 7.5, 1.9 Hz, 1H), 7.97-7.87 (m, 3H), 7.74 (dt, J=8.9, 1.9 Hz, 1H), 7.46 (ddd, J=7.5, 4.9, 1.7 Hz, 1H), 6.01 (dd, J=9.8, 2.5 Hz, 1H), 4.16-4.05 (m, 1H), 3.90 (ddd, J=11.5, 10.5, 3.1 Hz, 1H), 2.75-2.57 (m, 1H), 2.29-2.08 (m, 2H), 2.02-1.66 (m, 3H).

[0605] Compound 67.5-(4-(piperazine-1-carbonyl)phenyl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0606] [ka]

[0607] To a solution of 20-246 (20.0 mg, 0.0327 mmol) dissolved in DCM (1.0 mL), 4N HCl (0.50 ml, excess) dissolved in dioxane was added. The mixture was stirred and reacted overnight at 30°C. No starting material was observed from the TLC results. The solvent was evaporated under vacuum, MC was added, and the mixture was filtered to obtain compound 67 (9.0 mg, 0.0211 mmol, 65%) in the form of a yellow solid.

[0608] LCMS:[M+H] 427.2

[0609] 1H NMR (300 MHz, DMSO-d6) δ 14.46 (s, 1H), 11.85 (s, 1H), 9.42 (s, 2H), 8.85-8.69 (m, 2H), 8.55-8.40 (m, 3H), 7.93-7.78 (m, 3H), 7.62 (d, 2H), 3.89-3.62 (m, 4H), 3.25-3.10 (m, 4H).

[0610] Compound 68.5-(4-(piperazine-1-ylmethyl)phenyl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0611] [ka]

[0612] To a solution of 20-247 (20.0 mg, 0.0335 mmol) dissolved in DCM (1.0 mL), 4N HCl (0.50 ml, excess) dissolved in dioxane was added. The mixture was stirred and reacted overnight at 30°C. No starting material was observed from the TLC results. The solvent was evaporated under vacuum, MC was added, and the mixture was filtered to obtain compound 68 (10.7 mg, 0.0259 mmol, 77%) in the form of a grayish-white solid.

[0613] LCMS:[M+H] 413.2

[0614] 1H NMR (300 MHz, DMSO-d6) δ 14.44 (s, 1H), 11.85 (s, 1H), 9.54 (s, 2H), 8.87-8.67 (m, 2H), 8.56-8.41 (m, 3H), 7.91-7.79 (m, 3H), 7.78-7.67 (m, 2H), 4.45-4.22 (m, 2H), 3.63-3.53 (m, 2H), 3.34-3.22 (m, 4H), 3.17 (s, 2H).

[0615] Compound 69.5-(5-(piperazine-1-ylmethyl)furan-2-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0616] [ka]

[0617] 1) Synthesis of 5-(5-formylfuran-2-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0618] A water mixture of Na2CO3 (198 mg, 1.87 mmol) was introduced into a suspension of 20-117 (300 mg, 0.748 mmol), palladium catalyst (52.5 mg, 0.0748 mmol), and (5-formylfuran-2-yl)boronic acid (125 mg, 0.897 mmol) in dioxane, and the mixture was purged with nitrogen for 5 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using DCM / MeOH 7% to obtain 20-092 (136 mg, 0.326 mmol, 44%) as an orange solid.

[0619] 1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.65 (s, 1H), 8.71 (t, J=1.2 Hz, 1H), 8.52 (d, J=5.5 Hz, 2H), 8.11-8.02 (m, 2H), 7.99-7.93 (m, 2H), 7.70 (d, J=3.8 Hz, 1H), 7.40 (d, J=3.8 Hz, 1H), 6.07 (dd, J=10.1, 2.3 Hz, 1H), 4.06-3.95 (m, 1H), 3.91-3.79 (m, 1H), 2.67-2.55 (m, 1H), 2.16-1.98 (m, 2H), 1.90-1.76 (m, 1H), 1.70-1.58 (m, 2H).

