Azaindole compound and salt thereof, and crystal of said compound or said salt, method for synthesizing said compound, said salt or said crystal, synthetic intermediate, and medicine

Abstract

Disclosed are: a compound represented by formula (I), a salt of the compound, and a crystal of the compound or the salt; a method for synthesizing the compound, the salt, or the crystal; and a synthetic intermediate of the compound, the salt, or the crystal.

Description

Azaindole compounds, their salts and crystals, methods for synthesizing them, synthetic intermediates, and pharmaceuticals.

[0001] This disclosure relates to azaindole compounds, salts thereof and crystals thereof, methods for synthesizing them, synthetic intermediates thereof, and pharmaceuticals.

[0002] MALT1 (Mucosa associated lymphoid tissue lymphoma transmission protein 1) is an important signaling component of the NF-κB pathway. MALT1 is the only paracaspase in humans and transmits signals from B cell receptors and T cell receptors. MALT1 functions as a subunit of the activated CBM (CARD11 / BCL10 / MALT1) complex and activates the NF-κB pathway through two mechanisms. First, it activates the NF-κB pathway by recruiting proteins such as TRAF6, TAK1, and IKKα / β as scaffold proteins, and 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 diffuse large B-cell lymphoma) and PCNSL (primary central nervous system lymphoma) (see, for example, Non-Patent Documents 2 and 3). BTK inhibitors such as ibrutinib suppress the B cell receptor pathway and have been reported to be clinically effective against ABC-DLBCL and PCNSL (see, for example, Non-Patent Documents 4 and 5). Although ibrutinib is ineffective against ABC-DLBCL with downstream CARD11 mutations (see, for example, Non-Patent Document 4), MALT1 protease inhibitors are effective against ABC-DLBCL with CARD11 mutations because MALT1 is located downstream of BTK signaling (see, for example, Non-Patent Document 6). MALT1 protease inhibitors have shown efficacy in multiple nonclinical ABC-DLBCL models (see, for example, Non-Patent Document 6).

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

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

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

[0007] Popularityら、Foundation of a fivefold feeling Aesthetics,2016,73,4544300000000000000000000000000000 It is a sentimental feeling 010,2, 10000000ら、FYS Feelings, Feelings & Thanksgiving,2020,21,7460000ら、not Chemistry,2015,21,9229274 Thanksgiving,2020,9,4000000ら、S snowflake a snowflake Emotional,2018,128 ,444412 THIS IS YOUR LIFEら、Christianity,2003,302,1 81158440000ら、2000 The scientist is a scientist 1003,132,151 158Absolutelyら、fiction & smile smile,2018,96,4199 smileら、THE snowflake a snowflake The sense of humor,2012,122 488440982000ら、S THIS IS THE Thanks,2014,33,26522410000ら、9 FIFA,2019,540,12116FINANCIALら、FINANCIAL Yes feeling Fiction,2016,22,135150 The scientistら、scientific The scientists,2014, 56,18660000ら、Shana 2019,64,1 40119400000ら、0 2018,9,1254 212543 THISら、SAP Emotions,2017,77,4054444000ら、2000 The emotional snowflake Chemistry,2020,24,7507462

[0008] The object of this disclosure is to provide compounds having MALT1 inhibitory activity, pharmaceutically acceptable salts thereof and their crystals, as well as methods for synthesizing them and their synthetic intermediates.

[0009] This disclosure relates, for example, to the following matters:

[0010] (Term X1) The following formula (I): Crystals of the monophosphate salt of the compound shown by (X2). The powder X-ray diffraction pattern by Cu-Kα rays shows peaks at 2θ values ​​of at least 12.3°±0.2°, 19.1°±0.2°, 22.0°±0.2°, 25.6°±0.2° and 26.9°±0.2°, as shown in equation (I): A type I crystal of the monophosphate of the compound shown by, which may be the crystal described in item X1. (Item X3) A powder X-ray diffraction pattern by Cu-Kα rays showing peaks at 2θ values ​​of at least 12.3°±0.2°, 16.2°±0.2°, 17.9°±0.2°, 19.1°±0.2°, 20.7°±0.2°, 22.0°±0.2°, 23.5°±0.2°, 25.6°±0.2° and 26.9°±0.2°, given by the following formula (I): A type I crystal of the monophosphate of the compound shown, which may be the crystal described in item X1 or item X2. (Item X4) A type I crystal having an endothermic peak at 214.8 ± 3.0 °C in differential thermal analysis, of the following formula (I): (X5) A type I crystal of the monophosphate salt of the compound shown, which may be a crystal according to any one of items X1 to X3. (X6) A crystal according to any one of items X1 to X4 having a crystal purity of 90% or more. (X7) A crystal according to any one of items X1 to X6 having a crystal purity of 99% or more. (X8) A pharmaceutical composition containing the crystal according to any one of items X1 to X7 as an active ingredient. (X9) A MALT1 inhibitor containing the crystal according to any one of items X1 to X7 as an active ingredient. (X10) A method for inhibiting MALT1, comprising administering the crystal according to any one of items X1 to X7 to a subject requiring it. (X11) A crystal according to any one of items X1 to X7 for use in MALT1 inhibition. (Item X12) Use of the crystal described in any one of items X1 to X7 in the manufacture of a MALT1 inhibitor. (Item X13) A prophylactic or therapeutic agent for a disease involving MALT1, comprising the crystal described in any one of items X1 to X7 as an active ingredient. (Item X14) A method for the prevention or treatment of a disease involving MALT1, comprising administering the crystal described in any one of items X1 to X7 to a subject in need thereof. (Item X15) A crystal described in any one of items X1 to X7 is contained as an active ingredient in multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, organ transplant rejection, aplastic anemia, Behçet's disease, nephrotic syndrome, generalized myasthenia gravis, atopic dermatitis, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, multiple myeloma, BENTA A treatment for syndrome, adult T-cell leukemia / lymphoma, peripheral T-cell lymphoma, Sézary syndrome, primary exudative lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia, primary central nervous system lymphoma, intraocular lymphoma, primary macroglobulinemia, lymphoplasmacytic lymphoma, brain tumors, malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural mesplenomegaly, colorectal cancer, or esophageal cancer.(Item X16) A method for producing the crystal according to any one of items X1 to X7, comprising contacting the compound represented by formula (I) with phosphoric acid in a solvent containing acetone. (Item X17) The method according to item X16, wherein the solvent containing acetone is acetone. (Item X18) The following formula (II): A method for producing the compound shown by the following formula (VII): A method comprising the step of converting a compound represented by formula (II) into a compound represented by formula (II). (Item X19) Formula (II) below: A method for producing the compound shown by the following formula (VI): The compound shown by the following formula (VII): A method, which may be the method of item X18, comprising the step of converting to the compound shown by (item X20) below formula (II): A method for producing the compound shown by the following formula (V): The compound shown by the following formula (VI): A method, which may be the method described in item X18 or X19, comprising the step of converting to a compound shown by the following formula (II): (Item X21) A method for producing the compound shown by the following formula (IV): The compound shown by the following formula (V): A method which may be the method of any one of items X18 to X20, comprising the step of converting to a compound shown by the following formula (II): (Item X22) Formula (II): A method for producing the compound shown by the following formula (III): The compound shown by the following formula (IV): A method according to any one of items X18 to X21, comprising the step of converting to a compound shown by (Item X23) below formula (V): The compound shown by (item X24). Formula (VI): The compound shown by (item X25). Formula (VII): The compound shown by (item X26). Formula (I) below: A method for producing the compound shown by the following formula (II): The compound shown by the following formula (A): A method comprising the step of obtaining a compound represented by formula (I) by contacting it with a compound represented by the following formula (A): (Item Y1) Formula (A): A method for producing the compound shown by the following formula (F1): The compound shown by the following formula (F2): The compound shown by or the following formula (F3): The compound shown by the following formula (G): A method comprising the step of converting to the compound shown by (Item Y2) below formula (A): A method for producing the compound shown by the following formula (E): The compound shown by the following formula (F1): The compound shown by the following formula (F2): The compound shown by or the following formula (F3): A method, which may be the method described in item Y1, comprising the step of converting to the compound shown by (Item Y3) below formula (A): A method for producing the compound shown by the following formula (D): The compound shown by the following formula (E): A method that includes a step of converting to the compound shown by (Y4) below (A): A method for producing the compound shown in the following formula (B): The compound shown by the following formula (C): By contacting the compound shown in (D): A method which may be the method described in any one of items Y1 to Y3, comprising the step of obtaining the compound shown by (Item Y5) The following formula (A): A method for producing the compound shown by the following formula (G): A method according to any one of items Y1 to Y4, comprising the step of converting the compound represented by (A) into the compound represented by formula (A). (Item Y6) The following chemical reaction formula: The compound shown: Method of synthesis. (Term Y7) The following formula (D): The compound shown by (Section Y8) below formula (E): The compound shown by (Section Y9) below (F1): The compound shown by (item Y10). Formula (F2): The compound shown by (item Y11). Formula (F3): A compound represented by: (Item Y12) The method of item X26, wherein the compound represented by formula (II) is produced according to the method of any one of items X18 to X22. (Item Y13) The method of item X26 or Y12, wherein the compound represented by formula (A) is produced according to the method of any one of items Y1 to Y5. (Item Y14) The method of item X16 or X17, wherein the compound represented by formula (I) is produced according to the method of item X26, Y12 or Y13. (Item Z1) Any of the following chemical reaction equations: The compound shown: (i.e., 5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine) or its methanesulfonate: Method of synthesis. (Section Z2) The following chemical reaction equation: The compound shown: Method for synthesizing (i.e., [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone). (Section Z3) Compound: (i.e., [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone) and phosphoric acid are mixed in a solvent containing acetone to produce a monophosphate: Method for synthesizing type I crystals. (Section Z4) 1. Phosphate: Type I crystals or solvates thereof. (Item Z5) Monophosphate with a crystal purity of 90% or more: Type I crystals of or solvates thereof. (Item Z6) Monophosphate with a crystal purity of 95% or higher: Type I crystals of or solvates thereof. (Item Z7) Monophosphate with a crystal purity of 99% or higher: Type I crystals of or solvates thereof. (Item Z8) One-phosphates whose powder X-ray diffraction pattern by Cu-Kα radiation shows peaks at 2θ values ​​of at least 12.3°±0.2°, 19.1°±0.2°, 22.0°±0.2°, 25.6°±0.2° and 26.9°±0.2°: Type I crystals of or solvates thereof. (Item Z9) One-phosphates whose powder X-ray diffraction pattern by Cu-Kα radiation shows peaks at 2θ values ​​of at least 12.3°±0.2°, 16.2°±0.2°, 17.9°±0.2°, 19.1°±0.2°, 20.7°±0.2°, 22.0°±0.2°, 23.5°±0.2°, 25.6°±0.2° and 26.9°±0.2°: Type I crystals, or their solvates. (Item Z10) A compound selected from the group consisting of the following compounds (1) to (36), or a pharmaceutically acceptable salt thereof, or a solvate thereof: (1) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (2) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (3) {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}acetonitrile, (4) [5-chloro-1-(2-hydroxyethyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (5) 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-yl)ethane-1-one, (6) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (7) [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone,(8) [5-chloro-1-propyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (9) [5-chloro-1-(3-hydroxypropyl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (10) [5-chloro-1-(oxetan-3-yl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (11) [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (12) [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (13) [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (14) [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (15) [5-chloro-1-(3-hydroxypropyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone,(16) [5-chloro-1-cyclopropyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (17) [5-chloro-1-isopropyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (18) [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (19) [5-chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (20) [5-chloro-1-(oxan-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (21) {5-chloro-1-[(3S)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl} [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (22) {5-chloro-1-[(3R)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone,(23) [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(5-fluoronaphthalene-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (24) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (25) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(thieno[2,3-c]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (26) [5-chloro-1-propyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (27) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(pyrazoleo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (28) [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl] [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (29) [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (30) 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}isoquinoline-1(2H)-one,(31) 9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one, (32) (5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)[1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (33) [(2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl] [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (34) [(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidine-4-yl] [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (35) {5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-yl}(piperazine-1-yl)methanone, (36) [(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone. (Item Z11) A pharmaceutical composition containing the compound described in (Item Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of (Item Z4) to (Item Z9) above, or a solvate thereof, as an active ingredient. (Item Z12) A MALT1 inhibitor containing the compound described in (Item Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of (Item Z4) to (Item Z9) above, or a solvate thereof, as an active ingredient. (Item Z13)A method for inhibiting MALT1, comprising administering the compound described in (Section Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of (Section Z4) to (Section Z9), or a solvate thereof, to a subject requiring such treatment. (Section Z14) The compound described in (Section Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of (Section Z4) to (Section Z9), or a solvate thereof, for use in MALT1 inhibition. (Section Z15) Use of the compound described in (Section Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of (Section Z4) to (Section Z9), or a solvate thereof, in the manufacture of a MALT1 inhibitor. (Item Z16) A preventive or therapeutic agent for a disease involving MALT1, comprising the compound described in (Item Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of (Item Z4) to (Item Z9) above, or a solvate thereof, as an active ingredient. (Item Z17) A method for preventing or treating a disease involving MALT1, comprising administering the compound described in (Item Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of (Item Z4) to (Item Z9) above, or a solvate thereof, to a subject in need thereof. (Item Z18) The compound described in (Item Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of (Item Z4) to (Item Z9) above, or a solvate thereof, for use in the prevention or treatment of a disease involving MALT1. (Item Z19) In the manufacture of a preventive or therapeutic agent for a disease involving MALT1, the compound described in (Item Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of (Item Z4) to (Item Z9) above, or a solvate thereof. (Item Z20)A compound described in item (Z10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a salt described in any of items (Z4) to (Z9) above, or a solvate thereof, is contained as an active ingredient in multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, organ transplant rejection, aplastic anemia, Behçet's disease, nephrotic syndrome, generalized myasthenia gravis, atopic dermatitis, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, multiple myeloma, BENTA A preventive or therapeutic agent for syndrome, adult T-cell leukemia / lymphoma, peripheral T-cell lymphoma, Sézary syndrome, primary exudative lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia, primary central nervous system lymphoma, intraocular lymphoma, primary macroglobulinemia, lymphoplasmacytic lymphoma, brain tumor, malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural mesplenomegaly, colorectal cancer, or esophageal cancer.

[0011] This disclosure provides compounds having MALT1 inhibitory activity, pharmaceutically acceptable salts thereof and crystals thereof, as well as methods for synthesizing them and synthetic intermediates thereof.

[0012] This figure shows the TG and DTA measurement results of the type I crystal of the monophosphate of compound (I) obtained in Synthesis Example 12. This figure shows the powder X-ray diffraction data of the type I crystal of the monophosphate of compound (I) obtained in Synthesis Example 12.

[0013] The following describes in detail the forms for implementing this disclosure. However, this disclosure is not limited to the following embodiments.

[0014] In this specification, "alkyl group" means a monovalent group obtained by removing one hydrogen atom from a saturated hydrocarbon. Alkyl groups may be linear or branched. Alkyl groups are C １ ~C ６ It may be an alkyl group, C １ ~C ４ It may be an alkyl group, C １ ~C ３may be an alkyl group. In the present specification, "C ａ ~C ｂ " means that the number of carbon atoms is from a to b. Specific examples of alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group (1-methylethyl group), n-butyl group, sec-butyl group, isobutyl group (2-methylpropyl group), tert-butyl group, n-pentyl group, neopentyl group, isopentyl group, sec-pentyl group, 3-pentyl group, tert-pentyl group, n-hexyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1,1,2,2-tetramethylethyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, and the like.

[0015] In the present specification, "substituted alkyl group" means a group in which one or more hydrogen atoms of an alkyl group are substituted with a substituent. Examples of the substituent in the substituted alkyl group include a hydroxy group, a cyano group, a halogen, 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, an oxo group, and the like. These substituents may be further substituted with other substituents, and may be bonded to each other to form a ring.

[0016] In the present specification, "cycloalkyl group" means a monovalent group obtained by removing one hydrogen atom from a cyclic saturated hydrocarbon. A cycloalkyl group may be a C ３ ~C ８ cycloalkyl group, may be a C ３ ~C ６ cycloalkyl group, and may be a C ３ ~C ４ cycloalkyl group. Specific examples of cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and the like.

[0017] In this specification, "substituted cycloalkyl group" means a cycloalkyl group in which one or more hydrogen atoms are substituted with substituents. Examples of substituents in a substituted cycloalkyl group include those described above.

[0018] In this specification, "heterocyclic group" means a non-aromatic, cyclic, monovalent group containing a heteroatom in the ring. Specific examples of heteroatoms include nitrogen, oxygen, and sulfur. The number of heteroatoms in the ring of a heterocyclic group may be, for example, 1 to 5, 1 to 3, 1 to 2, or 1. The heterocyclic group may be a monocyclic or a fused ring. The heterocyclic group may have an unsaturated bond in the ring (unsaturated heterocyclic group) or may not have an unsaturated bond (saturated heterocyclic group). Specific examples of heterocyclic groups include oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, azetidinyl group, tetrahydro-1,1-dioxide-2H-thiopyranyl group, and quinolidinone group.

[0019] In this specification, "substituted heterocyclic group" means a group in which one or more elements of a heterocycle (elements not constituting the ring) are substituted with substituents. Examples of substituents in a substituted heterocyclic group include those described above.

[0020] In this specification, "aryl group" means a monovalent group of a cyclic aromatic hydrocarbon. The aryl group may be a monocyclic or fused ring. Specific examples of aryl groups include the phenyl group and the naphthyl group.

[0021] In this specification, "substituted aryl group" means a group in which one or more elements (elements that do not constitute a ring) of an aryl group are substituted with substituents. Examples of substituents in a substituted aryl group include those described above.

[0022] In this specification, "heteroaryl group" means an aromatic, cyclic, monovalent group containing a heteroatom in the ring. Specific examples of heteroatoms include nitrogen, sulfur, and oxygen. The number of heteroatoms in the ring of a heteroaryl group may be, for example, 1 to 5, 1 to 3, 1 to 2, or 1. The heteroaryl group may be a monocyclic or fused ring. Specific examples of heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, isoquinolyl, quinolidinyl, 1,2,3-benzothiadiazolyl, thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl, 1(2H)-oxoisoquinolyl, pyrazolo[1,5-a]pyridyl, 2,7-naphthilidinyl, and furyl groups.

[0023] In this specification, "substituted heteroaryl group" means a heteroaryl group in which one or more elements (elements that do not constitute a ring) are substituted with substituents. Examples of substituents in a substituted heteroaryl group include those described above.

[0024] In this specification, "alkoxy group" means an oxy group to which an alkyl group is attached. Specific examples of alkoxy groups include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group, pentyloxy group, 3-methylbutoxy group, and the like.

[0025] In this specification, "substituted alkoxy group" means a group in which one or more hydrogen atoms of an alkoxy group are substituted with substituents. Examples of substituents in a substituted alkoxy group include those described above.

[0026] In this specification, "aryloxy group" means an oxy group to which an aryl group is attached. Specific examples of aryloxy groups include phenoxy group and naphthyloxy group.

[0027] In this specification, "substituted aryloxy group" means a group in which one or more elements (elements that do not constitute a ring) of the aryloxy group are substituted with substituents. Examples of substituents in a substituted aryloxy group include those described above.

[0028] In this specification, "heteroaryloxy group" means an oxy group to which a heteroaryl group is attached. Specific examples of heteroaryloxy groups include furyloxy group, thienyloxy group, pyrrolyloxy group, imidazolyloxy group, pyrazolyloxy group, thiazolyloxy group, piperazinyloxy group, and the like.

[0029] In this specification, "substituted heteroaryloxy group" means a group in which one or more elements (elements that do not constitute a ring) of the heteroaryloxy group are substituted with substituents. Examples of substituents in a substituted heteroaryloxy group include those described above.

[0030] In this specification, "halogen" means a group consisting of a halogen atom (halogeno group). Examples of halogens include fluoro groups, chloro groups, bromo groups, and iodo groups.

[0031] The disclosed compounds are compounds represented by general formula (1), or pharmaceutically acceptable salts thereof, or solvates thereof.

[0032] In general formula (1), R １ This indicates a group represented by general formula (2) or general formula (3).

[0033] In general formula (1), R ２ This represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group, and is a hydrogen atom, a substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C ３ ~C ８ It is preferably a cycloalkyl group or a saturated heterocyclic group of substituted or unsubstituted monocyclic form, and the atoms are hydrogen atoms, C １ ~C ６C substituted with alkyl, hydroxyl, or cyano groups １ ~C ６ Alkyl alkyl group, C ３ ~C ６ It is more preferably a monocyclic saturated heterocyclic group substituted with a cycloalkyl group, an acetyl group, or an oxo group, or an unsubstituted monocyclic saturated heterocyclic group, and even 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 even more preferably a methyl group, an ethyl group, or an n-propyl group, and particularly preferably a methyl group.

