Azaindole compounds and pharmaceuticals

Abstract

The present invention relates to a compound represented by general formula (1) and a pharmaceutically acceptable salt thereof. [In general formula (1), R1 denotes a group represented by general formula (2) or general formula (3), R2 denotes a hydrogen atom or the like, R3 denotes a substituted or unsubstituted aryl group or the like, R4 denotes a halogen, R5 denotes a substituted or unsubstituted aryl group or the like, R6 and R7 each independently denote a hydrogen atom or the like, R8 denotes a substituted or unsubstituted aryl group or the like, R9 and R10 each independently denote a substituted or unsubstituted alkyl group or the like, R9 and R10 may bond to each other to form a ring, and R11 denotes a substituted or unsubstituted aryl group or the like.]

Description

[Technical Field]

[0001] This invention relates to azaindole compounds and pharmaceuticals. [Background technology]

[0002] MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a key signaling component of the NF-κB pathway. MALT1 is the only paracaspase in humans and transmits signals from B cell receptors and T cell receptors. MALT1 functions as a subunit of the activated CBM (CARD11 / BCL10 / MALT1) complex and activates the NF-κB pathway through two mechanisms: firstly, by recruiting proteins such as TRAF6, TAK1, and IKKα / β as scaffold proteins; and secondly, by cleaving negative regulators of the NF-κB pathway such as RelB, A20, and CYLD as a cysteine ​​protease (see, for example, Non-Patent Literature 1).

[0003] Diseases in which the NF-κB pathway is constitutively activated due to mutations in the B cell receptor pathway, such as CD79A / B, CARD11, MYD88, or A20, include ABC-DLBCL (activated B-cell diffuse large B-cell lymphoma) and PCNSL (primary central nervous system lymphoma) (see, for example, Non-Patent Documents 2 and 3). BTK inhibitors such as ibrutinib suppress the B cell receptor pathway and have been reported to be clinically effective against ABC-DLBCL and PCNSL (see, for example, Non-Patent Documents 4 and 5). Although ibrutinib is ineffective against ABC-DLBCL with downstream CARD11 mutations (see, for example, Non-Patent Document 4), MALT1 protease inhibitors are effective against ABC-DLBCL with CARD11 mutations because MALT1 is located downstream of BTK signaling (see, for example, Non-Patent Document 6). MALT1 protease inhibitors have shown efficacy in several nonclinical ABC-DLBCL models (see, for example, Non-Patent Document 6).

[0004] MALT1 plays a crucial role in both innate and adaptive immunity. MALT1-deficient mice grow and reproduce normally, but exhibit a reduced lymphocyte immune response (see, for example, Non-Patent Document 7). Humans with MALT1-deficient mutations have normal lymphocyte counts but exhibit a reduced immune response (see, for example, Non-Patent Document 8). MALT1 protease inhibitors suppress IL-2 production from T cells and inhibit T cell proliferation (see, for example, Non-Patent Document 9). MALT1 protease inhibitors also reduce the onset and progression of multiple sclerosis (see, for example, Non-Patent Document 10).

[0005] On the other hand, MALT1 protease-deficient mice develop autoimmune disease-like conditions along with a decrease in regulatory T cells (see, for example, Non-Patent Document 11). Furthermore, since MALT1 protease inhibitors enhance the tumor-suppressive effect of anti-PD-1 antibodies through the degeneration of regulatory T cells in malignant melanoma, it is thought that MALT1 protease inhibitors have tumor immune-activating effects (see, for example, Non-Patent Document 12).

[0006] Therefore, MALT1 inhibitors are expected to be effective against a variety of inflammatory diseases, hematological malignancies, and solid tumors. Specifically, inflammatory diseases include multiple sclerosis (see, e.g., Non-Patent Document 10), rheumatoid arthritis, psoriasis (see, e.g., Patent Document 13), immune thrombocytopenia (see, e.g., Non-Patent Document 14), and spinal cord injury (see, e.g., Non-Patent Document 15). Furthermore, because they suppress T cell activation, they are expected to be effective against graft-versus-host disease associated with bone marrow transplantation, organ transplant rejection, aplastic anemia, Behçet's disease, nephrotic syndrome, generalized myasthenia gravis, and atopic dermatitis, similar to cyclosporine. In hematological malignancies, efficacy is expected against diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, multiple myeloma, Benta syndrome, adult T-cell leukemia / lymphoma, peripheral T-cell lymphoma, Sézary syndrome, primary exudative lymphoma (see, e.g., Non-Patent Document 16), chronic lymphocytic leukemia / small lymphocytic leukemia (see, e.g., Non-Patent Document 17), primary central nervous system lymphoma (see, e.g., Non-Patent Document 3), intraocular lymphoma, primary macroglobulinemia, and lymphoplasmacytic lymphoma. In solid tumors, efficacy is expected against brain tumors (see, e.g., Non-Patent Document 18). Furthermore, through tumor immune activation, it is expected to be effective against malignant melanoma (see, for example, Non-Patent Document 12), non-small cell lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural mesplenomegaly, colorectal cancer, and esophageal cancer, in which anti-PD-1 antibodies are effective. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Jaworski et al., Cellular and Molecular Life Sciences,2016,73,459-473. [Non-Patent Document 2] Staudt et al., Cold Spring Harbor Perspectives in Biology,2010,2, 1-30. [Non-Patent Document 3] Chihara et al., Clinical Lymphoma, Myeloma & Leukemia,2020,21,73-79. [Non-Patent Document 4] Wilson et al., Nature Medicine, 2015, 21, 922-927. [Non-Patent Document 5] Low et al., CNS Oncology, 2020, 9, CNS51. [Non-Patent Document 6] Fontan et al., The Jornal of Clinical Investigation, 2018, 128, 4397-4412. [Non-Patent Document 7] Ruefli-Brasse et al., Science, 2003, 302, 1581-1584. [Non-Patent Document 8] Jabara et al., Journal of Allergy and Clinical Immunology, 2003, 132, 151-158. [Non-Patent Document 9] Bardet et al., Immunology & Cell Biology,2018,96,81-99. [Non-Patent Document 10] Brustle et al., The Jornal of Clinical Investigation, 2012, 122, 4698-4709. [Non-Patent Document 11] Jaworski et al., The EMBO Journal,2014,33,2765-2781. [Non-Patent Document 12] Pilato et al., Nature, 2019, 570, 112-116. [Non-Patent Document 13] Demeyer et al., Trends in Molecular Medicine, 2016, 22, 135-150. [Non-Patent Document 14] Nakamura et al., International Immunopharmacology,2018,56,193-196. [Non-Patent Document 15] Zhang et al., Science Bulletin, 2019, 64, 1179-1194. [Non-Patent Document 16] Juilland et al., Oncotarget,2018,9,12542-12543. [Non-Patent Document 17] Saba et al., Cancer Research, 2017, 77, 7038-7048. [Non-Patent Document 18] Liu et al., Journal of Cellular and Molecular Medicine, 2020, 24, 7550-7562. [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of the present invention is to provide a compound having MALT1 inhibitory activity, or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0009] In other words, the present invention can be described as follows: (Item 1) to (Item 11).

[0010] (Section 1) Compounds represented by general formula (1), or pharmaceutically acceptable salts thereof (hereinafter collectively referred to as "the compounds of the present invention"): [ka] [In general formula (1), R 1 This indicates a group represented by general formula (2) or general formula (3), [ka]

Chem.

Chem.

Chem.

[0011] (Section 4) A compound selected from the group consisting of the following compounds (1) to (36), or a compound thereof that is pharmaceutically acceptable. salt. (1)[5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (2)[5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (3) {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}acetonitrile, (4)[5-Chloro-1-(2-hydroxyethyl)-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (5) 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-yl)ethane-1-one, (6)[5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (7)[5-Chloro-1-ethyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (8)[5-Chloro-1-propyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (9)[5-Chloro-1-(3-hydroxypropyl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (10)[5-chloro-1-(oxetan-3-yl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (11)[5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (12)[5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (13)[5-Chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (14)[5-Chloro-1-ethyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (15)[5-Chloro-1-(3-hydroxypropyl)-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (16)[5-Chloro-1-cyclopropyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (17)[5-chloro-1-isopropyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (18)[5-Chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (19)[5-Chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (20)[5-chloro-1-(oxan-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (21){5-chloro-1-[(3S)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (22){5-chloro-1-[(3R)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (23)[5-Chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(5-fluoronaphthalene-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (24)[5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (25)[5-Chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-c]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (26)[5-Chloro-1-propyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (27)[5-Chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-( Pirazoro [1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (28)[1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (29)[1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (30) 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}isoquinoline-1(2H)-one, (31)9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one, (32)(5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)[1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (33)[(2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (34)[(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (35){5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-yl}(piperazine-1-yl)methanone, (36)[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone. (Section 5) A pharmaceutical composition containing any of the compounds described in (Item 1) to (Item 4) above, or a pharmaceutically acceptable salt thereof, as an active ingredient. (Section 6) A MALT1 inhibitor containing one of the compounds described in any of the above items (1) to (4), or a pharmaceutically acceptable salt thereof, as an active ingredient. (Section 7) A method for inhibiting MALT1, comprising administering a compound described in any of the above items (1) to (4), or a pharmaceutically acceptable salt thereof, to a subject requiring such treatment. (Section 8) A compound described in any of the above (items 1) to (4), or a pharmaceutically acceptable salt thereof, for use in MALT1 inhibition. (Section 9) Use of any of the compounds described in (1) to (4) above, or pharmaceutically acceptable salts thereof, in the manufacture of MALT1 inhibitors. (Section 10) A preventive or therapeutic agent for diseases involving MALT1, comprising any of the compounds described in (item 1) to (item 4) above, or a pharmaceutically acceptable salt thereof, as an active ingredient. (Section 11) A method for preventing or treating a disease involving MALT1, comprising administering a compound described in any of the above items (1) to (4), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. (Section 12) The present invention's compounds, or pharmaceutically acceptable salts thereof, for use in the prevention or treatment of diseases involving MALT1. (Section 13) Use of the compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a preventive or therapeutic agent for a disease involving MALT1. (Section 14) A compound described in any of items (1) to (4), or a pharmaceutically acceptable salt thereof, is contained as an active ingredient in multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, organ transplant rejection, aplastic anemia, Behçet's disease, nephrotic syndrome, generalized myasthenia gravis, atopic dermatitis, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, multiple myeloma, BENTA A treatment for syndrome, adult T-cell leukemia / lymphoma, peripheral T-cell lymphoma, Sézary syndrome, primary exudative lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia, primary central nervous system lymphoma, intraocular lymphoma, primary macroglobulinemia, lymphoplasmacytic lymphoma, brain tumors, malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural mesplenomegaly, colorectal cancer, or esophageal cancer. [Modes for carrying out the invention]

[0012] The following describes in detail embodiments for carrying out the present invention. However, the present invention is not limited to the following embodiments.

[0013] In this specification, "alkyl group" means a monovalent group obtained by removing one hydrogen atom from a saturated hydrocarbon. Alkyl groups may be linear or branched. Alkyl groups may be C1-C6 alkyl groups, C1-C4 alkyl groups, or C1-C3 alkyl groups. In this specification, "C a ~C b " means that the number of carbon atoms is a to b. Specific examples of alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group (1-methylethyl group), n-butyl group, sec-butyl group, isobutyl group (2-methylpropyl group), tert-butyl group, n-pentyl group, neopentyl group, isopentyl group, sec-pentyl group, 3-pentyl group, tert-pentyl group, n-hexyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1,1,2,2-tetramethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, etc.

[0014] In this specification, "substituted alkyl group" means a group in which one or more hydrogen atoms of an alkyl group are substituted with substituents. Examples of substituents in a substituted alkyl group include hydroxyl groups, cyano groups, halogens, amino groups, monosubstituted amino groups, disubstituted amino groups, nitro groups, alkyl groups, alkoxy groups, aryloxy groups, heteroaryloxy groups, saturated heterocyclic groups, aryl groups, heteroaryl groups, acyl groups, oxo groups, and the like. These substituents may be further substituted with other substituents, or they may be bonded to each other to form a ring.

[0015] In this specification, "cycloalkyl group" means a monovalent group obtained by removing one hydrogen atom from a cyclic saturated hydrocarbon. A cycloalkyl group may be a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C3-C4 cycloalkyl group. Specific examples of cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.

[0016] In this specification, "substituted cycloalkyl group" means a group in which one or more hydrogen atoms of a cycloalkyl group are substituted with substituents. Examples of substituents in a substituted cycloalkyl group include those described above.

