Novel tetrahydroisoquinoline- or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivatives selectively inhibiting JAK1, and uses thereof

Abstract

The present invention provides a novel tetrahydroisoquinoline or isoindoline-substituted [1,2,4] triazolo [1,5-a] pyridine derivative selectively inhibiting JAK1, and a pharmaceutical composition comprising same as an active ingredient for preventing or treating cancer, rheumatoid arthritis, psoriatic arthritis, atopy, Crohn's disease, or ulcerative colitis.

Description

Novel tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivatives selectively inhibiting JAK1 and uses thereof

[0001] The present invention relates to a novel tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivative that is a JAK1 selective inhibitor and to the medicinal use thereof.

[0002] The present invention relates to various anticancer agents, pharmaceutical compositions for the prevention or treatment of rheumatoid arthritis, psoriatic arthritis, atopy, Crohn's disease, or ulcerative colitis, of tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivatives that are JAK1 selective inhibitors.

[0003] Janus kinase (JAK) is an enzyme of the intracellular non-receptor tyrosine kinase family that transmits cytokine-mediated signals through the JAK-STAT (signal transducer and activator of transcription) pathway.

[0004] Initially, because they were merely two of many discoveries made through PCR-based screening, they were referred to as "just another kinase 1 and 2," but they were ultimately named "Janus kinases." This name is derived from Janus, the Roman god with two faces, because JAK possesses two nearly identical phosphate transport domains. These two domains are located at the N-terminus of the JAK molecule and are called JH1 and JH2, respectively. JH1 primarily regulates the enzymatic activity of JAK, while JH2 regulates protein degradation and inhibits JAK. In other words, these structures and roles imply that this enzyme plays a crucial role in carrying out complex cellular signaling processes.

[0005] There are four families of JAK: JAK1, JAK2, JAK3, and TYK2. Transgenic mice in which JAK1 is not expressed show defective responses to certain cytokines, such as interferon-gamma. JAK1 and JAK2 are involved in type 11 interferon (interferon-gamma) signaling, whereas JAK1 and TYK2 (tyrosine kinase 2) are involved in type 1 interferon signaling. Mice with blocked TYK2 expression show defects in natural killer cell function. Because type 1 cytokine receptors (e.g., hemopoietin receptors) and type 1 cytokine receptors (e.g., interferons type 1, 2, 3, etc.) lack kinase activity, they rely on tyrosine kinases of JAKs in the cytoplasm to phosphorylate and activate downstream proteins involved in signaling pathways. The receptors exist as a pair of polypeptides and have two intracellular signaling domains. JAKs are associated with a proline-rich region of the intracellular domain called the box1 / box2 region adjacent to the cell membrane.

[0006] JAK1 was first identified during screening for novel kinases (Andrew F. Wilks, 1989). Genetic and biochemical studies revealed that JAK1 is functionally and physically related to type I interferon (e.g., IFN alpha), type II interferon (e.g., IFN gamma), IL-2, and IL-6 cytokine receptor complexes (Kisseleva T. et al., 2002; David E Levy et al., 2002; John J O'Shea et al., 2002). JAK1 knockout mice die before and after birth due to defects in LIF receptor signaling (Kisseleva et al., 2002; John J O'Shea et al., 2002), and characterization of tissues derived from JAK1 knockout mice has demonstrated that the kinase plays an important role in the IFN, IL-10, IL-2 / IL-4, and IL-6 pathways.

[0007] JAK inhibitors are drugs that inhibit Janus kinase, which regulates immunity, inflammation, and cell growth. They are used not only to treat conditions such as erythrocytosis vera and myeloid metaplasia accompanied by myelofibrosis, but also for cancer, rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and Crohn's disease. They are also being studied for alopecia, psoriasis, essential thrombocytosis, lupus erythematosus, ankylosing spondyloarthritis, ulcerative colitis, and vitiligo.

[0008] As prior art for triazolopyridine compounds that are JAK inhibitors, Korean Published Patent No. 2011-0031475 discloses a method in which a compound of the following chemical formula I, its enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt is used as a JAK kinase inhibitor for cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune disease, atherosclerotic arteriosclerosis, restenosis, psoriasis, allergic disorder, inflammation, inflammatory disease, nervous system disorder, neurodegenerative disease, hormone-related disease, organ transplantation-related condition, immunodeficiency disorder, destructive bone disorder, proliferative disorder, infectious disease, apoptosis-related condition, thrombin-induced platelet aggregation, liver disease, pathological immune state accompanied by T-cell activation, CNS disorder, or myeloproliferative disorder.

[0009]

[0010] In addition, Chinese registered patent CN 114394965 B discloses a triazolopyridine compound of the following chemical formula A that inhibits any one of JAK1, JAK2, and JAK3 kinases as a treatment for cancer, inflammation, and autoimmune diseases.

[0011]

[0012] However, the aforementioned prior art contains no description or suggestion of tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivative compounds and their excellent inhibitory effects on JAK1.

[0013] The inventors completed the present invention by discovering, through many research results, tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivative compounds and their selective inhibitory activity against JAK1.

[0014] The object of the present invention is to provide pharmaceutical compositions for the prevention or treatment of various anticancer agents, rheumatoid arthritis, psoriatic arthritis, atopy, Crohn's disease, or ulcerative colitis, of tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivatives that are JAK1 selective inhibitors.

[0015] The present invention relates to a compound represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0016] [Chemical Formula 1]

[0017]

[0018] In the above chemical formula 1,

[0019] R1 is hydrogen, -CH2R3, -(CH2) 0-2 SO2-R3, -SO2(CH2) 0-2 R3, -C(=O)(CH2) 0-1 R3, -C(=O)CH2CN, -CH2CN or -tert-butoxycarbonyl group;

[0020] The above R3 is hydrogen, substituted or unsubstituted C1-C3 alkyl, halo C1-C3 alkyl, cyano, C1-C 10 Alkoxy, substituted or unsubstituted C3-C9 cycloalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C5-C 12 Heterocycloalkyl, substituted or unsubstituted C5-C 12 Aryl, or substituted or unsubstituted C5-C 12 It is heteroaryl, and

[0021] The above-mentioned substituted alkyl, cycloalkyl, heterocycloalkyl, benzyl, aryl, or heteroaryl each have one or more hydrogen atoms that are halogen, hydroxy, cyano, C1-C3alkyl, halo C1-C3alkyl, or C1-C 10 Substituted with alkoxy, -C(=O)C1-C3alkyl, -SO2F;

[0022] R2 is hydrogen, or is;

[0023] R4 is a hydrogen or a tert-butoxycarbonyl group;

[0024] m is independently 1 or 2 and;

[0025] n is an integer from 1 to 3.

[0026] In addition, the present invention relates to a compound represented by the above formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0027] In the above chemical formula 1,

[0028] R1 is hydrogen, -CH2R3, -(CH2) 0-2 SO2-R3, -SO2(CH2) 0-2 R3, -C(=O)(CH2) 0-1 R3, -C(=O)CH2CN, -CH2CN or -Boc(t-butoxycarbonyl);

[0029] The above R3 is hydrogen, substituted or unsubstituted C1-C3 alkyl, halo C1-C3 alkyl, cyano, C1-C 10 Alkoxy, substituted or unsubstituted cyclopropyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted dibenzofuranyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolo[2,1-b]thiazolyl, substituted or unsubstituted pyrazoleo[5,1-b]thiazolyl, or substituted or unsubstituted imidazo[2,1-b]thiazolyl, and

[0030] The above-mentioned substituted alkyl, cyclopropyl, tetrahydropyranyl, benzodioxanyl, phenyl, pyridinyl, pyrazinyl, benzothiophenyl, indazolyl, quinolinyl, dibenzofuranyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolo[2,1-b]thiazolyl, pyrazoleo[5,1-b]thiazolyl, or imidazo[2,1-b]thiazolyl each have one or more hydrogen atoms that are halogen, hydroxy, cyano, C1-C3 alkyl, halo C1-C3 alkyl, C1-C 10 Substituted with alkoxy, -C(=O)C1-C3alkyl, -SO2F;

[0031] R2 is is;

[0032] R4 is hydrogen or -t-Boc(t-butoxycarbonyl) and;

[0033] m is independently 1 or 2, respectively;

[0034] n is an integer from 1 to 3.

[0035] In addition, the present invention relates to a compound represented by the above formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0036] In the above chemical formula 1,

[0037] R1 is -(CH2) 0-2 SO2-R3, -SO2(CH2) 0-2 R3, -C(=O)(CH2) 0-1 R3 or -C(=O)CH2CN and;

[0038] The above R3 is hydrogen, substituted or unsubstituted C1-C3 alkyl, halo C1-C3 alkyl, cyano, C1-C 10Alkoxy, substituted or unsubstituted cyclopropyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted dibenzofuranyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolo[2,1-b]thiazolyl, substituted or unsubstituted pyrazoleo[5,1-b]thiazolyl, or substituted or unsubstituted imidazo[2,1-b]thiazolyl, and

[0039] The above-mentioned substituted alkyl, cyclopropyl, tetrahydropyranyl, benzodioxanyl, phenyl, pyridinyl, pyrazinyl, benzothiophenyl, indazolyl, quinolinyl, dibenzofuranyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolo[2,1-b]thiazolyl, pyrazoleo[5,1-b]thiazolyl, or imidazo[2,1-b]thiazolyl each have one or more hydrogen atoms that are halogen, hydroxy, cyano, C1-C3 alkyl, halo C1-C3 alkyl, C1-C 10 Substituted with alkoxy, -C(=O)C1-C3alkyl, -SO2F;

[0040] R2 is is;

[0041] m are independently 1 or 2 and sum to an integer of 3;

[0042] n is an integer from 1 to 3.

[0043] In addition, the present invention relates to a compound represented by the above formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0044] In the above chemical formula 1,

[0045] R1 is -(CH2) 0-2SO2R3, -SO2(CH2) 0-2 R3, or -C(=O)(CH2) 0-1 It is R3;

[0046] The above R3 is hydrogen, substituted or unsubstituted C1-C3 alkyl, halo C1-C3 alkyl, cyano, C1-C 10 Alkoxy, substituted or unsubstituted cyclopropyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted dibenzofuranyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolo[2,1-b]thiazolyl, substituted or unsubstituted pyrazoleo[5,1-b]thiazolyl, or substituted or unsubstituted imidazo[2,1-b]thiazolyl, and

[0047] The above-mentioned substituted alkyl, cyclopropyl, tetrahydropyranyl, benzodioxanyl, phenyl, pyridinyl, pyrazinyl, benzothiophenyl, indazolyl, quinolinyl, dibenzofuranyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolo[2,1-b]thiazolyl, pyrazoleo[5,1-b]thiazolyl, or imidazo[2,1-b]thiazolyl each have one or more hydrogen atoms that are halogen, hydroxy, cyano, C1-C3 alkyl, halo C1-C3 alkyl, C1-C 10 Substituted with alkoxy, -C(=O)C1-C3alkyl, -SO2F;

[0048] R2 is is;

[0049] m are independently 1 or 2 and sum to an integer of 3;

[0050] n is an integer of 1.

[0051] More specifically, the compounds of the present invention are exemplified as follows:

[0052] N-(5-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 1);

[0053] N-(5-(1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide(compound 2);

[0054] N-(5-(2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 3);

[0055] N-(5-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 4);

[0056] N-(5-(1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide(compound 5);

[0057] N-(5-(2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 6);

[0058] tert-butyl 7-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (compound 7);

[0059] N-(5-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 8);

[0060] N-(5-(2-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 9);

[0061] tert-butyl 5-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridine-5-yl)isoindolin-2-carboxylate (compound 10);

[0062] N-(5-(isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 11);

[0063] N-(5-(2-(2-(methylsulfonyl)ethyl)isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 12);

[0064] N-(5-(2-(methylsulfonyl)isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 13);

[0065] N-(5-(2-(ethylsulfonyl)isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 14);

[0066] N-(5-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 15);

[0067] N-(5-(2-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 16);

[0068] tert-butyl 6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (compound 17);

[0069] N-(5-(1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide hydrochloride (compound 18);

[0070] N-(5-(2-acetyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 19);

[0071] N-(5-(2-nicotinoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 20);

[0072] N-(5-(2-((5-chloro-3-methylbenzo[b]thiophene-2-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 21);

[0073] N-(5-(2-(thiophene-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 22);

[0074] N-(5-(2-(quinoline-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 23);

[0075] N-(5-(2-(6-methylpicolinoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 24);

[0076] N-(5-(2-(isopropylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 25);

[0077] N-(5-(2-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 26);

[0078] N-(5-(2-(5-chloro-1H-indazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 27);

[0079] N-(5-(2-(3,4-difluorobenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 28);

[0080] N-(5-(2-((2-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 29);

[0081] N-(5-(2-((2,4-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 30);

[0082] N-(5-(2-(2-cyanoacetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 31);

[0083] N-(5-(2-(3-bromo-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 32);

[0084] N-(5-(2-((4-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 33);

[0085] N-(5-(2-((trifluoromethyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 34);

[0086] N-(5-(2-(1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 35);

[0087] N-(5-(2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 36);

[0088] N-(5-(2-(2-(2-bromophenyl)acetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 37);

[0089] N-(5-(2-(pyrazine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 38);

[0090] N-(5-(2-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 39);

[0091] N-(5-(2-(1H-indazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 40);

[0092] N-(5-(2-((5-fluoro-2-methylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 41);

[0093] N-(5-(2-(benzylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 42);

[0094] N-(5-(2-((1-methyl-1H-imidazole-4-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 43);

[0095] N-(5-(2-(4-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 44);

[0096] N-(5-(2-((4-bromo-2-methylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 45);

[0097] N-(5-(2-((2,5-dimethylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 46);

[0098] N-(5-(2-(2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 47);

[0099] N-(5-(2-(5-chloro-2-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 48);

[0100] N-(5-(2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 49);

[0101] N-(5-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 50);

[0102] N-(5-(2-((4-chlorobenzyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 51);

[0103] N-(5-(2-((4-bromo-2-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 52);

[0104] N-(5-(2-(pyridine-3-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 53);

[0105] N-(5-(2-(pyridine-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 54);

[0106] N-(5-(2-((4-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 55);

[0107] N-(5-(2-((5-chlorothiophene-2-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 56);

[0108] N-(5-(2-(dibenzo[b,d]furan-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 57);

[0109] N-(5-(2-((3-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 58);

[0110] N-(5-(2-((tetrahydro-2H-pyran-4-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 59);

[0111] N-(5-(2-((3-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 60);

[0112] N-(5-(2-((5-methylthiophene-2-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 61);

[0113] N-(5-(2-((3-cyano-5-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 62);

[0114] N-(5-(2-(thiophene-3-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 63);

[0115] N-(5-(2-(5-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 64);

[0116] N-(5-(2-(5-cyanothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 65);

[0117] N-(5-(2-(thiazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 66);

[0118] N-(5-(2-(2,4-dimethylthiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 67);

[0119] N-(5-(2-(4-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 68);

[0120] N-(5-(2-(4-methylthiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 69);

[0121] N-(5-(2-(cyanomethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 70);

[0122] 4-((6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)benzenesulfonyl fluoride (compound 71);

[0123] N-(5-(2-(2-chlorothiazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 72);

[0124] N-(5-(2-(isothiazol-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 73);

[0125] N-(5-(2-(pyrrolo[2,1-b]thiazole-6-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 74);

[0126] N-(5-(2-(thiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 75);

[0127] N-(5-(2-((6-chloroimidazo[2,1-b]thiazole-5-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 76);

[0128] N-(5-(2-(4-(trifluoromethyl)thiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 77);

[0129] N-(5-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 78);

[0130] (6-(2-amino-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3,4-dihydroisoquinoline-2(1H)-yl)(4-chlorothiazole-5-yl)methanone(compound 79);

[0131] tert-butyl 3-((5-(2-(4-chlorothiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)carbamoyl)azetidine-1-carboxylate (compound 80); and

[0132] N-(5-(2-(4-chlorothiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (Compound 81); is selected from the group consisting of

[0133] In addition, the present invention relates to a pharmaceutical composition for the prevention or treatment of cancer, rheumatoid arthritis, psoriatic arthritis, atopy, Crohn's disease, or ulcerative colitis, comprising as an active ingredient a compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0134] The above cancer may be a solid tumor or a blood cancer.

[0135] The above solid tumors may be selected from the group consisting of lung cancer, brain tumors, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cavity cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, gastric cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colorectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumors, penile cancer, prostate cancer, female genital tumors, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, and skin cancer, but are not specifically limited thereto. no.

