Azaindole compound and medical drug

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

Azaindole compounds and pharmaceuticals

[0001] The present invention relates to an azaindole compound and a medicine.

[0002] Mucosa associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an important signaling component of the NF-κB pathway. MALT1 is the only paracaspase in humans and transduces 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. First, it activates the NF-κB pathway by recruiting proteins such as TRAF6, TAK1, and IKKα / β as a scaffolding protein. Second, it activates the NF-κB pathway by cleaving negative regulators of the NF-κB pathway, such as RelB, A20, and CYLD, as a cysteine ​​protease (see, for example, Non-Patent Document 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 type 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). Ibrutinib is ineffective against ABC-DLBCL with downstream CARD11 mutations (see, for example, Non-Patent Document 4). However, because MALT1 is present downstream of BTK signaling, MALT1 protease inhibitors are also effective against ABC-DLBCL with CARD11 mutations (see, for example, Non-Patent Document 6). MALT1 protease inhibitors have shown efficacy in multiple preclinical ABC-DLBCL models (see, for example, Non-Patent Document 6).

[0004] MALT1 plays an important role in innate and adaptive immunity. MALT1-deficient mice grow and reproduce normally, but exhibit a reduced immune response of lymphocytes (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, mice lacking the function of MALT1 protease develop autoimmune disease-like pathologies along with a decrease in regulatory T cells (see, for example, Non-Patent Document 11). Furthermore, because MALT1 protease inhibitors enhance the tumor-suppressing effect of anti-PD-1 antibodies in malignant melanoma through the degeneration of regulatory T cells, MALT1 protease inhibitors are thought to have an effect of activating tumor immunity (see, for example, Non-Patent Document 12).

[0006] Therefore, MALT1 inhibitors are expected to be effective against various inflammatory diseases, hematological tumors, and solid tumors. Specific examples of inflammatory diseases include multiple sclerosis (see, for example, Non-Patent Document 10), rheumatoid arthritis, psoriasis (see, for example, Patent Document 13), immune thrombocytopenia (see, for example, Non-Patent Document 14), and spinal cord injury (see, for example, Non-Patent Document 15). Furthermore, because MALT1 inhibitors suppress T cell activation, they are expected to be effective against graft-versus-host disease associated with bone marrow transplantation, rejection associated with organ transplantation, aplastic anemia, Behçet's disease, nephrotic syndrome, generalized myasthenia gravis, and atopic dermatitis, similar to cyclosporine. In hematological tumors, it is expected to be effective against diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, Burkitt's lymphoma, multiple myeloma, BENTA syndrome, adult T-cell leukemia / lymphoma, peripheral T-cell lymphoma, Sézary syndrome, primary effusion lymphoma (see, for example, Non-Patent Document 16), chronic lymphocytic leukemia / small lymphocytic leukemia (see, for example, Non-Patent Document 17), primary central nervous system malignant lymphoma (see, for example, Non-Patent Document 3), intraocular malignant lymphoma, primary macroglobulinemia, and lymphoplasmacytic lymphoma. In solid tumors, it is expected to be effective against brain tumors (see, for example, Non-Patent Document 18). Furthermore, through tumor immunity 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 splenomegaly, colorectal cancer, and esophageal cancer, for which anti-PD-1 antibodies are effective.

[0007] Jaworski et al., Cellular and Molecular Life Sciences, 2016, 73, 459-473. Staudt et al., Cold Spring Harbor Perspectives in Biology, 2010, 2, 1-30. Chihara et al., Clinical Lymphoma, Myeloma & Leukemia, 2020, 21, 73-79. Wilson et al., Nature Medicine, 2015, 21, 922-927. Low et al., CNS Oncology, 2020, 9, CNS 51. Fontan et al., The Journal of Clinical Investigation, 2018, 128, 4397-4412. Ruefli-Brasse et al., Science, 2003, 302, 1581-1584. Jabara et al., Journal of Allergy and Clinical Immunology, 2003, 132, 151-158. Bardet et al., Immunology & Cell Biology, 2018, 96, 81-99. Brustle et al., The Journal of Clinical Investigation, 2012, 122, 4698-4709. Jaworski et al., The EMBO Journal, 2014, 33, 2765-2781. Pilato et al., Nature, 2019, 570, 112-116. Demeyer et al., Trends in Molecular Medicine, 2016, 22, 135-150. Nakamura et al., International Immunopharmacology, 2018, 56, 193-196. Zhang et al., Science Bulletin, 2019, 64, 1179-1194. Juiland et al., Oncotarget, 2018, 9, 12542-12543. Saba et al., Cancer Research, 2017, 77, 7038-7048. Liu et al., Journal of Cellular and Molecular Medicine, 2020, 24, 7550-7562.

[0008] An object of the present invention is to provide a compound having MALT1 inhibitory activity or a pharmaceutically acceptable salt thereof.

[0009] That is, the present invention can include the following (Item 1) to (Item 11).

[0010] (Item 1) A compound represented by general formula (1) or a pharmaceutically acceptable salt thereof (hereinafter collectively referred to as the "compound of the present invention"): [In general formula (1), R １ represents a group represented by general formula (2) or general formula (3), R ２ 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 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, a substituted or unsubstituted heteroaryloxy group, a group represented by general formula (4), or a group represented by general formula (5), R ４ represents a halogen, and R ５ represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, R ６ and R ７ each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group, R ８ represents 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 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 may be linked to each other to form a ring, R １１represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group, and in general formulas (2), (3), (4), and (5), a wavy line represents a bond.] (Item 2) The compound is a compound represented by general formula (6), The R ３ 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), or a pharmaceutically acceptable salt thereof. (Item 3) The compound according to (Item 1), wherein the compound is a compound represented by general formula (7), The R ３ 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, or a pharmaceutically acceptable salt thereof.

[0011] (Item 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-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, (2) [5-chloro-1-methyl-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, (3) {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}acetonitrile, (4) [5-chloro-1-(2-hydroxyethyl)-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, (5) 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}azetidin-1-yl)ethan-1-one, (6) [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (7) [5-chloro-1-ethyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone,(8) [5-chloro-1-propyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (9) [5-chloro-1-(3-hydroxypropyl)-6-(pyrimidin-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, (10) [5-chloro-1-(oxetan-3-yl)-6-(pyrimidin-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, (11) [5-chloro-1-methyl-6-(pyrimidin-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, (12) [5-chloro-1-methyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (13) [5-chloro-1-ethyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (14) [5-chloro-1-ethyl-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, (15) [5-chloro-1-(3-hydroxypropyl)-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,(16) [5-chloro-1-cyclopropyl-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, (17) [5-chloro-1-isopropyl-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, (18) [5-chloro-1-ethyl-6-(pyrimidin-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, (19) [5-chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-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) [5-chloro-1-(oxan-4-yl)-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, (21) {5-chloro-1-[(3S)-oxolan-3-yl]-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, (22) {5-chloro-1-[(3R)-oxolan-3-yl]-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,(23) [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (24) [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (25) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (26) [5-chloro-1-propyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (27) [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(pyrazole o[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (28) [1-(1,2,3-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (29) [1-(1,2,3-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-1-methyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (30) 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}isoquinolin-1(2H)-one,(31) 9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-4H-quinolizin-4-one, (32) (5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)[1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (33) [(2RS,4RS)-1-(5-bromopyrimidin-4-yl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (34) [(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (35) {5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}(piperazin-1-yl)methanone, (36) [(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone. (Item 5) A pharmaceutical composition comprising the compound according to any one of (Item 1) to (Item 4) above, or a pharmaceutically acceptable salt thereof, as an active ingredient. (Item 6) A MALT1 inhibitor comprising, as an active ingredient, the compound according to any one of (Items 1) to (Item 4) above, or a pharmaceutically acceptable salt thereof. (Item 7) A method for inhibiting MALT1, comprising administering to a subject in need thereof the compound according to any one of (Items 1) to (Item 4) above, or a pharmaceutically acceptable salt thereof. (Item 8) A compound according to any one of (Items 1) to (Item 4) above, or a pharmaceutically acceptable salt thereof, for use in inhibiting MALT1. (Item 9)Use of the compound of any one of (Items 1) to (Item 4) above, or a pharmaceutically acceptable salt thereof, in the manufacture of a MALT1 inhibitor. (Item 10) A preventive or therapeutic agent for a disease involving MALT1, comprising, as an active ingredient, the compound of any one of (Items 1) to (Item 4) above, or a pharmaceutically acceptable salt thereof. (Item 11) A method for the prevention or treatment of a disease involving MALT1, comprising administering to a subject in need thereof the compound of any one of (Items 1) to (Item 4) above, or a pharmaceutically acceptable salt thereof. (Item 12) The compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease involving MALT1. (Item 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. (Item 14) A compound according to any one of (Items 1) to (Item 4) or a pharmaceutically acceptable salt thereof is contained as an active ingredient, and the compound is used for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, rejection associated with organ transplantation, aplastic anemia, Behcet'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 therapeutic agent for treating idiopathic leukemia / lymphoma, peripheral T-cell lymphoma, Sezary syndrome, primary effusion lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia, primary central nervous system malignant lymphoma, intraocular malignant lymphoma, primary macroglobulinemia, lymphoplasmacytic lymphoma, brain tumor, malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural splenomegaly, colorectal cancer, or esophageal cancer.

[0012] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0013] In this specification, the term "alkyl group" refers to a monovalent group obtained by removing one hydrogen atom from a saturated hydrocarbon. The alkyl group may be linear or branched. The alkyl group may be any of C １ ~C ６ may be an alkyl group,１ ~C ４ may be an alkyl group, １ ~C ３ In the present specification, the term "C ａ ~C ｂ " means that the number of carbon atoms is a to b. Specific examples of the alkyl group include a 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, and 2-ethylbutyl group.

[0014] As used herein, the term "substituted alkyl group" refers to an alkyl group in which one or more hydrogen atoms have been substituted with a substituent. Examples of the substituent in the substituted alkyl group include a hydroxy group, a cyano group, a halogen atom, an amino group, a mono-substituted amino group, a di-substituted amino group, a nitro group, an alkyl group, an alkoxy group, an aryloxy group, a heteroaryloxy group, a saturated heterocyclic group, an aryl group, a heteroaryl group, an acyl group, and an oxo group. These substituents may be further substituted with other substituents, or may be bonded to each other to form a ring.