[0034] In general formula (1), R ３ This refers to a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a group represented by general formula (4), or a group represented by general formula (5). [In general formula (4), R ９ and R １０ Each of these independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, R ９ and R １０ They may be connected to each other, forming a ring. [In general formula (5), R １１ This indicates a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group.

[0035] R ３It is preferably an aryl group, a heteroaryl group, an alkoxy group, an aryloxy group, a heteroaryloxy group, a group represented by general formula (4), or a group represented by general formula (5); more preferably a heteroaryl group, an alkoxy group, a group represented by general formula (4), or a group represented by general formula (5); even more preferably a 1,2,3-triazolyl group (e.g., a 2-1,2,3-triazolyl group), a pyrimidyl group (e.g., a 2-pyrimidyl group), a methoxy group, a group represented by general formula (4), or a group represented by general formula (5); and even more preferably a 1,2,3-triazolyl group or a pyrimidyl group.

[0036] In general formula (4), R ９ and R １０ Each of these independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. ９ and R １０ They may be connected to each other, forming a ring. ９ and R １０ Preferably, they are connected to each other and form a ring, R ９ and R １０ It is more preferable that the nitrogen atom to which it is bonded forms a piperazine ring.

[0037] In general formula (5), R １１ This represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group, preferably a saturated heterocyclic group, and more preferably a piperazinyl group (e.g., a 1-piperazinyl group).

[0038] In general formula (1), R ４ The group exhibits a halogen, and is preferably a chloro group.

[0039] In general formula (2), R ５This represents 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, chloro group, fluoro group, amino group, or iodo group, or a heteroaryl group substituted with a bromo group, chloro group, fluoro group, amino group, or iodo group, more preferably a phenyl group substituted with a bromo group, chloro group, fluoro group, amino group, or iodo group, or a pyridinyl group substituted with a bromo group, chloro group, fluoro group, or iodo group, even more preferably a 1-amino-3-fluorophenyl group (e.g., 6-1-amino-3-fluorophenyl group), a 5-bromopyrimidinyl group (e.g., 6-5-bromopyrimidinyl group), or a 3-iodo-5-fluoropyrimidinyl group (e.g., 2-3-iodo-5-fluoropyrimidinyl group), and particularly preferably a 3-iodo-5-fluoropyrimidinyl group.

[0040] In general formula (2), R ６ and R ７ Each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group, preferably a substituted or unsubstituted alkyl group, C １ ~C ６ It is more preferably an alkyl group, C １ ~C ３ It is more preferably an alkyl group, and even more preferably a methyl group. ６ and R ７ It is particularly preferable that all of them are methyl groups. ６ If R is not a hydrogen atom, ６ The carbon atom to which it is bonded becomes the chiral center. In this case, the stereochemistry may be R or S, but R is preferred. Similarly, R ７ If R is not a hydrogen atom, ７ The carbon atom to which it is bonded becomes the chiral center. The stereochemistry in this case may be R or S, but R is preferred. ６ The carbon atom to which it is bonded, and R ７When both carbon atoms to which are bonded are chiral centers, it is particularly preferable that the stereochemistry of both is R.

[0041] In general formula (3), R ８ This represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group, preferably a substituted or unsubstituted aryl group of a fused ring, a substituted or unsubstituted heteroaryl group of a fused ring, or a substituted or unsubstituted heterocyclic group of a fused ring, more preferably a fluoro-substituted aryl group of a fused ring, a fluoro-substituted heteroaryl group of a fused ring, an unsubstituted heteroaryl group of a fused ring, an oxo-substituted heterocyclic group of a fused ring, or an unsubstituted heterocyclic group of a fused ring, and is an 8-fluoroisoquinolyl group (e.g., 4-8-fluoroisoquinolyl group), a 4-quinolidinone group (e.g., It is more preferable that the group is an 8-4-quinolidinone group, a 1-fluoronaphthyl group (e.g., a 5-1-fluoronaphthyl group), a 1,2,3-benzothiadiazolyl group (e.g., a 7-1,2,3-benzothiadiazolyl group), a pyrazolo[1,5-a]pyridyl group (e.g., a 4-pyrazolo[1,5-a]pyridyl group), a thieno[2,3-b]pyridyl group (e.g., a 4-thieno[2,3-b]pyridyl group), a thieno[2,3-c]pyridyl group (e.g., a 3-thieno[2,3-c]pyridyl group), or a 1(2H)-oxoisoquinolyl group (e.g., a 5-1(2H)-oxoisoquinolyl group), and even more preferably an 8-fluoroisoquinolyl group.

[0042] In general formulas (1), (2), (3), (4), and (5), the dashed lines indicate couplings.

[0043] The compound according to this embodiment may be a compound represented by general formula (6), a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0044] In general formula (6), R ２ , R ３ , R ４ , R ５ , R ６ and R ７ This is equivalent to what was explained in general formula (1).

[0045] The compound according to this embodiment may be a compound represented by general formula (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0046] In general formula (7), R ２ , R ３ , R ４ and R ８ This is equivalent to what was explained in general formula (1).

[0047] Specific examples of compounds represented by general formula (1) include, for example, the following compounds (1) to (36): (1) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (2) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (3) {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}acetonitrile, (4) [5-chloro-1-(2-hydroxyethyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (5) 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-yl)ethane-1-one, (6) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (7) [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (8) [5-chloro-1-propyl-6-(2H-1,2,(3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (9)[5-chloro-1-(3-hydroxypropyl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (10) [5-chloro-1-(oxetan-3-yl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (11) [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (12) [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (13) [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (14) [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (15) [5-chloro-1-(3-hydroxypropyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (16) [5-chloro-1-cyclopropyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,(17) [5-chloro-1-isopropyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (18) [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (19) [5-chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (20) [5-chloro-1-(oxan-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (21) {5-chloro-1-[(3S)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (22) {5-chloro-1-[(3R)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (23) [5-chloro-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(5-fluoronaphthalene-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (24)[5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (25) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(thieno[2,3-c]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (26) [5-chloro-1-propyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (27) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(pyrazoleo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (28) [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl] [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (29) [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl] [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (30) 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}isoquinoline-1(2H)-one, (31) 9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,(3-b) Pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one, (32) (5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl) [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (33) [(2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl] [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (34) [(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidine-4-yl] [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone, (35) {5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-yl} (piperazine-1-yl)methanone, (36) [(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone.

[0048] The disclosed compounds can be prepared using known compounds or intermediates readily synthesized from known compounds, for example, by the method described below, the synthesis examples, examples, or known methods. In the preparation of the disclosed compounds, if the starting materials have substituents that affect the reaction, it is common practice to protect the starting materials with appropriate protecting groups using known methods before proceeding with the reaction. The protecting groups can be deprotected after the reaction using known methods.

[0049] The meanings of the terms used in this specification are explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms.

[0050] The abbreviations used in this specification have the following meanings. In the synthesis examples and 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(diphenylphosphin)ferrocene]-dichloropalladium(II) dichloromethane adduct PPh ３ Triphenylphosphine Boc ２ O: Di-tert-butyl dicarbonate HATU: O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU: O-(benzotriazole-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); TG-DTA: Differential Thermal-Thermogravimetric Analysis System

[0051] Examples of pharmaceutically acceptable salts of the compounds disclosed herein include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; or salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by commonly used methods.

[0052] For example, if the disclosed compound is a hydrochloride salt, it can be obtained by dissolving the free base of the disclosed compound in an alcoholic solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentyl methyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.

[0053] The disclosed compounds may incorporate solvent molecules and become solvates by being left in the atmosphere or by recrystallization, and such solvates are also included in the disclosed compounds. Examples of such solvates include solvates with solvent molecules such as methanol, ethanol, isopropyl alcohol, butanol, dimethyl sulfoxide, and acetonitrile, as well as monohydrates and dihydrates. As for methods for producing solvates or hydrates, for example, J. See Keith Guillory, Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids, POLYMORPHISM IN PHARMACEUTICAL SOLIDS, edited by Harry G. Britain, pages 183–226 (1999).

[0054] Some of the compounds disclosed herein have an asymmetric carbon, and all optical isomers and mixtures thereof are included in this disclosure. Stereoisomers can be produced, for example, by optical resolution from a racemate using its basicity with an optically active acid (tartaric acid, dibenzoyl tartaric acid, mandelic acid, 10-camphor sulfonic acid, etc.) by known methods, or by using a pre-prepared optically active compound as a starting material. They can also be produced by optical resolution using a chiral column or by asymmetric synthesis. Furthermore, in the disclosed compounds, the structural formula of the compound may represent a certain isomer for convenience, but this disclosure includes geometric isomers arising from the structure of the compound, optical isomers based on an asymmetric carbon, stereoisomers, tautomers, and other isomers and mixtures of isomers. Also, unless otherwise specifically specified in a particular claim, this disclosure is not limited to the description of the formula for convenience, and is not limited to any other isomer, and all are included.

[0055] The disclosed compound has MALT1 inhibitory activity, as shown in the test examples described below.

[0056] Accordingly, one embodiment of the present disclosure provides a MALT1 inhibitor containing the disclosed compound. The disclosed compound in this embodiment also includes the formula (IA) compound and its crystals (e.g., type I crystals) described later.

[0057] Furthermore, one embodiment of the present disclosure provides a method for inhibiting MALT1, comprising administering the disclosed compound to a subject requiring its use. The disclosed compound in this embodiment also includes the compound of formula (IA) and its crystals (e.g., type I crystals), which will be described later.

[0058] Furthermore, one embodiment of the present disclosure provides a compound for use in MALT1 inhibition. The compound of the present disclosure according to this embodiment also includes the compound of formula (IA) and its crystals (e.g., type I crystals) described later.

[0059] Furthermore, one embodiment of the present disclosure provides the use of the disclosed compound in the manufacture of a MALT1 inhibitor. The disclosed compound according to this embodiment also includes the formula (IA) compound and its crystals (e.g., type I crystals) described later.

[0060] One embodiment of the present disclosure provides a preventive or therapeutic agent for a disease involving MALT1, which contains the compound of the present disclosure. The compound of the present disclosure according to this embodiment also includes the compound of formula (IA) and its crystals (e.g., type I crystals) described later.

[0061] Furthermore, one embodiment of the present disclosure provides a method for preventing or treating a disease involving MALT1, which includes administering the disclosed compound to a subject in need thereof. The disclosed compound according to this embodiment also includes the compound of formula (IA) and its crystals (e.g., type I crystals) described later.

[0062] Furthermore, one embodiment of the present disclosure provides a compound for use in the prevention or treatment of diseases involving MALT1. The compound of the present disclosure according to this embodiment also includes the compound of formula (IA) and its crystals (e.g., type I crystals) described later.

[0063] Furthermore, one embodiment of the present disclosure provides the use of the disclosed compound in the manufacture of a preventive or therapeutic agent for a disease involving MALT1. The disclosed compound in this embodiment also includes the formula (IA) compound and its crystals (e.g., type I crystals) described later.

[0064] Diseases to which the disclosed compound can be applied include, for example, multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, organ transplant rejection, aplastic anemia, Behçet's disease, nephrotic syndrome, generalized myasthenia gravis, atopic dermatitis, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, multiple myeloma, and BENTA. Examples include syndrome, adult T-cell leukemia / lymphoma, peripheral T-cell lymphoma, Sézary syndrome, primary exudative lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia, primary central nervous system lymphoma, intraocular lymphoma, primary macroglobulinemia, lymphoplasmacytic lymphoma, brain tumors, malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, gastric cancer, malignant pleural mesplenomegaly, colorectal cancer, or esophageal cancer.

[0065] "Subject" means a human or non-human animal that has or is suspected of having a disease involving MALT1 or a disease involving MALT1. In one embodiment of this disclosure, the subject is a mammal. In one embodiment of this disclosure, the subject is a human.

[0066] The disclosed compound can be used as is, or mixed with a pharmaceutically acceptable carrier, to form a pharmaceutical composition containing, for example, 0.001% to 99.5% by weight, preferably 0.1% to 90% by weight, which can then be used as a preventive or therapeutic agent for the various diseases described above in mammals such as humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, and monkeys.

[0067] As a carrier, one or more conventionally accepted pharmaceutically acceptable solid, semi-solid, or liquid diluents, fillers, and other formulation aids are used. The pharmaceutical composition according to this disclosure is preferably administered in dose units. The pharmaceutical composition can be administered intratissue, orally, intravenously, topically (transdermally, ophthalmoscopy, intraperitoneally, intrathoracically, etc.), or rectally. The pharmaceutical composition according to this disclosure is administered in a dosage form suitable for these administration methods.

[0068] The dosage as a medicine should preferably be adjusted considering the patient's condition, such as age, weight, type and severity of the disease, the route of administration, the type of compound disclosed, whether it is a salt or not, and the type of salt. However, for adults, the appropriate amount of the active ingredient of the compound disclosed or its pharmaceutically acceptable salt is usually within the range of 0.01 mg to 5 g per adult per day, preferably within the range of 1 mg to 500 mg per adult, when administered orally. In some cases, a lower dose may suffice, or conversely, a higher dose may be required. It is usually administered once a day or in several divided doses, or, in the case of intravenous administration, it can be administered rapidly or continuously over a period of 24 hours or less.

[0069] One or more hydrogen, carbon, and / or other atoms in the disclosed compounds may be substituted with isotopes of hydrogen, carbon, and / or other atoms. Examples of such isotopes include, ２ H, ３ H, １１ C, １３C, １４ C, １５ N, １８ O, １７ O, ３１ P, ３２ P, ３５ S, １８ F, １２３ I and ３６ Cl, that is, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. Isotope-substituted compounds of this type are also useful as pharmaceuticals, and the present disclosure includes all radiolabeled forms of the disclosed compounds.

[0070] The compounds of the present disclosure can be produced from compounds known per se or intermediates that can be easily prepared from known compounds, for example, according to the methods described below, the synthetic examples and working examples described hereinafter, or known methods.

[0071] When the solvents, reagents and starting materials used in each step of the following production methods are commercially available, commercially available products can be used as they are. In addition, the compounds obtained in each step of the production methods described hereinafter and the starting materials used therein may form salts, and can be converted into other types of salts or free forms by known methods. Conversely, when the compounds obtained in each step of the following production methods and the starting materials used therein are in free form, they can be converted into the target salts by known methods. Examples of such salts are the same as those used for the compounds of the present disclosure mentioned above.

[0072] In the production of the compounds disclosed herein, if the starting materials have substituents that may affect the reaction, protecting groups may be introduced to these substituents in advance by known methods, and the target compounds can be obtained by removing the protecting groups as needed after the reaction. Examples of such protecting groups include those shown in "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, Thieme, 2005, and these may be appropriately selected and used depending on the reaction conditions.

[0073] The compounds obtained in each step of the following manufacturing method can be isolated or purified by conventional methods such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, and chromatography, or they can be used in the next step in the form of a reaction mixture or crude product.

[0074] Unless otherwise specified, the reactions in each step of the following manufacturing methods are based on known methods, such as "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition" by R.C. Larock, published by John Wiley & Sons Inc. This is carried out by appropriately modifying or combining methods described in "Experimental Chemistry Course," 4th edition, edited by the Chemical Society of Japan, 1999, Maruzen; "Organic Synthesis Strategies Learned from Named Reactions," by L. Kuerti and B. Czako, supervised translation by Kiyoshi Tomioka, Kagaku Dojin, 2006; and "Latest Organic Synthesis Methods: Design and Strategies," by G.S. Zweifel and M.H. Nantz, translated by Tamejiro Hiyama, Kagaku Dojin, 2009, etc., or by methods described in synthesis examples and examples.

[0075] [1] Synthesis of compound (1) and its salt <Variation 1> <Variation 2> <Variation 3> <Variation 4> (R １ , R ２ , R ３ , R ４ , R ５ , R ６ and R ７ are as defined above. X １ represents chloro or bromo, and X ２ represents chloro, bromo, mesylate or triflate.)

[0076] Step 1 of Variation 1 This step is a step for obtaining compound CCa by subjecting compound AA, which is commercially available or synthesized by a known method, to Friedel-Crafts acylation reaction with acid halide BB in a solvent such as methylene chloride or dichloroethane in the presence of a Lewis acid such as aluminum chloride at 0°C to 150°C, preferably 60°C to 120°C, for 1 hour to 48 hours, preferably 12 hours to 24 hours. Acid halide BB can be obtained by reacting compound LL or LLL described below, or compound PP with oxalyl chloride or oxalyl bromide in a solvent such as methylene chloride or dichloroethane in the presence of a catalytic amount of dimethylformamide at 0°C to 50°C, preferably 0°C to room temperature, for 1 hour to 48 hours, preferably 1 hour to 12 hours.

[0077] Step 1 of Variation 2 (including Variations 3 and 4): This step involves a Friedel-Crafts acylation reaction between compound QQ, synthesized commercially or by known methods, and a carboxylic acid or acid halide BB, carried out in a solvent such as methylene chloride or dichloroethane, or using an Eaton reagent prepared from polyphosphate or phosphorus pentoxide-methanesulfonic acid, in the presence of an acid such as trifluoromethanesulfonic acid (TfOH), aluminum chloride, or tin chloride, and optionally in the presence of trifluoroacetic anhydride (TFAA), for 1 to 48 hours, preferably 12 to 24 hours, at 0°C to 150°C, preferably 60°C to 120°C. A detailed example of this step is to bring compound QQ and a carboxylic acid or acid halide BB into contact in dichloromethane in the presence of trifluoromethanesulfonic acid and trifluoroacetic anhydride.

[0078] Step 2 of Variation 1 This step involves alkylating compound CCa using alkylating agent DD in the presence of a base to obtain compound (1), and can be carried out according to known alkylation methods. The reaction can be carried out by reacting compound CCa with alkylating agent DD in a solvent such as dimethylformamide or tetrahydrofuran, in the presence of a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, or cesium carbonate, at a temperature of 0°C to 120°C, preferably room temperature to 120°C, for 1 to 48 hours, preferably 1 to 12 hours.

[0079] Step 2 (salt formation) of Variation 2 (including Variations 3 and 4) This step can be performed by isolating compound (1), i.e., the free base form, from the reaction solution in a suitable solvent in the presence of an acid containing the anion of the desired salt form, for example, by crystallization, precipitation, evaporation, etc. The acid used is in equimolar ratios or other ratios, depending on whether a monobasic or polybasic acid is involved in this step and which salt is preferred. Thus, in the acid addition salts of this disclosure, the acid and the free base form may be substantially in a 1:1 stoichiometric ratio or other ratios, for example, a stoichiometric ratio of about 1:2 to about 2:1. Non-integer stoichiometric ratios, for example, 1:1.5 or 1.5:1, are also possible. Examples of acid addition salts by inorganic or organic acids include, but are not limited to, hydrochlorides, methanesulfons, hydrobroms, acetates, fumarates, sulfates, succinates, citrates, phosphates, maleates, tartrates, lactates, benzoates, and carbonates.

[0080] [2] Synthesis of compound AAa (R ４ This is synonymous with the above. R ３ａ X represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted heteroaryloxy group. ２ L represents chloro, bromo, or triflate. １ (where P represents boronic acid, boronic acid ester, alkyltin, zinc halide, etc.) Step 1 This step is to obtain compound FF by a coupling reaction between compound CC and EE. Examples of this reaction include Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, Stille coupling, etc. In a solvent or mixed solvent such as dioxane, toluene, DMSO, DMF, DME, THF, water, etc., compound CC is subjected to Pd(PPh 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 potassium carbonate, sodium carbonate, potassium phosphate, and boronic acid, boronic acid ester, trialkyltin, or zinc halide, which have been synthesized by commercially available or known methods, to 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 is described in "Greene's Protective Groups in Organic Synthesis," 4th edition, by Wuts and Greene, John Wiley & Sons Inc. Step 2 is a step in which the protecting group of compound FF is deprotected to obtain AAa, and can be done by referring to Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc. 2006, or by referring to Kosienski (P.J. Kosienski), "Protecting Groups", 3rd edition, Thiemes 2005.

[0081] [3] Synthesis of compound AAb (R ４ This is equivalent to the one described in general formula (1). This step involves adding compound GG, which has been synthesized by a commercially available or known method, to HH in a solvent such as acetonitrile in the presence of a base such as potassium carbonate, at a temperature of 0°C to 100°C for 1 to 48 hours, preferably 12 to 24 hours, to obtain compound AAb.

[0082] [4] Synthesis of Compound LL and Compound LLL <Variation 1> (R５ , R ６ , R ７ and X ２ This is synonymous with the above. R represents alkyl such as methyl and ethyl.) <Variation 2> (R, R ６ , R ７ and X １ This is synonymous with the above. R ５ａ (where represents a bromo group, chloro group, fluoro group, or iodine group, and A represents an aryl or heteroaryl group.)

[0083] Step 1 of Variation 1: This step involves a nucleophilic substitution reaction (S) of compound II, synthesized by a commercially available or known method, in a solvent such as DMSO or DMF, in the presence of TEA, DIPEA, and compound JJ, at a temperature of 0°C to 150°C, preferably 120°C to 150°C, for 1 hour to 48 hours, preferably 1 hour to 10 hours. Ｎ This is a step to obtain compound KK by performing Ar.