[0136] The above blood cancers may be selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), Abelson oncogene-associated CML (Bcr-ABL translocation), myelodysplastic syndrome (MDS), acute B lymphoblastic leukemia (B-ALL), acute T lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myeloproliferative neoplasm (MPN), Richter syndrome, hairy cell leukemia (HCL), blastoplasmic plasma cell dendritic neoplasm (BPDCN), non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Hodgkin lymphoma, systemic mastocytosis, and Burkitt lymphoma, but are not particularly limited thereto.

[0137] Additionally, the following terms in the present invention have the following meanings unless otherwise indicated. Any undefined term has the meaning understood in the art.

[0138] The above term “halogen” means fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0139] The term “alkyl” above refers to a straight or branched hydrocarbon group with a single bond. Examples include methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, etc.

[0140] The above term “-Boc” means a tert-butoxycarbonyl group.

[0141] The term “alkoxy” above refers to an oxygen group to which a saturated hydrocarbon of a straight or branched chain with a single bond is bonded. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy, etc.

[0142] The above terms “cycloalkyl” or “cycloalkyl” refer to a saturated hydrocarbon group with a cyclic single bond. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0143] The above term “aryl” means an aromatic substituent having at least one ring having a shared pi electron system, including, for example, phenyl, benzyl, etc., but not limited thereto.

[0144] The above term “heterocycloalkyl” refers to a saturated hydrocarbon group with a single bond in a ring shape containing one or more heteroatoms such as N, O, or S, and includes, but is not limited to, tetrahydropyranyl, benzodioxanyl, tetrahydropyranyl, etc., depending on the number and type of heteroatoms included in the ring and the number of carbon atoms.

[0145] The above term “heteroaryl” refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and includes, but is not limited to, pyridinyl, pyrazinyl, benzothiophenyl, indazole, quinolinyl, dibenzofuranyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolo[2,1-b]thiazolyl, pyrazolo[5,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, etc., depending on the number and type of heteroatoms included in the ring and the number of carbon atoms.

[0146] The term “haloalkyl” above refers to an alkyl group substituted with one or more halogens, and the halogens and alkyls are as disclosed above. Depending on the number of halogen substitutions (1 to 3), it includes all meanings referred to as monohaloalkyl, dihaloalkyl, and trihaloalkyl, and specifically includes monofluoromethyl, difluoromethyl, difluoroethyl, 1,2-difluoropropyl, trifluoromethyl, trichloromethyl, trifluoroethyl, etc., but is not limited thereto.

[0147] In the present invention, the above-mentioned pharmaceutically acceptable salt refers to a salt or complex of Formula 1 having desirable biological activity. Examples of such salts are not limited thereto, but include acid addition salts formed from inorganic acids [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.], and 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, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid. It includes a salt formed from an organic acid. The compound may also be administered as a pharmaceutically acceptable quaternary salt known to those skilled in the art, in particular, chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate [e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate].The compound of Formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.

[0148] The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., adding an organic acid or an inorganic acid to produce a precipitate, filtering and drying it, or by vacuum distilling the solvent and excess acid, drying it, and crystallizing it under an organic solvent.

[0149] In addition, pharmaceutically acceptable metal salts can be produced using a base. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to produce sodium, potassium, or calcium salts as the metal salts. In addition, the corresponding salts are obtained by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0150] 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 diastereomers are included within the scope of the present invention.

[0151] The pharmaceutical composition according to the present invention can be formulated into a suitable form with a commonly used pharmaceutically acceptable carrier. “Pharmaceutically acceptable” means a composition that is physiologically acceptable and, when administered to humans, does not typically cause allergic reactions or similar reactions such as gastrointestinal disorders or dizziness. Additionally, the composition can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, as well as topical preparations, suppositories, and sterile injectable solutions, each according to conventional methods.

[0152] Carriers, excipients, and diluents that may be included in the above composition may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl parahydroxybenzoate, propyl parahydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulating, it is prepared using commonly used fillers, stabilizers, binders, disintegrants, surfactants, diluents, or excipients. Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing at least one excipient, for example, starch, microcrystalline cellulose, sucrose or lactose, low-substituted hydroxypropyl cellulose, hypromellose, etc. with the compound of the present invention. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid dosage forms for oral administration include suspensions, liquid formulations, emulsions, syrups, etc., and may include various excipients, for example, humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspension solvents. Witepsol, macrogol, Tween 61, cocoa paste, laurin paste, glycerol, gelatin, etc. may be used as bases for suppositories.To formulate a parenteral administration formulation, a tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof may be mixed with water to prepare a solution or suspension with sterile and / or adjuvants such as preservatives, stabilizers, hydrating agents or emulsifying promoters, salts and / or buffers for osmotic pressure regulation, and other therapeutically useful substances, and may be prepared in an ampoule or vial unit administration form.

[0153] The above pharmaceutical composition provides a pharmaceutical composition comprising a tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivative compound of Formula 1 and an excipient. The compound may be added in an amount preferably from 0.001% to 50% by weight, more preferably from 0.001% to 40% by weight, and most preferably from 0.001% to 30% by weight, based on the total weight of the composition.

[0154] A pharmaceutical composition comprising the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals, such as rats, livestock, and humans, via various routes. Any mode of administration may be anticipated, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura mater, or intracerebrovascular injection. The dosage will vary depending on the age, sex, and body weight of the subject to treatment, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the time of administration, the route of administration, the absorption, distribution, and excretion rates of the drug, the types of other drugs used, and the judgment of the prescriber. The determination of the dosage based on these factors is within the level of a person skilled in the art, and generally, the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferred dosage is from 1 mg / kg / day to 500 mg / kg / day. Administration may be performed once a day or divided into several doses. The above dosage does not limit the scope of the present invention in any way.

[0155] The present invention may provide a novel tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivative that selectively inhibits JAK1, and a pharmaceutical composition for the prevention or treatment of cancer, rheumatoid arthritis, psoriatic arthritis, atopy, Crohn's disease, or ulcerative colitis comprising the same as an active ingredient.

[0156] 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 introduced herein is provided to be thorough and complete and to sufficiently convey the concept of the present invention to those skilled in the art.

[0157] <Example 1. Synthesis of Tetrahydroisoquinoline or Isoindoline-Substituted [1,2,4]Triazolo[1,5-a]Pyridine Derivative Compounds and Confirmation of Physicochemical Properties>

[0158] Compounds 1 to 81 of the present invention synthesized various tetrahydroisoquinoline or isoindoline-substituted [1,2,4]triazolo[1,5-a]pyridine derivatives, and their physicochemical properties are as follows.

[0159] Compound 1. N-(5-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0160]

[0161] Step 1: Synthesis of 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 1-2-A)

[0162] TFAA (4.00 mL, 28.3 mmol) was added at room temperature to a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (Combi-blocks, ST-6471) (2.00 g, 9.43 mmol) dissolved in DCM (25 mL). When TEA (3.94 mL, 28.3 mmol) was added dropwise to this mixture using a syringe over 30 minutes in an ice bath, the generation of a colorless gas was observed, and the resulting yellow reaction mixture was stirred at room temperature for 2 hours. TLC indicated the consumption of the starting material. The reaction mixture was quenched with 50 mL of water, and the reaction mixture was placed in a separatory funnel and shaken to precipitate. The DCM layer was separated, and the remaining aqueous layer was extracted with DCM (50 mL x 2). The DCM layer was washed with 1 N HCl (aq) (50 mL) to remove excess TEA. The DCM layer was dried with sodium sulfate, filtered, and concentrated under vacuum. The residue was dried under high vacuum at room temperature for 12 hours to obtain compound 1-2-A (2.20 g, 7.14 mmol, 76%) as an ivory solid.

[0163] 1 H NMR (500 MHz, Chloroform-d) δ 7.42-7.30 (m, 2H), 7.11-7.04 (m, 1H), 4.77 (d,J= 25.9 Hz, 2H), 3.94-3.82 (m, 2H), 2.93 (q,J= 6.6 Hz, 2H).

[0164] Step 2: Synthesis of 2,2,2-trifluoro-1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 1-2)

[0165] B2Pin2 (89.0 mg, 0.350 mmol), Pd(dppf)Cl2 (12.0 mg, 0.0146 mmol), and AcOK (86.0 mg, 0.876 mmol) were placed in a flask under a nitrogen atmosphere. Next, compound 1-2-A (90.0 mg, 0.292 mmol) and 1,4-dioxane (6 mL) were added. The resulting mixture was microwaved at 110 °C for 2 hours. The crude reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (3 × 25 mL). The combined organic layer was washed with water (2 x 10 mL) and brine (2 x 10 mL), dried with MgSO4, and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using EA / Hex 50% to obtain compound 1-2 (80.0 mg, 0.225 mmol, 77%) in the form of a yellow oil.

[0166] LCMS 356.3 [M + H] +

[0167] 1H NMR (400 MHz, Chloroform-d) δ 7.71-7.62 (m, 1H), 7.49-7.37 (m, 1H), 7.26-7.14 (m, 1H), 4.90-4.75 (m, 2H), 3.99-3.83 (m, 2H), 3.09-2.94 (m, 2H), 1.37 (s, 6H), 1.29 (s, 6H).

[0168] Step 3: Synthesis of N-(5-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Compound 1)

[0169] A mixture of Na2CO3 (33.0 mg, 0.306 mmol) in water (2 mL) was added to a suspension of compound 1-1 (Merck, Catalog No: Chemscene, CS-0028305) (43.0 mg, 0.153 mmol), palladium catalyst (11.0 mg, 0.0153 mmol), and compound 1-2 (60.0 mg, 0.168 mmol) in dioxane (5 mL), and purged with nitrogen for 5 minutes. The resulting mixture was irradiated in a microwave at 110 °C for 90 minutes. The reaction mixture was filtered on a Celite bed, washed with dioxane, and concentrated under vacuum to obtain a crude mixture, which was further purified by silica gel column chromatography to obtain compound 1 (33.0 mg, 0.0768 mmol, 50%) as a white solid.

[0170] 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.95-7.86 (m, 2H), 7.75-7.67 (m, 2H), 7.42 (d, 1H), 7.29 (d,J= 6.6 Hz, 1H), 4.86 (d,J= 12.2 Hz, 2H), 3.92-3.85 (m, 2H), 3.06-2.99 (m, 2H), 2.09-1.97 (m, 1H), 0.85-0.79 (m, 4H).

[0171] Compound 2. N-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0172]

[0173] A solution of Compound 1 (30.0 mg, 0.0698 mmol) dissolved in THF (2 mL), MeOH (1 mL), and H2O (0.5 mL) was added, and lithium hydroxide monohydrate (5.90 mg, 0.139 mmol) was added at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. The crude reaction mixture was concentrated under vacuum, dissolved in water, acidified with 1 N HCl, and washed again with DCM (20 mL). The aqueous layer was basicized with NaHCO3, the aqueous layer was extracted with DCM (50 mL x 2), and then concentrated under vacuum to obtain Compound 2 (22.0 mg, 0.0659 mmol, 95%) as a white solid.

[0174] 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.77-7.61 (m, 4H), 7.28-7.21 (m, 2H), 3.91 (s, 2H), 2.99 (t,J= 6.0 Hz, 2H), 2.77 (t,J= 6.0 Hz, 2H), 2.09-1.99 (m, 1H), 1.26-1.14 (m, 1H), 0.84-0.78 (m, 4H).

[0175] Compound 3. N-(5-(2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0176]

[0177] Compound 2 (15.0 mg, 0.0449 mmol) and methylsulfonylethene (4.80 mg, 0.139 mmol) were added to dichloromethane and stirred at 35 °C for 14 hours. The solution was concentrated, and the reaction mixture was purified by column chromatography using 5% MeOH / DCM to obtain Compound 3 (15.0 mg, 0.0341 mmol, 76%) as a white solid.

[0178] LC / MS 440.4[M + H] +

[0179] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.78-7.65 (m, 4H), 7.32-7.23 (m, 2H), 3.71 (s, 2H), 3.42 (t,J= 6.7 Hz, 2H), 3.03 (s, 3H), 2.97-2.86 (m, 4H), 2.79 (t,J= 5.8 Hz, 2H), 2.01 (d,J= 14.2 Hz, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0180] Compound 4. N-(5-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0181]

[0182] Step 1: Synthesis of 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 4-1-A)

[0183] TFAA (3.30 mL, 23.5 mmol) was added at room temperature to a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (Combi-blocks, QA-0847) (2.00 g, 9.42 mmol) dissolved in DCM (25 mL). When TEA (3.27 mL, 23.5 mmol) was added dropwise to this mixture using a syringe over 30 minutes in an ice bath, the generation of a colorless gas was observed, and the resulting yellow reaction mixture was stirred at room temperature for 2 hours. TLC indicated the consumption of the starting material. The reaction mixture was quenched with 50 mL of water, and the reaction mixture was placed in a separatory funnel and shaken to precipitate. The DCM layer was separated, and the remaining aqueous layer was extracted with DCM (50 mL x 2). The DCM layer was washed with 1 N HCl (aq) (50 mL) to remove excess TEA. The DCM layer was dried with sodium sulfate, filtered, and concentrated under vacuum. The residue was dried under high vacuum at room temperature for 12 hours to obtain compound 4-1-A (2.50 g, 8.11 mmol, 86%) as an ivory solid.

[0184] 1H NMR (400 MHz, Chloroform-d) δ 7.42-7.32 (m, 2H), 7.09-6.99 (m, 1H), 4.74 (d,J= 18.9 Hz, 2H), 3.93-3.82 (m, 2H), 2.96 (q,J= 5.8 Hz, 2H).

[0185] Step 2: Synthesis of 2,2,2-trifluoro-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 4-1)

[0186] B2Pin2 (33.0 mg, 0.129 mmol), Pd(dppf)Cl2 (3.00 mg, 0.00324 mmol), and AcOK (19.0 mg, 0.194 mmol) were placed in a flask under a nitrogen atmosphere. Next, compound 4-1-A (20.0 mg, 0.0649 mmol) and DMF (2 mL) were added. The resulting mixture was microwaved at 110 °C for 2 hours. The crude reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (3 × 25 mL). The combined organic layer was washed with water (2 x 10 mL) and brine (2 x 10 mL), dried with MgSO4, and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using EA / Hex 50% to obtain compound 4-1 (12.0 mg, 0.0337 mmol, 52%) in the form of a yellow oil.

[0187] LCMS 356.3 [M + H] +

[0188] 1H NMR (300 MHz, Chloroform-d) δ 7.73-7.60 (m, 1H), 7.50-7.35 (m, 1H), 7.27-7.12 (m, 1H), 4.89-4.76 (m, 2H), 4.00-3.82 (m, 2H), 3.10-2.92 (m, 2H), 1.37 (s, 6H), 1.28 (s, 6H).

[0189] Step 3: Synthesis of N-(5-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Compound 4)

[0190] A mixture of Na2CO3 (38.0 mg, 0.358 mmol) in water (2 mL) was added to a suspension of compound 1-1 (50.0 mg, 0.179 mmol), palladium catalyst (13.0 mg, 0.0179 mmol), and compound 4-1 (70.0 mg, 0.195 mmol) in dioxane (5 mL), and purged with nitrogen for 5 minutes. The resulting mixture was irradiated in a microwave at 110 °C for 40 minutes. The reaction mixture was filtered on a Celite bed, washed with dioxane, and concentrated under vacuum to obtain a crude mixture, which was further purified by column chromatography using 5% DCM:MeOH to obtain compound 4 (52.0 mg, 0.0768 mmol, 32%) as a white solid.

[0191] LC / MS 430.4[M + H] +

[0192] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (d, J= 72.6 Hz, 1H), 7.91-7.82 (m, 1H), 7.75-7.69 (m, 1H), 7.66-7.51 (m, 2H), 7.51-7.44 (m, 1H), 7.30-7.27 (m, 1H), 4.87 (d,J= 12.0 Hz, 2H), 3.91-3.85 (m, 2H), 3.04-2.98 (m, 2H), 2.09 (s, 1H), 0.88-0.80 (m, 4H).

[0193] Compound 5. N-(5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0194]

[0195] A solution of Compound 4 (40 mg, 0.093 mmol) was added to THF (2 mL), MeOH (1 mL), and H2O (0.5 mL), and lithium hydroxide monohydrate (8.0 mg, 0.18 mmol) was added at room temperature, followed by stirring the reaction mixture at room temperature for 4 hours. The crude reaction mixture was concentrated under vacuum, dissolved in water, acidified with 1N HCl, and washed again with DCM (20 mL). The aqueous layer was basicized with NaHCO3, the aqueous layer was extracted with DCM (50 mL x 2), and then concentrated under vacuum to obtain Compound 5 (22 mg, 0.065 mmol, 45%) as a white solid.

