Azaindole compounds and intermediate for synthesizing same, method for synthesizing these, and pharmaceutical

Abstract

Disclosed is a method for producing a compound represented by formula (A), the method including a step for converting a compound represented by formula (F1) into a compound represented by formula (G).

Description

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

[0001] This disclosure relates to azaindole compounds and their synthetic intermediates, methods for synthesizing them, 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、Feel of a fine feeling Aesthetics,2016,73,45443000000000000000000000000000000 The aesthetic is the emotional attitude 010,2, 10000000ら、smiles Reasonableness, Reasonableness & Thanksgiving,2020,21,7460000ら、no Chemistry,2015,21,9229274 Thanksgiving,2020,9,4000000ら、THE snowflake a snowflake Emotional,2014,128 ,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 Sweetness,2012,122 488440982000ら、S THIS IS THE Thanks,2014,33,26522710000ら、9 FIFA,2019,540,12116FINANCIALら、FINANCIAL Yes feeling Fiction,2016,22,135150 The scientistら、scientific The scientists,2014, 56,18160000ら、scientists 2019,64,1 40119400000ら、9 Emotion,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, synthetic intermediates thereof, methods for synthesizing them, and pharmaceutically acceptable salts thereof.

[0009] This disclosure relates, for example, to the following matters (Sections 1) to (22).

[0010] (Item 1) The following 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 a compound represented by the following 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 1, comprising the step of converting to a compound shown by the following formula (A): A method for producing the compound shown by the following formula (D): The compound shown by the following formula (E): A method, which may be the method of item 1 or item 2, comprising the step of converting to a compound represented by the following formula (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 of any one of claims 1 to 3, comprising the step of obtaining a compound represented by the following formula (A): A method for producing the compound shown by the following formula (G): A method according to any one of claims 1 to 4, comprising the step of converting the compound represented by formula (A) into the compound represented by formula (A). (Clause 6) The following chemical reaction formula: The compound shown: Method of synthesis. (Section 7) Formula (D) below: A compound represented by (item 8). Formula (E): The compound shown by (item 9). Formula (F1): The compound shown by (item 10). Formula (F2): The compound shown by (item 11). Formula (F3): Compounds represented by (12) A compound selected from the group consisting of the following compounds (1) to (36), or a pharmaceutically acceptable salt thereof: (1) [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (2) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (3) {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}acetonitrile, (4) [5-chloro-1-(2-hydroxyethyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (5) 1-(3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-yl)ethane-1-one, (6) [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (7) [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (8) [5-chloro-1-propyl-6-(2H-1,2,(3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (9)[5-chloro-1-(3-hydroxypropyl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (10) [5-chloro-1-(oxetan-3-yl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (11) [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (12) [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (13) [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone, (14) [5-chloro-1-ethyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (15) [5-chloro-1-(3-hydroxypropyl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl] [(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone, (16) [5-chloro-1-cyclopropyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,(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. (Item 13) A pharmaceutical composition containing the compound described in (Item 12) above, or a pharmaceutically acceptable salt thereof, as an active ingredient. (Item 14) A MALT1 inhibitor containing the compound described in (Item 12) above, or a pharmaceutically acceptable salt thereof, as an active ingredient. (Item 15) A method for inhibiting MALT1, comprising administering the compound described in (Item 12) above, or a pharmaceutically acceptable salt thereof, to a subject requiring it. (Item 16) The compound described in (Item 12) above, or a pharmaceutically acceptable salt thereof, for use in MALT1 inhibition. (Item 17) Use of the compound described in (Item 12) above, or a pharmaceutically acceptable salt thereof, in the manufacture of a MALT1 inhibitor. (Item 18) A prophylactic or therapeutic agent for a disease involving MALT1, containing the compound described in (Item 12) above, or a pharmaceutically acceptable salt thereof, as an active ingredient. (Item 19) A method for preventing or treating a disease involving MALT1, comprising administering the compound described in (Item 12) above, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. (Item 20) The disclosed compound, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease involving MALT1. (Item 21) Use of the disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a prophylactic or therapeutic agent for a disease involving MALT1. (Item 22) A compound described in (Item 12), or a pharmaceutically acceptable salt thereof, is contained as an active ingredient in multiple sclerosis, rheumatoid arthritis, psoriasis, immune thrombocytopenia, spinal cord injury, graft-versus-host disease associated with bone marrow transplantation, organ transplant rejection, aplastic anemia, Behçet's disease, nephrotic syndrome, generalized myasthenia gravis, atopic dermatitis, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, multiple myeloma, BENTA A treatment 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 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.

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

[0012] The following describes in detail the forms for implementing this disclosure. However, this disclosure is not limited to the following embodiments.

[0013] In this specification, "alkyl group" means a monovalent group obtained by removing one hydrogen atom from a saturated hydrocarbon. Alkyl groups may be linear or branched. Alkyl groups are C １ ~C ６ It may be an alkyl group, C １ ~C ４ It may be an alkyl group, C １ ~C ３ It may be an alkyl group. In this specification, "C ａ ~C ｂ " means that the number of carbon atoms is a to b. Specific examples of alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group (1-methylethyl group), n-butyl group, sec-butyl group, isobutyl group (2-methylpropyl group), tert-butyl group, n-pentyl group, neopentyl group, isopentyl group, sec-pentyl group, 3-pentyl group, tert-pentyl group, n-hexyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1,1,2,2-tetramethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, etc.