[0015] In the present specification, the term "cycloalkyl group" refers to a monovalent group obtained by removing one hydrogen atom from a cyclic saturated hydrocarbon. ３ ~C ８ may be a cycloalkyl group, ３ ~C ６ may be a cycloalkyl group, ３ ~C ４ It may be a cycloalkyl group. Specific examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0016] In the present specification, the term "substituted cycloalkyl group" refers to a cycloalkyl group in which one or more hydrogen atoms are substituted with a substituent. Examples of the substituent in the substituted cycloalkyl group include the substituents described above.

[0017] In this specification, the term "heterocyclic group" refers to a non-aromatic, cyclic, monovalent group containing a heteroatom in the ring. The number of heteroatoms contained in the ring of the heterocyclic group may be, for example, 1 to 5, 1 to 3, 1 to 2, or 1. The heterocyclic group may be a monocyclic ring 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 an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an azetidinyl group, a tetrahydro-1,1-dioxide-2H-thiopyranyl group, and a quinolidinone group.

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

[0019] In this specification, the term "aryl group" refers to a monovalent cyclic aromatic hydrocarbon group. The aryl group may be a single ring or a condensed ring. Specific examples of the aryl group include a phenyl group and a naphthyl group.

[0020] In this specification, the term "substituted aryl group" refers to an aryl group in which one or more elements (elements not constituting a ring) are substituted with a substituent. Examples of the substituent in the substituted aryl group include the substituents described above.

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

[0022] In the present specification, the term "substituted heteroaryl group" refers to a heteroaryl group in which one or more elements (elements not constituting the ring) are substituted with a substituent. Examples of the substituent in the substituted heteroaryl group include the substituents described above.

[0023] In this specification, the term "alkoxy group" refers to an oxy group having an alkyl group bonded thereto. Specific examples of the alkoxy group include a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, a pentyloxy group, and a 3-methylbutoxy group.

[0024] In the present specification, the term "substituted alkoxy group" refers to an alkoxy group in which one or more hydrogen atoms have been substituted with a substituent. Examples of the substituent in the substituted alkoxy group include the substituents described above.

[0025] In this specification, the term "aryloxy group" refers to an oxy group to which an aryl group is bonded. Specific examples of the aryloxy group include a phenoxy group and a naphthyloxy group.

[0026] In the present specification, the term "substituted aryloxy group" refers to an aryloxy group in which one or more elements (elements not constituting a ring) are substituted with a substituent. Examples of the substituent in the substituted aryloxy group include the substituents described above.

[0027] In the present specification, the term "heteroaryloxy group" refers to an oxy group having a heteroaryl group bonded thereto. Specific examples of the heteroaryloxy group include a furyloxy group, a thienyloxy group, a pyrrolyloxy group, an imidazolyloxy group, a pyrazolyloxy group, a thiazolyloxy group, and a piperazinyloxy group.

[0028] In the present specification, the term "substituted heteroaryloxy group" refers to a heteroaryloxy group in which one or more elements (elements not constituting the ring) are substituted with a substituent. Examples of the substituent in the substituted heteroaryloxy group include the substituents described above.

[0029] In this specification, the term "halogen" refers to a group consisting of a halogen atom (halogeno group). Examples of halogen include a fluoro group, a chloro group, a bromo group, and an iodo group.

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

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

[0032] In general formula (1), R ２ represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group, and １ ~C ６ alkyl group, substituted or unsubstituted C ３ ~C ８ A cycloalkyl group or a substituted or unsubstituted monocyclic saturated heterocyclic group is preferred, and a hydrogen atom, C １ ~C ６ C substituted with an alkyl group, a hydroxy group, or a cyano group １ ~C ６ Alkyl group, C ３ ~C ６It is more preferably a cycloalkyl group, a monocyclic saturated heterocyclic group substituted with an acetyl group or an oxo group, or an unsubstituted monocyclic saturated heterocyclic group, and is more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group, a 2-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 is even more preferably a methyl group, an ethyl group, or an n-propyl group, and is particularly preferably a methyl group.

[0033] In general formula (1), R ３ 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, a substituted or unsubstituted heteroaryloxy group, a group represented by general formula (4), or a group represented by general formula (5). [In general formula (4), R ９ and R １０ each 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 may be linked to each other to form a ring. [In general formula (5), R １１ represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group.]

[0034] R ３is 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 (for example, a 2-1,2,3-triazolyl group), a pyrimidyl group (for example, 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 R each 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 may be linked to each other to form a ring. ９ and R １０ are preferably linked to each other to form a ring, and R ９ and R １０ More preferably, these groups form a piperazine ring together with the nitrogen atom to which they are bonded.

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

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

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

[0039] In general formula (2), R ６ and R ７ each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group, and is preferably a substituted or unsubstituted alkyl group; C １ ~C ６ It is more preferably an alkyl group, and C １ ~C ３ An alkyl group is more preferred, and a methyl group is even more preferred. ６ and R ７ It is particularly preferable that R are all methyl groups. ６ is not a hydrogen atom, R ６ The carbon atom to which is bonded is the asymmetric center. In this case, the configuration may be either R or S, but is preferably R. Similarly, R ７ is not a hydrogen atom, R ７ The carbon atom to which is bonded is the asymmetric center. In this case, the configuration may be either R or S, but is preferably R. ６ and the carbon atom to which R ７ When both of the carbon atoms to which are bonded are asymmetric centers, it is particularly preferred that the configurations of both are R.

[0040] In general formula (3), R ８ represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group, and is preferably a substituted or unsubstituted fused ring aryl group, a substituted or unsubstituted fused ring heteroaryl group, or a substituted or unsubstituted fused ring heterocyclic group, more preferably a fused ring aryl group substituted with a fluoro group, a fused ring heteroaryl group substituted with a fluoro group, an unsubstituted fused ring heteroaryl group, a fused ring heterocyclic group substituted with an oxo group, or an unsubstituted fused ring heterocyclic group, and is preferably an 8-fluoroisoquinolyl group (e.g., 4-8-fluoroisoquinolyl group), a 4-quinolidinone group (e.g.,

[0044] More preferably, the alkyl group is a 1,8-4-quinolidinone group), a 1-fluoronaphthyl group (for example, a 5-1-fluoronaphthyl group), a 1,2,3-benzothiadiazolyl group (for example, a 7-1,2,3-benzothiadiazolyl group), a pyrazolo[1,5-a]pyridyl group (for example, a 4-pyrazolo[1,5-a]pyridyl group), a thieno[2,3-b]pyridyl group (for example, a 4-thieno[2,3-b]pyridyl group), a thieno[2,3-c]pyridyl group (for example, a 3-thieno[2,3-c]pyridyl group), or a 1(2H)-oxoisoquinolyl group (for example, a 5-1(2H)-oxoisoquinolyl group), and even more preferably an 8-fluoroisoquinolyl group.

[0041] In general formula (1), general formula (2), general formula (3), general formula (4) and general formula (5), wavy lines indicate bonds.

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

[0043] In general formula (6), R ２ , R ３ , R ４ , R ５ , R ６ and R ７ has the same meaning as that explained in the general formula (1).

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

[0045] In general formula (7), R ２ , R ３ , R ４ and R ８ has the same meaning as that explained in the general formula (1).

[0046] Specific examples of the compound represented by general formula (1) include the following compounds (1) to (36): (1) [5-chloro-1-(oxetan-3-yl)-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, (2) [5-chloro-1-methyl-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, (3) {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}acetonitrile, (4) [5-chloro-1-(2-hydroxyethyl)-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, (5) 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}azetidin-1-yl)ethan-1-one, (6) [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (7) [5-chloro-1-ethyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (8) [5-chloro-1-propyl-6-(2H-1,2,(3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (9) [5-chloro-1-(3-hydroxypropyl)-6-(pyrimidin-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, (10) [5-chloro-1-(oxetan-3-yl)-6-(pyrimidin-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, (11) [5-chloro-1-methyl-6-(pyrimidin-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, (12) [5-chloro-1-methyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (13) [5-chloro-1-ethyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (14) [5-chloro-1-ethyl-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, (15) [5-chloro-1-(3-hydroxypropyl)-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, (16) [5-chloro-1-cyclopropyl-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, (17) [5-chloro-1-isopropyl-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, (18) [5-chloro-1-ethyl-6-(pyrimidin-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, (19) [5-chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-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) [5-chloro-1-(oxan-4-yl)-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, (21) {5-chloro-1-[(3S)-oxolan-3-yl]-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, (22) {5-chloro-1-[(3R)-oxolan-3-yl]-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, (23) [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,(3-b)pyridin-3-yl][1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (24) [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (25) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (26) [5-chloro-1-propyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (27) [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(pyrazole o[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (28) [1-(1,2,3-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (29) [1-(1,2,3-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-1-methyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (30) 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}isoquinolin-1(2H)-one, (31) 9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,(3-b)pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-4H-quinolizin-4-one, (32) (5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)[1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (33) [(2RS,4RS)-1-(5-bromopyrimidin-4-yl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (34) [(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (35) {5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}(piperazin-1-yl)methanone, (36) [(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone.

[0047] The compound of the present invention can be produced using known compounds or intermediates that can be easily synthesized from known compounds, for example, by the methods described below, the Examples described below, or known methods. In producing the compound of the present invention, if the raw material has a substituent that affects the reaction, it is common to first protect the raw material with an appropriate protecting group by a known method before carrying out the reaction. The protecting group can be deprotected by a known method after the reaction.

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

[0049] The abbreviations used in this specification have the following meanings. In the examples, the following abbreviations are used: Pd-C: palladium-carbon Pd(PPh ３ ) ４ : Tetrakistriphenylphosphine palladium PdCl ２ (PPh ３ ) ２ : Bis(triphenylphosphine)palladium(II) dichloride Pd(OAc) ２ : Palladium (II) acetate Pd(dppf) ２ Cl ２ : [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct PPh ３ : Triphenylphosphine Boc ２ O: di-tert-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] Pharmaceutically acceptable salts of the compounds of the present invention include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., salts with 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, methanesulfonic acid, etc., salts with alkali metals such as lithium, potassium, sodium, etc., salts with alkaline earth metals such as magnesium, calcium, etc., salts with organic bases such as ammonium salts, etc. These salts can be formed by conventional methods.

[0051] For example, when the compound of the present invention is a hydrochloride, the hydrochloride can be obtained by dissolving the free base of the compound of the present invention in an alcohol 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 compound of the present invention may take up solvent molecules to form a solvate when left in the air or when recrystallized, and such solvates are also included in the compound of the present invention. Examples of such solvates include solvates with solvent molecules such as methanol solvate, ethanol solvate, isopropyl alcohol solvate, butanol solvate, dimethyl sulfoxide solvate, and acetonitrile solvate, as well as monohydrates and dihydrates.