[0196] LC / MS 334.4[M + H] +

[0197] 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.79 - 7.58 (m, 4H), 7.28 - 7.23 (m, 1H), 7.19 (d,J= 8.0 Hz, 1H), 3.93 (s, 2H), 2.99 (t,J= 5.8 Hz, 2H), 2.77 (t,J= 5.8 Hz, 2H), 2.05 (s, 1H), 0.85 - 0.79 (m, 4H).

[0198] Compound 6. N-(5-(2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0199]

[0200] (Methylsulfonyl)ethene (7.00 mg, 0.0607 mmol) was added dropwise to a solution of Compound 18 (15.0 mg, 0.0405 mmol) and triethylamine (9.00 mg, 0.0810 mmol) stirred in DCM (5 mL) at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 6 (11.0 mg, 0.0250 mmol, 62%) as a white solid.

[0201] LC / MS 440.4 [M + H] +

[0202] 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.80-7.65 (m, 4H), 7.29-7.20 (m, 2H), 3.74 (s, 2H), 3.43 (t,J= 6.8 Hz, 2H), 3.04 (s, 3H), 2.97-2.87 (m, 4H), 2.80 (t,J= 5.8 Hz, 2H), 2.09-1.92 (m, 1H), 0.82 (d,J= 5.5 Hz, 4H).

[0203] Compound 7. tert-butyl 7-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0204]

[0205] A mixture of Na2CO3 (38.0 mg, 0.354 mmol) dissolved in water (2 mL) was added to a suspension of Compound 1-1 (50.0 mg, 0.177 mmol), palladium catalyst (13.0 mg, 0.0177 mmol), and Compound 7-1 (Chemscene, CS-W000580) (70.0 mg, 0.195 mmol) suspended in dioxane (5 mL), and purged with nitrogen for 5 minutes. The resulting mixture was irradiated in a microwave at 110 °C for 40 minutes. The reaction mixture was filtered on a Celite bed, washed with dioxane, and concentrated under vacuum to obtain a crude mixture, which was further purified by silica gel column chromatography to obtain Compound 7 (45 mg, mmol, 65%) as a white solid.

[0206] LC / MS 434.5 [M + H] +

[0207] 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.82 (d,J= 7.8 Hz, 2H), 7.75-7.62 (m, 2H), 7.40-7.23 (m, 2H), 4.59 (s, 2H), 3.61 (t,J= 5.8 Hz, 2H), 2.88 (t,J= 6.0 Hz, 2H), 2.05 (s, 1H), 1.45 (s, 9H), 0.82 (d,J= 6.2 Hz, 4H).

[0208] Compound 8. N-(5-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0209]

[0210] Step 1: Synthesis of N-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Compound 8-1)

[0211] 4 N HCl dissolved in dioxane (0.5 ml) was added to a solution of Compound 7 (45.0 mg, 0.103 mmol) dissolved in DCM (2 ml). The reaction mixture was stirred at room temperature for 2 hours. The crude material was concentrated under vacuum, and the resulting oil was dissolved in water and then washed with DCM (10 mL). The aqueous layer was then basicized with saturated NaHCO3, the aqueous layer was extracted with DCM (20 mL), and then concentrated under vacuum to obtain Compound 8-1 (30 mg, 0.0899 mmol, 86%) as a white solid.

[0212] LC / MS 334.1 [M + H] +

[0213] 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.80-7.58 (m, 4H), 7.33-7.15 (m, 2H), 3.91 (s, 2H), 3.00 (d, J = 5.9 Hz, 2H), 2.77 (t, J = 5.8) Hz, 2H), 2.04 (s, 1H), 0.89-0.72 (m, 4H).

[0214] Step 2: Synthesis of N-(5-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Compound 8)

[0215] Methanesulfonyl chloride (7.70 mg, 0.0673 mmol) was added dropwise to a solution of Compound 8-1 (15.0 mg, 0.0449 mmol) and triethylamine (9.10 mg, 0.0898 mmol) stirred in DCM (5 mL) at 0°C, the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Compound 8 (18.0 mg, 0.0437 mmol, 97%) as a white solid.

[0216] LC / MS 412.4 [M + H] +

[0217] 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.90-7.81 (m, 2H), 7.76-7.67 (m, 2H), 7.39 (d,J= 8.1 Hz, 1H), 7.32-7.27 (m, 1H), 4.46 (s, 2H), 3.50 (t,J= 6.0 Hz, 2H), 3.01 (d,J= 15.1 Hz, 5H), 2.04 (s, 1H), 0.83 (d,J= 6.2 Hz, 4H).

[0218] Compound 9. N-(5-(2-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0219]

[0220] Ethanolsulfonyl chloride (8.70 mg, 0.0673 mmol) was added dropwise to a solution of compound 8-1 (15.0 mg, 0.0449 mmol) and triethylamine (9.10 mg, 0.0898 mmol) stirred in DCM (5 mL) at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 9 (18.3 mg, 0.0430 mmol, 96%) as a white solid.

[0221] LC / MS 426.4 [M + H] +

[0222] 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.90-7.79 (m, 2H), 7.75-7.65 (m, 2H), 7.38 (d,J= 8.1 Hz, 1H), 7.29 (d,J= 6.8 Hz, 1H), 4.51 (s, 2H), 3.57 (t,J= 6.0 Hz, 2H), 3.17 (q,J= 7.4 Hz, 2H), 2.99 (t,J= 5.8 Hz, 2H), 2.03 (s, 1H), 1.24 (t,J= 7.3 Hz, 3H), 0.83 (d,J=6.2 Hz, 4H).

[0223] Compound 10. tert-butyl 5-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)isoindoline-2-carboxylate

[0224]

[0225] A mixture of Na2CO3 (76.0 mg, 0.710 mmol) in water (2 mL) was added to a suspension of compound 1-1 (100 mg, 0.355 mmol), palladium catalyst (25.0 mg, 0.0355 mmol), and compound 10-1 (Chemscene, CS-W023015) (147 mg, 0.426 mmol) in dioxane (5 mL), and purged with nitrogen for 5 minutes. The resulting mixture was irradiated in a microwave at 110 °C for 40 minutes. The reaction mixture was filtered on a Celite bed, washed with dioxane, and concentrated under vacuum to obtain a crude mixture, which was further purified by column chromatography using 5% DCM:MeOH to obtain compound 10 (107 mg, 0.255 mmol, 72%) as a white solid.

[0226] LC / MS 420.9 [M + H] +

[0227] 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.93 (d, J= 6.3 Hz, 2H), 7.76-7.65 (m, 2H), 7.55-7.49 (m, 1H), 7.30-7.24 (m, 1H), 4.68 (t,J= 10.7 Hz, 4H), 2.03 (s, 1H), 1.49 (s, 9H), 0.82 (d,J= 5.4 Hz, 4H).

[0228] Compound 11. N-(5-(isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0229]

[0230] 4 N HCl dissolved in dioxane (1 ml) was added to a solution of Compound 10 (90.0 mg, 0.214 mmol) dissolved in DCM (2 ml). The reaction mixture was stirred overnight at room temperature. The crude product was vacuum concentrated, the resulting crude product was dissolved in water, and then washed with DCM (10 mL). The aqueous layer was then basicized with saturated NaHCO3, the aqueous layer was extracted with DCM (20 mL), and then vacuum concentrated to obtain Compound 11 (45.0 mg, 0.140 mmol, 66%) as a white solid.

[0231] LC / MS 320.4 [M + H] +

[0232] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.95-7.77 (m, 2H), 7.73-7.64 (m, 2H), 7.64-7.54 (m, 1H), 7.45 (d,J= 7.8 Hz, 1H), 7.26 (d,J= 7.8 Hz, 1H), 4.16 (s, 4H), 2.01 (d,J= 13.1 Hz, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0233] Compound 12. N-(5-(2-(2-(methylsulfonyl)ethyl)isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0234]

[0235] Compound 11 (10.0 mg, 0.0313 mmol) and methylsulfonylethene (6.64 mg, 0.0626 mmol) were added to dichloromethane and stirred at 35 °C for 14 hours. The solution was concentrated, and the reaction mixture was purified by silica gel column chromatography using 5% MeOH / DCM to obtain Compound 12 (4.3 mg, 0.0101 mmol, 33%) as a white solid.

[0236] LC / MS 426.4 [M + H] +

[0237] 1 H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.86 (s, 1H), 7.82 (d,J= 7.7 Hz, 1H), 7.75-7.65 (m, 2H), 7.44 (d,J= 7.8 Hz, 1H), 7.27 (dd,J= 6.2, 2.3 Hz, 1H), 4.01 (s, 4H), 3.41 (t,J= 6.8 Hz, 2H), 3.15 (t,J= 6.8 Hz, 2H), 3.06 (s, 3H), 2.03-1.91 (m, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0238] Compound 13. N-(5-(2-(methylsulfonyl)isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0239]

[0240] Compound 11 (10.0 mg, 0.0313 mmol) and triethylamine (6.40 mg, 0.0626 mmol) were added to DCM (5 mL) and stirred at 0 °C. Methanesulfonyl chloride (5.40 mg, 0.0469 mmol) was added dropwise to the solution, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous solution was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Compound 13 (7.2 mg, 0.0181 mmol, 58%) as a white solid.

[0241] LC / MS 398.4 [M + H] +

[0242] 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.95 (d,J= 9.4 Hz, 2H), 7.77-7.67 (m, 2H), 7.53 (d,J= 7.9 Hz, 1H), 7.31-7.24 (m, 1H), 4.73 (d,J= 4.6 Hz, 4H), 3.03 (s, 3H), 2.02 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0243] Compound 14. N-(5-(2-(ethylsulfonyl)isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0244]

[0245] Ethanolsulfonyl chloride (9.10 mg, 0.0703 mmol) was added dropwise to a solution of Compound 11 (15.0 mg, 0.0469 mmol) and triethylamine (9.50 mg, 0.0939 mmol) stirred in DCM (5 mL) at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Compound 14 (12.0 mg, 0.0291 mmol, 62%) as a white solid.

[0246] LC / MS 412.4 [M + H] +

[0247] 1 H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.00-7.90 (m, 2H), 7.76-7.68 (m, 2H), 7.53 (d,J= 8.0 Hz, 1H), 7.28 (dd,J= 6.3, 2.2 Hz, 1H), 4.81-4.68 (m, 4H), 3.24 (q,J= 7.4 Hz, 2H), 2.08-1.93 (m, 1H), 1.26 (t,J= 7.4 Hz, 3H), 0.82 (d,J= 6.2 Hz, 4H).

[0248] Compound 15. N-(5-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0249]

[0250] Methanesulfonyl chloride (7.00 mg, 0.0607 mmol) was added dropwise to a solution of Compound 18 (15.0 mg, 0.0405 mmol) and triethylamine (9.00 mg, 0.0810 mmol) stirred in DCM (5 mL) at 0 °C, the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 15 (9.6 mg, 0.0233 mmol, 58%) as a white solid.

[0251] LC / MS 412.4 [M + H] +

[0252] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.90-7.79 (m, 2H), 7.76-7.67 (m, 2H), 7.39 (d,J= 8.1 Hz, 1H), 7.29 (dd,J= 6.5, 2.1 Hz, 1H), 4.48 (s, 2H), 3.50 (t,J= 5.9 Hz, 2H), 3.00 (d,J= 2.9 Hz, 5H), 2.03 (s, 1H), 0.89-0.71 (m, 4H).

[0253] Compound 16. N-(5-(2-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0254]

[0255] Ethanolsulfonyl chloride (8.00 mg, 0.0607 mmol) was added dropwise to a solution of Compound 18 (15.0 mg, 0.0405 mmol) and triethylamine (9.00 mg, 0.0810 mmol) stirred in DCM (5 mL) at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 16 (12.5 mg, 0.0293 mmol, 73%) as a white solid.

[0256] LC / MS 426.4 [M + H] +

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.88-7.80 (m, 2H), 7.74-7.66 (m, 2H), 7.37 (d,J= 8.1 Hz, 1H), 7.29 (dd,J= 6.6, 2.1 Hz, 1H), 4.53 (s, 2H), 3.57 (t,J= 5.9 Hz, 2H), 3.18 (q,J= 7.3 Hz, 2H), 2.97 (t,J= 5.9 Hz, 2H), 2.10-1.89 (m, 1H), 1.24 (t,J= 7.4 Hz, 3H), 0.90-0.70 (m, 4H).

[0258] Compound 17. tert-butyl 6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0259]

[0260] A mixture of Na2CO3 (124 mg, 1.17 mmol) dissolved in water (2 mL) was introduced into a suspension of Compound 1-1 (150 mg, 0.533 mmol), palladium catalyst (37.0 mg, 0.0533 mmol), and Compound 17-1 (BLD Pharmatech, BC152964) (287 mg, 0.800 mmol) dissolved in dioxane (5 mL), and purged with nitrogen for 5 minutes. The resulting mixture was microwaved at 110 °C for 40 minutes. The reaction mixture was filtered on a Celite bed, washed with dioxane, and concentrated under vacuum to obtain a crude mixture, which was further purified by silica gel column chromatography to obtain Compound 17 (170 mg, 0.392 mmol, 73%) as a white solid.

[0261] LC / MS 434.5 [M + H] +

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.86-7.77 (m, 2H), 7.75-7.65 (m, 2H), 7.37 (d,J= 8.1 Hz, 1H), 7.27 (dd,J= 6.5, 2.0 Hz, 1H), 4.60 (s, 2H), 3.61 (t,J= 5.8 Hz, 2H), 2.86 (t,J= 6.0 Hz, 2H), 2.04 (s, 1H), 1.45 (s, 9H), 0.82 (d,J= 6.2 Hz, 4H).

[0263] Compound 18. N-(5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide hydrochloride

[0264]

[0265] 4 N HCl dissolved in dioxane (1.5 ml) was added to a solution of compound 17 (45.0 mg, 0.103 mmol) dissolved in DCM (5 ml). The reaction mixture was stirred overnight. The crude product was concentrated under vacuum, the resulting crude product was washed with ether and dried under vacuum to obtain compound 18 (35.0 mg, 0.0950 mmol, 91%) as a white solid.

[0266] LC / MS 334.4 [M + H] +

[0267] 1 H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.63 (s, 2H), 7.86 (d,J= 6.7 Hz, 2H), 7.80-7.70 (m, 2H), 7.42 (d,J= 8.3 Hz, 1H), 7.34 (dd,J= 7.0, 1.6 Hz, 1H), 4.36 (d,J= 4.6 Hz, 2H), 3.47-3.35 (m, 2H), 3.10 (t,J= 6.2 Hz, 2H), 2.04 (s, 1H), 0.90 -0.74 (m, 4H).

[0268] Compound 19. N-(5-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0269]

[0270] Acetic anhydride (9.00 mg, 0.0810 mmol) was added dropwise to a solution of Compound 18 (15.0 mg, 0.0405 mmol) and triethylamine (17.0 mg, 0.162 mmol) stirred in DCM (5 mL) at 0 °C, the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 19 (12.0 mg, 0.0319 mmol, 79%) as a white solid.

[0271] LC / MS 376.4 [M + H] +

[0272] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.91-7.76 (m, 2H), 7.74-7.64 (m, 2H), 7.43-7.34 (m, 1H), 7.30-7.18 (m, 1H), 4.72 (d,J= 24.7 Hz, 2H), 3.72 (t,J= 5.9 Hz, 2H), 2.95 (t,J= 5.9 Hz, 1H), 2.84 (t,J= 5.9 Hz, 1H), 2.12 (d,J= 2.7 Hz, 4H), 0.82 (d,J= 6.3 Hz, 4H).

[0273] Compound 20. N-(5-(2-nicotinoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0274]

[0275] Dipea (21.0 mg, 0.162 mmol) was added to a suspension of nicotinic acid (5.50 mg, 0.0445 mmol) in DMF (2 mL), followed by the addition of HATU (39.0 mg, 0.101 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (15.0 mg, 0.0405 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 20 (8.00 mg, 0.0182 mmol, 45%) as a beige solid.