[0014] In this specification, the "substituted alkyl group" means a group in which one or more hydrogens of an alkyl group are substituted with substituents. Examples of the substituents in the substituted alkyl group include, for example, 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, etc. These substituents may be further substituted with other substituents, or may be bonded to each other to form a ring.

[0015] In this specification, the "cycloalkyl group" means a monovalent group obtained by removing one hydrogen atom from a cyclic saturated hydrocarbon. The cycloalkyl group may be a C ３ - C ８ cycloalkyl group, and may be a C ３ - C ６ cycloalkyl group, and may be a C ３ - C ４ cycloalkyl group. Specific examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.

[0016] In this specification, the "substituted cycloalkyl group" means a group in which one or more hydrogens of a cycloalkyl group are substituted with substituents. Examples of the substituents in the substituted cycloalkyl group can be the above-mentioned substituents.

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

[0018] 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.

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

[0020] In this specification, "substituted aryl group" means 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.

[0021] In this specification, "heteroaryl group" means an aromatic, cyclic, monovalent group containing a heteroatom in the ring. Specific examples of heteroatoms include nitrogen and sulfur. 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, and 2,7-naphthilidinyl.

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

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

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

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

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

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

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

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

[0030] The disclosed compounds are compounds represented by general formula (1), or pharmaceutically acceptable salts thereof.

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

[0032] In general formula (1), R ２ This represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group, 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 ６ C 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.

[0033] In general formula (1), R ３This 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.

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

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

[0036] 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).

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

[0038] In general formula (2), R ５ This represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, with a substituted aryl group or a substituted heteroaryl group being preferred, and it is more 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, and 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, and 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.

[0039] In general formula (2), R ６ and R ７ Each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group, preferably a substituted or unsubstituted alkyl group, 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 R７ 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 ７ When both carbon atoms to which are bonded are chiral centers, it is particularly preferable that the stereochemistry of both is R.

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

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

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

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

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

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

[0046] Specific examples of compounds represented by general formula (1) include, 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.

[0047] 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.

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

[0049] The abbreviations used 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)

[0050] 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.

[0051] 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.

[0052] The disclosed compounds may incorporate solvent molecules and become solvates when 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.

[0053] 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.

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

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

[0056] Furthermore, one embodiment of the present disclosure provides a method for inhibiting MALT1, comprising administering the disclosed compound to a subject requiring its use.

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

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

[0059] 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.

[0060] 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.

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

[0062] 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.

[0063] 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.

[0064] "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.

[0065] 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 therapeutic agent for various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, and monkeys.

[0066] As the carrier, one or more of the commonly used pharmaceutically acceptable solid, semi-solid or liquid diluents, fillers and other formulation aids are used. The pharmaceutical composition according to the present disclosure is preferably administered in unit dosage form. The pharmaceutical composition can be administered by intratissue administration, oral administration, intravenous administration, topical administration (transdermal administration, eye drops, intraperitoneal, intrathoracic, etc.) or rectally. The pharmaceutical composition according to the present disclosure is administered in a dosage form suitable for these administration methods.

[0067] The dosage as a medicine is preferably adjusted in consideration of the patient's condition such as age, weight, type and degree of disease, administration route, type of the compound of the present disclosure, whether it is a salt or not, type of the salt, etc. Usually, for adults, as the effective ingredient amount of the compound of the present disclosure or its pharmaceutically acceptable salt, in the case of oral administration, within the range of 0.01 mg to 5 g / adult per day, preferably within the range of 1 mg to 500 mg / adult is appropriate. In some cases, less than this may be sufficient, and conversely, a dosage more than this may be required. Usually, it can be administered once a day or divided into several times, or in the case of intravenous administration, it can be administered rapidly or continuously within 24 hours.

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

[0069] The disclosed compounds can be produced from compounds that are known themselves or intermediates that can be easily prepared from known compounds, for example, by the methods described below, the synthesis examples, examples, or known methods described later.

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

[0071] 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.

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

[0073] In each step of the following manufacturing method, unless otherwise specified, the reactions are carried out by appropriately modifying or combining methods described in known references such as "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition" by R. C. Larock, John Wiley & Sons Inc., 1999, "Experimental Chemistry Course" edited by the Chemical Society of Japan, 4th Edition, Maruzen, 1992, "Learning Organic Synthesis Strategies from Name Reactions" by L. Kürti and B. Czakó, translated by Kiyoshi Tomioka, Kagaku Dojin, 2006, "Modern Organic Synthesis Methods: Design and Strategy" by G. S. Zweifel and M. H. Nantz, translated by Tamejiro Hiyama, Kagaku Dojin, 2009, or methods described in synthesis examples and examples, etc.