[0084] Step 2 of Variation 1: This step involves hydrolyzing the ester of compound KK to obtain compound LL, and can be synthesized by referring to "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., Wuts and Greene, 2006, or "Protecting Groups," 3rd edition, Thiemes, 2005, P.J. Kocienski.

[0085] Step 1 of Variation 2: This step involves reacting compound BBB, synthesized by a commercially available or known method, in a solvent such as DMSO or DMF in the presence of TEA, DIPEA, and compound JJJ at 0°C to 150°C, preferably 120°C to 150°C, for 1 hour to 48 hours, preferably 1 hour to 10 hours, in an aromatic nucleophilic substitution reaction (S Ｎ This is a step to obtain compound KKK1 by performing Ar(A).

[0086] Step 2 of Variation 2 This step is to obtain the amine compound KKK2 by reducing the nitro group of compound KKK1. This reduction reaction is achieved, for example, by iron reduction using reduced iron and ammonium chloride in a suitable solvent, or by zinc reduction using zinc powder and ammonium chloride or acetic acid. Examples of reducing agents that can be used in this reduction reaction include reduced iron, zinc powder, and tin(II) chloride. When using the above metal reagents in this reduction reaction, an acid is usually used. Examples of acids that can be used include hydrochloric acid, acetic acid, and ammonium chloride. The solvent used in this step is not particularly limited as long as it does not participate in the reaction, but examples include hydrocarbons such as toluene and 1,4-dioxane, ethers such as THF and DME, esters such as ethyl acetate, ketones such as acetone, nitriles such as acetonitrile, amides such as DMF, or alcohols such as methanol, ethanol, 2-propanol, and tert-butanol, water, or mixed solvents thereof. The reaction temperature varies depending on the type of raw materials and reagents used, but is generally suitable within the range of 0°C to 200°C. The reaction time varies depending on the type of raw materials and reagents used and the reaction temperature, but is generally suitable within the range of 1 hour to 24 hours. In this reaction, it is preferable to carry it out at 80°C in an ethanol-water solvent in the presence of reduced iron and ammonium chloride.

[0087] Steps 3 and 4 of Variation 2 are reactions in which an amino group is converted to a diazonium salt and then to a halogen atom by known methods, such as the Sandmeyer reaction or the Balz-Schiemann reaction. In the Sandmeyer reaction, chlorine, bromine, and iodine atoms can be introduced using copper chloride, copper bromide, and copper iodide. In the Valt-Siemann reaction, a diazonium fluoroborate salt KKK3 is formed by reacting in a hydrocarbon solvent such as chlorobenzene or hexane, or an alcohol solvent such as methanol or ethanol, with an alkali metal nitrite salt such as isoamyl nitrite, tert-butyl nitrite, or sodium nitrite, or an alkaline earth metal nitrite salt, and tetrafluoroboric acid, sodium tetrafluoroborate, or ammonium tetrafluoroborate at 0°C to 200°C, preferably 0°C to 50°C, for 10 minutes to 48 hours, preferably 30 minutes to 2 hours (step 3). After that, the compound KKK4 can be obtained by introducing a fluorine atom through thermal decomposition (step 4). For example, this can be done by the method described in Bioorganic Medicinal Chemistry Letters 2002, Vol. 12, pp. 1651-1655.

[0088] Step 5 of Variation 2: This step involves hydrolyzing compound KKK4 to obtain compound LLL, which can be synthesized by referring to "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., Wuts and Greene, 2006, or "Protecting Groups," 3rd edition, Thiemes, 2005, P.J. Kocienski.

[0089] [5] Synthesis of compound PP (R ８(This is the same as above. R represents alkyl such as methyl and ethyl.) Step 1 This step involves reacting compound MM and compound NN, synthesized by commercially available or known methods, in a solvent such as ethanol or ether at 0°C to 80°C, preferably ethanol at 60°C to 80°C, for 1 hour to 48 hours, preferably 1 hour to 10 hours, to obtain compound OO. Step 2 This step involves hydrolyzing the ester of compound OO to obtain compound PP. (Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc.) This can be synthesized by referring to P.J. Kocienski, "Protecting Groups," 3rd edition, Thiemes, 2005.

[0090] [6] Synthesis of compound (1) (R １ , R ２ , R ３ and R ４ This is synonymous with the above. X １(wherein represents a hydroxyl group, chloro, or bromo.) Step 1 This step involves performing a Friedel-Crafts acylation reaction on compound QQ, which has been synthesized commercially or by known methods, in a solvent such as methylene chloride or dichloroethane, in the presence of an acid such as aluminum chloride, phosphorus pentoxide-methanesulfonic acid mixture (EATON'S REAGEN) or trifluoromethanesulfonic acid (TfOH), and optionally in the presence of trifluoroacetic anhydride (TFAA), etc., with a carboxylic acid or acid halide BB 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). The acid used in the Friedel-Crafts acylation reaction may be a Lewis acid such as aluminum chloride, iron(III) chloride, and a boron trifluoride ether complex; or a Brønsted acid such as sulfuric acid, phosphoric acid, methanesulfonic acid, or trifluoromethanesulfonic acid; or a mixture thereof with phosphorus pentoxide or trifluoroacetic anhydride. A detailed example of this process involves contacting compound QQ with a carboxylic acid or acid halide BB in dichloromethane in the presence of trifluoromethanesulfonic acid and trifluoroacetic anhydride. Acid halide BB can be obtained by reacting compound LL or LLL, or compound PP, with oxalil chloride or oxalil bromide in a solvent such as methylene chloride or dichloroethane, in the presence of a catalytic amount of dimethylformamide, at a temperature of 0°C to 50°C, preferably 0°C to room temperature, for 1 to 48 hours, preferably 1 to 12 hours. As carboxylic acid BB, compound LL or LLL, or compound PP can be used as is. It should be noted that "[1] Synthesis of Compound (1) and its Salt" can also be considered an embodiment of "[6] Synthesis of Compound (1)". Therefore, the embodiments described in "[1] Synthesis of Compound (1) and its Salt" can also be applied to "[6] Synthesis of Compound (1)". One specific embodiment of this synthesis is one in which compound QQ is the compound of formula (II) described below, acid halide BB is the compound of formula (A) described below, and compound (1) is the compound represented by the following formula (I) (formula (I) compound).The chemical name of compound (I) is [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone). A more detailed embodiment of this invention is Synthesis Example 11 of the present invention. In this embodiment, the acid in the Friedel-Crafts acylation reaction may be a mixture of methanesulfonic acid and phosphorus pentoxide, the reaction temperature may be 70°C, the reaction time may be 6 hours, and no solvent may be used (i.e., the reaction may take place in methanesulfonic acid). This embodiment can be said to be an embodiment of Variations 2, 3 and 4 of the above-described "Synthesis of Compound (1) and its Salt". Therefore, the embodiments described for these variations can also be incorporated into this embodiment.

[0091] [7] Synthesis of compound VV (R ２ , R ４ and X ２ (This is the same as above.) Step 1 (RR → SS) In this step, compound RR is subjected to an alkylating agent (R) in the presence of a base. ２ -X ２This step involves alkylating the compound SS using a base, and can be carried out according to known alkylation methods. Examples of alkylating agents include methyl iodide, methyl p-toluenesulfonate, ethyl iodide, 1-bromobutane, 1-iodobutane, and 1-bromo-2-methoxyethane. Methyl p-toluenesulfonate is preferred. The amount of alkylating agent used is appropriate to be in the range of 1 to 1.5 molar equivalents relative to compound RR. Examples of bases used include sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and DBU. Potassium tert-butoxide is preferred. The amount of base used is appropriate to be in the range of 1 to 2 molar equivalents relative to compound RR. The solvent used in this step is not particularly limited as long as it does not participate in the reaction, but examples include amides such as DMF and DMA, ethers such as THF, nitriles such as acetonitrile, DMSO, or mixed solvents thereof. THF is preferred. The reaction temperature varies depending on the type of raw materials, reagents, and solvent used, but is usually preferably 0°C to 150°C, more preferably 0°C to 100°C, and even more preferably room temperature to 50°C. Step 2 (SS → TT) This step involves reacting compound SS with a reagent such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide in a suitable solvent such as THF or ether at 0°C to 80°C, preferably 0°C to 50°C, and more preferably 10°C to 40°C to obtain compound TT, and can be carried out according to known methods. In this reaction, TT can be obtained by treating with an acid such as hydrochloric acid and then neutralizing with a base such as an aqueous sodium hydroxide solution. However, it is also possible to isolate it as a hydrochloride salt without neutralization.Step 3 (TT → VV) This step involves reacting compound TT in a suitable solvent such as ethanol or isopropyl alcohol, preferably isopropyl alcohol, in the presence of compound UU, at a temperature of 0°C to 120°C, preferably 20°C to 100°C, and more preferably 40°C to 100°C, to obtain compound VV. This step can be carried out according to known methods.

[0092] Next, a detailed embodiment of Variation 2 of "[4] Synthesis of Compound LL and Compound LLL" will be described. This embodiment also relates to a method for producing a synthetic intermediate of the disclosed compound. The production method of this embodiment relates to a method for producing a compound represented by the following formula (A) (formula (A) compound). Formula (A) compound is (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid. Formula (A) compound is the starting material for Synthesis Example 21 and Synthesis Example 25 of the present invention and is one of the synthetic intermediates of the disclosed compound.

[0093] The manufacturing method of this embodiment includes at least one, two, three, four, or five steps selected from the group consisting of steps I to V below. The manufacturing method of this embodiment may include isolating and purifying the target product of each step in accordance with a conventional method after the completion of each step. Isolation and purification of the target product may include, for example, liquid-liquid phase separation, column chromatography, and / or recrystallization. Step I: A step of obtaining a compound represented by formula (D) (formula (D) compound) by contacting a compound represented by formula (C) (formula (C) compound). Step II: A step of converting the compound represented by formula (D) to a compound represented by formula (E) (formula (E) compound). Step III: A step of converting the compound represented by formula (E) to a compound represented by formula (F1) (formula (F1) compound), a compound represented by formula (F2) (formula (F2) compound), or a compound represented by formula (F3) (formula (F3) compound). Step IV: A step to convert a compound of formula (F1), a compound of formula (F2), or a compound of formula (F3) into a compound represented by formula (G) (a compound of formula (G)). Step V: A step to convert a compound of formula (G) into a compound of formula (A).

[0094] The chemical name of compound (B) is ethyl(2R,6R)-2,6-dimethylpiperidine-4-carbokillate. The chemical name of compound (C) is 2-chloro-3-iodo-5-nitropyridine. The chemical name of compound (D) is ethyl(2R,6R)-1-(3-iodo-5-nitropyridine-2-yl)-2,6-dimethylpiperidine-4-carbokillate. The chemical name of compound (E) is ethyl(2R,6R)-1-(5-amino-3-iodo-2-pyridyl)-2,6-dimethylpiperidine-4-carbokillate. The chemical name of compound (F1) is 6-[(2R,6R)-4-ethoxycarbonyl-2,6-dimethylpiperidine-1-yl]-5-iodopyridine-3-diazonium-tetrafluoroborate. The chemical name of compound (F2) is 6-[(2R,6R)-4-ethoxycarbonyl-2,6dimethylpiperidine-1-yl]-5-iodopyridine-3-diazonium-hexafluorophosphate. The chemical name of compound (F3) is 6-[(2R,6R)-4-ethoxycarbonyl-2,6dimethylpiperidine-1-yl]-5-iodopyridine-3-diazonium-hexafluoroantimonate. The chemical name of compound (G) is ethyl-(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate. This embodiment may also be any of these compounds.

[0095] Compounds of formula (A), (B), (C), (D), (E), and (G) may be in free form or in salt form unless otherwise specified. Furthermore, compounds of formula (F1), (F2), and (F3) may form salts with other acids or bases. Examples of salts in these compounds include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, boronic acid, tetrafluoroboric acid, hexafluorophosphate, and hexafluoroantimonic acid ions; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by commonly used methods.

[0096] Compounds of formula (A), (B), (C), (D), (E), and (G) may be in the form of solvates or solvates of salts, unless otherwise specified to exclude the solvate form. Compounds of formula (F1), (F2), and (F3) may be in the form of solvates of salts, unless otherwise specified to exclude the solvate form. Examples of such solvates include solvates with solvent molecules such as methanol, ethanol, isopropyl alcohol, butanol, dimethyl sulfoxide, and acetonitrile, as well as monohydrates and dihydrates.

[0097] In step I, compound (D) is obtained by contacting compound (B) with compound (C). Although we do not wish to be bound by any theory, in step I, compound (D) is obtained by an aromatic nucleophilic substitution reaction. Compound (B) may be in the form of, for example, a salt of an inorganic or organic acid, and preferably in the form of a hydrochloride salt. The hydrochloride salt of compound (B) is represented by the following formula (B').

[0098] The solvent in step I is not particularly limited as long as the compound of formula (D) is obtained. The solvent in step I may satisfy the requirements of being a polar solvent and / or having a boiling point of 100°C or higher. The solvent in step I may be, for example, butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone, and in a particular embodiment, butyl acetate.

[0099] The contact between compound (B) and compound (C) in step I may be carried out in the presence of a base. The base in step I is not particularly limited as long as compound (D) is obtained. The base in step I may be, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydride, sodium tertiboxide, sodium methoxide, potassium methoxide, triethylamine, or N,N-diisopropylethylamine, and in a particular embodiment it may be sodium carbonate.

[0100] The contact between compound (B) and compound (C) in step I may be carried out while removing water from the reaction solution. When the contact is carried out while removing water, side reactions are less likely to occur. The method of removing water may be one that is commonly used by those skilled in the art, for example, by adding molecular sieves (e.g., molecular sieves 4A) to the reaction solution, or by using a device that removes water from the reaction system, such as a Dean-Stark apparatus.

[0101] The reaction time in step I is not particularly limited as long as the compound of formula (D) is obtained, but may be, for example, 15 minutes or more, 30 minutes or more, 1 hour or more, 3 hours or more, 6 hours or more, 12 hours or more, or 24 hours or more, and may be 168 hours or less, 72 hours or less, 48 ​​hours or less, 30 hours or less, 18 hours or less, 10 hours or less, 7 hours or less, 5 hours or less, 4 hours or less, or 2 hours or less, and these upper and lower limits may be freely combined.

[0102] The reaction temperature in step I is not particularly limited as long as the compound of formula (D) is obtained, but may be, for example, 50°C or higher, 80°C or higher, 100°C or higher, 110°C or higher, 120°C or higher, or 130°C or higher, and may be 200°C or lower, 180°C or lower, 160°C or lower, 150°C or lower, 140°C or lower, or 130°C or lower, and these upper and lower limits may be freely combined. In one particular embodiment, the reaction temperature in step I may be 130°C. The reaction in step I may be carried out under heating reflux (reflux).

[0103] In step I, the amount of compound (C) relative to one molar equivalent of compound (B) is not particularly limited, but may be, for example, 0.1 molar equivalents or more and 10 molar equivalents or less, 0.3 molar equivalents or more and 3.0 molar equivalents or less, or 0.5 molar equivalents or more and 2.0 molar equivalents or less.

[0104] In step I, the amount of base relative to 1 part by mass of compound (B) is not particularly limited, but may be, for example, 0.1 parts by mass or more and 10 parts by mass or less, 0.3 parts by mass or more and 3.0 parts by mass or less, or 0.5 parts by mass or more and 2.0 parts by mass or less.

[0105] In step II, compound (D) is converted to compound (E). While we do not wish to be bound by any theory, in step II, compound (E) is obtained by reducing the nitro in compound (D) to an amino.

[0106] In step II, the reducing agent for reducing nitro is not particularly limited as long as the compound of formula (E) is obtained, but may be, for example, a metal, hydrazine, or hydrogen.

[0107] The reduction reaction of nitro in which the reducing agent is a metal is known as Bechamp reduction. In Bechamp reduction, a metal and an acid are brought into contact with a compound of formula (D). The metal and acid are not particularly limited as long as a compound of formula (E) is obtained. The metal in Bechamp reduction may be, for example, iron, tin, tin(II) chloride, or zinc. The metal in Bechamp reduction may be, for example, in powder form. The acid in Bechamp reduction is not particularly limited and may be, for example, ammonium chloride, hydrochloric acid, or acetic acid. In a particular embodiment of Bechamp reduction, the metal may be iron powder and the acid may be ammonium chloride.

[0108] The solvent for Bechamp reduction is not particularly limited as long as the compound of formula (E) is obtained, but may be, for example, a mixed solvent of water and alcohol, water, or alcohol. The alcohol in these may be, for example, ethanol, methanol, or isopropanol, and in one embodiment it may be ethanol. In the mixed solvent of water and alcohol, the volume ratio of water to alcohol may be, for example, 1:10 to 10:1, 1:3 to 3:1, or 1:2 to 2:1. In a particular embodiment, the solvent for Bechamp reduction may be a mixed solvent of water and ethanol with a volume ratio of 1:1.

[0109] The reaction time for Bechamp reduction is not particularly limited as long as the compound of formula (E) is obtained, but may be, for example, 5 minutes or more, 15 minutes or more, 30 minutes or more, 1 hour or more, or 2 hours or more, and may be 24 hours or less, 12 hours or less, 9 hours or less, 6 hours or less, 4 hours or less, or 2 hours or less, and these upper and lower limits may be freely combined. In a particular embodiment, the reaction time for Bechamp reduction may be 2 hours.

[0110] The reaction temperature for Bechamp reduction is not particularly limited as long as the compound of formula (E) is obtained, but may be, for example, 30°C or higher, 50°C or higher, 60°C or higher, or 70°C or higher, and may also be 100°C or lower, 90°C or lower, 80°C or lower, or 70°C or lower, and these upper and lower limits may be freely combined. In one particular embodiment, the reaction temperature for Bechamp reduction may be 70°C.

[0111] The reduction reaction of nitro compounds with hydrazine as the reducing agent can also be carried out, for example, by a method using a catalytic amount of iron salt and hydrazine. In this method, for example, iron(III) chloride can be used as a catalyst in the presence of activated carbon, and hydrazine can act as the reducing agent. In this embodiment, the addition of acid is not essential, and the reaction can be carried out under neutral or weakly acidic conditions. The solvent, reaction time, and reaction temperature for the reduction reaction of nitro compounds with hydrazine as the reducing agent are not particularly limited as long as the compound of formula (E) is obtained.

[0112] The reduction reaction of nitro compounds in which the reducing agent is hydrogen is known as catalytic hydrogenation. In catalytic hydrogenation, the compound of formula (D) is contacted with hydrogen or a hydrogen source in the presence of a metal catalyst. The metal catalyst and the hydrogen or hydrogen source are not particularly limited as long as the compound of formula (E) is obtained. The metal catalyst in catalytic hydrogenation may be, for example, Pd / C (palladium-carbon), Rh / C (rhodium-carbon), Ru / C (ruthenium-carbon), or Raney nickel. The hydrogen or hydrogen source may be, for example, hydrogen or hydrazine, or hydrogen. In catalytic hydrogenation according to one particular embodiment, the compound of formula (D) may be contacted with hydrogen in the presence of Pd / C. The solvent, reaction time, and reaction temperature of catalytic hydrogenation are not particularly limited as long as the compound of formula (E) is obtained.

[0113] In step III, the compound of formula (E) is converted to the compound of formula (F1), the compound of formula (F2), or the compound of formula (F3). In step III, the amino of the compound of formula (E) is diazotized. The compound of formula (F1) is in the form of a tetrafluoroborate. The compound of formula (F2) is in the form of a hexafluorophosphate. The compound of formula (F3) is in the form of a hexafluoroantimonate. Therefore, if the product obtained by the diazotization reaction is in a form other than a tetrafluoroborate, hexafluorophosphate, or hexafluoroantimonate, the product may be converted to the form of a tetrafluoroborate, hexafluorophosphate, or hexafluoroantimonate. In one preferred embodiment, in step III, the compound of formula (E) may be converted to the compound of formula (F1).

[0114] The method for diazotizing aminos in step III is not particularly limited as long as a compound of formula (F1), a compound of formula (F2), or a compound of formula (F3) is obtained, but for example, a nitrosonium ion (NO) can be added to compound (E). ＋ ) or a nitrosonium salt may be brought into contact. Nitrosonium ions can be generated from nitrite esters or nitrite salts in the presence of an acid. That is, for example, in step III, the compound of formula (E) and a nitrite ester or nitrite salt may be brought into coexistence in the presence of an acid. Nitrosonium salts include, for example, nitrosonium triflate (NOTf) and nitrosonium tetrafluoroborate (NOBF). ４ ) or nitrosonium hexafluorophosphate (NOPF ６ ) is acceptable.

[0115] The nitrite ester is not particularly limited, but may be, for example, an alkyl nitrite ester, isoamyl nitrite, ethyl nitrite, or tert-butyl nitrite. When a nitrite ester is used as the nitrosonium ion source, the solvent in step III may be, for example, an organic solvent. The organic solvent may be, for example, a polar solvent, an alcohol-based solvent, or ethanol, methanol, or isopropanol.