[0053] Some of the compounds of the present invention have asymmetric carbon atoms, and both optical isomers and mixtures thereof are encompassed by the present invention. Stereoisomers can be produced, for example, by optical resolution of a racemate using an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid) by known methods, taking advantage of its basicity, or by using a pre-prepared optically active compound as a starting material. Alternatively, stereoisomers can be produced by optical resolution using a chiral column or asymmetric synthesis. Furthermore, while the structural formula of the compounds of the present invention may conveniently represent certain isomers, the present invention also encompasses geometric isomers arising from the structure of the compounds, optical isomers based on asymmetric carbon atoms, stereoisomers, tautomers, and other isomers and mixtures of isomers. Furthermore, unless otherwise specifically specified in a particular claim, the present invention is not limited to the description of convenient formulas, and all are encompassed within the present invention.

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

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

[0056] Furthermore, in one embodiment of the present invention, there is provided a method of inhibiting MALT1, comprising administering a compound of the present invention to a subject in need thereof.

[0057] Furthermore, in one embodiment of the present invention, there is provided a compound of the present invention for use in inhibiting MALT1.

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

[0059] In one embodiment of the present invention, there is provided a preventive or therapeutic agent for a disease involving MALT1, which comprises the compound of the present invention.

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

[0061] Furthermore, one embodiment of the present invention provides the compound of the present invention for use in the prevention or treatment of a disease in which MALT1 is involved.

[0062] Furthermore, one embodiment of the present invention provides use of the compound of the present invention in the manufacture of an agent for the prophylaxis or treatment of a disease in which MALT1 is involved.

[0063] Examples of diseases to which the compound of the present invention can be applied include multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, rejection associated with organ transplantation, aplastic anemia, Behcet'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 of such cancers include idiopathic leukemia, idiopathic leukemia, idiopathic pulmonary fibrosis ...

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

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

[0066] The carrier may be one or more conventional pharmaceutically acceptable solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries. The pharmaceutical composition of the present invention is preferably administered in a dosage unit form. The pharmaceutical composition may be administered intramuscularly, orally, intravenously, topically (transdermally, by eye drop, intraperitoneally, intrapleurally, etc.), or rectally. The pharmaceutical composition of the present invention is administered in a dosage form suitable for these administration methods.

[0067] The pharmaceutical dose is desirably adjusted taking into consideration the patient's condition, such as age, body weight, type and severity of disease, the route of administration, the type of compound of the present invention, whether or not it is a salt, and the type of salt, but typically, in the case of oral administration to an adult, the amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt thereof is within the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, per day. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Typically, the compound is administered once a day or in divided doses, or in the case of intravenous administration, it can be administered as a bolus or continuously for up to 24 hours.

[0068] One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with an isotope of the hydrogen, carbon and / or other atom, respectively. Examples of such isotopes include, but are not limited to, 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 The isotope-substituted compounds are useful as pharmaceuticals and include all radiolabeled compounds of the present invention.

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

[0070] When the solvents, reagents, and raw materials used in each step in the following production methods are commercially available, the commercially available products can be used as they are. Furthermore, the compounds obtained in each step in the production methods described below and the raw materials used may form salts, which can be converted into other types of salts or free forms by known methods. Conversely, when the compounds obtained in each step in the following production methods and the raw materials used are in free forms, they can be converted into the desired salts by known methods. Examples of such salts include the same salts as those used for the compounds of the present invention described above.

[0071] In the production of the compound of the present invention, when a raw material has a substituent that may affect the reaction, a protecting group may be introduced into the substituent in advance by a known method, and the target compound can be obtained by removing the protecting group after the reaction, as necessary. Examples of such a protecting group include the protecting groups described in Wuts and Greene, "Greene's Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons Inc., 2006, or P.J. Kocienski, "Protecting Groups," 3rd Edition, Thieme, 2005, and the like, and the protecting group may be appropriately selected depending on the reaction conditions.

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

[0073] Unless otherwise specified, the reactions in each step in the following production methods are carried out according to known methods, for example, those described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition" by R.C. Larock, John Wiley & Sons Inc. , 1999, "Experimental Chemistry Lectures" edited by the Chemical Society of Japan, 4th edition, Maruzen, 1992, "Strategies in Organic Synthesis Learned from Named Reactions" by L. Kuerti and B. Czako, translated and supervised by Tomioka Kiyoshi, Kagaku Dojin, 2006, "Latest Organic Synthesis Methods: Design and Strategy" by G. S. Zweifel and M. H. Nantz, translated by Hiyama Tamijiro, Kagaku Dojin, 2009, or the methods described in the examples can be suitably modified or combined for use.

[0074] [1] Synthesis of compound (1) (R １ , R ３ , R ３ and R ４ has the same meaning as above. １ represents chloro or bromo, and X ２represents chloro, bromo, mesylate, or triflate.) Step 1: This step involves subjecting Compound AA, which is commercially available or synthesized by a known method, to a Friedel-Crafts acylation reaction with Acid Halide BB in the presence of a Lewis acid such as aluminum chloride in a solvent such as methylene chloride or dichloroethane at 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 below, with oxalyl chloride or oxalyl bromide in the presence of a catalytic amount of dimethylformamide in a solvent such as methylene chloride or dichloroethane at 0°C to 50°C, preferably 0°C to room temperature, for 1 to 48 hours, preferably 1 to 12 hours. Step 2: This step involves alkylating compound CC with alkylating agent DD in the presence of a base to obtain compound (1), which can be carried out in accordance with a known method for alkylation reactions. The reaction can be carried out by reacting compound CC with alkylating agent DD in the presence of a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, or cesium carbonate in a solvent such as dimethylformamide or tetrahydrofuran at 0°C to 120°C, preferably room temperature to 120°C, for 1 hour to 48 hours, preferably 1 hour to 12 hours.

[0075] [2] Synthesis of Compound AAa (R ４ has the same meaning as above. ３ａ 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 represents chloro, bromo, or triflate. １represents boronic acid, boronic acid ester, alkyltin, zinc halide, etc. P represents a protecting group, such as Boc, Cbz, Bn, etc. Step 1 This step is a step of obtaining compound FF by a coupling reaction between compound CC and EE. Examples of such reactions include Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, Stille coupling, etc. Compound CC is reacted with Pd(PPh) in a solvent or mixed solvent such as dioxane, toluene, DMSO, DMF, DME, THF, water, etc. ３ ) ４ , Pd(OAc) ２ , PdCl ２ (PPh ３ ) ２ , Pd(dppf) ２ Cl ２ Compound FF can be obtained by adding a palladium catalyst such as boronic acid, boronic acid ester, trialkyltin, or zinc halide, a base such as potassium carbonate, sodium carbonate, or potassium phosphate, and a commercially available or synthesized by a known method, and reacting the resulting 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 selected from the group consisting of the protecting group (P) described in Wuts and Greene, "Greene's Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons Inc. 2006, or P.J. Kocienski, "Protecting Groups", 3rd Edition, Thiemes, 2005. Step 2 This step is a step of deprotecting the protecting group of compound FF to obtain AAa, and can be introduced with reference to Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th Edition, John Wiley & Sons Inc., 2006, or P.J. Kocienski, "Protecting Groups", 3rd Edition, Thiemes, 2005.

[0076] [3] Synthesis of Compound AAb (R ４ has the same meaning as that explained in relation to general formula (1).) In this step, compound GG, which is commercially available or synthesized by a known method, is subjected to an addition reaction with HH in a solvent such as acetonitrile in the presence of a base such as potassium carbonate at 0°C to 100°C for 1 hour to 48 hours, preferably 12 hours to 24 hours, to obtain compound AAb.

[0077] [4] Synthesis of Compound LL (R ５ , R ６ , R ７ X ２ has the same meaning as above. R represents alkyl such as methyl, ethyl, etc.) Step 1 In this step, Compound II, which is commercially available or synthesized by a known method, is subjected to an aromatic nucleophilic substitution reaction (S Ｎ Step 2 is a step of hydrolyzing the ester of compound KK to obtain compound LL, and the compound can be synthesized with reference to "Greene's Protective Groups in Organic Synthesis" by Wuts and Greene, 4th Edition, John Wiley & Sons Inc., 2006, or "Protecting Groups" by P.J. Kocienski, 3rd Edition, Thiemes, 2005.

[0078] [5] Synthesis of compound (PP) (R ８has the same meaning as above. R represents alkyl such as methyl or ethyl.) Step 1 This step is a step of obtaining compound OO by reacting compound MM, which is commercially available or synthesized by a known method, and compound NN in a solvent such as ethanol or ether at 0°C to 80°C, preferably in ethanol at 60°C to 80°C, for 1 hour to 48 hours, preferably 1 hour to 10 hours. Step 2 This step is a step of obtaining compound PP by hydrolyzing the ester of compound OO, and is described in Wuts and Greene, "Greene's Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons Inc. 2006, or P.J. Kocienski, "Protecting Groups", 3rd Edition, Thiemes 2005.

[0079] The present invention will be explained in more detail below with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited to these examples.

[0080] MS was measured by LCMS. ESI was used as the ionization method. The observed mass spectrometry values ​​are expressed as m / z.

[0081] The LCMS measurement conditions were as follows: Analytical instrument: ACQUITY UPLC MS / PDA system (Waters Corporation) Mass spectrometer: Waters 3100 MS detector Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210 to 400 nm) Column: Acquity BEH C18, 1.7 μm, 2.1 × 50 mm Flow rate: 0.5 mL / min Column temperature: 40°C Solvent: Solution A: 0.1% formic acid / H ２ Solution B: 0.1% formic acid / acetonitrile (v / v; the same applies below)

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

[0083] １ H NMR spectra were measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE Co., Ltd.) and 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] For microwave experiments, an Initiator 60 (Biotage) was used, which can achieve temperatures of 40-250°C and pressures up to 20 bar.

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

[0086] The melting points were measured using a micromelting point analyzer (Buchi, Model B-565).

[0087] The compound names in this specification are determined using naming software conforming to IUPAC rules, ACD / NAME (registered trademark, Advanced Chemistry Development Inc.), or ChemBioDraw (version 19.1, manufactured by Cambridge Soft), or are determined according to the IUPAC nomenclature.

[0088] The r and s (lower case) in the compound names indicate the stereochemistry of the pseudo-asymmetric carbon atom according to IUPAC rules.