[0017] In this specification, "heterocyclic group" means a non-aromatic, cyclic, monovalent group containing a heteroatom in the ring. The number of heteroatoms in the ring of a heterocyclic group may be, for example, 1 to 5, 1 to 3, 1 to 2, or 1. The heterocyclic group may be a monocyclic or a fused ring. The heterocyclic group may have an unsaturated bond in the ring (unsaturated heterocyclic group) or may not have an unsaturated bond (saturated heterocyclic group). Specific examples of heterocyclic groups include oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, azetidinyl group, tetrahydro-1,1-dioxide-2H-thiopyranyl group, and quinolidinone group.

[0018] In this specification, "substituted heterocycle" means a group in which one or more elements (elements not constituting the ring) of the heterocycle are substituted with substituents. Examples of substituents in a substituted heterocycle include those described above.

[0019] In this specification, "aryl group" means a monovalent group of a cyclic aromatic hydrocarbon. The aryl group may be a monocyclic or fused ring. Specific examples of aryl groups include the phenyl group and the naphthyl group.

[0020] In this specification, "substituted aryl group" means an aryl group in which one or more elements (elements that do not constitute a ring) are substituted with substituents. Examples of substituents in a substituted aryl group include those described above.

[0021] In this specification, "heteroaryl group" means an aromatic, cyclic, monovalent group containing a heteroatom in the ring. The number of heteroatoms in the ring of a heteroaryl group may be, for example, 1 to 5, 1 to 3, 1 to 2, or 1. The heteroaryl group may be a monocyclic or a fused ring. Specific examples of heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, isoquinolyl, quinolidinyl, 1,2,3-benzothiadiazolyl, thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl, 1(2H)-oxoisoquinolyl, pyrazolo[1,5-a]pyridyl, and 2,7-naphthilidinyl.

[0022] In this specification, "substituted heteroaryl group" means a heteroaryl group in which one or more elements (elements that do not constitute a ring) are substituted with substituents. Examples of substituents in a substituted heteroaryl group include those described above.

[0023] In this specification, "alkoxy group" means an oxy group to which an alkyl group is attached. Specific examples of alkoxy groups include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group, pentyloxy group, and 3-methylbutoxy group.

[0024] In this specification, "substituted alkoxy group" means a group in which one or more hydrogen atoms of an alkoxy group are substituted with substituents. Examples of substituents in a substituted alkoxy group include those described above.

[0025] In this specification, "aryloxy group" means an oxy group to which an aryl group is attached. Specific examples of aryloxy groups include phenoxy group and naphthyloxy group.

[0026] In this specification, "substituted aryloxy group" means a group in which one or more elements (elements that do not constitute a ring) of the aryloxy group are substituted with substituents. Examples of substituents in a substituted aryloxy group include those described above.

[0027] In this specification, "heteroaryloxy group" means an oxy group to which a heteroaryl group is attached. Specific examples of heteroaryloxy groups include furyloxy group, thienyloxy group, pyrrolyloxy group, imidazolyloxy group, pyrazolyloxy group, thiazolyloxy group, piperazinyloxy group, and the like.

[0028] In this specification, "substituted heteroaryloxy group" means a group in which one or more elements (elements that do not constitute a ring) of the heteroaryloxy group are substituted with substituents. Examples of substituents in a substituted heteroaryloxy group include those described above.

[0029] In this specification, "halogen" means a group consisting of a halogen atom (halogeno group). Examples of halogens include fluoro groups, chloro groups, bromo groups, and iodo groups.

[0030] The compound of the present invention is a compound represented by general formula (1), or a pharmaceutically acceptable salt thereof. [ka]

[0031] In general formula (1), R 1 This indicates a group represented by general formula (2) or general formula (3). [ka] [ka]

[0032] In general formula (1), R 2 This represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group, preferably a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted monocyclic saturated heterocyclic group, more preferably a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a hydroxyl group or a cyano group, a C3-C6 cycloalkyl group, a monocyclic saturated heterocyclic group substituted with an acetyl group or an oxo group, or an unsubstituted monocyclic saturated heterocyclic group, and more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group, 2 It is more preferably a hydroxyethyl group, a 3-hydroxypropyl group, a cyanomethyl group, an oxetanyl group (e.g., a 3-oxetanyl group), a tetrahydrofuranyl group (e.g., a 3-tetrahydrofuranyl group), a tetrahydropyranyl group (e.g., a 4-tetrahydropyranyl group), a cyclopropyl group, a cyclobutyl group, a 1-acetylazetidinyl group (e.g., a 3-1-acetylazetidinyl group), or a tetrahydro-1,1-dioxide-2H-thiopyranyl group (e.g., a 4-tetrahydro-1,1-dioxide-2H-thiopyranyl group), and even more preferably a methyl group, an ethyl group, or an n-propyl group, and particularly preferably a methyl group.

[0033] In general formula (1), R 3 This refers to a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a group represented by general formula (4), or a group represented by general formula (5). [ka] [In general formula (4), R 9 and R 10Each of these independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, R 9 and R 10 They may be connected to each other, forming a ring. [ka] [In general formula (5), R 11 This indicates a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group.

[0034] R 3 It is preferably an aryl group, a heteroaryl group, an alkoxy group, an aryloxy group, a heteroaryloxy group, a group represented by general formula (4), or a group represented by general formula (5); more preferably a heteroaryl group, an alkoxy group, a group represented by general formula (4), or a group represented by general formula (5); even more preferably a 1,2,3-triazolyl group (e.g., a 2-1,2,3-triazolyl group), a pyrimidyl group (e.g., a 2-pyrimidyl group), a methoxy group, a group represented by general formula (4), or a group represented by general formula (5); and even more preferably a 1,2,3-triazolyl group or a pyrimidyl group.

[0035] In general formula (4), R 9 and R 10 Each of these independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. 9 and R 10 They may be connected to each other, forming a ring. 9 and R 10 Preferably, they are connected to each other and form a ring, R 9 and R 10 It is more preferable that the nitrogen atom to which it is bonded forms a piperazine ring.

[0036] In general formula (5), R 11This represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group, preferably a saturated heterocyclic group, and more preferably a piperazinyl group (e.g., a 1-piperazinyl group).

[0037] In general formula (1), R 4 The group exhibits a halogen, and is preferably a chloro group.

[0038] In general formula (2), R 5 This represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, with a substituted aryl group or a substituted heteroaryl group being preferred, an aryl group substituted with a bromo group, chloro group, fluoro group, amino group, or iodo group, or a heteroaryl group substituted with a bromo group, chloro group, fluoro group, amino group, or iodo group being preferred, a phenyl group substituted with a bromo group, chloro group, fluoro group, amino group, or iodo group, a pyridinyl group substituted with a bromo group, chloro group, fluoro group, or iodo group being more preferred, a 1-amino-3-fluorophenyl group (e.g., 6-1-amino-3-fluorophenyl group), a 5-bromopyrimidinyl group (e.g., 6-5-bromopyrimidinyl group), a 3-iodo-5-fluoropyrimidinyl group (e.g., 2-3-iodo-5-fluoropyrimidinyl group) being more preferred, and a 3-iodo-5-fluoropyrimidinyl group being particularly preferred.

[0039] In general formula (2), R 6 and R 7 Each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group, preferably a substituted or unsubstituted alkyl group, more preferably a C1-C6 alkyl group, even more preferably a C1-C3 alkyl group, and still more preferably a methyl group. 6 and R 7 It is particularly preferable that all of them are methyl groups. 6 If R is not a hydrogen atom, 6The carbon atom to which it is bonded becomes the chiral center. In this case, the stereochemistry may be R or S, but R is preferred. Similarly, R 7 If R is not a hydrogen atom, 7 The carbon atom to which it is bonded becomes the chiral center. In this case, the stereochemistry may be R or S, but R is preferred. 6 The carbon atom to which it is bonded, and R 7 When both carbon atoms to which are bonded are chiral centers, it is particularly preferable that the stereochemistry of both is R.

[0040] In general formula (3), R 8 This represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group, preferably a substituted or unsubstituted aryl group of a fused ring, a substituted or unsubstituted heteroaryl group of a fused ring, or a substituted or unsubstituted heterocyclic group of a fused ring, more preferably a fluoro-substituted aryl group of a fused ring, a fluoro-substituted heteroaryl group of a fused ring, an unsubstituted heteroaryl group of a fused ring, an oxo-substituted heterocyclic group of a fused ring, or an unsubstituted heterocyclic group of a fused ring, and is an 8-fluoroisoquinolyl group (e.g., 4-8-fluoroisoquinolyl group), a 4-quinolidinone group (e.g., It is more preferably an 8-4-quinolidinone group, a 1-fluoronaphthyl group (e.g., a 5-1-fluoronaphthyl group), a 1,2,3-benzothiadiazolyl group (e.g., a 7-1,2,3-benzothiadiazolyl group), a pyrazolo[1,5-a]pyridyl group (e.g., a 4-pyrazolo[1,5-a]pyridyl group), a thieno[2,3-b]pyridyl group (e.g., a 4-thieno[2,3-b]pyridyl group), a thieno[2,3-c]pyridyl group (e.g., a 3-thieno[2,3-c]pyridyl group), or a 1(2H)-oxoisoquinolyl group (e.g., a 5-1(2H)-oxoisoquinolyl group), and even more preferably an 8-fluoroisoquinolyl group.

[0041] In general formulas (1), (2), (3), (4), and (5), the dashed lines indicate couplings.

[0042] The compound according to this embodiment may be a compound represented by general formula (6). [ka]

[0043] In general formula (6), R 2 , R 3 , R 4 , R 5 , R 6 and R 7 This is equivalent to what was explained in general formula (1).

[0044] The compound according to this embodiment may be a compound represented by general formula (7). [ka]

[0045] In general formula (7), R 2 , R 3 , R 4 and R 8 This is equivalent to what was explained in general formula (1).

[0046] Specific examples of compounds represented by general formula (1) include the following compounds (1) to (36). (1)[5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (2)[5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (3) {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}acetonitrile, (4)[5-Chloro-1-(2-hydroxyethyl)-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (5) 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-yl)ethane-1-one, (6)[5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (7)[5-Chloro-1-ethyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (8)[5-Chloro-1-propyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (9)[5-Chloro-1-(3-hydroxypropyl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (10)[5-chloro-1-(oxetan-3-yl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (11)[5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (12)[5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (13)[5-Chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (14)[5-Chloro-1-ethyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (15)[5-Chloro-1-(3-hydroxypropyl)-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (16)[5-Chloro-1-cyclopropyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (17)[5-chloro-1-isopropyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (18)[5-Chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (19)[5-Chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (20)[5-chloro-1-(oxan-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (21){5-chloro-1-[(3S)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (22){5-chloro-1-[(3R)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (23)[5-Chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(5-fluoronaphthalene-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (24)[5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (25)[5-Chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-c]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (26)[5-Chloro-1-propyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (27)[5-Chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-( Pirazoro [1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (28)[1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (29)[1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (30) 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}isoquinoline-1(2H)-one, (31)9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one, (32)(5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)[1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (33)[(2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (34)[(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (35){5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-yl}(piperazine-1-yl)methanone, (36)[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone.

[0047] The compounds of the present invention can be produced using known compounds or intermediates readily synthesized from known compounds, for example, by the method described below, the examples described later, or other known methods. In the production of the compounds of the present invention, if the starting materials have substituents that affect the reaction, it is common practice to protect the starting materials with an appropriate protecting group beforehand using a known method before carrying out the reaction. The protecting group can be deprotected after the reaction using a known method.

[0048] The meanings of the terms used in this specification are explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms.

[0049] The abbreviations used herein have the following meanings: The following abbreviations are used in the examples. Pd-C: Palladium-Carbon Pd(PPh3)4: Tetraxtriphenylphosphine palladium PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride Pd(OAc)2: Palladium(II) acetate Pd(dppf)2Cl2:[1,1'-bis(diphenylphosphin)ferrocene]-dichloropalladium(II)·dichloromethane adduct PPh3: Triphenylphosphine Boc2O: Ditert-butyl dicarbonate HATU:O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU:O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBt: 1-hydroxybenzotriazole THF: Tetrahydrofuran DMF: Dimethylformamide DMSO: Dimethyl sulfoxide DIPA: Diisopropylamine DIPEA: N,N-diisopropylethylamine TEA: Triethylamine Boc:tert-butoxycarbonyl Cbz: Benzyloxycarbonyl Bn: Benzyl MS: Mass Spectrometry LCMS: High-performance liquid chromatography-mass spectrometry ESI: Electron Spray Ionization M: Molar concentration (mol / L)

[0050] Examples of pharmaceutically acceptable salts of the compounds of the present invention include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; or salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by conventional methods.