[0276] LC / MS 439.4 [M + H] +

[0277] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.81-8.59 (m, 2H), 8.06-7.61 (m, 5H), 7.58-7.19 (m, 3H), 4.79 (d,J= 81.6 Hz, 2H), 3.93 (s, 1H), 3.63 (s, 1H), 2.97 (s, 2H), 2.02 (d,J= 16.9 Hz, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0278] Compound 21. N-(5-(2-((5-chloro-3-methylbenzo[b]thiophen-2-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0279]

[0280] Compound 18 (30.0 mg, 0.0810 mmol) and triethylamine (24.62 mg, 0.243 mmol) were added to DCM (5 mL) and stirred at 0 °C. To the solution, 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (34.2 mg, 0.122 mmol) was added dropwise, the resulting solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 21 (35.0 mg, 0.081 mmol, 74.6%) as a white solid.

[0281] LC / MS 579.3 [M + H] +

[0282] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.21-8.03 (m, 2H), 7.90-7.55 (m, 5H), 7.41 (d,J= 8.2 Hz, 1H), 7.28-7.17 (m, 1H), 4.53 (s, 2H), 3.59 (t,J= 5.9 Hz, 2H), 3.05-2.86 (m, 2H), 2.72 (s, 3H), 2.02 (s, 1H), 0.81 (d,J= 6.2 Hz, 4H).

[0283] Compound 22. N-(5-(2-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0284]

[0285] Thiophene-2-sulfonyl chloride (22.2 mg, 0.122 mmol) was added dropwise to a solution of compound 18 (30.0 mg, 0.0810 mmol) and triethylamine (24.62 mg, 0.243 mmol) stirred in DCM (5 mL) at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain compound 22 (34.0 mg, 0.0710 mmol, 87%) as a white solid.

[0286] LC / MS 480.3 [M + H] +

[0287] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.11-8.04 (m, 1H), 7.85 (d,J= 8.1 Hz, 1H), 7.80-7.63 (m, 4H), 7.40 (d,J= 8.2 Hz, 1H), 7.34-7.22 (m, 2H), 4.36 (s, 2H), 3.39 (t,J= 5.9 Hz, 2H), 2.98 (t,J= 6.1 Hz, 2H), 2.03 (s, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0288] Compound 23. N-(5-(2-(quinoline-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0289]

[0290] Dipaea (42.0 mg, 0.324 mmol) was added to a suspension of quinoline-3-carboxylic acid (15.4 mg, 0.0890 mmol) in DMF (5 mL), followed by the addition of HATU (77.0 mg, 0.203 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (30.0 mg, 0.0810 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 23 (10.0 mg, 0.0200 mmol, 26%) as a beige solid.

[0291] LC / MS [M + H] +

[0292] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.00 (s, 1H), 8.58 (s, 1H), 8.11 (d, J= 8.5 Hz, 2H), 7.96-7.63 (m, 5H), 7.52 (s, 1H), 7.29 (s, 1H), 4.88 (d,J= 56.7 Hz, 2H), 3.99 (s, 1H), 3.74 (s, 1H), 3.02 (s, 2H), 2.02 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0293] Compound 24. N-(5-(2-(6-methylpicolinoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0294]

[0295] DIPEA (42.0 mg, 0.324 mmol) was added to a suspension of 6-methylpicolinic acid in DMF (5 mL), followed by the addition of EDCl and HOBt at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (30.0 mg, 0.0810 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 24 (24 mg, 0.053 mmol, 65%) as a beige solid.

[0296] LC / MS [M + H] +

[0297] 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.17 - 7.58 (m, 5H), 7.58 - 7.04 (m, 4H), 4.90 (s, 1H), 4.72 (s, 1H), 3.93 (t,J= 6.0 Hz, 1H), 3.67 (t,J= 5.7 Hz, 1H), 2.98 (dt,J= 11.2, 5.8 Hz, 2H), 2.53 (s, 3H), 2.22 - 1.81 (m, 1H), 1.09 - 0.36 (m, 4H).

[0298] Compound 25. N-(5-(2-(isopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0299]

[0300] Propane-2-sulfonyl chloride (21.8 mg, 0.216 mmol) was added dropwise to a solution of Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (11.5 mg, 0.0810 mmol) stirred in DCM (5 mL) at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 25 (6.0 mg, 0.014 mmol, 25.2%) as a white solid.

[0301] LC / MS [M + H] +

[0302] 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.89-7.71 (m, 2H), 7.76-7.61 (m, 2H), 7.36 (d,J= 7.9 Hz, 1H), 7.33-7.24 (m, 1H), 4.57 (s, 1H), 3.62 (t,J= 5.9 Hz, 2H), 3.54-3.34 (m, 2H), 2.95 (t,J= 5.7 Hz, 2H), 2.08-1.89 (m, 1H), 1.27 (d,J= 6.8 Hz, 6H), 0.82 (d,J= 6.3 Hz, 4H).

[0303] Compound 26. N-(5-(2-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0304]

[0305] Cyclopropanesulfonyl chloride (11.4 mg, 0.0810 mmol) was added dropwise to a solution of compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) stirred in DMF (5 mL) at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain compound 26 (18.4 mg, 0.042 mmol, 78%) as a white solid.

[0306] LC / MS 438.4 [M + H] +

[0307] 1 H NMR (300 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.92 - 7.80 (m, 2H), 7.75 - 7.64 (m, 2H), 7.40 (d,J= 8.1 Hz, 1H), 7.33 - 7.24 (m, 1H), 4.54 (s, 2H), 3.58 (t,J= 5.9 Hz, 2H), 3.00 (t,J= 5.8 Hz, 2H), 2.75 - 2.61 (m, 1H), 2.04 (s, 1H), 1.07 - 0.94 (m, 4H), 0.82 (d,J= 6.2 Hz, 4H).

[0308] Compound 27. N-(5-(2-(5-chloro-1H-indazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0309]

[0310] DIPEA (28.0 mg, 0.216 mmol) was added to a suspension of 5-chloro-1H-indazole-3-carboxylic acid (11.6 mg, 0.0590 mmol) in DMF (2 mL), followed by the addition of EDCl (12.4 mg, 0.0650 mmol) and HOBt (8.77 mg, 0.0650 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (20.0 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain a prepared mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain compound 27 (8.8 mg, 0.017 mmol, 31.8%) as a beige solid.

[0311] LC / MS 512.2 [M + H] +

[0312] 1 H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.03 (s, 1H), 8.01 - 7.91 (m, 2H), 7.84 (d, J= 2.2 Hz, 1H), 7.83 - 7.79 (m, 1H), 7.72 - 7.68 (m, 1H), 7.53 - 7.46 (m, 1H), 7.41 (d,J= 8.5 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.23 - 7.16 (m, 1H), 4.94 (s, 2H), 3.94 (t,J= 5.8 Hz, 2H), 3.02 (d,J= 5.8 Hz, 2H), 1.98 (t,J= 10.5 Hz, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0313] Compound 28. N-(5-(2-(3,4-difluorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0314]

[0315] DIPEA (28.0 mg, 0.216 mmol) was added to a suspension of 3,4-difluorobenzoic acid (8.55 mg, 0.0540 mmol) in DMF (2 mL), followed by the addition of EDCl (12.4 mg, 0.0650 mmol) and HOBt (8.77 mg, 0.0650 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (20.0 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain compound 28 (21.5 mg, 0.045 mmol, 84%) as a white solid.

[0316] LC / MS 474.4 [M + H] +

[0317] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.85 (d, J= 18.4 Hz, 2H), 7.75-7.51 (m, 4H), 7.50-7.17 (m, 3H), 4.85 (s, 1H), 4.67 (s, 1H), 3.89 (s, 1H), 3.62 (s, 1H), 2.96 (s, 2H), 2.06 (d,J= 23.1 Hz, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0318] Compound 29. N-(5-(2-((2-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0319]

[0320] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. To the solution, 2-cyanobenzenesulfonyl chloride (16.35 mg, 0.0810 mmol) was added dropwise, the resulting solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 29 (15 mg, 0.030 mmol, 55.6%) as a white solid.

[0321] LC / MS 499.4 [M + H] +

[0322] 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.23-8.11 (m, 2H), 8.01-7.87 (m, 2H), 7.83 (d,J= 8.6 Hz, 1H), 7.78 (s, 1H), 7.74-7.64 (m, 2H), 7.35 (d,J= 8.2 Hz, 1H), 7.30-7.20 (m, 1H), 4.53 (s, 2H), 3.63 (t,J= 5.9 Hz, 2H), 2.96 (t,J= 5.8 Hz, 2H), 2.02 (s, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0323] Compound 30. N-(5-(2-((2,4-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0324]

[0325] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. To the solution, 2,4-dichlorobenzene-sulfonyl chloride (19.91 mg, 0.0810 mmol) was added dropwise, the resulting solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 30 (24 mg, 0.044 mmol, 82%) as a white solid.

[0326] LC / MS 544.2 [M + H] +

[0327] 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.09 (d,J= 8.6 Hz, 1H), 7.94 (d,J= 2.1 Hz, 1H), 7.86-7.78 (m, 2H), 7.75-7.63 (m, 3H), 7.37 (d,J= 8.1 Hz, 1H), 7.31-7.23 (m, 1H), 4.58 (s, 2H), 3.64 (t,J= 5.9 Hz, 2H), 2.92 (t,J= 5.8 Hz, 2H), 2.09 (s, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0328] Compound 31. N-(5-(2-(2-cyanoacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0329]

[0330] DIPEA (56.0 mg, 0.433 mmol) was added to a suspension of 2-cyanoacetic acid (11.0 mg, 0.130 mmol) in DMF (5 mL), followed by the addition of HATU (82.0 mg, 0.216 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (40.0 mg, 0.108 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 31 (20 mg, 0.050 mmol, 46.2%) as a white solid.

[0331] LC / MS 401.4 [M + H] +

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.83 (t,J= 9.1 Hz, 2H), 7.78-7.60 (m, 2H), 7.49-7.19 (m, 2H), 4.71 (d,J= 12.2 Hz, 2H), 4.18 (s, 2H), 3.82-3.53 (m, 2H), 3.07-2.77 (m, 2H), 2.02 (d,J= 17.6 Hz, 1H), 0.82 (d,J= 6.3 Hz, 4H).

[0333] Compound 32. N-(5-(2-(3-bromo-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0334]

[0335] 3-bromo-2-methylbenzoic acid (12.7 mg, 0.0590 mmol) was suspended in DMF (5 mL), followed by the addition of DIPEA (28.0 mg, 0.216 mmol), and then HATU (41.1 mg, 0.108 mmol) was added at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (20.0 mg, 0.540 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 32 (22 mg, 0.041 mmol, 77%) as a white solid.

[0336] LC / MS 531.4 [M + H] +

[0337] 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.91 - 7.82 (m, 1H), 7.79 (d,J= 8.5 Hz, 1H), 7.75 - 7.65 (m, 3H), 7.48 (d,J= 8.1 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.24 (d,J= 4.4 Hz, 2H), 5.10 - 4.76 (m, 1H), 4.44 (d,J= 4.5 Hz, 1H), 4.05 - 3.85 (m, 1H), 3.44 (t,J= 6.0 Hz, 1H), 3.00 (s, 1H), 2.94 - 2.74 (m, 1H), 2.26 (d,J= 30.8 Hz, 3H), 2.04 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0338] Compound 33. N-(5-(2-((4-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0339]

[0340] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. Then, 4-acetylbenzenesulfonyl chloride (17.74 mg, 0.0810 mmol) was added dropwise to the solution, the resulting solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 33 (21 mg, 0.041 mmol, 75%) as a white solid.

[0341] LC / MS 516.4 [M + H] +

[0342] 1 H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.18 (d,J= 8.4 Hz, 2H), 8.01 (d,J= 8.3 Hz, 2H), 7.83 (d,J= 8.4 Hz, 1H), 7.76 (s, 1H), 7.74-7.64 (m, 2H), 7.36 (d,J= 8.2 Hz, 1H), 7.28-7.21 (m, 1H), 4.38 (s, 2H), 3.44 (t,J= 5.9 Hz, 2H), 2.95 (d,J= 5.8 Hz, 2H), 2.64 (s, 3H), 2.02 (s, 1H), 0.81 (d,J= 6.2 Hz, 4H).

[0343] Compound 34. N-(5-(2-((trifluoromethyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0344]

[0345] Trifluoromethanesulfonyl chloride (13.67 mg, 0.0810 mmol) was added dropwise to a solution of compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) stirred in DMF (5 mL) at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain compound 34 (10 mg, 0.021 mmol, 39.7%) as a white solid.

[0346] LC / MS 466.4 [M + H] +

[0347] 1 H NMR (300 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.94-7.83 (m, 2H), 7.77-7.65 (m, 2H), 7.45 (d,J= 8.1 Hz, 1H), 7.36-7.24 (m, 1H), 4.82 (s, 2H), 3.85 (d,J= 6.3 Hz, 2H), 3.04 (t,J= 6.0 Hz, 2H), 2.24-1.81 (m, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0348] Compound 35. N-(5-(2-(1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0349]

[0350] DIPEA (28.0 mg, 0.216 mmol) was added to a suspension of 1H-pyrrole-2-carboxylic acid (6.61 mg, 0.0590 mmol) in DMF (2 mL), followed by the addition of EDCl (12.4 mg, 0.0650 mmol) and HOBt (8.77 mg, 0.0650 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (20.0 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain compound 35 (13 mg, 0.030 mmol, 56.4%) as a white solid.

[0351] LC / MS 427.4 [M + H]+

[0352] 1 H NMR (300 MHz, DMSO-d6) δ 11.54 (s, 1H), 11.03 (s, 1H), 7.85 (d,J= 7.2 Hz, 2H), 7.76-7.58 (m, 2H), 7.45 (d,J= 8.2 Hz, 1H), 7.32-7.18 (m, 1H), 7.02-6.83 (m, 1H), 6.68 (s, 1H), 6.26-6.00 (m, 1H), 4.94 (s, 2H), 4.04-3.81 (m, 2H), 3.00 (t,J= 5.8 Hz, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0353] 화합물 36. N-(5-(2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0354]

[0355] DipEA (28.0 mg, 0.216 mmol) was added to a suspension of tetrahydro-2H-pyran-4-carboxylic acid (7.74 mg, 0.0590 mmol) in DMF (2 mL), followed by the addition of EDCl (12.4 mg, 0.0650 mmol) and HOBt (8.77 mg, 0.0650 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (20.0 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain compound 36 (12 mg, 0.027 mmol, 49.8%) as a white solid.

[0356] LC / MS 446.5 [M + H] +

[0357] 1 H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.82 (t,J= 9.7 Hz, 2H), 7.78-7.61 (m, 2H), 7.40 (d,J= 8.2 Hz, 1H), 7.28 (dd,J= 6.2, 2.3 Hz, 1H), 4.85 (s, 1H), 4.70 (s, 1H), 3.94-3.69 (m, 4H), 3.50-3.43 (m, 1H), 3.45-3.35 (m, 1H), 3.09-2.92 (m, 2H), 2.85 (s, 1H), 2.02 (s, 1H), 1.60 (s, 4H), 0.82 (d,J= 6.2 Hz, 4H).

[0358] Compound 37. N-(5-(2-(2-(2-bromophenyl)acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0359]

[0360] DIPEA (28.0 mg, 0.216 mmol) was added to a suspension of 2-(2-bromophenyl)acetic acid (12.7 mg, 0.0590 mmol) in DMF (2 mL), followed by the addition of EDCl (12.4 mg, 0.0650 mmol) and HOBt (8.77 mg, 0.0650 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (20.0 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain compound 37 (8.8 mg, 0.017 mmol, 30.7%) as a white solid.

[0361] LC / MS 532.4 [M + H] +

[0362] 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.91-7.79 (m, 2H), 7.71 (d,J= 7.7 Hz, 2H), 7.61 (d,J= 8.0 Hz, 1H), 7.41 (d,J= 8.1 Hz, 1H), 7.34 (d,J= 5.0 Hz, 2H), 7.29 (d,J= 6.7 Hz, 1H), 7.24-7.16 (m, 1H), 4.91 (s, 1H), 4.74 (s, 1H), 3.96 (s, 2H), 3.85 (t,J= 6.0 Hz, 1H), 3.77 (t,J= 5.9 Hz, 1H), 2.99 (d,J= 6.3 Hz, 1H), 2.89 (s, 1H), 2.13-1.88 (m, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0363] 화합물 38. N-(5-(2-(pyrazine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0364]

[0365] DIPEA (28.0 mg, 0.216 mmol) was added to a suspension of pyrazine-2-carboxylic acid (7.38 mg, 0.0590 mmol) in DMF (2 mL), followed by the addition of EDCl (12.4 mg, 0.0650 mmol) and HOBt (8.77 mg, 0.0650 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (20.0 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain compound 38 (18 mg, 0.041 mmol, 76%) as a white solid.

