Ketoamide compounds and their pharmaceutical uses

Abstract

This invention provides ketoamide compounds having LMP7 inhibitory activity or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and pharmaceutical uses thereof. [Solution] A compound represented by formula [1a] or a pharmaceutically acceptable salt thereof. TIFF2026064226000144.tif72165 It will be provided.

Description

[Technical Field]

[0001] The present invention relates to ketoamide compounds having LMP7 inhibitory activity or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and pharmaceutical uses thereof. [Background technology]

[0002] There are two main types of proteasomes: constitutive proteasomes, which are ubiquitously expressed, and immunoproteasomes, which are mainly expressed on immune cells. Low-molecular Mass Protein-7 (LMP7) is one of the β subunits of the immunoproteasome and is a protease that plays a part in protein degradation by the immunoproteasome (Non-Patent Literature 1). Proteasomes contribute to the unfolded protein response (UPR) by degrading defective proteins generated during protein synthesis. It is known that inhibition of proteasome function disrupts the UPR and causes cell death, and this mechanism is thought to be particularly strongly involved in B cells and plasma cells, which are highly active in protein synthesis (Non-Patent Literature 2). Furthermore, plasma cells are known to be involved in autoimmune diseases through the production of autoantibodies (Non-Patent Literature 3). Therefore, LMP7 inhibitors are expected to be effective against autoimmune diseases in which autoantibodies are involved in the pathogenesis, as well as against plasma cell carcinoma and B cell carcinoma.

[0003] Examples of autoimmune diseases include the following: Systemic lupus erythematosus (SLE), lupus nephritis (LN) SLE is thought to be a disease in which various autoantibodies are produced and deposited in tissues as immune complexes, causing inflammation (Non-Patent Document 4). In non-clinical studies, the efficacy of non-selective proteasome inhibitors and immunoproteasome inhibitors in mouse SLE and mouse LN models has been reported (Non-Patent Documents 5, 6, 38). In addition, the efficacy of non-selective proteasome inhibitors in treating SLE has been reported in small-scale clinical trials (Non-Patent Documents 7, 8). Therefore, LMP7 inhibitors are expected to show therapeutic effects against SLE and LN.

[0004] Myasthenia gravis (MG) Myasthenia gravis (MG) is thought to be a disease in which motor dysfunction occurs due to the production of anti-AChR antibodies and anti-MuSK antibodies, which inhibit ACh signaling at the neuromuscular junction. It is classified into ocular myasthenia gravis, characterized only by ocular symptoms, and generalized myasthenia gravis, which includes muscle weakness in muscles other than the ocular muscles (Non-Patent Literature 9). In non-clinical studies, the effectiveness of non-selective proteasome inhibitors and immunoproteasome inhibitors in rat MG models has been reported (Non-Patent Literature 10, 29). Therefore, LMP7 inhibitors are expected to show therapeutic effects against MG.

[0005] Immunotoxic thrombocytopenia, Idiopathic thrombocytopenic purpura (ITP) ITP is known to be a disease in which anti-platelet antibodies are produced, and these antibodies remove or destroy platelets, leading to thrombocytopenic bleeding (Non-Patent Literature 11). In non-clinical studies, the effectiveness of non-selective proteasome inhibitors in mouse ITP models has been reported (Non-Patent Literature 12). Therefore, LMP7 inhibitors are expected to show therapeutic effects against ITP.

[0006] Autoimmune hemolytic anemia (AIHA) AIHA is known to be a disease in which anti-red blood cell antibodies are produced, and these antibodies remove or destroy red blood cells, leading to hemolytic anemia (Non-Patent Literature 13). Several small-scale clinical studies have reported the effectiveness of non-selective proteasome inhibitors against AIHA (Non-Patent Literature 14). Therefore, LMP7 inhibitors are expected to show therapeutic effects against AIHA.

[0007] Chronic inflammatory demyelinating polyneuropathy (CIDP) CIDP is thought to be a disease in which autoantibodies are produced against myelin components of peripheral nerves, and these antibodies destroy myelin, leading to muscle weakness or sensory impairment in the limbs (Non-Patent Literature 15). In non-clinical studies, the effectiveness of non-selective proteasome inhibitors in a mouse model of CIDP has been reported (Non-Patent Literature 16). Therefore, LMP7 inhibitors are expected to show therapeutic effects against CIDP.

[0008] Multiple sclerosis (MS) In non-clinical studies, the efficacy of immunoproteasome inhibitors in mouse MS models has been reported (Non-Patent Literature 30). Therefore, LMP7 inhibitors are expected to show therapeutic effects against MS.

[0009] Hashimoto's disease In non-clinical studies, the effectiveness of immunoproteasome inhibitors in a mouse model of Hashimoto's disease has been reported (Non-Patent Literature 31). Therefore, LMP7 inhibitors are expected to show therapeutic effects against Hashimoto's disease.

[0010] Inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.) In non-clinical studies, the effectiveness of immunoproteasome inhibitors in treating mouse models of inflammatory bowel disease has been reported (Non-Patent Literature 32). Therefore, LMP7 inhibitors are expected to show therapeutic effects against inflammatory bowel disease.

[0011] Rheumatoid arthritis (RA) In non-clinical studies, the effectiveness of immunoproteasome inhibitors in treating mouse RA models has been reported (Non-Patent Literature 33). Therefore, LMP7 inhibitors are expected to show therapeutic effects against RA.

[0012] Sjögren's syndrome In nonclinical studies, the effectiveness of non-selective proteasome inhibitors in a mouse model of Sjögren's syndrome has been reported (Non-Patent Literature 34). Therefore, LMP7 inhibitors are expected to show therapeutic effects against Sjögren's syndrome.

[0013] Polymyositis (PM) In non-clinical studies, the effectiveness of immunoproteasome inhibitors in mouse PM models has been reported (Non-Patent Literature 35). Therefore, LMP7 inhibitors are expected to show therapeutic effects against PM.

[0014] Other autoimmune diseases Autoimmune diseases such as pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), neuromyelitis optica, immune complex-associated small vessel vasculitis (anti-GBM antibody-associated disease, cryoglobulin vasculitis, IgA vasculitis, hypocomplemental urticarial vasculitis, etc.), Graves' disease, thyroid eye disease, type 1 diabetes, Lambert-Eaton myasthenic syndrome, systemic sclerosis, dermatomyositis, IgA nephropathy, IgG4-associated disease, autoimmune hepatitis, and Kawasaki disease are suggested to involve the contribution of autoantibodies (Non-patent documents 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 37), and LMP7 inhibitors may show therapeutic effects.

[0015] Furthermore, examples of plasma cell carcinoma and B cell carcinoma include the following diseases: Multiple myeloma (MM) MM is a disease in which plasma cells become cancerous and mainly proliferate in the bone marrow. Non-selective proteasome inhibitors have been approved as therapeutic agents for MM. In addition, in non-clinical studies, the efficacy of administering immunotype proteasome inhibitors to a mouse MM model has been reported (Non-Patent Document 28). Therefore, it is expected that the LMP7 inhibitor will show a therapeutic effect against MM.

[0016] Mantle cell lymphoma (MCL) MCL is a disease in which abnormal B cells derived from the mantle zone of lymph nodes proliferate. In clinical studies, the efficacy of administering non-selective proteasome inhibitors to MCL has been reported (Non-Patent Document 36), and it has been approved as a therapeutic agent for MCL. Therefore, it is expected that the LMP7 inhibitor will show a therapeutic effect against MCL.

Prior art documents

Non-Patent Documents

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Non-Patent Document 1

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Non-licensed literature 9

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Summary of the Invention

[0018] The present invention provides a ketoamide compound having LMP7 inhibitory activity, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and their pharmaceutical uses, etc. That is, the present invention includes the aspects exemplified below.

[0019] [Item 1] A compound represented by formula [I] (hereinafter, in this specification, the "compound represented by formula [I]" is also referred to as "compound [I]") or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0018] , , 4-6 , , , , , , , , , , , ,

[0019] , , 4-6 , , 1 , , , , is (1) C 4-6 cycloalkyl, (2) C 4-6 cycloalkenyl, (3) A 4- to 6-membered heterocycloalkyl containing one heteroatom selected from the group consisting of oxygen and nitrogen atoms in addition to carbon atoms as ring-constituting atoms, (4) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms as ring-constituting atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms, (5) A 7- to 11-membered spiroheterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms selected from the group consisting of nitrogen and sulfur atoms (where the sulfur atom may be appropriately oxidized to form a sulfonyl), (6) Phenyl, or (7) A 5- or 6-membered heteroaryl containing, in addition to carbon atoms as ring-constituting atoms, one or two nitrogen atoms ; and R 1 are each independently [[ID=[]] (1) Halogen, [[]](2) C 1-4 Haloalkyl, (3) C 1-4 Alkoxy, (4) COR 6 (where R 6 is C 1-4 Alkyl or C 1-4 Alkoxy), or (5) SO2R 7 (where R 7 is C 1-4 Alkyl or C 3-4 Cycloalkyl) ; and R 2 is halogen; R 3 are each independently halogen or alternatively, two R 3 bonded to the same carbon atom may together with that carbon atom optionally form a C 3-4 Cycloalkane; R 4 is (1) Hydrogen, (2) Halogen, or (3) C 1-4 Alkyl ; and R 5 is hydrogen or C 1-4It is alkyl; m is 0, 1, or 2; p is either 0 or 1; q is 0, 1, or 2; t1 is either 1 or 2; t2 is either 1 or 2; t3 is 1, 2, or 3; and n is either 0 or 1. When n is 0, X 1 , X 2 , and X 4 Each is independently either CH or N, X 3 and X 5 Each is independently C or N, X 1 , X 2 , X 3 , X 4 and X 5 Together, they form a 5-membered heteroarylene (where the heteroarylene may be appropriately substituted with halogens) containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. When n is 1, X 1 , X 2 , X 4 , and X 6 Each is independently either CH or N, X 3 and X 5 Each is independently C or N, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 Together, they form a six-membered heteroarylene (where the heteroarylene may be optionally substituted with halogens) containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms.

[0020] [Section 2] Formula [II]: [ka] [In the formula, Cy 1 , R 1 , R 2 , R 3 , R 4 , R 5 m, p, q, t1, t2, and t3 are synonymous with the definitions in item 1. A compound described in item 1, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0021] [Section 3] A compound or a pharmaceutically acceptable salt thereof as described in item 1 or 2, wherein t1 is 2, t2 is 1, and t3 is 1.

[0022] [Section 4] R 4 is hydrogen, R 5 A compound or a pharmaceutically acceptable salt thereof, as described in any one of items 1 to 3, wherein p is hydrogen and p is 0.

[0023] [Section 5] The following structural formula: [ka] A compound selected from the group consisting of the compounds shown, or a pharmaceutically acceptable salt thereof.

[0024] [Section 6] A pharmaceutical composition comprising a compound described in any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0025] [Section 7] An LMP7 inhibitor comprising a compound described in any one of items 1 to 5 or a pharmaceutically acceptable salt thereof.

[0026] [Section 8] A therapeutic or prophylactic agent for a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma, comprising any compound described in any one of paragraphs 1 to 5 or a pharmaceutically acceptable salt thereof.

[0027] [Section 9] Autoimmune diseases include systemic lupus erythematosus, myasthenia gravis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), multiple sclerosis, neuromyelitis optica, and immune complex-associated small vessel vasculitis (anti-GBM antibody-associated disease, cryo-associated disease). A therapeutic or prophylactic agent as described in item 8 for a disease selected from the group consisting of globulinic vasculitis, IgA vasculitis, hypocomplementary urticarial vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic scleroderma, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, and Kawasaki disease.

[0028] [Section 10] A method for inhibiting LMP7, comprising administering a therapeutically effective dose of any one of items 1 to 5 or a pharmaceutically acceptable salt thereof to a mammal.

[0029] [Section 11] A method for treating or preventing a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of items 1 to 5 to a mammal.

[0030] [Section 12] Autoimmune diseases include systemic lupus erythematosus, myasthenia gravis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), multiple sclerosis, neuromyelitis optica, and immune complex-associated small vessel vasculitis (anti-GBM antibody-associated disease, etc.). The method according to item 11, wherein the disease is selected from the group consisting of rioglobulinic vasculitis, IgA vasculitis, hypocomplementary urticarial vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, and Kawasaki disease.

[0031] [Section 13] Use of any compound described in any one of sections 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of an LMP7 inhibitor.

[0032] [Section 14] Use of any one of the compounds described in paragraphs 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma.

[0033] [Section 15] Autoimmune diseases include systemic lupus erythematosus, myasthenia gravis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), multiple sclerosis, neuromyelitis optica, and immune complex-associated small vessel vasculitis (anti-GBM antibody-associated disease, etc.). Use as described in item 14 for diseases selected from the group consisting of rioglobulinic vasculitis, IgA vasculitis, hypocomplementary urticarial vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, and Kawasaki disease.

[0034] [Section 16] A compound described in any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, for use in inhibiting LMP7.

[0035] [Section 17] A compound or a pharmaceutically acceptable salt thereof, as described in any one of items 1 to 5, for use in the treatment or prevention of a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma.

[0036] [Section 18] Autoimmune diseases include systemic lupus erythematosus, myasthenia gravis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), multiple sclerosis, neuromyelitis optica, and immune complex-associated small vessel vasculitis (anti-GBM antibody-associated disease, cryoglobulin A disease selected from the group consisting of vasculitis, IgA vasculitis, hypocomplement urticarial vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, and Kawasaki disease, the compound described in item 17 or a pharmaceutically acceptable salt thereof.

[0037] [Section 19] A commercial package comprising the pharmaceutical composition described in item 6, and a statement relating to the pharmaceutical composition that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma.

[0038] [Section 20] A commercial kit comprising a pharmaceutical composition as described in item 6, and a description relating to the pharmaceutical composition that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma.

[0039] [Section A1] A compound represented by formula [Ia] (hereinafter, in this specification, "compound represented by formula [Ia]" is also referred to as "compound [Ia]") or a pharmaceutically acceptable salt thereof. [ka] [In the formula, Cy 1w teeth, (1) C 4-6 Cycloalkyl, (2) C 4-6 Cycloalkenyl, (3) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms as ring constituent atoms. (4) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (5) A 7- to 11-membered spiroheterocycloalkyl, containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of nitrogen and sulfur atoms (wherein the sulfur atom may be appropriately oxidized to form sulfonyl), (6) Phenyl, (7) A 5- or 6-membered heteroaryl having one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms, (8) C 5-8 Cross-linked cycloalkyl and; Y 1w teeth, (1) combination; (2) -CH2-, or (3) -CONHCH2- and; R 1w Each of them operates independently. (1) Halogen, (2) C 1-4 Alkyl, (3) C 1-4 Haloalkyl, (4) C 1-4 Alkoxy, (5) COR 6 (Here, R 6 C 1-4 Alkyl or C 1-4 (It is an alkoxy), (6) SO2R 7w (Here, R 7w C may be replaced with NHCOMe. 1-4 Alkyl or C 3-4 (It is cycloalkyl), or (7) C 3-4 Cycloalkyl and; R 3 Each of them is independently a halogen, Or two R atoms bonded to the same carbon atom 3 It combines with that carbon atom, as appropriate, C 3-4 They may form cycloalkanes; R 4 teeth, (1) Hydrogen, (2) Halogen, or (3) C 1-4 Alkyl and; R 5 is hydrogen or C 1-4 It is alkyl; Cy 2w teeth, (1) A 5- or 6-membered heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms, or (2) A 9- or 10-membered condensed heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms. And, R 2w It is a halogen, and R 13w is a halogen, or R 2w and R 13w R 2w The benzene ring to which Cy 2w Together with the ring, it may form a tricyclic condensed heterocycle containing, in addition to carbon atoms, one to four heteroatoms independently selected from the group consisting of nitrogen atoms or oxygen atoms as ring constituent atoms; mw is 0, 1, 2, or 3; p is either 0 or 1; q is 0, 1, or 2; t1 is either 1 or 2; t2w is 1, 2, or 3; t3 is 1, 2, or 3; and [uw is either 0 or 1]

[0040] [Section A2] Y1w is a bond, and R 2w and R 13w are both halogen, the compound according to item A1 or a pharmaceutically acceptable salt thereof.

[0041] [Item A3] Cy 2w is a 5- or 6-membered heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, the compound according to item A1 or A2 or a pharmaceutically acceptable salt thereof.

[0042] [Item A4] Formula [IIa]:

Chemical formula

[0043] ]> [Item A5] p is 0, mw is 1, and R<管理番号 4 and R<管理番号 5 are both hydrogen, the compound according to any one of items A1 to A4 or a pharmaceutically acceptable salt thereof.

[0044] [Item A6] t1 is 2, and t2w and t3 are both 1, the compound according to any one of items A1 to A5 or a pharmaceutically acceptable salt thereof.

[0045] [Item A7] Formula [IVa]:

Chemical formula

[0046] [Item A8] Y 1w is -CONHCH2-, the compound according to item A1 or A7, or a pharmaceutically acceptable salt thereof.

[0047] [Item A9] The following structural formula:

Chemical formula

[0048] [Item A10] A pharmaceutical composition comprising the compound according to any one of items A1 to A9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0049] [Item A11] An LMP7 inhibitor comprising the compound according to any one of items A1 to A9 or a pharmaceutically acceptable salt thereof.

[0050] [Item A12] A therapeutic or prophylactic agent for a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma, comprising the compound according to any one of items A1 to A9 or a pharmaceutically acceptable salt thereof.

[0051] [Item A13] Autoimmune diseases include systemic lupus erythematosus, lupus nephritis, myasthenia gravis (ocular myasthenia gravis, generalized myasthenia gravis, etc.), immune thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), multiple sclerosis, neuromyelitis optica, immune complex vasculitis ( A therapeutic or prophylactic agent as described in item A12, for a disease selected from the group consisting of anti-GBM antibody-related disease, cryoglobulin vasculitis, IgA vasculitis, hypocomplement urticarial vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, autoimmune hepatitis, and Kawasaki disease.

[0052] [Section A14] The therapeutic or prophylactic agent described in item A13, wherein the myasthenia gravis is ocular myasthenia gravis or generalized myasthenia gravis.

[0053] [Section A15] A method for inhibiting LMP7, comprising administering a therapeutically effective dose of a compound or a pharmaceutically acceptable salt thereof described in any one of items A1 to A9 to a mammal.

[0054] [Section A16] A method for treating or preventing a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of items A1 to A9 to a mammal.

[0055] [Section A17] Autoimmune diseases include systemic lupus erythematosus, lupus nephritis, myasthenia gravis (ocular myasthenia gravis, generalized myasthenia gravis, etc.), immune thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), multiple sclerosis, neuromyelitis optica, and immune complex nephrosis. The method according to item A16, wherein the disease is selected from the group consisting of vasculitis (anti-GBM antibody-associated disease, cryoglobulin vasculitis, IgA vasculitis, hypocomplement urticarial vasculitis, etc.), Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-associated disease, autoimmune hepatitis, and Kawasaki disease.

[0056] [Section A18] The method according to item A17, wherein the myasthenia gravis is ocular myasthenia gravis or generalized myasthenia gravis.

[0057] [Section A19] Use of any compound described in any one of sections A1 to A9 or a pharmaceutically acceptable salt thereof for the manufacture of an LMP7 inhibitor.

[0058] [Section A20] Use of any one of the compounds described in sub-sub

[0059] [Section A21] Autoimmune diseases include systemic lupus erythematosus, lupus nephritis, myasthenia gravis (ocular myasthenia gravis, generalized myasthenia gravis, etc.), immune thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), multiple sclerosis, neuromyelitis optica, and immune complex nephrosis. Use as described in item A20 for diseases selected from the group consisting of vasculitis (anti-GBM antibody-associated disease, cryoglobulin vasculitis, IgA vasculitis, hypocomplementary urticarial vasculitis, etc.), Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-associated disease, autoimmune hepatitis, and Kawasaki disease.

[0060] [Section A22] Use as described in item A21, where myasthenia gravis is ocular myasthenia gravis or generalized myasthenia gravis.

[0061] [Section A23] A compound described in any one of sections A1 to A9, or a pharmaceutically acceptable salt thereof, for use in inhibiting LMP7.