[0051] For example, if the compound of the present invention is a hydrochloride salt, it can be obtained by dissolving the free base of the compound of the present invention in an alcoholic solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentyl methyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.

[0052] The compounds of the present invention may incorporate solvent molecules and become solvates when left in the atmosphere or by recrystallization, and such solvates are also included in the compounds of the present invention. Examples of such solvates include solvates with solvent molecules such as methanol, ethanol, isopropyl alcohol, butanol, dimethyl sulfoxide, and acetonitrile, as well as monohydrates and dihydrates.

[0053] Some of the compounds of the present invention have a chiral carbon, and each optical isomer and mixture thereof are all included in the present invention. Stereoisomers can be produced, for example, by optical resolution from a racemate using its basicity with an optically active acid (tartaric acid, dibenzoyl tartaric acid, mandelic acid, 10-camphor sulfonic acid, etc.) by known methods, or by using a pre-prepared optically active compound as a starting material. They can also be produced by optical resolution using a chiral column or by asymmetric synthesis. Furthermore, in the compounds of the present invention, the structural formula of the compound may represent a certain isomer for convenience, but the present invention includes geometric isomers arising from the structure of the compound, optical isomers based on a chiral carbon, stereoisomers, tautomers, and other isomers and mixtures of isomers. Also, unless otherwise specifically specified in a particular claim, the present invention is not limited to the description of the formula for convenience, and is not limited to any of the above, and all are included.

[0054] The compound of the present invention has MALT1 inhibitory activity, as shown in the test examples described below.

[0055] Therefore, one embodiment of the present invention provides a MALT1 inhibitor containing the compound of the present invention.

[0056] Furthermore, one embodiment of the present invention provides a method for inhibiting MALT1, comprising administering the compound of the present invention to a target that requires it.

[0057] Furthermore, one embodiment of the present invention provides a compound for use in MALT1 inhibition.

[0058] Furthermore, one embodiment of the present invention provides the use of the compound of the present invention in the production of a MALT1 inhibitor.

[0059] One embodiment of the present invention provides a preventive or therapeutic agent for a disease involving MALT1, which contains the compound of the present invention.

[0060] Furthermore, in one embodiment of the present invention, a method for preventing or treating a disease involving MALT1 is provided, comprising administering the compound of the present invention to a subject in need thereof.

[0061] Furthermore, in one embodiment of the present invention, a compound of the present invention is provided for use in the prevention or treatment of diseases involving MALT1.

[0062] Furthermore, one embodiment of the present invention provides the use of the compound of the present invention in the manufacture of a preventive or therapeutic agent for a disease involving MALT1.

[0063] Diseases to which the compounds of the present invention can be applied include, for example, multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, organ transplant rejection, aplastic anemia, Behçet's disease, nephrotic syndrome, generalized myasthenia gravis, atopic dermatitis, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, multiple myeloma, and BENTA. Examples include syndrome, adult T-cell leukemia / lymphoma, peripheral T-cell lymphoma, Sézary syndrome, primary exudative lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia, primary central nervous system lymphoma, intraocular lymphoma, primary macroglobulinemia, lymphoplasmacytic lymphoma, brain tumors, malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural mesplenomegaly, colorectal cancer, or esophageal cancer.

[0064] "Subject" refers to a human or non-human animal that has or is suspected of having a disease involving MALT1 or a disease involving MALT1. In one embodiment of the present invention, the subject is a mammal. In one embodiment of the present invention, the subject is a human.

[0065] The compound of the present invention can be used as is, or mixed with a pharmaceutically acceptable carrier, to form a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, which can then be used as a therapeutic agent for various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, and monkeys.

[0066] As a carrier, one or more conventionally accepted pharmaceutically acceptable solid, semi-solid, or liquid diluents, fillers, and other formulation aids are used. The pharmaceutical composition according to the present invention is preferably administered in dose unit form. The pharmaceutical composition can be administered intra-tissue, orally, intravenously, topically (transdermally, ophthalmoscopy, intraperitoneally, intrathoracically, etc.), or rectally. The pharmaceutical composition according to the present invention is administered in a dosage form suitable for these administration methods.

[0067] The dosage of the compound used as a medicine should preferably be adjusted considering the patient's condition, such as age, weight, type and severity of the disease, the route of administration, the type of compound of the present invention, whether it is a salt or not, and the type of salt. However, for adults, the appropriate amount of the active ingredient of the compound of the present invention or its pharmaceutically acceptable salt is usually within the range of 0.01 mg to 5 g per adult per day, preferably within the range of 1 mg to 500 mg per adult, when administered orally. In some cases, a lower dose may suffice, or conversely, a higher dose may be required. It is usually administered once a day or in several divided doses, or, in the case of intravenous administration, it can be administered rapidly or continuously over a period of 24 hours or less.

[0068] One or more hydrogen, carbon, and / or other atoms in the compounds of the present invention may be substituted with isotopes of hydrogen, carbon, and / or other atoms. Examples of such isotopes include, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S,18 F, 123 I and 36 Cl, that is, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, is included. Compounds substituted with such isotopes are also useful as pharmaceuticals and include all radiolabeled forms of the compounds of the present invention.

[0069] The compounds of the present invention can be produced from compounds that are known themselves or intermediates that can be easily prepared from known compounds, for example, by the following methods, the examples described later, or known methods.

[0070] If the solvents, reagents, and raw materials used in each step of the following manufacturing method are commercially available, they may be used as is. Furthermore, the compounds obtained in each step of the manufacturing method described below, and the raw materials used, may form salts and can be converted to other types of salts or free forms by known methods. Conversely, if the compounds obtained in each step of the manufacturing method below, or the raw materials used, are free forms, they can be converted to the desired salt by known methods. Examples of such salts include those similar to the salts used in the compounds of the present invention described above.

[0071] In the production of the compound of the present invention, if the starting material has substituents that may affect the reaction, protecting groups may be introduced to these substituents by known methods beforehand, and the target compound can be obtained by removing the protecting groups as needed after the reaction. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., 2006, by Wuts and Greene, or "Protecting Groups," 3rd edition, Thieme, 2005, by PJ Kocienski, and these may be appropriately selected and used depending on the reaction conditions.

[0072] The compounds obtained in each step of the following manufacturing method can be isolated or purified by conventional methods such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, and chromatography, or they can be used in the next step in the form of a reaction mixture or crude product.

[0073] Unless otherwise specified, the reactions in each step of the following manufacturing methods are carried out by appropriately modifying or combining methods described in, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition" by R.C. Larock, John Wiley & Sons Inc., 1999; "Experimental Chemistry Course" 4th edition, edited by the Chemical Society of Japan, Maruzen, 1992; "Organic Synthesis Strategies Learned from Named Reactions" by L. Kuerti and B. C. Zako, supervised translation by Kiyoshi Tomioka, Kagaku Dojin, 2006; "Latest Organic Synthesis Methods: Design and Strategy" by GS Zweifel and M.H. Nantz, translated by Tamejiro Hiyama, Kagaku Dojin, 2009; or methods described in the examples.

[0074] [1] Synthesis of compound (1) [ka] (R 1 , R 3 , R 3 and R 4 This is synonymous with the above. X 1 represents chloro and bromo, X 2 (These represent chloro, bromo, mesylate, and triflate.) Step 1 This step involves performing a Friedel-Crafts acylation reaction on compound AA, which has been synthesized commercially or by a known method, with acid halide BB in a solvent such as methylene chloride or dichloroethane, in the presence of a Lewis acid such as aluminum chloride, at a temperature of 0°C to 150°C, preferably 60°C to 120°C, for 1 to 48 hours, preferably 12 to 24 hours, to obtain compound (1). Acid halide BB can be obtained by reacting compound LL or compound PP, described later, with oxalyl chloride or oxalyl bromide in a solvent such as methylene chloride or dichloroethane, in the presence of a catalytic amount of dimethylformamide, at a temperature of 0°C to 50°C, preferably 0°C to room temperature, for 1 to 48 hours, preferably 1 to 12 hours. step2 This step involves alkylating compound CC with alkylating agent DD in the presence of a base to obtain compound (1), and can be carried out according to known alkylation methods. The reaction can be carried out by reacting compound CC with alkylating agent DD in a solvent such as dimethylformamide or tetrahydrofuran, in the presence of a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, or cesium carbonate, at a temperature of 0°C to 120°C, preferably room temperature to 120°C, for 1 to 48 hours, preferably 1 to 12 hours.

[0075] [2] Synthesis of compound AAa [ka] (R 4 This is synonymous with the above. 3a X represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted heteroaryloxy group. 2 L represents chloro, bromo, and triflate. 1 (where represents boronic acid, boronic acid ester, alkyltin, zinc halide, etc., and P represents a protecting group, such as Boc, Cbz, Bn, etc.) Step 1 This step involves obtaining compound FF by a coupling reaction between compound CC and EE. Examples of such reactions include the Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, and Stille coupling. Compound FF can be obtained by adding a palladium catalyst such as Pd(PPh3)4, Pd(OAc)2, PdCl2(PPh3)2, or Pd(dppf)2Cl2, a base such as potassium carbonate, sodium carbonate, or potassium phosphate, and commercially available or known synthesized boronic acid, boronic acid ester, trialkyltin, or zinc halide to compound CC in a solvent or mixed solvent such as dioxane, toluene, DMSO, DMF, DME, THF, or water, and reacting the mixture under a nitrogen atmosphere at 0°C to 150°C, preferably 60°C to 120°C, for 0.5 to 24 hours, preferably 1 to 12 hours. The protecting group (P) of compound CC can be introduced by referring to "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., 2006, by Wuts and Greene, or "Protecting Groups," 3rd edition, Thiemes, 2005, by PJ Kocienski. step2 This step involves deprotecting the protecting group of compound FF to obtain AAa, and can be introduced by referring to "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., 2006, by Wuts and Greene, or "Protecting Groups," 3rd edition, Thiemes, 2005, by PJ Kocienski.

[0076] [3] Synthesis of compound AAb [ka] (R 4This is equivalent to what was explained in general formula (1). This process involves adding compound GG, synthesized commercially or by known methods, to HH in a solvent such as acetonitrile in the presence of a base such as potassium carbonate, at a temperature of 0°C to 100°C for 1 to 48 hours, preferably 12 to 24 hours, to obtain compound AAb.

[0077] [4] Synthesis of compound LL [ka] (R 5 , R 6 , R 7 X 2 This is synonymous with the above. R represents alkyl groups such as methyl and ethyl. Step 1 This step involves a nucleophilic substitution reaction (S) of compound II, synthesized by a commercially available or known method, in a solvent such as DMSO or DMF, in the presence of TEA, DIPEA, and compound JJ, at 0°C to 150°C, preferably 120°C to 150°C, for 1 to 48 hours, preferably 1 to 10 hours. N This is a step to obtain compound KK by performing Ar. step2 This step involves hydrolyzing the ester of compound KK to obtain compound LL, and can be synthesized by referring to "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., Wuts and Greene, 2006, or "Protecting Groups," 3rd edition, Thiemes, 2005, PJ Kocienski.

[0078] [5] Synthesis of compound (PP) [ka] (R 8 This is synonymous with the above. R represents alkyl groups such as methyl and ethyl. Step 1 This process involves reacting compound MM and compound NN, synthesized by commercially available or known methods, in a solvent such as ethanol or ether at 0°C to 80°C, preferably ethanol at 60°C to 80°C, for 1 to 48 hours, preferably 1 to 10 hours, to obtain compound OO. step2 This process involves hydrolyzing the ester of compound OO to obtain compound PP, and can be synthesized by referring to "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., 2006, by Wuts and Greene, or "Protecting Groups," 3rd edition, Thiemes, 2005, by PJ Kocienski. [Examples]

[0079] The present invention will be described in more detail below with reference examples, examples, and test examples, but these are not the only examples that define the present invention.

[0080] Mass spectrometry (MS) was measured using LCMS. ESI (electrolysis-like infiltration) was used as the ionization method. The observed mass spectrometry values ​​are expressed in m / z.