[0366] LC / MS 440.4 [M + H] +

[0367] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.92 (d,J= 12.1 Hz, 1H), 8.77 (d,J= 24.9 Hz, 2H), 7.91-7.78 (m, 2H), 7.76-7.64 (m, 2H), 7.49 (d,J= 8.1 Hz, 1H), 7.32-7.22 (m, 1H), 4.94 (s, 1H), 4.78 (s, 1H), 3.96 (t,J= 6.0 Hz, 1H), 3.73 (t,J= 5.8 Hz, 1H), 3.05-2.93 (m, 2H), 2.03 (s, 1H), 0.82 (d,J= 6.4 Hz, 4H).

[0368] Compound 39. N-(5-(2-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0369]

[0370] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. Then, 4-(trifluoromethyl)benzenesulfonyl chloride (19.8 mg, 0.0810 mmol) was added dropwise to the solution, the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 39 (5 ​​mg, 9.23 μmol, 17.07%) as a white solid.

[0371] LC / MS 542.4 [M + H] +

[0372] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.17-7.95 (m, 4H), 7.83 (d,J= 8.2 Hz, 1H), 7.76 (s, 1H), 7.69 (d,J= 6.4 Hz, 2H), 7.36 (d,J= 8.2 Hz, 1H), 7.25 (d,J= 6.3 Hz, 1H), 4.40 (s, 2H), 3.47 (t,J= 6.0 Hz, 2H), 3.01-2.87 (m, 2H), 2.07-1.97 (m, 1H), 0.81 (d,J= 6.2 Hz, 4H).

[0373] Compound 40. N-(5-(2-(1H-indazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0374]

[0375] DIPEA (28.0 mg, 0.216 mmol) was added to a suspension of 1H-indazole-3-carboxylic acid (9.65 mg, 0.0590 mmol) in DMF (2 mL), followed by the addition of EDCl (12.4 mg, 0.0650 mmol) and HOBt (8.77 mg, 0.0650 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (20.0 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain a crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain compound 40 (3 mg, 6.28 μmol, 11.62%) as a white solid.

[0376] LC / MS [M + H] +

[0377] 1 H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H), 11.02 (s, 1H), 8.02 (d,J= 8.1 Hz, 1H), 7.86 (d,J= 12.6 Hz, 2H), 7.75-7.67 (m, 2H), 7.64 (d,J= 8.4 Hz, 1H), 7.54-7.38 (m, 2H), 7.25 (dd,J= 18.2, 10.5 Hz, 2H), 5.33 (s, 1H), 4.98 (s, 1H), 4.28 (d,J= 4.6 Hz, 1H), 4.01 (s, 1H), 3.04 (s, 2H), 1.96 (d,J= 14.3 Hz, 1H), 0.82 (d,J= 5.3 Hz, 4H).

[0378] Compound 41. N-(5-(2-((5-fluoro-2-methylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0379]

[0380] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. To the solution, 5-fluoro-2-methylbenzenesulfonyl chloride (16.92 mg, 0.0810 mmol) was added dropwise, the resulting solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 41 (22 mg, 0.044 mmol, 80%) as a white solid.

[0381] LC / MS 506.5 [M + H] +

[0382] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.86-7.79 (m, 2H), 7.73-7.65 (m, 3H), 7.55-7.45 (m, 2H), 7.39 (d,J= 8.1 Hz, 1H), 7.27 (dd,J= 6.5, 2.1 Hz, 1H), 4.50 (s, 2H), 3.58 (t,J= 5.9 Hz, 2H), 2.93 (t,J= 6.0 Hz, 2H), 2.55 (s, 3H), 2.03 (s, 1H), 0.82 (d,J= 5.1 Hz, 4H).

[0383] Compound 42. N-(5-(2-(benzylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0384]

[0385] Benzylsulfonyl chloride (15.4 mg, 0.0810 mmol) was added dropwise to a solution of compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) stirred in DMF (5 mL) at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain compound 42 (22 mg, 0.045 mmol, 83%) as a white solid.

[0386] LC / MS 488.5 [M + H] +

[0387] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.84 (dd,J= 8.1, 1.9 Hz, 1H), 7.79 (d,J= 1.8 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.43 (dd,J= 6.8, 3.0 Hz, 2H), 7.37 (dd,J= 5.0, 2.1 Hz, 3H), 7.32 (d,J= 8.1 Hz, 1H), 7.28 (dd,J= 6.5, 2.1 Hz, 1H), 4.54 (s, 2H), 4.47 (s, 2H), 3.44 (t,J= 5.8 Hz, 2H), 2.88 (t,J= 5.9 Hz, 2H), 2.01 (d,J= 15.9 Hz, 1H), 0.82 (d,J= 5.3 Hz, 4H).

[0388] Compound 43. N-(5-(2-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0389]

[0390] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. To the solution, 1-methyl-1H-imidazole-4-sulfonyl chloride (14.65 mg, 0.0810 mmol) was added dropwise, the resulting solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 43 (21 mg, 0.044 mmol, 81%) as a white solid.

[0391] LC / MS 478.5 [M + H] +

[0392] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.90 (d,J= 1.4 Hz, 1H), 7.86-7.79 (m, 2H), 7.77 (s, 1H), 7.73-7.65 (m, 2H), 7.36 (d,J= 8.1 Hz, 1H), 7.27 (dd,J= 6.5, 2.2 Hz, 1H), 4.40 (s, 2H), 3.71 (s, 3H), 3.41 (t,J= 5.9 Hz, 2H), 2.95 (t,J= 5.8 Hz, 2H), 2.03 (s, 1H), 0.82 (d,J= 5.6 Hz, 4H).

[0393] Compound 44. N-(5-(2-(4-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0394]

[0395] 4-chlorothiazole-2-carboxylic acid (9.73 mg, 0.0590 mmol) was suspended in DMF (5 mL), after which DIPEA, EDCl (12.5 mg, 0.0650 mmol), and HOBt (8.77 mg, 0.0650 mmol) were added at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 18 (20.0 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 44 (9.4 mg, 0.020 mmol, 36.3%) as a white solid.

[0396] LC / MS 479.4 [M + H] +

[0397] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.28 (s, 1H), 7.84 (s, 2H), 7.75-7.64 (m, 2H), 7.47 (s, 1H), 7.29 (dd,J= 6.5, 2.1 Hz, 1H), 4.89 (s, 1H), 4.72 (s, 1H), 3.92 (s, 1H), 3.68 (s, 1H), 2.99 (s, 2H), 2.01 (d,J= 15.2 Hz, 1H), 0.82 (d,J= 5.6 Hz, 4H).

[0398] Compound 45. N-(5-(2-((4-bromo-2-methylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0399]

[0400] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. To the solution, 4-bromo-2-methylbenzenesulfonyl chloride (21.8 mg, 0.0810 mmol) was added dropwise, the resulting solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 45 (25 mg, 0.044 mmol, 82%) as a white solid.

[0401] LC / MS 568,4 [M + H] +

[0402] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.86-7.81 (m, 2H), 7.79 (d,J= 1.8 Hz, 1H), 7.75 (d,J= 2.0 Hz, 1H), 7.72-7.65 (m, 3H), 7.38 (d,J= 8.1 Hz, 1H), 7.27 (dd,J= 6.4, 2.2 Hz, 1H), 4.46 (s, 2H), 3.55 (t,J= 5.9 Hz, 2H), 2.93 (t,J= 5.9 Hz, 2H), 2.57 (s, 3H), 2.01 (d,J= 14.8 Hz, 1H), 0.85-0.78 (m, 4H).

[0403] Compound 46. N-(5-(2-((2,5-dimethylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0404]

[0405] 2,5-dimethylbenzenesulfonyl chloride (16.6 mg, 0.0810 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 46 (22 mg, 0.044 mmol, 81%) as a white solid.

[0406] LC / MS 502.5 [M + H] +

[0407] 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.83 (dd,J= 8.0, 1.9 Hz, 1H), 7.79 (d,J= 1.8 Hz, 1H), 7.73 (d,J= 2.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.43-7.36 (m, 2H), 7.34 (d,J= 7.7 Hz, 1H), 7.27 (dd,J= 6.5, 2.1 Hz, 1H), 4.45 (s, 2H), 3.52 (t,J= 5.9 Hz, 2H), 2.92 (t,J= 5.9 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 2.03 (s, 1H), 0.82 (d,J= 5.1 Hz, 4H).

[0408] Compound 47. N-(5-(2-(2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0409]

[0410] DIPEA, EDCl (12.5 mg, 0.0650 mmol), and HOBt (8.77 mg, 0.0650 mmol) were added to a suspension of 2-hydroxybenzoic acid (8.22 mg, 0.0590 mmol) dissolved in DMF (5 mL) at room temperature, and the reaction mixture was stirred for 15 minutes. After adding Compound 18 (20.0 mg, 0.0540 mmol), the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and vacuum concentrated to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 47 (18 mg, 0.040 mmol, 73.4%) as a beige solid.

[0411] LC / MS 454.5 [M + H]+

[0412] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.86 (s, 1H), 7.81 (d,J= 18.2 Hz, 2H), 7.74-7.64 (m, 2H), 7.41 (d,J= 36.9 Hz, 1H), 7.31-7.23 (m, 2H), 7.17 (d,J= 7.6 Hz, 1H), 6.96-6.81 (m, 2H), 4.87 (s, 1H), 4.53 (s, 1H), 3.90 (s, 1H), 3.51 (s, 1H), 2.91 (s, 2H), 2.01 (d,J= 15.5 Hz, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0413] Compound 48. N-(5-(2-(5-chloro-2-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0414]

[0415] DIPEA, EDCl (12.5 mg, 0.0650 mmol), and HOBt (8.77 mg, 0.0650 mmol) were added to a suspension of 5-chloro-2-fluorobenzoic acid (9.44 mg, 0.0540 mmol) dissolved in DMF (5 mL) at room temperature, and the reaction mixture was stirred for 15 minutes. After adding Compound 18 (20.0 mg, 0.0540 mmol), the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and vacuum concentrated to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 48 (16 mg, 0.033 mmol, 60.4%) as a beige solid.

[0416] LC / MS 490.5 [M + H] +

[0417] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.92-7.85 (m, 1H), 7.85-7.78 (m, 1H), 7.74-7.66 (m, 2H), 7.66-7.56 (m, 2H), 7.50-7.37 (m, 2H), 7.32-7.22 (m, 1H), 4.91 (s, 1H), 4.57 (s, 1H), 3.94 (t,J= 5.9 Hz, 1H), 3.56 (t,J= 5.8 Hz, 1H), 2.99 (t,J= 5.9 Hz, 1H), 2.90 (s, 1H), 2.10-1.97 (m, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0418] Compound 49. N-(5-(2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0419]

[0420] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. To the resulting solution, benzenesulfonyl chloride (14.33 mg, 0.081 mmol) was added dropwise, the solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 49 (21 mg, 0.044 mmol, 82%) as a white solid.

[0421] LC / MS 474.5 [M + H] +

[0422] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.91-7.83 (m, 2H), 7.83 (dd,J= 8.1, 1.9 Hz, 1H), 7.80-7.69 (m, 2H), 7.73-7.62 (m, 4H), 7.36 (d,J= 8.2 Hz, 1H), 7.25 (dd,J= 6.3, 2.3 Hz, 1H), 4.32 (s, 2H), 3.39 (d,J= 5.8 Hz, 2H), 2.94 (t,J= 5.9 Hz, 2H), 2.11-1.96 (m, 1H), 0.81 (d,J= 6.1 Hz, 4H).

[0423] 화합물 50. N-(5-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0424]

[0425] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred. To the stirred solution, 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride (19.03 mg, 0.081 mmol) was added dropwise at 0 °C, and the resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL) to cool the reaction mixture, the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 50 (19.3 mg, 0.036 mmol, 67.1%) as a white solid.

[0426] LC / MS 532.5 [M + H] +

[0427] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.83 (dd,J= 8.1, 1.9 Hz, 1H), 7.77 (d,J= 1.8 Hz, 1H), 7.75-7.63 (m, 2H), 7.40-7.28 (m, 3H), 7.26 (dd,J= 6.4, 2.2 Hz, 1H), 7.11 (d,J= 8.4 Hz, 1H), 4.37-4.29 (m, 4H), 4.28 (s, 2H), 3.36 (s, 2H), 2.95 (t,J= 5.8 Hz, 2H), 2.01 (d,J= 14.3 Hz, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0428] Compound 51. N-(5-(2-((4-chlorobenzyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0429]

[0430] (4-chlorophenyl)methanesulfonyl chloride (18.26 mg, 0.081 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 51 (13 mg, 0.025 mmol, 46.1%) as a white solid.

[0431] LC / MS 522.5 [M + H] +

[0432] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.86-7.81 (m, 1H), 7.79 (d,J= 1.9 Hz, 1H), 7.74-7.66 (m, 2H), 7.45 (s, 4H), 7.32 (d,J= 8.1 Hz, 1H), 7.30-7.25 (m, 1H), 4.57 (s, 2H), 4.49 (s, 2H), 3.46 (t,J= 5.8 Hz, 2H), 2.90 (t,J= 5.9 Hz, 2H), 2.01 (d,J= 14.3 Hz, 1H), 0.82 (d,J= 5.4 Hz, 4H).

[0433] Compound 52. N-(5-(2-((4-bromo-2-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0434]

[0435] 4-bromo-2-fluorobenzenesulfonyl chloride (22.18 mg, 0.081 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 52 (20 mg, 0.035 mmol, 64.8%) as a white solid.

[0436] LC / MS 570.4 [M + H] +

[0437] 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.94-7.88 (m, 1H), 7.87-7.79 (m, 2H), 7.77 (d,J= 1.9 Hz, 1H), 7.74-7.64 (m, 3H), 7.37 (d,J= 8.2 Hz, 1H), 7.31-7.22 (m, 1H), 4.48 (s, 2H), 3.57 (t,J= 5.9 Hz, 2H), 2.93 (t,J= 5.9 Hz, 2H), 2.01 (d,J= 12.0 Hz, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0438] Compound 53. N-(5-(2-(pyridin-3-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0439]

[0440] Pyridine-3-sulfonyl chloride (14.41 mg, 0.081 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 53 (15.5 mg, 0.033 mmol, 60.4%) as a white solid.

[0441] LC / MS 475.5 [M + H] +

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.10-8.96 (m, 1H), 8.94-8.79 (m, 1H), 8.31-8.20 (m, 1H), 7.88-7.79 (m, 1H), 7.76 (d,J= 1.9 Hz, 1H), 7.73-7.59 (m, 3H), 7.36 (d,J= 8.2 Hz, 1H), 7.30-7.16 (m, 1H), 4.41 (s, 2H), 3.47 (t,J= 5.9 Hz, 2H), 2.94 (t,J= 6.0 Hz, 2H), 2.01 (d,J= 15.9 Hz, 1H), 0.82 (d,J= 5.7 Hz, 4H).

[0443] Compound 54. N-(5-(2-(pyridin-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0444]

[0445] Pyridine-2-sulfonyl chloride (14.41 mg, 0.081 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 54 (21 mg, 0.044 mmol, 82%) as a white solid.

[0446] LC / MS 475.4 [M + H] +

[0447] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.80-8.67 (m, 1H), 8.18-8.07 (m, 1H), 8.05-7.99 (m, 1H), 7.88-7.81 (m, 1H), 7.76 (d,J= 1.9 Hz, 1H), 7.73-7.60 (m, 3H), 7.36 (d,J= 8.2 Hz, 1H), 7.29-7.22 (m, 1H), 4.57 (s, 2H), 3.60 (t,J= 5.9 Hz, 2H), 2.94 (t,J= 5.9 Hz, 2H), 2.01 (d,J= 15.5 Hz, 1H), 0.82 (d,J= 5.4 Hz, 4H).

[0448] Compound 55. N-(5-(2-((4-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0449]

[0450] 4-cyanobenzenesulfonyl chloride (16.35 mg, 0.0810 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 55 (23 mg, 0.046 mmol, 85%) as a white solid.