[0116] The nitrite is not particularly limited, but may be, for example, a metal nitrite or sodium nitrite. When a nitrite is used as the nitrosonium ion source, the solvent in step III may be, for example, water or a mixed solvent of water and an organic solvent.

[0117] The acid used in step III is not particularly limited as long as the compound of formula (F1), formula (F2), or formula (F3) is obtained. Examples of the acid used in step III may be diethyl ether tetrafluoroborate complex, tetrafluoroboric acid, hexafluorophosphate, hexafluoroantimonic acid, hydrochloric acid, bromic acid, sulfuric acid, or trifluoroacetic acid. The amount of acid in step III is not particularly limited as long as the reaction solution becomes acidic and the compound of formula (F1), formula (F2), or formula (F3) is obtained.

[0118] In one particular embodiment, in step III, the compound of formula (E) and isoamyl nitrite may be present together in the presence of an acid.

[0119] In step III, the amount of nitrite ester, nitrite salt, or nitrosonium salt per 1 part by mass of compound (E) is not particularly limited, but may be, for example, 0.1 parts by mass or more and 10 parts by mass or less, 0.3 parts by mass or more and 3.0 parts by mass or less, or 0.5 parts by mass or more and 2.0 parts by mass or less.

[0120] The reaction time in step III is not particularly limited as long as compound (F1), compound (F2), or compound (F3) of formula is obtained, but may be, for example, 5 minutes or more, 15 minutes or more, 30 minutes or more, or 1 hour or more, and may be 24 hours or less, 12 hours or less, 6 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less, and these upper and lower limits may be freely combined. In a particular embodiment, the reaction time in step III may be 1 hour.

[0121] The reaction temperature in step III is not particularly limited as long as the compound of formula (F1), the compound of formula (F2), or the compound of formula (F3) is obtained, but may be, for example, -100°C or higher, -78°C or higher, -25°C or higher, -10°C or higher, or 0°C or higher, and may be 25°C or lower, 10°C or lower, 5°C or lower, or 0°C or lower, and these upper and lower limits may be freely combined. In one particular embodiment, the reaction temperature in step III may be 0°C.

[0122] In step IV, compound (F1), compound (F2), or compound (F3) is converted to compound (G). Although we do not wish to be bound by any theory, in step IV, compound (G) is obtained by the Balz-Schiemann reaction. In the Balz-Schiemann reaction, a compound having fluoro on the aromatic ring is obtained by the thermal decomposition of a tetrafluoroborate, hexafluorophosphate, or hexafluoroantimonate of a compound having diazo on the aromatic ring. In a preferred embodiment, in step IV, compound (F1) may be converted to compound (G).

[0123] The solvent in step IV is not particularly limited as long as the compound of formula (G) is obtained. The solvent in step IV may include, for example, a solvent that is aprotic and non-nucleophilic and has a boiling point of 100°C or higher. The solvent in step IV may be, for example, a mixed solvent of butyl acetate and cyclohexane, with a volume ratio of, for example, 1:1. The solvent in step IV may also be, for example, a solvent having a benzene ring, and may be a benzene substituted with at least one chloro and / or nitro group. The solvent in step IV may be a dehydrated solvent.

[0124] In step IV, a tetrafluoroborate may be further added to the solvent to which the compound of formula (F1), the compound of formula (F2), or the compound of formula (F3) has been added. The tetrafluoroborate may be, for example, lithium tetrafluoroborate or potassium tetrafluoroborate. The amount of tetrafluoroborate added per 1 part by mass of the compound of formula (F1), the compound of formula (F2), or the compound of formula (F3) is not particularly limited, but may be, for example, 0.1 parts by mass or more and 10 parts by mass or less, 0.3 parts by mass or more and 3.0 parts by mass or less, or 0.5 parts by mass or more and 2.0 parts by mass or less.

[0125] The reaction time in step IV is not particularly limited as long as the compound of formula (G) is obtained, but may be, for example, 5 minutes or more, 15 minutes or more, 30 minutes or more, or 1 hour or more, and may be 24 hours or less, 12 hours or less, 6 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less, and these upper and lower limits may be freely combined. In a particular embodiment, the reaction time in step IV may be 1 hour.

[0126] The reaction temperature in step III is not particularly limited as long as the compound of formula (G) is obtained, but may be, for example, 40°C or higher, 70°C or higher, 80°C or higher, 90°C or higher, or 100°C or higher, and may be 200°C or lower, 150°C or lower, 130°C or lower, 120°C or lower, 110°C or lower, or 100°C or lower, and these upper and lower limits may be freely combined. In a particular embodiment, the reaction temperature in step III may be 100°C. The reaction in step III may be carried out under heating reflux (reflux).

[0127] In step V, the compound of formula (G) is converted to the compound of formula (A). In step V, the ethyl ester of the compound of formula (G) is converted to the carboxyl. The method of converting the ethyl ester to the carboxyl is not particularly limited and may be, for example, base hydrolysis, acid decomposition, or acid hydrolysis, and in a particular embodiment, it may be base hydrolysis. The conversion in step V may be carried out according to a method commonly used by those skilled in the art, for example, according to the method of Synthesis Example 5 or Synthesis Example 20 of the present invention.

[0128] Next, a detailed embodiment of "[7] Synthesis of Compound VV" will be described. One embodiment of this embodiment also relates to a method for producing a synthetic intermediate of the disclosed compound. The production method of this embodiment relates to a method for producing a compound represented by the following formula (II) (formula (II) compound). Formula (II) compound is 5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine. Formula (II) compound is the starting material for Synthesis Example 11 and Example 29 of the present invention and is one of the synthetic intermediates of the disclosed compound. A more detailed embodiment of the production method of this embodiment is Synthesis Examples 6 to 10 of the present invention.

[0129] The manufacturing method of this embodiment includes at least one, two, three, four, or five steps selected from the group consisting of steps VI, VII, VIII, IX, and X. The manufacturing method of this embodiment may include isolating and purifying the target product of each step in accordance with a conventional method after the completion of each step. Isolation and purification of the target product may include, for example, liquid-liquid phase separation, column chromatography, and / or recrystallization. Step VI: A step of converting a compound represented by formula (III) (formula (III) compound) to a compound represented by formula (IV) (formula (IV) compound). Step VII: A step of converting a compound represented by formula (IV) (formula (V) compound). Step VIII: A step of converting a compound represented by formula (V) (formula (VI) compound). Step IX: A step of converting a compound represented by formula (VII) (formula (VII) compound). Step X: A step to convert compound (VII) into compound (II).

[0130] The chemical name of compound (III) is 5-chloro-1H-pyrrolo[2,3-b]pyridine, and the CAS number of compound (III) is 866546-07-8. The chemical name of compound (IV) is 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide, and the CAS number of compound (IV) is 916176-51-7. The chemical name of compound (V) is 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile, and the CAS number of compound (V) is 1260384-05-1. The chemical name of compound (VI) is 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxyimidoamide. The chemical name of compound (VII) is 5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine. This embodiment may also be any of these compounds.

[0131] Compounds of formula (II), formula (III), formula (IV), formula (V), formula (VI), and formula (VII) may be in free form or in salt form, unless otherwise specified. Examples of salts of these compounds include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, boronic acid, tetrafluoroboric acid, hexafluorophosphate, and hexafluoroantimonic acid ions; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by commonly used methods.

[0132] Compounds of formula (II), formula (III), formula (IV), formula (V), formula (VI), and formula (VII) may be in the form of solvates or solvates of salts, unless otherwise specified. Examples of such solvates include solvates with solvent molecules such as methanol, ethanol, isopropyl alcohol, butanol, dimethyl sulfoxide, and acetonitrile, as well as monohydrates and dihydrates.

[0133] In step VI, the compound of formula (III) is converted to the compound of formula (IV). Although we do not wish to be bound by any theory, in step VI, the nitrogen atom on the pyridine ring of the compound of formula (III) is oxidized, and the pyridine substructure is converted to pyridine N-oxide.

[0134] The oxidizing agent and solvent in step VI should be capable of selectively oxidizing the nitrogen atom at position 7 of the azaindole ring in the compound of formula (III). For example, the oxidizing agent and solvent in step VI should be capable of oxidizing the nitrogen atom at position 7 of the azaindole ring in the compound of formula (III) without excessively oxidizing other parts of the azaindole ring, including the nitrogen atom at position 1.

[0135] The oxidizing agent in step VI may be, for example, a peracid or hydrogen peroxide. The peracid may be, for example, trifluoroperacetic acid, m-chloroperbenzoic acid (m-CPBA), peracetic acid, or performic acid, and in one embodiment, trifluoroperacetic acid may be used from the viewpoint of reaction efficiency. These peracids may be generated in situ using the corresponding peroxide and hydrogen peroxide or hydrogen peroxide urea (UHP), or they may be added as peracids themselves. In particular, highly reactive peracids such as trifluoroperacetic acid and performic acid may be generated in situ. For example, trifluoroperacetic acid can be generated in situ by adding trifluoroacetic anhydride (TFAA) and hydrogen peroxide urea (UHP) to the solvent. Hydrogen peroxide may be added as, for example, hydrogen peroxide urea (UHP) or hydrogen peroxide solution. The amount of oxidizing agent relative to one molar equivalent of formula (III) compound is not particularly limited, but may be, for example, 0.8 molar equivalents or more and 3.0 molar equivalents or less, 1.0 molar equivalent or more and 2.5 molar equivalents or less, or 1.2 molar equivalents or more and 2.0 molar equivalents or less.

[0136] The solvent in step VI may be any solvent that is stable with respect to the oxidizing agent and its source. The solvent in step VI may be, for example, acetonitrile, dichloromethane, dichloroethane, or chloroform, and in one embodiment it may be acetonitrile.

[0137] The reaction temperature in step VI is not particularly limited as long as the compound of formula (IV) is obtained, but may be, for example, -25°C or higher, -10°C or higher, 0°C or higher, or 10°C or higher, and may be 50°C or lower, 40°C or lower, or 30°C or lower, and these upper and lower limits may be freely combined. In one particular embodiment, the reaction temperature in step VI may be room temperature of about 25°C.

[0138] The reaction time in step VI is not particularly limited as long as the compound of formula (IV) is obtained, but may be, for example, 5 minutes or more, 15 minutes or more, 30 minutes or more, or 1 hour or more, and may be 24 hours or less, 12 hours or less, 6 hours or less, 3 hours or less, or 2 hours or less, and these upper and lower limits may be freely combined. In a particular embodiment, the reaction time in step VI may be 1.5 hours.

[0139] Step VII converts compound (IV) to compound (V). While we do not wish to be bound by any theory, in step VII, a cyano is introduced to the 6th position of the azaindole ring in compound (IV) (i.e., the position adjacent to the N-oxideized nitrogen atom) by the Reissert-Henze reaction. In the Reissert-Henze reaction, first, an activator introduces a functional group to the oxygen atom of the N-oxide at position 7 of the azaindole ring, thereby activating its adjacent position (position 6). Next, a cyano source introduces a cyano to this activated adjacent position. Finally, base treatment eliminates the oxygen atom on the nitrogen atom, the functional group introduced by the activator, and the hydrogen atom adjacent to its adjacent position (position 6). These reactions may be carried out sequentially in one reaction system (i.e., one-pot), or in two or more independent reaction systems, but for simplicity, they may be carried out in one pot.

[0140] The functional group introduced by the activator is any group that selectively introduces to the oxygen atom of the N-oxide at position 7 of the azaindole ring, thereby regioselectively causing the introduction of the following cyano group. The functional group introduced may be, for example, an alkyl, acyl, or sulfonyl group, where the alkyl may be, for example, methyl, and the acyl may be, for example, benzoyl or acetyl. When the functional group introduced is methyl, the activator may be, for example, dimethyl sulfate or iodomethane, and in one embodiment, dimethyl sulfate. When the functional group introduced is benzoyl, the activator may be, for example, benzoyl chloride.

[0141] The amount of activator relative to one molar equivalent of formula (IV) compound is not particularly limited, but may be, for example, 0.5 molar equivalents or more and 3.0 molar equivalents or less, 0.8 molar equivalents or more and 2.0 molar equivalents or less, or 1.0 molar equivalent or more and 1.5 molar equivalents or less, and in a particular embodiment it may be 1.1 molar equivalents.

[0142] The solvent in the reaction with the activator can be any solvent that is stable to the activator and the activated intermediate generated thereby, for example, a hydrophilic solvent, or acetonitrile, N,N-dimethylformamide, DMSO, 1,4-dioxane, or tetrahydrofuran, or a mixed solvent of these with water, and in a particular embodiment, acetonitrile may be used.

[0143] The reaction temperature in the reaction with the activator may be, for example, 40°C or higher, 70°C or higher, 80°C or higher, 90°C or higher, or 100°C or higher, and may also be 200°C or lower, 150°C or lower, 130°C or lower, 120°C or lower, 110°C or lower, or 100°C or lower, and these upper and lower limits may be freely combined. In a particular embodiment, the reaction with the activator may be carried out under reflux.

[0144] The reaction time in the reaction with the activator may be, for example, 5 minutes or more, 15 minutes or more, 30 minutes or more, or 1 hour or more, and may be 24 hours or less, 12 hours or less, 6 hours or less, 3 hours or less, or 2 hours or less, and these upper and lower limits may be freely combined. In a particular embodiment, the reaction time with the activator may be 2 hours.

[0145] The cyano source can be any substance capable of introducing cyano to the 6-position of the activated azaindole ring, such as a salt of a cyanide ion or a silyl cyanide compound. The salt of a cyanide ion can be, for example, a salt of a cyanide ion with an alkali metal, such as sodium cyanide or potassium cyanide. The silyl cyanide compound can be, for example, a trialkyl cyanide or a trimethyl cyanide.

[0146] The amount of cyano source relative to one molar equivalent of formula (IV) compound is not particularly limited, but may be, for example, 0.5 molar equivalents or more and 3.0 molar equivalents or less, 0.8 molar equivalents or more and 2.5 molar equivalents or less, or 1.0 molar equivalent or more and 2.0 molar equivalents or less, and in a particular embodiment it may be 1.5 molar equivalents.

[0147] The solvent used in the reaction with the cyano source may be any solvent that is stable to the activator and the active intermediate generated thereby. For example, it may be a hydrophilic solvent, or it may be acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or tetrahydrofuran, or a mixture of these with water. In one particular embodiment, it may be a mixture of acetonitrile and water. In addition, the solvent may further contain a base such as ammonium chloride.

[0148] The reaction temperature in the reaction with the cyano source may be, for example, -25°C or higher, -10°C or higher, 0°C or higher, or 10°C or higher, and may also be 50°C or lower, 40°C or lower, or 30°C or lower, and these upper and lower limits may be freely combined. In one particular embodiment, the reaction temperature in the reaction with the cyano source may be room temperature of about 25°C.

[0149] The reaction time in the reaction with the cyano source may be, for example, 15 minutes or more, 30 minutes or more, 1 hour or more, 3 hours or more, 6 hours or more, 12 hours or more, or 24 hours or more, and may be 168 hours or less, 72 hours or less, 48 ​​hours or less, 30 hours or less, 18 hours or less, 10 hours or less, 7 hours or less, 5 hours or less, 4 hours or less, or 2 hours or less, and these upper and lower limits may be freely combined.

[0150] The base used in the base treatment is not particularly limited, and may include, for example, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or DBU. The solvent used in the base treatment may be a mixed solvent of, for example, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or tetrahydrofuran with water, and in a particular embodiment, a mixed solvent of acetonitrile and water. The reaction temperature in the base treatment may be, for example, -10°C or higher or 0°C or higher, and may be 40°C or lower, 25°C or lower, 10°C or lower, or 4°C or lower, and in a particular embodiment, it may be 0°C. The duration of the base treatment may be the time required to obtain compound (V), and for example, it may be 2 hours.

[0151] In step VIII, compound (V) is converted to compound (VI). Since step VIII is one aspect of step 1 (RR → SS) of "[7] Synthesis of compound VV" described above, it can be carried out according to the method described for step 1 (RR → SS).

[0152] In step IX, compound (VI) is converted to compound (VII). Although we do not wish to be bound by any theory, in step IX, the cyano is converted to an amidine by a nucleophilic addition reaction followed by desilylation by acid treatment. Since step IX is an embodiment of step 2 (SS → TT) of "[7] Synthesis of compound VV" described above, it can be carried out according to the method described for step 2 (SS → TT).

[0153] Step X converts the compound of formula (VII) to the compound of formula (II). Step X is a step that converts amidine to a pyrimidine ring. Since Step X is an embodiment of step 3 (TT → VV) of the above-described "[7] Synthesis of Compound VV", it can be carried out according to the method described for step 3 (TT → VV). In Step X, compound TT is the compound of formula (VII), compound UU is 3-(dimethylamino)acrolein, and compound VV is the compound of formula (II). Although we do not wish to be bound by any theory, in Step X, first the nitrogen atom of amidine nucleophilically attacks 3-(dimethylamino)acrolein, and then intramolecular condensation closure forms a pyrimidine ring.

[0154] The compound of formula (II) obtained according to the method described above may be used in the form of a free compound or a salt as a starting material for the above-mentioned "synthesis of compound (1) and its salt" and "synthesis of compound (1)" as shown in Synthesis Example 11 and Example 29 of the present invention. One embodiment of the salt of compound (II) is the methanesulfonate of compound (II), which is the compound represented by the following formula (IIA) (compound (IIA)). Compound (IIA) can be produced by contacting compound (II) with methanesulfonic acid in an organic solvent (for example, a mixed solvent of ethyl acetate, toluene, and isopropyl alcohol), and then isolating the precipitated solid by filtration or the like.

[0155] Next, a monophosphate (1-phosphate) and its crystals relating to one aspect of this embodiment will be described. The monophosphate of the compound of formula (I) is the compound represented by the following formula (IA) (compound of formula (IA)).

[0156] Compounds of formula (IA) may also be in the form of salt solvates unless otherwise specified. Examples of such solvates include solvates with solvent molecules such as methanol, ethanol, isopropyl alcohol, butanol, dimethyl sulfoxide, and acetonitrile, as well as monohydrates and dihydrates.

[0157] Compound (IA) is obtained by contacting compound (I) or a salt thereof with phosphoric acid in a specific organic solvent such as acetone. When compound (I) or a salt thereof is contacted with phosphoric acid in a solvent other than a specific organic solvent such as acetone, a salt of compound (I) may be formed that contains more than one molecule of phosphoric acid or less than one molecule of compound (I) per molecule of compound (I). The method for preparing (synthesis, production, and preparation) compound (I) is as described above. Crystals of compound (IA) are obtained by contacting compound (IA) or a salt thereof with phosphoric acid in a specific organic solvent such as acetone, and then isolating the precipitated solid by filtration or the like.

[0158] A preferred embodiment of the crystal of the compound of formula (IA) may be a type I crystal. A type I crystal is a stable crystal form of the compound of formula (IA).

[0159] The type I crystals of the compound of formula (IA) may exhibit peaks in their powder X-ray diffraction pattern using Cu-Kα rays at at least 12.3°±0.2°, 19.1°±0.2°, 22.0°±0.2°, 25.6°±0.2°, and 26.9°±0.2° at 2θ values. Furthermore, the type I crystals of the compound of formula (IA) may exhibit peaks in their powder X-ray diffraction pattern using Cu-Kα rays at at least 12.3°±0.2°, 16.2°±0.2°, 17.9°±0.2°, 19.1°±0.2°, 20.7°±0.2°, 22.0°±0.2°, 23.5°±0.2°, 25.6°±0.2°, and 26.9°±0.2° at 2θ values. Furthermore, the type I crystal of the compound of formula (IA) may have a powder X-ray diffraction pattern using Cu-Kα rays that is shown in Figure 1. In this disclosure, the powder X-ray diffraction spectrum using Cu-Kα rays may be measured using a MiniFlex 600 (manufactured by Rigaku Corporation) under the conditions of a voltage of 40 kV, a current of 15 mA, a solar slit of 5.0 degrees, a scanning range of 4 to 40 degrees, and a scan speed / counting time of 20.0.

[0160] Type I crystals of compound (IA) may have an endothermic peak at 214.8 ± 3.0°C in differential thermal analysis (DTA). In this disclosure, differential thermal analysis (DTA) may be performed as TG (thermogravimetric) / DTA using a TG-8120 (manufactured by Rigaku Corporation) under the conditions of an alumina (open) cell, nitrogen gas, a heating rate of 10.0°C / min, a hold temperature of 300°C, and a hold time of 0 minutes.

[0161] The crystal purity of type I crystals of the compound of formula (IA) according to one embodiment may be above a predetermined lower limit. The predetermined lower limit may be, for example, 50%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%. In this disclosure, crystal purity means the proportion of type I crystal molecules included in the aggregate of crystals of the compound of formula (I) or its salt. Crystal purity may be determined, for example, as the ratio (%) of the area of ​​the endothermic peaks derived from type I crystals of the compound of formula (IA) (e.g., an endothermic peak at 214.8 ± 3.0 °C, or an endothermic peak that a person skilled in the art can determine to originate from type I crystals of the compound of formula (IA) based on the decrease in the melting point in the mixture or the difference in measurement characteristics between DTA and DSC) to the sum of the areas of all endothermic peaks detected in differential thermal analysis (DTA) or differential scanning calorimetry (DSC).