[0074] [1] Synthesis of Compound (1) (R １ , R ２ , R ３ and R ４ are as defined above. X １ represents chloro or bromo, X ２(wherein represents chloro, bromo, mesylate, or triflate.) Step 1 This step involves performing a Friedel-Crafts acylation reaction with compound AA, synthesized by a commercially available or known method, in a solvent such as methylene chloride or dichloroethane, in the presence of a Lewis acid such as aluminum chloride, with 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). Acid halide BB can be obtained by reacting compound LL or compound PP, described later, with oxalyl chloride or oxalyl bromide in a solvent such as methylene chloride or dichloroethane, in the presence of a catalytic amount of dimethylformamide, at 0°C to 50°C, preferably 0°C to room temperature, for 1 to 48 hours, preferably 1 to 12 hours. Step 2 This step involves alkylating compound 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.

[0075] [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 introduced 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.

[0076] [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.

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

[0078] [5] Synthesis of compound (PP) (R 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.

[0079] One aspect of this embodiment 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.

[0080] 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).

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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').

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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).

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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).

[0101] The method for diazotizing amino 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) is added to the compound of formula (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.

[0102] 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.

[0103] 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.

[0104] 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. For example, 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.

[0105] In a particular embodiment, step III may involve the coexistence of compound (E) and isoamyl nitrite in the presence of an acid.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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).

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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).

[0114] 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.

[0115] 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.

[0116] 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.

[0117] The measurement conditions for LC-MS are as follows: Analytical instrument: ACQUITY UPLC MS / PDA system (Waters Corporation) Mass spectrometer: Waters 3100 MS Detector: Photodiode array Detector: ACQUITY PDA detector (UV detection wavelength: 210-400 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

[0118] 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)

[0119] 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).

[0120] 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.

[0121] 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

[0122] The melting point was measured using a micro-melting point analyzer (Buchi, B-565 model).

[0123] 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.

[0124] The lowercase letters r and s in the compound names indicate the stereochemistry of the pseudo-chiral carbon atom, according to IUPAC rules.

[0125] 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)

[0126] 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)

[0127] 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.

[0128] 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.

[0129] 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)

[0130] Synthesis Example 6 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.

[0131] Synthesis Example 7 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) in acetonitrile (80 mL), m-chlorobenzoic acid (2.4 g) was added and stirred at room temperature for 30 minutes. Dimethyl sulfate (1.5 mL) was then added and the mixture was stirred at an ambient temperature of 75°C for 20 hours. After the reaction mixture had cooled, potassium carbonate (11 g), 1,2,3-triazole (3.2 g), and acetonitrile (60 mL) were added sequentially and the mixture was stirred at an ambient temperature of 60°C for 6 hours. After the reaction mixture had cooled, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain a crude, pink solid residue. The residue was slurry-washed with ethyl acetate (10 mL) to obtain 1.6 g of the target compound as a pink solid.

[0132] Synthesis Example 8 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), a premixed suspension of bis(trimethylsilyl)amine (2.9 mL), 5-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (2.0 g), and toluene (60 mL) was added and the mixture was stirred at room temperature for 2 hours. 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.

[0133] Synthesis Example 9 Synthesis of 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine 3.9 g of 1-benzoyl-6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine was mixed with 38 mL of tetrahydrofuran and 76 mL of methanol. 12 mL of aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with 0.10 L of aqueous sodium hydroxide solution (2.0 M), and extraction was performed with chloroform. After washing the organic phase with saturated brine, it was dried over magnesium sulfate, and the solvent was removed by vacuum distillation to obtain 2.7 g of the target compound as a pale yellow solid.

[0134] Synthesis Example 10 Synthesis of tert-butyl 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate A solution of 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (1.0 g) in N,N-dimethylformamide (10 mL) 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.

[0135] Synthesis Example 11 Synthesis of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine To a solution of tert-butyl 6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.4 g) in dimethyl sulfoxide (8.3 mL), tetrakis(triphenylphosphine)palladium (0) (0.96 g), lithium chloride (0.53 g), copper(I) chloride (82 mg), and 2-(tributylstannyl)pyrimidine (1.7 g) were sequentially added, and the mixture was stirred overnight at an ambient temperature of 80°C. After the reaction mixture cooled, it was purified by direct column chromatography, followed by reverse-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.

[0136] Synthesis Example 12 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 distillation under reduced pressure. The obtained residue was purified by column chromatography to obtain 4.6 g of the target compound as a colorless oily substance.

[0137] Synthesis Example 13 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) 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)

[0138] Synthesis Example 14 Synthesis of tert-butyl (2R,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate 12 g of tert-butyl (7R,9R)-7,9-dimethyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate 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.

[0139] Synthesis Example 15 Synthesis of tert-butyl (2R,6R)-4-cyano-2,6-dimethylpiperidine-1-carboxylate To a mixed solution of tert-butyl (2R,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate (8.9 g), tert-butyl alcohol (47 mL), and 1,2-dimethoxyethane (0.19 L), toluenesulfonylmethyl isocyanide (hereinafter referred to as "TosMIC") (12 g) was added. After cooling the reaction mixture on ice, tert-butoxypotassium (13 g) was added, and the mixture was stirred at the same temperature for 30 minutes, then stirred at room temperature for 15 hours. After cooling the reaction mixture on ice, it was diluted with water, and the reaction solvent was removed by vacuum distillation. Extraction was performed with ethyl acetate, the organic phase was washed with water, then with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 5.4 g of the target compound as a pale yellow solid.