[0089] ​Reference Example 1 Synthesis of 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide m-Chloroperbenzoic acid (94 g) was added in three portions to a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (30 g) in diethyl ether (1.4 L), and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, and the resulting yellow-green residue was suspended in water (0.72 L), followed by addition of 23% (w / v) aqueous potassium carbonate solution (0.31 kg), and the mixture was stirred overnight at room temperature. The reaction solution was filtered, and the resulting residue 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 m-Chlorobenzoic acid (2.4 g) was added to a suspension of 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (2.6 g) in acetonitrile (80 mL). After stirring at room temperature for 30 minutes, dimethyl sulfate (1.5 mL) was added and the mixture was stirred at an external temperature of 75°C for 20 hours. After allowing the reaction solution to cool, 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 external temperature of 60°C for 6 hours. After allowing the reaction solution to cool, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and then dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain a crude residue as a pink solid. The residue was washed with ethyl acetate (10 mL) to give 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 an ice-cooled solution of benzoyl bromide (3.5 mL) in toluene (60 mL), a premixed 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. Saturated aqueous sodium bicarbonate was added to the reaction solution, which was then 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 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 Aqueous sodium hydroxide solution (2.0 M, 12 mL) was added to a mixed solution of 1-benzoyl-6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (3.9 g) in tetrahydrofuran (38 mL) and methanol (76 mL), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with aqueous sodium hydroxide solution (2.0 M, 0.10 L) and extracted with chloroform. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure 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 A solution of 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (1.0 g) in N,N-dimethylformamide (10 mL) was diluted with di-tert-butyl dicarbonate (hereinafter referred to as "Boc"). ２ To the reaction mixture were added 1.5 mL of 4-dimethylaminopyridine (hereinafter referred to as "DMAP"), 1.8 mL of triethylamine, and 53 mg of 4-dimethylaminopyridine (hereinafter referred to as "DMAP"), and the mixture was stirred overnight at room temperature. The reaction mixture was directly purified by column chromatography to obtain 1.4 g of the target compound as a colorless oil.

[0094] Reference Example 6 Synthesis of 5-chloro-6-(pyrimidin-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 added in that order, and the mixture was stirred overnight at an external temperature of 80°C. After allowing the reaction solution to cool, it was directly purified by column chromatography and then purified by reverse phase column chromatography (H ２ O / 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 Ethylene glycol (6.8 mL) and pyridinium p-toluenesulfonate (hereinafter referred to as "PPTS") (1.5 g) were added sequentially to a solution of tert-butyl (2R)-2-methyl-4-oxopiperidine-1-carboxylate (5.2 g) in toluene (0.10 L), and the mixture was heated under reflux with stirring at an external temperature of 145°C for 15 hours. The reaction solution was allowed to cool and then neutralized with saturated aqueous sodium bicarbonate. Next, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and then with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain 4.6 g of the target compound as a colorless oil.

[0096] Reference Example 8 Synthesis of tert-butyl (7R,9R)-7,9-dimethyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate This was synthesized according to the method of Feringa et al. (Org. Biomol. Chem., 2008, Vol. 6, pp. 3464-3466). Tetramethylethylenediamine (hereinafter referred to as "TMEDA") (13 mL) was added 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). The reaction solution was cooled to -78°C in a dry ice acetone bath, and then a sec-butyllithium hexane solution (1.22 M, 72 mL) was added dropwise, followed by stirring 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, and then 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 evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain 8.5 g of the target compound (trans:cis = 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

[0046] 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) was diluted with p-toluenesulfonic acid monohydrate (hereinafter referred to as "PTSA.H"). ２ 0") (9.1 g) was added and stirred at room temperature for 1.5 hours. After ice-cooling the reaction solution, an aqueous solution (69 g) of sodium carbonate (6.3 g) was added to neutralize it, and the reaction solvent was evaporated 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 evaporated 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) was added toluenesulfonylmethyl isocyanide (hereinafter referred to as "TosMIC") (12 g). After ice-cooling the reaction solution, tert-butoxypotassium (13 g) was added and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 15 hours. After ice-cooling the reaction solution, it was diluted with water, and the reaction solvent was evaporated under reduced pressure. Extraction was performed with ethyl acetate, and the organic phase was washed with water and then with saturated brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. 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 Step 1 Potassium hydroxide (18 g) was added to a mixed solution of tert-butyl (2R,6R)-4-cyano-2,6-dimethylpiperidine-1-carboxylate (13 g) in ethanol (0.11 L) and water (0.11 L), and the mixture was heated under reflux and stirred at an external temperature of 95°C for 20 hours. After cooling, the reaction solution was diluted with water and neutralized with 20% (w / v) aqueous citric acid solution to a pH of 5. An extraction operation was performed with ethyl acetate, and the organic phase was washed with water and then with saturated brine, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a residue (14 g) as a white solid. Step 2: The residue (13 g) obtained in Step 1 was dissolved in a hydrochloric acid ethanol solution (2.0 M, 0.68 L) and heated under reflux and stirring at an external temperature of 120°C for 30 hours. After allowing the reaction solution to cool, the reaction solvent was distilled off under reduced pressure. The resulting residue was ice-cooled, and an aqueous sodium hydroxide solution (2.0 M) was added to adjust the pH to 13. An extraction operation was performed with chloroform, and the organic phase was washed with saturated saline and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 8.9 g 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-nitropyridin-2-yl)-2,6-dimethylpiperidine-4-carboxylate N,N-Diisopropylethylamine (hereinafter referred to as "DIPEA") (4.0 mL) and 2,5-difluoro-3-nitropyridine (2.1 g) were added sequentially to a solution of ethyl (2R,6R)-2,6-dimethylpiperidine-4-carboxylate (2.2 g) in dimethyl sulfoxide (24 mL), and the mixture was stirred for 3 hours at an external temperature of 140° C. The reaction solution was allowed to cool and then directly purified by 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-fluoropyridin-2-yl)-2,6-dimethylpiperidine-4-carboxylate Pt / C type STD (Pt 3%) (1.1 g) was added to a solution of ethyl (2R,6R)-1-(5-fluoro-3-nitropyridin-2-yl)-2,6-dimethylpiperidine-4-carboxylate (3.4 g) in methanol (0.10 L), and the mixture was stirred under a hydrogen gas atmosphere (5.0 atm) at an external temperature of 45°C for 4 hours. After allowing the reaction solution to cool, it was filtered through Celite, and the solvent was evaporated 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-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carboxylate Isoamyl nitrite (6.4 mL) was added to a solution of ethyl (2R,6R)-1-(3-amino-5-fluoropyridin-2-yl)-2,6-dimethylpiperidine-4-carboxylate (8.0 g) in diiodomethane (80 mL), and the mixture was stirred for 7 hours at an external temperature of 80° C. The reaction solution was allowed to cool and then directly purified by 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-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid Ethyl (2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carboxylate (4.5 g) in tetrahydrofuran (55 mL), methanol (22 mL), and water (33 mL) were mixed and added with lithium hydroxide monohydrate (1.2 g), followed by stirring overnight at room temperature. After ice-cooling the reaction solution, aqueous hydrochloric acid (1.0 M) was added to adjust the pH to 2. An extraction operation was performed with ethyl acetate, and the organic phase was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated 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-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 Step 1 N,N-Dimethylformamide (2.5 μL) and oxalyl chloride (35 μL) were added to a solution of (2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid (0.12 g) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure to give a yellow amorphous substance. Step 2: Aluminum trichloride (0.21 g) was added 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 (2.0 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the pale yellow amorphous 1,2-dichloroethane (4.0 mL) obtained in Step 1 was added dropwise to the reaction mixture, followed by stirring at an external temperature of 50°C for 2 hours. After ice-cooling 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 evaporated under reduced pressure. 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-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 [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) N,N-dimethylformamide (0.50 mL) solution was added potassium carbonate (21 mg), (2-bromoethoxy) (tert-butyl) dimethylsilane (37 mg) sequentially, and stirred at an external temperature of 50 ° C for 1 hour. 2-Bromoethoxy-tert-butyldimethylsilane (37 mg) was added again, and stirred at an external temperature of 50 ° C for 1 hour. After cooling, the reaction solution was directly purified by 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-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}azetidine-1-carboxylate [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 (45 mg) in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (27 mg), tert-butyl 3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-yl]azetidine-1-carboxylate 3-Iodoazetidine-1-carboxylate (0.11 g) was added sequentially, and the mixture was stirred for 10 hours at an external temperature of 100° C. The reaction solution was allowed to cool and then directly purified by reverse phase column chromatography (HO / 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-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Step 1 To a solution of 1-(8-fluoroisoquinolin-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 stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure to give a pale yellow solid. Step 2: Aluminum trichloride (0.18 g) was added to a solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (60 mg) in 1,2-dichloroethane (2.5 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the pale yellow solid obtained in Step 1 in 1,2-dichloroethane (2.5 mL) was added dropwise to the reaction mixture, and the mixture was stirred at an external temperature of 75°C for 3 hours. After ice-cooling 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 evaporated 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-(pyrimidin-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 Step 1 N,N-Dimethylformamide (3.6 μL) and oxalyl chloride (59 μL) were added to a dichloromethane (3.0 mL) solution of (2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid (0.18 g), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure to give a yellow amorphous substance. Step 2: Aluminum trichloride (0.29 g) was added to a solution of 5-chloro-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.10 g) in 1,2-dichloroethane (3.0 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the yellow amorphous 1,2-dichloroethane (3.0 mL) obtained in Step 1 was added dropwise to the reaction mixture, followed by stirring at an external temperature of 50°C for 2 hours. The mixture was further stirred overnight at an external temperature of 70°C. After ice-cooling the reaction mixture, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and then dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 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-(pyrimidin-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 [5-chloro-6-(pyrimidin-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) N,N-dimethylformamide (0.50 mL) solution was added potassium carbonate (35 mg), (3-bromopropoxy) (tert-butyl) dimethylsilane (64 mg) sequentially, and stirred for 3 hours at an external temperature of 50° C. The reaction solution was allowed to cool and then purified directly by column chromatography to obtain 47 mg of the target compound as a colorless oily substance.

[0110] Reference Example 22 Synthesis of [5-chloro-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Step 1 To a solution of 1-(8-fluoroisoquinolin-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 solution was evaporated under reduced pressure to give a pale yellow solid. Step 2: Aluminum trichloride (0.26 g) was added to a solution of 5-chloro-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine (90 mg) in 1,2-dichloroethane (2.0 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the pale yellow solid obtained in Step 1 in 1,2-dichloroethane (2.0 mL) was added dropwise to the reaction mixture, followed by stirring at an external temperature of 75°C for 4 hours. The mixture was further heated and refluxed with stirring at an external temperature of 100°C for 2 hours. After ice-cooling the reaction mixture, it was diluted with water and extracted with ethyl acetate. The organic phase was washed twice with aqueous sodium hydroxide (2.0 M), then with saturated aqueous sodium bicarbonate, and finally with saturated brine. It was then dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain a crude residue. The resulting residue was suspended in methanol and collected by filtration 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 added successively, and the mixture was stirred at room temperature for 4 hours. The reaction solution was directly purified by 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 Triethylamine (0.54 mL) and methanesulfonyl chloride (0.22 mL) were added sequentially to a solution of oxan-4-ol (0.20 g) in dichloromethane (4.8 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was directly purified by column chromatography to obtain 0.34 g of the target compound as a white solid.