[0062] [Section A24] A compound or a pharmaceutically acceptable salt thereof, as described in any one of items A1 to A9, for use in the treatment or prevention of a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma.

[0063] [Section A25] Autoimmune diseases include systemic lupus erythematosus, lupus nephritis, myasthenia gravis (ocular myasthenia gravis, generalized myasthenia gravis, etc.), immune thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), multiple sclerosis, neuromyelitis optica, and immune complex vasculitis (anti-GBM). A compound or a pharmaceutically acceptable salt thereof, described in item A24, is a disease selected from the group consisting of antibody-related diseases, cryoglobulin vasculitis, IgA vasculitis, hypocomplementary urticarial vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, autoimmune hepatitis, and Kawasaki disease.

[0064] [Section A26] The compound described in item A25 or a pharmaceutically acceptable salt thereof, wherein the myasthenia gravis is ocular myasthenia gravis or generalized myasthenia gravis.

[0065] [Section A27] A commercial package comprising the pharmaceutical composition described in item A10, and a description relating to the pharmaceutical composition that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma.

[0066] [Section A28] A commercial kit comprising a pharmaceutical composition as described in item A10, and a description relating to the pharmaceutical composition that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma. [Modes for carrying out the invention]

[0067] The definitions of terms used in this specification are as follows: "Halogens" include, for example, fluorine, chlorine, bromine, and iodine. Preferred halogens include fluorine, chlorine, and bromine.

[0068] "C 1-4 "Alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 "Alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Preferred "C 1-4 Examples of "alkyl" include methyl and ethyl.

[0069] "C 1-4 "Haloalkyl" refers to the above "C" which is substituted with 1 to 5 halogens independently selected from the above "halogen" group. 1-4 It means "alkyl". 1-4 "Haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 1-fluoro-1-methylethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl. Preferred "C 1-4 Examples of "haloalkyl" include difluoromethyl and trifluoromethyl.

[0070] "C 1-4 "Alkoxy" refers to the above "C 1-4 "Alkyl" refers to a group bonded to an oxygen atom. 1-4 "Alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy. Preferred "C 1-4 An example of an "alkoxy" is methoxy.

[0071] "C 3-4 "Cycloalkyl" refers to a monocyclic saturated hydrocarbon ring group with 3 or 4 carbon atoms.3-4 "Cycloalkyl" includes cyclopropyl and cyclobutyl. Preferred "C 3-4 An example of a "cycloalkyl" is cyclopropyl.

[0072] "C 3-4 "Cycloalkane" refers to a monocyclic saturated hydrocarbon ring with 3 or 4 carbon atoms. 3-4 "Cycloalkanes" include cyclopropane and cyclobutane. Preferred "C 3-4 Cyclopropane is an example of a "cycloalkane."

[0073] "C 4-6 "Cycloalkyl" refers to a monocyclic saturated hydrocarbon ring group with 4 to 6 carbon atoms. 4-6 "Cycloalkyl" includes cyclobutyl, cyclopentyl, and cyclohexyl. Preferred "C 4-6 Examples of "cycloalkyl" include cyclobutyl and cyclohexyl.

[0074] "C 4-6 "Cycloalkenyl" refers to a monocyclic partially unsaturated hydrocarbon ring group having 4 to 6 carbon atoms and at least one carbon-carbon double bond. 4-6 "Cycloalkenyl" includes cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. Preferred "C 4-6 Cyclohexenyl is an example of a "cycloalkenyl."

[0075] "C 5-8 "Cross-linked cycloalkyl" refers to a cross-linked cyclic saturated hydrocarbon ring group with 5 to 8 carbon atoms. 5-8 "Cross-linked cycloalkyls" include, for example, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Preferred "C 5-8 An example of a "crosslinked cycloalkyl" is bicyclo[2.2.1]heptyl.

[0076] "A 4- to 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of oxygen and nitrogen atoms" means a 4- to 6-membered monocyclic saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen and nitrogen atoms, in addition to carbon atoms, as a ring constituent atom. Examples of "4- to 6-membered heterocycloalkyl groups containing one heteroatom selected from the group consisting of oxygen and nitrogen atoms" include azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidyl, and tetrahydropyranil. Preferred examples of "4- to 6-membered heterocycloalkyl groups containing one heteroatom selected from the group consisting of oxygen and nitrogen atoms" include azetidinyl, piperidyl, and tetrahydropyranil.

[0077] "A 4- to 6-membered heterocycloalkyl group containing one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms" means a 4- to 6-membered monocyclic saturated heterocyclic group containing one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms, in addition to carbon atoms, as ring constituent atoms. Examples of "4- to 6-membered heterocycloalkyl groups containing one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms" include azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidyl, tetrahydropyranil, piperazinyl, dioxanil, and morpholinil. Preferred "4- to 6-membered heterocycloalkyl groups containing one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms" include azetidinyl, piperidyl, tetrahydropyranil, and piperazinyl.

[0078] A "4- to 6-membered heterocycloalkenyl containing one heteroatom selected from the group consisting of oxygen and nitrogen atoms" refers to a 4- to 6-membered monocyclic partially unsaturated heterocyclic group that, in addition to carbon atoms, contains one heteroatom selected from the group consisting of oxygen and nitrogen atoms as ring constituent atoms, and has at least one double bond. Examples of "4- to 6-membered heterocycloalkenyls containing one heteroatom selected from the group consisting of oxygen and nitrogen atoms" include the following groups: [ka] Preferred "4- to 6-membered heterocycloalkenyls containing one heteroatom selected from the group consisting of oxygen and nitrogen atoms" include the following groups: [ka]

[0079] "A 7- to 11-membered spiroheterocycloalkyl group containing one or two heteroatoms independently selected from the group consisting of nitrogen and sulfur atoms (wherein the sulfur atoms may be appropriately oxidized to form sulfonyl atoms)" means a 7- to 11-membered bicyclic saturated heterocyclic group containing one or two heteroatoms independently selected from the group consisting of nitrogen and sulfur atoms, in addition to carbon atoms as ring constituent atoms, and containing two rings sharing one common atom. Examples of "a 7- to 11-membered spiroheterocycloalkyl group containing one or two heteroatoms independently selected from the group consisting of nitrogen and sulfur atoms (wherein the sulfur atoms may be appropriately oxidized to form sulfonyl atoms)" include the following groups. [ka]

[0080] A "5- or 6-membered heteroaryl containing one or two nitrogen atoms" refers to a 5- or 6-membered aromatic heterocyclic group that contains one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. Examples of "5- or 6-membered heteroaryls containing one or two nitrogen atoms" include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. Preferred "5- or 6-membered heteroaryls containing one or two nitrogen atoms" include pyrazolyl and pyridyl.

[0081] "A 5- or 6-membered heteroarylene containing 1 to 3 nitrogen atoms" means a divalent 5- or 6-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms. Examples of "5- or 6-membered heteroarylenes containing 1 to 3 nitrogen atoms" include pyrrolylene, imidazoylene, pyrazolylene, triazolylene, pyridylene, pyridinylene, pyrimidinylene, pyridadinylene, and triadinylene. Preferred "5- or 6-membered heteroarylenes containing 1 to 3 nitrogen atoms" include pyrazolylene, triazolylene, pyridylene, and pyrimidinylene.

[0082] "A 9- or 10-membered condensed heteroarylene containing 1 to 3 nitrogen atoms" refers to a divalent 9- or 10-membered bicyclic aromatic heterocyclic group that contains 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms, and contains two rings sharing two common atoms. Examples of "9- or 10-membered condensed heteroarylene containing 1 to 3 nitrogen atoms" include the following groups: [ka]

[0083] A "five-membered heteroarylene containing one or two nitrogen atoms" refers to a divalent five-membered aromatic heterocyclic group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. Examples of "five-membered heteroarylenes containing one or two nitrogen atoms" include pyrrolylene, imidazoylene, and pyrazolylene. A preferred "five-membered heteroarylene containing one or two nitrogen atoms" is pyrazolylene.

[0084] "A six-membered heteroarylene containing one or two nitrogen atoms" refers to a divalent six-membered aromatic heterocyclic group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. Examples of "six-membered heteroarylenes containing one or two nitrogen atoms" include pyridinylene, pyradinylene, pyrimidinylene, and pyridadinylene. Preferred "six-membered heteroarylenes containing one or two nitrogen atoms" include pyridinylene and pyrimidinylene.

[0085] "A 4- to 6-membered heterocycloalkyl group containing one nitrogen atom" refers to a monocyclic saturated heterocyclic group with 4 to 6 members that contains one nitrogen atom in addition to carbon atoms as ring constituents. Examples of "4- to 6-membered heterocycloalkyl groups containing one nitrogen atom" include azetidinyl, pyrrolidinyl, and piperidyl.

[0086] "A 4- to 6-membered heterocycloalkyl group containing one or two nitrogen atoms" refers to a 4- to 6-membered monocyclic saturated heterocyclic group that contains one or two nitrogen atoms in addition to carbon atoms as ring constituents. Examples of "4- to 6-membered heterocycloalkyl groups containing one or two nitrogen atoms" include azetidinyl, pyrrolidinyl, piperidyl, and piperazinyl.

[0087] A "tricyclic condensed heterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means an 8 to 17-membered tricyclic condensed partially unsaturated or unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, in addition to carbon atoms, as ring constituent atoms, and the heterocycle contains at least one benzene ring. Examples of "tricyclic condensed heterocycles containing 1 to 4 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" include the following rings. [ka]

[0088] In compound [Ia], "Y 1w However, compound [Ia] which is -CONHCH2- is defined as compound [Ia] being [ka] [In the formula, Cy 1w Cy 2w , R 1w , R 2w , R 3 , R 4 , R 5 , R 13w mw, p, q, t1, t2w, t3, and uw are synonymous with the definitions in [Section A1] above. It means that.

[0089] The phrase "may be substituted with substituent β as appropriate" means that substituent α is either unsubstituted or substituted with substituent β at any substitutable position on substituent α (i.e., any hydrogen atom of substituent α is replaced by substituent β). For example, "a five-membered heteroarylene that may be substituted with halogen as appropriate" means that the five-membered heteroarylene is either unsubstituted or any hydrogen atom in the five-membered heteroarylene is substituted with halogen.

[0090] Specific embodiments of the substituents of compound [I] and compound [Ia] are illustrated below, but each substituent of compound [I] and compound [Ia] is not limited to these specific embodiments, and compound [I] and compound [Ia] also include embodiments that combine any two or more specific embodiments of each substituent. First, specific examples of substituents on compound [I] are given below.

[0091] Cy 1 Preferably, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (3) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (4) A 7 to 11-membered spiroheterocycloalkyl, which contains, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of nitrogen and sulfur atoms (wherein the sulfur atom may be appropriately oxidized to form sulfonyl), or (5) Phenyl That is the case.

[0092] R 1 Preferably, each is independent of the others. (1) Halogen, (2) C 1-4 Alkoxy, or (3) SO2R 7 (Here, R 7 C 1-4 Alkyl or C 3-4 (It is cycloalkyl) That is the case.

[0093] R 4 Preferably, it is hydrogen.

[0094] R 5 Preferably, it is hydrogen.

[0095] m is preferably 0 or 1.

[0096] p is preferably 0.

[0097] q is preferably 0.

[0098] t1 is preferably 2.

[0099] t2 is preferably 1.

[0100] t3 is preferably 1.

[0101] Substructure: [ka] (In the formula, *1 is the Cy in compound [I]. 1 This represents the connection point with, *2 represents the bond site with the benzene ring in compound [I]. Preferably, the substructure formula is: [ka] (In the formula, *1 and *2 are as described above.) That is the case.

[0102] One preferred embodiment of compound [I] is compound [II]: [ka] [In the formula, Cy 1 , R 1 , R 2 , R 3 , R 4 , R 5 m, p, q, t1, t2, and t3 are synonymous with the definitions in item 1. It is a compound represented by [formula].

[0103] Further preferred specific embodiments of compound [I] include the compounds described in Examples 1 to 46 and Example 2-001, which will be discussed later.

[0104] Next, specific embodiments of each substituent in compound [Ia] are illustrated below. Note that compound [Ia] includes compound [I].

[0105] Cy 1w Preferably, (1) C 4-6 Cycloalkyl, (2) C 4-6 Cycloalkenyl, (3) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms as ring constituent atoms. (4) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (5) Phenyl, or (6) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. That is the case.

[0106] Cy 1w In another embodiment, preferably, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms as ring constituent atoms. (3) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (4) Phenyl, or (5) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. That is the case.

[0107] Cy1w In another embodiment, preferably, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms as ring constituent atoms. (3) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, or (4) Phenyl That is the case.

[0108] Cy 1w In another embodiment, preferably, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkyl, which contains one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms, in addition to carbon atoms, as ring constituent atoms, or (3) Phenyl That is the case.

[0109] Cy 1w In another embodiment, preferably, These are cyclohexenyl, azetidinyl, piperidyl, or phenyl.

[0110] Cy 1w In another embodiment, preferably, (1) C 4-6 Cycloalkyl, (2) Phenyl, or (3) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. That is the case.

[0111] Cy 1w In another embodiment, preferably, It is cyclobutyl, cyclohexyl, phenyl, or pyridyl.

[0112] Cy 1w In another embodiment, preferably, the ring constituent atoms include one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms, in addition to carbon atoms, and are 4 to 6 membered heterocycloalkyls.

[0113] Cy 1w In another embodiment, preferably, it is azetidinil.

[0114] Cy 2w Preferably, it is a 5- or 6-membered heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms.

[0115] Cy 2w In another embodiment, preferably, These are pyrazolylene, triazolylene, pyridylene, or pyrimidylene.

[0116] Cy 2w In another embodiment, preferably, is a 9- or 10-membered condensed heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms.

[0117] Y 1w Preferably, (1) Combination, or (2) -CONHCH2- That is the case.

[0118] Y 1w In another aspect, preferably, it is a combination.

[0119] Y 1w In another embodiment, preferably, it is -CONHCH2-.

[0120] R 1w Preferably, each is independent of the others. (1) Halogen, (2) C 1-4 Alkyl, (3) C 1-4 Haloalkyl, (4) C 1-4 Alkoxy, (5) SO2R 7w (Here, R 7w C may be replaced with NHCOMe. 1-4 Alkyl or C 3-4 (It is cycloalkyl), or (6) C 3-4 Cycloalkyl That is the case.

[0121] R 1w In another embodiment, preferably, each independently, (1) Halogen, (2) C 1-4 Alkoxy, or (3) SO2R 7w (Here, R 7w C may be replaced with NHCOMe. 1-4 Alkyl or C 3-4 (It is cycloalkyl) That is the case.

[0122] R 1w In another embodiment, preferably, each independently, (1) Halogen, (2) C 1-4 Alkoxy, or (3) SO2R 7w (Here, R 7w C 1-4 (It is alkyl.) That is the case.

[0123] R 1w In another embodiment, preferably, each independently, It is fluorine, methoxy, or methylsulfonyl.

[0124] R 1w In another embodiment, preferably, each independently, SO2R 7w (Here, R 7w C 1-4 It is alkyl.

[0125] R1w In another embodiment, preferably, each independently, (1) Halogen, (2) C 1-4 Alkyl, (3) C 1-4 Haloalkyl, (4) C 1-4 Alkoxy, or (5) C 3-4 Cycloalkyl That is the case.

[0126] R 1w In another embodiment, preferably, each independently, These are fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, methylsulfonyl, or cyclopropyl.

[0127] R 3 Preferably, each of these is a halogen, independently of the others. Two R atoms bonded to the same carbon atom 3 Preferably, it combines with its carbon atoms to form cyclopropane.

[0128] R 4 Preferably, it is hydrogen. R 5 Preferably, it is hydrogen.

[0129] R 2w Preferably, it is a halogen. R 13w Preferably, it is a halogen.

[0130] MW is preferably 1, 2, or 3. In another embodiment, mw is preferably 1 or 2. In another embodiment, mw is preferably 2 or 3.

[0131] p is preferably 0. In another embodiment, p is preferably 1.

[0132] q is preferably 0 or 2. In another embodiment, q is preferably 0.

[0133] t1 is preferably 2. t2w is preferably 1. t3 is preferably 1.

[0134] uw is preferably 0. In another embodiment, uw is preferably 1.

[0135] Substructure: [ka] [In the formula, *a is Y in compound [Ia] 1w This represents the connection point with, *b represents the bond site with the oxalamide moiety (C(=O)-C(=O)-NH-) in compound [Ia]. Cy 2w , R 2w , R 13w The definitions of p and uw are the same as those in the above [Section A1]. Preferably, the substructure formula is: [ka] [In the formula, X 11w is CH or N, *a and *b are synonymous with the above. That is the case.

[0136] One preferred embodiment of compound [Ia] is, Y 1w This is a bond, and R 2w and R 13w It is compound [Ia], where both are halogens.

[0137] Another preferred embodiment of compound [Ia] is Cy 2wHowever, it is a compound [Ia] which is a 5- or 6-membered heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms.

[0138] Another preferred embodiment of compound [Ia] is formula [IIa]: [ka] [In the formula, Cy 1w , R 1w , R 3 , R 4 , R 5 , mw, p, q, t1, t2w, and t3 are synonymous with the definitions in [Section A1] above, R 2w It is a halogen. It is a compound represented by [formula].

[0139] Another preferred embodiment of compound [Ia] is one in which p is 0, mw is 1, and R 4 and R 5 It is a compound [Ia] in which both are hydrogen atoms.

[0140] Another preferred embodiment of compound [Ia] is compound [Ia] in which t1 is 2 and both t2w and t3 are 1.

[0141] Another preferred embodiment of compound [Ia] is formula [IIIa]: [ka] [In the formula, Cy 1w , R 1w , R 3 , and q are synonymous with the definition in [Section A1] above. It is a compound represented by [formula].

[0142] Another preferred embodiment of compound [Ia] is, Cy 1w but, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkyl, which contains one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms, in addition to carbon atoms, as ring constituent atoms, or (3) Phenyl And, R 1w but, (1) Halogen, (2) C 1-4 Alkoxy, or (3) SO2R 7w (Here, R 7w C 1-4 (It is alkyl.) It is a compound represented by formula [IIIa].

[0143] Another preferred embodiment of compound [Ia] is formula [IVa]: [ka] [In the formula, X 11w is CH or N, Cy 1w , Y 1w , R 1w , R 3 mw, q, t1, t2w, and t3 are synonymous with the definitions in [Section A1] above. It is a compound represented by [formula].

[0144] Another preferred embodiment of compound [Ia] is, Cy 1w but, (1) C 4-6 Cycloalkyl, (2) Phenyl, or (3) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. And, Y 1w However, it is -CONHCH2-, R 1w However, each is independent of the others. (1) Halogen, (2) C 1-4Alkyl, (3) C 1-4 Haloalkyl, (4) C 1-4 Alkoxy, or (5) C 3-4 Cycloalkyl It is a compound represented by formula [IVa].

[0145] Another preferred embodiment of compound [Ia] is formula [Va]: [ka] [In the formula, X 12w is CH or N, Cy 1w , R 1w , R 3 mw, q, t1, t2w, and t3 are synonymous with the definitions in [Section A1] above. It is a compound represented by [formula].

[0146] Further preferred specific embodiments of compound [Ia] include the compounds described in Examples 1-46, 2-001, and 3-001-3-029, which will be discussed later.

[0147] As used herein, "pharmaceutically acceptable salt" refers to any salt known in the art that does not impose excessive toxicity. Specifically, this includes salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, etc. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977); (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002); (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007).

[0148] The pharmaceutically acceptable salts thereof can be obtained by reacting compound [I] or compound [Ia] with an inorganic acid, an organic acid, an inorganic base, or an organic base according to methods known to the present day.

[0149] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid. Preferably, salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, or hydrobromic acid are used.

[0150] Examples of salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetate, ethane-1,2-disulfonic acid, dodecyl sulfate, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcinic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, Examples include salts with malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid. Preferably, salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 2-hydroxy-1-ethanesulfonic acid are used.

[0151] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium. Preferably, salts with sodium, potassium, calcium, magnesium, or zinc are used.

[0152] Examples of salts with organic bases include salts with arecoline, betaine, choline, cremisole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine. Preferably, salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine are used.