[0140] Synthesis Example 16 Synthesis of Ethyl (2R,6R)-2,6-dimethylpiperidine-4-carboxylate Step 1 13 g of tert-butyl (2R,6R)-4-cyano-2,6-dimethylpiperidine-1-carboxylate was mixed with ethanol (0.11 L) and water (0.11 L), to which potassium hydroxide (18 g) was added, 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) citric acid aqueous solution to pH = 5. Extraction was performed with ethyl acetate, the organic phase was washed with water, then with saturated brine, dried with magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a residue (14 g) as a white solid. Step 2 13 g of the residue obtained in Step 1 was dissolved in hydrochloric acid ethanol solution (2.0 M, 0.68 L), and the mixture was heated under reflux and stirred at an ambient temperature of 120°C for 30 hours. After the reaction mixture cooled, the reaction solvent was removed by vacuum distillation. The resulting residue was cooled with ice, and a 2.0 M aqueous sodium hydroxide solution was added to adjust the pH to 13. Extraction was performed with chloroform, the organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation 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)

[0141] Synthesis Example 17 Synthesis of Ethyl (2R,6R)-1-(5-fluoro-3-nitropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate To a solution of ethyl (2R,6R)-2,6-dimethylpiperidine-4-carboxylate (2.2 g) in dimethyl sulfoxide (24 mL), N,N-diisopropylethylamine (hereinafter referred to as "DIPEA") (4.0 mL) and 2,5-difluoro-3-nitropyridine (2.1 g) were sequentially added, and the mixture was stirred at an ambient temperature of 140°C for 3 hours. After the reaction mixture 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.

[0142] Synthesis Example 18 Synthesis of Ethyl (2R,6R)-1-(3-amino-5-fluoropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate To a solution of ethyl (2R,6R)-1-(5-fluoro-3-nitropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate (3.4 g) in methanol (0.10 L), Pt / C type STD (Pt 3%) (1.1 g) was added and the mixture was stirred for 4 hours under a hydrogen gas atmosphere (5.0 atm) at an ambient temperature of 45°C. After the reaction mixture 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.

[0143] Synthesis Example 19 Synthesis of Ethyl (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate Ethyl (2R,6R)-1-(3-amino-5-fluoropyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylate (8.0 g) was dissolved in diiodomethane (80 mL) and isoamyl nitrite (6.4 mL) was added, and the mixture was stirred at an 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.

[0144] Synthesis Example 20 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) 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.

[0145] Synthesis Example 21 Synthesis Step 1 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 (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid) in a solution of dichloromethane (2.0 mL) was mixed with N,N-dimethylformamide (2.5 μL) and oxalyl chloride (35 μL) and stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a yellow amorphous solution. Step 2: 70 mg of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 2.0 mL of 1,2-dichloroethane, to which 0.21 g of aluminum trichloride was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale yellow amorphous solution of 1,2-dichloroethane obtained in Step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 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.

[0146] Synthesis Example 22: Synthesis of [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone To a solution of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) in N,N-dimethylformamide (0.50 mL), potassium carbonate (21 mg) and (2-bromoethoxy)(tert-butyl)dimethylsilane (37 mg) were sequentially added, and the mixture was stirred at 50°C for 1 hour. Another 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.

[0147] Synthesis Example 23 Synthesis of tert-butyl 3-{5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}azetidine-1-carboxylate [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (45 mg) in N,N-dimethylformamide (1.0 mL) with potassium carbonate (27 mg) and 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.

[0148] Synthesis Example 24: 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. To a solution of 1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.10 g) (synthesized according to WO2018 / 119036) in dichloromethane (2.5 mL), N,N-dimethylformamide (2.4 μL) and oxalyl chloride (33 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a pale yellow solid. Step 2: 60 mg of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 2.5 mL of 1,2-dichloroethane, to which 0.18 g of aluminum trichloride was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the pale yellow solid solution of 1,2-dichloroethane obtained in Step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 75°C for 3 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was slurry-washed with methanol to obtain 0.13 g of the target compound as a pale brown solid.

[0149] Synthesis Example 25: Synthesis Step 1 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 (2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carboxylic acid) in a solution of dichloromethane (3.0 mL). N,N-dimethylformamide (3.6 μL) and oxalyl chloride (59 μL) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a yellow amorphous solution. Step 2: 0.29 g of aluminum trichloride was added to a solution of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.10 g) in 1,2-dichloroethane (3.0 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, the yellow amorphous 1,2-dichloroethane solution (3.0 mL) obtained in Step 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 50°C for 2 hours. The mixture was then stirred overnight at an ambient temperature of 70°C. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 0.10 g of the target compound as a white solid.

[0150] Synthesis Example 26: 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 To a solution 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 (30 mg) 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.

[0151] Synthesis Example 27: 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: 90 mg of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 2.0 mL of 1,2-dichloroethane, to which 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. The mixture was then heated under reflux and stirred at an ambient temperature of 100°C for 2 hours. After cooling the reaction mixture with ice, it was diluted with water and extracted with ethyl acetate. The organic phase was washed twice with 2.0 M aqueous sodium hydroxide solution, then with saturated sodium bicarbonate solution, and finally with saturated brine. After drying with magnesium sulfate, the solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was suspended in methanol and filtered to obtain 46 mg of the target compound as a pale yellow solid.