[0081] The measurement conditions for LCMS are as follows: Analytical equipment: ACQUITY UPLC MS / PDA system (Waters Corporation) Mass spectrometer: Waters 3100 MS detector Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210~400nm) Column: Acquity BEH C18, 1.7 μm, 2.1 × 50 mm Flow rate: 0.5mL / min Column temperature: 40℃ solvent; Solution A: 0.1% formic acid / H2O (v / v; the same applies below) Solution B: 0.1% formic acid / acetonitrile

[0082] The measurement conditions for chiral column chromatography are as follows. Analytical instrument: i-Series UHPLC model LC-2060C 3D (PDA model) (manufactured by Shimadzu Corporation) Detection wavelength: 220nm Column: CHIRALPAK IB, 0.46 cm I.D. × 25 cm L Flow rate: 1.0 mL / min Column temperature: 40°C Mobile phase: n-Hexane / IPA = 92 / 8 (v / v)

[0083] 1 1H NMR spectra were measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE Inc.). Observed peaks are expressed as chemical shift values δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = double doublet, dt = double triplet).

[0084] Microwave experiments were performed using an Initiator 60 (manufactured by Biotage). A temperature of 40 to 250°C can be achieved, and a pressure of up to 20 bar can be reached.

[0085] Specific optical rotation [α] 589 The measurement conditions are as follows. Analytical instrument: Automatic polarimeter SEPA-500 (manufactured by HORIBA, Ltd.) Optical path length: 50mm

[0086] Melting point was measured using a micro melting point apparatus (Buchi, model B-565).

[0087] The compound names used herein were named using IUPAC-compliant naming software, ACD / NAME (registered trademark, Advanced Chemistry Development Inc.), ChemBioDraw (version 19.1, Cambridge Soft), or in accordance with IUPAC nomenclature.

[0088] The 'r' and 's' (lowercase) in compound names indicate the stereochemistry of the pseudo-chiral carbon atom, according to IUPAC rules.

[0089] Reference Example 1: Synthesis of 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide 5-chloro-1H-pyrrolo[2,3-b]pyridine (30 g) was dissolved in diethyl ether (1.4 L), to which m-chloroperbenzoic acid (94 g) was added in three separate additions, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the resulting yellowish-green filtrate was suspended in water (0.72 L). Then, 23% (w / v) potassium carbonate aqueous solution (0.31 kg) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the resulting filtrate was dried to obtain 25 g of the target compound as a grayish-brown solid.

[0090] Reference Example 2: Synthesis of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (2.6 g) was suspended in acetonitrile (80 mL) and m-chlorobenzoic acid (2.4 g) was added. The mixture was stirred at room temperature for 30 minutes, then dimethyl sulfate (1.5 mL) was added and the mixture was stirred at an ambient temperature of 75°C for 20 hours. After the reaction mixture cooled, potassium carbonate (11 g), 1,2,3-triazole (3.2 g), and acetonitrile (60 mL) were added sequentially and the mixture was stirred at an ambient temperature of 60°C for 6 hours. After the reaction mixture cooled, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain a crude pink solid residue. This residue was slurry-washed with ethyl acetate (10 mL) to obtain 1.6 g of the target compound as a pink solid.

[0091] Reference Example 3: Synthesis of 1-benzoyl-6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine To a toluene (60 mL) solution of ice-cooled benzoyl bromide (3.5 mL), a pre-mixed suspension of bis(trimethylsilyl)amine (2.9 mL), 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (2.0 g), and toluene (60 mL) was added, and the mixture was stirred at room temperature for 2 hours. After adding saturated sodium bicarbonate solution to the reaction mixture, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography to obtain 1.7 g of the target compound as a white solid.

[0092] Reference Example 4: Synthesis of 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine 3.9 g of 1-benzoyl-6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine was mixed with 38 mL of tetrahydrofuran and 76 mL of methanol. 12 mL of 2.0 M aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with 0.10 L of 2.0 M aqueous sodium hydroxide solution, and extraction was performed with chloroform. After washing the organic phase with saturated brine, it was dried over magnesium sulfate, and the solvent was removed by vacuum distillation to obtain 2.7 g of the target compound as a pale yellow solid.

[0093] Reference Example 5: Synthesis of tert-butyl 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate To a solution of 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (1.0 g) in N,N-dimethylformamide (10 mL), di-tert-butyl dicarbonate (hereinafter referred to as "Boc2O") (1.5 mL), triethylamine (1.8 mL), and 4-dimethylaminopyridine (hereinafter referred to as "DMAP") (53 mg) were sequentially added, and the mixture was stirred overnight at room temperature. The reaction mixture was purified by direct column chromatography to obtain 1.4 g of the target compound as a colorless oily substance.

[0094] Reference Example 6: Synthesis of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine To a solution of tert-butyl 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.4 g) in dimethyl sulfoxide (8.3 mL), tetrakis(triphenylphosphine)palladium(0) (0.96 g), lithium chloride (0.53 g), copper(I) chloride (82 mg), and 2-(tributylstannyl)pyrimidine (1.7 g) were sequentially added, and the mixture was stirred overnight at an ambient temperature of 80°C. After the reaction mixture cooled, it was purified by direct column chromatography, and then again by reversed-phase column chromatography (H2O / MeOH) to obtain 0.45 g of the target compound as a pale yellow solid.

[0095] Reference Example 7: Synthesis of tert-butyl (7R)-7-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate To a solution of tert-butyl (2R)-2-methyl-4-oxopiperidine-1-carboxylate (5.2 g) in toluene (0.10 L), ethylene glycol (6.8 mL) and pyridinium p-toluenesulfonate (hereinafter referred to as "PPTS") (1.5 g) were sequentially added, and the mixture was heated under reflux and stirred at an ambient temperature of 145°C for 15 hours. After the reaction mixture was allowed to cool, it was neutralized with saturated sodium bicarbonate solution. Next, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, then with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 4.6 g of the target compound as a colorless oily substance.

[0096] Reference Example 8: Synthesis of tert-butyl (7R,9R)-7,9-dimethyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate It was synthesized according to the method of Feringa et al. (Org. Biomol. Chem., 2008, Vol. 6, pp. 3464-3466). To a solution of tert-butyl (7R)-7-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (15 g) in diethyl ether (0.16 L), tetramethylethylenediamine (hereinafter referred to as "TMEDA") (13 mL) was added. After cooling the reaction mixture to -78°C in a dry ice acetone bath, sec-butyllithium hexane solution (1.22 M, 72 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Subsequently, a solution of methyl iodide (7.3 mL) in diethyl ether (15 mL) was added dropwise, and the mixture was stirred at -78°C for 1 hour, followed by stirring at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography to obtain 8.5 g of the target compound (trans isomer:cis isomer = 10:1) as a white solid. Specific rotation [α] D 21 = +4.79° (c=1.0, chloroform)

[0097] Reference Example 9: Synthesis of tert-butyl (2R,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate To a solution of tert-butyl (7R,9R)-7,9-dimethyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (12 g) in acetone (0.61 L), p-toluenesulfonic acid monohydrate (hereinafter referred to as "PTSA·H2O") (9.1 g) was added and the mixture was stirred at room temperature for 1.5 hours. After cooling the reaction mixture on ice, an aqueous solution of sodium carbonate (6.3 g) (69 g) was added to neutralize the mixture, and the reaction solvent was removed by distillation under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography to obtain 8.9 g of the target compound (trans isomer:cis isomer = 10:1) as a white solid.

[0098] Reference Example 10: Synthesis of tert-butyl (2R,6R)-4-cyano-2,6-dimethylpiperidine-1-carboxylate To a mixed solution of tert-butyl (2R,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate (8.9 g), tert-butyl alcohol (47 mL), and 1,2-dimethoxyethane (0.19 L), toluenesulfonylmethyl isocyanide (hereinafter referred to as "TosMIC") (12 g) was added. After cooling the reaction mixture on ice, tert-butoxypotassium (13 g) was added, and the mixture was stirred at the same temperature for 30 minutes, then stirred at room temperature for 15 hours. After cooling the reaction mixture on ice, it was diluted with water, and the reaction solvent was removed by vacuum distillation. Extraction was performed with ethyl acetate, the organic phase was washed with water, then with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 5.4 g of the target compound as a pale yellow solid.

[0099] Reference Example 11: Synthesis of ethyl (2R,6R)-2,6-dimethylpiperidine-4-carboxylate Process 1 Potassium hydroxide (18g) was added to a mixed solution of tert-butyl (2R,6R)-4-cyano-2,6-dimethylpiperidine-1-carboxylate (13g) in ethanol (0.11L) and water (0.11L), and the mixture was heated under reflux and stirred at an ambient temperature of 95°C for 20 hours. After the reaction mixture cooled, it was diluted with water and neutralized with a 20% (w / v) citric acid aqueous solution to pH=5. Extraction was performed with ethyl acetate, the organic phase was washed with water, then with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a residue (14g) as a white solid. Process 2 The residue (13g) obtained in step 1 was dissolved in hydrochloric acid ethanol solution (2.0M, 0.68L) and heated under reflux and stirred at an ambient temperature of 120°C for 30 hours. After the reaction mixture was allowed to cool, the reaction solvent was removed by distillation under reduced pressure. After cooling the obtained residue with ice, aqueous sodium hydroxide solution (2.0M) was added to adjust the pH to 13. Extraction was performed with chloroform, the organic phase was washed with saturated saline solution, dried with magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 8.9g of the target compound as a yellow oily substance. Specific rotation [α] D 20 = -16.66° (c=1.0, chloroform)

[0100] Reference Example 12: Synthesis of ethyl (2R,6R)-1-(5-fluoro-3-nitropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate To a solution of ethyl (2R,6R)-2,6-dimethylpiperidine-4-carboxylate (2.2 g) in dimethyl sulfoxide (24 mL), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA") (4.0 mL) and 2,5-difluoro-3-nitropyridine (2.1 g) were sequentially added, and the mixture was stirred at an ambient temperature of 140°C for 3 hours. After the reaction mixture cooled, it was purified by direct column chromatography to obtain 2.9 g of the target compound as an orange oily substance.

[0101] Reference Example 13: Synthesis of ethyl (2R,6R)-1-(3-amino-5-fluoropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate To a solution of ethyl (2R,6R)-1-(5-fluoro-3-nitropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate (3.4 g) in methanol (0.10 L), Pt / C type STD (Pt 3%) (1.1 g) was added and the mixture was stirred for 4 hours under a hydrogen gas atmosphere (5.0 atm) at an ambient temperature of 45°C. After the reaction mixture cooled, it was filtered by Celite and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography to obtain 3.0 g of the target compound as a white solid.

[0102] Reference Example 14: Synthesis of ethyl (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate To a solution of ethyl (2R,6R)-1-(3-amino-5-fluoropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate (8.0 g) in diiodomethane (80 mL), isoamyl nitrite (6.4 mL) was added and the mixture was stirred at ambient temperature of 80°C for 7 hours. After the reaction mixture cooled, it was purified by direct column chromatography to obtain 4.5 g of the target compound as a pale yellow oily substance.

[0103] Reference Example 15: Synthesis of (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid To a mixed solution of ethyl (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate (4.5 g) in tetrahydrofuran (55 mL), methanol (22 mL), and water (33 mL), lithium hydroxide monohydrate (1.2 g) was added and the mixture was stirred overnight at room temperature. After cooling the reaction mixture on ice, aqueous hydrochloric acid (1.0 M) was added to adjust the pH to 2. Extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography to obtain 4.1 g of the target compound as a white solid.

[0104] Reference Example 16: Synthesis of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone Process 1 To a solution of (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid (0.12 g) in dichloromethane (2.0 mL), N,N-dimethylformamide (2.5 μL) and oxalyl chloride (35 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a yellow amorphous solution. Process 2 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (70 mg) was dissolved in 1,2-dichloroethane (2.0 mL), to which aluminum trichloride (0.21 g) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale yellow amorphous solution of 1,2-dichloroethane (4.0 mL) obtained in step 1 was added dropwise to the reaction mixture, and the mixture was stirred at ambient temperature of 50°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 0.17 g of the target compound as a white solid.

[0105] Reference Example 17: Synthesis of [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone To a solution of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) in N,N-dimethylformamide (0.50 mL), potassium carbonate (21 mg) and (2-bromoethoxy)(tert-butyl)dimethylsilane (37 mg) were sequentially added, and the mixture was stirred at 50°C for 1 hour. 2-bromoethoxy-tert-butyldimethylsilane (37 mg) was added again, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture cooled, it was purified by direct column chromatography to obtain 42 mg of the target compound as a colorless oily substance.

[0106] Reference Example 18: Synthesis of tert-butyl 3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-carboxylate [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (45 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (27 mg) and tert-butyl 3-iodoazetidine-1-carboxylate (0.11 g) were sequentially added, and the mixture was stirred at an ambient temperature of 100°C for 10 hours. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain 59 mg of the target compound as a light brown solid.