[0162] Type I crystals of the compound of formula (IA) can be produced (synthesized and obtained) by contacting the compound of formula (I) with phosphoric acid in a solvent containing acetone. In other words, one aspect of this embodiment can be described as a method for producing type I crystals of the compound of formula (IA), which includes contacting the compound of formula (I) with phosphoric acid in a solvent containing acetone (contact step). The compound of formula (I) that is contacted with phosphoric acid in the contact step may be in the form of a free compound or a salt, but in one embodiment it may be in the form of a free compound. A detailed example of this embodiment is Synthesis Example 12 of the present embodiment.

[0163] The solvent in the contact process is an acetone-containing solvent, which may be, for example, acetone, or a mixed solvent of acetone and another solvent, or acetone, or a mixed solvent of acetone and a polar solvent, or in one embodiment, acetone, or a mixed solvent of acetone and water, and in a preferred embodiment, acetone. The volume percentage (v / v%) of acetone in the acetone-containing solvent may be, for example, 50% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100%, and in a preferred embodiment, it may be 100%. In addition, the volume percentage (v / v%) of acetone in the mixed solvent of acetone and water may be, for example, 50% or more and 99% or less, or 70% or more and 95% or less.

[0164] In the contact step, the amount of phosphoric acid to be contacted with one molar equivalent of the compound of formula (I) may be, for example, 1.0 molar equivalent or more and 20.0 molar equivalents or less, 1.2 molar equivalents or more and 5.0 molar equivalents or less, or 1.5 molar equivalents or more and 2.5 molar equivalents or less, and in a particular embodiment, it may be 2.0 molar equivalents.

[0165] The temperature at which the compound of formula (I) is brought into contact with phosphoric acid during the contact step may be any temperature at which type I crystals of the compound of formula (IA) are formed, for example, 0°C or higher, 25°C or higher, 30°C or higher, or 40°C or higher, and may also be 60°C or lower, 50°C or lower, 40°C or lower, 35°C or lower, 30°C or lower, or 25°C or lower, and these upper and lower limits may be freely combined. In one particular embodiment, the temperature at which the compound of formula (I) is brought into contact with phosphoric acid during the contact step may be 50°C. The contact between the compound of formula (I) and phosphoric acid during the contact step may be carried out under heating reflux (Reflux).

[0166] In the contact step, the type I crystals of the compound of formula (IA) that are produced may be isolated as a solid precipitated in the solvent by filtration or the like. From the viewpoint of facilitating the precipitation of type I crystals of the compound of formula (IA), the reaction solution after contact with phosphoric acid may be cooled to room temperature of about 25°C or to around 0-10°C.

[0167] The method for producing type I crystals of the compound of formula (IA) according to this embodiment may include a step of grinding the type I crystals of the compound of formula (IA) obtained in the contact step (grinding step) after the contact step. The type I crystals of the compound of formula (IA) contained in the above-mentioned agent, pharmaceutical composition, and pharmaceutical, etc. may be ground or not. The grinding method in the grinding step may be any method that does not cause a change in the crystalline form of the compound of formula (IA), and may be, for example, grinding using an air-jet grinding device such as a jet mill, an impact mill such as a pin mill or hammer mill, a ball mill, a vibration mill, or a roller mill. In one embodiment, grinding may be performed using an air-jet grinding device such as a jet mill from the viewpoint of being able to grind until fine particles are obtained without causing a change in the crystalline form of the compound of formula (IA).

[0168] The present disclosure will be further described below with reference to synthesis examples, examples, and test examples, but this disclosure is not limited to these.

[0169] Mass spectrometry (MS) was measured using LC-MS. ESI (Electron Stimulation Injection) was used as the ionization method. The observed mass spectrometry values ​​are expressed in m / z.

[0170] The measurement conditions for LC-MS are as follows: Analytical instrument: ACQUITY UPLC MS / PDA system (Waters) Mass spectrometer: Waters 3100 MS detector: Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210-400 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 O (v / v; the same applies below) Solution B: 0.1% formic acid / acetonitrile

[0171] The measurement conditions for chiral column chromatography are as follows: Analytical instrument: i-Series UHPLC model LC-2060C 3D (PDA model) (Shimadzu Corporation) Detection wavelength: 220 nm Column: CHIRALPAK IB, 0.46 cmI.D. × 25 cmL Flow rate: 1.0 mL / min Column temperature: 40°C Mobile phase: n-Hexane / IPA = 92 / 8 (v / v)

[0172] １ The 1H NMR spectrum was measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE, Inc.). Observed peaks are expressed as chemical shift values ​​δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = double doublet, dt = double triplet).

[0173] The microwave experiment was conducted using an Initiator 60 (manufactured by Biotage). It can achieve temperatures of 40-250°C and pressures up to 20 bar.

[0174] Specific optical rotation [α] ５８９ The measurement conditions are as follows: Analytical instrument: Automatic polarimeter SEPA-500 (manufactured by Horiba, Ltd.) Optical path length: 50 mm

[0175] The melting point was measured using a micro-melting point analyzer (Buchi, B-565 model). TG-DTA measurement conditions: TG / DTA was measured using a TG-8120 (manufactured by Rigaku Corporation) (cell: alumina (open), gas: nitrogen, heating rate: 10.0°C / min, hold temperature: 300°C, hold time: 0 minutes).

[0176] XRPD measurement conditions: Powder X-ray diffraction spectra were measured using MiniFlex 600 (manufactured by Rigaku Corporation) (voltage: 0.40kV, current: 0.15mA, wavelength: CuKα, solar slit: 5.0 degrees, scanning range: 4-40 degrees, scan speed / counting time: 20.0).

[0177] The compound names used herein were named using IUPAC-compliant naming software, ACD / NAME (registered trademark, Advanced Chemistry Development Inc.), ChemBioDraw (version 19.1, Cambridge Soft), or in accordance with IUPAC nomenclature.

[0178] ​Synthesis Example 1 Synthesis of ethyl(2R,6R)-1-(3-iodo-5-nitropyridine-2-yl)-2,6-dimethylpiperidine-4-carbochylate (compound of formula (D)) Ethyl(2R,6R)-2,6-dimethylpiperidine-4-carbochylate hydrochloride (150 g) and 2-chloro-3-iodo-5-nitropyridine (231 g) were suspended in butyl acetate (1.5 L). Sodium carbonate (215 g) and molecular sieves 4A 1 / 8 (187 g) were added to the reaction mixture and heated and stirred at ambient temperature of 130°C. After cooling to room temperature, ethyl acetate (1.5 L), diethylenetriamine (53 mL), Celite (150 g), and purified white heron (150 g) were added and stirred at room temperature for 1 hour. The reaction mixture was filtered and washed with ethyl acetate (1.5 L). Water (1.5 L) was added to the filtrate and separated, and the organic layer was separated twice with 10% citric acid aqueous solution (1.5 L). Isopropyl alcohol (600 mL) was added to the residue and stirred at an ambient temperature of 80°C. Water (3 L) was added dropwise, and after cooling to room temperature, the reaction mixture was stirred under ice cooling. The mixture was filtered, and 229.4 g of the target compound was obtained as a brown powder. MS (ESI+) m / z 433.8 (M+1)

[0179] Synthesis Example 2 Synthesis of ethyl(2R,6R)-1-(5-amino-3-iodo-2-pyridyl)-2,6-dimethylpiperidine-4-carbokillate (compound of formula (E)) Ethyl(2R,6R)-1-(3-iodo-5-nitropyridine-2-yl)-2,6-dimethylpiperidine-4-carbokillate (197 g) was mixed with ethanol (788 mL) and water (788 mL) and stirred at room temperature. Ammonium chloride (146 g) and reduced iron (127 g) were added sequentially and the mixture was heated and stirred at an ambient temperature of 70°C for 2 hours. Ethyl acetate (2364 mL) and Celite (197 g) were added to the reaction mixture and stirred. The mixture was filtered, washed with ethyl acetate (591 mL), and water (591 mL) was added. The mixture was separated and the organic layer was concentrated. Acetonitrile (788 mL) was added to the residue, and water (3940 mL) was added dropwise. The mixture was filtered, and 165 g of the target compound was obtained as a brown powder. MS (ESI+) m / z 403.9 (M+1)

[0180] Synthesis Example 3 Synthesis of 6-[(2R,6R)-4-ethoxycarbonyl-2,6dimethylpiperidine-1-yl]-5-iodopyridine-3-diazonium-tetrafluoroborate (compound of formula (F1)) A solution of ethyl (2R,6R)-1-(5-amino-3-iodo-2-pyridyl)-2,6-dimethyl-piperidine-4-carbochylate (73 g) in ethanol (584 mL) was stirred under ice cooling. Diethyl ether tetrafluoroborate complex (124 mL) and isoamyl nitrite (31 mL) were added sequentially, and the mixture was stirred under ice cooling for one hour. After adding diethoxymethane (1459 mL) to the reaction mixture, the reaction mixture was filtered to obtain 87.09 g of the target compound as a yellow powder.

[0181] Synthesis Example 4 Synthesis of ethyl-(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate (compound of formula (G)) 6-[(2R,6R)-4-ethoxycarbonyl-2,6dimethylpiperidine-1-yl]-5-iodopyridine-3-diazonium-tetrafluoroborate (52 g) and lithium tetrafluoroborate (49 g) were mixed with butyl acetate (416 mL) and cyclohexane (416 mL), and stirred at an ambient temperature of 100°C for 1 hour. After the reaction mixture was allowed to cool, ethyl acetate (520 mL) and 10% saturated sodium bicarbonate solution (520 mL) were added and the mixture was separated. The organic layer was concentrated to obtain 59.98 g of the target product as a brown oily substance.

[0182] Synthesis Example 5 Synthesis of (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid (compound of formula (A)) 10 g of ethyl-(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate was mixed with ethanol (41 mL), tetrahydrofuran (41 mL), and water (41 mL). 2.6 g of lithium hydroxide monohydrate was added and the mixture was stirred overnight at room temperature. 100 mL of aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was concentrated, and 60 mL of ethanol was added to the residue. The mixture was heated and stirred at an ambient temperature of 60°C, and 50 mL of water was added dropwise. After cooling to room temperature, the mixture was stirred under ice. The mixture was filtered, and 8.66 g of the target compound was obtained as a yellow powder. MS (ESI+) m / z 378.9 (M+1)

[0183] Synthesis Example 6 Synthesis of 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (compound of formula (IV)) 60 g of 5-chloro-1H-pyrrolo[2,3-b]pyridine (compound of formula (III)) and urea peroxide (55 g) were mixed with acetonitrile (600 mL) and stirred. Anhydrous trifluoroacetic acid (82 mL) was added dropwise under ice cooling, and the mixture was heated to room temperature and stirred for 1.5 hours. Potassium carbonate aqueous solution (prepared with potassium carbonate (108 g) and water (600 mL)), sodium thiosulfate aqueous solution (prepared with sodium thiosulfate pentahydrate (97 g) and water (600 mL)), and water (600 mL) were added sequentially to the reaction mixture. After stirring under ice cooling for 1 hour, the mixture was filtered to obtain 60.7 g of the target product as a gray powder.

[0184] Synthesis Example 7 Synthesis of 5-chloro-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (compound of formula (V)) 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (58 g) obtained in Synthesis Example 6 was mixed with acetonitrile (464 mL) and stirred. Dimethyl sulfate (47 g) was added to the reaction mixture and stirred under reflux for 2 hours. After cooling to room temperature, aqueous ammonium chloride solution (prepared with ammonium chloride (9.2 g) and water (580 mL)) and aqueous sodium cyanide solution (prepared with sodium cyanide (25 g) and water (174 mL)) were added sequentially to the reaction mixture. After stirring overnight at room temperature, aqueous sodium hydroxide solution (prepared with sodium hydroxide (13.8 g) and water (710 mL)) was added dropwise. After cooling on ice and stirring for 2 hours, the mixture was filtered to obtain 50.3 g of the target product as a gray powder.

[0185] Synthesis Example 8 Synthesis of 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (compound of formula (VI)) 5-chloro-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (48 g) obtained in Synthesis Example 7 was mixed with tetrahydrofuran (720 mL) and stirred. Potassium tert-butoxide (45 g) was added to the reaction mixture and stirred at room temperature for 0.5 hours. Then, methyl p-toluenesulfonate (75.5 g) was added dropwise under ice cooling. The mixture was heated to room temperature and stirred for 3 hours, after which water (580 mL) was added to the reaction mixture. After stirring under ice cooling for 2 hours, the mixture was filtered to obtain 50.1 g of the target product as a gray powder.

[0186] Synthesis Example 9 Synthesis of 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboximamide (compound of formula (VII)) 48 g of 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile obtained in Synthesis Example 8 was mixed with lithium bis(trimethylsilyl)amide (approximately 26% tetrahydrofuran solution, 290 mL) and stirred overnight at room temperature. Under ice cooling, aqueous hydrochloric acid solution (2 M, 380 mL) was added dropwise to the reaction mixture and stirred. Subsequently, aqueous sodium hydroxide solution (prepared with sodium hydroxide (30 g) and water (180 mL)) was added dropwise. After stirring under ice cooling for 1 hour, the mixture was filtered to obtain 45.0 g of the target product as a brown powder.

[0187] Synthesis Example 10 Synthesis of 5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridinemethanesulfonate (methanesulfonate of formula (II) compound, i.e., formula (IIA) compound) 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxyimidoamide (38 g) and 3-(dimethylamino)acrolein (20 g) obtained in Synthesis Example 9 were combined with isopropyl alcohol (114 mL). The mixture was stirred at an ambient temperature of 80°C for 5 hours. After cooling to room temperature, the reaction mixture was concentrated. Toluene (380 mL) and ethyl acetate (380 mL) were added to the residue. The organic layer was washed three times with aqueous hydrochloric acid solution (0.01 M, 380 mL), and the organic layer was dried over magnesium sulfate (28 g). After filtration, toluene (76 mL) and isopropyl alcohol (190 mL) were added to the organic layer, and then methanesulfonic acid (11.8 mL) was added dropwise under ice cooling. After stirring under ice cooling for 1 hour, the mixture was filtered to obtain 53.2 g of the target product as a yellow powder.

[0188] Synthesis Example 11: Synthesis of [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (compound of formula (I)). 21 g of phosphoric anhydride was mixed with 147 mL of methanesulfonic acid, then 24 g of (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid (compound of formula (A)) obtained in Synthesis Example 5 was added, and the mixture was stirred at room temperature for 0.5 hours. 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridinemethanesulfonate (15 g, compound (IIA)) obtained in Synthesis Example 10 was added to the reaction mixture, and the mixture was heated and stirred at an ambient temperature of 70°C. After 6 hours, the mixture was allowed to cool at room temperature, and dichloromethane (75 mL) was added to the reaction mixture. Under ice cooling, the reaction mixture was added dropwise to water (600 mL). After stirring at room temperature for 1 hour, the mixture was separated. The organic layer was concentrated, and acetonitrile (75 mL) and water (30 mL) were added to the resulting residue, and the slurry was stirred at room temperature. The mixture was filtered to obtain 22.3 g of the target product as a pale yellow powder.

[0189] Synthesis Example 11A: Synthesis of [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (formula (I) compound). 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine (formula (IIA) compound) obtained in Synthesis Example 10 and (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid (formula (A) compound) obtained in Synthesis Example 5 were combined with dichloromethane (500 mL). Subsequently, trifluoromethanesulfonic acid (58.5 mL) and trifluoroanhydride (91.95 mL) were added, and the mixture was heated and stirred at an ambient temperature of 40°C. After 23 hours, water (2000 mL) was added dropwise to the reaction mixture under ice cooling. After liquid-liquid separation, the organic layer was concentrated, and acetonitrile (250 mL) and water (100 mL) were added to the resulting residue. The slurry was stirred at room temperature. The mixture was filtered, and 59.88 g of the target product was obtained as a pale yellow powder.

[0190] Synthesis Example 12 Synthesis of type I crystals of [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone monophosphate (monophosphate of formula (I) compound, i.e., formula (IA) compound) Synthesis of type I crystals of [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (22 g) obtained in Synthesis Example 11 was mixed with acetone (89 mL) and stirred. Under reflux, phosphoric acid (6.38 g) was added dropwise to the reaction mixture. The mixture was allowed to cool at room temperature and stirred for 5 hours. It was filtered, yielding 22.3 g of the target product as a pale yellow powder. MS (ESI+) m / z 604.9, melting point 214–215°C.

[0191] Figure 1 shows the TG and DTA measurements of the type I crystal of the monophosphate (monophosphate) of the compound of formula (I) obtained in synthesis example 12. An endothermic peak was observed at 214.8°C.

[0192] Figure 2 shows the powder X-ray diffraction data of the type I crystal of the monophosphate (monophosphate) of the compound of formula (I) obtained in synthesis example 12. Major peaks were observed at 2θ values ​​of 12.3°±0.2°, 16.2°±0.2°, 17.9°±0.2°, 19.1°±0.2°, 20.7°±0.2°, 22.0°±0.2°, 23.5°±0.2°, 25.6°±0.2°, and 26.9°±0.2°, particularly at 12.3°±0.2°, 19.1°±0.2°, 22.0°±0.2°, 25.6°±0.2°, and 26.9°±0.2°.

[0193] Synthesis Example 13 Grinding of the monophosphate of compound (I) (i.e., compound (IA)) The monophosphate (33.3 g) of compound (I) obtained in Synthesis Example 12 was finely ground using a jet mill to obtain 31.9 g of the ground monophosphate.

[0194] Synthesis Example 14 Synthesis of 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (30 g) in diethyl ether (1.4 L), m-chloroperbenzoic acid (94 g) was added in three parts, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the resulting yellowish-green filtrate was suspended in water (0.72 L). Then, 23% (w / v) potassium carbonate aqueous solution (0.31 kg) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the resulting filtrate was dried to obtain 25 g of the target compound as a grayish-brown solid.

[0195] Synthesis Example 15 Synthesis of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine To a suspension of 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (2.6 g) obtained in Synthesis Example 14 in acetonitrile (80 mL), m-chlorobenzoic acid (2.4 g) was added and stirred at room temperature for 30 minutes, then dimethyl sulfate (1.5 mL) was added and stirred at ambient temperature of 75°C for 20 hours. After the reaction mixture was allowed to cool, potassium carbonate (11 g), 1,2,3-triazole (3.2 g), and acetonitrile (60 mL) were added sequentially and stirred at ambient temperature of 60°C for 6 hours. After the reaction mixture was allowed to cool, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was purified by column chromatography to obtain a crude, pink solid residue. The residue was slurry-washed with ethyl acetate (10 mL) to obtain 1.6 g of the target compound as a pink solid.

[0196] Synthesis Example 16 Synthesis of 1-benzoyl-6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine To a solution of ice-cooled benzoyl bromide (3.5 mL) in toluene (60 mL), premixed bis(trimethylsilyl)amine (2.9 mL), 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (2.0 g) obtained in Synthesis Example 14, and a suspension in toluene (60 mL) were added and the mixture was stirred at room temperature for 2 hours. After adding saturated sodium bicarbonate solution to the reaction mixture, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated saline solution, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 1.7 g of the target compound as a white solid.

[0197] Synthesis Example 17 Synthesis of 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine 3.9 g of 1-benzoyl-6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine obtained in Synthesis Example 16 was mixed with tetrahydrofuran (38 mL) and methanol (76 mL) and 12 mL of aqueous sodium hydroxide solution was added, 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. After washing the organic phase with saturated brine, it was dried over magnesium sulfate, and the solvent was removed by vacuum distillation to obtain 2.7 g of the target compound as a pale yellow solid.

[0198] Synthesis Example 18 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) obtained in Synthesis Example 17 in N,N-dimethylformamide (10 mL) is mixed with di-tert-butyl dicarbonate (hereinafter referred to as "Boc ２ 1.5 mL of (O), 1.8 mL of triethylamine, and 53 mg of 4-dimethylaminopyridine (hereinafter referred to as "DMAP") were added sequentially, and the mixture was stirred overnight at room temperature. The reaction mixture was purified by direct column chromatography to obtain 1.4 g of the target compound as a colorless oily substance.

[0199] Synthesis Example 19 Synthesis of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine To a solution of tert-butyl 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.4 g) obtained in Synthesis Example 18 in dimethyl sulfoxide (8.3 mL), tetrakis(triphenylphosphine)palladium (0) (0.96 g), lithium chloride (0.53 g), copper(I) chloride (82 mg), and 2-(tributylstannyl)pyrimidine (1.7 g) were sequentially added, and the mixture was stirred overnight at an ambient temperature of 80°C. After the reaction mixture cooled, it was purified by direct column chromatography, followed by reversed-phase column chromatography (H ２ By further purification using O / MeOH, 0.45 g of the target compound was obtained as a pale yellow solid.