[0152] Synthesis Example 28 Synthesis of 1,1-Dioxotetrahydro-2H-thiopyran-4-ylmethanesulfonate To a solution of 4-hydroxytetrahydro-2H-thiopyran-1,1-dioxide (0.20 g) in dichloromethane (3.3 mL), triethylamine (0.37 mL) and methanesulfonyl chloride (0.15 mL) were sequentially added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by direct column chromatography to obtain 0.28 g of the target compound as a white solid.

[0153] Synthesis Example 29 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.

[0154] Synthesis Example 30 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.

[0155] Synthesis Example 31 Synthesis of (3S)-oxolan-3-ylmethanesulfonate To a solution of (3S)-oxolan-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.

[0156] 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-(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: Add 0.12 g of aluminum trichloride to a solution of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine (40 mg) in 1,2-dichloroethane (2.5 mL) and stir at room temperature for 10 minutes. Subsequently, add the light brown solid solution of 1,2-dichloroethane (2.5 mL) obtained in Step 1 dropwise to the reaction mixture and stir at ambient temperature of 75°C for 4 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 resulting residue was slurry washed with ethyl acetate and methanol to obtain 0.062 g of the target compound as a light brown solid.

[0157] Synthesis Example 33 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) 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.

[0158] Synthesis Example 34: 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 tetrahydrofuran (1.5 mL). N,N-dimethylformamide (2.6 μL) and oxalyl chloride (36 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction 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) 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 distillation under reduced pressure. The obtained residue was slurry-washed with methanol to obtain a crude residue. The obtained residue was purified by column chromatography to obtain a crude residue. The obtained residue was slurry-washed with methanol to obtain 120 mg of the target compound as a white solid.

[0159] Synthesis Example 35 Synthesis of 5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine Potassium carbonate (930 mg) and methyl iodide (420 μL) were sequentially added to a solution of 5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine in N,N-dimethylformamide (3.0 mL), and the mixture was stirred at room temperature for 30 minutes. Further, methyl iodide (250 μL) was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with water, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 130 mg of the target compound as a pale yellow solid.

[0160] Synthesis Example 36: 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) 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.

[0161] Synthesis Example 37 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.

[0162] Synthesis Example 38 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. 9-bromo-4H-quinoridine-4-one (500 mg), sodium tert-butoxide (420 mg), and hydrazine hydrate (220 mg) were sequentially added to the reaction mixture and the mixture was stirred at ambient temperature of 50°C under an argon atmosphere for 4 hours. The reaction mixture was filtered through Celite, washed with tetrahydrofuran, and the mother liquor was concentrated to obtain a brown solid. 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.

[0163] Synthesis Example 39 Synthesis of 1-(4-oxo-4H-quinoridine-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid Ethyl 1-(4-oxo-4H-quinoridine-9-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (130 mg) was dissolved in tetrahydrofuran (3.0 mL), to which 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 adjust the pH to 5. The solvent in the reaction mixture was removed by reduced pressure. The resulting residue was purified by reverse-phase column chromatography to obtain 120 mg of the target compound as a yellow solid.

[0164] Synthesis Example 40 Step 1 of 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) 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: 70 mg of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 2.5 mL of 1,2-dichloroethane, to which 0.21 g of aluminum trichloride was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, the 2.5 mL suspension of the brown solid obtained in Step 1 in 1 was added dropwise to the reaction mixture, and the mixture was stirred at an ambient temperature of 75°C for 3 hours. 100 mg of aluminum trichloride 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 vacuum distillation. The resulting residue was slurry-washed with methanol to obtain 120 mg of the target compound as a yellowish-brown solid.

[0165] Synthesis Example 41 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 vacuum distillation. 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.

[0166] Synthesis Example 42 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).

[0167] Synthesis Example 43 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.

[0168] Synthesis Example 44 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.

[0169] Synthesis Example 45 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 (cisthracemic) (45 mg) in dichloromethane (2.5 mL), N,N-dimethylformamide (1.1 μL) and oxalyl chloride (15 μL) were added and the mixture was stirred at room temperature for 30 minutes. A white solid was obtained by distilling off the reaction mixture under reduced pressure. 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) in 1,2-dichloroethane (2.5 mL) and the mixture was stirred at room temperature for 10 minutes. Subsequently, the 1,2-dichloroethane (2.5 mL) suspension 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.

[0170] Synthesis Example 46 Synthesis of (2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-carboxylic acid To a solution of ethyl (2RS,4RS)-2-methylpiperidine-4-carboxylate (200 mg) in dimethyl sulfoxide (2.0 mL), DIPEA (0.40 mL) and 1,4-difluoro-2-nitrobenzene (270 mg) were sequentially added, and the mixture was stirred under an argon atmosphere at an ambient temperature of 50°C for 60 minutes. The mixture was then stirred 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 resulting residue was purified by column chromatography to obtain 240 mg of the target compound as a yellow oil. To a mixed solution of the 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.

[0171] Synthesis Example 47: Synthesis Step 1 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) in dichloromethane (2.0 mL), N,N-dimethylformamide (2.7 μL) and oxalyl chloride (37 μL) were added, and the mixture was stirred at room temperature for 30 minutes. The residue was obtained by distilling the reaction mixture under reduced pressure. Step 2: 30 mg of 5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 1,2-dichloroethane (1.0 mL), to which 180 mg of aluminum trichloride was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, 3.0 mL of the residue 1,2-dichloroethane obtained in Step 1 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.