[0113] Reference Example 25 Synthesis of (3R)-oxolan-3-yl methanesulfonate To a solution of (3R)-oxolan-3-ol (0.20 g) in dichloromethane (5.6 mL), triethylamine (0.63 mL) and methanesulfonyl chloride (0.26 mL) were added successively, and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly purified by column chromatography to obtain 0.36 g of the target compound as a pale yellow oil.

[0114] Reference Example 26 Synthesis of (3S)-oxolan-3-yl methanesulfonate Triethylamine (0.94 mL) and methanesulfonyl chloride (0.39 mL) were added sequentially to a solution of (3S)-oxolan-3-ol (0.30 g) in dichloromethane (8.5 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was directly purified by column chromatography to obtain 0.40 g of the target compound as a pale yellow oil.

[0115] Reference Example 27 Synthesis of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Step 1 To a solution of 1-(thieno[2,3-b]pyridin-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), N,N-dimethylformamide (1.6 μL) and oxalyl chloride (32 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure to give a light brown solid. Step 2: Aluminum trichloride (0.12 g) was added to a solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (40 mg) in 1,2-dichloroethane (2.5 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown solid obtained in Step 1 in 1,2-dichloroethane (2.5 mL) was added dropwise to the reaction mixture, followed by stirring at an external temperature of 75°C for 4 hours. After ice-cooling 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 evaporated 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]pyridin-3-yl][1-(pyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Step 1 N,N-Dimethylformamide (1.7 μL) and oxalyl chloride (23 μL) were added to a solution of 1-(pyrazolo[1,5-a]pyridin-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), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure to give a pale brown oil. Step 2: Aluminum trichloride (120 mg) was added to a solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (40 mg) in 1,2-dichloroethane (2.5 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown oil obtained in Step 1 in 1,2-dichloroethane (2.5 mL) was added dropwise to the reaction mixture, followed by stirring at an external temperature of 75°C for 5 hours. After ice-cooling 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 evaporated 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-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone Step 1 To a solution of 1-(1,2,3-benzothiadiazol-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), N,N-dimethylformamide (2.6 μL) and oxalyl chloride (36 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure to give a light brown solid. Step 2: Aluminum trichloride (210 mg) was added 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 (3.1 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown solid obtained in Step 1 in 1,2-dichloroethane (2.5 mL) was added dropwise to the reaction mixture, and the mixture was stirred at an external temperature of 75°C for 5 hours. After ice-cooling 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 evaporated under reduced pressure. The resulting residue was subjected to slurry washing with methanol to obtain a crude residue. The resulting residue was purified by column chromatography to obtain a crude residue. The resulting residue was subjected to slurry washing 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-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine Potassium carbonate (930 mg) and methyl iodide (420 μL) were added sequentially to a solution of 5-chloro-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine in N,N-dimethylformamide (3.0 mL), 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 30 minutes. The reaction solution 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 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-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Step 1 To a solution of 1-(1-methoxyisoquinolin-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), 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 reaction solution was evaporated under reduced pressure to give a light brown solid. Step 2: Aluminum trichloride (200 mg) was added to a solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (68 mg) in 1,2-dichloroethane (3.0 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown solid obtained in Step 1 in 1,2-dichloroethane (2.5 mL) was added dropwise to the reaction mixture, and the mixture was stirred at an external temperature of 75°C for 6 hours. After ice-cooling 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 evaporated under reduced pressure. The resulting residue was subjected to slurry washing with ethyl acetate and methanol to obtain a crude residue. The resulting 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-quinolizin-4-one Step 1: A solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 13 mL) was cooled to -60°C in a dry ice / 40% water / methanol bath, and then a solution of 3-bromo-2-methyl-pyridine in tetrahydrofuran (3.4 g, 40 mL) was added dropwise and stirred at the same temperature for 1 hour. Subsequently, diethyl ethoxymethylenemalonate (4.0 g) was added dropwise, and the temperature was raised to -20°C in a dry ice / 70% water / methanol bath and stirred at the same temperature for 3 hours. After adding an aqueous ammonium chloride solution to the reaction solution, extraction was performed with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography to obtain 4.3 g of a yellow oil. Step 2: Polyphosphoric acid (25 g) was added to the yellow oil obtained in Step 1, and the mixture was stirred at an external temperature of 140°C for 6 hours. The reaction mixture was cooled with ice, 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 evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain a crude residue. The resulting residue was slurry-washed with a small amount of ice-cold ethyl acetate to obtain 1.5 g of the target compound as a yellow solid.

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

[0122] Reference Example 34 Synthesis of 1-(4-oxo-4H-quinolizin-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid Water (1.5 mL) and lithium hydroxide monohydrate (38 mg) were added to a solution of ethyl 1-(4-oxo-4H-quinolizin-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (130 mg) in tetrahydrofuran (3.0 mL), 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 5. The solvent of the reaction solution was evaporated under reduced pressure. The resulting residue was purified by reversed-phase column chromatography to obtain 4.1 g of the target compound as a white solid. After cooling, the solid was directly purified by column chromatography (H ２ 0 / MeOH) to obtain 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-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-4H-quinolizin-4-one Step 1 To a solution of 1-(4-oxo-4H-quinolizin-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg) in dichloromethane (2.5 mL) and a suspension 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. The reaction solution was evaporated under reduced pressure to give a brown solid. Step 2: Aluminum trichloride (0.21 g) was added 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), 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, and the mixture was stirred 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. After ice-cooling the reaction solution, 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 evaporated under reduced pressure. The resulting residue was slurry-washed with methanol to obtain 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 After ice-cooling 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), sodium hydride (100 mg) was added and stirred at the same temperature for 5 minutes. Methyl iodide (0.18 mL) was added to the reaction solution, and 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 extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (H ２290 mg of a white solid was obtained by purifying the white solid obtained in Step 1 in methanol (1.2 mL). Step 2: Potassium carbonate (100 mg) was added to a suspension of the white solid obtained in Step 1 in methanol (1.2 mL), and the mixture was stirred overnight at an external temperature of 50° C. The reaction solution was directly purified by column chromatography to obtain 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 the mixture was stirred at room temperature for 30 minutes. Under a hydrogen gas atmosphere (0.4 MPa), the mixture was stirred at an external temperature of 50°C for 8 hours and then at room temperature for 12 hours. The mixture was further stirred at an external temperature of 60°C for 8 hours. After ice-cooling the reaction solution, it was diluted with methanol and filtered through Celite, and the solvent was evaporated 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. Step 2 Sulfuric acid (10 mL) was added dropwise to a solution of the white solid (3.6 g) obtained in Step 1 in ethanol (100 mL), and the mixture was stirred at an external temperature of 95°C for 42 hours. The solvent was evaporated under reduced pressure, and the resulting residue was diluted with ethyl acetate, neutralized with a 2.0 M aqueous solution of sodium hydroxide under ice-cooling, 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 to give the target compound (3.3 g) as a pale yellow oil.

[0126] Reference Example 38 Synthesis of ethyl (2RS,4RS)-1-(5-bromopyrimidin-4-yl)-2-methylpiperidine-4-carboxylate DIPEA (0.20 mL) and 5-bromo-4-chloro-pyrimidine (140 mg) were added sequentially to a solution of ethyl 2-methylpiperidine-4-carboxylate (cis racemate) (100 mg) in dimethyl sulfoxide (1.0 mL), and the mixture was stirred for 90 minutes at an external temperature of 140° C. The reaction solution was allowed to cool and then directly purified by column chromatography to obtain 110 mg of the target compound as a yellow oil.