[0620] 2) Synthesis of tert-butyl 4-((5-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)furan-2-yl)methyl)piperazine-1-carboxylate

[0621] To a solution of 20-092 (30.0 mg, 0.0720 mmol) dissolved in DMF (1 mL), tert-butylpiperazine-1-carboxylate (14.8 mg, 0.0792 mmol) was added, and the reaction was carried out at room temperature for 1 hour with stirring, using AcOH (0.1 ml) as a catalyst. Sodium borohydride cyanohydride (6.79 mg, 0.108 mmol) was added, and the reaction was stirred at room temperature until completion. After the reaction was complete, the compound was quenched with 2 ml of water and extracted with ethyl acetate (2 × 15 ml). The organic layer was washed with water and salt solution, dried on sodium sulfate, and the solvent was evaporated under vacuum. The crude mixture was purified by column chromatography using DCM / MeOH 7%, and 20-097 (19.3 mg, 0.0329 mmol, 46%) was obtained as a white solid.

[0622] LC / MS 587.5[M + H]+

[0623] 1H NMR (300 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.59 (dd, J=1.6, 0.8 Hz, 1H), 8.49-8.40 (m, 2H), 8.06-7.98 (m, 2H), 7.84 (dd, J=8.9, 1.6 Hz, 1H), 7.72-7.66 (m, 1H), 6.72 (d, J=3.3 Hz, 1H), 6.35 (d, J=3.3 Hz, 1H), 5.82 (dd, J=9.7, 2.5 Hz, 1H), 4.19-4.08 (m, 1H), 3.89-3.80 (m, 1H), 3.48 (q, J=8.4, 6.7 Hz, 4H), 2.53 (t, J=5.1 Hz, 4H), 2.21-2.11 (m, 3H), 1.88-1.74 (m, 3H), 1.46 (s, 9H).

[0624] 3) Synthesis of 5-(5-(piperazine-1-ylmethyl)furan-2-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide

[0625] To a solution of 20-097 (14.0 mg, 0.0239 mmol) dissolved in DCM (1 ml), 4N HCl (0.50 ml) dissolved in dioxane was added. The reaction mixture was stirred overnight at room temperature and concentrated under vacuum to obtain compound 69 (4.6 mg, 0.0114 mmol, 48%) in the form of a white solid.

[0626] LC / MS 403.5[M + H]+

[0627] 1H NMR (400 MHz, Methanol-d4) δ 8.62 (t, J=1.2 Hz, 1H), 8.48 (d, 2H), 7.95 (d, 2H), 7.84 (dt, J=8.5, 1.5 Hz, 1H), 7.70-7.64 (m, 1H), 6.80 (d, 1H), 6.48 (d, J=3.3 Hz, 1H), 3.78 (d, J=5.4 Hz, 2H), 3.20-3.13 (m, 4H), 2.79 (q, J=5.3, 4.2 Hz, 4H).

[0628] Compound 70.5-(5-(piperidine-1-ylmethyl)furan-2-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide

[0629] [ka]

[0630] A solution of 20-092 (30.0 mg, 0.0720 mmol) in DMF (1 mL) was added to piperidine (6.74 mg, 0.0792 mmol) and sodium triacetoxyborohydride (22.9 mg, 0.108 mmol). The reaction was stirred at room temperature for 5 hours. The reaction mixture was quenched with 2 ml of water, extracted with EA (5 ml x 2), and the organic layer was washed with water and salt solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated under vacuum. The crude mixture was purified by column chromatography using DCM / MeOH 7% to obtain compound 70 (3.9 mg, 0.00803 mmol, 11%) in the form of a light brown solid.

[0631] LC / MS 486.7[M + H]+

[0632] 1H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.71-8.65 (m, 1H), 8.64-8.53 (m, 2H), 7.89-7.81 (m, 1H), 7.77-7.71 (m, 2H), 7.69 (d, J=0.9 Hz, 1H), 6.73 (t, J=3.1 Hz, 1H), 6.42 (dd, J=29.5, 3.3 Hz, 1H), 5.81 (dd, J=9.5, 2.6 Hz, 1H), 4.18-4.09 (m, 1H), 3.89-3.84 (m, 1H), 3.82 (s, 2H), 2.69 (s, 3H), 2.60 (t, J=12.1 Hz, 1H), 2.26-2.11 (m, 2H), 1.87-1.83 (m, 1H), 1.78-1.70 (m, 3H), 1.50 (s, 1H).