[0107] Reference Example 19: Synthesis of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Process 1 To a solution of 1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.10 g) (synthesized according to WO2018 / 119036) in dichloromethane (2.5 mL), N,N-dimethylformamide (2.4 μL) and oxalyl chloride (33 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a pale yellow solid. Process 2 60 mg of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 2.5 mL of 1,2-dichloroethane, to which 0.18 g of aluminum trichloride was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale yellow solid solution of 1,2-dichloroethane obtained in step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 75°C for 3 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was slurry-washed with methanol to obtain 0.13 g of the target compound as a pale brown solid.

[0108] Reference Example 20: Synthesis of [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone Process 1 To a solution of (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid (0.18 g) in dichloromethane (3.0 mL), N,N-dimethylformamide (3.6 μL) and oxalyl chloride (59 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a yellow amorphous solution. Process 2 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.10 g) was dissolved in 1,2-dichloroethane (3.0 mL) and aluminum trichloride (0.29 g) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, the yellow amorphous 1,2-dichloroethane solution (3.0 mL) obtained in step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 50°C for 2 hours. The mixture was then stirred overnight at an ambient temperature of 70°C. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 0.10 g of the target compound as a white solid.

[0109] Reference Example 21: Synthesis of [1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (35 mg) and (3-bromopropoxy)(tert-butyl)dimethylsilane (64 mg) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 3 hours. After the reaction mixture cooled, it was purified by direct column chromatography to obtain 47 mg of the target compound as a colorless oily substance.

[0110] Reference Example 22: Synthesis of [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Process 1 To a solution of 1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.15 g) (synthesized according to WO2018 / 119036) in dichloromethane (3.0 mL), N,N-dimethylformamide (3.6 μL) and oxalyl chloride (49 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a pale yellow solid. Process 2 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine (90 mg) was dissolved in 1,2-dichloroethane (2.0 mL) and aluminum trichloride (0.26 g) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale yellow solid solution of 1,2-dichloroethane (2.0 mL) obtained in step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 75°C for 4 hours. Further heating and reflux stirring were carried out at an ambient temperature of 100°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed twice with aqueous sodium hydroxide solution (2.0 M), then with saturated sodium bicarbonate solution, and finally with saturated brine. After drying with magnesium sulfate, the solvent was removed by vacuum distillation. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was suspended in methanol and filtered to obtain 46 mg of the target compound as a pale yellow solid.

[0111] Reference Example 23: Synthesis of 1,1-dioxotetrahydro-2H-thiopyran-4-yl methanesulfonate To a solution of 4-hydroxytetrahydro-2H-thiopyran-1,1-dioxide (0.20 g) in dichloromethane (3.3 mL), triethylamine (0.37 mL) and methanesulfonyl chloride (0.15 mL) were sequentially added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by direct column chromatography to obtain 0.28 g of the target compound as a white solid.

[0112] Reference Example 24: Synthesis of Oxan-4-yl Methanesulfonate To a solution of oxan-4-ol (0.20 g) in dichloromethane (4.8 mL), triethylamine (0.54 mL) and methanesulfonyl chloride (0.22 mL) were sequentially added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by direct column chromatography to obtain 0.34 g of the target compound as a white solid.

[0113] Reference Example 25: Synthesis of (3R)-oxolan-3-ylmethanesulfonate (3R)-oxolan-3-ol (0.20 g) was dissolved in dichloromethane (5.6 mL), to which triethylamine (0.63 mL) and methanesulfonyl chloride (0.26 mL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by direct column chromatography to obtain 0.36 g of the target compound as a pale yellow oily substance.

[0114] Reference Example 26: Synthesis of (3S)-oxolan-3-ylmethanesulfonate (3S)-oxolan-3-ol (0.30 g) was dissolved in dichloromethane (8.5 mL), to which triethylamine (0.94 mL) and methanesulfonyl chloride (0.39 mL) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by direct column chromatography to obtain 0.40 g of the target compound as a pale yellow oily substance.

[0115] Reference Example 27: Synthesis of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Process 1 A solution of 1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (65 mg) (synthesized according to WO2018 / 119036) in dichloromethane (1.5 mL) and tetrahydrofuran (1.5 mL) was mixed with N,N-dimethylformamide (1.6 μL) and oxalyl chloride (32 μL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then removed by distillation under reduced pressure to obtain a light brown solid. Process 2 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (40 mg) was dissolved in 1,2-dichloroethane (2.5 mL) and aluminum trichloride (0.12 g) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, the light brown solid solution of 1,2-dichloroethane (2.5 mL) obtained in step 1 was added dropwise to the reaction mixture, and the mixture was stirred at ambient temperature of 75°C for 4 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was slurry washed with ethyl acetate and methanol to obtain 0.062 g of the target compound as a light brown solid.

[0116] Reference Example 28: Synthesis of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(pyrazolo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Process 1 A solution of 1-(pyrazolo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (65 mg) (synthesized according to WO2018 / 119036) in dichloromethane (1.5 mL) and tetrahydrofuran (1.5 mL) was mixed with N,N-dimethylformamide (1.7 μL) and oxalyl chloride (23 μL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then removed by distillation under reduced pressure to obtain a light brown oily substance. Process 2 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (40 mg) was dissolved in 1,2-dichloroethane (2.5 mL) and aluminum trichloride (120 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown oily substance obtained in step 1, dissolved in 1,2-dichloroethane (2.5 mL), was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 75°C for 5 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was slurry-washed with methanol to obtain 0.081 g of the target compound as a light brown solid.

[0117] Reference Example 29: Synthesis of [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone Process 1 A solution of 1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (100 mg) (synthesized according to WO2018 / 119036) in dichloromethane (1.5 mL) and tetrahydrofuran (1.5 mL) was mixed with N,N-dimethylformamide (2.6 μL) and oxalyl chloride (36 μL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then removed by distillation under reduced pressure to obtain a light brown solid. Process 2 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (70 mg) was dissolved in 1,2-dichloroethane (3.1 mL), to which aluminum trichloride (210 mg) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale brown solid solution of 1,2-dichloroethane (2.5 mL) obtained in step 1 was added dropwise to the reaction mixture, and the mixture was stirred at ambient temperature of 75°C for 5 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was slurry washed with methanol to obtain a crude residue. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry washed with methanol to obtain 120 mg of the target compound as a white solid.

[0118] Reference Example 30: Synthesis of 5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine To a solution of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine in N,N-dimethylformamide (3.0 mL), potassium carbonate (930 mg) and methyl iodide (420 μL) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Further, methyl iodide (250 μL) was added, and the mixture was stirred at the same temperature for another 30 minutes. The reaction mixture was diluted with water, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography to obtain 130 mg of the target compound as a pale yellow solid.

[0119] Reference Example 31: Synthesis of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(1-methoxyisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Process 1 A solution of 1-(1-methoxyisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg) (synthesized according to WO2018 / 119036) in dichloromethane (1.7 mL) and tetrahydrofuran (1.7 mL) was mixed with N,N-dimethylformamide (2.7 μL) and oxalyl chloride (37 μL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then removed by distillation under reduced pressure to obtain a light brown solid. Process 2 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (68 mg) was dissolved in 1,2-dichloroethane (3.0 mL) and aluminum trichloride (200 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale brown solid solution of 1,2-dichloroethane (2.5 mL) obtained in step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 75°C for 6 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was slurry washed with ethyl acetate and methanol to obtain a crude residue. The obtained residue was purified by column chromatography to obtain 68 mg of the target compound as a pale yellow solid.

[0120] Reference Example 32: Synthesis of 9-bromo-4H-quinoridine-4-one Process 1 A 2.0 M, 13 mL solution of lithium diisopropylamide in tetrahydrofuran was cooled to -60°C in a dry ice, 40% water, and methanol bath. Then, a 3.4 g, 40 mL solution of 3-bromo-2-methylpyridine in tetrahydrofuran was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Subsequently, 4.0 g of diethyl ethoxymethylene malonate was added dropwise, and the mixture was heated to -20°C in a dry ice, 70% water, and methanol bath, and stirred at the same temperature for 3 hours. After adding an aqueous ammonium chloride solution to the reaction mixture, extraction was performed with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography to obtain 4.3 g of a yellow oily substance. Process 2 Polyphosphate (25g) was added to the yellow oily substance obtained in step 1, and the mixture was stirred at an ambient temperature of 140°C for 6 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate and tetrahydrofuran. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry-washed with a small amount of ice-cooled ethyl acetate to obtain 1.5g of the target compound as a yellow solid.

[0121] Reference Example 33: Synthesis of ethyl 1-(4-oxo-4H-quinoridine-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate Process 1 To a solution of palladium (1-phenylallyl) chloride dimer (57 mg) in 1,4-dioxane (10 mL), 4-{2-[di(adamantan-1-yl)phosphanyl]phenyl}morpholine (100 mg) was added and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. 9-bromo-4H-quinoridine-4-one (500 mg), sodium tert-butoxide (420 mg), and hydrazine hydrate (220 mg) were sequentially added to the reaction mixture and the mixture was stirred at ambient temperature of 50°C under an argon atmosphere for 4 hours. The reaction mixture was filtered through Celite, washed with tetrahydrofuran, and the mother liquor was concentrated to obtain a brown solid. Process 2 To a suspension of the brown solid obtained in Step 1 in ethanol (10 mL) were added triethylamine (0.62 mL) and ethyl (2Z)-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate, and the mixture was stirred at an external temperature of 80°C for 12 hours. After allowing the reaction solution to cool, the solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography to give a crude purified residue. Slurry washing of the obtained residue with a small amount of diethyl ether gave 130 mg of the target compound as an orange solid.

[0122] Reference Example 34: Synthesis of 1-(4-oxo-4H-quinoridine-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid To a solution of ethyl 1-(4-oxo-4H-quinolizidin-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (130 mg) in tetrahydrofuran (3.0 mL) were added water (1.5 mL) and lithium hydroxide monohydrate (38 mg), and the mixture was stirred at room temperature for 2 hours. An aqueous hydrochloric acid solution (1.0 M) was added to the reaction solution to adjust the pH to 5. The solvent of the reaction solution was evaporated under reduced pressure. The obtained residue was purified by reverse phase column chromatography to give 4.1 g of the target compound as a white solid; after cooling, purification was directly performed by column chromatography (H2O / MeOH) to give 120 mg of the target compound as a yellow solid.

[0123] Reference Example 35: Synthesis of 9-{4-[5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one Step 1 To a solution of 1-(4-oxo-4H-quinolizidin-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg) in dichloromethane (2.5 mL) and a suspension of the same in tetrahydrofuran (1.5 mL) were added N,N-dimethylformamide (2.7 μL) and oxalyl chloride (39 μL), and the mixture was stirred at room temperature for 30 minutes. Evaporation of the reaction solution under reduced pressure gave a brown solid. Step 2 To a solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (70 mg) in 1,2-dichloroethane (2.5 mL) was added aluminum trichloride (0.21 g), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a suspension of the brown solid obtained in Step 1 in 1,2-dichloroethane (2.5 mL) was added dropwise to the reaction solution, followed by stirring at an external temperature of 75°C for 3 hours. Aluminum trichloride (100 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was ice-cooled, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was slurry-washed with methanol, to give 120 mg of the target compound as a yellowish-brown solid.

[0124] Reference Example 36: Synthesis of 5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine Step 1 A solution of 5-chloro-6-fluoro-1H-pyrrolo[2,3-b]pyridine (300 mg, synthesized according to WO2021 / 062316) in tetrahydrofuran (8.7 mL) was ice-cooled, sodium hydride (100 mg) was added thereto, and the mixture was stirred at the same temperature for 5 minutes. Methyl iodide (0.18 mL) was added to the reaction solution, the mixture was stirred at the same temperature for 30 minutes, then warmed to room temperature and stirred for 2 hours. The reaction solution was diluted with water, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by reverse-phase column chromatography (H2O / MeOH), to give 290 mg of a white solid. Step 2 To a suspension of the white solid obtained in Step 1 in methanol (1.2 mL) was added potassium carbonate (100 mg), and the mixture was stirred overnight at an external temperature of 50°C. The reaction solution was directly purified by column chromatography, to give 16 mg of the target compound as a white solid.