[0127] Reference Example 39 Synthesis of (2RS,4RS)-1-(5-bromopyrimidin-4-yl)-2-methylpiperidine-4-carboxylic acid Lithium hydroxide monohydrate (36 mg) was added to a mixed solution of ethyl 1-(5-bromopyrimidin-4-yl)-2-methylpiperidine-4-carboxylate (cis racemate) (110 mg) in tetrahydrofuran (2.5 mL) and water (2.5 mL), 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 4. An extraction operation was performed with ethyl acetate, and the organic phase was washed with saturated brine and then dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was slurry-washed with a mixed solvent 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-bromopyrimidin-4-yl)-2-methylpiperidin-4-yl][5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone Step 1 To a solution of 1-(5-bromopyrimidin-4-yl)-2-methylpiperidine-4-carboxylic acid (cis racemate) (45 mg) in dichloromethane (2.5 mL) were added N,N-dimethylformamide (1.1 μL) and oxalyl chloride (15 μL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure to give a white solid. Step 2: Aluminum trichloride (91 mg) was added to a solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) in 1,2-dichloroethane (2.5 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a suspension of the white solid obtained in Step 1 in 1,2-dichloroethane (2.5 mL) was added dropwise to the reaction mixture, and the mixture was stirred at an external temperature of 50°C for 2 hours. After ice-cooling 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 evaporated under reduced pressure. 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 DIPEA (0.40 mL) and 1,4-difluoro-2-nitrobenzene (270 mg) were added sequentially to a solution of ethyl (2RS,4RS)-2-methylpiperidine-4-carboxylate (200 mg) in dimethyl sulfoxide (2.0 mL), and the mixture was stirred for 60 minutes at an external temperature of 50°C under an argon atmosphere. The mixture was further stirred for 6 hours at an external temperature of 120°C. After allowing the reaction solution to cool, it was diluted with water and subjected to extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography to obtain 240 mg of the target compound as a yellow oil. To a mixed solution of the obtained yellow oil in tetrahydrofuran (2.5 mL) and water (2.5 mL), lithium hydroxide monohydrate (82 mg) was added and stirred at room temperature for 3 hours. Lithium hydroxide monohydrate (65 mg) was added to the reaction solution and stirred at room temperature for 1 hour. Lithium hydroxide monohydrate (82 mg) was added to the reaction solution and stirred at room temperature for 2 hours. Lithium hydroxide monohydrate (98 mg) was added to the reaction solution and stirred at room temperature overnight. Aqueous hydrochloric acid (1.0 M) was added to the reaction solution to adjust the pH to 3. An extraction operation was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated 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-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidin-4-yl]methanone Step 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 reaction solution was evaporated under reduced pressure to obtain a residue. Step 2: Aluminum trichloride (180 mg) was added to a solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) in 1,2-dichloroethane (1.0 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the residue obtained in Step 1 in 1,2-dichloroethane (3.0 mL) was added dropwise to the reaction mixture, and the mixture was stirred for 2 hours at an external temperature of 50°C under an argon atmosphere. After ice-cooling the reaction mixture, 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 evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain a crude residue. The resulting 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-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidin-4-yl]methanone Potassium carbonate (25 mg) and methyl iodide (11 μL) were added sequentially to a solution of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidin-4-yl]methanone (30 mg) in N,N-dimethylformamide (0.50 mL), and the mixture was stirred under an argon atmosphere at an external temperature of 50° C. for 90 minutes. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２0 / 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 Step 1 Zinc cyanide (1.3 g) was added to a solution of 5,6-dichloro-1H-pyrrolo[2,3-b]pyridine (1.3 g) in N,N-dimethylformamide (29 mL), and the mixture was stirred for 6 hours at an external temperature of 100°C under an argon atmosphere. The reaction solution was allowed to cool and then directly purified by column chromatography to obtain a crude residue. The resulting residue was slurry-washed with a mixed solvent of diethyl ether and hexane to obtain 950 mg of a white solid. Step 2 Aqueous sodium hydroxide solution (2.0 M, 30 mL) was added to a solution of the white solid (610 mg) obtained in Step 1 in ethanol (30 mL), and the mixture was heated under reflux and stirred overnight at an external temperature of 100°C. After ice-cooling the reaction solution, aqueous hydrochloric acid (1.0 M) was added, the pH was adjusted to 3, and the precipitated solid was collected by filtration to obtain 710 mg as 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 stirred at room temperature for 4 hours. 10% trimethylsilyldiazomethane (5.3 mL) was added to the reaction solution and stirred overnight at room temperature. Acetic acid (0.72 mL) was added to the reaction solution and stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting 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-fluoropyridin-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. The reaction solution was allowed to cool, then 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 resulting residue was purified by column chromatography to obtain 2.9 g of the ethyl ester as a pale yellow oil. Step 2: Lithium hydroxide monohydrate (1.2 g) was added to a mixed solution of the pale yellow oil (2.9 g) obtained in Step 1 in tetrahydrofuran (30 mL) and water (30 mL), 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. Extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was slurry-washed with a mixture 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-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (cis racemate) Step 1 To a solution of (2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidine-4-carboxylic acid (280 mg) in dichloromethane (10 mL) were added N,N-dimethylformamide (7.9 μL) and oxalyl chloride (130 μL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure to give a pale brown oil. Step 2: To a solution of methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (180 mg) in 1,2-dichloroethane (10 mL), aluminum trichloride (560 mg) was added and stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown oil obtained in Step 1 in 1,2-dichloroethane (10 mL) was added dropwise to the reaction mixture, followed by stirring at an external temperature of 70°C for 2 hours. After ice-cooling the reaction mixture, it was diluted with water and adjusted to pH 3 by adding aqueous hydrochloric acid (1.0 M). Extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 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-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carbonyl}piperazine-1-carboxylate 5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (40 mg) in N,N-dimethylformamide (0.88 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate (HATU) (100 mg), DIPEA (76 μL), and tert-butyl piperazine-1-carboxylate (21 mg) and stirred at room temperature for 3 hours. A small amount of methanol was added to the reaction mixture, and the mixture was subjected to reverse phase column chromatography (H２ 0 / 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]pyridin-3-yl)[(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidin-4-yl]methanone Step 1 To a solution of (2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidine-4-carboxylic acid (cis racemic mixture) (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 solution was evaporated under reduced pressure to give a pale brown oil. Step 2: Aluminum trichloride (500 mg) was added to a solution of 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (170 mg) in 1,2-dichloroethane (10 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown oil obtained in Step 1 in 1,2-dichloroethane (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred at an external temperature of 50°C for 2 hours. After ice-cooling 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 evaporated under reduced pressure. 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]pyridin-3-yl][(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidin-4-yl]methanone To a solution of (6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)[(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidin-4-yl]methanone (64 mg) in 1,4-dioxane (2.6 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15 mg), DIPEA (91 μL), benzyl mercaptan (31 μL), and tris(dibenzylideneacetone)(chloroform)dipalladium (12 mg) were added sequentially, and the mixture was stirred at 110 ° C. in a microwave oven under an argon atmosphere for 30 minutes. The reaction mixture was purified directly by column chromatography to obtain 68 mg of the target compound as a yellow solid. To a solution of the obtained yellow solid in N,N-dimethylformamide (1.2 mL), potassium carbonate (53 mg) and methyl iodide (23 μL) were added successively, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was directly purified by 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-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl}piperazine-1-carboxylate To a mixture of [6-(benzylsulfanyl)-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl][(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidin-4-yl]methanone (70 mg) in acetic acid (1.8 mL) and water (0.2 mL), N-chlorosuccinimide (51 mg) was added and the mixture was stirred at room temperature for 1 hour. The mixture was further stirred at an external temperature of 40° C. for 2 hours. The reaction solution was evaporated under reduced pressure, and ice-cooled saturated aqueous sodium bicarbonate was added to the resulting residue, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a brown oil. To a solution of the resulting brown oil in tetrahydrofuran (1.0 mL), tert-butyl piperazine-1-carboxylate (47 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was directly purified by 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-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 [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 (50 mg) N,N-dimethylformamide (0.50 mL) solution of potassium carbonate (30 mg) and 3-iodooxetane (0.12 g) were added sequentially and stirred at an external temperature of 100 degrees for 10 hours. After cooling, the reaction mixture was directly purified by reverse phase column chromatography (HO / 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]pyridin-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidin-4-yl]methanone [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) N, N-dimethylformamide (0.50 mL) solution of potassium carbonate (14 mg) and methyl iodide (6.4 μL) were added sequentially, and the mixture was stirred at an external temperature of 50 degrees for 30 minutes. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２ The resulting mixture was purified by a 200 ml / MeOH (200 ml / MeOH mixture) to obtain 19 mg of the target compound as a white solid. MS (ESI+) m / z 594.0 (M+1) Specific rotation [α] Ｄ ２１ = +63.80° (c = 1.0, chloroform)

[0141] Example 3 {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}acetonitrile [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) N, N-dimethylformamide (0.50 mL) solution was added potassium carbonate (21 mg), 2-bromoacetonitrile (19 mg) sequentially, and the mixture was stirred at an external temperature of 50 degrees for 30 minutes. After allowing the reaction mixture to cool, it was directly purified by reverse phase column chromatography (HO / MeOH) to obtain 32 mg of the target compound 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]pyridin-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidin-4-yl]methanone [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-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 (42 mg) in methanol (2.5 mL), a mixed solution of dichloromethane (0.50 mL) and aqueous hydrochloric acid (1.0 M, 0.57 mL) was added and stirred at room temperature for 12 hours. The reaction solution was neutralized with aqueous sodium hydroxide solution (1.0 M), diluted with water, and subjected to extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 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-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}azetidin-1-yl)ethan-1-one Step 1 tert-Butyl Trifluoroacetic acid (0.50 mL) was added to a solution of 3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}azetidine-1-carboxylate (59 mg) in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and neutralized with aqueous sodium hydroxide (2.0 M) to pH = 8. The reaction solution 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 to give a residue (77 mg) as a pale yellow solid. 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, followed by stirring at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, which was then 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 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]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (40 mg) N,N-dimethylformamide (0.50 mL) solution was added potassium carbonate (31 mg) and methyl iodide (14 μL) in that order, and the mixture was stirred at an external temperature of 50 degrees for 30 minutes. After allowing the reaction mixture to cool, it was diluted with water and the precipitated solid was collected by filtration to obtain a pale brown residue. The obtained residue was purified by column chromatography and then purified by reverse phase column chromatography (H ２ The residue was purified again using a 200 ml / MeOH (200 ml / 200 ml) distillation column 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]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (35 mg) in N,N-dimethylformamide (0.50 mL) was added potassium carbonate (28 mg) and ethyl iodide (16 μL) in that order, and the mixture was stirred at an external temperature of 50° C. for 30 minutes. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２ The residue was purified by a slurry wash 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]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (35 mg) in N,N-dimethylformamide (0.50 mL) was added potassium carbonate (28 mg) and 1-bromopropane (18 μL) in that order, and the mixture was stirred at an external temperature of 50° C. for 2 hours. After allowing the reaction mixture to cool, it was directly analyzed by reverse phase column chromatography (H ２ The product was purified by hexane / MeOH to give 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-(pyrimidin-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 [1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-chloro-6-(pyrimidin-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 (47 mg) in tetrahydrofuran (1.0 mL), a mixed solution of methanol (1.0 mL) was added with aqueous hydrochloric acid (1.0 M, 1.0 mL) and stirred at room temperature for 3 days. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reversed-phase column chromatography (H ２ The residue was recrystallized from ethyl acetate / n-hexane to give 26 mg of the target compound as a pale yellow solid. MS (ESI+) m / z 649.2 (M+1) Specific rotation [α] Ｄ２０ = +30.36° (c = 1.0, chloroform)