[0153] Compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof may exist as a solvate. A "solvate" is, for example, a solvent molecule coordinated to compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof. The solvate can be any pharmaceutically acceptable solvate, such as a hydrate, acetate, acetone, ethanol, or dimethyl sulfoxide of compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof. Specifically, examples include the hemihydrate, monohydrate, dihydrate, monoacetate, monoacetone, monoacetone, or monoethanolate of compound [I] or compound [Ia], or the monohydrate, monoacetone, or monohydrochloride of the sodium salt of compound [I] or compound [Ia]. These solvates can be obtained by known methods.

[0154] Compound [I] or compound [Ia] may exist as a tautomer. In that case, compound [I] or compound [Ia] may exist as individual tautomers or as a mixture of tautomers.

[0155] Compound [I] or compound [Ia] may contain a carbon-carbon double bond. In that case, compound [I] or compound [Ia] may exist as the E-isomer, the Z-isomer, or a mixture of the E-isomer and the Z-isomer.

[0156] Compound [I] or compound [Ia] may have stereoisomers that should be recognized as cis / trans isomers. In such cases, compound [I] or compound [Ia] may exist as the cis isomer, the trans isomer, or a mixture of the cis and trans isomers.

[0157] Compound [I] or compound [Ia] may have one or more chiral carbon atoms. In that case, compound [I] or compound [Ia] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0158] Compound [I] or compound [Ia] may exist as an atropisomer. In that case, compound [I] or compound [Ia] may exist as individual atropisomers or as a mixture of atropisomers.

[0159] Compound [I] or compound [Ia] may simultaneously contain multiple structural features that give rise to the above-mentioned isomers. Furthermore, compound [I] or compound [Ia] may contain the above-mentioned isomers in any proportion.

[0160] Formulas, chemical structures, or compound names expressed herein without specifying stereochemistry include all possible isomers unless otherwise noted. For example, the following formula: [ka] The structure described above is, unless otherwise noted, (1) The following formula: [ka] A mixture of two enantiomers (S-isomer and R-isomer) represented by (2) S-enantiomer, and (3) R-enantiomer Includes all of the above.

[0161] Diastereomer mixtures can be separated into their individual diastereomers by conventional methods such as chromatography and crystallization. Alternatively, each diastereomer can be synthesized using stereochemically monolithic starting materials or through stereoselective reactions.

[0162] The separation of each single enantiomer from a mixture of enantiomers can be carried out by methods well known in this field. For example, from a mixture of enantiomers and a diastereomer mixture formed by reacting a substantially pure enantiomer known as a chiral auxiliary, a single diastereomer with an increased isomer ratio or substantially pure can be separated by standard methods such as fractional crystallization or chromatography. The separated diastereomer can then be converted to the desired enantiomer by removing the added chiral auxiliary through cleavage. Alternatively, the mixture of enantiomers can be directly separated by chromatography using a chiral stationary phase, a method well known in this field. Or, one of the enantiomers can be obtained by using substantially pure optically active starting materials, or by stereoselective synthesis (asymmetric induction) of a prochiral intermediate using a chiral auxiliary or an asymmetric catalyst.

[0163] The absolute configuration can be determined by X-ray crystallography of the crystalline product or intermediate. If necessary, a crystalline product or intermediate derived with a reagent having a known chiral center configuration may be used.

[0164] Compound [I] or Compound [Ia] is an isotope [ 2 H(D), 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 18 O, 18 F,35 S, 123 Compounds [I] or [Ia] may be labeled with an isotope. For example, if compound [I] or compound [Ia] has a methyl group, the methyl group may be replaced with a -CD3 group. Such labeled compound [I] or compound [Ia] are also included in the present invention. Compounds [I] or [Ia] labeled with an isotope may be useful in pharmaceuticals, pharmacokinetic studies, in vitro and / or in vivo assays, and / or diagnostics (positron emission tomography (PET), single-photon emission computed tomography (SPECT), etc.). Compounds [I] or [Ia] labeled with an isotope may be prepared using an isotope-labeled compound instead of a non-isotope-labeled compound according to known methods or the methods described herein.

[0165] Compound [I] or compound [Ia] may appropriately form a complex with one or more coformers in any molar ratio. The complex is a substance formed by intermolecular interactions such as ionic bonds and / or hydrogen bonds between compound [I] or compound [Ia] and the coformer, and may be crystalline. In addition to the inorganic acids, organic acids, inorganic bases, organic bases, or solvent molecules used to form solvates, the coformer may also be molecules such as amino acids, amides, and sugars, for example, (+)-camphoric acid, L-proline, N-acetylglycine, adipic acid, benzoic acid, D-(-)-mandelic acid, citric acid, D-(-)-isoascorbic acid, fumaric acid, 2,5-dihydroxybenzoic acid, glutaric acid, glycolic acid, hippuric acid, L-malic acid, L-pyrog Examples include lutamic acid, L-(+)-tartaric acid, maleic acid, malonic acid, nicotinamide, nicotinic acid, anthranilic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, o-sulfobenzimide, succinic acid, tris(hydroxymethyl)aminomethane, urea, oxalic acid, salicylic acid, trans-aconitic acid, DL-malic acid, DL-tartaric acid, p-toluenesulfonic acid, (1R)-(-)-camphor-10-sulfonic acid, and combinations thereof.

[0166] Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof is preferably substantially purified. More preferably, Compound [I] or Compound [Ia] or a pharmaceutically acceptable salt thereof is purified to a purity of 80% or higher.

[0167] The pharmaceutical compositions described herein may be prepared by mixing an active ingredient (e.g., compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof) with at least one pharmaceutically acceptable carrier, etc., as appropriate, according to methods known in the pharmaceutical technology. The content of the active ingredient in the pharmaceutical composition varies depending on the dosage form, dose, etc., but is, for example, 0.1 to 100% by weight of the total composition.

[0168] Dosage forms of pharmaceutical compositions containing compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0169] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, disintegrants, binders, fluidizers, lubricants, etc. in solid formulations; solvents, solubilizers, suspending agents, isotonic agents, buffers, analgesics, etc. in liquid formulations; and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solvents, solubilizers, suspending agents, etc. in semi-solid formulations. Furthermore, additives such as preservatives, antioxidants, colorants, and sweeteners may be added as needed.

[0170] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and gum arabic.

[0171] Examples of "disintegrants" include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose.

[0172] Examples of "binding agents" include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic.

[0173] Examples of "fluidizing agents" include light anhydrous silicic acid and magnesium stearate.

[0174] Examples of "lubricants" include magnesium stearate, calcium stearate, and talc.

[0175] Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.

[0176] Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.

[0177] Examples of "suspending agents" include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, and glyceryl monostearate.

[0178] Examples of "isotonic agents" include glucose, D-sorbitol, sodium chloride, and D-mannitol.

[0179] Examples of "buffering agents" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.

[0180] Examples of "pain-relieving agents" include benzyl alcohol.

[0181] Examples of "bases" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, refined lanolin, absorbent ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogol (macrogol 200-600, etc.), and combinations of two or more of these.

[0182] Examples of "preservatives" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.

[0183] Examples of "antioxidants" include sodium sulfite and ascorbic acid.

[0184] Examples of "coloring agents" include food colorings (such as Food Red No. 2 or 3, Food Yellow No. 4 or 5, etc.) and beta-carotene.

[0185] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, and aspartame.

[0186] The above-mentioned pharmaceutical composition can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to humans and other mammals (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.). The dosage (hereinafter also referred to as the "therapeutically effective dose" in this specification) varies depending on the target recipient, route of administration, target disease, symptoms, severity of the disease, dosage form, etc. For example, when administered orally to a human (adult patient, 60 kg body weight), the lower limit of the therapeutically effective dose may be approximately 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 10 mg, 20 mg, or 50 mg of compound [I] or compound [Ia] per day, and the upper limit of the therapeutically effective dose may be approximately 1 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 500 mg, or 1000 mg of compound [I] or compound [Ia] per day. In some embodiments, the therapeutically effective dose is approximately 0.01 mg to approximately 1000 mg of compound [I] or compound [Ia] per day, for example, approximately 0.1 mg to approximately 500 mg, for example, approximately 0.5 mg to approximately 200 mg, for example, approximately 1 mg to approximately 100 mg, for example, approximately 10 mg to approximately 50 mg, for example, approximately 20 mg to approximately 50 mg, for example, approximately 50 mg to approximately 100 mg. These amounts can be administered in divided doses once, twice, three times, or more times per day.

[0187] "Inhibiting LMP7" means inhibiting the function of LMP7, thereby eliminating or reducing its activity. For example, it means inhibiting the function of LMP7 based on the conditions of Test Example 1 described later. "Inhibiting LMP7" preferably means "inhibiting human LMP7."

[0188] An "LMP7 inhibitor" refers to a substance that inhibits the function of LMP7. Preferably, the "LMP7 inhibitor" is a "human LMP7 inhibitor."

[0189] Compound [I] or compound [Ia] or its pharmaceutically acceptable salts possess LMP7 inhibitory activity and may be useful in the treatment and / or prevention of various diseases or conditions that can be expected to improve by regulating LMP7 activity. Examples of diseases or conditions that can be expected to improve by inhibiting LMP7 activity include autoimmune diseases, multiple myeloma, and mantle cell lymphoma. Examples of autoimmune diseases include systemic lupus erythematosus, lupus nephritis, myasthenia gravis (ocular myasthenia gravis, generalized myasthenia gravis, etc.), immune thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus (bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, etc.), ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, etc.), multiple sclerosis, Examples include neuromyelitis optica, immune complex-mediated small vessel vasculitis (anti-GBM antibody-associated disease, cryoglobulin vasculitis, IgA vasculitis, hypocomplementary urticarial vasculitis, etc.), Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-associated disease, autoimmune hepatitis, and Kawasaki disease.

[0190] In this specification, “treatment” includes improvement of symptoms, prevention of worsening, maintenance of remission, prevention of relapse, and prevention of recurrence.

[0191] In this specification, "prevention" includes suppressing and delaying the onset of symptoms.

[0192] Kits (such as administration, treatment, and / or prevention kits), packages (such as packaging), and drug sets (and / or containers) are also useful, comprising a pharmaceutical composition containing compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof as an active ingredient or activator, and a description relating to the pharmaceutical composition stating that the pharmaceutical composition may or should be used for the treatment and / or prevention of a disease. Such kits, packages, and drug sets may comprise the pharmaceutical composition or one or more active ingredients or activators for use in the pharmaceutical composition, a description stating that the pharmaceutical composition or the active ingredients or activators may or should be used for the treatment and / or prevention of a disease, and one or more containers filled with other drugs or substances (or components). Examples of such kits, packages, and drug sets include commercial kits, commercial packages, and commercial drug sets appropriately directed for the treatment and / or prevention of target diseases. Such kits, packages, and drug sets may include warnings or package inserts in the form prescribed by government agencies that regulate the manufacture, use, or sale of pharmaceutical or biological products, indicating the approval of such government agency for the manufacture, use, or sale of the product in relation to human administration. The kits, packages, and drug sets may also include packaged products, and may include structures configured for appropriate dosage forms, or structures configured to achieve a more preferred medical treatment and / or prevention, including the treatment and / or prevention of the target disease.

[0193] In this specification, "approximately" means an approximate range and, when used with a number or range of numbers, includes a variation of up to 5% above or below that number.

[0194] In this specification, the presentation of preferred embodiments and options of compound [I] or compound [Ia] or its pharmaceutically acceptable salts, methods, uses and compositions also includes the presentation of any combination of such preferred embodiments and options, provided that they are combinatorial and inconsistent.

[0195] [General manufacturing method] Examples of general methods for producing compound [I] or compound [Ia] or its pharmaceutically acceptable salts are given below. However, the methods for producing compound [I] or compound [Ia] or its pharmaceutically acceptable salts are not limited to these methods. Furthermore, unless otherwise specified, the salts of each compound in the general methods may be appropriately selected from the "pharmaceutically acceptable salts" listed above.

[0196] The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, and column chromatography, as needed. However, in some cases, the process can proceed to the next step without isolation and / or purification. In this specification, room temperature refers to the temperature in an uncontrolled state, and one embodiment is a range of 1°C to 40°C.

[0197] [Manufacturing Method A1]: Method for producing compound [I] or its salt Compound [I] or a salt thereof can be produced, for example, by the following production method A1. [ka] [In the formula, P 1 This is an amine protecting group (e.g., tert-butoxycarbonyl, benzyloxycarbonyl, or 9-fluorenylmethyloxycarbonyl, etc.), L 1 is a halogen (e.g., chlorine or bromine, etc.) or hydroxyl, Cy 1 , R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 m, n, p, q, t1, t2, and t3 are synonymous with the definitions above.

[0198] (Process A1-1) Compound [A1-2] or its salt is P of compound [A1-1] or its salt. 1 It can be produced by removing P through a deprotection reaction. The deprotection reaction involves P 1 It should be carried out under conditions appropriate to the type. For example, P 1 If is tert-butoxycarbonyl, compound [A1-2] or its salt can be produced by reacting compound [A1-1] or its salt in a solvent in the presence of an acid. Depending on the conditions, the reaction may also be carried out without a solvent. Examples of solvents include alcoholic solvents such as methanol and halogenated solvents such as chloroform. The preferred solvent is chloroform. Examples of acids include trifluoroacetic acid, p-toluenesulfonic acid, and hydrochloric acid. The preferred acid is trifluoroacetic acid. The reaction temperature is, for example, 0°C to 100°C, preferably 0°C to 30°C. Compound [A1-1] or a salt thereof may be commercially available or produced from a commercially available product by known methods, for example, by the production methods B1, B2, B3, B4 and B5 described below.

[0199] (Process A1-2) Compound [I] or a salt thereof can be produced by reacting compound [A1-2] or a salt thereof with compound [A1-3] or a salt thereof. For example, L 1 If is a halogen, compound [I] or a salt thereof can be produced by reacting compound [A1-2] or a salt thereof with compound [A1-3] or a salt thereof in a solvent in the presence of a base. Examples of solvents include halogenated solvents such as chloroform and ether-based solvents such as tetrahydrofuran. The preferred solvent is chloroform. Examples of bases include triethylamine, N,N-diisopropylethylamine, and potassium carbonate. Preferred bases are triethylamine or N,N-diisopropylethylamine. The reaction temperature is, for example, -20°C to 50°C, preferably 0°C to 30°C. Compound [A1-3] or its salt may be commercially available or may be produced from a commercially available product by a known method.

[0200] (Process A1-3) Compound [I] or a salt thereof can be produced by reacting compound [A1-2] or a salt thereof with compound [A1-3] or a salt thereof. For example, L 1 If is hydroxyl, compound [I] or a salt thereof can be produced by reacting compound [A1-2] or a salt thereof with compound [A1-3] or a salt thereof in a solvent in the presence of a condensing agent and a base. Examples of solvents include amide solvents such as N,N-dimethylformamide, ester solvents such as ethyl acetate, halogen solvents such as dichloromethane, and mixtures thereof. The preferred solvent is N,N-dimethylformamide. Examples of condensing agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1,1'-carbonyldiimidazole, hexafluorophosphate (benzotriazole-1-yloxy)tripyrrolidinophosphonium, 1-propanephosphonic anhydride, and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride. Preferred condensing agents are 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 1-propanephosphonic anhydride. Examples of suitable bases include N,N-diisopropylethylamine, triethylamine, and pyridine. Preferred bases are N,N-diisopropylethylamine or triethylamine. The reaction temperature is, for example, -20°C to 50°C, preferably 0°C to 30°C.

[0201] [Manufacturing Method A2]: Method for producing compound [Ia] or its salt Compound [Ia] or its salt can be produced, for example, by the following production method A2. [ka] [In the formula, P 1 and L 1 This is synonymous with the above definition, Cy 1w Cy 2w , Y 1w , R 1w , R 2w , R 3 , R 4 , R 5 , R 13w mw, p, q, t1, t2w, t3, and uw are synonymous with the definitions in [Section A1] above.

[0202] (Process A2-1) Compound [A2-2] or its salt is P of compound [A2-1] or its salt. 1 It can be produced by removing P through a deprotection reaction. The deprotection reaction involves P 1 It should be carried out under conditions appropriate to the type. For example, P 1 If is tert-butoxycarbonyl, compound [A2-2] or a salt thereof can be produced by reacting compound [A2-1] or a salt thereof according to step A1-1. Compound [A2-1] or its salt may be commercially available or produced from a commercially available product by known methods, for example, by the production methods B6, B7, B8, B9 and B10 described below.

[0203] (Process A2-2) Compound [Ia] or a salt thereof can be produced by reacting compound [A2-2] or a salt thereof with compound [A1-3] or a salt thereof. For example, L 1If is a halogen, compound [Ia] or a salt thereof can be produced by reacting compound [A2-2] or a salt thereof with compound [A1-3] or a salt thereof according to step A1-2.

[0204] (Process A2-3) Compound [Ia] or a salt thereof can be produced by reacting compound [A2-2] or a salt thereof with compound [A1-3] or a salt thereof. For example, L 1 If is hydroxyl, compound [Ia] or a salt thereof can be produced by reacting compound [A2-2] or a salt thereof with compound [A1-3] or a salt thereof according to step A1-3.

[0205] [Manufacturing Method B1]: Method for producing compound [A1-1] or its salt The compound [A1-1] or its salt used in manufacturing method A1 can be produced, for example, by manufacturing method B1 shown below. [ka] [In the formula, P 2 This is an amine protecting group (e.g., tert-butoxycarbonyl, benzyloxycarbonyl, or 9-fluorenylmethyloxycarbonyl group, etc.), Cy 1 , R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 m, n, p, q, t1, t2, t3 and P 1 This is synonymous with the definition above.

[0206] (Process B1-1) Compound [B1-2] or its salt is P of compound [B1-1] or its salt. 2 It can be produced by removing P through a deprotection reaction. The deprotection reaction involves P2 It should be carried out under conditions appropriate to the type. For example, P 2 If is tert-butoxycarbonyl, compound [B1-2] or a salt thereof can be produced by reacting compound [B1-1] or a salt thereof according to step A1-1. Compound [B1-1] or its salt may be commercially available or produced from a commercially available product by known methods, for example, by the production methods C1, C2 and C3 described below.

[0207] (Process B1-2) Compound [A1-1] or a salt thereof can be produced by reacting compound [B1-2] or a salt thereof with compound [B1-3] or a salt thereof according to step A1-3. Compound [B1-3] or its salt may be commercially available or may be produced from a commercially available product by a known method, for example, by the production method M1 described below.

[0208] [Manufacturing Method B2]: Alternative method for producing compound [A1-1] or its salt Compound [A1-1] or its salt can also be produced, for example, by the production method B2 shown below. [ka] [In the formula, Cy 1 , R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 m, n, p, q, t1, t2, t3 and P 1 This is synonymous with the definition above.

[0209] (Process B2-1) Compound [B2-2] or a salt thereof can be produced by reacting compound [B1-2] or a salt thereof with compound [B2-1] or a salt thereof according to step A1-2.

[0210] (Process B2-2) Compound [B2-3] or its salt can be produced by hydrolyzing compound [B2-2] or its salt in a solvent in the presence of a base. Examples of solvents include ether-based solvents such as tetrahydrofuran, alcohol-based solvents such as ethanol, water, and mixtures thereof. Preferred solvents are a mixture of ethanol and water, a mixture of tetrahydrofuran and water, or a mixture of ethanol, tetrahydrofuran, and water. Examples of suitable bases include sodium hydroxide, lithium hydroxide monohydrate, and potassium hydroxide. A preferred base is sodium hydroxide. The reaction temperature is, for example, 0°C to 60°C, preferably 0°C to 30°C.

[0211] (Process B2-3) Compound [A1-1] or a salt thereof can be produced by reacting compound [B2-3] or a salt thereof with compound [B2-4] or a salt thereof according to step A1-3. Compound [B2-4] or its salt may be commercially available or produced from a commercially available product by a known method, for example, by the production method M2 described below.

[0212] [Manufacturing Method B3]: Method for producing compound [B3-3] or its salt In compound [A1-1] or its salt used in manufacturing method A1, n is 1, Cy 1 but, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (3) Phenyl, or (4) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. Compound [B3-3] or a salt thereof can be produced, for example, by the production method B3 shown below. [ka] [In the formula, L 2 These are halogens (e.g., fluorine, chlorine, bromine, or iodine), R 8 Each of them independently consists of hydrogen or C 1-4 Alkyl or one of the R 8 However, the other R 8 They may also combine to form a ring, Cy 1a teeth, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (3) Phenyl, or (4) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. And, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , m, p, q, t1, t2, t3 and P 1 This is synonymous with the definition above.