[0200] Synthesis Example 20 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 sequentially added 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 and stirred at an ambient temperature of 145°C for 15 hours. After the reaction mixture was allowed to cool, it was neutralized with saturated sodium bicarbonate solution. Next, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, then with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 4.6 g of the target compound as a colorless oily substance.

[0201] Synthesis Example 21 Synthesis of tert-butyl (7R,9R)-7,9-dimethyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate This compound was synthesized according to the method of Feringa et al. (Org. Biomol. Chem., 2008, Vol. 6, pp. 3464-3466). To a solution of tert-butyl (7R)-7-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (15 g) obtained in Synthesis Example 20 in diethyl ether (0.16 L), tetramethylethylenediamine (hereinafter referred to as "TMEDA") (13 mL) was added. After cooling the reaction mixture to -78°C in a dry ice acetone bath, sec-butyllithium hexane solution (1.22 M, 72 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Next, a solution of methyl iodide (7.3 mL) in diethyl ether (15 mL) was added dropwise, and the mixture was stirred at -78°C for 1 hour, followed by stirring at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography to obtain 8.5 g of the target compound (trans isomer:cis isomer = 10:1) as a white solid. Specific rotation [α] Ｄ ２１ = +4.79° (c=1.0, chloroform)

[0202] Synthesis Example 22 Synthesis of tert-butyl (2R,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate A solution of tert-butyl (7R,9R)-7,9-dimethyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (12 g) obtained in Synthesis Example 21 is dissolved in acetone (0.61 L) and p-toluenesulfonic acid monohydrate (hereinafter referred to as "PTSA·H") ２ 9.1 g of (O) was added and the mixture was stirred at room temperature for 1.5 hours. After cooling the reaction mixture with ice, an aqueous solution (69 g) of sodium carbonate (6.3 g) was added to neutralize it, and the reaction solvent was removed by vacuum distillation. The resulting residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was removed by vacuum distillation. 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.

[0203] Synthesis Example 23 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) obtained in Synthesis Example 22, tert-butyl alcohol (47 mL), and 1,2-dimethoxyethane (0.19 L) was mixed with toluenesulfonylmethyl isocyanide (hereinafter referred to as "TosMIC") (12 g). After cooling the reaction mixture on ice, tert-butoxypotassium (13 g) was added, and the mixture was stirred at the same temperature for 30 minutes, then stirred at room temperature for 15 hours. After cooling the reaction mixture on ice, it was diluted with water, and the reaction solvent was removed by vacuum distillation. Extraction was performed with ethyl acetate, the organic phase was washed with water, then with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 5.4 g of the target compound as a pale yellow solid.

[0204] Synthesis Example 24 Synthesis Step 1 of Ethyl (2R,6R)-2,6-dimethylpiperidine-4-carboxylate Potassium hydroxide (18 g) was added to a mixed solution of tert-butyl (2R,6R)-4-cyano-2,6-dimethylpiperidine-1-carboxylate (13 g) obtained in Synthesis Example 23 with ethanol (0.11 L) and water (0.11 L), and the mixture was heated under reflux and stirred at an ambient temperature of 95°C for 20 hours. After the reaction mixture was allowed to cool, it was diluted with water and neutralized with a 20% (w / v) aqueous citric acid solution to a pH of 5. Extraction was performed with ethyl acetate, the organic phase was washed with water, then with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a residue (14 g) as a white solid. Step 2 The residue (13 g) obtained in Step 1 was dissolved in hydrochloric acid ethanol solution (2.0 M, 0.68 L) and heated under reflux and stirred at an ambient temperature of 120°C for 30 hours. After the reaction mixture was allowed to cool, the reaction solvent was removed by distillation under reduced pressure. After cooling the obtained residue with ice, sodium hydroxide aqueous solution (2.0 M) was added to adjust the pH to 13. Extraction was performed with chloroform, the organic phase was washed with saturated saline solution, dried with magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 8.9 g of the target compound as a yellow oily substance. Specific rotation [α] Ｄ ２０ = -16.66° (c = 1.0, chloroform)

[0205] Synthesis Example 25 Synthesis of ethyl (2R,6R)-1-(5-fluoro-3-nitropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate To a solution of ethyl (2R,6R)-2,6-dimethylpiperidine-4-carboxylate (2.2 g) obtained in Synthesis Example 24 in dimethyl sulfoxide (24 mL), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA") (4.0 mL) and 2,5-difluoro-3-nitropyridine (2.1 g) were sequentially added, and the mixture was stirred at an ambient temperature of 140°C for 3 hours. After the reaction mixture was allowed to cool, it was purified by direct column chromatography to obtain 2.9 g of the target compound as an orange oily substance.

[0206] Synthesis Example 26 Synthesis of Ethyl (2R,6R)-1-(3-amino-5-fluoropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate To a solution of ethyl (2R,6R)-1-(5-fluoro-3-nitropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate (3.4 g) obtained in Synthesis Example 25 in methanol (0.10 L), Pt / C type STD (Pt 3%) (1.1 g) was added and the mixture was stirred for 4 hours under a hydrogen gas atmosphere (5.0 atm) at an ambient temperature of 45°C. After the reaction mixture was allowed to cool, it was filtered by Celite and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography to obtain 3.0 g of the target compound as a white solid.

[0207] Synthesis Example 27 Synthesis of Ethyl (2R,6R)-1-(5-Fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate To a solution of ethyl (2R,6R)-1-(3-amino-5-fluoropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate (8.0 g) obtained in Synthesis Example 26 in diiodomethane (80 mL), isoamyl nitrite (6.4 mL) was added and the mixture was stirred at ambient temperature of 80°C for 7 hours. After the reaction mixture was allowed to cool, it was purified by direct column chromatography to obtain 4.5 g of the target compound as a pale yellow oily substance.

[0208] Synthesis Example 28 Synthesis of (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid Ethyl (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate (4.5 g) obtained in Synthesis Example 27 was mixed with tetrahydrofuran (55 mL), methanol (22 mL), and water (33 mL) to which lithium hydroxide monohydrate (1.2 g) was added and stirred overnight at room temperature. After cooling the reaction mixture with ice, hydrochloric acid aqueous solution (1.0 M) was added to adjust the pH to 2. Extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was purified by column chromatography to obtain 4.1 g of the target compound as a white solid.

[0209] Synthesis Example 29: Step 1 of the synthesis of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone. To a solution of (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid (0.12 g) obtained in Synthesis Example 28 in dichloromethane (2.0 mL), N,N-dimethylformamide (2.5 μL) and oxalyl chloride (35 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a yellow amorphous substance. Step 2: To a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (70 mg) obtained in Synthesis Example 15 in 1,2-dichloroethane (2.0 mL), aluminum trichloride (0.21 g) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale yellow amorphous solution of 1,2-dichloroethane (4.0 mL) obtained in Step 1 was added dropwise to the reaction mixture and the mixture was stirred at ambient temperature of 50°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 0.17 g of the target compound as a white solid.

[0210] Synthesis Example 30 Synthesis of [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole- To a solution of 30 mg of 2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone in 0.50 mL of N,N-dimethylformamide, potassium carbonate (21 mg) and (2-bromoethoxy)(tert-butyl)dimethylsilane (37 mg) were sequentially added, and the mixture was stirred at 50°C for 1 hour. Another 37 mg of 2-bromoethoxy-tert-butyldimethylsilane (37 mg) was added, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture cooled, it was purified by direct column chromatography to obtain 42 mg of the target compound as a colorless oily substance.

[0211] Synthesis Example 31: Synthesis of tert-butyl 3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-carboxylate obtained in Synthesis Example 29: [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (45 mg) obtained in Synthesis Example 29, in a solution of N,N-dimethylformamide (1.0 mL), potassium carbonate (27 mg), tert-butyl 3-iodoazetidine-1-carboxylate (0.11 g) was added sequentially, and the mixture was stirred at ambient temperature of 100°C for 10 hours. After the reaction mixture cooled, direct reverse-phase column chromatography (H) was performed. ２ The target compound was purified using O / MeOH, yielding 59 mg of the compound as a light brown solid.

[0212] Synthesis Example 32: Synthesis Step 1 of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone. 0.10 g of 1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (synthesized according to WO2018 / 119036) was dissolved in 2.5 mL of dichloromethane. 2.4 μL of N,N-dimethylformamide and 33 μL of oxalyl chloride were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a pale yellow solid. Step 2: To a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (60 mg) obtained in Synthesis Example 15 in 1,2-dichloroethane (2.5 mL), aluminum trichloride (0.18 g) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale yellow solid solution of 1,2-dichloroethane (2.5 mL) obtained in Step 1 was added dropwise to the reaction mixture and the mixture was stirred at an ambient temperature of 75°C for 3 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was slurry-washed with methanol to obtain 0.13 g of the target compound as a pale brown solid.

[0213] Synthesis Example 33: Step 1 of the synthesis of [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone. To a solution of (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid (0.18 g) obtained in Synthesis Example 28 in dichloromethane (3.0 mL), N,N-dimethylformamide (3.6 μL) and oxalyl chloride (59 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a yellow amorphous substance. Step 2: To a solution of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.10 g) obtained in Synthesis Example 19 in 1,2-dichloroethane (3.0 mL), aluminum trichloride (0.29 g) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the yellow amorphous 1,2-dichloroethane (3.0 mL) solution obtained in Step 1 was added dropwise to the reaction mixture and the mixture was stirred at an ambient temperature of 50°C for 2 hours. The mixture was then stirred overnight at an ambient temperature of 70°C. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 0.10 g of the target compound as a white solid.

[0214] Synthesis Example 34: Synthesis of [1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 33: [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone obtained in Synthesis Example 33 To a solution of 30 mg of lol[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone in N,N-dimethylformamide (0.50 mL), potassium carbonate (35 mg) and (3-bromopropoxy)(tert-butyl)dimethylsilane (64 mg) were sequentially added, and the mixture was stirred at an ambient temperature of 50°C for 3 hours. After the reaction mixture cooled, it was purified by direct column chromatography to obtain 47 mg of the target compound as a colorless oily substance.

[0215] Synthesis Example 35: Synthesis Step 1 of [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone. To a solution of 1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.15 g) (synthesized according to WO2018 / 119036) in dichloromethane (3.0 mL), N,N-dimethylformamide (3.6 μL) and oxalyl chloride (49 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a pale yellow solid. Step 2: To a solution of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine (90 mg) obtained in Synthesis Example 19 in 1,2-dichloroethane (2.0 mL), aluminum trichloride (0.26 g) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale yellow solid solution of 1,2-dichloroethane (2.0 mL) obtained in Step 1 was added dropwise to the reaction mixture and the mixture was stirred at an ambient temperature of 75°C for 4 hours. Further heating and reflux stirring at an ambient temperature of 100°C for 2 hours was carried out. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed twice with aqueous sodium hydroxide solution (2.0 M), then with saturated sodium bicarbonate solution, and finally with saturated brine. After drying with magnesium sulfate, the solvent was removed by vacuum distillation. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was suspended in methanol and filtered to obtain 46 mg of the target compound as a pale yellow solid.

[0216] Synthesis Example 36 Synthesis of 1,1-Dioxotetrahydro-2H-thiopyran-4-ylmethanesulfonate 0.20 g of 4-hydroxytetrahydro-2H-thiopyran-1,1-dioxide was dissolved in 3.3 mL of dichloromethane, to which 0.37 mL of triethylamine and 0.15 mL of methanesulfonyl chloride were sequentially added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by direct column chromatography to obtain 0.28 g of the target compound as a white solid.

[0217] Synthesis Example 37 Synthesis of Oxan-4-Ilmethanesulfonate To a solution of oxan-4-ol (0.20 g) in dichloromethane (4.8 mL), triethylamine (0.54 mL) and methanesulfonyl chloride (0.22 mL) were sequentially added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by direct column chromatography to obtain 0.34 g of the target compound as a white solid.

[0218] Synthesis Example 38 Synthesis of (3R)-oxolan-3-ylmethanesulfonate 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 sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by direct column chromatography to obtain 0.36 g of the target compound as a pale yellow oily substance.

[0219] Synthesis Example 39 Synthesis of (3S)-oxolane-3-ylmethanesulfonate To a solution of (3S)-oxolane-3-ol (0.30 g) in dichloromethane (8.5 mL), triethylamine (0.94 mL) and methanesulfonyl chloride (0.39 mL) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by direct column chromatography to obtain 0.40 g of the target compound as a pale yellow oily substance.

[0220] Synthesis Example 40 Synthesis Step 1 of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone 1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (65 mg) (synthesized according to WO2018 / 119036) was dissolved 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 mixture was removed by distillation under reduced pressure to obtain a light brown solid. Step 2: To a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (40 mg) obtained in Synthesis Example 15 in 1,2-dichloroethane (2.5 mL), aluminum trichloride (0.12 g) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the solution of the light brown solid 1,2-dichloroethane (2.5 mL) obtained in Step 1 was added dropwise to the reaction mixture and the mixture was stirred at an ambient temperature of 75°C for 4 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was slurry-washed with ethyl acetate and methanol to obtain 0.062 g of the target compound as a light brown solid.

[0221] Synthesis Example 41 Synthesis Step 1 of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(pyrazolo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone 1-(pyrazolo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (65 mg) (synthesized according to WO2018 / 119036) was dissolved in dichloromethane (1.5 mL) and tetrahydrofuran (1.5 mL). N,N-dimethylformamide (1.7 μL) and oxalyl chloride (23 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a light brown oily substance. Step 2: Aluminum trichloride (120 mg) was added to a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (40 mg) obtained in Synthesis Example 15 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 oily substance 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 ambient temperature of 75°C for 5 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was slurry-washed with methanol to obtain 0.081 g of the target compound as a light brown solid.

[0222] Synthesis Example 42: Synthesis Step 1 of [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone. 100 mg of 1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (synthesized according to WO2018 / 119036) was dissolved in dichloromethane (1.5 mL) and tetralofuran (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 mixture was removed by distillation under reduced pressure to obtain a light brown solid. Step 2: Aluminum trichloride (210 mg) was added to a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (70 mg) obtained in Synthesis Example 15 in 1,2-dichloroethane (3.1 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, the light brown solid solution of 1,2-dichloroethane (2.5 mL) obtained in Step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 75°C for 5 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was slurry washed with methanol to obtain a crude residue. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry washed with methanol to obtain 120 mg of the target compound as a white solid.

[0223] Synthesis Example 43 Synthesis of 5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine To a solution of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine obtained in Synthesis Example 19 in N,N-dimethylformamide (3.0 mL), potassium carbonate (930 mg) and methyl iodide (420 μL) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Further, methyl iodide (250 μL) was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with water, and extraction was performed with ethyl acetate. After washing the organic phase with saturated brine, it was dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 130 mg of the target compound as a pale yellow solid.

[0224] Synthesis Example 44: Synthesis Step 1 of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(1-methoxyisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone. 120 mg of 1-(1-methoxyisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (synthesized according to WO2018 / 119036) was dissolved 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 mixture was removed by distillation under reduced pressure to obtain a light brown solid. Step 2: Aluminum trichloride (200 mg) was added to a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (68 mg) obtained in Synthesis Example 15 in 1,2-dichloroethane (3.0 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale brown solid solution of 1,2-dichloroethane (2.5 mL) obtained in Step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 75°C for 6 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was slurry washed with ethyl acetate and methanol to obtain a crudely purified residue. The obtained residue was purified by column chromatography to obtain 68 mg of the target compound as a pale yellow solid.

[0225] Synthesis Example 45 Synthesis of 9-bromo-4H-quinoridine-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-methylpyridine in tetrahydrofuran (3.4 g, 40 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Subsequently, diethyl ethoxymethylene malonate (4.0 g) was added dropwise, and the mixture was heated to -20°C in a dry ice 70% water methanol bath and stirred at the same temperature for 3 hours. After adding aqueous ammonium chloride solution to the reaction mixture, extraction was performed with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography to obtain 4.3 g of a yellow oily substance. Step 2 Polyphosphate (25 g) was added to the yellow oily substance obtained in Step 1, and the mixture was stirred at an ambient temperature of 140°C for 6 hours. The reaction mixture was cooled on 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 removed under reduced pressure. The resulting residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry-washed with a small amount of ice-cooled ethyl acetate to obtain 1.5 g of the target compound as a yellow solid.

[0226] Synthesis Example 46 Synthesis of Ethyl 1-(4-oxo-4H-quinoridine-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate Step 1 To a solution of palladium (1-phenylallyl) chloride dimer (57 mg) in 1,4-dioxane (10 mL), 4-{2-[di(adamantan-1-yl)phosphanyl]phenyl}morpholine (100 mg) was added and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. To the reaction mixture, 9-bromo-4H-quinoridine-4-one (500 mg) obtained in Synthesis Example 45, sodium tert-butoxide (420 mg), and hydrazine hydrate (220 mg) were sequentially added and the mixture was stirred at ambient temperature of 50°C under an argon atmosphere for 4 hours. The reaction mixture was filtered through Celite, washed with tetrahydrofuran, and the mother liquor was concentrated to obtain a brown solid. Step 2: Triethylamine (0.62 mL) and ethyl (2Z)-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate were added to the ethanol (10 mL) suspension of the brown solid obtained in Step 1, and the mixture was stirred at an ambient temperature of 80°C for 12 hours. After the reaction mixture cooled, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry-washed with a small amount of diethyl ether to obtain 130 mg of the target compound as an orange solid.

[0227] Synthesis Example 47 Synthesis of 1-(4-oxo-4H-quinoridine-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid To a solution of ethyl 1-(4-oxo-4H-quinoridine-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (130 mg) obtained in Synthesis Example 46 in tetrahydrofuran (3.0 mL), water (1.5 mL) and lithium hydroxide monohydrate (38 mg) were added and the mixture was stirred at room temperature for 2 hours. Hydrochloric acid aqueous solution (1.0 M) was added to the reaction mixture to make the pH = 5. The solvent in the reaction mixture was removed by reduced pressure. The obtained residue was purified by reverse-phase column chromatography to obtain 120 mg of the target compound as a yellow solid.

[0228] Synthesis Example 48 Step 1 of the synthesis of 9-{4-[5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one To a solution of 1-(4-oxo-4H-quinoridine-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg) obtained in Synthesis Example 47 in dichloromethane (2.5 mL) and a suspension in tetrahydrofuran (1.5 mL), N,N-dimethylformamide (2.7 μL) and oxalyl chloride (39 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a brown solid. Step 2: To a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (70 mg) obtained in Synthesis Example 15 in 1,2-dichloroethane (2.5 mL), aluminum trichloride (0.21 g) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the suspension of the brown solid 1,2-dichloroethane (2.5 mL) obtained in Step 1 was added dropwise to the reaction mixture and the mixture was stirred at ambient temperature of 75°C for 3 hours. Aluminum trichloride (100 mg) was added to the reaction mixture and the mixture was stirred at the same temperature for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was slurry-washed with methanol to obtain 120 mg of the target compound as a yellowish-brown solid.

[0229] Synthesis Example 49 Synthesis Step 1 of 5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine A solution of 5-chloro-6-fluoro-1H-pyrrolo[2,3-b]pyridine (300 mg) (synthesized according to WO2021 / 062316) in tetrahydrofuran (8.7 mL) was cooled on ice, then sodium hydride (100 mg) was added and the mixture was stirred at the same temperature for 5 minutes. Methyl iodide (0.18 mL) was added to the reaction mixture and the mixture was stirred at the same temperature for 30 minutes, then the temperature was raised to room temperature and the mixture was stirred for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was analyzed by reverse-phase column chromatography (H ２By purification using O / MeOH, 290 mg of a white solid was obtained. Step 2 Potassium carbonate (100 mg) was added to a methanol (1.2 mL) suspension of the white solid obtained in Step 1, and the mixture was stirred overnight at an ambient temperature of 50°C. The reaction mixture was purified by direct column chromatography to obtain 16 mg of the target compound as a white solid.

[0230] Synthesis Example 50 Synthesis of Ethyl (2RS,4RS)-2-methylpiperidine-4-carboxylate Step 1 Dioxoplatinum hydrate (0.37 g) was added to a suspension of 2-chloro-6-methylpyridine-4-carboxylic acid (10 g) in acetic acid (50 mL) and stirred at room temperature for 30 minutes. The mixture was stirred under a hydrogen gas atmosphere (0.4 MPa) at an ambient temperature of 50°C for 8 hours and at room temperature for 12 hours. The mixture was further stirred at an ambient temperature of 60°C for 8 hours. After cooling the reaction mixture on ice, it was diluted with methanol and filtered by Celite, and the solvent was removed by distillation under reduced pressure. The obtained 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 ambient temperature of 95°C for 42 hours. The solvent in the reaction mixture was removed by vacuum distillation, and the resulting residue was diluted with ethyl acetate. The residue was neutralized with 2.0 M aqueous sodium hydroxide solution under ice cooling, and then extracted with ethyl acetate. After washing the organic phase with saturated brine, it was dried over magnesium sulfate, and the solvent was removed by vacuum distillation to obtain the target compound as a pale yellow oily substance (3.3 g).