[0148] Example 10 [5-chloro-1-(oxetan-3-yl)-6-(pyrimidin-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 [5-chloro-6-(pyrimidin-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) N, N-dimethylformamide (1.0 mL) solution of potassium carbonate (18 mg) and 3-iodooxetane (75 mg) were added sequentially, and the mixture was stirred at an external temperature of 100 degrees for 11 hours. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２ The crude residue was purified by hexane / MeOH (2H O / MeOH) and then purified again by column chromatography to obtain a crude residue. The resulting residue was recrystallized from 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-(pyrimidin-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 [5-chloro-6-(pyrimidin-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 (22 mg) in N,N-dimethylformamide (0.50 mL) was added potassium carbonate (26 mg) and methyl iodide (7.0 μL) in that order, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly subjected to reverse phase column chromatography (H ２ The residue was purified by column chromatography (MeOH / O) and then re-purified 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-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone To a solution of [5-chloro-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (40 mg) in N,N-dimethylformamide (1.0 mL) were added potassium carbonate (51 mg) and methyl iodide (14 μL) in that order, and the mixture was stirred at room temperature for 1 hour. The reaction solution was directly purified by reverse phase column chromatography (H ２ The residue was recrystallized from ethyl acetate / n-hexane to give 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-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone To a solution of [5-chloro-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (40 mg) in N,N-dimethylformamide (1.0 mL) were added potassium carbonate (51 mg) and ethyl iodide (18 μL) in that order, and the mixture was stirred at room temperature for 1 hour. The reaction solution was directly purified by reverse phase column chromatography (H ２ The crude residue (25 mg) was purified using ethyl acetate / n-hexane (25 mg of ethyl acetate / MeOH) to give 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] pyridin-3-yl] [(2R, 6R) -1- (5-fluoro-3-iodopyridin-2-yl) -2,6-dimethylpiperidin-4-yl] methanone [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) N, N- dimethylformamide (1.0 mL) solution of potassium carbonate (36 mg), ethyl iodide (12 μL) was added sequentially and stirred at room temperature for 2 hours. The reaction mixture was directly purified by reverse phase column chromatography and then purified 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]pyridin-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidin-4-yl]methanone Step 1 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 (25 mg) in N,N-dimethylformamide (1.0 mL), potassium carbonate (18 mg) and (3-bromopropoxy)(tert-butyl)dimethylsilane (33 mg) were added sequentially, and the mixture was stirred overnight at an external temperature of 50°C. After allowing the reaction mixture to cool, it was directly analyzed by reverse phase column chromatography (H ２0 / MeOH) to obtain 33 mg of a white solid. Step 2 The white solid (33 mg) obtained in Step 1 was dissolved in a mixed solution of tetrahydrofuran (2.0 mL) and methanol (2.0 mL), and aqueous hydrochloric acid (1.0 M, 1.0 mL) was added, followed by stirring at room temperature overnight. The reaction solution was neutralized with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained 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]pyridin-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidin-4-yl]methanone [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 (40 mg) in 1,2-dichloroethane (1.0 mL) was added cyclopropylboronic acid (12 mg), 2,2'-bipyridine (16 mg), copper(II) acetate (19 mg), and sodium carbonate (15 mg), and the mixture was stirred at an external temperature of 70°C for 5 hours. After cooling, the reaction mixture was purified directly by column chromatography, and then purified by reverse phase column chromatography (H ２ The residue was recrystallized from ethyl acetate / n-hexane to give 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]pyridin-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidin-4-yl]methanone [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 (19 mg) N, N-dimethylformamide (1.0 mL) solution of potassium carbonate (22 mg), 2-bromopropane (9.0 μL) was added sequentially, and the mixture was stirred at an external temperature of 100 ° C for 1.5 hours. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２ The product was purified by ethanol (MeOH / MeOH) to give 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-(pyrimidin-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 [5-chloro-6-(pyrimidin-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 (42 mg) N,N-dimethylformamide (1.0 mL) solution was added potassium carbonate (49 mg) and ethyl iodide (17 μL) successively, and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly subjected to reverse phase column chromatography (H ２ The crude product was purified by column chromatography (MeOH / O) and then re-purified by column chromatography to give 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-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 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 (1.0 mL), potassium carbonate (36 mg) and 1,1-dioxotetrahydro-2H-thiopyran-4-yl methanesulfonate (0.12 g) were added sequentially, and the mixture was stirred at an external temperature of 100°C for 16 hours. After allowing the reaction mixture to cool, it was directly analyzed by reverse phase column chromatography (H ２ The resulting residue was purified by column chromatography and then reverse phase column chromatography (H ２ The product was purified with hexane (0.05% ethanol / MeOH) to give 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-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 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 (36 mg) in N,N-dimethylformamide (0.80 mL) was added potassium carbonate (42 mg), oxan-4-yl Methanesulfonate (0.11 g) was added sequentially, and the mixture was stirred at an external temperature of 100°C for 12 hours. After the reaction mixture was allowed to cool, it was directly purified by column chromatography to obtain a crude residue. The obtained residue was purified by reverse phase column chromatography (H ２The product was purified using a 200 ml / MeOH (200 ml) distillation column to give 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-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 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 (36 mg) in N,N-dimethylformamide (0.80 mL) was added potassium carbonate (42 mg), (3R)-oxolan-3-yl Methanesulfonate (0.10 g) was added sequentially, and the mixture was stirred at an external temperature of 100°C for 12 hours. After the reaction mixture was allowed to cool, it was directly purified by column chromatography to obtain a crude residue. The obtained residue was purified by reverse phase column chromatography (H ２ The product was purified using a hexane-hexane distillation column (MeOH / 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-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 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 (36 mg) in N,N-dimethylformamide (0.80 mL) was added potassium carbonate (42 mg), (3S)-oxolan-3-yl Methanesulfonate (0.10 g) was added sequentially, and the mixture was stirred at an external temperature of 100°C for 12 hours. After the reaction mixture was allowed to cool, it was directly purified by column chromatography to obtain a crude residue. The obtained residue was purified by reverse phase column chromatography (H ２ The product was purified with hexane (0.05% ethanol) and hexane (0.05% ethanol) to give 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]pyridin-3-yl][1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Step 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 solution was evaporated under reduced pressure to give a brown oil. Step 2: To a solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) in 1,2-dichloroethane (2.5 mL), aluminum trichloride (91 mg) was added and stirred at room temperature for 10 minutes. Subsequently, a solution of the brown oil obtained in Step 1 in 1,2-dichloroethane (2.5 mL) was added dropwise to the reaction mixture, followed by stirring at an external temperature of 75°C for 4 hours. The reaction mixture was cooled on ice, 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 resulting residue was purified by column chromatography to obtain a crude residue. The resulting residue was slurry-washed with ethyl acetate to obtain 0.018 g of the target compound as a yellow-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]pyridin-3-yl][1-(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Potassium carbonate (20 mg) and methyl iodide (9.0 μL) were added sequentially to a solution of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (25 mg) in N,N-dimethylformamide (0.50 mL), and the mixture was stirred at an external temperature of 50° C. for 15 minutes. The reaction mixture was allowed to cool, then diluted with water, and the precipitated solid was collected by filtration to obtain a crude residue. The resulting residue was washed with methanol to give 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-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Potassium carbonate (40 mg) and 3-iodooxetane (80 mg) were added sequentially to a solution of 1-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (30 mg) in N,N-dimethylformamide (1.0 mL), and the mixture was stirred at an external temperature of 100°C for 12 hours and then at room temperature over the weekend. The reaction solution was allowed to cool and then directly purified by column chromatography to obtain a crude residue. The resulting residue was washed with methanol as a slurry 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-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Potassium carbonate (51 mg) and 1-bromopropane (20 μL) were added sequentially to a solution of [5-chloro-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (40 mg) in N,N-dimethylformamide (1.0 mL), and the mixture was stirred at an external temperature of 60° C. for 2 hours. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２ The crude residue (35 mg) was recrystallized from ethyl acetate / n-hexane to give 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]pyridin-3-yl][1-(pyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Potassium carbonate (20 mg) and methyl iodide (9.3 μL) were added sequentially to a solution of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(pyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (25 mg) in N,N-dimethylformamide (0.50 mL), and the mixture was stirred at an external temperature of 50° C. for 15 minutes. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２ The residue was washed with diethyl ether to give 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-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone Potassium carbonate (12 mg) and methyl iodide (5.7 μL) were added sequentially to a solution of [1-(1,2,3-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (16 mg) in N,N-dimethylformamide (0.50 mL), and the mixture was stirred at an external temperature of 50° C. for 30 minutes. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２ The product was purified using a 200 ml / MeOH (200 ml) distillation column (O / 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-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-1-methyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone Step 1 To a solution of 1-(1,2,3-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (43 mg) (synthesized according to WO2018 / 119036) in dichloromethane (1.0 mL) were added N,N-dimethylformamide (1.0 μL) and oxalyl chloride (14 μL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure to give a light brown solid. Step 2: Aluminum trichloride (81 mg) was added to a solution of 5-chloro-1-methyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) in 1,2-dichloroethane (1.2 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown solid obtained in Step 1 in 1,2-dichloroethane (1.2 mL) was added dropwise to the reaction solution, and the mixture was heated under reflux and stirred at an external temperature of 110°C for 5 hours. After ice-cooling the reaction solution, 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 evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain a crude residue. The resulting residue was purified by reverse phase column chromatography (H ２ The residue was washed with isopropanol to give 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-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}isoquinolin-1(2H)-one Step 1 To a solution of [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (15 mg) in N,N-dimethylformamide (0.50 mL) were added potassium carbonate (11 mg) and bromocyclobutane (7.8 μL) successively, and the mixture was stirred at an external temperature of 100° C. for 11 hours. Potassium carbonate (38 mg) and bromocyclobutane (26 μL) were added to the reaction solution in that order, and the mixture was stirred overnight at the same temperature. The mixture was stirred for 5 hours at an external temperature of 110° C. After the reaction solution was allowed to cool, it was directly subjected to reverse phase column chromatography (H ２ The resulting residue was purified by reverse phase column chromatography (H ２ The product was purified using a 200 ml / MeOH (200 ml / MeOH mixture) to obtain 17 mg of the target compound 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-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-4H-quinolizin-4-one Potassium carbonate (27 mg) and methyl iodide (12 μL) were added sequentially to a solution of 9-{4-[5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-4H-quinolizin-4-one (35 mg) in N,N-dimethylformamide (0.50 mL), and the mixture was stirred at an external temperature of 50° C. for 15 minutes. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２The residue was washed with ethyl acetate to give 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]pyridin-3-yl)[1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone Step 1 To a solution of 1-(8-fluoroisoquinolin-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 solution was evaporated under reduced pressure to give a pale yellow solid. Step 2: Aluminum trichloride (54 mg) was added to a solution of 5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine (16 mg) in 1,2-dichloroethane (0.5 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, a suspension of the pale yellow solid obtained in Step 1 in 1,2-dichloroethane (0.5 mL) was added dropwise to the reaction mixture, which was then washed with 1,2-dichloroethane (0.5 mL) and stirred at an external temperature of 75°C for 1 hour. The mixture was further heated under reflux and stirred at an external 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 evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain a crude residue. The resulting residue was purified by reversed-phase column chromatography (H ２ The product was purified by ethanol (MeOH / MeOH) to give 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-bromopyrimidin-4-yl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone To a solution of (2RS,4RS)-[1-(5-bromopyrimidin-4-yl)-2-methylpiperidin-4-yl][5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (20 mg) obtained in Reference Example 40 in N,N-dimethylformamide (0.50 mL) were added potassium carbonate (16 mg) and methyl iodide (3.7 μL) successively, and the mixture was stirred at an external temperature of 50° C. for 30 minutes. After allowing the reaction mixture to cool, it was directly subjected to reverse phase column chromatography (H ２ The product was purified using a 200 ml / MeOH (200 ml) distillation column (O / 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-methylpiperidin-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone To a solution of [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidin-4-yl]methanone (25 mg) obtained in Reference Example 43 in methanol (5.0 mL) was added 1% platinum-activated carbon, Degussa Type CF 105R / W (75 mg), 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 evaporated under reduced pressure. The resulting residue was purified by reversed-phase column chromatography (H ２ The resulting residue was purified by reverse phase column chromatography (H ２ The product was purified using a 200 ml / MeOH (200 ml / MeOH mixture) 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-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}(piperazin-1-yl)methanone To a solution of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carbonyl}piperazine-1-carboxylate (41 mg) obtained in Reference Example 47 in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.50 mL), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reversed-phase column chromatography (H ２ The product was purified using a hexane-eluted hexane / MeOH mixture to obtain 25 mg of the target compound as a skin-colored solid. MS (ESI+) m / z 519.2 (M+1)