[0213] (Process B3-1) Compound [B3-3] or its salt can be produced by cross-coupling compound [B3-1] or its salt with compound [B3-2] or its salt in a solvent in the presence of a base and a palladium catalyst. Ligands may be added as needed. Examples of solvents include ether-based solvents such as dimethoxyethane, alcohol-based solvents such as ethanol, hydrocarbon-based solvents such as toluene, amide-based solvents such as N,N-dimethylacetamide, nitrile-based solvents such as acetonitrile, water, and mixtures thereof. A preferred solvent is a mixture of dimethoxyethane and water. Examples of suitable bases include potassium carbonate, cesium carbonate, sodium carbonate, tripotassium phosphate, and potassium acetate. Preferred bases are tripotassium phosphate or potassium carbonate. Examples of palladium catalysts include [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), tetrakis(triphenylphosphine)palladium(O), bis(triphenylphosphine)palladium(II) dichloride, dichlorobis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium(II), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, and palladium acetate. Preferred palladium catalysts are [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium(II). Examples of ligands include triphenylphosphine, dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine, and dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. The reaction temperature is, for example, 30°C to 120°C, preferably 60°C to 100°C. Compound [B3-1] or a salt thereof may be commercially available or may be produced from a commercially available product by a known method, for example, by the production method C4 described below. Compound [B3-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods. Substitute compound [B3-2] or its salt with R in a known reaction. 1 Functional groups that can be converted to Cy or protected functional groups 1a Using a compound or salt thereof, the present manufacturing method is carried out to obtain a compound or salt thereof corresponding to compound [B3-3], and then its functional group is R 1 Compound [B3-3] or a salt thereof may be produced by converting to [the specified compound].

[0214] [Manufacturing Method B4]: Method for producing compound [B4-3] or its salt In compound [A1-1] or its salt used in manufacturing method A1, n is 1, Cy 1 but, (1) C 4-6 Cycloalkyl, or (2) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom. Compound [B4-3] or a salt thereof can be produced, for example, by the following production method B4. [ka] [In the formula, Cy 1b teeth, (1) C 4-6 Cycloalkenyl, or (2) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom. And, Cy 1c teeth, (1) C 4-6 Cycloalkyl, or (2) A 4- to 6-membered heterocycloalkyl compound containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, R 9 Each of them independently consists of hydrogen or C 1-4 Alkyl or one of the R 9 However, the other R 9 They may also combine to form a ring, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , m, p, q, t1, t2, t3, L 2 and P 1 This is synonymous with the definition above.

[0215] (Process B4-1) Compound [B4-2] or a salt thereof can be produced by reacting compound [B3-1] or a salt thereof with compound [B4-1] or a salt thereof according to step B3-1. Compound [B4-1] or a salt thereof may be commercially available or may be produced from a commercially available product by known methods.

[0216] (Process B4-2) Compound [B4-3] or its salt can be produced by catalytic hydrogenation of compound [B4-2] or its salt in a solvent in the presence of a catalyst. Examples of solvents include alcoholic solvents such as methanol or ethanol, ether-based solvents such as tetrahydrofuran, and mixed solvents thereof. Preferred solvents are a mixed solvent of methanol and tetrahydrofuran or ethanol. Examples of catalysts include palladium / carbon, palladium hydroxide, and platinum oxide. The preferred catalyst is palladium / carbon. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 30°C. Substitute compound [B4-1] or its salt with R in a known reaction. 1 Functional groups that can be converted to Cy or protected functional groups 1b Using a compound or a salt thereof, the present manufacturing method is carried out to obtain a compound or a salt thereof corresponding to compound [B4-3], and then its functional group is R 1 Compound [B4-3] or a salt thereof may be produced by converting to [the specified compound].

[0217] [Manufacturing Method B5]: Method for producing compound [B5-2] or its salt In compound [A1-1] or its salt used in manufacturing method A1, n is 1, Cy 1 However, it contains one nitrogen atom in addition to carbon atoms as a ring constituent atom, and is a 4 to 6-membered heterocycloalkyl group. Compound [B5-2] or a salt thereof can be produced, for example, by the following production method B5. [ka] [In the formula, Cy 1d It is a 4- to 6-membered heterocycloalkyl group containing one nitrogen atom in addition to carbon atoms as ring constituent atoms. R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , m, p, q, t1, t2, t3, P 1 and L 2 This is synonymous with the definition above.

[0218] (Process B5-1) Compound [B5-2] or its salt can be produced by reacting compound [B3-1] or its salt with compound [B5-1] or its salt in a solvent in the presence of a base. Examples of solvents include amide solvents such as N,N-dimethylformamide and N-methylpyrrolidone, and ether solvents such as dioxane. The preferred solvent is N-methylpyrrolidone. Examples of bases include N,N-diisopropylethylamine, triethylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene. The preferred base is N,N-diisopropylethylamine. The reaction temperature is, for example, 100°C to 190°C, preferably 120°C to 170°C. Compound [B5-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0219] [Manufacturing Method B6]: Method for producing compound [A2-1] or its salt The compound [A2-1] or its salt used in manufacturing method A2 can be produced, for example, by manufacturing method B6 as shown below. [ka] [In the formula, P 1 and P 2 This is synonymous with the above definition, Cy 1w Cy 2w , Y 1w , R 1w , R 2w , R 3 , R 13w mw, p, q, t1, t2w, t3, and uw are synonymous with the definitions in [Section A1] above.

[0220] (Process B6-1) Compound [B6-2] or its salt is P of Compound [B6-1] or its salt. 2 It can be produced by removing P through a deprotection reaction. The deprotection reaction involves P 2 It should be carried out under conditions appropriate to the type. For example, P 2If is tert-butoxycarbonyl, compound [B6-2] or a salt thereof can be produced by reacting compound [B6-1] or a salt thereof according to step A1-1. Compound [B6-1] or its salt may be commercially available or produced from a commercially available product by known methods, for example, by the production methods C6, C7, C8, C9, C10, C11 and C12 described below.

[0221] (Process B6-2) Compound [A2-1] or a salt thereof can be produced by reacting compound [B6-2] or a salt thereof with compound [B6-3] or a salt thereof according to step A1-3. Compound [B6-3] or a salt thereof may be commercially available or may be produced from a commercially available product by a known method, for example, by the production method M3 described below.

[0222] [Manufacturing Method B7]: Alternative method for producing compound [A2-1] or its salt Compound [A2-1] or its salt can also be produced, for example, by the production method B7 shown below. [ka] [In the formula, P 1 This is synonymous with the above definition, Cy 1w Cy 2w , Y 1w , R 1w , R 2w , R 3 , R 13w mw, p, q, t1, t2w, t3, and uw are synonymous with the definitions in [Section A1] above.

[0223] (Process B7-1) Compound [B7-1] or a salt thereof can be produced by reacting compound [B6-2] or a salt thereof with compound [B2-1] or a salt thereof according to step A1-2.

[0224] (Process B7-2) Compound [B7-2] or a salt thereof can be produced by reacting compound [B7-1] or a salt thereof according to step B2-2.

[0225] (Process B7-3) Compound [A2-1] or a salt thereof can be produced by reacting compound [B7-2] or a salt thereof with compound [B7-3] or a salt thereof according to step A1-3. Compound [B7-3] or its salt may be commercially available or produced from a commercially available product by known methods, for example, by the production method M2 described below.

[0226] [Manufacturing Method B8]: Method for producing compound [B8-3] or its salt In compound [A2-1] or its salt used in manufacturing method A2, Cy 1w but, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (3) Phenyl, or (4) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms, Cy 2w However, it is a six-membered heteroarylene containing one to three nitrogen atoms in addition to carbon atoms as ring constituent atoms. Y 1w However, the compound [B8-3] or its salt, which is a bond, can be produced, for example, by the production method B8 shown below. [ka] [In the formula, X 7w , X 8w , X 9w and X 10w Each is independently either CH or N, However, X7w , X 8w , X 9w , and X 10w The total number of N is 1, 2, or 3. Cy 1a , R 8 , P 1 and L 2 This is synonymous with the above definition, R 1w , R 2w , R 3 , R 13w mw, p, q, t1, t2w, t3, and uw are synonymous with the definitions in [Section A1] above.

[0227] (Process B8-1) Compound [B8-3] or a salt thereof can be produced by reacting compound [B8-1] or a salt thereof with compound [B8-2] or a salt thereof according to the method of step B3-1. Compound [B8-1] or its salt may be commercially available or may be produced from a commercially available product by a known method, for example, by the production method C9 described below. Compound [B8-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods. Substitute compound [B8-2] or its salt with R in a known reaction. 1w Functional groups that can be converted to Cy or protected functional groups 1a Using a compound or a salt thereof, the present manufacturing method is carried out to obtain a compound or a salt thereof corresponding to compound [B8-3], and then its functional group is R 1w Compound [B8-3] or a salt thereof may be produced by converting to [the specified compound].

[0228] [Manufacturing Method B9]: Method for producing compound [B9-3] or its salt In compound [A2-1] or its salt used in manufacturing method A2, Cy 1w but, (1) C 4-6 Cycloalkyl, or (2) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom. And, Cy 2w However, it is a six-membered heteroarylene containing one to three nitrogen atoms in addition to carbon atoms as ring constituent atoms. Y 1w However, the compound [B9-3] or its salt, which is a bond, can be produced, for example, by the production method B9 shown below. [ka] [In the formula, X 7w , X 8w , X 9w , X 10w Cy 1b Cy 1c , R 9 , P 1 and L 2 This is synonymous with the above definition, R 1w , R 2w , R 3 , R 13w mw, p, q, t1, t2w, t3, and uw are synonymous with the definitions in [Section A1] above.

[0229] (Process B9-1) Compound [B9-2] or a salt thereof can be produced by reacting compound [B8-1] or a salt thereof with compound [B9-1] or a salt thereof according to step B3-1. Compound [B9-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0230] (Process B9-2) Compound [B9-3] or a salt thereof can be produced by reacting compound [B9-2] or a salt thereof according to step B4-2. Substitute compound [B9-1] or its salt with R in a known reaction. 1w Functional groups that can be converted to Cy or protected functional groups1b Using a compound or salt thereof, the present manufacturing method is carried out to obtain a compound or salt thereof corresponding to compound [B9-3], and then its functional group is R 1w Compound [B9-3] or a salt thereof may be produced by converting to [the specified compound].

[0231] [Manufacturing Method B10]: Method for producing compound [B10-2] or its salt In compound [A2-1] or its salt used in manufacturing method A2, Cy 1w However, it is a 4- to 6-membered heterocycloalkyl group that contains one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. And, Cy 2w However, it is a six-membered heteroarylene containing one to three nitrogen atoms in addition to carbon atoms as ring constituent atoms. Y 1w However, it is a combination. Compound [B10-2] or its salt can be produced, for example, by the production method B10 shown below. [ka] [In the formula, Cy 1fw It is a 4- to 6-membered heterocycloalkyl group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. X 7w , X 8w , X 9w , X 10w , P 1 and L 2 This is synonymous with the above definition, R 1w , R 2w , R 3 , R 13w mw, p, q, t1, t2w, t3, and uw are synonymous with the definitions in [Section A1] above.

[0232] (Process B10-1) Compound [B10-2] or a salt thereof can be produced by reacting compound [B8-1] or a salt thereof with compound [B10-1] or a salt thereof according to step B5-1. Compound [B10-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0233] [Manufacturing Method C1]: Method for producing compound [C1-4] or its salt In the compound [B1-1] or its salt used in manufacturing method B1, n is 1, Cy 1 but, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (3) Phenyl, or (4) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. Compound [C1-4] or a salt thereof can be produced, for example, by the following production method C1. [ka] [In the formula, L 3 These are halogens (e.g., chlorine, bromine, or iodine); R 10 Each of them independently consists of hydrogen or C 1-4 Alkyl or one of the R 10 However, the other R 10 They may also combine to form a ring, Cy 1a , R 1 , R 2 , R 8 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , m, p, P 2and L 2 This is synonymous with the definition above.

[0234] (Process C1-1) Compound [C1-3] or a salt thereof can be produced by reacting compound [C1-1] or a salt thereof with compound [C1-2] or a salt thereof according to step B3-1. Compound [C1-1] or a salt thereof may be commercially available or may be produced from a commercially available product by known methods. Compound [C1-2] or its salt may be commercially available or may be produced from a commercially available product by known methods.

[0235] (Process C1-2) Compound [C1-4] or a salt thereof can be produced by reacting compound [C1-3] or a salt thereof with compound [B3-2] or a salt thereof according to step B3-1. Substitute compound [B3-2] or its salt with R in a known reaction. 1 Functional groups that can be converted to Cy or protected functional groups 1a Using a compound or a salt thereof, the present manufacturing method is carried out to obtain a compound or a salt thereof corresponding to compound [C1-4], and then its functional group is R 1 Compound [C1-4] or a salt thereof may be produced by converting to [C1-4].

[0236] [Manufacturing Method C2]: Method for producing compound [C2-2] or its salt In the compound [B1-1] or its salt used in manufacturing method B1, n is 1, Cy 1 but, (1) C 4-6 Cycloalkyl, or (2) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom. Compound [C2-2] or a salt thereof can be produced, for example, by the following production method C2. [ka] [In the formula, Cy 1b Cy 1c , R 1 , R 2 , R 9 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , m, p, P 2 and L 2 This is synonymous with the definition above.

[0237] (Process C2-1) Compound [C2-1] or a salt thereof can be produced by reacting compound [C1-3] or a salt thereof with compound [B4-1] or a salt thereof according to step B3-1.

[0238] (Process C2-2) Compound [C2-2] or a salt thereof can be produced by reacting compound [C2-1] or a salt thereof according to step B4-2. Substitute compound [B4-1] or its salt with R in a known reaction. 1 Functional groups that can be converted to Cy or protected functional groups 1b Using a compound or salt thereof, the present manufacturing method is carried out to obtain a compound or salt thereof corresponding to compound [C2-2], and then its functional group is R 1 Compound [C2-2] or a salt thereof may be produced by converting to [C2-2].

[0239] [Manufacturing Method C3]: Method for producing compound [C3-1] or its salt In the compound [B1-1] or its salt used in manufacturing method B1, n is 1, Cy 1 However, it contains one nitrogen atom in addition to carbon atoms as a ring constituent atom, and is a 4 to 6-membered heterocycloalkyl group. Compound [C3-1] or a salt thereof can be produced, for example, by the following production method C3. [ka] [In the formula, Cy 1d , R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , m, p, P 2 and L 2 This is synonymous with the definition above.

[0240] (Process C3-1) Compound [C3-1] or a salt thereof can be produced by reacting compound [C1-3] or a salt thereof with compound [B5-1] or a salt thereof according to step B5-1.

[0241] [Manufacturing Method C4]: Method for producing compound [B3-1] or its salt The compound [B3-1] or its salt used in manufacturing methods B3, B4, and B5 can be produced, for example, by manufacturing method C4 shown below. [ka] [In the formula, R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , p, q, t1, t2, t3, P 1 , P 2 and L 2 This is synonymous with the definition above.

[0242] (Process C4-1) Compound [C4-1] or its salt is P of compound [C1-3] or its salt. 2It can be produced by removing it through a deprotection reaction. The deprotection reaction is P 2 It should be carried out under conditions appropriate to the type. For example, P 2 If is tert-butoxycarbonyl, compound [C4-1] or a salt thereof can be produced by reacting compound [C1-3] or a salt thereof according to step A1-1.

[0243] (Process C4-2) Compound [B3-1] or a salt thereof can be produced by reacting compound [C4-1] or a salt thereof with compound [B1-3] or a salt thereof according to step A1-3.

[0244] [Manufacturing Method C5]: Method for producing compound [C5-3] or its salt In the compound [B1-1] or its salt used in manufacturing method B1, n is 0, Compound [C5-3] or its salt can be produced, for example, by the following production method C5. [ka] [In the formula, L 4 These are halogens (e.g., chlorine, bromine, or iodine), Cy 1 , R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , X 5 , m, p and P 2 This is synonymous with the definition above.

[0245] (Process C5-1) Compound [C5-3] or a salt thereof can be produced by reacting compound [C5-1] or a salt thereof with compound [C5-2] or a salt thereof according to step B3-1. Compound [C5-1] or its salt may be commercially available or produced from a commercially available product by known methods, for example, by the production methods D1, D2, D3 and D4 described below. Compound [C5-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0246] [Manufacturing Method C6]: Method for producing compound [C6-4] or its salt In the compound [B6-1] or its salt used in manufacturing method B6, Cy 1w but, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (3) Phenyl, or (4) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. And, Cy 2w However, it is a six-membered heteroarylene containing one to three nitrogen atoms in addition to carbon atoms as ring constituent atoms. Y 1w However, it is a combination, R 2w However, it is a halogen, R 13w However, it is a halogen. Compound [C6-4] or its salt can be produced, for example, by the production method C6 shown below. [ka] [In the formula, R 2aw It is a halogen, R 13aw It is a halogen, X 7w , X 8w , X 9w , X 10w Cy 1a , L2 , L 3 , R 8 , R 10 , and P 2 This is synonymous with the above definition, R 1w mw, p, and uw are synonymous with the definitions in [Section A1] above.

[0247] (Process C6-1) Compound [C6-3] or a salt thereof can be produced by reacting compound [C6-1] or a salt thereof with compound [C6-2] or a salt thereof according to step B3-1. Compound [C6-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods. Compound [C6-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0248] (Process C6-2) Compound [C6-4] or a salt thereof can be produced by reacting compound [C6-3] or a salt thereof with compound [B8-2] or a salt thereof according to step B3-1. Substitute compound [B8-2] or its salt with R in a known reaction. 1w Functional groups that can be converted to Cy or protected functional groups 1a Using a compound or a salt thereof, the present manufacturing method is carried out to obtain a compound or a salt thereof corresponding to compound [C6-4], and then its functional group is R 1w Compound [C6-4] or a salt thereof may be produced by converting to [C6-4].

[0249] [Manufacturing Method C7]: Method for producing compound [C7-2] or its salt In the compound [B6-1] or its salt used in manufacturing method B6, Cy 1w but, (1) C 4-6 Cycloalkyl, or (2) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom. And, Cy 2w However, it is a six-membered heteroarylene containing one to three nitrogen atoms in addition to carbon atoms as ring constituent atoms. Y 1w However, it is a combination, R 2w However, it is a halogen, R 13w However, it is a halogen. Compound [C7-2] or its salt can be produced, for example, by the following production method C6. [ka] [In the formula, X 7w , X 8w , X 9w , X 10w Cy 1b Cy 1c , L 2 , R 2aw , R 9 , R 13aw and P 2 This is synonymous with the above definition, R 1w mw, p, and uw are synonymous with the definitions in [Section A1] above.

[0250] (Process C7-1) Compound [C7-1] or a salt thereof can be produced by reacting compound [C6-3] or a salt thereof with compound [B9-1] or a salt thereof according to step B3-1.

[0251] (Process C7-2) Compound [C7-2] or a salt thereof can be produced by reacting compound [C7-1] or a salt thereof according to step B4-2. Substitute compound [B9-1] or its salt with R in a known reaction. 1w Functional groups that can be converted to Cy or protected functional groups1b Using a compound or a salt thereof, the present manufacturing method is carried out to obtain a compound or a salt thereof corresponding to compound [C7-2], and then its functional group is R 1w Compound [C7-2] or a salt thereof may be produced by converting to .

[0252] [Manufacturing Method C8]: Method for producing compound [C8-1] or its salt In the compound [B6-1] or its salt used in manufacturing method B6, Cy 1w However, it is a 4- to 6-membered heterocycloalkyl group that contains one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. And, Cy 2w However, it is a six-membered heteroarylene containing one to three nitrogen atoms in addition to carbon atoms as ring constituent atoms. Y 1w However, it is a combination, R 2w However, it is a halogen, R 13w However, it is a halogen. Compound [C8-1] or its salt can be produced, for example, by the production method C8 shown below. [ka] [In the formula, X 7w , X 8w , X 9w , X 10w Cy 1fw , L 2 , R 2aw , R 13aw and P 2 This is synonymous with the above definition, R 1w mw, p, and uw are synonymous with the definitions in [Section A1] above.