[0633] Compound 71. N-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0634] [ka]

[0635] 1) Synthesis of N-(3,3-dimethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0636] To a suspension of 17-102 (23.2 mg, 0.0855 mmol) dissolved in THF (1 mL), DIPEA (30.2 mg, 0.0934 mmol) was added, followed by HATU (35.5 mg, 0.0934 mmol), and then 20-240 (20.0 mg, 0.0778 mmol). The reaction mixture was stirred overnight at room temperature. TLC analysis showed complete disappearance of the starting materials. The reaction mixture was evaporated, siRNA (20 mL) was added, and the organic layer was washed with water. The organic layer was dried over sodium sulfate and concentrated under vacuum. The reaction mixture was recrystallized in EA / Hex to obtain 20-256 (25.1 mg, 0.0491 mmol, 63%) in the form of a grayish-white solid.

[0637] *According to NMR data, the product was formed, but impurities were observed.

[0638] *After reduction, it may be removed by washing.

[0639] 2) Synthesis of N-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide

[0640] A solution of 20-256 (10.0 mg, 0.0196 mmol) dissolved in THF (1 ml), MeOH (0.5 ml), and H2O (0.25 ml) was prepared. Lithium hydroxide monohydrate (3.30 mg, 0.0782 mmol) was added at room temperature, and the reaction mixture was stirred overnight at room temperature to 50°C. TLC analysis showed complete disappearance of the starting material. The mixture was evaporated under vacuum, and the solid formed after the addition of H2O was filtered to obtain compound 71 (2.1 mg, 0.00505 mmol, 26%) as a yellow solid.

[0641] LCMS [M+H] 416.54

[0642] 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.45 (s, 1H), 8.34-8.13 (m, 2H), 7.84-7.44 (m, 5H), 7.10-6.94 (m, 1H), 3.88 (s, 2H), 2.65 (s, 2H), 1.24 (s, 1H), 1.07 (s, 6H).

[0643] Compound 72.5-(5-(piperidine-1-ylmethyl)furan-2-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide hydrochloride

[0644] [ka]

[0645] To a solution of 20-100 (20.4 mg, 0.0420 mmol) dissolved in DCM (1 ml), 4N HCl dissolved in dioxane (0.5 ml) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to obtain compound 72 (15.9 mg, 0.0363 mmol, 86%) in the form of a brown solid.

[0646] LC / MS 402.3[M + H]+

[0647] 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 11.82 (s, 1H), 10.75 (s, 1H), 8.78 (d, 2H), 8.57 (d, J=1.6 Hz, 1H), 8.47 (d, 2H), 7.99-7.78 (m, 2H), 7.12 (d, J=3.4 Hz, 1H), 6.90 (d, J=3.3 Hz, 1H), 4.46 (s, 2H), 3.11-2.81 (m, 3H), 1.96-1.54 (m, 5H), 1.51-1.27 (m, 1H).

[0648] Compound 73.5-(1-(piperidine-4-yl)-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide hydrochloride

[0649] [ka]

[0650] 1) tert-butyl 4-(4-(3-(pyridine-4-ylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate synthesis

[0651] A water mixture of Na2CO3 (31.8 mg, 0.300 mmol) was introduced into a suspension of 20-321 (40.0 mg, 0.0997 mmol), palladium catalyst (7.00 mg, 0.00997 mmol), and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (45.1 mg, 0.144 mmol) in dioxane, and the mixture was purged with nitrogen for 15 minutes. The resulting mixture was irradiated with microwaves at 110°C for 20 minutes. The crude reaction mixture was filtered through dioxane and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using MeOH / MC 5% to obtain 20-324 (18 mg, 0.031 mmol, 32%) as a white solid.

[0652] 1H NMR (300 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.50 (d, J=6.3 Hz, 2H), 8.37 (d, J=15.0 Hz, 2H), 8.00-7.87 (m, 4H), 7.80 (dd, J=8.8, 1.6 Hz, 1H), 6.01 (d, J=9.9 Hz, 1H), 4.54-4.29 (m, 1H), 4.19-3.94 (m, 3H), 3.89-3.72 (m, 1H), 3.07-2.82 (m, 2H), 2.65-2.55 (m, 1H), 2.20-1.97 (m, 4H), 1.93-1.74 (m, 3H), 1.72-1.57 (m, 2H), 1.44 (s, 9H).