[0172] Synthesis Example 48 Synthesis of [5-chloro-1-methyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(4-fluoro-2-nitrophenyl)-2-methylpiperidine-4-yl]methanone (30 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (25 mg) and methyl iodide (11 μL) were sequentially added, and the mixture was stirred for 90 minutes at an ambient temperature of 50°C under an argon atmosphere. After the reaction mixture has cooled, direct reverse-phase column chromatography (H) is performed. ２The target compound was purified using O / MeOH, yielding 27 mg of the compound as a yellow solid.

[0173] Synthesis Example 49 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 under an argon atmosphere at an ambient temperature of 100°C for 6 hours. After the reaction mixture was allowed to cool, it was purified by direct column chromatography to obtain a crude residue. The obtained residue was slurry-washed with a mixed solvent of diethyl ether and hexane to obtain 950 mg of a white solid. 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 the pH 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.

[0174] Synthesis Example 50 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) 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 saline solution, 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 oily substance. 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.

[0175] Synthesis Example 51 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) To a solution of (2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carboxylic acid (280 mg) in dichloromethane (10 mL), N,N-dimethylformamide (7.9 μL) and oxalyl chloride (130 μL) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure to obtain a light brown oily substance. Step 2: Add aluminum trichloride (560 mg) to a solution of methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (180 mg) in 1,2-dichloroethane (10 mL) and stir at room temperature for 10 minutes. Subsequently, add the 1,2-dichloroethane (10 mL) solution of the light brown oily substance obtained in Step 1 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.

[0176] Synthesis Example 52: Synthesis of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carbonyl}piperazine-1-carboxylate To a solution of 5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (40 mg) in N,N-dimethylformamide (0.88 mL), O-(7-azabenzotriazole-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.

[0177] Synthesis Example 53 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 (2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carboxylic acid (cisracemic) (250 mg) was dissolved in dichloromethane (10 mL), to which 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) 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.

[0178] Synthesis Example 54: Synthesis of [6-(benzylsulfanyl)-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone (6-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone (64 mg) was dissolved in 1,4-dioxane (2.6 mL) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15 mg), DIPEA (91 μL), benzyl mercaptan (31 μL), and tris(dibenzylideneacetone)(chloroform)dipalladium (12 mg) were sequentially added. The mixture was stirred under an argon atmosphere using a microwave at 110°C for 30 minutes. The reaction mixture was purified by direct column chromatography to obtain a yellow solid (68 mg). To a 1.2 mL solution of the resulting yellow solid in N,N-dimethylformamide, potassium carbonate (53 mg) and methyl iodide (23 μL) were 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.

[0179] Synthesis Example 55 Synthesis of tert-butyl 4-{5-chloro-3-[(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-carbonyl]-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl}piperazine-1-carboxylate [6-(benzylsulfanyl)-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl][(2RS,4RS)-1-(3-chloro-5-fluoropyridine-2-yl)-2-methylpiperidine-4-yl]methanone (70 mg) was mixed with acetic acid (1.8 mL) and water (0.2 mL), to which N-chlorosuccinimide (51 mg) was added and stirred at room temperature for 1 hour. Further stirring was carried out at ambient temperature of 40°C for 2 hours. The reaction mixture was removed by vacuum distillation, and the resulting residue was added to ice-cooled saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated 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.

[0180] Example 1 [5-chloro-1-(oxetan-3-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (50 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (30 mg) and 3-iodooxetane (0.12 g) were sequentially added, and the mixture was stirred at ambient temperature of 100°C for 10 hours. After the reaction mixture was allowed to cool, direct reverse-phase column chromatography (H) was performed. ２ The 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)

[0181] 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 [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 dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (14 mg) and methyl iodide (6.4 μL) were sequentially added, 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)

[0182] Example 3 {5-chloro-3-[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-carbonyl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl}acetonitrile [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which 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. ２ The target compound was purified using O / MeOH, yielding 32 mg as a light brown solid. MS (ESI+) m / z 619.1 (M+1)

[0183] 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 [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (42 mg) was mixed with methanol (2.5 mL) and dichloromethane (0.50 mL), to which aqueous hydrochloric acid (1.0 M, 0.57 mL) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was neutralized with aqueous sodium hydroxide (1.0 M), diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by column chromatography to obtain 31 mg of the target compound as a white solid. MS (ESI+) m / z 624.0 (M+1)

[0184] 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 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)

[0185] 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 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (31 mg) and methyl iodide (14 μL) were sequentially added, and the mixture was stirred 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)

[0186] 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 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (35 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (28 mg) and ethyl iodide (16 μL) were sequentially added, and the mixture was stirred at ambient temperature of 50°C for 30 minutes. 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. The residue was slurry-washed with methanol to obtain 37 mg of the target compound as a white solid. MS 555.1 (M+1)

[0187] 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 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (35 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (28 mg) and 1-bromopropane (18 μL) were sequentially added, and the mixture was stirred at ambient temperature of 50°C for 2 hours. After the reaction mixture was allowed to cool, direct reverse-phase column chromatography (H) was performed. ２ The target compound was purified using O / MeOH, yielding 32 mg as a white solid. MS (ESI+) m / z 569.1 (M+1)