[0231] Synthesis Example 51 Synthesis of Ethyl (2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-carboxylate To a solution of ethyl 2-methylpiperidine-4-carboxylate (cis-thracemic) (100 mg) in dimethyl sulfoxide (1.0 mL), DIPEA (0.20 mL) and 5-bromo-4-chloropyrimidine (140 mg) were sequentially added, and the mixture was stirred at an ambient temperature of 140°C for 90 minutes. After the reaction mixture was allowed to cool, it was purified by direct column chromatography to obtain 110 mg of the target compound as a yellow oily substance.

[0232] Synthesis Example 52 Synthesis of (2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-carboxylic acid Ethyl 1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-carboxylate (cis-thracemic) (110 mg) was mixed with tetrahydrofuran (2.5 mL) and water (2.5 mL), to which lithium hydroxide monohydrate (36 mg) was added and the mixture was stirred at room temperature for 2 hours. Hydrochloric acid aqueous solution (1.0 M) was added to the reaction mixture to make the pH 4. Extraction was performed with ethyl acetate, the organic phase was washed with saturated saline solution, dried with magnesium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was slurry washed with a mixture of ethyl acetate and diethyl ether to obtain 90 mg of the target compound as a white solid.

[0233] Synthesis Example 53 Synthesis Step 1 of (2RS,4RS)-[1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl][5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone 1. To a solution of 1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-carboxylic acid (cisracemic) (45 mg) in dichloromethane (2.5 mL), N,N-dimethylformamide (1.1 μL) and oxalyl chloride (15 μL) were added and the mixture was stirred at room temperature for 30 minutes. A white solid was obtained by distilling off the reaction mixture under reduced pressure. Step 2: Aluminum trichloride (91 mg) was added to a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) obtained in Synthesis Example 15 in 1,2-dichloroethane (2.5 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, the suspension of the white solid 1,2-dichloroethane (2.5 mL) obtained in Step 1 was added dropwise to the reaction mixture, and the mixture was stirred at ambient temperature of 50°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 42 mg of the target compound as a white solid.

[0234] Synthesis Example 54 Synthesis of (2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-carboxylic acid To a solution of ethyl (2RS,4RS)-2-methylpiperidine-4-carboxylate (200 mg) obtained in Synthesis Example 50 with dimethyl sulfoxide (2.0 mL), DIPEA (0.40 mL) and 1,4-difluoro-2-nitrobenzene (270 mg) were sequentially added and stirred under an argon atmosphere at an ambient temperature of 50°C for 60 minutes. Further stirring was carried out at an ambient temperature of 120°C for 6 hours. After the reaction mixture was allowed to cool, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was purified by column chromatography to obtain 240 mg of the target compound as a yellow oil. To a mixed solution of the resulting yellow oily substance (2.5 mL) and water (2.5 mL), lithium hydroxide monohydrate (82 mg) was added and the mixture was stirred at room temperature for 3 hours. Further, lithium hydroxide monohydrate (65 mg) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hour. Further, lithium hydroxide monohydrate (82 mg) was added to the reaction mixture and the mixture was stirred at room temperature for 2 hours. Finally, lithium hydroxide monohydrate (98 mg) was added to the reaction mixture and the mixture was stirred overnight at room temperature. Hydrochloric acid aqueous solution (1.0 M) was added to the reaction mixture to adjust the pH to 3. Extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried with sodium sulfate, and the solvent was removed under reduced pressure to obtain 210 mg of the target compound as a yellow solid.

[0235] Synthesis Example 55: Step 1 of the synthesis of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone. To a solution of (2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-carboxylic acid (100 mg) obtained in Synthesis Example 54 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 mixture was removed by distillation under reduced pressure to obtain the residue. Step 2: To a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) obtained in Synthesis Example 15 in 1,2-dichloroethane (1.0 mL), aluminum trichloride (180 mg) was added 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 under an argon atmosphere at an ambient temperature of 50°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry washed with a mixture of ethyl acetate and hexane to obtain 71 mg of the target compound as a yellow solid.

[0236] Synthesis Example 56 Synthesis of [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone (30 mg) obtained in Synthesis Example 55 was dissolved in N,N-dimethylformamide (0.50 mL) to which potassium carbonate (25 mg) and methyl iodide (11 μL) were sequentially added and stirred for 90 minutes at an ambient temperature of 50°C under an argon atmosphere. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed.２ The target compound was purified using O / MeOH, yielding 27 mg of the compound as a yellow solid.

[0237] Synthesis Example 57 Synthesis of Methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate Step 1 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 at an ambient temperature of 100°C for 6 hours under an argon atmosphere. After the reaction mixture was allowed to cool, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was slurry-washed with a mixed solvent of diethyl ether and hexane to obtain 950 mg of a white solid. Step 2 2. Sodium hydroxide aqueous 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 ambient temperature of 100°C. After the reaction mixture was cooled on ice, hydrochloric acid aqueous solution (1.0 M) was added to adjust the pH to 3, and the precipitated solid was filtered to obtain 710 mg of a white solid. Step 3: To a methanol (25 mL) solution of the white solid (500 mg) obtained in Step 2, a hexane solution of 10% trimethylsilyldiazomethane (7.9 mL) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 4 hours. 10% trimethylsilyldiazomethane (5.3 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Acetic acid (0.72 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After adding saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 310 mg of the target compound as a white solid.

[0238] Synthesis Example 58 Synthesis Step 1 of (2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carboxylic acid To a solution of ethyl (2RS,4RS)-2-methylpiperidine-4-carboxylate (3000 mg) obtained in Synthesis Example 50 in dimethyl sulfoxide (35 mL), DIPEA (6.0 mL) and 3-chloro-2,5-difluoropyridine (5.5 mL) were sequentially added, and the mixture was stirred at an ambient temperature of 140°C for 18 hours. After the reaction mixture was allowed to cool, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 2.9 g of ethyl ester as a pale yellow oil. Step 2: A mixture of tetrahydrofuran (30 mL) and water (30 mL) containing the pale yellow oily substance (2.9 g) obtained in Step 1 was mixed with lithium hydroxide monohydrate (1.2 g) and stirred at room temperature for 2 hours. Hydrochloric acid aqueous solution (1.0 M) was added to the reaction mixture to adjust the pH to 3. The mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. 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.

[0239] Synthesis Example 59 Synthesis Step 1 of 5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (cisracemic) Step 1 To a solution of (2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carboxylic acid (280 mg) obtained in Synthesis Example 58 in dichloromethane (10 mL), N,N-dimethylformamide (7.9 μL) and oxalyl chloride (130 μL) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a light brown oily substance. Step 2: Add aluminum trichloride (560 mg) to a solution of methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (180 mg) obtained in Synthesis Example 57 in 1,2-dichloroethane (10 mL), and stir at room temperature for 10 minutes. Subsequently, add a solution of the light brown oily substance obtained in Step 1 in 1,2-dichloroethane (10 mL) dropwise to the reaction mixture, and stir at ambient temperature of 70°C for 2 hours. After cooling the reaction mixture with ice, dilute with water, add aqueous hydrochloric acid (1.0 M) to adjust the pH to 3. Extract with ethyl acetate. Wash the organic phase with saturated brine, dry with magnesium sulfate, and remove the solvent under reduced pressure. The resulting residue was purified by column chromatography to obtain 110 mg of the target compound as a white solid.

[0240] Synthesis Example 60 Synthesis of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carbonyl}piperazine-1-carboxylate obtained in Synthesis Example 59 5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl To a solution of 40 mg of ]-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid in N,N-dimethylformamide (0.88 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate (HATU) (100 mg), DIPEA (76 μL), and tert-butylpiperazine-1-carboxylate (21 mg) were added, and the mixture was stirred at room temperature for 3 hours. A small amount of methanol was added to the reaction mixture, and reverse-phase column chromatography (H) was performed. ２ The target compound was purified using O / MeOH to obtain 41 mg of the compound as a white solid.

[0241] Synthesis Example 61 Synthesis Step 1 of (6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone Step 1 To a solution of (2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carboxylic acid (cis-thracemic mixture) (250 mg) obtained in Synthesis Example 58 in dichloromethane (10 mL), N,N-dimethylformamide (7.1 μL) and oxalyl chloride (110 μL) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a light brown oily substance. Step 2: Aluminum trichloride (500 mg) was added to a solution of 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (170 mg) obtained in Synthesis Example 17 in 1,2-dichloroethane (10 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of the light brown oily substance obtained in Step 1 in 1,2-dichloroethane (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 50°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 210 mg of the target compound as a white solid.

[0242] Synthesis Example 62 Synthesis of [6-(benzylsulfanyl)-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone obtained in Synthesis Example 61 (6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl] To a solution of 64 mg of [-2-methylpiperidine-4-yl]methanone in 2.6 mL of 1,4-dioxane, 15 mg of 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene, 91 μL of DIPEA, 31 μL of benzyl mercaptan, and 12 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were sequentially added, and the mixture was stirred under an argon atmosphere using a microwave at 110°C for 30 minutes. The reaction mixture was purified by direct column chromatography to obtain a yellow solid (68 mg). To a solution of the obtained yellow solid in 1.2 mL of N,N-dimethylformamide, potassium carbonate (53 mg) and methyl iodide (23 μL) were sequentially added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was purified by direct column chromatography to obtain 71 mg of the target compound as an orange oil.

[0243] Synthesis Example 63 Synthesis of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl}piperazine-1-carboxylate [6-(benzylsulfanyl)-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone (70 mg) obtained in Synthesis Example 62 was mixed with acetic acid (1.8 mL) and water (0.2 mL), to which N-chlorosuccinimide (51 mg) was added and stirred at room temperature for 1 hour. Further stirring was carried out at ambient temperature of 40°C for 2 hours. The reaction mixture was removed by vacuum distillation, and the resulting residue was added to ice-cooled saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a brown oily substance. To a solution of the obtained brown oily substance in tetrahydrofuran (1.0 mL), tert-butylpiperazine-1-carboxylate (47 mg) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by direct column chromatography to obtain 56 mg of the target compound as a white solid.

[0244] Example 1 [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole-2-yl] To a solution of 50 mg of )-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone in N,N-dimethylformamide (0.50 mL), potassium carbonate (30 mg) and 3-iodooxetane (0.12 g) were sequentially added, and the mixture was stirred at ambient temperature of 100°C for 10 hours. After the reaction mixture was allowed to cool, direct reverse-phase column chromatography (H) was performed. ２The target compound was purified by 0 / MeOH (O / MeOH) to obtain 44 mg as a white solid. MS (ESI+) m / z 636.1 (M+1)

[0245] Example 2 [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (20 mg) was added sequentially to a solution of N,N-dimethylformamide (0.50 mL) and potassium carbonate (14 mg) and methyl iodide (6.4 μL), and the mixture was stirred for 30 minutes at an ambient temperature of 50°C. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２ The target compound was purified by 0 / MeOH (O / MeOH) to obtain 19 mg as a white solid. MS (ESI+) m / z 594.0 (M+1) Specific rotation [α] Ｄ ２１ = +63.80° (c=1.0, chloroform)

[0246] Example 3 To a solution of {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}acetonitrile obtained in Synthesis Example 29, [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) obtained in N,N-dimethylformamide (0.50 mL), potassium carbonate (21 mg) and 2-bromoacetonitrile (19 mg) were sequentially added, and the mixture was stirred for 30 minutes at ambient temperature of 50°C. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２The target compound was purified using O / MeOH, yielding 32 mg as a light brown solid. MS (ESI+) m / z 619.1 (M+1)

[0247] Example 4 [5-chloro-1-(2-hydroxyethyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 30 [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-6 A mixture of (2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (42 mg) was mixed with methanol (2.5 mL) and dichloromethane (0.50 mL). Hydrochloric acid aqueous solution (1.0 M, 0.57 mL) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was neutralized with sodium hydroxide aqueous solution (1.0 M), diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 31 mg of the target compound as a white solid. MS (ESI+) m / z 624.0 (M+1)

[0248] Example 5 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-yl)ethane-1-one Step 1 Tert-butyl obtained in Synthesis Example 31 59 mg of 3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-carboxylate was dissolved in 1.0 mL of dichloromethane, to which 0.50 mL of trifluoroacetic acid was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and neutralized with 2.0 M aqueous sodium hydroxide solution to a pH of 8. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a pale yellow solid residue (77 mg). Step 2: The residue (77 mg) obtained in Step 1 was dissolved in tetrahydrofuran (1.5 mL), and DIPEA (69 μL) and acetyl chloride (7.1 μL) were added sequentially. The mixture was stirred at room temperature for 2 hours. After adding saturated sodium bicarbonate solution to the reaction mixture, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated saline solution, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The obtained 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)

[0249] Example 6 [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone obtained in Synthesis Example 32 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was added sequentially to a solution of N,N-dimethylformamide (0.50 mL) and potassium carbonate (31 mg) and methyl iodide (14 μL), and the mixture was stirred for 30 minutes at an ambient temperature of 50°C. After the reaction mixture cooled, it was diluted with water, and the precipitated solid was filtered off to obtain a light brown residue. The obtained residue was purified by column chromatography, followed by reversed-phase column chromatography (H ２ The target compound was re-purified using O / MeOH to obtain 21 mg as a white solid. MS (ESI+) m / z 541.1 (M+1)

[0250] Example 7 [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone obtained in Synthesis Example 32 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (35 mg) was added sequentially to a solution of N,N-dimethylformamide (0.50 mL) with potassium carbonate (28 mg) and ethyl iodide (16 μL), and the mixture was stirred for 30 minutes at an ambient temperature of 50°C. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２ The solution was purified using O / MeOH to obtain a crude residue. The residue was slurry-washed with methanol to obtain 37 mg of the target compound as a white solid. MS 555.1 (M+1)

[0251] Example 8 [5-chloro-1-propyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone obtained in Synthesis Example 32 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (35 mg) was added sequentially to a solution of N,N-dimethylformamide (0.50 mL) with potassium carbonate (28 mg) and 1-bromopropane (18 μL), and the mixture was stirred at ambient temperature of 50°C for 2 hours. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２ The target compound was purified by 0 / MeOH (O / MeOH) to obtain 32 mg as a white solid. MS (ESI+) m / z 569.1 (M+1)

[0252] Example 9 [5-chloro-1-(3-hydroxypropyl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 34 [1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-chloro- A mixture of 6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (47 mg) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) was mixed 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 sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was analyzed by reverse-phase column chromatography (H ２ The solution was purified using O / MeOH to obtain a crude residue. The obtained residue was recrystallized with ethyl acetate / n-hexane to obtain 26 mg of the target compound as a pale yellow solid. MS (ESI+) m / z 649.2 (M+1) Specific rotation [α]Ｄ ２０ = +30.36° (c=1.0, chloroform)

[0253] Example 10 [5-chloro-1-(oxetan-3-yl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 33 [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) obtained in Synthesis Example 33 was sequentially added to a solution of N,N-dimethylformamide (1.0 mL) with potassium carbonate (18 mg) and 3-iodooxetan (75 mg), and the mixture was stirred at ambient temperature of 100°C for 11 hours. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２ The crude residue was obtained by purification using O / MeOH, followed by further purification by column chromatography. The obtained residue was recrystallized with methanol / water to yield 18 mg of the target compound as a pale yellow solid. MS (ESI+) m / z 647.2 (M+1)

[0254] Example 11 [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 33 [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (22 mg) was added sequentially to a solution of N,N-dimethylformamide (0.50 mL) and potassium carbonate (26 mg) and methyl iodide (7.0 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly analyzed by reversed-phase column chromatography (H ２ The target compound was purified by O / MeOH (O / MeOH) and then again by column chromatography to obtain 15 mg of the target compound as a white solid. MS (ESI+) m / z 605.0 (M+1)

[0255] Example 12 [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone obtained in Synthesis Example 35 [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was added sequentially to a solution of N,N-dimethylformamide (1.0 mL) and potassium carbonate (51 mg) and methyl iodide (14 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then directly analyzed by reversed-phase column chromatography (H ２ The solution was purified using O / MeOH to obtain a crude residue. The resulting residue was recrystallized with ethyl acetate / n-hexane to obtain 31 mg of the target compound as a pale yellow solid. MS (ESI+) m / z 552.1 (M+1)

[0256] Example 13 [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone obtained in Synthesis Example 35 [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was added to a solution of N,N-dimethylformamide (1.0 mL), and potassium carbonate (51 mg) and ethyl iodide (18 μL) were added sequentially, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then directly analyzed by reverse-phase column chromatography (H ２ The compound was purified using O / MeOH to obtain a crude residue (25 mg). The obtained residue (25 mg) was recrystallized with ethyl acetate / n-hexane to obtain 19 mg of the target compound as a pale yellow solid. MS (ESI+) m / z 566.2 (M+1)

[0257] Example 14 [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) was added sequentially to a solution of N,N-dimethylformamide (1.0 mL) and potassium carbonate (36 mg) and ethyl iodide (12 μL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by direct reverse-phase column chromatography, followed by further purification by column chromatography to obtain 30 mg of the target compound as a white solid. MS (ESI+) m / z 608.2 (M+1)

[0258] Example 15 [5-chloro-1-(3-hydroxypropyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone Step 1 To a solution of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (25 mg) obtained in Synthesis Example 29 in N,N-dimethylformamide (1.0 mL), potassium carbonate (18 mg) and (3-bromopropoxy)(tert-butyl)dimethylsilane (33 mg) were sequentially added, and the mixture was stirred overnight at an ambient temperature of 50°C. After the reaction mixture cooled, direct reverse-phase column chromatography (H) was performed. ２The mixture was purified using O / MeOH to obtain 33 mg of a white solid. Step 2: The white solid (33 mg) obtained in Step 1 was mixed with tetrahydrofuran (2.0 mL) and methanol (2.0 mL), and 1.0 mL of aqueous hydrochloric acid (1.0 M) was added. The mixture was stirred overnight at room temperature. After neutralizing the reaction mixture with saturated sodium bicarbonate solution, extraction was performed with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The 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)

[0259] Example 16 [5-chloro-1-cyclopropyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b To a solution of 40 mg of pyridine-3-yl[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone in 1,2-dichloroethane (1.0 mL), 12 mg of cyclopropylboronic acid, 16 mg of 2,2'-bipyridine, 19 mg of copper(II) acetate, and 15 mg of sodium carbonate were added, and the mixture was stirred at an ambient temperature of 70°C for 5 hours. After the reaction mixture cooled, it was purified by direct column chromatography, followed by reverse-phase column chromatography (H ２ The crude residue was obtained by further purification using O / MeOH. The obtained residue was recrystallized with ethyl acetate / n-hexane to obtain 24 mg of the target compound as a white solid. MS (ESI+) m / z 620.0 (M+1)

[0260] Example 17 [5-chloro-1-isopropyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole-2-yl)- To a solution of 1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (19 mg) in N,N-dimethylformamide (1.0 mL), potassium carbonate (22 mg) and 2-bromopropane (9.0 μL) were sequentially added, and the mixture was stirred at ambient temperature of 100°C for 1.5 hours. After the reaction mixture cooled, direct reverse-phase column chromatography (H) was performed. ２ The target compound was purified by 0 / MeOH (O / MeOH) to obtain 18 mg as a white solid. MS (ESI+) m / z 622.1 (M+1)

[0261] Example 18 [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (42 mg) obtained in Synthesis Example 33 was dissolved in N,N-dimethylformamide (1.0 mL) to which potassium carbonate (49 mg) and ethyl iodide (17 μL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then directly analyzed by reverse-phase column chromatography (H ２ The target compound was purified by O / MeOH (O / MeOH) and then again by column chromatography to obtain 39 mg of the target compound as a white solid. MS (ESI+) m / z 619.1 (M+1)

[0262] Example 19 [5-chloro-1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo To a solution of [2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) in N,N-dimethylformamide (1.0 mL), potassium carbonate (36 mg) and 1,1-dioxotetrahydro-2H-thiopyran-4-ylmethanesulfonate (0.12 g) obtained in Synthesis Example 36 were sequentially added, and the mixture was stirred at ambient temperature of 100°C for 16 hours. After the reaction mixture was allowed to cool, direct reverse-phase column chromatography (H) was performed. ２ The residue was purified by (O / MeOH) to obtain a crude residue. The obtained residue was subjected to column chromatography, followed by reverse-phase column chromatography (H ２ By purification using O / MeOH, 11 mg of the target compound was obtained as a white solid. MS (ESI+) m / z 712.3 (M+1)

[0263] Example 20 Synthesis of [5-chloro-1-(oxan-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo To a solution of [2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (36 mg) in N,N-dimethylformamide (0.80 mL), potassium carbonate (42 mg) and oxan-4-ylmethanesulfonate (0.11 g) obtained in Synthesis Example 37 were sequentially added, and the mixture was stirred at an ambient temperature of 100°C for 12 hours. After the reaction mixture was allowed to cool, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was subjected to reverse-phase column chromatography (H ２ The target compound was purified using O / MeOH, yielding 24 mg as a pale yellow solid. MS (ESI+) m / z 664.2 (M+1)