[0653] 2) Synthesis of 5-(1-(piperidine-4-yl)-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide hydrochloride

[0654] A solution of 20-324 (15 mg, 0.0262 mmol) dissolved in DCM (1.0 mL) was mixed with 4N HCl / dioxane (0.5 mL). The mixture was stirred overnight at room temperature and reacted, and no starting material was observed from the TLC results. The solvent was evaporated under vacuum to obtain compound 73 (9.2 mg, 0.0217 mmol, 83%) as a brown solid.

[0655] LCMS:M+H 388.32

[0656] 1H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 11.82 (s, 1H), 9.21 (s, 1H), 9.01 (d, J=10.1 Hz, 1H), 8.79 (d, J=10.6, 6.5 Hz, 2H), 8.50 (d, J=6.6 Hz, 2H), 8.35 (d, 2H), 8.00 (s, 1H), 7.80 (dd, J=8.7, 1.6 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 4.65-4.48 (m, 1H), 3.20-3.01 (m, 3H), 2.36-2.12 (m, 5H).

[0657] <Example 2. Confirmation of TRIB2 or YAP inhibitory activity>

[0658] The TRIB2 kinase inhibitory activity and cancer cell proliferation inhibitory activity were confirmed using compounds 1 to 73 of the present invention synthesized in Example 1, and are shown in Table 1 below. The YAP inhibitory activity is shown in Figure 1.

[0659] The TRIB2 kinase activity assay was performed by Eurofins, and the simple procedure is as follows: Human TRIB2 enzyme was first mixed with 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 250 μM substrate (RRRFRPASPLRGPPK). The mixture was then treated with 10 mM magnesium acetate, 15 μM gamma-33P-ATP, and the test drug at varying concentrations, and the mixture was allowed to react at room temperature for 120 minutes. The reaction was then stopped by treatment with 0.5% phosphoric acid, and 10 μL of the reaction solution was transferred to a P30 filter. After washing with 0.425% phosphoric acid for 4 minutes four times, the filter was treated with methanol and dried, and the results were measured.

[0660] The method for inhibiting cancer cell proliferation was as follows: 4000 cells of the relevant cancer cell line were placed in each 96-well plate and stabilized for 24 hours. Subsequently, the cells were treated with the drug at 10 μM, and cell activity was measured 3 days later using Dojindo's Cell Counting Kit-8.

[0661] [Table 1]

[0662] In Figure 1, regarding YAP inhibitory activity, the compounds of the present invention reduced the phosphorylation of TRIB2 and YAP proteins in a concentration-dependent manner in the liver cancer cell line (HepG2), and a decrease in p-YAP by compound 17 was also confirmed in the ovarian cancer cell line A2780.

[0663] Based on the results of confirming TRIB2 kinase inhibitory activity and cancer cell proliferation inhibitory activity, the indazole derivative of the present invention exhibits IC2 activity. 50 The values ​​were shown to be concentrations of 0.001 to 1 μM, indicating excellent inhibitory activity. In the case of compound 17, it was confirmed that it exhibited excellent HepG2 growth inhibitory activity in liver cancer, and that it could also be used as a compound that promotes YAP protein degradation in addition to YAP inhibitory activity. In particular, compounds into which the tetrahydroisoquinoline substituted derivative of the present invention [Chemical Formula 2] was introduced showed remarkable TRIB2 kinase inhibitory activity and cancer cell proliferation inhibitory activity.

[0664] From this, it was found that the indazole derivative of the present invention can be usefully used for the prevention or treatment of diseases associated with TRIB2, such as cancer, lethargy, and fascial salts.

[0665] <Example of formulation 1. Manufacturing of powdered formulations>

[0666] Two g of the present invention compound 17(5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide) and one g of lactose were mixed and filled into an airtight cloth to produce a powder.

[0667] <Example of formulation 2. Manufacturing of tablets>

[0668] 100 mg of the present invention compound 17(5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide), 100 mg of microcrystalline cellulose, 60 mg of lactose monohydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed, and then tablets were manufactured by compressing the mixture using a conventional tablet manufacturing method.

[0669] <Example of formulation 3. Manufacturing of capsules>

[0670] 100 mg of the present invention compound 17(5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide), 100 mg of microcrystalline cellulose, 60 mg of lactose monohydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed together. The above components were then mixed using a conventional capsule manufacturing method and filled into gelatin capsules to produce capsules.