[0125] Reference Example 37: Synthesis of ethyl (2RS,4RS)-2-methylpiperidine-4-carboxylate Step 1 Dioxoplatinum hydrate (0.37 g) was added to a suspension of 2-chloro-6-methylpyridine-4-carboxylic acid (10 g) in acetic acid (50 mL) and stirred at room temperature for 30 minutes. The mixture was stirred under a hydrogen gas atmosphere (0.4 MPa) at ambient temperature of 50°C for 8 hours and at room temperature for 12 hours. Further stirring was carried out at ambient temperature of 60°C for 8 hours. After cooling the reaction mixture on ice, it was diluted with methanol and filtered by Celite, and the solvent was removed by distillation under reduced pressure. The resulting residue was slurry-washed with a mixture of ethyl acetate and methanol to obtain 10 g of a white solid. Process 2 To a solution of the white solid (3.6 g) obtained in step 1 in ethanol (100 mL), sulfuric acid (10 mL) was added dropwise, and the mixture was stirred at an ambient temperature of 95 °C for 42 hours. The solvent of the reaction mixture was removed by vacuum distillation, and the resulting residue was diluted with ethyl acetate. The residue was neutralized with aqueous sodium hydroxide solution (2.0 M) under ice cooling, and then extracted with ethyl acetate. After washing the organic phase with saturated brine, it was dried over magnesium sulfate, and the solvent was removed by vacuum distillation to obtain the target compound as a pale yellow oily substance (3.3 g).

[0126] Reference Example 38: Synthesis of ethyl (2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-carboxylate To a solution of ethyl 2-methylpiperidine-4-carboxylate (cisthracemic) (100 mg) in dimethyl sulfoxide (1.0 mL), DIPEA (0.20 mL) and 5-bromo-4-chloropyrimidine (140 mg) were sequentially added, and the mixture was stirred at an ambient temperature of 140°C for 90 minutes. After the reaction mixture cooled, it was purified by direct column chromatography to obtain 110 mg of the target compound as a yellow oily substance.

[0127] Reference Example 39: Synthesis of (2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-carboxylic acid A mixture of ethyl 1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-carboxylate (cisthracemide) (110 mg) in tetrahydrofuran (2.5 mL) and water (2.5 mL) was mixed with lithium hydroxide monohydrate (36 mg) and stirred at room temperature for 2 hours. A 1.0 M aqueous hydrochloric acid solution was added to the reaction mixture to adjust the pH to 4. Extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was slurry-washed with a mixture of ethyl acetate and diethyl ether to obtain 90 mg of the target compound as a white solid.

[0128] Reference Example 40: Synthesis of (2RS,4RS)-[1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl][5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone Process 1 To a solution of 1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-carboxylic acid (cisthracemic) (45 mg) in dichloromethane (2.5 mL), N,N-dimethylformamide (1.1 μL) and oxalyl chloride (15 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A white solid was obtained by distilling off the reaction mixture under reduced pressure. Process 2 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) was dissolved in 1,2-dichloroethane (2.5 mL) and aluminum trichloride (91 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, the 1,2-dichloroethane (2.5 mL) suspension of the white solid obtained in step 1 was added dropwise to the reaction mixture, and the mixture was stirred at ambient temperature of 50°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 42 mg of the target compound as a white solid.

[0129] Reference Example 41: Synthesis of (2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-carboxylic acid To a solution of ethyl (2RS,4RS)-2-methylpiperidine-4-carboxylate (200 mg) in dimethyl sulfoxide (2.0 mL), DIPEA (0.40 mL) and 1,4-difluoro-2-nitrobenzene (270 mg) were sequentially added, and the mixture was stirred for 60 minutes at an ambient temperature of 50°C under an argon atmosphere. Further stirring was carried out at an ambient temperature of 120°C for 6 hours. After the reaction mixture cooled, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 240 mg of the target compound as a yellow oil. Lithium hydroxide monohydrate (82 mg) was added to a mixed solution of the obtained yellow oil with tetrahydrofuran (2.5 mL) and water (2.5 mL), and the mixture was stirred at room temperature for 3 hours. Lithium hydroxide monohydrate (65 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 82 mg of lithium hydroxide monohydrate was added to the reaction mixture and stirred at room temperature for 2 hours. 98 mg of lithium hydroxide monohydrate was added to the reaction mixture and stirred overnight at room temperature. 1.0 M aqueous hydrochloric acid solution was added to the reaction mixture to adjust the pH to 3. Extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain 210 mg of the target compound as a yellow solid.

[0130] Reference Example 42: Synthesis of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone Process 1 To a solution of (2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-carboxylic acid (100 mg) in dichloromethane (2.0 mL), N,N-dimethylformamide (2.7 μL) and oxalyl chloride (37 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The residue was obtained by distilling the reaction mixture under reduced pressure. Process 2 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) was dissolved in 1,2-dichloroethane (1.0 mL), to which aluminum trichloride (180 mg) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the 1,2-dichloroethane solution of the residue obtained in step 1 (3.0 mL) was added dropwise to the reaction mixture, and the mixture was stirred under an argon atmosphere at an ambient temperature of 50°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry washed with a mixture of ethyl acetate and hexane to obtain 71 mg of the target compound as a yellow solid.

[0131] Reference Example 43: Synthesis of [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone (30 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (25 mg) and methyl iodide (11 μL) were sequentially added, and the mixture was stirred for 90 minutes at an ambient temperature of 50°C under an argon atmosphere. After the reaction mixture was allowed to cool, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain 27 mg of the target compound as a yellow solid.

[0132] Reference Example 44: Synthesis of methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate Process 1 5,6-Dichloro-1H-pyrrolo[2,3-b]pyridine (1.3 g) was dissolved in N,N-dimethylformamide (29 mL), to which zinc cyanide (1.3 g) was added and the mixture was stirred under an argon atmosphere at an ambient temperature of 100°C for 6 hours. After the reaction mixture was allowed to cool, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was slurry-washed with a mixed solvent of diethyl ether and hexane to obtain 950 mg of a white solid. Process 2 To a solution of the white solid (610 mg) obtained in Step 1 in ethanol (30 mL) was added aqueous sodium hydroxide solution (2.0 M, 30 mL), and the mixture was heated to reflux and stirred overnight at an external temperature of 100°C. After cooling the reaction solution with ice, aqueous hydrochloric acid (1.0 M) was added to adjust the pH to 3, and the precipitated solid was collected by filtration to obtain 710 mg of a white solid. Step 3 To a solution of the white solid (500 mg) obtained in Step 2 in methanol (25 mL), a hexane solution of 10% trimethylsilyldiazomethane (7.9 mL) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 4 hours. 10% trimethylsilyldiazomethane (5.3 mL) was added to the reaction solution, and the mixture was stirred overnight at room temperature. Acetic acid (0.72 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. After adding saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography to obtain 310 mg of the target compound as a white solid.

[0133] Reference Example 45: Synthesis of (2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carboxylic acid Step 1 To a solution of ethyl (2RS,4RS)-2-methylpiperidine-4-carboxylate (3000 mg) in dimethyl sulfoxide (35 mL), DIPEA (6.0 mL) and 3-chloro-2,5-difluoropyridine (5.5 mL) were added sequentially, and the mixture was stirred at an external temperature of 140°C for 18 hours. After allowing the reaction solution to cool, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography to obtain 2.9 g of the ethyl ester as a pale yellow oil. Step 2 To a mixed solution of the pale yellow oil (2.9 g) obtained in Step 1 in tetrahydrofuran (30 mL) and water (30 mL) was added lithium hydroxide monohydrate (1.2 g), and the mixture was stirred at room temperature for 2 hours. Aqueous hydrochloric acid (1.0 M) was added to the reaction solution to adjust the pH to 3. The mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was slurry-washed with a mixed solvent of diethyl ether and hexane to obtain 1.6 g of the target compound as a white solid.

[0134] Reference Example 46: Synthesis of 5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (cisracemic mixture) Process 1 To a solution of (2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carboxylic acid (280 mg) in dichloromethane (10 mL), N,N-dimethylformamide (7.9 μL) and oxalyl chloride (130 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a light brown oily substance. Process 2 180 mg of methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate was dissolved in 10 mL of 1,2-dichloroethane, to which aluminum trichloride (560 mg) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown oily substance obtained in step 1, 10 mL of 1,2-dichloroethane was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 70°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water, and aqueous hydrochloric acid (1.0 M) was added to adjust the pH to 3. Extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 110 mg of the target compound as a white solid.

[0135] Reference Example 47: Synthesis of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carbonyl}piperazine-1-carboxylate To a solution of 5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (40 mg) in N,N-dimethylformamide (0.88 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate (HATU) (100 mg), DIPEA (76 μL), and tert-butylpiperazine-1-carboxylate (21 mg) were added, and the mixture was stirred at room temperature for 3 hours. A small amount of methanol was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (H2O / MeOH) to obtain 41 mg of the target compound as a white solid.

[0136] Reference Example 48: Synthesis of (6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone Process 1 To a solution of (2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carboxylic acid (cisthracemic) (250 mg) in dichloromethane (10 mL), N,N-dimethylformamide (7.1 μL) and oxalyl chloride (110 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a light brown oily substance. Process 2 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (170 mg) was dissolved in 1,2-dichloroethane (10 mL) and aluminum trichloride (500 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, the 1,2-dichloroethane (10 mL) solution of the light brown oily substance obtained in step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 50°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 210 mg of the target compound as a white solid.

[0137] Reference Example 49: Synthesis of [6-(benzylsulfanyl)-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone (6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone (64 mg) was dissolved in 1,4-dioxane (2.6 mL) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15 mg), DIPEA (91 μL), benzyl mercaptan (31 μL), and tris(dibenzylideneacetone)(chloroform)dipalladium (12 mg) were sequentially added. The mixture was stirred under an argon atmosphere using a microwave at 110 °C for 30 minutes. The reaction mixture was purified by direct column chromatography to obtain 68 mg of the target compound as a yellow solid. To a 1.2 mL solution of the resulting yellow solid in N,N-dimethylformamide, potassium carbonate (53 mg) and methyl iodide (23 μL) were added sequentially, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was purified by direct column chromatography to obtain 71 mg of the target compound as an orange oil.

[0138] Reference Example 50: Synthesis of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl}piperazine-1-carboxylate [6-(benzylsulfanyl)-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone (70 mg) was mixed with acetic acid (1.8 mL) and water (0.2 mL), to which N-chlorosuccinimide (51 mg) was added and stirred at room temperature for 1 hour. Further stirring was carried out at ambient temperature of 40°C for 2 hours. The reaction mixture was removed by vacuum distillation, and the resulting residue was added to ice-cooled saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated saline solution, dried over magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a brown oily substance. To a solution of the obtained brown oily substance in tetrahydrofuran (1.0 mL), tert-butylpiperazine-1-carboxylate (47 mg) was added and stirred at room temperature for 30 minutes. The reaction mixture was purified by direct column chromatography to obtain 56 mg of the target compound as a white solid.

[0139] Example 1 [5-Chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (50 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (30 mg) and 3-iodooxetane (0.12 g) were sequentially added, and the mixture was stirred at 100°C for 10 hours. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain 44 mg of the target compound as a white solid. MS(ESI+)m / z 636.1(M+1)

[0140] Example 2 [5-Chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone To a solution of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidin-4-yl]methanone (20 mg) in N,N-dimethylformamide (0.50 mL) were added potassium carbonate (14 mg) and methyl iodide (6.4 μL) sequentially, followed by stirring at an external temperature of 50°C for 30 minutes. After allowing the reaction solution to cool, it was directly purified by reverse phase column chromatography (H2O / MeOH), and 19 mg of the target compound was obtained as a white solid. MS (ESI+) m / z 594.0 (M+1) Specific optical rotation [α] D 21 =+63.80° (c=1.0, chloroform)

[0141] Example 3 {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}acetonitrile To a solution of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidin-4-yl]methanone (30 mg) in N,N-dimethylformamide (0.50 mL) were added potassium carbonate (21 mg) and 2-bromoacetonitrile (19 mg) sequentially, followed by stirring at an external temperature of 50°C for 30 minutes. After allowing the reaction solution to cool, it was directly purified by reverse phase column chromatography (H2O / MeOH), and 32 mg of the target compound was obtained as a light brown solid. MS (ESI+) m / z 619.1 (M+1)

[0142] Example 4 [5-Chloro-1-(2-hydroxyethyl)-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (42 mg) was mixed with methanol (2.5 mL) and dichloromethane (0.50 mL), to which aqueous hydrochloric acid (1.0 M, 0.57 mL) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was neutralized with aqueous sodium hydroxide (1.0 M), diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 31 mg of the target compound as a white solid. MS(ESI+)m / z 624.0(M+1)