[0451] LC / MS 499.5 [M + H] +

[0452] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.20-8.08 (m, 2H), 8.08-7.97 (m, 2H), 7.83 (dd,J= 8.0, 1.9 Hz, 1H), 7.74 (d,J= 1.9 Hz, 1H), 7.71-7.61 (m, 2H), 7.35 (d,J= 8.2 Hz, 1H), 7.25 (dd,J= 6.2, 2.4 Hz, 1H), 4.40 (s, 2H), 3.47 (t,J= 5.9 Hz, 2H), 2.93 (t,J= 6.0 Hz, 2H), 2.01 (d,J= 15.0 Hz, 1H), 0.88-0.74 (m, 4H).

[0453] Compound 56. N-(5-(2-((5-chlorothiophen-2-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0454]

[0455] 5-chlorothiophene-2-sulfonyl chloride (17.61 mg, 0.0810 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 56 (23 mg, 0.045 mmol, 83%) as a beige solid.

[0456] LC / MS 514.5 [M + H] +

[0457] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.89-7.83 (m, 1H), 7.80 (d,J= 1.9 Hz, 1H), 7.72-7.63 (m, 3H), 7.43-7.34 (m, 2H), 7.30-7.24 (m, 1H), 4.40 (s, 2H), 3.44 (t,J= 5.9 Hz, 2H), 3.00 (t,J= 6.0 Hz, 2H), 2.13-1.90 (m, 1H), 0.82 (d,J= 5.4 Hz, 4H).

[0458] Compound 57. N-(5-(2-(dibenzo[b,d]furan-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0459]

[0460] Dibenzo[b,d]furan-2-sulfonyl chloride (21.6 mg, 0.0810 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 57 (27 mg, 0.048 mmol, 89%) as a white solid.

[0461] LC / MS 564.6 [M + H] +

[0462] 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.76 (d, J= 1.9 Hz, 1H), 8.42-8.33 (m, 1H), 8.04-7.93 (m, 2H), 7.84-7.75 (m, 2H), 7.73 (d,J= 1.9 Hz, 1H), 7.70-7.59 (m, 3H), 7.53-7.46 (m, 1H), 7.36 (d,J= 8.1 Hz, 1H), 7.16 (dd,J= 5.2, 3.4 Hz, 1H), 4.39 (s, 2H), 3.46 (t,J= 5.9 Hz, 2H), 2.96 (t,J= 6.0 Hz, 2H), 2.02 (s, 1H), 0.80 (d,J= 6.2 Hz, 4H).

[0463] Compound 58. N-(5-(2-((3-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0464]

[0465] 3-cyanobenzenesulfonyl chloride (16.35 mg, 0.0810 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 58 (23 mg, 0.046 mmol, 85%) as a white solid.

[0466] LC / MS 499.5 [M + H] +

[0467] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.33 (dd,J= 3.7, 2.0 Hz, 1H), 8.23-8.12 (m, 2H), 7.88-7.80 (m, 2H), 7.76 (s, 1H), 7.73-7.65 (m, 2H), 7.36 (dd,J= 8.3, 2.9 Hz, 1H), 7.29-7.20 (m, 1H), 4.40 (d,J= 2.9 Hz, 2H), 3.54-3.41 (m, 2H), 2.95 (d,J= 7.5 Hz, 2H), 2.03 (s, 1H), 0.82 (t,J= 4.4 Hz, 4H).

[0468] Compound 59. N-(5-(2-((tetrahydro-2H-pyran-4-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0469]

[0470] Tetrahydro-2H-pyran-4-sulfonyl chloride (14.5 mg, 0.0810 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 59 (12.3 mg, 0.026 mmol, 47.2%) as a white solid.

[0471] LC / MS 482.5 [M + H] +

[0472] 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.88-7.78 (m, 2H), 7.76-7.63 (m, 2H), 7.36 (d,J= 8.1 Hz, 1H), 7.28 (dd,J= 6.6, 2.0 Hz, 1H), 4.58 (s, 2H), 3.94 (dd,J= 11.5, 4.4 Hz, 2H), 3.70-3.47 (m, 4H), 3.30 (s, 1H), 2.95 (t,J= 5.8 Hz, 2H), 2.01 (d,J= 14.1 Hz, 1H), 1.89 (d,J= 12.3 Hz, 2H), 1.75-1.58 (m, 2H), 0.92-0.69 (m, 4H).

[0473] Compound 60. N-(5-(2-((3-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0474]

[0475] 3-acetylbenzenesulfonyl chloride (17.7 mg, 0.0810 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 60 (17 mg, 0.033 mmol, 61.0%) as a white solid.

[0476] LC / MS 516.5 [M + H] +

[0477] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.29-8.25 (m, 2H), 8.15-8.08 (m, 1H), 7.86-7.79 (m, 2H), 7.75 (d,J= 1.9 Hz, 1H), 7.72-7.65 (m, 2H), 7.37 (d,J= 8.1 Hz, 1H), 7.27-7.21 (m, 1H), 4.38 (s, 2H), 3.44 (t,J= 6.0 Hz, 2H), 2.93 (t,J= 6.0 Hz, 2H), 2.66 (s, 3H), 2.11-1.93 (m, 1H), 0.81 (d,J= 6.2 Hz, 4H).

[0478] Compound 61. N-(5-(2-((5-methylthiophen-2-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0479]

[0480] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. To the solution, 5-methylthiophene-2-sulfonyl chloride (15.6 mg, 0.0810 mmol) was added dropwise, the resulting solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 61 (10 mg, 0.020 mmol, 37.5%) as a white solid.

[0481] LC / MS 494.5 [M + H] +

[0482] 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.85 (d,J= 8.6 Hz, 1H), 7.80 (s, 1H), 7.74-7.65 (m, 2H), 7.57 (d,J= 3.7 Hz, 1H), 7.39 (d,J= 8.2 Hz, 1H), 7.32-7.23 (m, 1H), 7.06-6.98 (m, 1H), 4.34 (s, 2H), 3.38 (d,J= 6.0 Hz, 3H), 3.32 (s, 1H), 2.99 (t,J= 5.8 Hz, 2H), 2.09 (s, 1H), 1.24 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0483] Compound 62. N-(5-(2-((3-cyano-5-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0484]

[0485] Compound 18 (20.0 mg, 0.0540 mmol) and triethylamine (21.9 mg, 0.216 mmol) were added to DMF (5 mL) and stirred at 0 °C. To the solution, 3-cyano-5-fluorobenzenesulfonyl chloride (17.8 mg, 0.0810 mmol) was added dropwise, the resulting solution was heated to room temperature, and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 62 (8 mg, 0.015 mmol, 28.6%) as a white solid.

[0486] LC / MS 517.5 [M + H] +

[0487] 1H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.30-8.24 (m, 1H), 8.22 (d,J= 1.4 Hz, 1H), 8.11 (dt,J= 7.8, 2.2 Hz, 1H), 7.84 (dd,J= 7.9, 1.9 Hz, 1H), 7.77 (d,J= 1.8 Hz, 1H), 7.74-7.65 (m, 2H), 7.35 (d,J= 8.1 Hz, 1H), 7.26 (dd,J= 5.9, 2.6 Hz, 1H), 4.44 (s, 2H), 3.50 (t,J=6.0 Hz, 2H), 2.95 (t,J= 5.9 Hz, 2H), 2.06 (d,J= 17.5 Hz, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0488] Compound 63. N-(5-(2-(thiophen-3-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0489]

[0490] Thiophene-3-sulfonyl chloride (14.8 mg, 0.0810 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (20.0 mg, 0.0540 mmol) dissolved in DMF (5 mL) and triethylamine (21.9 mg, 0.216 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 63 (21 mg, 0.044 mmol, 81%) as a white solid.

[0491] LC / MS 480.4 [M + H] +

[0492] 1 H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.36 (dd,J= 3.0, 1.3 Hz, 1H), 7.87-7.81 (m, 2H), 7.77 (d,J= 1.8 Hz, 1H), 7.73-7.67 (m, 2H), 7.42 (dd,J= 5.1, 1.4 Hz, 1H), 7.36 (d,J= 8.2 Hz, 1H), 7.26 (dd,J= 5.9, 2.7 Hz, 1H), 4.34 (s, 2H), 3.39 (t,J= 5.9 Hz, 2H), 2.95 (t,J= 5.8 Hz, 2H), 2.06 (d,J= 17.5 Hz, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0493] 화합물 64. N-(5-(2-(5-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0494]

[0495] N-(5-(2-(5-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0496] DIPEA (140 mg, 1.08 mmol) was added to a suspension of Compound 18 (100 mg, 0.270 mmol) dissolved in DMF (5 mL), followed by the addition of HATU (206 mg, 0.541 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. 5-chlorothiazole-2-carboxylic acid (53.1 mg, 0.324 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 64 (47 mg, 0.098 mmol, 36.3%) as a beige solid.

[0497] LC / MS 479.4 [M + H] +

[0498] 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.12 (d,J= 7.1 Hz, 1H), 7.91-7.78 (m, 2H), 7.76-7.64 (m, 2H), 7.51-7.34 (m, 1H), 7.28 (d,J= 6.5 Hz, 1H), 5.52 (s, 1H), 4.90 (s, 1H), 4.49 (d,J= 6.1 Hz, 1H), 3.93 (s, 1H), 3.03 (d,J= 8.7 Hz, 2H), 2.03 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0499] Compound 65. N-(5-(2-(5-cyanothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0500]

[0501] DIPEA (140 mg, 1.08 mmol) was added to a suspension of Compound 18 (100 mg, 0.270 mmol) dissolved in DMF (5 mL), followed by the addition of DMTMM (112 mg, 0.406 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. 2-Cyanothiazole-5-carboxylic acid (62.5 mg, 0.406 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 65 (54 mg, 0.115 mmol, 42.5%) as a beige solid.

[0502] LC / MS 470.5 [M + H] +

[0503] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.59 (s, 1H), 7.86 (s, 2H), 7.79-7.60 (m, 2H), 7.59-7.33 (m, 1H), 7.29 (d, J= 6.9 Hz, 1H), 5.06-4.76 (m, 2H), 3.90 (d,J= 3.7 Hz, 2H), 3.03 (s, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0504] Compound 66. N-(5-(2-(thiazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0505]

[0506] DIPEA (140 mg, 1.08 mmol) was added to a suspension of Compound 18 (100 mg, 0.270 mmol) dissolved in DMF (5 mL), followed by the addition of DMTMM (112 mg, 0.406 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Thiazole-4-carboxylic acid (52.4 mg, 0.406 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 66 (77 mg, 0.173 mmol, 64.1%) as a beige solid.

[0507] LC / MS 445.5 [M + H] +

[0508] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.23 (d,J= 1.9 Hz, 1H), 8.26 (s, 1H), 7.94-7.76 (m, 2H), 7.76-7.63 (m, 2H), 7.55-7.18 (m, 2H), 5.10-4.82 (m, 2H), 3.93 (t,J= 5.8 Hz, 2H), 2.99 (t,J= 5.8 Hz, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.3 Hz, 4H).

[0509] Compound 67. N-(5-(2-(2,4-dimethylthiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0510]

[0511] DIPEA (140 mg, 1.08 mmol) was added to a suspension of Compound 18 (100 mg, 0.270 mmol) dissolved in DMF (5 mL), followed by the addition of HATU (206 mg, 0.541 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. 2,4-dimethylthiazole-5-carboxylic acid (52.4 mg, 0.406 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 67 (66 mg, 0.140 mmol, 51.7%) as a beige solid.

[0512] LC / MS 473.5 [M + H] +

[0513] 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.90-7.77 (m, 2H), 7.76-7.64 (m, 2H), 7.40 (d,J= 7.9 Hz, 1H), 7.28 (dd,J= 6.5, 2.1 Hz, 1H), 4.79 (s, 2H), 3.79 (s, 2H), 2.94 (t,J= 6.0 Hz, 2H), 2.65 (s, 3H), 2.32 (s, 3H), 2.08 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0514] Compound 68. N-(5-(2-(4-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0515]

[0516] DIPEA (700 mg, 5.41 mmol) was added to a suspension of Compound 18 (500 mg, 1.35 mmol) dissolved in DMF (10 mL), followed by the addition of DMTMM (561 mg, 2.02 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. 4-chlorothiazole-2-carboxylic acid (332 mg, 2.02 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 68 (411 mg, 0.858 mmol, 63.5%) as a white solid.

[0517] LC / MS 479.2 [M + H] +

[0518] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.11 (s, 1H), 7.93-7.80 (m, 2H), 7.78-7.64 (m, 2H), 7.53-7.35 (m, 1H), 7.29 (d,J= 6.2 Hz, 1H), 5.47 (s, 1H), 4.91 (s, 1H), 4.44 (s, 1H), 4.01-3.87 (m, 1H), 3.16-2.88 (m, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0519] Compound 69. N-(5-(2-(4-methylthiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0520]

[0521] DIPEA (140 mg, 1.08 mmol) was added to a suspension of Compound 18 (100 mg, 0.270 mmol) dissolved in DMF (5 mL), followed by the addition of DMTMM (112 mg, 0.406 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. 4-methylthiazole-5-carboxylic acid (58.1 mg, 0.406 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 69 (67 mg, 0.146 mmol, 54.0%) as a beige solid.

[0522] LC / MS 459.4 [M + H] +

[0523] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.14 (d,J= 1.8 Hz, 1H), 7.93-7.78 (m, 2H), 7.73-7.58 (m, 2H), 7.40 (s, 1H), 7.34-7.18 (m, 1H), 4.80 (s, 2H), 3.78 (s, 2H), 2.95 (s, 2H), 2.41 (s, 3H), 2.18-1.80 (m, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0524] Compound 70. N-(5-(2-(cyanomethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0525]

[0526] 2-bromoacetonitrile (48.6 mg, 0.406 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (100 mg, 0.270 mmol) dissolved in DMF (5 mL) and triethylamine (109 mg, 1.08 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 70 (69 mg, 0.185 mmol, 68.5%) as a beige solid.

[0527] LC / MS 373.4 [M + H] +

[0528] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.86-7.74 (m, 2H), 7.74 -7.63 (m, 2H), 7.34-7.23 (m, 2H), 3.97 (s, 2H), 3.78 (s, 2H), 2.95 (d,J= 6.0 Hz, 2H), 2.83 (d,J= 5.8 Hz, 2H), 2.05 (s, 1H), 0.82 (d,J= 7.1 Hz, 4H).

[0529] Compound 71. 4-((6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzenesulfonyl fluoride

[0530]

[0531] 4-(bromomethyl)benzenesulfonyl fluoride (51.3 mg, 0.203 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (50.0 mg, 0.135 mmol) dissolved in DMF (2 mL) and triethylamine (54.7 mg, 0.541 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was treated with water (10 mL), the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 71 (39 mg, 0.077 mmol, 57.1%) as a beige solid.

[0532] LC / MS 506.5 [M + H] +

[0533] 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.14 (d,J= 8.0 Hz, 2H), 7.83 (d,J= 8.1 Hz, 2H), 7.76 (d,J= 5.7 Hz, 2H), 7.73-7.64 (m, 2H), 7.31-7.17 (m, 2H), 3.89 (s, 2H), 3.70 (s, 2H), 2.94 (d,J= 6.4 Hz, 2H), 2.80 (d,J= 5.7 Hz, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0534] Compound 72. N-(5-(2-(2-chlorothiazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0535]

[0536] DIPEA (140 mg, 1.08 mmol) was added to a suspension of Compound 18 (100 mg, 0.270 mmol) dissolved in DMF (5 mL), followed by the addition of DMTMM (112 mg, 0.406 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. 2-chlorothiazole-4-carboxylic acid (58.1 mg, 0.406 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 72 (77 mg, 0.161 mmol, 59.5%) as a beige solid.

[0537] LC / MS 479.3 [M + H] +

[0538] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.19 (s, 1H), 7.93-7.75 (m, 2H), 7.75-7.63 (m, 2H), 7.55-7.19 (m, 2H), 5.01-4.78 (m, 2H), 3.89 (t,J= 5.8 Hz, 2H), 2.98 (d,J= 6.7 Hz, 2H), 2.04 (s, 1H), 0.82 (d,J= 7.2 Hz, 4H).

[0539] Compound 73. N-(5-(2-(isothiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0540]

[0541] DIPEA (70.0 mg, 0.541 mmol) was added to a suspension of Compound 18 (50.0 mg, 0.135 mmol) dissolved in DMF (2 mL), followed by the addition of DMTMM (56.1 mg, 0.203 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Isothiazole-5-carboxylic acid (19.2 mg, 0.149 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 73 (20 mg, 0.045 mmol, 33.3%) as a beige solid.