[0671] <Formulation Example 4. Manufacturing of Pills>

[0672] 90 mg of the present invention compound 17(5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide), 5 mg of glutinous rice starch, and 5 mg of purified water were mixed with small amounts of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives to inhibit hygroscopicity, and then 100 mg of pills were prepared by a conventional method.

[0673] <Example of formulation 5. Manufacturing of injectable drugs>

[0674] The compound 17(5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide) of the present invention was mixed with an appropriate amount of sterile distilled water for injection and an appropriate amount of pH adjusting agent, and then prepared with the above component content per ampoule (2 ml) by a conventional method for manufacturing injectable preparations.

Claims

1. Chemical formula 1 below: 【Chemistry 1】 (In the above chemical formula 1, 【change】 Displayed A compound characterized by the above, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

2. R ８ This is selected from the group consisting of hydrogen, methyl, propyl, isopropyl, benzyl, or piperidine. A compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

3. The compound according to Claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

4. tert-butyl-4-(5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide)piperidine-1-carboxylate (compound 1); 5-(2-fluoropyridine-3-yl)-N-(piperidine-4-yl)-1H-indazole-3-carboxamide (compound 2); 5-(2-fluoropyridine-3-yl)-1-methyl-N-(piperidine-4-yl)-1H-indazole-3-carboxamide (compound 9); 1-Benzoyl-N-(1-benzoylpiperidine-4-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 10); 1-(cyclopropanecarbonyl)-N-(1-(cyclopropanecarbonyl)piperidine-4-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 11); N-(1-benzoylpiperidine-4-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 12); 5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 17); 5-(2-fluoropyridine-3-yl)-N-(pyrrolidine-3-yl)-1H-indazole-3-carboxamide (compound 20); 5-(2-fluoropyridine-3-yl)-N-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide (compound 24); 5-(1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 26); 5-(1-isopropyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 28); 5-(1-methyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 29); 5-(1-benzyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 33); 5-(1-propyl-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide (compound 36); 5-(2-fluoropyridine-3-yl)-N-(pyridine-4-ylmethyl)-1H-indazole-3-carboxamide (compound 51); 5-(2-fluoropyridine-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide (compound 53); 5-(2-fluoropyridine-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide (compound 54); 5-(2-fluoropyridine-3-yl)-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide hydrochloride (compound 55); N-(1,1-dimethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 58); N-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 59); 5-(2-fluoropyridine-3-yl)-N-(1-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 60); 5-(2-fluoropyridine-3-yl)-N-(1-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-indazole-3-carboxamide (compound 63); 5-(2-fluoropyridine-3-yl)-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-indazole-3-carboxamide (compound 64); 5-(2-fluoropyridine-3-yl)-N-(1-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-1H-indazole-3-carboxamide (compound 65); 5-(2-fluoropyridine-3-yl)-N-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (compound 66); N-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(2-fluoropyridine-3-yl)-1H-indazole-3-carboxamide (compound 71); and Selected from the group consisting of 5-(1-(piperidine-4-yl)-1H-pyrazole-4-yl)-N-(pyridine-4-yl)-1H-indazole-3-carboxamide hydrochloride (compound 73); A compound characterized by the above, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

5. The active ingredient comprises the compound represented by chemical formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for the prevention or treatment of cancer, lethargy, and fasciitis, characterized by the above.

6. The aforementioned cancers are selected from the group consisting of lung cancer, liver cancer, stomach cancer, colorectal cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, thyroid cancer, melanoma, hematological cancer, colon cancer, non-small cell lung cancer, pancreatic cancer, skin cancer, head and neck cancer, small intestine cancer, rectal cancer, endometrial cancer, vaginal cancer, testicular cancer, esophageal cancer, biliary tract cancer, lymphatic cancer, gallbladder cancer, endocrine cancer, adrenal cancer, lymphoma, multiple myeloma, thymoma, mesothelioma, kidney cancer, brain cancer, central nervous system tumors, brainstem glioma, and pituitary adenoma. The pharmaceutical composition for the prevention or treatment of cancer, lethargy, and fasciitis according to claim 5.

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