[0143] Example 5: 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-yl)ethane-1-one Step 1: A solution of tert-butyl 3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-carboxylate (59 mg) in dichloromethane (1.0 mL) was mixed with trifluoroacetic acid (0.50 mL) and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and neutralized with aqueous sodium hydroxide solution (2.0 M) to pH=8. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a pale yellow solid residue (77 mg). Step 2: The residue (77 mg) obtained in Step 1 was dissolved in tetrahydrofuran (1.5 mL), and DIPEA (69 μL) and acetyl chloride (7.1 μL) were added sequentially. The mixture was stirred at room temperature for 2 hours. After adding saturated sodium bicarbonate solution to the reaction mixture, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 40 mg of the target compound as a light brown solid. MS(ESI+)m / z 677.2(M+1)

[0144] Example 6 [5-Chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (31 mg) and methyl iodide (14 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 30 minutes. After the reaction mixture cooled, it was diluted with water, and the precipitated solid was collected by filtration to obtain a light brown residue. The obtained residue was purified by column chromatography, and then again by reverse-phase column chromatography (H2O / MeOH) to obtain 21 mg of the target compound as a white solid. MS(ESI+)m / z 541.1(M+1)

[0145] Example 7 [5-Chloro-1-ethyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (35 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (28 mg) and ethyl iodide (16 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 30 minutes. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was slurry-washed with methanol to obtain 37 mg of the target compound as a white solid. MS 555.1(M+1)

[0146] Example 8 [5-Chloro-1-propyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (35 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (28 mg) and 1-bromopropane (18 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 2 hours. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain 32 mg of the target compound as a white solid. MS(ESI+)m / z 569.1(M+1)

[0147] Example 9 [5-Chloro-1-(3-hydroxypropyl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (47 mg) was mixed with tetrahydrofuran (1.0 mL) and methanol (1.0 mL), to which aqueous hydrochloric acid (1.0 M, 1.0 mL) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was recrystallized with ethyl acetate / n-hexane to obtain 26 mg of the target compound as a pale yellow solid. MS(ESI+)m / z 649.2(M+1) Specific rotation [α] D 20 = +30.36° (c=1.0, chloroform)

[0148] Example 10 [5-Chloro-1-(oxetan-3-yl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (18 mg) and 3-iodooxetane (75 mg) were sequentially added, and the mixture was stirred at an ambient temperature of 100°C for 11 hours. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH), and then again by column chromatography to obtain a crude residue. The obtained residue was recrystallized in methanol / water to obtain 18 mg of the target compound as a pale yellow solid. MS(ESI+)m / z 647.2(M+1)

[0149] Example 11 [5-Chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (22 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (26 mg) and methyl iodide (7.0 μL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by direct reverse-phase column chromatography (H2O / MeOH), and then again by column chromatography to obtain 15 mg of the target compound as a white solid. MS(ESI+)m / z 605.0(M+1)

[0150] Example 12 [5-Chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (51 mg) and methyl iodide (14 μL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was recrystallized with ethyl acetate / n-hexane to obtain 31 mg of the target compound as a pale yellow solid. MS(ESI+)m / z 552.1(M+1)

[0151] Example 13 [5-Chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (51 mg) and ethyl iodide (18 μL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue (25 mg). The obtained residue (25 mg) was recrystallized with ethyl acetate / n-hexane to obtain 19 mg of the target compound as a pale yellow solid. MS(ESI+)m / z 566.2(M+1)

[0152] Example 14 [5-Chloro-1-ethyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (36 mg) and ethyl iodide (12 μL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by direct reverse-phase column chromatography, and then again by column chromatography to obtain 30 mg of the target compound as a white solid. MS(ESI+)m / z 608.2(M+1)

[0153] Example 15 [5-Chloro-1-(3-hydroxypropyl)-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone Step 1: Potassium carbonate (18 mg) and (3-bromopropoxy)(tert-butyl)dimethylsilane (33 mg) were sequentially added to a solution of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (25 mg) in N,N-dimethylformamide (1.0 mL), and the mixture was stirred overnight at an ambient temperature of 50°C. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain 33 mg of a white solid. Step 2: The white solid (33 mg) obtained in Step 1 was mixed with tetrahydrofuran (2.0 mL) and methanol (2.0 mL), and hydrochloric acid aqueous solution (1.0 M, 1.0 mL) was added. The mixture was stirred overnight at room temperature. After neutralizing the reaction mixture with saturated sodium bicarbonate solution, extraction was performed with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain a crude residue. The obtained residue was recrystallized with ethyl acetate / n-hexane to obtain 26 mg of the target compound as a white solid. MS(ESI+)m / z 638.2(M+1)

[0154] Example 16 [5-Chloro-1-cyclopropyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (40 mg) was dissolved in 1,2-dichloroethane (1.0 mL) and cyclopropylboronic acid (12 mg), 2,2'-bipyridine (16 mg), copper(II) acetate (19 mg), and sodium carbonate (15 mg) were added. The mixture was stirred at an ambient temperature of 70°C for 5 hours. After the reaction mixture cooled, it was purified by direct column chromatography, and then again by reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was recrystallized with ethyl acetate / n-hexane to obtain 24 mg of the target compound as a white solid. MS(ESI+)m / z 620.0(M+1)

[0155] Example 17 [5-Chloro-1-isopropyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (19 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (22 mg) and 2-bromopropane (9.0 μL) were sequentially added, and the mixture was stirred at 100°C for 1.5 hours. After cooling the reaction mixture, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain 18 mg of the target compound as a white solid. MS(ESI+)m / z 622.1(M+1)

[0156] Example 18 [5-Chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (42 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (49 mg) and ethyl iodide (17 μL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by direct reverse-phase column chromatography (H2O / MeOH), and then again by column chromatography to obtain 39 mg of the target compound as a white solid. MS(ESI+)m / z 619.1(M+1)

[0157] Example 19 [5-Chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (36 mg) and 1,1-dioxotetrahydro-2H-thiopyran-4-yl methanesulfonate (0.12 g) were sequentially added, and the mixture was stirred at an ambient temperature of 100°C for 16 hours. After the reaction mixture was allowed to cool, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was purified by column chromatography, followed by reverse-phase column chromatography (H2O / MeOH) to obtain 11 mg of the target compound as a white solid. MS(ESI+)m / z 712.3(M+1)

[0158] Example 20: Synthesis of [5-chloro-1-(oxan-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (36 mg) was dissolved in N,N-dimethylformamide (0.80 mL), to which potassium carbonate (42 mg) and oxan-4-yl methanesulfonate (0.11 g) were sequentially added, and the mixture was stirred at 100°C for 12 hours. After cooling the reaction mixture, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain 24 mg of the target compound as a pale yellow solid. MS(ESI+)m / z 664.2(M+1)

[0159] Example 21: Synthesis of {5-chloro-1-[(3S)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (36 mg) was dissolved in N,N-dimethylformamide (0.80 mL), to which potassium carbonate (42 mg) and (3R)-oxolan-3-yl methanesulfonate (0.10 g) were sequentially added, and the mixture was stirred at 100°C for 12 hours. After cooling the reaction mixture, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain 30 mg of the target compound as a white solid. MS(ESI+)m / z 650.2(M+1)

[0160] Example 22: Synthesis of {5-chloro-1-[(3R)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (36 mg) was dissolved in N,N-dimethylformamide (0.80 mL), to which potassium carbonate (42 mg) and (3S)-oxolan-3-yl methanesulfonate (0.10 g) were sequentially added, and the mixture was stirred at 100°C for 12 hours. After cooling the reaction mixture, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain 30 mg of the target compound as a white solid. MS(ESI+)m / z 650.2(M+1)

[0161] Example 23: Synthesis of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(5-fluoronaphthalene-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Process 1 To a solution of 1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.055 g) (synthesized according to WO2018 / 119036) in dichloromethane (2.5 mL), N,N-dimethylformamide (1.3 μL) and oxalyl chloride (17 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a brown oily substance. Process 2 30 mg of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 2.5 mL of 1,2-dichloroethane, to which aluminum trichloride (91 mg) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, a 2.5 mL solution of the brown oily substance obtained in step 1, dissolved in 1,2-dichloroethane, was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 75°C for 4 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry-washed with ethyl acetate to obtain 0.018 g of the target compound as a yellowish-brown solid. MS(ESI+)m / z 526.1(M+1)

[0162] Example 24: Synthesis of [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (25 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (20 mg) and methyl iodide (9.0 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 15 minutes. After the reaction mixture cooled, it was diluted with water, and the precipitated solid was filtered to obtain a crude residue. The obtained residue was slurry-washed with methanol to obtain 19 mg of the target compound as a white solid. MS(ESI+)m / z 529.1(M+1)

[0163] Example 25: Synthesis of [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-c]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone To a solution of 1-(thieno[2,3-c]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (30 mg) in N,N-dimethylformamide (1.0 mL), potassium carbonate (40 mg) and 3-iodooxetane (80 mg) were sequentially added, and the mixture was stirred at room temperature for 12 hours at an ambient temperature of 100°C. After cooling the reaction mixture, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was slurry-washed with methanol to obtain 24 mg of the target compound as a pale yellow solid. MS(ESI+)m / z 571.1(M+1)

[0164] Example 26: Synthesis of [5-chloro-1-propyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (51 mg) and 1-bromopropane (20 μL) were sequentially added, and the mixture was stirred at 60°C for 2 hours. After cooling the reaction mixture, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue (35 mg). The obtained residue (35 mg) was recrystallized with ethyl acetate / n-hexane to obtain 26 mg of the target compound as a pale yellow solid. MS(ESI+)m / z 580.2(M+1)

[0165] Example 27: Synthesis of [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(pyrazolo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(pyrazolo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (25 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (20 mg) and methyl iodide (9.3 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 15 minutes. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was slurry-washed with diethyl ether to obtain 15 mg of the target compound as a white solid. MS(ESI+)m / z 512.1(M+1)

[0166] Example 28: Synthesis of [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone (16 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (12 mg) and methyl iodide (5.7 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 30 minutes. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain 16 mg of the target compound as a pale yellow solid. MS(ESI+)m / z 530.1(M+1)

[0167] Example 29: Synthesis of [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone Process 1 To a solution of 1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (43 mg) (synthesized according to WO2018 / 119036) in dichloromethane (1.0 mL), N,N-dimethylformamide (1.0 μL) and oxalyl chloride (14 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a light brown solid. Process 2 5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) was dissolved in 1,2-dichloroethane (1.2 mL) and aluminum trichloride (81 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale brown solid solution of 1,2-dichloroethane (1.2 mL) obtained in step 1 was added dropwise to the reaction mixture, and the mixture was heated under reflux and stirred at an ambient temperature of 110°C for 5 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was slurry washed with isopropanol to obtain 33 mg of the target compound as a pale yellow solid. MS(ESI+)m / z 541.1(M+1)

[0168] Example 30 Synthesis of 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}isoquinoline-1(2H)-one Process 1 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(1-methoxyisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (15 mg) was added sequentially to a solution of N,N-dimethylformamide (0.50 mL) with potassium carbonate (11 mg) and bromocyclobutane (7.8 μL), and the mixture was stirred at an ambient temperature of 100°C for 11 hours. Potassium carbonate (38 mg) and bromocyclobutane (26 μL) were added sequentially to the reaction mixture and the mixture was stirred overnight at the same temperature. The mixture was stirred at an ambient temperature of 110°C for 5 hours. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain a white solid. Process 2 To the white solid dioxane solution (1.0 mL) obtained in Step 1, 1.0 mL of 4N dioxane hydrochloride was added, and the mixture was stirred at an ambient temperature of 50°C for 5 hours. After the reaction mixture cooled, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (H2O / MeOH), and 17 mg of the target compound was obtained as a white solid. MS(ESI+)m / z 579.2(M+1)

[0169] Example 31 Synthesis of 9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one 9-{4-[5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one (35 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (27 mg) and methyl iodide (12 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 15 minutes. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was slurry-washed with ethyl acetate to obtain 29 mg of the target compound as a yellow solid. MS(ESI+)m / z 539.1(M+1)

[0170] Example 32: Synthesis of (5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)[1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Process 1 To a solution of 1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (35 mg) (synthesized according to WO2018 / 119036) in dichloromethane (1.0 mL), N,N-dimethylformamide (0.83 μL) and oxalyl chloride (11 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a pale yellow solid. Process 2 5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine (16 mg) was dissolved in 1,2-dichloroethane (0.5 mL) and aluminum trichloride (54 mg) was added, and the mixture was stirred at room temperature for 5 minutes. Subsequently, the pale yellow solid suspension of 1,2-dichloroethane (0.5 mL) obtained in step 1 was added dropwise to the reaction mixture, washed with 1,2-dichloroethane (0.5 mL), and stirred at an ambient temperature of 75°C for 1 hour. Furthermore, the mixture was heated under reflux and stirred at an ambient temperature of 105°C for 3 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain 7.8 mg of the target compound as a white solid. MS(ESI+)m / z 503.8(M+1)