[0188] Example 9 [5-chloro-1-(3-hydroxypropyl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (47 mg) was mixed with tetrahydrofuran (1.0 mL) and methanol (1.0 mL), to which aqueous hydrochloric acid solution (1.0 M, 1.0 mL) was added 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 using reversed-phase column chromatography (H2). 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] Ｄ２０ = +30.36° (c=1.0, chloroform)

[0189] Example 10 [5-chloro-1-(oxetan-3-yl)-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (18 mg) and 3-iodooxetan (75 mg) were sequentially added, 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)

[0190] Example 11 [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (22 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (26 mg) and methyl iodide (7.0 μL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was 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 15 mg of the target compound as a white solid. MS (ESI+) m / z 605.0 (M+1)

[0191] Example 12 [5-chloro-1-methyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (51 mg) and methyl iodide (14 μL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly analyzed by reverse-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)

[0192] Example 13 [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (51 mg) and ethyl iodide (18 μL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was 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)

[0193] Example 14: Potassium carbonate (36 mg) and ethyl iodide (12 μL) were sequentially added to a solution of [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 (30 mg) in N,N-dimethylformamide (1.0 mL), 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)

[0194] 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) 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)

[0195] 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 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 (40 mg) in 1,2-dichloroethane (1.0 mL), cyclopropylboronic acid (12 mg), 2,2'-bipyridine (16 mg), copper(II) acetate (19 mg), and sodium carbonate (15 mg) were added, and the mixture was stirred at ambient temperature of 70°C for 5 hours. After the reaction mixture cooled, it was purified by direct column chromatography, followed by reversed-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)

[0196] Example 17: Potassium carbonate (22 mg) and 2-bromopropane (9.0 μL) were sequentially added to a solution of [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 (19 mg) in N,N-dimethylformamide (1.0 mL), and the mixture was stirred at ambient temperature of 100°C for 1.5 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 18 mg as a white solid. MS (ESI+) m / z 622.1 (M+1)

[0197] Example 18 [5-chloro-1-ethyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (42 mg) was dissolved in N,N-dimethylformamide (1.0 mL), to which potassium carbonate (49 mg) and ethyl iodide (17 μL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was 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 39 mg of the target compound as a white solid. MS (ESI+) m / z 619.1 (M+1)

[0198] 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 To a solution of [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (30 mg) in N,N-dimethylformamide (1.0 mL), potassium carbonate (36 mg) and 1,1-dioxotetrahydro-2H-thiopyran-4-ylmethanesulfonate (0.12 g) were sequentially added, and the mixture was stirred at ambient temperature of 100°C for 16 hours. After the reaction mixture cooled, 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)

[0199] Example 20: Synthesis of [5-chloro-1-(oxan-4-yl)-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (36 mg) was dissolved in N,N-dimethylformamide (0.80 mL), to which potassium carbonate (42 mg) and oxan-4-ylmethanesulfonate (0.11 g) 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 then subjected to reverse-phase column chromatography (H ２The target compound was purified using 0 / MeOH (O / MeOH) to obtain 24 mg as a pale yellow solid. MS (ESI+) m / z 664.2 (M+1)

[0200] Example 21 Synthesis of {5-chloro-1-[(3S)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (36 mg) was dissolved in N,N-dimethylformamide (0.80 mL), to which potassium carbonate (42 mg) and (3R)-oxolan-3-ylmethanesulfonate (0.10 g) 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 then subjected to reverse-phase column chromatography (H ２ The 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)

[0201] Example 22 Synthesis of {5-chloro-1-[(3R)-oxolan-3-yl]-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl}[(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][(2R,6R)-1-(5-fluoro-3-iodopyridine-2-yl)-2,6-dimethylpiperidine-4-yl]methanone (36 mg) was dissolved in N,N-dimethylformamide (0.80 mL), to which potassium carbonate (42 mg) and (3S)-oxolan-3-ylmethanesulfonate (0.10 g) 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 then 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)

[0202] 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 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 then stirred at 75°C (ambient temperature) 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)

[0203] 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 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(thieno[2,3-b]pyridine-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (25 mg) was dissolved in N,N-dimethylformamide (0.50 mL), to which potassium carbonate (20 mg) and methyl iodide (9.0 μL) were sequentially added, and the mixture was stirred for 15 minutes at an 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)

[0204] 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)

[0205] Example 26 Synthesis of [5-chloro-1-propyl-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone [5-chloro-6-(pyrimidine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(8-fluoroisoquinoline-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (40 mg) in N,N-dimethylformamide (1.0 mL) was sequentially mixed with potassium carbonate (51 mg) and 1-bromopropane (20 μL) and stirred at ambient temperature of 60°C for 2 hours. After the reaction mixture cooled, it was directly subjected to reverse-phase column chromatography (H 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)

[0206] 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 [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) in N,N-dimethylformamide (0.50 mL) was sequentially mixed with potassium carbonate (20 mg) and methyl iodide (9.3 μL) and stirred for 15 minutes at 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)

[0207] 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) in N,N-dimethylformamide (0.50 mL) was sequentially mixed with potassium carbonate (12 mg) and methyl iodide (5.7 μL) and 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 16 mg as a pale yellow solid. MS (ESI+) m / z 530.1 (M+1)