[0253] (Process C8-1) Compound [C8-1] or a salt thereof can be produced by reacting compound [C6-3] or a salt thereof with compound [B10-1] or a salt thereof according to step B5-1.

[0254] [Manufacturing Method C9]: Method for producing compound [B8-1] or its salt The compound [B8-1] or its salt used in manufacturing methods B8, B9, and B10 can be produced, for example, by manufacturing method C9 shown below. [ka] [In the formula, X 7w , X 8w , X 9w , X 10w , P 1 , P 2 and L 2 This is synonymous with the above definition, R 2w , R 3 , R 13w p, q, t1, t2w, t3, and uw are synonymous with the definitions in [Section A1] above.

[0255] (Process C9-1) Compound [C9-1] or its salt is P of compound [C6-3] or its salt. 2 It can be produced by removing it through a deprotection reaction. The deprotection reaction is P 2 It should be carried out under conditions appropriate to the type. For example, P 2 If is tert-butoxycarbonyl, compound [C9-1] or a salt thereof can be produced by reacting compound [C6-3] or a salt thereof according to step A1-1.

[0256] (Process C9-2) Compound [B8-1] or a salt thereof can be produced by reacting compound [C9-1] or a salt thereof with compound [B6-3] or a salt thereof according to step A1-3.

[0257] [Manufacturing Method C10]: Method for producing compound [C10-2] or its salt In the compound [B6-1] or its salt used in manufacturing method B6, Cy 2wHowever, it is a 5-membered heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms. Y 1w However, it is a combination. Compound [C10-2] or its salt can be produced, for example, by the production method C10 shown below. [ka] [In the formula, Join: [ka] These are single or double bonds, X 1w , X 2w , and X 4w is CH or N, X 3w and X 5w is C or N, X 1w , X 2w , X 3w , X 4w and X 5w Together, they form a 5-membered heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms. L 4 and P 2 This is synonymous with the above definition, Cy 1w , R 1w , R 2w , R 13w mw, p, and uw are synonymous with the definitions in [Section A1] above.

[0258] (Process C10-1) Compound [C10-2] or a salt thereof can be produced by reacting compound [C10-1] or a salt thereof with compound [C5-2] or a salt thereof according to step B3-1. Compound [C10-1] or its salt may be commercially available or produced from a commercially available product by known methods, for example, by the production methods D5, D6, D7 and D8 described below.

[0259] [Manufacturing Method C11]: Method for producing compound [C11-5] or its salt In the compound [B6-1] or its salt used in manufacturing method B6, Y 1w However, it is -CONHCH2-; Cy 2w However, it is a 5-membered heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms. R 2w It is a halogen, and R 13w is a halogen, or R 2w and R 13w However, R 2w The benzene ring to which Cy 2w Together with the ring, it may form a tricyclic condensed heterocycle containing, in addition to carbon atoms, one to four heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms as ring constituent atoms. Compound [C11-5] or its salt can be produced, for example, by the following production method C11. [ka] [In the formula, X 13w is CH or N, P 2 This is synonymous with the definition above, Cy 1w , R 1w , R 2w , R 13w mw, p, and uw are synonymous with the definitions in [Section A1] above.

[0260] (Process C11-1) Compound [C11-2] or its salt can be produced by azidating compound [C11-1] or its salt in a solvent in the presence of a base and an azidating agent. Examples of azidating agents include diphenyl phosphate azide, sodium azide, and bis(4-nitrophenyl) phosphate. The preferred azidating agent is diphenyl phosphate azide. Examples of suitable bases include 1,8-diazabicyclo[5.4.0]undeca-7-ene and boron trifluoride diethyl etherate. The preferred base is 1,8-diazabicyclo[5.4.0]undeca-7-ene. Examples of solvents include ether-based solvents such as tetrahydrofuran and 1,4-dioxane, and aromatic hydrocarbon solvents such as toluene. Tetrahydrofuran is a preferred solvent. The reaction temperature is, for example, 0°C to 90°C, preferably 0°C to 30°C. Compound [C11-1] or its salt may be commercially available or produced from a commercially available product by known methods, for example, by the production methods D9 and D10 described below.

[0261] (Process C11-2) Compound [C11-3] or its salt can be produced by reducing compound [C11-2] or its salt in a solvent in the presence of a reducing agent. Examples of reducing agents include triphenylphosphine, hydrogen gas, lithium aluminum hydride, sodium borohydride, zinc, and iron. The preferred reducing agent is triphenylphosphine. Examples of solvents include ether-based solvents such as tetrahydrofuran, alcohol-based solvents such as ethanol, and mixed solvents of these with water. A preferred solvent is a mixed solvent of tetrahydrofuran and water. The reaction temperature is, for example, 0°C to 80°C, preferably 0°C to 30°C.

[0262] (Process C11-3) Compound [C11-5] or a salt thereof can be produced by reacting compound [C11-3] or a salt thereof with compound [C11-4] or a salt thereof according to step A1-3. Compound [C11-4] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0263] [Manufacturing Method C12]: Method for producing compound [C11-5] or its salt In the compound [B6-1] or its salt used in manufacturing method B6, Cy 1w However, it is a 4- to 6-membered heterocycloalkyl group that contains one nitrogen atom in addition to carbon atoms as ring constituent atoms. Cy 2w However, it is a 9-membered condensed heteroarylene that contains 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms. Y 1w However, it is a combination, MW is 1, uw is 0, Compound [C12-5] or its salt can be produced, for example, by the following production method C12. [ka] [In the formula, L 8w , L 9w and L 10w These are, independently, halogens (e.g., bromine or iodine), X 12w is CH or N, Cy 1d , R 2aw , R 10 and P 2 As stated above, R 1w And p is synonymous with the definition in [Section A1] above.

[0264] (Process C12-1) Compound [C12-3] or its salt can be produced by cross-coupling compound [C12-1] or its salt with compound [C12-2] or its salt in a solvent in the presence of a zincating reagent and a metal catalyst. Ligands may be added as needed. Examples of zincating reagents include combinations of zinc powder, trimethylsilane chloride, and 1,2-dibromoethane; combinations of zinc chloride, thionyl chloride, lithium, and naphthalene; and combinations of zinc powder and tetrabutylammonium iodide. The preferred zincating reagent is a combination of zinc powder, trimethylsilane chloride, and 1,2-dibromoethane. Examples of metal catalysts include [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, tetrakis(triphenylphosphine)palladium(O), bis(triphenylphosphine)palladium(II) dichloride, dichlorobis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium(II), and (2-dicyclohexylphosphino-2',4',6'-trichlorophosphate). Sopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium acetate, (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium(Xphos Examples of metal catalysts include Pd G4), nickel(II) chloride ethylene glycol dimethyl ether complex, [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride, [1,2-bis(diphenylphosphino)ethane]dichloronickel(II), [1,3-bis(diphenylphosphino)propane]dichloronickel(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloronickel(II), copper(I) iodide, copper(I) cyanide, and copper(I) acetate. A preferred metal catalyst is a combination of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex and copper(I) iodide. Examples of ligands include triphenylphosphine, dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine, dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine, 4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine, and 2,2':6',2''-terpyridine. Examples of solvents include amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide, ester solvents such as ethyl acetate, halogen solvents such as dichloromethane, and ether solvents such as tetrahydrofuran. The preferred solvent is N,N-dimethylacetamide. The reaction temperature is, for example, 25°C to 100°C, preferably 70°C to 90°C. Compound [C12-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods. Compound [C12-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0265] (Process C12-2) Compound [C12-4] or its salt can be produced by reacting compound [C12-3] or its salt in a solvent in the presence of a halogenating agent. Examples of halogenating agents include N-bromosuccinimide and N-iodosuccinimide. The preferred halogenating agent is N-iodosuccinimide. Examples of solvents include amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide, ester solvents such as ethyl acetate, halogen solvents such as dichloromethane, and nitrile solvents such as acetonitrile. The preferred solvent is acetonitrile. The reaction temperature is, for example, 0°C to 50°C, preferably 0°C to 10°C.

[0266] (Process C12-3) Compound [C12-5] or a salt thereof can be produced by reacting compound [C12-4] or a salt thereof with compound [C6-2] or a salt thereof according to step B3-1. Substitute compound [C12-2] or its salt with R in known reactions. 1w Functional groups that can be converted to Cy or protected functional groups 1d Using a compound or salt thereof, the present manufacturing method is carried out to obtain a compound or salt thereof corresponding to compound [C12-5], and then its functional group is R 1w Compound [C12-5] or a salt thereof may be produced by converting to [the specified compound].

[0267] [Manufacturing Method D1]: Method for producing compound [D1-3] or its salt In compound [C5-1] or its salt used in manufacturing method C5, Substructure: [ka] (In the formula, *3 indicates that in compound [C5-1] or its salt, Cy 1 This represents the connection point with, *4 represents the bond site with the benzene ring in compound [C5-1] or its salt. However, the substructure formula is: [ka] (In the formula, *3 and *4 are as described above.) And, Cy 1 However, it contains one heteroatom selected from the group consisting of oxygen and nitrogen atoms, in addition to carbon atoms, as a ring constituent atom, and is a 4 to 6-membered heterocycloalkyl group. Compound [D1-3] or a salt thereof can be produced, for example, by the following production method D1. [ka] [In the formula, Cy 1eIt is a 4- to 6-membered heterocycloalkyl compound containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom. L 5 This is a leaving group (for example, methanesulfonyloxy, p-toluenesulfonyloxy, chlorine, bromine, or iodine), R 1 , R 2 , m, p and L 4 This is synonymous with the definition above.

[0268] (Process D1-1) Compound [D1-3] or a salt thereof can be produced by reacting compound [D1-1] or a salt thereof with compound [D1-2] or a salt thereof in accordance with step B5-1. Compound [D1-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods. Compound [D1-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0269] [Manufacturing Method D2]: Method for producing compound [D2-2] or its salt In compound [C5-1] or its salt used in manufacturing method C5, Substructure: [ka] (In the formula, *3 and *4 are as described above.) However, the substructure formula is: [ka] (In the formula, *3 and *4 are as described above.) And, Cy 1 However, it contains one heteroatom selected from the group consisting of oxygen and nitrogen atoms, in addition to carbon atoms, as a ring constituent atom, and is a 4 to 6-membered heterocycloalkyl group. Compound [D2-2] or a salt thereof can be produced, for example, by the production method D2 shown below. [ka] [In the formula, Cy 1e , R 1 , R 2 , m, p, L 4 and L 5 This is synonymous with the definition above.

[0270] (Process D2-1) Compound [D2-2] or a salt thereof can be produced by reacting compound [D2-1] or a salt thereof with compound [D1-2] or a salt thereof in accordance with step B5-1. Compound [D2-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0271] [Manufacturing Method D3]: Method for producing compound [D3-5] or its salt In compound [C5-1] or its salt used in manufacturing method C5, Substructure: [ka] (In the formula, *3 and *4 are as described above.) However, the substructure formula is: [ka] (In the formula, *3 and *4 are as described above.) And, Cy 1 but, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (3) Phenyl, or (4) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms. Compound [D3-5] or a salt thereof can be produced, for example, by the production method D3 shown below. [ka] [In the formula, L 6 These are halogens (e.g., chlorine, bromine, and iodine), P 3 This is an amine protecting group (e.g., tert-butoxycarbonyl), R 11 Each of them independently consists of hydrogen or C 1-4 Alkyl or one of the R 11 However, the other R 11 They may also combine to form a ring, Cy 1a , R 1 , R 2 , R 8 , m, p and L 4 This is synonymous with the definition above.

[0272] (Process D3-1) Compound [D3-2] or a salt thereof can be produced by reacting compound [D3-1] or a salt thereof with compound [D1-2] or a salt thereof according to step B3-1. Compound [D3-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0273] (Process D3-2) Compound [D3-3] or its salt is P of compound [D3-2] or its salt. 3 It can be produced by removing it through a deprotection reaction. The deprotection reaction is P 3 It should be carried out under conditions appropriate to the type. For example, P 3 If is tert-butoxycarbonyl, compound [D3-3] or a salt thereof can be produced by reacting compound [D3-2] or a salt thereof according to step A1-1.

[0274] (Process D3-3) Compound [D3-5] or its salt can be produced by reacting compound [D3-3] or its salt with compound [D3-4] or its salt in an air or oxygen atmosphere, in a solvent, in the presence of a copper catalyst and a base. Examples of solvents include alcohol-based solvents such as methanol, halogen-based solvents such as dichloromethane, or amide-based solvents such as N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. Examples of copper catalysts include copper(I) oxide, copper(II) trifluoromethanesulfonate, and copper(II) acetate. The preferred copper catalyst is copper(II) acetate. Examples of suitable bases include triethylamine, pyridine, and sodium hydroxide. Pyridine is the preferred base. The reaction temperature is, for example, 20°C to 120°C, preferably 50°C to 90°C. Compound [D3-4] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0275] [Manufacturing Method D4]: Method for producing compound [D4-5] or its salt In compound [C5-1] or its salt used in manufacturing method C5, Substructure: [ka] (In the formula, *3 and *4 are as described above.) However, the substructure formula is: [ka] (In the formula, *3 and *4 are as described above.) And, Cy 1 However, it contains one heteroatom selected from the group consisting of oxygen and nitrogen atoms, in addition to carbon atoms, as a ring constituent atom, and is a 4 to 6-membered heterocycloalkyl group. Compound [D4-5] or a salt thereof can be produced, for example, by the production method D4 shown below. [ka] [In the formula, Cy 1e , R 1 , R 2 , m, p and L 4 This is synonymous with the definition above.

[0276] (Process D4-1) Compound [D4-3] or its salt can be produced by reacting compound [D4-1] or its salt with compound [D4-2] or its salt in a solvent. Examples of solvents include amide solvents such as N,N-dimethylformamide and ether solvents such as dioxane. The preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 100°C to 150°C, preferably 120°C to 140°C. Compound [D4-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0277] (Process D4-2) Compound [D4-5] or its salt can be produced by reacting compound [D4-3] or its salt with compound [D4-4] or its salt in a solvent. Examples of solvents include alcohol-based solvents such as ethanol and carboxylic acid-based solvents such as acetic acid. Ethanol is a preferred solvent. The reaction temperature is, for example, 60°C to 150°C, preferably 70°C to 110°C. Compound [D4-4] or its salt may be commercially available or may be produced from a commercially available product by known methods.

[0278] [Manufacturing Method D5]: Method for producing compound [D5-3] or its salt In the compound [C10-1] or its salt used in the manufacturing method C10, X 1w and X 2w However, it is CH, X 3w and X 4wHowever, N is, X 5w However, C is, Cy 1w However, it is a 4- to 6-membered heterocycloalkyl compound that contains, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom. uw is 0, R 2w It is a halogen. Compound [D5-3] or its salt can be produced, for example, by the production method D5 shown below. [ka] [In the formula, Cy 1e , R 2aw , L 4 and L 5 As stated above, R 1w , mw and p are synonymous with the definitions in [Section A1] above.

[0279] (Process D5-1) Compound [D5-3] or its salt is compound [D5-1] or its salt and compound [D5-2] or its salt, It can be manufactured by carrying out the reaction according to process B5-1. Compound [D5-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods. Compound [D5-2] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0280] [Manufacturing Method D6]: Method for producing compound [D6-2] or its salt In the compound [C10-1] or its salt used in the manufacturing method C10, X 1w and X 4w However, it is CH, X 2w and X 3w N is, X 5w However, C is, Cy 1wHowever, it is a 4- to 6-membered heterocycloalkyl compound that contains, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom. uw is 0, R 2w It is a halogen. Compound [D6-2] or its salt can be produced, for example, by the production method D6 shown below. [ka] [In the formula, Cy 1e , R 2aw , L 4 and L 5 As stated above, R 1w , mw and p are synonymous with the definitions in [Section A1] above.

[0281] (Process D6-1) Compound [D6-2] or a salt thereof can be produced by reacting compound [D6-1] or a salt thereof with compound [D5-2] or a salt thereof according to step B5-1. Compound [D6-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0282] [Manufacturing Method D7]: Method for producing compound [D7-5] or its salt In the compound [C10-1] or its salt used in the manufacturing method C10, X 1w and X 2w However, it is CH, X 3w However, C is, X 4w and X 5w However, N is, Cy 1w but, (1) C 4-6 Cycloalkenyl, (2) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (3) Phenyl, or (4) A 5- or 6-membered heteroaryl compound containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms, uw is 0, R 2w It is a halogen. Compound [D7-5] or its salt can be produced, for example, by the production method D7 shown below. [ka] [In the formula, L 4 , L 6 , P 3 Cy 1a , R 2aw , R 8 , and R 11 As stated above, R 1w , mw and p are synonymous with the definitions in [Clause A1].

[0283] (Process D7-1) Compound [D7-2] or a salt thereof can be produced by reacting compound [D7-1] or a salt thereof with compound [B8-2] or a salt thereof according to step B3-1. Compound [D7-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0284] (Process D7-2) Compound [D7-3] or its salt is P of compound [D7-2] or its salt. 3 It can be produced by removing it through a deprotection reaction. The deprotection reaction is P 3 It should be carried out under conditions appropriate to the type. For example, P 3 If is tert-butoxycarbonyl, compound [D7-3] or a salt thereof can be produced by reacting compound [D7-2] or a salt thereof according to step A1-1.

[0285] (Process D7-3) Compound [D7-5] or a salt thereof can be produced by reacting compound [D7-3] or a salt thereof with compound [D7-4] or a salt thereof according to step D3-3. Compound [D7-4] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0286] [Manufacturing Method D8]: Method for producing compound [D8-4] or its salt In the compound [C10-1] or its salt used in the manufacturing method C10, X 1w , X 2w and X 3w However, C is, X 4w and X 5w However, N is, Cy 1w but, A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as ring constituent atoms. And, uw is 0, Compound [D8-4] or its salt can be produced, for example, by the production method D8 shown below. [ka] [In the formula, Cy 1e , R 2aw and L 4 As stated above, R 1w , mw and p are synonymous with the definitions in [Clause A1].

[0287] (Process D8-1) Compound [D8-2] or a salt thereof can be produced by reacting compound [D8-1] or a salt thereof with compound [D4-2] or a salt thereof according to step D4-1. Compound [D8-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0288] (Process D8-2) Compound [D8-4] or a salt thereof can be produced by reacting compound [D8-2] or a salt thereof with compound [D8-3] or a salt thereof according to step D4-2. Compound [D8-3] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0289] [Manufacturing Method D9]: Method for producing compound [D9-9] or its salt In the compound [C11-1] or its salt used in manufacturing method C11, X 13w N is, R 2w and R 13w R 2w Together with the benzene ring to which it is bonded and the heteroring to which the benzene ring is bonded, it forms a tricyclic condensed heteroring containing, in addition to carbon atoms, four heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms. Compound [D9-9] or a salt thereof can be produced, for example, by the following manufacturing method D9. [ka] [In the formula, L 11w These are halogens (for example, bromine or iodine, etc.), P 7w These are hydroxyl protecting groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyl, etc.), P 2 This is as stated above.

[0290] (Process D9-1) Compound [D9-2] or a salt thereof can be produced by reacting compound [D9-1] or a salt thereof with chloroacetonitrile in a solvent in the presence of a base. Examples of bases include cesium carbonate and potassium carbonate. The preferred base is cesium carbonate. Examples of solvents include amide solvents such as N,N-dimethylformamide, ester solvents such as ethyl acetate, halogen solvents such as dichloromethane, and ketone solvents such as acetone. The preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 20°C to 70°C, preferably 20°C to 30°C. Compound [D9-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0291] (Process D9-2) Compound [D9-4] or its salt can be produced by reacting compound [D9-2] or its salt with compound [D9-2] in a solvent in the presence of an acid and sodium nitrite in a diazoniumization reaction, followed by reaction with a base and compound [D9-3] in a solvent. Examples of acids used in the diazoniumization reaction include hydrochloric acid, tetrafluoroboric acid, and acetic acid. Hydrochloric acid is the preferred acid. Examples of solvents used in the diazoniumization reaction include water, ethanol, acetone, and acetonitrile. Water is the preferred solvent. The reaction temperature in the diazoniumization reaction is, for example, -10°C to 20°C, preferably -10°C to 0°C. Examples of bases used in the reaction with compound [D9-3] include sodium acetate. A preferred base is sodium acetate. Examples of solvents for the reaction with compound [D9-3] include methanol, ethanol, water, and mixtures thereof. A preferred solvent is a mixture of water and methanol. The reaction temperature in the reaction with compound [D9-3] is, for example, -10°C to 20°C, preferably 0°C to 10°C.