[0264] Example 21 Synthesis of {5-chloro-1-[(3S)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo To a solution of [2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (36 mg) in N,N-dimethylformamide (0.80 mL), potassium carbonate (42 mg) and (3R)-oxolan-3-ylmethanesulfonate (0.10 g) obtained in Synthesis Example 38 were sequentially added, and the mixture was stirred at an ambient temperature of 100°C for 12 hours. After the reaction mixture was allowed to cool, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was subjected to reverse-phase column chromatography (H ２The target compound was purified using 0 / MeOH (O / MeOH) to obtain 30 mg as a white solid. MS (ESI+) m / z 650.2 (M+1)

[0265] Example 22 Synthesis of {5-chloro-1-[(3R)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone obtained in Synthesis Example 29 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo To a solution of [2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (36 mg) in N,N-dimethylformamide (0.80 mL), potassium carbonate (42 mg) and (3S)-oxolan-3-ylmethanesulfonate (0.10 g) obtained in Synthesis Example 39 were sequentially added, and the mixture was stirred at an ambient temperature of 100°C for 12 hours. After the reaction mixture was allowed to cool, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was subjected to reverse-phase column chromatography (H ２ By purification using O / MeOH, 30 mg of the target compound was obtained as a white solid. MS (ESI+) m / z 650.2 (M+1)

[0266] Example 23 Synthesis Step 1 of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Step 1 1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.055 g) (synthesized according to WO2018 / 119036) was dissolved in dichloromethane (2.5 mL), to which N,N-dimethylformamide (1.3 μL) and oxalyl chloride (17 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a brown oily substance. Step 2: 30 mg of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine obtained in Synthesis Example 15 was dissolved in 2.5 mL of 1,2-dichloroethane. Aluminum trichloride (91 mg) was added to the solution and stirred at room temperature for 10 minutes. Subsequently, a 2.5 mL solution of the brown oily substance obtained in Step 1, dissolved in 1,2-dichloroethane, was added dropwise to the reaction mixture. The mixture was stirred at an ambient temperature of 75°C for 4 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry-washed with ethyl acetate to obtain 0.018 g of the target compound as a yellowish-brown solid. MS (ESI+) m / z 526.1 (M+1)

[0267] Example 24 Synthesis of [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone obtained in Synthesis Example 40: Potassium carbonate (20 mg) and methyl iodide (9.0 μL) were sequentially added to a solution of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (25 mg) obtained in Synthesis Example 40 in N,N-dimethylformamide (0.50 mL), and the mixture was stirred for 15 minutes at ambient temperature of 50°C. After the reaction mixture cooled, it was diluted with water, and the precipitated solid was collected by filtration to obtain a crude purified residue. The obtained residue was slurry-washed with methanol to obtain 19 mg of the target compound as a white solid. MS (ESI+) m / z 529.1 (M+1)

[0268] Example 25 Synthesis of [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-c]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Potassium carbonate (40 mg) and 3-iodooxetane (80 mg) were sequentially added to a solution of 1-(thieno[2,3-c]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (30 mg) in N,N-dimethylformamide (1.0 mL), and the mixture was stirred at room temperature for 12 hours at an ambient temperature of 100°C. After the reaction mixture cooled, it was purified by direct column chromatography to obtain the crude purified residue. The resulting residue was slurry-washed with methanol to obtain 24 mg of the target compound as a pale yellow solid. MS (ESI+) m / z 571.1 (M+1)

[0269] Example 26 Synthesis of [5-chloro-1-propyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone To a solution of [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) obtained in Synthesis Example 35 in N,N-dimethylformamide (1.0 mL), potassium carbonate (51 mg) and 1-bromopropane (20 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 60°C for 2 hours. After the reaction mixture was allowed to cool, direct reverse-phase column chromatography (H) was performed. ２ The solution was purified using O / MeOH to obtain a crude residue (35 mg). The resulting residue (35 mg) was recrystallized with ethyl acetate / n-hexane to obtain 26 mg of the target compound as a pale yellow solid. MS (ESI+) m / z 580.2 (M+1)

[0270] Example 27 Synthesis of [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(pyrazoleo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone obtained in Synthesis Example 41: [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(pyrazolo[1,5-a]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (25 mg) obtained in Synthesis Example 41 was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (20 mg) and methyl iodide (9.3 μL) were sequentially added, and the mixture was stirred for 15 minutes at an ambient temperature of 50°C. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２ The compound was purified using O / MeOH to obtain a crude residue. The residue was slurry-washed with diethyl ether to obtain 15 mg of the target compound as a white solid. MS (ESI+) m / z 512.1 (M+1)

[0271] Example 28 Synthesis of [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone (16 mg) obtained in Synthesis Example 42 was dissolved in N,N-dimethylformamide (0.50 mL) with potassium carbonate (12 mg) and methyl iodide (5.7 μL) in sequence, and the mixture was stirred for 30 minutes at an ambient temperature of 50°C. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２ The target compound was purified using 0 / MeOH (O / MeOH) to obtain 16 mg as a pale yellow solid. MS (ESI+) m / z 530.1 (M+1)

[0272] Example 29 Synthesis Step 1 of [1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl][5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone 1. To a solution of 1-(1,2,3-benzothiadiazole-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (43 mg) (synthesized according to WO2018 / 119036) in dichloromethane (1.0 mL), N,N-dimethylformamide (1.0 μL) and oxalyl chloride (14 μL) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a light brown solid. Step 2: Add aluminum trichloride (81 mg) to a solution of 5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg) obtained in Synthesis Example 43 in 1,2-dichloroethane (1.2 mL) and stir at room temperature for 10 minutes. Subsequently, add the light brown solid solution of 1,2-dichloroethane (1.2 mL) obtained in Step 1 dropwise to the reaction mixture and heat under reflux and stir at ambient temperature of 110°C for 5 hours. After cooling the reaction mixture with ice, dilute with water and extract with ethyl acetate. Wash the organic phase with saturated brine, dry with magnesium sulfate, and remove the solvent under reduced pressure. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was subjected to reverse-phase column chromatography (H ２ The compound was purified using O / MeOH to obtain a crude residue. The residue was slurry-washed with isopropanol to obtain 33 mg of the target compound as a pale yellow solid. MS (ESI+) m / z 541.1 (M+1)

[0273] Example 30 Synthesis Step 1 of 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}isoquinoline-1(2H)-one Step 1 To a solution of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(1-methoxyisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (15 mg) obtained in Synthesis Example 44 in N,N-dimethylformamide (0.50 mL), potassium carbonate (11 mg) and bromocyclobutane (7.8 μL) were sequentially added, and the mixture was stirred at an ambient temperature of 100°C for 11 hours. Potassium carbonate (38 mg) and bromocyclobutane (26 μL) were added sequentially to the reaction mixture, and the mixture was stirred overnight at the same temperature. The mixture was stirred at an ambient temperature of 110°C for 5 hours. After the reaction mixture cooled, it was directly subjected to reverse-phase column chromatography (H). ２ The mixture was purified by 0 / MeOH to obtain a white solid. Step 2: 1.0 mL of 4N dioxane hydrochloride was added to a 1.0 mL solution of the white solid obtained in Step 1, and the mixture was stirred at an ambient temperature of 50°C for 5 hours. After the reaction mixture cooled, the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to reverse-phase column chromatography (H ２ The target compound was purified using 0 / MeOH (O / MeOH) to obtain 17 mg as a white solid. MS (ESI+) m / z 579.2 (M+1)

[0274] Example 31 Synthesis of 9-{4-[5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one To a solution of 9-{4-[5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}-4H-quinoridine-4-one (35 mg) obtained in Synthesis Example 48 in N,N-dimethylformamide (0.50 mL), potassium carbonate (27 mg) and methyl iodide (12 μL) were sequentially added, and the mixture was stirred for 15 minutes at an ambient temperature of 50°C. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２ The compound was purified using O / MeOH to obtain a crude residue. The obtained residue was slurry-washed with ethyl acetate to obtain 29 mg of the target compound as a yellow solid. MS (ESI+) m / z 539.1 (M+1)

[0275] Example 32 Synthesis Step 1 of (5-chloro-6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)[1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone Step 1 1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (35 mg) (synthesized according to WO2018 / 119036) was dissolved in dichloromethane (1.0 mL), to which N,N-dimethylformamide (0.83 μL) and oxalyl chloride (11 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a pale yellow solid. 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) obtained in Synthesis Example 49 in 1,2-dichloroethane (0.5 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, the pale yellow solid suspension of 1,2-dichloroethane (0.5 mL) obtained in Step 1 was added dropwise to the reaction mixture, washed with 1,2-dichloroethane (0.5 mL), and stirred at ambient temperature of 75°C for 1 hour. Furthermore, the mixture was heated under reflux and stirred at ambient temperature of 105°C for 3 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was subjected to reverse-phase column chromatography (H ２ The target compound was purified by 0 / MeOH (O / MeOH) to obtain 7.8 mg as a white solid. MS (ESI+) m / z 503.8 (M+1)

[0276] Example 33 Synthesis of [(2RS,4RS)-1-(5-bromopyrimidine-4-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone (20 mg) obtained in Synthesis Example 53 was dissolved in N,N-dimethylformamide (0.50 mL) and potassium carbonate (16 mg) and methyl iodide (3.7 μL) were added sequentially, and the mixture was stirred at ambient temperature of 50°C for 30 minutes. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２ The target compound was purified using 0 / MeOH (O / MeOH) to obtain 17 mg as a white solid. MS (ESI+) m / z 517.0 (M+1)

[0277] Example 34 Synthesis of [(2RS,4RS)-1-(2-amino-4-fluorophenyl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone obtained in Synthesis Example 56 [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone (25 mg) obtained in Synthesis Example 56 was mixed with methanol (5.0 mL) and 1% platinum-activated carbon, degussa type CF 105R / W (75 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen gas atmosphere (4.0 atm). The reaction mixture was filtered through Celite, and the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to reverse-phase column chromatography (H ２ The residue was purified by (H) 0 / MeOH to obtain a crude purified residue. The obtained residue was subjected to reverse-phase column chromatography (H) ２ The target compound was purified using 0 / MeOH (O / MeOH) to obtain 14 mg as a white solid. MS (ESI+) m / z 468.2 (M+1)

[0278] Example 35 Synthesis of {5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-yl}(piperazine-1-yl)methanone obtained in Synthesis Example 60. 0.50 mL of trifluoroacetic acid was added to a solution of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carbonyl}piperazine-1-carboxylate (41 mg) obtained in Synthesis Example 60 in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was subjected to reverse-phase column chromatography (H). ２ The target compound was purified using 0 / MeOH (O / MeOH) to obtain 25 mg as a flesh-colored solid. MS (ESI+) m / z 519.2 (M+1)

[0279] Example 36 Synthesis of [(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl][5-chloro-1-methyl-6-(piperazine-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]methanone tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl}piperazine-1-carboxylate (56 mg) obtained in Synthesis Example 63 was dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. After adding saturated sodium bicarbonate solution to the reaction mixture, extraction was performed with ethyl acetate. The organic phase was washed with saturated saline solution, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was subjected to reverse-phase column chromatography (H2). ２ The solution was purified using O / MeOH to obtain a crude residue. The resulting 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)

[0280] Example 37 Synthesis of [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone sulfate The [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (5.0 g) obtained in Example 6 was dissolved in acetone (50 mL) and several mg of seed crystals were added, followed by the addition of sulfuric acid (0.74 mL) dropwise, and the mixture was stirred overnight at room temperature. By filtering the precipitated solid, 5.6 g of the target compound was obtained as a beige solid. Elemental analysis value: C ２４ H １３ CLF ４ N ８ O.H. ２ SO ４ +0.2H ２ Calculated values ​​(%) C: 44.86 H: 2.41 N: 17.43 Measured values ​​(%) C: 45.15 H: 2.23 N: 17.10

[0281] Example 38 Synthesis of [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone monophosphate Synthesis of [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (180 g) obtained in Example 11 was dissolved in acetonitrile (3.0 L) and 85% phosphoric acid aqueous solution (40 mL) was added dropwise and stirred overnight at room temperature. The precipitated solid was filtered off 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 ２５H ２３ ClFIN ６ O·H ３ PO ４ Calculated value (%) C: 42.72 H: 3.73 N: 11.96 Found value (%) C: 42.49 H: 3.51 N: 11.98

[0282] The structural formulas of Examples 1 to 38 are shown in Tables 1 to 8.

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291] Hereinafter, biological test examples of the compounds used in the present disclosure are shown.

[0292] <Test Example 1 MALT1 protease inhibitory action> In order to confirm the enzyme inhibitory effect of the test substance on MALT1, an enzyme activity inhibition test was carried out using the C-terminal enzyme of MALT1 (amino acid residues 329-824). 1. Preparation of test substance The test substance was adjusted to 10 mM with dimethyl sulfoxide (DMSO), and further diluted with DMSO to concentrations of 1000, 100, 10, 1, and 0.1 μM, respectively. The mixture was further diluted 25-fold with assay buffer to prepare a test substance solution. The composition of the assay buffer is 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 action 5 μL of the test substance solution was added to a 384-well Black plate (#6007270, PerkinElmer) (n=2, final concentrations 10000, 1000, 100, 10, 1, 0.1 nM), then 10 μL of MALT1 enzyme was added, and finally 5 μL of substrate solution (Ac-Leu-Arg-Ser-Arg-AMC, Peptide Institute, Inc., final concentration 50 μM in the reaction solution) was added. After stirring, the reaction was allowed to proceed at 30°C for 2 hours. Fluorescence (excitation: 380 nm, emission: 460 nm) was detected using a microplate reader (Envision, PerkinElmer). 3. Analysis of measurement results Using the measurement data, non-linear regression analysis based on a 2-parameter logistic model was performed by Spotfire (PerkinElmer) to obtain IC ５０ was calculated. The results are shown in Table 9 below.

[0293]

[0294] <Test Example 2: Inhibitory Effect on Reporter Activity in HEK293 / API2-MALT1 / NF-κB Reporter Cells> The API2-MALT1 fusion protein expressed in MALT lymphoma is known to constitutively activate the NF-κB pathway. To confirm that the test substance suppresses the NF-κB pathway in cells, a reporter activity suppression test was performed using HEK293 / API2-MALT1 / NF-κB reporter cells. 1. Preparation of Test Substance The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO), and then diluted with DMSO to concentrations of 1000, 300, 100, and 10 μM. Further dilutions were made 100-fold in DMEM medium containing 10% FBS to prepare the test substance solution. 2. Measurement of reporter cell proliferation inhibitory effect: HEK293 / API2-MALT1 / NF-κB reporter cells and 293T / CMV reporter cells (used as negative control) were cultured in DMEM medium containing 10% FBS. 6000 cells of each were seeded in 30 μL of a 384-well plate (#781080, Greiner), and after 24 hours of incubation, 3.3 μL of the prepared test substance solution was added (final concentrations 10000, 1000, 100, 10 nM). 37°C, 5% CO2 ２ After incubation in an incubator for 24 hours, 33 μL of One-glo (Promega) was added. After incubation at room temperature for 5 minutes, luminescence was detected using a microplate reader (Envision, PerkinElmer). 3. Analysis of measurement results Using the measurement data, nonlinear regression analysis was performed using the SAS system (SAS Institute Inc.) and IC ５０ The values ​​were estimated. The results are shown in Table 10 below.

[0295]

[0296] <Test Example 3: Proliferation 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 proliferation inhibitory effect associated with the MALT1 inhibitory effect of the test substance, a proliferation inhibition test was conducted using ABC-DLBCL cell lines. 1. Preparation of Test Substance The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO), and then diluted with DMSO to concentrations of 3000, 1000, 300, 100, 30, and 10 μM. Further dilutions were made 100-fold in IMDM medium containing 10% FBS to prepare the test substance solution. 2. Measurement of ABC-DLBCL cell proliferation inhibitory effect: OCI-Ly3 cell line (ABC-DLBCL, NF-κB pathway-dependent) was cultured in IMDM containing 10% FBS, and SU-DHL-4 cell line (GCB-DLBCL, NF-κB pathway-independent, used as a negative control) was cultured in RPMI-1640 containing 10% FBS. 100 μL of each cell line (2000 OCI-Ly3 cells, 4000 SU-DHL-4 cells) were seeded into 96-well plates, and 11 μL of the prepared test substance solution was added (final concentrations 10000, 3000, 1000, 300, 100, 30, 10 nM). 37°C, 5% CO2 ２ After incubation in an incubator for 96 hours, 10 μL of Cell Counting Kit-8 (Dojin Chemical) was added. After incubation at 37°C for 4 hours, the absorbance at 450 nm was detected using a microplate reader (Envision, PerkinElmer). 3. Analysis of measurement results Using the measurement data, nonlinear regression analysis using a two-parameter logistic model was performed with Spotfire (PerkinElmer), and IC ５０ The values ​​were estimated. The results are shown in Tables 11 and 12 below.

[0297]

[0298]

[0299] <Test Example 5: Central Nervous System Distribution Test in Mice> A central nervous system distribution test was conducted using mice to confirm the central nervous system distribution of the test substance. 1. Administration and Collection 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 obtained as plasma by centrifugation. After bleeding from the abdominal vena cava, the cerebrum was collected. 2. Measurement and Analysis of Plasma and Brain Concentrations The drug concentrations in the collected plasma and cerebrum were measured by LC-MS / MS. To evaluate the brain distribution of the drug, the ratio of brain tissue concentration to plasma concentration (Kp value) was calculated. The results are shown in Table 13 below.

[0300]

Claims

1. The following formula (I): Crystals of the monophosphate salt of the compound shown.

2. The powder X-ray diffraction pattern using Cu-Kα rays shows peaks at 2θ values ​​of at least 12.3°±0.2°, 19.1°±0.2°, 22.0°±0.2°, 25.6°±0.2°, and 26.9°±0.2°, as shown in equation (I): A type I crystal of the compound monophosphate shown.

3. The powder X-ray diffraction pattern by Cu-Kα rays shows peaks at 2θ values ​​of at least 12.3°±0.2°, 16.2°±0.2°, 17.9°±0.2°, 19.1°±0.2°, 20.7°±0.2°, 22.0°±0.2°, 23.5°±0.2°, 25.6°±0.2°, and 26.9°±0.2°, as shown in equation (I): A type I crystal of the compound monophosphate shown.

4. In differential thermal analysis, the following formula (I) has an endothermic peak at 214.8 ± 3.0°C: A type I crystal of the compound monophosphate shown.

5. The crystal according to any one of claims 1 to 4, wherein the crystal purity is 90% or higher.

6. The crystal according to any one of claims 1 to 4, wherein the crystal purity is 95% or higher.

7. The crystal according to any one of claims 1 to 4, wherein the crystal purity is 99% or higher.

8. A pharmaceutical composition containing the crystal described in any one of claims 1 to 4 as an active ingredient.

9. A MALT1 inhibitor containing the crystal described in any one of claims 1 to 4 as an active ingredient.

10. A method for inhibiting MALT1, comprising administering the crystal described in any one of claims 1 to 4 to a subject that requires it.

11. The crystal according to any one of claims 1 to 4 for use in MALT1 inhibition.

12. Use of the crystal according to any one of claims 1 to 4 in the manufacture of a MALT1 inhibitor.

13. A preventive or therapeutic agent for a disease involving MALT1, comprising the crystal described in any one of claims 1 to 4 as an active ingredient.

14. A method for preventing or treating a disease involving MALT1, comprising administering the crystal described in any one of claims 1 to 4 to a subject in need thereof.

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

16. A method for producing the crystal according to any one of claims 1 to 4, comprising contacting the compound represented by formula (I) with phosphoric acid in a solvent containing acetone.

17. The method according to claim 16, wherein the solvent containing acetone is acetone.

18. Equation (II) below: A method for producing the compound shown by the following formula (VII): A method comprising the step of converting a compound represented by formula (II) into a compound represented by formula (II).

19. The following formula (VI): The method according to claim 18, further comprising the step of converting a compound represented by formula (VII) to a compound represented by formula (VII).

20. The following equation (V): The method according to claim 19, further comprising the step of converting a compound represented by formula (VI) into a compound represented by formula (VI).

21. The following formula (IV): The method according to claim 20, further comprising the step of converting a compound represented by formula (V) into a compound represented by formula (V).

22. The following equation (III): The method according to claim 21, further comprising the step of converting a compound represented by formula (IV) into a compound represented by formula (IV).

23. The following equation (V): The compound shown by [this symbol].

24. The following formula (VI): The compound shown by [this symbol].

25. The following formula (VII): The compound shown by [this symbol].

26. The following formula (I): A method for producing the compound shown by the following formula (II): The compound shown by the following formula (A): A method comprising the step of obtaining a compound represented by formula (I) by contacting it with a compound represented by formula (I).

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