[0542] LC / MS 445.4 [M + H] +

[0543] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.67 (s, 1H), 7.85 (s, 2H), 7.78 (s, 1H), 7.76-7.65 (m, 2H), 7.54-7.33 (m, 1H), 7.29 (d,J= 6.4 Hz, 1H), 4.88 (s, 2H), 4.02-3.72 (m, 2H), 3.00 (t,J= 5.6 Hz, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0544] Compound 74. N-(5-(2-(pyrrolo[2,1-b]thiazole-6-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0545]

[0546] DIPEA (70.0 mg, 0.541 mmol) was added to a suspension of Compound 18 (50.0 mg, 0.135 mmol) dissolved in DMF (2 mL), followed by the addition of DMTMM (56.1 mg, 0.203 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Pyrrolo[2,1-b]thiazole-6-carboxylic acid (24.8 mg, 0.149 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The prepared reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the prepared mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 74 (29 mg, 0.060 mmol, 44.5%) as a beige solid.

[0547] LC / MS 483.5 [M + H] +

[0548] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.82 (d,J= 3.9 Hz, 3H), 7.78-7.64 (m, 3H), 7.47-7.33 (m, 1H), 7.32-7.22 (m, 1H), 7.16 (d,J= 4.1 Hz, 1H), 6.52 (s, 1H), 4.90 (s, 2H), 3.92 (s, 2H), 2.98 (t,J= 5.6 Hz, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0549] Compound 75. N-(5-(2-(thiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0550]

[0551] DIPEA (70.0 mg, 0.541 mmol) was added to a suspension of Compound 18 (50.0 mg, 0.135 mmol) dissolved in DMF (2 mL), followed by the addition of DMTMM (56.1 mg, 0.203 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Thiazole-5-carboxylic acid (17.4 mg, 0.149 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 75 (26 mg, 0.058 mmol, 43.3%) as a beige solid.

[0552] LC / MS 445.5 [M + H] +

[0553] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.29 (s, 1H), 8.36 (s, 1H), 7.85 (s, 2H), 7.71 (d,J= 7.3 Hz, 2H), 7.45 (s, 1H), 7.29 (d,J= 6.4 Hz, 1H), 4.91 (s, 2H), 3.91 (t,J= 5.7 Hz, 2H), 3.02 (s, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.1 Hz, 4H).

[0554] Compound 76. N-(5-(2-((6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0555]

[0556] 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (52.1 mg, 0.203 mmol) was added dropwise at 0 °C to a stirred solution of Compound 18 (50.0 mg, 0.135 mmol) dissolved in DMF (2 mL) and triethylamine (54.7 mg, 0.541 mmol). The resulting solution was heated to room temperature and stirred for 4 hours. The reaction mixture was quenched with water (10 mL) to cool the reaction mixture, the layers were separated, the aqueous layer was extracted with DCM (15 mL), the combined organic layer was dried with Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash silica chromatography using 5% MeOH / DCM to obtain Compound 76 (49 mg, 0.088 mmol, 65.4%) as a beige solid.

[0557] LC / MS 554.4 [M + H] +

[0558] 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.14 (d,J= 4.4 Hz, 1H), 7.82 (d,J= 8.0 Hz, 1H), 7.75 (s, 1H), 7.69 (t,J= 4.0 Hz, 2H), 7.64 (d,J= 4.2 Hz, 1H), 7.34 (d,J= 8.2 Hz, 1H), 7.28-7.20 (m, 1H), 4.56 (s, 2H), 3.68-3.59 (m, 2H), 2.94 (d,J= 6.5 Hz, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0559] Compound 77. N-(5-(2-(4-(trifluoromethyl)thiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0560]

[0561] DIPEA (70.0 mg, 0.541 mmol) was added to a suspension of Compound 18 (50.0 mg, 0.135 mmol) in DMF (2 mL), followed by the addition of DMTMM (56.1 mg, 0.203 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. 4-(trifluoromethyl)thiazole-2-carboxylic acid (29.3 mg, 0.149 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 77 (30 mg, 0.059 mmol, 43.3%) as a beige solid.

[0562] LC / MS [M + H] +

[0563] 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.83 (s, 1H), 7.94-7.80 (m, 2H), 7.76-7.65 (m, 2H), 7.48 (d,J= 8.1 Hz, 1H), 7.36-7.23 (m, 1H), 5.45 (s, 1H), 4.93 (s, 1H), 4.41 (t,J= 5.5 Hz, 1H), 3.96 (s, 1H), 3.06 (s, 2H), 2.04 (s, 1H), 0.82 (d,J= 6.2 Hz, 4H).

[0564] Compound 78. N-(5-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0565]

[0566] DIPEA (70.0 mg, 0.541 mmol) was added to a suspension of Compound 18 (50.0 mg, 0.135 mmol) dissolved in DMF (2 mL), followed by the addition of DMTMM (56.1 mg, 0.203 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Pyrazole[5,1-b]thiazole-7-carboxylic acid (25.0 mg, 0.149 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The prepared reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the prepared mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 78 (54 mg, 0.112 mmol, 83%) as a beige solid.

[0567] LC / MS 484.5 [M + H] +

[0568] 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.43 (s, 1H), 8.35 (d,J= 2.9 Hz, 1H), 7.92-7.80 (m, 2H), 7.78-7.64 (m, 2H), 7.55 (t,J= 3.1 Hz, 1H), 7.51 (d,J= 7.9 Hz, 1H), 7.30 (d,J= 6.1 Hz, 1H), 4.98 (s, 2H), 3.98 (s, 2H), 3.03 (s, 2H), 2.04 (s, 1H), 0.95-0.69 (m, 4H).

[0569] Compound 79. (6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-chlorothiazol-5-yl)methanone

[0570]

[0571] Step 1: Synthesis of tert-butyl 6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 79-1-A)

[0572] A mixture of Na2CO3 (219 mg, 2.065 mmol) dissolved in water (2.500 ml) was suspended in dioxane (10 ml) along with 5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (BLD Pharmatech, BD163675) (200 mg, 0.939 mmol), Pd(PPh3)2Cl2 (65.9 mg, 0.094 mmol), 2(1H)-isoquinolinecarboxylic acid, 3,4-dihydro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-, 1,1-dimethylethyl ester (BLD Pharmatech, BD152964) (506 mg, 1.408 mmol) and purged with nitrogen for 15 minutes. The resulting mixture was heated at 110 °C for 14 hours. The reaction mixture was filtered on a Celite bed, washed with dioxane, and concentrated under vacuum to obtain the crude mixture, which was further purified by column chromatography using DCM:MeOH 5% to obtain compound 79-1-A (300 mg, 0.821 mmol, 87%) as a white solid.

[0573] LC / MS 366.42 [M + H] +

[0574] 1H NMR (400 MHz, DMSO) δ 7.82-7.65 (m, 2H), 7.50 (dd,J= 8.8, 7.3 Hz, 1H), 7.41-7.25 (m, 2H), 6.99 (dd,J= 7.3, 1.3 Hz, 1H), 6.02 (s, 2H), 4.58 (s, 2H), 3.60 (t,J= 5.8 Hz, 2H), 2.85 (t,J= 5.9 Hz, 2H), 1.45 (s, 9H).

[0575] Step 2: Synthesis of 5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine hydrochloride (Compound 79-1)

[0576] 4 N HCl dissolved in dioxane (1.00 mL) was added to a solution of compound 79-1-A (300 mg, 0.821 mmol) dissolved in DCM (2 mL). The reaction mixture was stirred overnight at room temperature. The crude material was concentrated under vacuum, and the resulting solid was washed with ether and filtered to obtain compound 79-1 (251 mg, 0.832 mmol, 101%) as a white solid.

[0577] LCMS 266.31 [M + H] +

[0578] 1 H NMR (300 MHz, DMSO) δ 9.83 (s, 2H), 7.97-7.82 (m, 1H), 7.82-7.70 (m, 2H), 7.64 (dd,J= 8.7, 1.2 Hz, 1H), 7.40 (dd,J= 10.9, 8.0 Hz, 2H), 4.99 (s, 2H), 4.36 (d,J= 4.8 Hz, 2H), 3.49-3.31 (m, 2H), 3.10 (t,J= 6.2 Hz, 2H).

[0579] Step 3: Synthesis of (6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-chlorothiazol-5-yl)methanone (Compound 79)

[0580] DIPEA (0.887 ml, 4.97 mmol) was added to a suspension of 4-chlorothiazole-5-carboxylic acid (271 mg, 1.657 mmol) dissolved in DMF (10 ml), followed by the addition of HATU (945 mg, 2.485 mmol) at room temperature, and the reaction mixture was stirred for 15 minutes. Compound 79-1 (500 mg, 1.657 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried with MgSO4 and concentrated under vacuum to obtain the crude mixture, which was purified by column chromatography using 5% MeOH / DCM to obtain Compound 79 (386 mg, 0.939 mmol, 56.7%) as a yellow solid.

[0581] LC / MS 411.25 [M + H] +

[0582] 1 H NMR (300 MHz, DMSO) δ 9.29 (s, 1H), 7.77 (S, 2H), 7.57-7.30 (m, 3H), 7.01 (dd, J = 7.3, 1.3 Hz, 1H), 6.04 (s, 2H), 4.88 (s, 1H), 4.70 (s, 1H), 3.91 (s, 1H), 3.67 (s, 1H), 2.98 (d, J = 6.5 Hz, 2H).

[0583] Compound 80. tert-butyl 3-((5-(2-(4-chlorothiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)carbamoyl)azetidine-1-carboxylate

[0584]

[0585] A mixture of Compound 79 (380 mg, 0.925 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (279 mg, 1.387 mmol), and EDCI (355 mg, 1.850 mmol) was suspended in pyridine (5 ml). The reaction mixture was stirred at 60 °C for 18 hours. The reaction mixture was partitioned into EtOAc and water, and the phases were separated. The organic phase was washed with 1N HCl, Aq NaHCO3, water, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated. The reaction mixture was purified by column chromatography to obtain the title compound 80 (535 mg, 0.901 mmol, 97%) as a beige solid.

[0586] LC / MS 594.19 [M + H] +

[0587] 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 9.28 (s, 1H), 7.86 (s, 2H), 7.78-7.65 (m, 2H), 7.30 (dd, J = 6.6, 2.0 Hz, 2H), 4.97-4.58 (m, 2H), 4.16-3.80 (m, 7H), 3.00 (t, J = 6.0 Hz, 2H), 1.38 (d, J = 1.4 Hz, 9H).

[0588] Compound 81. N-(5-(2-(4-chlorothiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

[0589]

[0590] A solution of compound 80 (530 mg, 0.892 mmol) was added to DCM (10 ml) and TFA (6 ml, 0.892 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was concentrated under vacuum, and the resulting solid was washed with ether and filtered to obtain compound 81 (494 mg, 0.813 mmol, 91%) as a beige solid.

[0591] LC / MS 494.16 [M + H] +

[0592] 1 H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.29 (s, 1H), 8.72 (s, 2H), 7.83 (s, 2H), 7.80-7.64 (m, 2H), 7.49 (s, 1H), 7.41-7.27 (m, 1H), 4.98-4.58 (m, 2H), 4.22-4.03 (m, 5H), 4.02-3.59 (m, 2H), 2.99 (s, 2H).

[0593] <Experimental Example 1. JAK1, JAK2, JAK3 Enzyme Activity & Selectivity>

[0594] Experimental Method for JAK1, JAK2, and JAK3 Enzyme Activity - Compound Preparation and Testing Control Group

[0595] All compounds are prepared in 100% DMSO at 50 times the final assay concentration. The working stock of these compounds is added to the assay well along with the first component of the reaction, and then the remaining components are added as detailed in the general assay protocol below.

[0596] JAK1(h)

[0597] JAK1(h) is cultured with 20 mM Tris / HCl pH 7.5, 0.2 mM EDTA, 500 μM GEEPLYWSFPAKKK, 10 mM magnesium acetate, and [γ33P]-ATP (specific activity and concentration as needed).

[0598] JAK2(h)

[0599] JAK2(h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10 mM magnesium acetate, and [γ33P]-ATP (specific activity and concentration as needed).

[0600] JAK3(h)

[0601] JAK3(h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 μM GGEEEEYFELVKKKK,

[0602] Incubate with 10 mM magnesium acetate and [γ33P]-ATP (specific activity and concentration as needed).

[0603] TYK2(h)

[0604] TYK2(h) is cultured with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM GGMEDIYFEFMGGKKK, 10 mM magnesium acetate, and [γ33P]-ATP (specific activity and concentration as needed).

[0605] The reaction is initiated by adding the Mg / ATP mixture. After incubating at room temperature for 40 minutes, the reaction is stopped by adding phosphate at a concentration of 0.5%. Then, 10 μL of the reaction mixture is dropped onto a P30 filter mat, washed four times for 4 minutes in 0.425% phosphate and once in methanol, and then dried and scintillated.

[0606] The inhibitory activities of compounds 16, 40, 44 of the present invention and filgotinib (Filgotinib, GLPG0634, comparative substance) against JAK1, JAK2, JAK3, and TYK2, respectively, are as shown in Tables 1 and 2 below.

[0607] IC 50 (nM)Filgotinib Compounds 16 Compounds 40 Compounds 44JAK1(h)8231808JAK2(h)566158144102JAK3(h)>3,000149010831694TYK2(h)14913413183

[0608] Compound Activity (%) JAK 1 JAK 2 JAK 310 nM100 nM10 nM100 nM10 nM100 nM Filgotinib 8629927711493 Compound 1641311084108101 Compound 2925910489119116 Compound 395271059910597 Compound 4682311175117100 Compound 5127801131209998 Compound 69030126859097 Compound 79547106899393 Compound 88335106749093 Compound 98433956110290 Compound 10108851079410196 Compound 11105951051169597 Compound 12108621129410198 Compound 13925610810410096 Compound 1486311128898101 Compound 157232103869499 Compound 16611393559797 Compound 17623399729793 Compound 188970959710394 Compound 1963411071049796 Compound 20843810388103107 Compound 217642 Compound 224912 Compound 237126 Compound 2410057 Compound 257840 Compound 268132 Compound 277431 Compound 288953 Compound 29489 Compound 305612 Compound 317922 Compound 327622 Compound 33549 Compound 346838 Compound 358759 Compound 369140 Compound 379838 Compound 387843 Compound 397644 Compound 407119 Compound 416617 Compound 425311 Compound 438631 Compound 445013 Compound 457017 Compound 466315 Compound 478832 Compound 486315 Compound 495411 Compound 50467 514211 Compound 524510 Compound 535713 Compound 547124 Compound 555610 Compound 565810 Compound 577730 Compound 586112 Compound 596116 Compound 604811 Compound 615313 Compound 62529 Compound 636113 Compound 649683 Compound 65428 Compound 669257 Compound 678727 Compound 688130 Compound 697122 Compound 708639 Compound 719457 Compound 728844 Compound 736115 Compound 748741 Compound 758122 Compound 768026 Compound 778438 Compound 788634 Compound 7910381 Compound8011096 Compound 81108110

[0609] Compounds 16 and 40 showed JAK1 inhibitory activity similar to filgotinib, but compound 44 showed superior JAK1 / JAK2 selectivity and inhibitory activity compared to filgotinib.

[0610] <Experimental Example 2. Pharmacokinetics>

[0611] The pharmacokinetic test method for the compound of the present invention is as follows.

[0612] - Experiment Overview: By studying changes in the body's kinetics, such as absorption, distribution, metabolism, and excretion of a compound, through in vivo pharmacokinetic experiments, the drug-likeness of the drug can be identified, and furthermore, information necessary for interpreting the drug's efficacy and toxicity manifestation can be obtained. After administering the drug to 9-week-old ICR mice that had undergone an acclimatization period, blood was collected at predetermined times (15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours).

[0613] - Preparation of the administered substance: The concentration of the prepared solution was 2 mg / mL (PO), and it was dissolved or suspended by adding DMSO equivalent to 5% of the total amount of the drug, then PEC400 equivalent to 40% of the total amount of the drug was added, and finally sterile distilled water equivalent to 55% of the remaining total amount of the drug was added.

[0614] - Sample Pretreatment: ① Centrifuge blood (13,000 rpm, 4 o C, 2 min) After separating plasma -70 oStore at C, add 9 times the volume of cold acetonitrile containing the internal standard, and deproteinize. ② After centrifugation (13,000 rpm, 4 ℃, 10 min), analyze the supernatant by LC-MS / MS. ③ For the calibration curve sample (0.5-8,000 ng / mL), prepare it by adding a 10 times high-concentration solution to the blank plasma and prepare it using the same method as the test sample.