[0171] Example 33: Synthesis of [(2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone To a solution of (2RS,4RS)-[1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl][5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone (20 mg) obtained in Reference Example 40, potassium carbonate (16 mg) and methyl iodide (3.7 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 30 minutes. After the reaction mixture cooled, it was purified by direct reverse-phase column chromatography (H2O / MeOH) to obtain 17 mg of the target compound as a white solid. MS(ESI+)m / z 517.0(M+1)

[0172] Example 34 Synthesis of [(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone To a methanol (5.0 mL) solution of [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone (25 mg) obtained in Reference Example 43, 1% platinum-activated carbon, degussa type CF 105R / W (75 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen gas atmosphere (4.0 atm). The reaction mixture was filtered through Celite, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain 14 mg of the target compound as a white solid. MS(ESI+)m / z 468.2(M+1)

[0173] Example 35 Synthesis of {5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-yl}(piperazine-1-yl)methanone To a solution of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carbonyl}piperazine-1-carboxylate (41 mg) obtained in Reference Example 47, trifluoroacetic acid (0.50 mL) was added and the mixture was stirred at room temperature for 2 hours. After adding saturated sodium bicarbonate solution to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain 25 mg of the target compound as a flesh-colored solid. MS(ESI+)m / z 519.2(M+1)

[0174] Example 36: Synthesis of [(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone Synthesizing tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl}piperazine-1-carboxylate (56 mg) obtained in Reference Example 50, trifluoroacetic acid (1.0 mL) was added to a solution of dichloromethane (2.0 mL) and the mixture was stirred at room temperature for 2 hours. After adding saturated sodium bicarbonate solution to the reaction mixture, extraction was performed with ethyl acetate. The organic phase was washed with saturated saline solution, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by reverse-phase column chromatography (H2O / MeOH) to obtain a crude residue. The obtained residue was purified by aminosilica gel column chromatography to obtain 30 mg of the target compound as a white solid. MS(ESI+)m / z 569.2(M+1)

[0175] Example 37: Synthesis of [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone sulfate To a solution of [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (5.0 g) in acetone (50 mL), several mg of seed crystals were added, and sulfuric acid (0.74 mL) was added dropwise. The mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration to obtain 5.6 g of the target compound as a beige solid. Elemental analysis value C 24 H 13 ClF4N8O·H2SO4+0.2H2O Calculated values ​​(%) C: 44.86 H: 2.41 N: 17.43 Measured values ​​(%) C: 45.15 H: 2.23 N: 17.10

[0176] Example 38: Synthesis of [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone monophosphate [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (180 g) was dissolved in acetonitrile (3.0 L), to which 40 mL of 85% phosphoric acid aqueous solution was added dropwise and stirred overnight at room temperature. The precipitated solid was collected by filtration to obtain 210 g of the target compound as a yellow solid. Melting point: 186-188°C Specific rotation [α] D 20 = +57.99° (c=0.6, chloroform) Elemental analysis value C 25 H 23 ClFIN6O·H3PO4 Calculated values ​​(%) C: 42.72 H: 3.73 N: 11.96 Actual values ​​(%) C:42.49 H:3.51 N:11.98

[0177] The structural formulas of Examples 1 to 38 are shown in Tables 1 to 8.

[0178] [Table 1]

[0179] [Table 2]

[0180] [Table 3]

[0181] [Table 4]

[0182] [Table 5]

[0183] [Table 6]

[0184] [Table 7]

[0185] [Table 8]

[0186] The following are examples of biological tests of the compounds used in the present invention.

[0187] <Test Example 1: MALT1 Protease Inhibition Effect> To confirm the enzyme inhibitory effect of the test substance on MALT1, an enzyme activity inhibition test was performed using the C-terminal enzyme of MALT1 (amino acid residues 329-824). 1. Preparation of the test substance The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO), and then further diluted with DMSO to concentrations of 1000, 100, 10, 1, and 0.1 μM. The test substance solution was then further diluted 25-fold with assay buffer. The assay buffer consisted of 200 mM Tris / HCl HEPES (pH 7.5), 0.8 M Na Citrate, 100 μM DTT, and 0.05% CHAPS. 2. Measurement of MALT1 protease inhibitory activity 5 μL of the test substance solution was added to a 384-well Black plate (#6007270, PerkinElmer) (n=2, final concentrations 10000, 1000, 100, 10, 1, 0.1, nM). Next, 10 μL of MALT1 enzyme was added, followed by 5 μL of substrate solution (Ac-Leu-Arg-Ser-Arg-AMC, Peptide Laboratories Inc., final concentration in reaction mixture 50 μM). After stirring, the mixture was reacted at 30°C for 2 hours. Fluorescence (excitation: 380 nm, fluorescence: 460 nm) was detected using a microplate reader (Envision, PerkinElmer). 3. Analysis of measurement results Using the measurement data, a nonlinear regression analysis using a two-parameter logistic model was performed with Spotfire (PerkinElmer), and IC was calculated. 50 The following calculation was performed. The results are shown in Table 9 below.

[0188] [Table 9]

[0189] <Test Example 2: Inhibitory effect on reporter activity in HEK293 / API2-MALT1 / NF-κB reporter cells> The API2-MALT1 fusion protein expressed in MALT lymphoma is known to constitutively activate the NF-κB pathway. To confirm that the test substance suppresses the NF-κB pathway in cells, a reporter activity suppression test was performed using HEK293 / API2-MALT1 / NF-κB reporter cells. 1. Preparation of the test substance The test substance was prepared in dimethyl sulfoxide (DMSO) to a concentration of 10 mM, and then diluted with DMSO to concentrations of 1000, 300, 100, and 10 μM. Further dilutions were made 100-fold in DMEM medium containing 10% FBS to prepare the test substance solution. 2. Measurement of reporter cell proliferation inhibitory effect HEK293 / API2-MALT1 / NF-κB reporter cells and 293T / CMV reporter cells (used as negative control) were cultured in DMEM medium containing 10% FBS. 6000 cells of each were seeded in 30 μL of a 384-well plate (#781080, Greiner), and after 24 hours of incubation, 3.3 μL of the prepared test substance solution was added (final concentrations 10000, 1000, 100, and 10 nM). After 24 hours of incubation at 37°C in a 5% CO2 incubator, 33 μL of One-glo (Promega) was added. After incubation at room temperature for 5 minutes, luminescence was detected using a microplate reader (Envision, PerkinElmer). 3. Analysis of measurement results Using the measurement data, nonlinear regression analysis was performed using the SAS system (SAS Institute Inc.), and IC 50 The values ​​were estimated. The results are shown in Table 10 below.

[0190] [Table 10]

[0191] <Test Example 3: Proliferation inhibitory effect on ABC-DLBCL cell line> In the ABC-DLBCL cell line, the NF-κB pathway is constitutively activated due to mutations in the B cell receptor pathway. To confirm the growth inhibitory effect associated with the MALT1 inhibitory effect of the test substance, a growth inhibition test was conducted using the ABC-DLBCL cell line. 1. Preparation of the test substance The test substance was prepared in dimethyl sulfoxide (DMSO) to a concentration of 10 mM, and then diluted with DMSO to concentrations of 3000, 1000, 300, 100, 30, and 10 μM. Further dilutions were made 100-fold in IMDM medium containing 10% FBS to prepare the test substance solution. 2. Measurement of ABC-DLBCL cell proliferation inhibitory effect OCI-Ly3 cell lines (ABC-DLBCL, NF-κB pathway-dependent) were cultured in IMDM containing 10% FBS, and SU-DHL-4 cell lines (GCB-DLBCL, NF-κB pathway-independent, used as a negative control) were cultured in RPMI-1640 containing 10% FBS. 100 μL of each cell line (2000 OCI-Ly3 cells, 4000 SU-DHL-4 cells) were seeded into 96-well plates, and 11 μL of the prepared test substance solution was added (final concentrations 10000, 3000, 1000, 300, 100, 30, 10 nM). After 96 hours of incubation at 37°C in a 5% CO2 incubator, 10 μL of Cell Counting Kit-8 (Dojin Chemical) was added. After incubation at 37°C for 4 hours, the absorbance at 450 nm was detected using a microplate reader (Envision, PerkinElmer). 3. Analysis of measurement results Using the measurement data, a nonlinear regression analysis using a two-parameter logistic model was performed with Spotfire (PerkinElmer), and IC was calculated. 50 The values ​​were estimated. The results are shown in Tables 11 and 12 below.

[0192] [Table 11]

[0193] [Table 12]

[0194] <Test Example 5: Central Nervous System Distribution Test in Mice> To confirm the central nervous system penetration of the test substance, a central nervous system penetration test was conducted using mice. 1. Administration of test substance and sample collection Six-week-old female BALB / cCrSlc mice (Japan SLC) were used. The test substance, suspended in 0.5% methylcellulose, was administered intraperitoneally to mice at a dose of 30 mg / kg. Three hours later, blood was collected from the abdominal vena cava under isoflurane anesthesia and obtained plasma by centrifugation. After bleeding from the abdominal vena cava, the cerebrum was collected. 2. Measurement and analysis of plasma and brain concentrations Drug concentrations in collected plasma and cerebral tissue were measured by LC-MS / MS. To evaluate the brain penetration of the drugs, the ratio of brain tissue concentration to plasma concentration (Kp value) was calculated. The results are shown in Table 13 below.

[0195] [Table 13]

Claims

1. Compounds represented by general formula (1), or pharmaceutically acceptable salts thereof: 【Chemistry 1】 [In general formula (1), R １ This indicates a group represented by general formula (2) or general formula (3), 【Chemistry 2】 【Transformation 3】 R ２ This represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. R ３ This refers to a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a group represented by general formula (4), or a group represented by general formula (5). 【Chemistry 4】 【Transformation 5】 R ４ This indicates a halogen, R ５ This indicates a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. R ６ and R ７ Each of these independently represents a hydrogen atom or a substituted or unsubstituted alkyl group. R ８ This indicates a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group. R ９ and R １０ each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R9 and R10 may be linked to each other to form a ring, R １１ This indicates a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group. In general formulas (2), (3), (4), and (5), the dashed line indicates a coupling.

2. The aforementioned compound is a compound represented by general formula (6), 【Transformation 6】 The aforementioned R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a group represented by general formula (4), or a group represented by general formula (5).

3. The aforementioned compound is a compound represented by general formula (7), 【Transformation 7】 The aforementioned R ３ The compound according to claim 1, which exhibits a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted heteroaryloxy group, or a pharmaceutically acceptable salt thereof.

4. A compound selected from the group consisting of the following compounds (1) to (36), or a pharmaceutically acceptable salt thereof. (1) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (2) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (3) {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}acetonitrile, (4) [5-chloro-1-(2-hydroxyethyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (5) 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-yl)ethane-1-one, (6) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (7) [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (8) [5-chloro-1-propyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (9) [5-chloro-1-(3-hydroxypropyl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (10) [5-chloro-1-(oxetan-3-yl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (11) [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (12) [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (13) [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (14) [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (15) [5-chloro-1-(3-hydroxypropyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (16) [5-chloro-1-cyclopropyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (17) [5-chloro-1-isopropyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (18) [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (19) [5-chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (20) [5-chloro-1-(oxan-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (21) {5-chloro-1-[(3S)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (22) {5-chloro-1-[(3R)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (23) [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(5-fluoronaphthalene-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (24) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (25) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(thieno[2,3-c]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (26) [5-chloro-1-propyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (27) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(pyrazolo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (28) [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl] [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (29) [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl] [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (30) 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}isoquinoline-1(2H)-one, (31) 9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one, (32) (5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl) [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (33) [(2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl] [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (34) [(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidine-4-yl] [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (35) {5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-yl}(piperazine-1-yl)methanone, (36) [(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone.

5. A pharmaceutical composition containing a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, as an active ingredient.

6. A MALT1 inhibitor containing a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, as an active ingredient.

7. A preventive or therapeutic agent for a disease involving MALT1, comprising a compound described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, as an active ingredient.

8. A compound described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, is contained as an active ingredient in multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, organ transplant rejection, aplastic anemia, Behçet's disease, nephrotic syndrome, generalized myasthenia gravis, atopic dermatitis, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, multiple myeloma, BENTA A treatment for syndrome, adult T-cell leukemia / lymphoma, peripheral T-cell lymphoma, Sézary syndrome, primary exudative lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia, primary central nervous system lymphoma, intraocular lymphoma, primary macroglobulinemia, lymphoplasmacytic lymphoma, brain tumors, malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural mesplenomegaly, colorectal cancer, or esophageal cancer.

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