[0292] (Process D9-3) Compound [D9-5] or a salt thereof can be produced by reacting compound [D9-4] or a salt thereof in a solvent in the presence of a base. Examples of suitable bases include triethylamine and sodium ethoxide. The preferred base is triethylamine. Examples of solvents include amide solvents such as N,N-dimethylformamide, ester solvents such as ethyl acetate, halogen solvents such as dichloromethane, hydrocarbon solvents such as benzene and toluene, and alcohol solvents such as ethanol. Toluene is a preferred solvent. The reaction temperature is, for example, 80°C to 110°C, preferably 100°C to 115°C.

[0293] (Process D9-4) Compound [D9-6] or its salt can be produced by reducing compound [D9-5] or its salt in a solvent in the presence of a reducing agent. Examples of reducing agents include sodium borohydride and lithium aluminum hydride. A preferred reducing agent is sodium borohydride. Examples of solvents include ether-based solvents such as tetrahydrofuran, alcohol-based solvents such as ethanol, and mixed solvents thereof. A preferred solvent is a mixed solvent of ethanol and tetrahydrofuran. The reaction temperature is, for example, 0°C to 80°C, preferably 50°C to 70°C.

[0294] (Process D9-5) Compound [D9-7] or its salt contains a protecting group P in compound [D9-6] or its salt. 7w It can be manufactured by introducing a protective group. 7w It should be carried out under conditions appropriate to the type of product. For example, P 7w If is tert-butyldimethylsilyl, compound [D9-7] or its salt can be produced by reacting compound [D9-6] or its salt in a solvent in the presence of a base and tert-butyldimethylsilyl chloride. Examples of suitable bases include imidazole, triethylamine, and dimethylaminopyridine. The preferred base is imidazole. Examples of solvents include amide solvents such as N,N-dimethylformamide, ester solvents such as ethyl acetate, and halogen solvents such as dichloromethane. The preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 0°C to 80°C, preferably 15°C to 30°C.

[0295] (Process D9-6) Compound [D9-8] or a salt thereof can be produced by reacting compound [D9-7] or a salt thereof with compound [C5-2] or a salt thereof according to step B3-1.

[0296] (Process D9-7) Compound [D9-9] or its salt is P of compound [D9-8] or its salt. 7w It can be produced by removing P through a deprotection reaction. The deprotection reaction involves P 7w It should be carried out under conditions appropriate to the type of product. For example, P 7w If is tert-butyldimethylsilyl, compound [D9-9] or its salt can be produced by reacting compound [D9-8] or its salt with tetrabutylammonium fluoride in a solvent. Examples of solvents include ether-based solvents such as tetrahydrofuran. Tetrahydrofuran is a preferred solvent. The reaction temperature is, for example, 0°C to 60°C, preferably 15°C to 35°C.

[0297] [Manufacturing Method D10]: Method for producing compound [D10-4] or its salt In the compound [C11-1] or its salt used in manufacturing method C11, uw is 0, R 2w It is a halogen. Compound [D10-4] or its salt can be produced, for example, by the production method D10 shown below. [ka] [In the formula, X 13w , R 2aw , R 11 , L 4 and P 2 As stated above, p is synonymous with the definition in [Section A1] above.

[0298] (Process D10-1) Compound [D10-2] or a salt thereof can be produced by reacting compound [D10-1] or a salt thereof with compound [D7-4] or a salt thereof according to step D3-3. Compound [D10-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0299] (Process D10-2) Compound [D10-3] or a salt thereof can be produced by reacting compound [D10-2] or a salt thereof with compound [C5-2] or a salt thereof according to step B3-1.

[0300] (Process D10-3) Compound [D10-4] or a salt thereof can be produced by reacting compound [D10-3] or a salt thereof according to step D9-4.

[0301] [Manufacturing Method M1]: Method for producing compound [B1-3] or its salt The compounds [B1-3] or their salts used in manufacturing methods B1 and C4 can be produced, for example, by manufacturing method M1 shown below. [ka] [In the formula, R 3 q, t1, t2, t3 and P 1 This is synonymous with the definition above.

[0302] (Process M1-1) Compound [M1-1] or a salt thereof can be produced by reacting compound [B2-4] or a salt thereof with compound [B2-1] or a salt thereof according to step A1-2.

[0303] (Process M1-2) Compound [B1-3] or a salt thereof can be produced by reacting compound [M1-1] or a salt thereof according to step B2-2.

[0304] [Manufacturing Method M2]: Method for producing compound [M2-10] or its salt In the compounds [B2-4] or their salts used in manufacturing methods B2 and M1, t1 is 2, t2 is 1, t3 is 1, Is q 2, or In the compound [B7-3] or its salt used in manufacturing methods B7 and M3, t1 is 2, t2w is 1, t3 is 1, q is 2, Compound [M2-10] or its salt can be produced, for example, by the production method M2 shown below. [ka] [In the formula, R 12 C 1-4 Alkyl (e.g., methyl or ethyl), L 7 These are halogens (e.g., chlorine, bromine, or iodine), P 4 is an amine protecting group (e.g., tert-butoxycarbonyl), P 5 This is an amine protecting group (e.g., trifluoroacetyl or methoxycarbonyl), R 3 This is synonymous with the definition above.

[0305] (Process M2-1) Compound [M2-3] or its salt can be produced by reacting compound [M2-1] or its salt with compound [M2-2] or its salt in a solvent. Examples of solvents include nitrile solvents such as acetonitrile, amide solvents such as N,N-dimethylformamide, or ester solvents such as ethyl acetate. The preferred solvent is ethyl acetate. The reaction temperature is, for example, 20°C to 60°C, preferably 30°C to 50°C. Compound [M2-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0306] (Process M2-2) Compound [M2-5] or its salt can be produced by reacting compound [M2-3] or its salt with compound [M2-4] or its salt in a solvent in the presence of a base. Examples of solvents include ether-based solvents such as tetrahydrofuran. Tetrahydrofuran is a preferred solvent. Examples of suitable bases include lithium diisopropylamide and lithium bis(trimethylsilyl)amide. The preferred base is lithium bis(trimethylsilyl)amide. The reaction temperature is, for example, -78°C to 0°C, preferably -70°C to -50°C. Compound [M2-4] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0307] (Process M2-3) Compound [M2-6] or its salt is P of compound [M2-5] or its salt. 4 It can be produced by removing it through a deprotection reaction. The deprotection reaction is P 4 It should be carried out under conditions appropriate to the type. For example, P 4 If is tert-butoxycarbonyl, compound [M2-6] or a salt thereof can be produced by reacting compound [M2-5] or a salt thereof according to step A1-1.

[0308] (Process M2-4) Compound [M2-7] or its salt can be produced by reacting compound [M2-6] or its salt in a solvent in the presence of a reducing agent and a metal reagent. Examples of solvents include ether-based solvents such as tetrahydrofuran and diethyl ether, as well as mixed solvents thereof. Tetrahydrofuran is the preferred solvent. Lithium aluminum hydride is an example of a reducing agent. A preferred reducing agent is lithium aluminum hydride. Aluminum(III) chloride is an example of a metallic reagent. Aluminum(III) chloride is a preferred metallic reagent. The reaction temperature is, for example, -20°C to 30°C, preferably -20°C to 30°C.

[0309] (Process M2-5) Compound [M2-8] or its salt contains a protecting group P on compound [M2-7] or its salt. 5 It can be manufactured by introducing a protective group. 5 It should be carried out under conditions appropriate to the type. For example, P 5 If trifluoroacetyl is present, compound [M2-8] or its salt can be produced by reacting compound [M2-7] or its salt in a solvent in the presence of a trifluoroacetylating agent and a base. Examples of solvents include halogenated solvents such as dichloromethane and ether-based solvents such as tetrahydrofuran. Tetrahydrofuran is a preferred solvent. Examples of trifluoroacetylating agents include trifluoroacetic anhydride and N-trifluoroacetylimidazole. The preferred trifluoroacetylating agent is trifluoroacetic anhydride. Examples of suitable bases include 4-dimethylaminopyridine, triethylamine, and pyridine. The preferred base is triethylamine. The reaction temperature is, for example, -20°C to 30°C, preferably 0°C to 30°C.

[0310] (Process M2-6) Compound [M2-9] or its salt protects the benzyl group of compound [M2-8] or its salt with a protecting group P 1 It can be manufactured by converting to protective group P. 1 The conversion to P 1 It should be carried out under conditions appropriate to the type. For example, P 1 If is tert-butoxycarbonyl, compound [M2-9] or its salt can be produced by catalytic hydrogenation of compound [M2-8] or its salt in a solvent in the presence of a tert-butoxycarbonylating agent and a catalyst. Examples of solvents include alcohol-based solvents such as methanol and ester-based solvents such as ethyl acetate. The preferred solvent is ethyl acetate. Di-tert-butyl dicarbonate is an example of a tert-butoxycarbonylating agent. A preferred tert-butoxycarbonylating agent is di-tert-butyl dicarbonate. Examples of catalysts include palladium / carbon and palladium hydroxide. The preferred catalyst is palladium hydroxide. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 40°C.

[0311] (Process M2-7) Compound [M2-10] or its salt is P of Compound [M2-9] or its salt. 5 It can be produced by removing it through a deprotection reaction. The deprotection reaction is P 5 It should be carried out under conditions appropriate to the type. For example, P 5 If trifluoroacetyl is present, compound [M2-10] or its salt can be produced by reacting compound [M2-9] or its salt in a solvent in the presence of a base. Examples of solvents include alcohol-based solvents such as methanol and ether-based solvents such as tetrahydrofuran. The preferred solvent is methanol. Potassium carbonate is an example of a base. Potassium carbonate is a preferred base. The reaction temperature is, for example, -20°C to 50°C, preferably 0°C to 30°C.

[0312] [Manufacturing Method M3]: Method for producing compound [B6-3] or its salt The compound [B6-3] or its salt used in manufacturing methods B6 and C9 can be produced, for example, by manufacturing method M3 shown below. [ka] [In the formula, P 1 This is synonymous with the definition above, R 3 q, t1, t2w, and t3 are equivalent to the definitions in [Section A1] above.

[0313] (Process M3-1) Compound [M3-1] or a salt thereof can be produced by reacting compound [B7-3] or a salt thereof with compound [B2-1] or a salt thereof according to step A1-2.

[0314] (Process M3-2) Compound [B6-3] or a salt thereof can be produced by reacting compound [M3-1] or a salt thereof according to step B2-2. [Examples]

[0315] Next, a method for producing compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof will be specifically described with reference to production examples. However, the method for producing compound [I] or compound [Ia] or a pharmaceutically acceptable salt thereof is not limited to these.

[0316] [Production Example 1]: Synthesis of each optically active form of 2-(2-acryloyl-2,5-diazaspiro[3.4]octan-5-yl)-N-(3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)benzyl)-2-oxoacetamide (Examples 28 and 29) [ka] (1) 4-(methylsulfonyl)cyclohexa-1-en-1-yl trifluoromethylsulfonate [ka] At room temperature, 2,6-di-tert-butyl-4-methylpyridine (7.96 g) and trifluoromethanesulfonic anhydride (5.75 mL) were added to a mixture of 4-(methylsulfonyl)cyclohexane-1-one (4.96 g) and dichloromethane (30 mL), and the mixture was stirred at 50°C for 4 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, washed with ethyl acetate, and the filtrate was removed by reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate: 90% / 10% to 30% / 70%). The hexane / ethyl acetate mixture was added to the residue and stirred. The precipitated solid was filtered to obtain the title compound (4.96 g). 1 H-NMR (DMSO-D6) δ: 5.98-5.97 (1H, m), 3.40-3.37 (1H, m), 3.00 (3H, s), 2.61-2.57 (1H, m), 2.51-2.46 (2H, m), 2.43-2.41 (1H, m), 2.30-2.27 (1H, m), 1.85-1.74 (1H, m).

[0317] (2) 4,4,5,5-Tetramethyl-2-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)-1,3,2-dioxaborolane [ka] At room temperature, a mixture of 4-(methylsulfonyl)cyclohexa-1-en-1-yl trifluoromethylsulfonate (4.96 g), bis(pinacolate)diborone (4.90 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (1.31 g) and potassium acetate (4.74 g) was mixed with dimethyl sulfoxide (49.6 mL), degassed, and heated and stirred at 90°C for 17 hours under an argon atmosphere. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture and filtered through Celite. The filtrate was separated into layers, and the organic layer was washed sequentially with water and saturated brine. The resulting organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate: 80% / 20% to 20% / 80%). The hexane / ethyl acetate mixture was added to the residue and stirred. The title compound (2.73 g) was obtained by filtering the precipitated solid. 1 H-NMR (DMSO-D6) δ: 6.44-6.42 (1H, br m), 3.25-3.19 (1H, m), 2.92 (3H, s), 2.43-2.40 (1H, br m), 2.29-2.25 (2H, br m), 2.11-2.05 (2H, br m), 1.46-1.41 (1H, br m), 1.12 (12H, s).

[0318] (3) 2-bromo-6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine [ka] At room temperature, a mixture of 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)-1,3,2-dioxaborolane (1.31 g), 2,6-dibromopyridine (4.33 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.373 g) and tripotassium phosphate (2.91 g) was added to 1,2-dimethoxyethane (26.2 mL) and water (6.54 mL). The mixture was then degassed and heated and stirred at 70°C for 2 hours under an argon atmosphere. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture, and the organic layers were separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were washed sequentially with water and saturated brine. The resulting organic layers were dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate: 50% / 50% to 20% / 80%) to obtain the title compound (1.45 g). 1 H-NMR (DMSO-D6) δ: 7.72 (1H, t, J = 7.5 Hz), 7.58 (1H, d, J = 7.5 Hz), 7.49 (1H, d, J = 7.5 Hz), 6.78-6.78 (1H, m), 3.40-3.34 (1H, m), 3.00 (3H, s), 2.79-2.76 (1H, m), 2.69-2.64 (1H, m), 2.45-2.41 (2H, m), 2.35-2.32 (1H, m), 1.70-1.64 (1H, m).

[0319] (4) tert-butyl (3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)benzyl)carbamate [ka] At room temperature, a mixture of 2-bromo-6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine (1.20 g), (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (1.24 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.310 g) and tripotassium phosphate (2.42 g) was added to 1,2-dimethoxyethane (24.0 mL) and water (6.00 mL). The mixture was then degassed and heated and stirred at 70°C under an argon atmosphere for 4 hours. After cooling to room temperature, the mixture was filtered through Celite and washed with ethyl acetate. Ethyl acetate was added to the filtrate for extraction, and the organic layer was sequentially washed with water and saturated brine. The resulting organic layer was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate: 40% / 60% to 0% / 100%) to obtain the title compound (1.56 g). 1 H-NMR (DMSO-D6) δ: 8.01 (1H, s), 7.96 (1H, d, J = 8.1 Hz), 7.86 (1H, t, J = 7.8 Hz), 7.79 (1H, d, J = 8.1 Hz), 7.52 (1H, d, J = 8.1 Hz), 7.48-7.42 (2H, m), 7.30 (1H, d, J = 7.5 Hz), 6.86-6.85 (1H, m), 4.22 (2H, d, J = 5.9 Hz), 3.42-3.38 (1H, m), 3.01 (3H, s), 2.96-2.95 (1H, m), 2.71-2.67 (1H, m), 2.57-2.54 (2H, m), 2.37-2.34 (1H, m), 1.75-1.69 (1H, m), 1.41 (9H, s).

[0320] (5) (3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)phenyl)methanamine dihydrochloride [ka] At room temperature, 17.6 mL of 4M hydrogen chloride-ethyl acetate solution was added to a mixture of tert-butyl (3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)benzyl)carbamate (1.56 g) and methanol (7.79 mL), and the mixture was stirred at room temperature for 1 hour and 30 minutes. Ethyl acetate (25 mL) was added to the reaction mixture and the mixture was stirred at room temperature. After filtering off the precipitated solid, it was washed with ethyl acetate to obtain the title compound (1.42 g). 1 H-NMR (DMSO-D6) δ: 8.35 (3H, br s), 8.26 (1H, br s), 8.14-8.14 (1H, m), 7.92-7.85 (2H, m), 7.56-7.54 (3H, m), 6.90-6.89 (1H, m), 4.52 (1H, br s), 4.14-4.13 (2H, m), 3.43-3.39 (1H, m), 3.02 (3H, s), 2.98-2.97 (1H, m), 2.73-2.65 (1H, m), 2.61-2.53 (2H, m), 2.40-2.36 (1H, m), 1.76-1.70 (1H, m).

[0321] (6) tert-butyl 5-(2-ethoxy-2-oxoacetyl)-2,5-diazaspiro[3,4]octane-2-carboxylate [ka] Under ice cooling, ethyl chloroglyoxylate (1.67 g) was added dropwise over 2 minutes to a mixture of tert-butyl 2,5-diazaspiro[3.4]octane-2-carboxylate (2.00 g) and diisopropylethylamine (2.44 g) in tetrahydrofuran (20.0 mL), and the mixture was stirred for 1 hour. The reaction mixture was diluted with a hexane / ethyl acetate mixture and purified by silica gel column chromatography (hexane / ethyl acetate: 67% / 33% to 33% / 67%) to obtain the title compound (2.87 g). 1H-NMR (CDCl3) δ: 4.78-4.71 (2H, br m), 4.36 (2H, q, J = 7.2 Hz), 3.73-3.71 (2H, m), 3.64-3.63 (2H, m), 2.29-2.25 (2H, m), 1.92-1.86 (2H, m), 1.48 (9H, s), 1.40 (3H, t, J = 7.2 Hz).

[0322] (7) 2-(2-(tert-butoxycarbonyl)-2,5-diazaspiro[3,4]octan-5-yl)-2-oxoacetate [ka] 2.40 g of tert-butyl 5-(2-ethoxy-2-oxoacetyl)-2,5-diazaspiro[3.4]octane-2-carboxylate was added to tetrahydrofuran (24.0 mL) and stirred for 1 hour. 2.31 mL of 4 M hydrogen chloride-ethyl acetate solution was added to the reaction mixture and extracted twice with ethyl acetate. The organic layers were combined and washed with saturated brine. The resulting organic layers were dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (2.18 g). 1 H-NMR (CDCl3) δ: 4.68 (2H, d, J = 9.2 Hz), 4.04 (2H, t, J = 6.7 Hz), 3.77 (2H, d, J = 9.2 Hz), 2.24 (2H, t, J = 6.7 Hz), 1.94-1.88 (2H, m), 1.47 (9H, s).

[0323] (8) tert-butyl 5-(2-((3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)benzyl)amino)-2-oxoacetyl)-2,5-diazaspiro[3,4]octane-2-carboxylate [ka] To a mixture of 2-(2-(tert-butoxycarbonyl)-2,5-diazaspiro[3.4]octan-5-yl)-2-oxoacetic acid (0.414 g) and N,N-dimethylformamide (5.50 mL), (3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)phenyl)methaneamine dihydrochloride (0.550 g) and triethylamine (1.07 g) were added. The reaction mixture was cooled on ice, and 1.7 M propylphosphonic anhydride-ethyl acetate solution (2.34 mL) was added, and the mixture was stirred at room temperature for 4 hours. Saturated sodium carbonate aqueous solution and water were added to the reaction mixture, and it was extracted twice with ethyl acetate. The organic layers were combined and washed sequentially with water and saturated brine. The resulting organic layers were dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate: 40% / 60% to 0% / 100%) to obtain the title compound (0.648 g). 1 H-NMR (DMSO-D6) δ: 9.30 (1H, t, J = 6.2 Hz), 8.06 (1H, s), 8.00 (1H, d, J = 8.1 Hz), 7.86 (1H, t, J = 7.8 Hz), 7.80 (1H, d, J = 7.5 Hz), 7.53 (1H, d, J = 7.5 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.35 (1H, d, J = 8.1 Hz), 6.86-6.85 (1H, m), 4.53-4.47 (2H, m), 4.41 (2H, d, J = 6.5 Hz), 3.68-3.58 (4H, m), 3.44-3.36 (1H, m), 3.01 (3H, s), 2.96-2.95 (1H, m), 2.72-2.65 (1H, m), 2.61-2.54 (1H, m), 2.47-2.45 (1H, m), 2.38-2.36 (1H, m), 2.14-2.13 (2H, m), 1.72-1.69 (3H, m), 1.36 (9H, s).