[0174] Example 36 Synthesis of [(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone Synthesis of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl}piperazine-1-carboxylate obtained in Reference Example 50 (56 mg) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reversed-phase column chromatography (H ２ The 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-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone sulfate A few mg of seed crystals were added to a solution of [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (5.0 g) in acetone (50 mL), followed by dropwise addition of sulfuric acid (0.74 mL) and stirring 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 ClF ４ N ８ O.H. ２ SO ４ +0.2H ２ O Calculated value (%) C: 44.86 H: 2.41 N: 17.43 Measured value (%) C: 45.15 H: 2.23 N: 17.10

[0176] Example 38 Synthesis of [5-chloro-1-methyl-6-(pyrimidin-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 monophosphate [5-chloro-1-methyl-6-(pyrimidin-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 (180 g) in acetonitrile (3.0 L) was added dropwise to an 85% aqueous phosphoric acid solution (40 mL) 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℃ Specific rotation [α] Ｄ ２０ = +57.99° (c = 0.6, chloroform) Elemental analysis value C ２５ H ２３ClFIN ６ O.H. ３ P.O. ４ Calculated values ​​(%) C: 42.72 H: 3.73 N: 11.96 Measured 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]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

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

[0187] Test Example 1: MALT1 Protease Inhibitory Effect To confirm the enzyme inhibitory effect of the test substance on MALT1, an enzyme activity inhibition test was conducted using the C-terminal enzyme of MALT1 (amino acid residues 329-824). 1. Preparation of Test Substance The test substance was prepared at 10 mM with dimethyl sulfoxide (DMSO) and further diluted with DMSO to concentrations of 1000, 100, 10, 1, and 0.1 μM. This was further diluted 25-fold with assay buffer to prepare a test substance solution. 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 test substance solution was added to a 384-well black plate (#6007270, PerkinElmer) (n=2, final concentrations 10,000, 1,000, 100, 10, 1, 0.1 nM), followed by 10 μL of MALT1 enzyme and finally 5 μL of substrate solution (Ac-Leu-Arg-Ser-Arg-AMC, Peptide Institute, final concentration in reaction solution 50 μM). After stirring, the mixture was allowed to react at 30°C for 2 hours. Fluorescence (excitation: 380 nm, emission: 460 nm) was detected using a microplate reader (Envision, PerkinElmer). Analysis of measurement results Using the measurement data, nonlinear regression analysis was performed using a two-parameter logistic model using Spotfire (PerkinElmer) to obtain IC ５０ The results are shown in Table 9 below.

[0188]

[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 inhibits the NF-κB pathway intracellularly, a reporter activity inhibition test was performed using HEK293 / API2-MALT1 / NF-κB reporter cells. 1. Preparation of test substance. The test substance was prepared at 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to concentrations of 1000, 300, 100, and 10 μM. This was further diluted 100-fold with DMEM medium containing 10% FBS to prepare a 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 a negative control) were cultured in DMEM medium containing 10% FBS. 6,000 cells were seeded in 30 μL of a 384-well plate (#781080, Greiner) and cultured for 24 hours. After that, 3.3 μL of the prepared test substance solution was added (final concentrations: 10,000, 1,000, 100, and 10 nM). The incubation temperature was 37°C and 5% CO ２ After 24 hours of culture in an incubator, 33 μL of One-glo (Promega) was added. After 5 minutes of incubation at room temperature, luminescence was detected using a microplate reader (Envision, PerkinElmer). 3. Analysis of measurement results Nonlinear regression analysis was performed using the measurement data with the SAS system (SAS Institute Inc.) to determine the IC ５０ The results are shown in Table 10 below.

[0190]

[0191] Test Example 3: Growth-inhibitory effect on ABC-DLBCL cell line In ABC-DLBCL cell lines, the NF-κB pathway is constitutively activated due to mutations in the B cell receptor pathway. To confirm the growth-inhibitory effect of the test substance associated with the MALT1 inhibitory effect, a growth-inhibitory test was carried out using the ABC-DLBCL cell line. 1. Preparation of test substance The test substance was prepared at 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to concentrations of 3000, 1000, 300, 100, 30, and 10 μM. This was further diluted 100-fold with IMDM medium containing 10% FBS to prepare a test substance solution. 2. Measurement of ABC-DLBCL cell proliferation inhibitory effect. The OCI-Ly3 cell line (ABC-DLBCL, NF-κB pathway dependent) was cultured in IMDM containing 10% FBS, and the SU-DHL-4 cell line (GCB-DLBCL, NF-κB pathway independent, used as a negative control) was cultured in RPMI-1640 containing 10% FBS. 2,000 OCI-Ly3 cells and 4,000 SU-DHL-4 cells were seeded in a 96-well plate in 100 μL, and 11 μL of the prepared test substance solution was added (final concentrations: 10,000, 3,000, 1,000, 300, 100, 30, and 10 nM). The incubation temperature was 37°C, 5% CO ２ After 96 hours of culture in an incubator, 10 μL of Cell Counting Kit-8 (Dojin Chemical) was added. After 4 hours of incubation at 37°C, absorbance at 450 nm was detected using a microplate reader (Envision, PerkinElmer). 3. Analysis of Measurement Results Using the measurement data, nonlinear regression analysis was performed using a two-parameter logistic model with Spotfire (PerkinElmer) to determine the IC. ５０ The results are shown in Tables 11 and 12 below.

[0192]

[0193]

[0194] Test Example 5: Central Distribution Test in Mice A central distribution test was conducted using mice to confirm the central distribution of the test substance. 1. Administration and Sampling of Test Substance: Six-week-old female BALB / cCrSlc (Japan SLC) mice were used. The test substance suspended in 0.5% methylcellulose was administered intraperitoneally to the mice at a dose of 30 mg / kg. Three hours later, blood was collected from the abdominal vena cava under isoflurane anesthesia and centrifuged to obtain plasma. The cerebrum was collected after exsanguination from the abdominal vena cava. 2. Measurement and Analysis of Plasma and Brain Concentrations: Drug concentrations in the collected plasma and cerebrum were measured using LC-MS / MS. To evaluate the drug's brain distribution, the ratio of brain tissue concentration to plasma concentration (Kp value) was calculated. The results are shown in Table 13 below.

[0195]

Claims

1. A compound represented by general formula (1) or a pharma- ceutically acceptable salt thereof: [In general formula (1), R １ represents a group represented by general formula (2) or general formula (3), R ２ 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 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, a substituted or unsubstituted heteroaryloxy group, a group represented by general formula (4), or a group represented by general formula (5), R ４ represents a halogen; ５ represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R ６ and R ７ each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group; R ８ represents 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 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 may be linked together to form a ring, R １１ represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group, and in general formulas (2), (3), (4), and (5), a wavy line represents a bond.

2. The compound is represented by general formula (6), The R ３ 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), or a pharma- ceutically acceptable salt thereof.

3. The compound is represented by general formula (7), The R ３ 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, or a pharma- ceutically acceptable salt thereof.

4. A compound selected from the group consisting of the following compounds (1) to (36), or a pharma- ceutically acceptable salt thereof: (1) [5-chloro-1-(oxetan-3-yl)-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, (2) [5-chloro-1-methyl-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, (3) {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}acetonitrile, (4) [5-chloro-1-(2-hydroxyethyl)-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, (5) 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridin-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}azetidin-1-yl)ethan-1-one, (6) [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (7) [5-chloro-1-ethyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (8) [5-chloro-1-propyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (9) [5-chloro-1-(3-hydroxypropyl)-6-(pyrimidin-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, (10) [5-chloro-1-(oxetan-3-yl)-6-(pyrimidin-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, (11) [5-chloro-1-methyl-6-(pyrimidin-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, (12) [5-chloro-1-methyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (13) [5-chloro-1-ethyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (14) [5-chloro-1-ethyl-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, (15) [5-chloro-1-(3-hydroxypropyl)-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, (16) [5-chloro-1-cyclopropyl-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, (17) [5-chloro-1-isopropyl-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, (18) [5-chloro-1-ethyl-6-(pyrimidin-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, (19) [5-chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-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) [5-chloro-1-(oxan-4-yl)-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, (21) {5-chloro-1-[(3S)-oxolan-3-yl]-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, (22) {5-chloro-1-[(3R)-oxolan-3-yl]-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, (23) [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,(3-b]pyridin-3-yl][1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (24) [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (25) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (26) [5-chloro-1-propyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (27) [5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl][1-(pyrazole o[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (28) [1-(1,2,3-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (29) [1-(1,2,3-benzothiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl][5-chloro-1-methyl-6-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (30) 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}isoquinolin-1(2H)-one, (31) 9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-4H-quinolizin-4-one, (32) (5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)[1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone, (33) [(2RS,4RS)-1-(5-bromopyrimidin-4-yl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (34) [(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, (35) {5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}(piperazin-1-yl)methanone, (36) [(2RS,4RS)-1-(3-chloro-5-fluoropyridin-2-yl)-2-methylpiperidin-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone.

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof as an active ingredient.

6. A MALT1 inhibitor comprising the compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof as an active ingredient.

7. A preventive or therapeutic agent for a disease involving MALT1, comprising the compound according to any one of claims 1 to 4 or a pharma- ceutical acceptable salt thereof as an active ingredient.

8. A compound according to any one of claims 1 to 4 or a medicamentously acceptable salt thereof, which comprises as an active ingredient a compound for treating multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, rejection associated with organ transplantation, aplastic anemia, Behcet'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, or BENTA. A therapeutic agent for treating idiopathic pulmonary fibrosis syndrome, adult T-cell leukemia / lymphoma, peripheral T-cell lymphoma, Sezary syndrome, primary effusion lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia, primary central nervous system malignant lymphoma, intraocular malignant lymphoma, primary macroglobulinemia, lymphoplasmacytic lymphoma, brain tumor, malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural splenomegaly, colorectal cancer, or esophageal cancer.

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