[0208] 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) 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)

[0209] Example 30 Synthesis of 5-{4-[5-chloro-1-cyclobutyl-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl}isoquinoline-1(2H)-one Step 1 [5-chloro-6-(2H-1,2,3-triazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl][1-(1-methoxyisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-yl]methanone (15 mg) in N,N-dimethylformamide (0.50 mL) was sequentially mixed with potassium carbonate (11 mg) and bromocyclobutane (7.8 μL) and stirred at 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)

[0210] 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 35 mg 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 was dissolved in 0.50 mL of N,N-dimethylformamide, to which 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. ２The 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)

[0211] 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) in 1,2-dichloroethane (0.5 mL) and 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)

[0212] 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 obtained in Synthesis Example 45 (20 mg) was dissolved in N,N-dimethylformamide (0.50 mL) to which potassium carbonate (16 mg) and methyl iodide (3.7 μL) were sequentially added, 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 17 mg as a white solid. MS (ESI+) m / z 517.0 (M+1)

[0213] 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 48 [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) was added to a methanol (5.0 mL) solution of 1% platinum-activated carbon, degussa type CF 105R / W (75 mg), and the mixture was stirred overnight at room temperature under a hydrogen gas atmosphere (4.0 atm). The reaction mixture was filtered through Celite, and the solvent was 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)

[0214] 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 52. Trifluoroacetic acid (0.50 mL) 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 52 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)

[0215] 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 55 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)

[0216] 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 [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) 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. The precipitated solid was filtered to obtain 5.6 g of the target compound as a beige solid. Elemental analysis value: C ２４ H １３ CLF ４ N ８ O.H. ２ SO ４ +0.2H ２ Calculated values ​​(%) C: 44.86 H: 2.41 N: 17.43 Measured values ​​(%) C: 45.15 H: 2.23 N: 17.10

[0217] 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) in acetonitrile (3.0 L) was mixed dropwise with 85% phosphoric acid aqueous solution (40 mL) and stirred overnight at room temperature. The precipitated solid was filtered to obtain 210 g of the target compound as a yellow solid. Melting point 186-188℃ Specific rotation [α] Ｄ ２０ = +57.99° (c=0.6, chloroform) Elemental analysis value C ２５ H ２３cliFIN ６ O.H. ３ PO ４ Calculated values ​​(%) C: 42.72 H: 3.73 N: 11.96 Measured values ​​(%) C: 42.49 H: 3.51 N: 11.98

[0218] The structural formulas of Examples 1 to 38 are shown in Tables 1 to 8.

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227] Examples of biological tests of the compounds used in this disclosure are shown below.

[0228] <Test Example 1: MALT1 Protease Inhibitory Effect> To confirm the enzyme inhibitory effect of the test substance on MALT1, an enzyme activity inhibition test was performed using the C-terminal enzyme of MALT1 (amino acid residues 329-824). 1. Preparation of the Test Substance The test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO), and then further diluted with DMSO to concentrations of 1000, 100, 10, 1, and 0.1 μM. The test substance solution was then prepared by further dilution 25-fold with assay buffer. The assay buffer composition was 200 mM Tris / HCl HEPES (pH 7.5), 0.8 M Na Citralate, 100 μM DTT, and 0.05% CHAPS. 2. To measure the inhibitory effect of MALT1 protease, 5 μL of the test substance solution was added to a 384-well Black plate (#6007270, PerkinElmer) (n=2, final concentrations 10000, 1000, 100, 10, 1, 0.1, nM). Next, 10 μL of MALT1 enzyme was added, followed by 5 μL of substrate solution (Ac-Leu-Arg-Ser-Arg-AMC, Peptide Laboratories Inc., final concentration in reaction solution 50 μM). After stirring, the mixture was reacted at 30°C for 2 hours. Fluorescence (excitation: 380 nm, fluorescence: 460 nm) was detected using a microplate reader (Envision, PerkinElmer). 3. Analysis of measurement results: Using the measurement data, a nonlinear regression analysis using a two-parameter logistic model was performed with Spotfire (PerkinElmer), and IC ５０ The result was calculated and is shown in Table 9 below.

[0229]

[0230] <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.

[0231]

[0232] <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.

[0233]

[0234]

[0235] <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.

[0236]

Claims

1. The following formula (A): A method for producing the compound shown by the following formula (F1): The compound shown by the following formula (G): A method comprising the step of converting to a compound shown in [the formula].

2. The following formula (E): The method according to claim 1, further comprising the step of converting a compound represented by formula (F1) into a compound represented by formula (F1).

3. The following formula (D): The method according to claim 2, further comprising the step of converting a compound represented by formula (E) into a compound represented by formula (E).

4. The following formula (B): The compound represented by is contacted with the compound represented by the following formula (C): The method according to claim 3, further comprising a step of obtaining the compound represented by the formula (D) by the contact.

5. The method according to claim 4, further comprising the step of converting the compound represented by formula (G) into the compound represented by formula (A).

6. The following formula (D): The compound shown by [this symbol].

7. The following formula (E): The compound shown by [this symbol].

8. The following formula (F1): The compound shown by [this symbol].

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