[0324] (9) N-(3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)benzyl)-2-oxo-2-(2,5-diazaspiro[3.4]octan-5-yl)acetamide [ka] tert-butyl 5-(2-((3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)benzyl)amino)-2-oxoacetyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (0.648 g) was mixed with chloroform (3.24 mL) and trifluoroacetic acid (3.24 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was removed by distillation under reduced pressure and azeotropically twice with toluene. The concentrated residue was added to saturated sodium carbonate aqueous solution and extracted three times with chloroform. The organic layers were combined and dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (0.546 g). 1 H-NMR (DMSO-D6) δ: 9.25 (1H, t, J = 5.9 Hz), 8.10 (1H, s), 8.01 (1H, d, J = 7.5 Hz), 7.88 (1H, t, J = 7.9 Hz), 7.81 (1H, d, J = 7.9 Hz), 7.54 (1H, d, J = 7.5 Hz), 7.47 (1H, t, J = 7.7 Hz), 7.36 (1H, d, J = 7.9 Hz), 6.90-6.89 (1H, m), 4.48 (2H, d, J = 7.0 Hz), 4.43 (2H, d, J = 7.0 Hz), 3.53 (2H, t, J = 6.6 Hz), 3.44-3.42 (1H, m), 3.05-3.00 (6H, m), 2.69-2.52 (4H, m), 2.40-2.38 (1H, m), 2.18 (2H, t, J = 6.6 Hz), 1.75-1.70 (3H, m).

[0325] (10) Optically active compounds of 2-(2-acryloyl-2,5-diazaspiro[3,4]octan-5-yl)-N-(3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)benzyl)-2-oxoacetamide [ka] Under ice cooling, triethylamine (0.334 g) and acryloyl chloride (0.199 g) were sequentially added to a mixture of N-(3-(6-(4-(methylsulfonyl)cyclohexa-1-en-1-yl)pyridine-2-yl)benzyl)-2-oxo-2-(2,5-diazaspiro[3.4]octan-5-yl)acetamide (0.560 g) in tetrahydrofuran (5.60 mL), and the mixture was stirred at room temperature for 1 hour and 30 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted three times with ethyl acetate. The organic layers were combined and sequentially washed with water and saturated brine. The resulting organic layers were dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol: 100% / 0% to 90% / 10%) to obtain a racemic mixture (0.452 g) of the title compound. The racemic mixture (80 mg) was optically resolved using HPLC (instrument name: Nippon Analytical Industries Automatic Recycling Preparative HPLC LaboACE LC-7080, column: Daicel CHIRALPAK IG, 20 mm (ID) x 250 mm (L), 5 μm, guard column: Daicel CHIRALPAK IG, 10 mm (ID) x 20 mm (L), 5 μm, mobile phase flow rate: 17 mL / min, mobile phase mixing ratio: isocratic, MeCN / EtOH = 20 / 80 (V / V)) to obtain the first peak fraction (24.6 - 33.3 min.) and the second peak fraction (34.5 - 48.0 min.), thereby obtaining the compound of Example 28 (first peak fraction: 0.0163 g, 99% ee) and the compound of Example 29 (second peak fraction: 0.0305 g). g, 91%ee) was obtained. (Compound of Example 28) 11H-NMR (DMSO-D6) δ: 9.33 (1H, t, J = 5.9 Hz), 8.06 (1H, s), 7.99 (1H, d, J = 8.1 Hz), 7.86 (1H, t, J = 7.8 Hz), 7.80 (1H, d, J = 7.0 Hz), 7.53 (1H, d, J = 7.5 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.35 (1H, d, J = 7.5 Hz), 6.86 (1H, t, J = 2.4 Hz), 6.30 (1H, dd, J = 16.8, 10.2 Hz), 6.09 (1H, dd, J = 16.8, 2.4 Hz), 5.66 (1H, dd, J = 10.2, 2.4 Hz), 4.77 (1H, d, J = 8.6 Hz), 4.54 (1H, d, J = 9.7 Hz), 4.42 (2H, d, J = 6.5 Hz), 4.08 (1H, d, J = 8.4 Hz), 3.77 (1H, d, J = 9.7 Hz), 3.65 - 3.63 (2H, m), 3.44 - 3.36 (1H, m), 3.02 (3H, s), 2.99 - 2.95 (1H, m), 2.72 - 2.65 (1H, m), 2.61 - 2.52 (2H, m), 2.38 - 2.35 (1H, m), 2.20 - 2.16 (2H, m), 1.76 - 1.69 (3H, m). (Compound of Example 29) 1H-NMR (DMSO-D6) δ: 9.30 (1H, t, J = 6.2 Hz), 8.04 (1H, s), 7.98-7.96 (1H, m), 7.84 (1H, t, J = 7.8 Hz), 7.77 (1H, d, J = 7.0 Hz), 7.50 (1H, d, J = 7.5 Hz), 7.43 (1H, t, J = 7.5 Hz), 7.33-7.31 (1H, m), 6.84-6.83 (1H, m), 6.28 (1H, dd, J = 16.7, 10.2 Hz), 6.07 (1H, dd, J = 16.7, 2.2 Hz), 5.63 (1H, dd, J = 10.2, 2.2 Hz), 4.74 (1H, d, J = 8.6 Hz), 4.51 (1H, d, J = 9.7 Hz), 4.40-4.38 (2H, m), 4.05 (1H, d, J = 8.6 Hz), 3.74 (1H, d, J = 9.7 Hz), 3.62-3.60 (2H, m), 3.40-3.36 (1H, m), 2.99 (3H, s), 2.93-2.92 (1H, m), 2.68-2.64 (1H, m), 2.59-2.57 (2H, m), 2.35-2.31 (1H, m), 2.17-2.14 (2H, m), 1.73-1.70 (3H, m).

[0326] [Production Example 2]: Synthesis of 2-(2-acryloyl-2,5-diazaspiro[3.4]octan-5-yl)-N-(3-(6-(4-(methylsulfonyl)phenyl)pyridine-2-yl)benzyl)-2-oxoacetamide (Example 33) [ka] (1) tert-butyl (3-(6-chloropyridine-2-yl)benzyl)carbamate [ka] Under an argon atmosphere, (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (6.11 g), 2,6-dichloropyridine (4.00 g), tripotassium phosphate (11.5 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (1.10 g) were mixed with 1,2-dimethoxyethane (60.0 mL) and water (24.0 mL), and the mixture was heated and stirred at 95°C for 2 hours. After cooling, ethyl acetate was added to the reaction mixture, and the layers were separated. The organic layer was dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate: 80% / 20%) to obtain the title compound (4.50 g). 1 H-NMR (CDCl3) δ: 7.96 (1H, br s), 7.91-7.90 (1H, m), 7.75 (1H, t, J = 7.8 Hz), 7.68 (1H, dd, J = 7.8, 0.9 Hz), 7.47 (1H, t, J = 8.4 Hz), 7.41-7.39 (1H, m), 7.32-7.31 (1H, m), 4.95 (1H, br s), 4.44 (2H, d, J = 5.7 Hz), 1.49 (9H, s).

[0327] (2) (3-(6-chloropyridine-2-yl)phenyl)methanamine dihydrochloride [ka] A mixture of tert-butyl (3-(6-chloropyridine-2-yl)benzyl)carbamate (1.60 g) and ethanol (3 mL) was mixed with 4 M hydrogen chloride-ethyl acetate solution (15 mL) and stirred for 3 hours. After filtering off the precipitated solid, it was washed with ethyl acetate to obtain the title compound (1.39 g). 1H-NMR (DMSO-D6) δ: 8.33 (2H, br s), 8.23 ​​(1H, br s), 8.09-8.08 (1H, m), 8.04-7.99 (2H, m), 7.59-7.58 (2H, m), 7.56-7.53 (1H, m), 4.65 (2H, br s), 4.16-4.14 (2H, m).

[0328] (3) tert-butyl 5-(2-((3-(6-chloropyridine-2-yl)benzyl)amino)-2-oxoacetyl)-2,5-diazaspiro[3.4]octane-2-carboxylate [ka] (3-(6-chloropyridine-2-yl)phenyl)methanamine dihydrochloride (0.400 g) was mixed with N,N-dimethylformamide (4.00 mL) to which 2-(2-(tert-butoxycarbonyl)-2,5-diazaspiro[3.4]octan-5-yl)-2-oxoacetic acid (0.390 g), triethylamine (0.694 g), and 1.7 M propylphosphonic anhydride-ethyl acetate solution (1.61 mL) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water and saturated brine. The resulting organic layer was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate: 50% / 50%) to obtain the title compound (0.440 g). 1H-NMR (CDCl3) δ: 7.95-7.94 (1H, m), 7.90-7.87 (2H, m), 7.72 (1H, t, J = 7.7 Hz), 7.66-7.64 (1H, m), 7.45 (1H, t, J = 7.7 Hz), 7.39-7.36 (1H, m), 7.29-7.27 (1H, m), 4.67 (2H, d, J = 8.8 Hz), 4.54 (2H, d, J = 6.2 Hz), 4.04-4.02 (2H, m), 3.69 (2H, d, J = 8.8 Hz), 2.16 (2H, t, J = 6.6 Hz), 1.86-1.79 (2 hours, m), 1.45 hours (9 hours, s).

[0329] (4) tert-butyl 5-(2-((3-(6-(4-(methylsulfonylphenyl)phenyl)pyridine-2-yl)benzyl)amino)-2-oxoacetyl)-2,5-diazaspiro[3.4]octane-2-carboxylate [ka] Under an argon atmosphere, 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (0.0279 g), tert-butyl 5-(2-((3-(6-chloropyridine-2-yl)benzyl)amino)-2-oxoacetyl)-2,5-diazaspiro[3,4]octane-2-carboxylate (0.0400 g), potassium carbonate (0.0228 g), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.00555 g) were mixed with 1,2-dimethoxyethane (1.00 mL) and water (0.200 mL), and the mixture was heated and stirred at 95°C for 3 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture, and the layers were separated. The organic layer was dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate: 50% / 50% to 0% / 100%) to obtain the title compound (0.0500 g). 1H-NMR (CDCl3) δ: 8.35-8.33 (2H, m), 8.08-8.05 (4H, m), 7.91-7.89 (2H, m), 7.81-7.76 (2H, m), 7.50 (1H, t, J = 7.7 Hz), 7.41-7.39 (1H, m), 4.67 (2H, d, J = 8.6 Hz), 4.58 (2H, d, J = 6.2 Hz), 4.05-4.03 (2H, m), 3.69 (2H, d, J = 8.3 Hz), 3.11 (3H, s), 2.17-2.16 (2H, m), 1.86-1.79 (2H, m), 1.44 (9H, s).

[0330] (5) 2-(2-acryloyl-2,5-diazaspiro[3,4]octan-5-yl)-N-(3-(6-(4-(methylsulfonyl)phenyl)pyridine-2-yl)benzyl)-2-oxoacetamide [ka] tert-butyl 5-(2-((3-(6-(4-(methylsulfonyl)phenyl)pyridine-2-yl)benzyl)amino)-2-oxoacetyl)-2,5-diazaspiro[3.4]octane-2-carboxylate (0.0490 g) was mixed with chloroform (0.500 mL) and trifluoroacetic acid (0.500 mL) and stirred for 1 hour. The reaction mixture was removed by distillation under reduced pressure, and N,N-dimethylformamide (0.980 mL) and diisopropylethylamine (0.0628 g) were added and stirred. Acryloyl chloride (0.0293 g) was added and stirred for 1 hour. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / ethanol: 100% / 0% to 91% / 9%) to obtain the title compound (0.0400 g). 1H-NMR (DMSO-D6) δ: 9.36 (1H, t, J = 6.2 Hz), 8.50-8.44 (2H, m), 8.17 (1H, br s), 8.12-7.99 (6H, m), 7.51 (1H, t, J = 7.7 Hz), 7.40 (1H, d, J = 7.7 Hz), 6.30 (1H, dd, J = 17.0, 10.3 Hz), 6.09 (1H, dd, J = 17.0, 2.2 Hz), 5.65 (1H, dd, J = 10.3, 2.2 Hz), 4.77 (1H, d, J = 8.2 Hz), 4.54 (1H, d, J = 9.9 Hz), 4.46 (2H, d, J = 6.3 Hz), 4.07 (1H, d, J = 8.2 Hz), 3.77 (1H, d, J = 9.9 Hz), 3.60-3.63 (2H, m), 3.29 (3H, s), 2.20-2.13 (2H, m), 1.73-1.68 (2H, m).

[0331] [Production Example 3]: Synthesis of a complex of 2-(2-acryloyl-2,5-diazaspiro[3,4]octan-5-yl)-N-(3-(6-(4-(methylsulfonyl)phenyl)pyridine-2-yl)benzyl)-2-oxoacetamide p-toluenesulfonic acid 4-hydroxybenzoic acid (1:1:1) (Example 2-001) [ka] (1) A complex of 2-(2-acryloyl-2,5-diazaspiro[3,4]octan-5-yl)-N-(3-(6-(4-(methylsulfonyl)phenyl)pyridine-2-yl)benzyl)-2-oxoacetamide p-toluenesulfonic acid 4-hydroxybenzoic acid (1:1:1) [ka] To a mixture of 4-hydroxybenzoic acid (0.0297 mg) and acetonitrile (2.00 mL), p-toluenesulfonic acid monohydrate (51.1 mg) was added, and a solution of 2-(2-acryloyl-2,5-diazaspiro[3.4]octan-5-yl)-N-(3-(6-(4-(methylsulfonyl)phenyl)pyridine-2-yl)benzyl)-2-oxoacetamide (0.100 mg) in acetonitrile (0.20 mL) was added dropwise over 1 minute. The mixture was combined with a washing solution of acetonitrile (0.20 mL), and the mixture was stirred at room temperature for 18 hours. After filtering off the precipitated solid, it was washed with acetonitrile (1.00 mL). The resulting solid was dried under reduced pressure at 50°C for 1 hour to obtain the title compound (0.135 mg). Single-crystal X-ray diffraction (scXRD) data analysis confirmed that the title compound is a 1:1:1 composite crystal. 1 H-NMR (DMSO-D6) δ: 10.12 (1H, br s), 9.36 (1H, t, J = 6.4 Hz), 8.47-8.46 (2H, m), 8.18 (1H, br s), 8.11-7.98 (6H, m), 7.80-7.77 (2H, m), 7.53-7.39 (4H, m), 7.12 (2H, d, J = 7.9 Hz), 6.83-6.81 (2H, m), 6.31 (1H, dd, J = 16.9, 10.3 Hz), 6.09 (1H, dd, J = 16.9, 2.2 Hz), 5.66 (1H, dd, J = 10.3, 2.2 Hz), 4.77 (1H, d, J = 8.3 Hz), 4.54 (1H, d, J = 9.7 Hz), 4.46 (2H, d, J = 6.6 Hz), 4.07 (1H, d, J = 7.9 Hz), 3.77 (1H, d, J = 9.7 Hz), 3.64 (2H, t, J = 6.8 Hz), 3.30 (3H, s),2.29 (3H, s), 2.18-2.14 (2H, m), 1.72-1.68 (2H, m).

[0332] [Production Example 4]: Synthesis of N-((8-((2-(2-acryloyl-2,5-diazaspiro[3,4]octan-5-yl)-2-oxoacetamide)methyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-2-yl)methyl)-1,4,4-trifluorocyclohexane-1-carboxamide (Example 3-005) [ka] (1) 5-bromo-2-(propane-2-in-1-yloxy)aniline [ka] Under ice cooling, propargyl bromide (3.32 g) was added in four portions to a mixture of 2-amino-4-bromophenol (5.00 g) and cesium carbonate (11.3 g) in N,N-dimethylformamide (25.0 mL). After addition, the mixture was stirred under water cooling for 1 hour and 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the insoluble matter was filtered off. Hexane was added to the filtrate to separate the layers, and the resulting organic layer was washed twice with water and then sequentially with saturated brine. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (4.06 g). 1 H-NMR (DMSO-D6) δ: 6.80 (1H, d, J = 5.7 Hz), 6.79 (1H, s), 6.63-6.61 (1H, m), 5.04 (2H, s), 4.75 (2H, d, J = 2.3 Hz), 3.57 (1H, t, J = 2.3 Hz).

[0333] (2) Ethyl (Z)-2-(2-(5-bromo-2-(propa-2-in-1-yloxy)phenyl)hydrazinylidene)-2-chloroacetate [ka] To a mixture of 5-bromo-2-(propa-2-in-1-yloxy)aniline (3.05 g) and 0.5 M hydrochloric acid (76.0 mL), an aqueous solution of sodium nitrite (1.02 g) (8.24 mL) was added under ice cooling and the mixture was stirred for 1 hour. Sodium acetate (2.77 g) was added to the reaction mixture, and then a methanol (8.24 mL) solution of ethyl 2-chloro-3-oxobutanoate (2.33 g) was added over 2 minutes. Ethyl acetate was added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were washed together with saturated brine and dried over sodium sulfate. After removing the solvent under reduced pressure, the residue azeotropically removed with toluene was used in the next reaction.

[0334] (3) Ethyl 8-bromo-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazine-2-carboxylate [ka] A mixture of ethyl (Z)-2-(2-(5-bromo-2-(propa-2-in-1-yloxy)phenyl)hydrazinylidene)-2-chloroacetate (4.85 g) and triethylamine (5.46 g) in toluene (48.5 mL) was stirred at 100°C. After 4 hours, water and ethyl acetate were added to the reaction mixture and the mixture was separated into layers. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After removing the solvent under reduced pressure, the resulting solid was washed with hexane / ethyl acetate: 40% / 60% (15 mL) to obtain the title compound (1.66 g). 1 H-NMR (DMSO-D6) δ: 7.91 (1H, d, J = 2.5 Hz), 7.45 (1H, dd, J = 8.9, 2.5 Hz), 7.15 (1H, d, J = 8.9 Hz), 6.84 (1H, s), 5.46 (2H, s), 4.34 (2H, q, J = 7.1 Hz), 1.32 (3H, t, J = 7.1 Hz).

[0335] (4) (8-bromo-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-2-yl)methanol [ka] To a mixture of ethyl 8-bromo-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazine-2-carboxylate (400 mg) in tetrahydrofuran (4 mL) and ethanol (4 mL), sodium borate (117 mg) was added and the mixture was stirred at 60°C for 7 hours and 15 minutes. The reaction mixture was added dropwise to a saturated aqueous sodium bicarbonate solution, followed by the addition of water and ethyl acetate, and the mixture was stirred for 15 minutes to separate the organic layer. The resulting organic layer was washed with saturated brine and dried over sodium sulfate. After removing the solvent under reduced pressure, the resulting solid was stirred as a slurry with hexane / ethyl acetate (91% / 9%) to obtain the title compound (320 mg). 1 H-NMR (DMSO-D6) δ: 7.77 (1H, d, J = 2.7 Hz), 7.32 (1H, dd, J = 8.6, 2.7 Hz), 7.08 (1H, d, J = 8.6 Hz), 6.33 (1H, s), 5.40 (2H, s), 5.25 (1H, t, J = 5.9 Hz), 4.50 (2H, d, J = 5.9 Hz).

[0336] (5) 8-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazine [ka] (8-bromo-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-2-yl)methanol (315 mg) and imidazole (153 mg) were mixed in N,N-dimethylformamide (3.15 mL). Tert-butyldimethylsilyl chloride (253 mg) was added, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with hexane / ethyl acetate (50% / 50%). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (410 mg). 1H-NMR (DMSO-D6) δ: 7.76 (1H, d, J = 2.5 Hz), 7.33 (1H, dd, J = 8.6, 2.5 Hz), 7.08 (1H, d, J = 8.6 Hz), 6.32 (1H, s), 5.41 (2H, s), 4.71 (2H, s), 0.89 (9H, s), 0.09 (6H, s).