[0615] - Analysis equipment: Mass sepctrometry (Agilent 6460) with HPLC (Agilent 1260)

[0616] - PK parameter analysis: Calculated using the Phoenix WinNonlin (Pharsight ver 6.4, USA) non-compartmental analysis model.

[0617] Table 3 below shows the PK parameters of filgotinib, Compound 40, and Compound 44 in male mice. As shown in the experimental results of the pharmacokinetic data in Table 3, when administered orally, Compound 40 and Compound 44 of the present invention compared to filgotinib, C max It was confirmed that the AUC data was superior.

[0618] - Pharmacokinetic parameters of selected compounds in male mice

[0619] - PO 10 mg / kg and IV 5 mg / kg

[0620] - NA, Not applicable, PO: Oral, IV: Intravenous injection

[0621] parameters Filgotinib compound 40 compound 44POIVPOIVPOIVC max (μg / mL)2.53NA7.51NA4.84NAT 1 / 2 (h)3.23.432.793.502.93.64T max 0.25NA0.25NA0.33NAAUC last(μg.h / mL)3.313.047.147.929.076.52AUC8(μg.h / mL)3.313.057.157.939.096.53CL (L / h / kg)NA1.65NA0.65NA0.80V ss (L / kg)NA2.10NA0.93NA1.41F t (%)54.3NA45.1NA69.6NA

[0622] <Experimental Example 3. Metabolic Stability Experiment Using Mouse and Human Microsomes>

[0623] In this drug metabolic stability experiment, the drug's phase I stability is measured by exposing liver microsomes, whose metabolic enzyme systems are activated by NADPH, to the drug for a certain period and quantifying the remaining drug amount using LC-MS / MS. The activity of the enzyme system was confirmed by the % remaining value of the reference compound, buspirone, obtained after a 30-minute reaction in these systems (<10% for humans, <5% for rats and mice). The detailed experimental method is as follows:

[0624] (1) Microsomes diluted with potassium phosphate buffer are cultured at 37°C for 5 minutes, then the drug and NADPH are added and reacted at 37°C for 30 minutes. (test compound final concentration: 1μM, microsome final concentration: 0.5mg / mL)

[0625] (2) To terminate the reaction, add cold acetonitrile containing internal standard to deproteinize.

[0626] (3) After centrifugation (4000 rpm, 4℃, 15 min), 100 μL of the supernatant is analyzed by LC-MS / MS.

[0627] The experimental materials are as follows:

[0628] 1) Buspirone hydrochloride (Cat# B7148, Sigma)

[0629] 2) Test Compound stock solution (10mM in DMSO)

[0630] 3) 0.5 M Potassium Phosphate buffer (pH 7.4) (Cat# 451201, Corning)

[0631] 4) Mouse liver microsomes (Cat# 452701, Corning), Mixed Gender Pooled 150-donor Human liver microsomes (Cat# 452117, Corning)

[0632] 5) NADPH Solution A (Cat# 451220, Corning), NADPH Solution B (Cat# 451200, Corning)

[0633] Table 4 shows the results of measuring the metabolic stability of the compounds using mouse and human microsomes. When compared to filgotinib, compounds 16, 34, 40, 44, 65, 69, and 75 of the present invention were found to have similar metabolic stability.

[0634] Compound Liver MSP Pharmacokinetics Mouse (%) Human (%) (PO) 10 mg / kg T max (h)C max(ug / mL)T1 / 2 (h)AUCt (ug·h / mL)AUC (ug·h / mL)Filgotinib 80.30± 0.66 86.62± 2.45 Compound 167 3.94± 5.24 83.9± 3.6 Compound 195 4.34± 4.96 86.79± 8.95 Compound 347 0.61± 1.84 73.64± 5.11 Compound 384 7.07± 1.62 69.33± 0.87 Compound 406 8.86± 4.34 68.07± 4.94 0.25± 0.7.51± 1.35 2.79± 0.97 7.14± 1.94 7.15± 1.93 Compound 4466.35± 2.4375.81± 0.440.33± 0.144.84± 1.262.9± 0.119.07± 2.69.09± 2.61 Compound 6570.47± 3.1470.28± 3.67 Compound 6772.06± 2.0975.49± 6.530.25± 020.31± 0.912.31± 0.0626.07± 0.5926.08± 0.59 Compound 6977.05± 2.3881.17± 5.53 Compound 7562.48± 4.4669.4± 0.68

[0635] <Preparation Example 1. Preparation of Powder>

[0636] 1 2g of the compound of the present invention and 1g of lactose were mixed and filled into an airtight bag to prepare a powder.

[0637] <Preparation Example 2. Preparation of Tablets>

[0638] 100 mg of compound 1 of the present invention, 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 them according to a conventional method for manufacturing tablets.

[0639] <Preparation Example 3. Preparation of Capsules>

[0640] 100 mg of compound 1 of the present invention, 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 the above ingredients were mixed according to a conventional method for manufacturing capsules and filled into a gelatin capsule to produce a capsule.

[0641] <Preparation Example 4. Preparation of Pills>

[0642] 90 mg of the compound of the present invention, 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 that inhibit hygroscopicity, and then 100 mg of pills were prepared according to a conventional method.

[0643] <Preparation Example 5. Preparation of Injectable>

[0644] 10 mg of the compound of the present invention, an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjuster were mixed, and then prepared according to a conventional method of preparing an injectable drug, with the above-mentioned ingredient content per ampoule (2 ml).

Claims

1. A compound represented by the following chemical formula 1, its stereoisomers, its solvates, or pharmaceutically acceptable salts thereof. [Chemical Formula 1] In the above chemical formula 1, R1 is hydrogen, -CH2R3, -(CH2) 0-2 SO2R3, -SO2(CH2) 0-2 R3, -C(=O)(CH2) 0-1 R3, -C(=O)CH2CN, -CH2CN or -tert-butoxycarbonyl group; The above R3 is hydrogen, substituted or unsubstituted C1-C3 alkyl, halo C1-C3 alkyl, cyano, C1-C 10 Alkoxy, substituted or unsubstituted C3-C9 cycloalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C5-C 12 Heterocycloalkyl, substituted or unsubstituted C5-C 12 Aryl, or substituted or unsubstituted C5-C 12 It is heteroaryl, and The above-mentioned substituted alkyl, cycloalkyl, heterocycloalkyl, benzyl, aryl, or heteroaryl each have one or more hydrogen atoms that are halogen, hydroxy, cyano, C1-C3alkyl, halo C1-C3alkyl, or C1-C 10 Substituted with alkoxy, -C(=O)C1-C3alkyl, -SO2F; R2 is hydrogen, or is; R4 is a hydrogen or a tert-butoxycarbonyl group; m is independently 1 or 2 and; n is an integer from 1 to 3.

2. In Paragraph 1, In the above chemical formula 1, R1 is hydrogen, -CH2R3, -(CH2) 0-2 SO2R3, -SO2(CH2) 0-2 R3, -C(=O)(CH2) 0-1 R3, -C(=O)CH2CN, -CH2CN or -Boc(t-butoxycarbonyl); The above R3 is hydrogen, substituted or unsubstituted C1-C3 alkyl, halo C1-C3 alkyl, cyano, C1-C 10 Alkoxy, substituted or unsubstituted cyclopropyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted dibenzofuranyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolo[2,1-b]thiazolyl, substituted or unsubstituted pyrazoleo[5,1-b]thiazolyl, or substituted or unsubstituted imidazo[2,1-b]thiazolyl, and The above-mentioned substituted alkyl, cyclopropyl, tetrahydropyranyl, benzodioxanyl, phenyl, pyridinyl, pyrazinyl, benzothiophenyl, indazolyl, quinolinyl, dibenzofuranyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolo[2,1-b]thiazolyl, pyrazoleo[5,1-b]thiazolyl, or imidazo[2,1-b]thiazolyl each have one or more hydrogen atoms that are halogen, hydroxy, cyano, C1-C3 alkyl, halo C1-C3 alkyl, C1-C 10 Substituted with alkoxy, -C(=O)C1-C3alkyl, -SO2F; R2 is is; R4 is hydrogen or t-Boc(t-butoxycarbonyl); m is independently 1 or 2, respectively; n is an integer from 1 to 3; A compound characterized by being, its stereoisomer, its solvate, or its pharmaceutically acceptable salt.

3. In Paragraph 1, In the above chemical formula 1, R1 is -(CH2) 0-2 SO2R3, -SO2(CH2) 0-2 R3, -C(=O)(CH2) 0-1 R3 or -C(=O)CH2CN and; The above R3 is hydrogen, substituted or unsubstituted C1-C3 alkyl, halo C1-C3 alkyl, cyano, C1-C 10 Alkoxy, substituted or unsubstituted cyclopropyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted dibenzofuranyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolo[2,1-b]thiazolyl, substituted or unsubstituted pyrazoleo[5,1-b]thiazolyl, or substituted or unsubstituted imidazo[2,1-b]thiazolyl, and The above-mentioned substituted alkyl, cyclopropyl, tetrahydropyranyl, benzodioxanyl, phenyl, pyridinyl, pyrazinyl, benzothiophenyl, indazolyl, quinolinyl, dibenzofuranyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolo[2,1-b]thiazolyl, pyrazoleo[5,1-b]thiazolyl, or imidazo[2,1-b]thiazolyl each have one or more hydrogen atoms that are halogen, hydroxy, cyano, C1-C3 alkyl, halo C1-C3 alkyl, C1-C 10 Substituted with alkoxy, -C(=O)C1-C3alkyl, -SO2F; R2 is is; m are independently 1 or 2 and sum to an integer of 3; n is an integer from 1 to 3; A compound characterized by being, its stereoisomer, its solvate, or its pharmaceutically acceptable salt.

4. In Paragraph 1, In the above chemical formula 1, R1 is -(CH2) 0-2 SO2R3, -SO2(CH2) 0-2 R3, or -C(=O)(CH2) 0-1 It is R3; The above R3 is hydrogen, substituted or unsubstituted C1-C3 alkyl, halo C1-C3 alkyl, cyano, C1-C 10 Alkoxy, substituted or unsubstituted cyclopropyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted dibenzofuranyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolo[2,1-b]thiazolyl, substituted or unsubstituted pyrazoleo[5,1-b]thiazolyl, or substituted or unsubstituted imidazo[2,1-b]thiazolyl, and The above-mentioned substituted alkyl, cyclopropyl, tetrahydropyranyl, benzodioxanyl, phenyl, pyridinyl, pyrazinyl, benzothiophenyl, indazolyl, quinolinyl, dibenzofuranyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolo[2,1-b]thiazolyl, pyrazoleo[5,1-b]thiazolyl, or imidazo[2,1-b]thiazolyl each have one or more hydrogen atoms that are halogen, hydroxy, cyano, C1-C3 alkyl, halo C1-C3 alkyl, C1-C 10 Substituted with alkoxy, -C(=O)C1-C3alkyl, -SO2F; R2 is is; m are independently 1 or 2 and sum to an integer of 3; n is an integer of 1; A compound characterized by being, its stereoisomer, its solvate, or its pharmaceutically acceptable salt.

5. In Paragraph 1, The compound of Chemical Formula 1 above is N-(5-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 1); N-(5-(1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide(compound 2); N-(5-(2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 3); N-(5-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 4); N-(5-(1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide(compound 5); N-(5-(2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 6); tert-butyl 7-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (compound 7); N-(5-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 8); N-(5-(2-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 9); tert-butyl 5-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridine-5-yl)isoindolin-2-carboxylate (compound 10); N-(5-(isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 11); N-(5-(2-(2-(methylsulfonyl)ethyl)isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 12); N-(5-(2-(methylsulfonyl)isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 13); N-(5-(2-(ethylsulfonyl)isoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 14); N-(5-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 15); N-(5-(2-(ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 16); tert-butyl 6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (compound 17); N-(5-(1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide hydrochloride (compound 18); N-(5-(2-acetyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 19); N-(5-(2-nicotinoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 20); N-(5-(2-((5-chloro-3-methylbenzo[b]thiophene-2-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 21); N-(5-(2-(thiophene-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 22); N-(5-(2-(quinoline-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 23); N-(5-(2-(6-methylpicolinoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 24); N-(5-(2-(isopropylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 25); N-(5-(2-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 26); N-(5-(2-(5-chloro-1H-indazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 27); N-(5-(2-(3,4-difluorobenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 28); N-(5-(2-((2-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 29); N-(5-(2-((2,4-dichlorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 30); N-(5-(2-(2-cyanoacetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 31); N-(5-(2-(3-bromo-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 32); N-(5-(2-((4-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 33); N-(5-(2-((trifluoromethyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 34); N-(5-(2-(1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 35); N-(5-(2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 36); N-(5-(2-(2-(2-bromophenyl)acetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 37); N-(5-(2-(pyrazine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 38); N-(5-(2-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 39); N-(5-(2-(1H-indazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 40); N-(5-(2-((5-fluoro-2-methylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 41); N-(5-(2-(benzylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 42); N-(5-(2-((1-methyl-1H-imidazole-4-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 43); N-(5-(2-(4-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 44); N-(5-(2-((4-bromo-2-methylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 45); N-(5-(2-((2,5-dimethylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 46); N-(5-(2-(2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 47); N-(5-(2-(5-chloro-2-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 48); N-(5-(2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 49); N-(5-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 50); N-(5-(2-((4-chlorobenzyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 51); N-(5-(2-((4-bromo-2-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 52); N-(5-(2-(pyridine-3-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 53); N-(5-(2-(pyridine-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 54); N-(5-(2-((4-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 55); N-(5-(2-((5-chlorothiophene-2-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 56); N-(5-(2-(dibenzo[b,d]furan-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 57); N-(5-(2-((3-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 58); N-(5-(2-((tetrahydro-2H-pyran-4-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 59); N-(5-(2-((3-acetylphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 60); N-(5-(2-((5-methylthiophene-2-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 61); N-(5-(2-((3-cyano-5-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 62); N-(5-(2-(thiophene-3-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 63); N-(5-(2-(5-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 64); N-(5-(2-(5-cyanothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 65); N-(5-(2-(thiazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 66); N-(5-(2-(2,4-dimethylthiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 67); N-(5-(2-(4-chlorothiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 68); N-(5-(2-(4-methylthiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 69); N-(5-(2-(cyanomethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 70); 4-((6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)benzenesulfonyl fluoride (compound 71); N-(5-(2-(2-chlorothiazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 72); N-(5-(2-(isothiazol-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 73); N-(5-(2-(pyrrolo[2,1-b]thiazole-6-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 74); N-(5-(2-(thiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 75); N-(5-(2-((6-chloroimidazo[2,1-b]thiazole-5-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 76); N-(5-(2-(4-(trifluoromethyl)thiazole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 77); N-(5-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopropanecarboxamide (compound 78); (6-(2-amino-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3,4-dihydroisoquinoline-2(1H)-yl)(4-chlorothiazole-5-yl)methanone(compound 79); tert-butyl 3-((5-(2-(4-chlorothiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)carbamoyl)azetidine-1-carboxylate (compound 80); and N-(5-(2-(4-chlorothiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (Compound 81); A compound or a pharmaceutically acceptable salt thereof characterized by being selected from the group consisting of 6. A pharmaceutical composition for the prevention or treatment of cancer, rheumatoid arthritis, psoriatic arthritis, atopy, Crohn's disease, or ulcerative colitis, comprising as an active ingredient a compound of any one of claims 1 to 5, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

7. In Paragraph 6, A pharmaceutical composition characterized in that the above cancer is a solid tumor or a blood cancer.

8. In Paragraph 7, A pharmaceutical composition characterized in that the above-mentioned solid tumor is lung cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cavity cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, small intestine cancer, colorectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, or skin cancer.

9. In Paragraph 7, A pharmaceutical composition characterized in that the above blood cancer is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), Abelson oncogene-associated CML (Bcr-ABL translocation), myelodysplastic syndrome (MDS), acute B lymphoblastic leukemia (B-ALL), acute T lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myeloproliferative neoplasm (MPN), Richter syndrome, hairy cell leukemia (HCL), blastoplasmic plasma cell dendritic neoplasm (BPDCN), non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Hodgkin lymphoma, systemic mastocytosis, or Burkitt lymphoma.

10. In Paragraph 6, The above pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of cancer, rheumatoid arthritis, psoriatic arthritis, atopy, Crohn's disease, or ulcerative colitis, characterized by selectively inhibiting Janus kinase-1 (JAK-1).

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