[0337] (6) tert-butyl((2-(((tert-butyldimethylsilyl)oxy)methyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-8-yl)methyl)carbamate [ka] (8-bromo-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-2-yl)methanol (405 mg), potassium[[(tert-butoxycarbonyl)amino]methyl]trifluoroborate (607 mg), palladium acetate (46.0 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (168 mg), and potassium carbonate (566 mg) were mixed with 1,4-dioxane (7.29 mL) and water (1.82 mL). After degassing under reduced pressure, the mixture was stirred at 100°C for 3 hours under an inert gas atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was filtered by Celite. The filtrate was separated into layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (398 mg). 1H-NMR (DMSO-D6) δ: 7.60 (1H, br s), 7.45 (1H, t, J = 6.3 Hz), 7.04 (1H, d, J = 8.1 Hz), 7.00 (1H, dd, J = 8.1, 2.2 Hz), 6.29 (1H, s), 5.34 (2H, s), 4.71 (2H, s), 4.11 (2H, d, J = 6.3 Hz), 1.39 (9H, s), 0.89 (9H, s), 0.09 (6H, s).

[0338] (7) tert-butyl ((2-(hydroxymethyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-8-yl)methyl)carbamate [ka] Under ice cooling, 117 mg of tert-butyl((2-(((tert-butyldimethylsilyl)oxy)methyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-8-yl)methyl)carbamate was added to 1.17 mL of tetrahydrofuran solution with 0.316 mL of 1 M tetrabutylammonium fluoride-tetrahydrofuran solution, and the mixture was heated to room temperature. After stirring for 2 hours and 30 minutes, saturated ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate: 40% / 60% to 0% / 100%) to obtain the title compound (76.7 mg). 1 H-NMR (DMSO-D6) δ: 7.61 (1H, br s), 7.45 (1H, t, J = 6.4 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.00 (1H, dd, J = 8.3, 1.9 Hz), 6.29 (1H, s), 5.34 (2H, s), 5.23-5.21 (1H, br m), 4.50 (2H, br s), 4.11 (2H, d, J = 6.4 Hz), 1.39 (9H, s).

[0339] (8) tert-butyl((2-(azidomethyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-8-yl)methyl)carbamate [ka] To a solution of tert-butyl ((2-(hydroxymethyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-8-yl)methyl)carbamate (76.7 mg) in tetrahydrofuran, diphenyl phosphoryl azide (70.1 mg) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (38.8 mg) were added and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate: 90% / 10% to 60% / 40%) to obtain the title compound (74.4 mg). 1 H-NMR (DMSO-D6) δ: 7.64 (1H, br s), 7.46 (1H, t, J = 6.4 Hz), 7.08-7.03 (2H, m), 6.41 (1H, s), 5.37 (2H, s), 4.49 (2H, s), 4.12 (2H, d, J = 6.4 Hz), 1.39 (9H, s).

[0340] (9) tert-butyl((2-(aminomethyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-8-yl)methyl)carbamate [ka] To a mixture of tert-butyl((2-(azidomethyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-8-yl)methyl)carbamate (75.7 mg) and tetrahydrofuran (1.51 mL), water (0.151 mL) and triphenylphosphine (84.0 mg) were added, and the mixture was stirred at room temperature for 13 hours. The concentrated residue of the reaction mixture was used in the next reaction.

[0341] (10) tert-butyl((2-((1,4,4-trifluorocyclohexane-1-carboxamide)methyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazine-8-yl)methyl)carbamate [ka] Under ice cooling, a mixture of tert-butyl((2-(aminomethyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-8-yl)methyl)carbamate (70.6 mg) and N,N-dimethylformamide (0.706 mL) was mixed with N,N-diisopropylethylamine (160 mg), 1,4,4-trifluorocyclohexane-1-carboxylic acid (46.7 mg), and 1.7 M propylphosphonic anhydride-ethyl acetate solution (0.114 mL), and the mixture was stirred at room temperature for 15 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was sequentially washed with water, 10% citric acid aqueous solution, water, saturated sodium bicarbonate aqueous solution, water, and saturated brine, and dried over magnesium sulfate. The solvent was removed by reduced pressure distillation, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate: 75% / 25% to 50% / 50%) to obtain the title compound (81.6 mg). 1H-NMR (DMSO-D6) δ: 8.84-8.82 (1H, br m), 7.60 (1H, br s), 7.45 (1H, t, J = 6.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.00 (1H, dd, J = 8.5, 1.9 Hz), 6.19 (1H, s), 5.32 (2H, s), 4.36 (2H, d, J = 6.5 Hz), 4.11 (2H, d, J = 6.5 Hz), 2.13-1.97 (8H, m), 1.39 (9H, s).

[0342] (11) N-((8-(aminomethyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-2-yl)methyl)-1,4,4-trifluorocyclohexane-1-carboxamide hydrochloride [ka] To a mixture of tert-butyl((2-((1,4,4-trifluorocyclohexane-1-carboxamide)methyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazine-8-yl)methyl)carbamate (81.6 mg) and ethyl acetate (0.816 mL), 4M hydrogen chloride-ethyl acetate solution (0.413 mL) and methanol (2.82 mL) were added, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated, and ethyl acetate was added to the residue after azeotropic removal with toluene to crystallize it. The obtained crystals were filtered and washed with ethyl acetate to obtain the title compound (76.3 mg). 1 H-NMR (DMSO-D6) δ: 8.87-8.85 (1H, br m), 8.18 (3H, br s), 7.88 (1H, d, J = 2.2 Hz), 7.24 (1H, dd, J = 8.6, 2.2 Hz), 7.14 (1H, d, J = 8.6 Hz), 6.24 (1H, s), 5.38 (2H, s), 4.36 (2H, d, J = 5.9 Hz), 4.05 (2H, s), 2.10-2.04 (8H, br m).

[0343] (12) tert-butyl 5-(2-oxo-2-(((2-((1,4,4-trifluorocyclohexane-1-carboxamide)methyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-8-yl)methyl)amino)acetyl)-2,5-diazaspiro[3,4]octane-2-carboxylate [ka] Under water cooling, a mixture of N-((8-(aminomethyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazine-2-yl)methyl)-1,4,4-trifluorocyclohexane-1-carboxamide hydrochloride (35.0 mg) and 2-(2-(tert-butoxycarbonyl)-2,5-diazaspiro[3.4]octan-5-yl)-2-oxoacetic acid (27.7 mg) in N,N-dimethylformamide (0.525 mL) was mixed with triethylamine (49.3 mg) and 1.7 M propylphosphonic anhydride-ethyl acetate solution (0.096 mL), and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with saturated sodium bicarbonate aqueous solution and saturated brine, and dried over sodium sulfate. The solvent was removed by reduced pressure distillation, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate: 70% / 30% to 0% / 100%) to obtain the title compound (33.0 mg). 1H-NMR (CDCl3) δ: 7.88-7.87 (1H, br m), 7.76 (1H, d, J = 2.2 Hz), 7.10 (1H, dd, J = 8.1, 2.2 Hz), 7.03-6.98 (2H, m), 6.16 (1H, s), 5.28 (2H, s), 4.69 (2H, d, J = 8.4 Hz), 4.57 (2H, d, J = 6.0 Hz), 4.48 (2H, d, J = 6.0 Hz), 4.05 (2H, t, J = 6.5 Hz), 3.71 (2H, d, J = 8.4 Hz), 2.45-2.27 (2H, m), 2.15-2.09 (8H, m), 1.88-1.85 (2H, m), 1.48 (9H, s).

[0344] (13) N-((8-((2-(2-acryloyl-2,5-diazaspiro[3,4]octan-5-yl)-2-oxoacetamide)methyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazin-2-yl)methyl)-1,4,4-trifluorocyclohexane-1-carboxamide [ka] tert-butyl 5-(2-oxo-2-(((2-((1,4,4-trifluorocyclohexane-1-carboxamide)methyl)-4H-benzo[b]pyrazolo[1,5-d][1,4]oxazine-8-yl)methyl)amino)acetyl)-2,5-diazaspiro[3,4]octane-2-carboxylate (33 mg) was mixed with chloroform (0.33 mL) and trifluoroacetic acid (0.33 mL) and stirred at room temperature for 35 minutes. The reaction mixture was concentrated, and tetrahydrofuran (0.99 mL), N,N-diisopropylethylamine (32.3 mg), and acrylate chloride (9.04 mg) were added to the residue after azeotropic reaction with toluene and stirred at room temperature for 1 hour and 30 minutes. Ethanol (0.050 mL) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was concentrated, and the resulting residue was purified by thin-layer silica gel column chromatography (chloroform / methanol: 94% / 6%) to obtain the title compound (27.0 mg). 1 H-NMR (CDCl3) δ: 7.82 (1H, t, J = 5.9 Hz), 7.72 (1H, d, J = 2.0 Hz), 7.06 (1H, dd, J = 8.4, 1.9 Hz), 7.03-6.94 (2H, m), 6.34 (1H, dd, J = 17.0, 1.8 Hz), 6.19 (1H, dd, J = 17.0, 10.4 Hz), 6.13 (1H, s), 5.66 (1H, dd, J = 10.4, 1.8 Hz), 5.25 (2H, s), 4.96 (1H, d, J = 7.8 Hz), 4.74 (1H, d, J = 9.7 Hz), 4.54 (2H, d, J = 5.4 Hz), 4.45 (2H, d, J = 5.9 Hz), 4.07 (2H, t, J = 6.7 Hz), 3.98 (1H, d, J = 7.8 Hz), 3.87 (1H, d, J = 9.7 Hz), 2.44-1.95 (10H, m), 1.92-1.82 (2H, m).

[0345] Compounds of other examples were obtained by the same manufacturing method or method as described above, or by using known methods as necessary. The structural formulas and physical properties of the compounds of Examples 1 to 46, Example 2-001, and Examples 3-001 to 3-029 are shown in the table below. [Table 1] TIFF2026064226000106.tif244167 TIFF2026064226000107.tif237169 TIFF2026064226000108.tif228169 TIFF2026064226000109.tif246169 TIFF2026064226000110.tif222169 TIFF2026064226000111.tif250169 TIFF2026064226000112.tif250163 TIFF2026064226000113.tif225169 TIFF2026064226000114.tif250163 TIFF2026064226000115.tif213167 TIFF2026064226000116.tif238169 TIFF2026064226000117.tif87169

[0346] [Table 2] TIFF2026064226000119.tif192167 TIFF2026064226000120.tif219167 TIFF2026064226000121.tif230167 TIFF2026064226000122.tif222169 TIFF2026064226000123.tif249169 TIFF2026064226000124.tif219167 TIFF2026064226000125.tif209167 TIFF2026064226000126.tif238169 TIFF2026064226000127.tif208167 TIFF2026064226000128.tif233169 TIFF2026064226000129.tif181167 TIFF2026064226000130.tif218167 TIFF2026064226000131.tif250164 TIFF2026064226000132.tif250164 TIFF2026064226000133.tif250164 TIFF2026064226000134.tif250164 TIFF2026064226000135.tif250164 TIFF2026064226000136.tif250164 TIFF2026064226000137.tif209169

[0347] Test Example 1: Evaluation of Human LMP7 Inhibitory Activity The human LMP7 inhibitory activity of the test compound was calculated using human 20S immunotype proteasomes (cat. E-370, R&D Systems) and the following solution: Proteasome-Glo TM The procedure was carried out according to the protocol attached to the Chymotrypsin-Like Assay (cat. G8621, Promega). (1) Preparation of the solution The assay buffer (25 mM HEPES (pH 7.6), 150 mM NaCl, 1 mM DTT, 0.005% Surfactant P-20, 0.1% BSA, 4% DMSO) was prepared by dissolving HEPES (Nacalai Tesque), NaCl (Nacalai Tesque), DTT (Life Technologies), Surfactant P-20 (GE HealthCare), BSA (Sigma-Aldrich), and DMSO (Nacalai Tesque) in purified water. The enzyme solution (0.02 nM human 20S immunotyped proteasome) was prepared by dissolving human 20S immunotyped proteasome in assay buffer. The substrate solution is Proteasome-Glo TM Proteasome-Glo included with Chymotrypsin-Like Assay TM Buffer, Suc-LLVY-Glo TM The solution was prepared by mixing the Substrate and Luciferin Detection Reagent. The test compound solution was prepared by dissolving the test compound in DMSO. (2) Method In a 384-well plate (PerkinElmer ProxiPlate-384 Plus), 0.2 μL / well of the test compound solution or DMSO (control) and 10 μL / well of the substrate solution were added to each well and mixed. Then, 10 μL / well of the enzyme solution or assay buffer (blank) was added and mixed. After reacting at room temperature for 60 minutes, the luminescence of each well was measured using a multi-label plate reader, EnVision (PerkinElmer). (3) Aggregation The data was obtained by subtracting the luminescence of the blank well from the luminescence of each well. The LMP7 inhibition rate (%) for each concentration of the test compound was calculated using the following formula: 50% inhibitory concentration (IC) of the test compound. 50 The inhibition rate of the test compound concentration was calculated by fitting it to a logistic curve.

number

[0348] The results are shown in the table below. [Table 3]

[0349] Examples of formulations of the present invention include the following formulations. However, the present invention is not limited to these examples of formulations. Formulation Example 1 (Capsule Manufacturing) (1) Compound from Example 1: 30 mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19mg (4) Magnesium stearate 1 mg Mix ingredients (1), (2), (3), and (4) and fill them into gelatin capsules. Formulation example 2: Tablet manufacturing (1) Compound from Example 1: 10g (2) Lactose 50g (3) Corn starch 15g (4) Carmellose calcium 44g (5) Magnesium stearate 1g The entire amounts of components (1), (2), and (3) and 30 g of component (4) are kneaded with water, vacuum-dried, and then granulated. 14 g of component (4) and 1 g of component (5) are mixed into this granulated powder and compressed into tablets using a tablet press. In this way, 1000 tablets are obtained, each containing 10 mg of the compound of Example 1. [Industrial applicability]

[0350] Compound [I] or compound [Ia] of the present invention, or a pharmaceutically acceptable salt thereof, possesses LMP7 inhibitory activity and may therefore be useful for the treatment and / or prevention of various diseases or conditions involving LMP7.

Claims

1. A compound represented by formula [Ia] or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, Cy 1w teeth, (1) C 4-6 Cycloalkyl, (2) C 4-6 Cycloalkenyl, (3) A 4- to 6-membered heterocycloalkyl group containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen atoms as ring constituent atoms. (4) A 4- to 6-membered heterocycloalkenyl containing, in addition to carbon atoms, one heteroatom selected from the group consisting of oxygen and nitrogen atoms as a ring constituent atom, (5) A 7- to 11-membered spiroheterocycloalkyl, containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of nitrogen and sulfur atoms (wherein the sulfur atom may be appropriately oxidized to form sulfonyl), (6) Phenyl, (7) A 5- or 6-membered heteroaryl having one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms, (8) C 5-8 Cross-linked cycloalkyl And; Y 1w teeth, (1) combination; (2) -CH 2 -, or (3) -CONHCH 2 - And; R 1w Each of them operates independently. (1) Halogen, (2) C 1-4 alkyl (3) C 1-4 Haloalkyl, (4) C 1-4 Alkoxy, (5) COR 6 (Here, R 6 C 1-4 Alkyl or C 1-4 (It is an alkoxy.) (6) SO 2 R 7w (Here, R 7w C may be replaced with NHCOMe. 1-4 Alkyl or C 3-4 (It is cycloalkyl), or (7) C 3-4 Cycloalkyl And; R 3 Each of them is independently a halogen, Or two R atoms bonded to the same carbon atom 3 It combines with that carbon atom, as appropriate, C 3-4 They may also form cycloalkanes; R 4 teeth, (1) Hydrogen, (2) Halogen, or (3) C 1-4 Alkyl And; R 5 is hydrogen or C 1-4 It is alkyl; Cy 2w teeth, (1) A 5- or 6-membered heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms, or (2) A 9- or 10-membered condensed heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms. And, R 2w It is a halogen, and R 13w is a halogen, or R 2w and R 13w R 2w The benzene ring to which Cy 2w Together with the ring, it may form a tricyclic condensed heterocycle containing, in addition to carbon atoms, one to four heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms as ring constituent atoms; mw is 0, 1, 2, or 3; p is either 0 or 1; q is 0, 1, or 2; t1 is either 1 or 2; t2w is 1, 2, or 3; t3 is 1, 2, or 3; and [uw is either 0 or 1]

2. Y 1w This is a bond, and R 2w and R 13w The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein both are halogens.

3. Cy 2w The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a 5- or 6-membered heteroarylene containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring constituent atoms.

4. Formula [IIa]: 【Chemistry 2】 [In the formula, Cy 1w , R 1w , R 3 , R 4 , R 5 , mw, p, q, t1, t2w, and t3 are the same as the definitions in claim 1, R 2w It is a halogen. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, represented by [formula].

5. p is 0, mw is 1, R 4 and R 5 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein t1 is 2 and both t2w and t3 are 1.

7. Formula [IVa]: 【Transformation 3】 [In the formula, X 11w is CH or N, Cy 1w , Y 1w , R 1w , R 3 , mw, q, t1, t2w, and t3 are the same as the definitions in claim 1. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by [formula].

8. Y 1w However, -CONHCH 2 -The compound according to claim 1 or 7 or a pharmaceutically acceptable salt thereof.

9. The following structural formula: 【Chemistry 4】 A compound selected from the group consisting of the compounds shown, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. An LMP7 inhibitor comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

12. A therapeutic or prophylactic agent for a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma, comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

13. The therapeutic or prophylactic agent according to claim 12, wherein the autoimmune disease is a disease selected from the group consisting of systemic lupus erythematosus, lupus nephritis, myasthenia gravis, immune thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus, ANCA-associated vasculitis, multiple sclerosis, neuromyelitis optica, immune complex vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic scleroderma, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, autoimmune hepatitis, and Kawasaki disease.

14. The therapeutic or prophylactic agent according to claim 13, wherein the myasthenia gravis is ocular myasthenia gravis or generalized myasthenia gravis.

15. A method for inhibiting LMP7, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 9 to a mammal.

16. A method for treating or preventing a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 9 to a mammal.

17. The method according to claim 16, wherein the autoimmune disease is a disease selected from the group consisting of systemic lupus erythematosus, lupus nephritis, myasthenia gravis, immune thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus, ANCA-associated vasculitis, multiple sclerosis, neuromyelitis optica, immune complex vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic scleroderma, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, autoimmune hepatitis, and Kawasaki disease.

18. The method according to claim 17, wherein the myasthenia gravis is ocular myasthenia gravis or generalized myasthenia gravis.

19. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the production of an LMP7 inhibitor.

20. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma.

21. The use according to claim 20, wherein the autoimmune disease is a disease selected from the group consisting of systemic lupus erythematosus, lupus nephritis, myasthenia gravis, immune thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus, ANCA-associated vasculitis, multiple sclerosis, neuromyelitis optica, immune complex vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, autoimmune hepatitis, and Kawasaki disease.

22. The use according to claim 21, wherein the myasthenia gravis is ocular myasthenia gravis or generalized myasthenia gravis.

23. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in inhibiting LMP7.

24. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from the group consisting of autoimmune diseases, multiple myeloma, and mantle cell lymphoma.

25. The compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein the autoimmune disease is a disease selected from the group consisting of systemic lupus erythematosus, lupus nephritis, myasthenia gravis, immune thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, pemphigus, ANCA-associated vasculitis, multiple sclerosis, neuromyelitis optica, immune complex vasculitis, Graves' disease, Hashimoto's disease, thyroid eye disease, type 1 diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, Lambert-Eaton myasthenic syndrome, systemic sclerosis, Sjögren's syndrome, polymyositis, dermatomyositis, IgA nephropathy, IgG4-related disease, autoimmune hepatitis, and Kawasaki disease.

26. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, wherein the myasthenia gravis is ocular myasthenia gravis or generalized myasthenia gravis.

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