Nitrogen-containing heterocyclic compound having nrf2 activation effect

Abstract

To provide a compound having the ability to activate Nrf2.SOLUTION: The present invention provides a compound represented by formula (1) or a salt thereof, or a solvate thereof, (where Xa1 is CRa1 or N, Xa3 is CRa3 or N, Ra1, Ra2, and Ra3 are each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkoxy, Xb1, Xb2, and Xb3 are each independently selected from the group consisting of CH2, O, NH, S, and C=O, Y is a C6-C10 aryl optionally having a substituent or a 5- to 10-membered heteroaryl optionally having a substituent, and Z is a C6-C10 aryl optionally having a substituent, a 5- to 10-membered heteroaryl optionally having a substituent, or a C1-C6 alkyl optionally having a substituent).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a nitrogen-containing heterocyclic compound having an Nrf2 activating action, a salt thereof, a solvate thereof, and their uses. Further, the present invention relates to a pharmaceutical and a pharmaceutical composition containing them as an active ingredient.

Background Art

[0002] Nrf2 is a regulator of a group of genes involved in various biological defenses and is a transcription factor that is activated in response to oxidative stress. In the normal state, Nrf2 binds to Keap1, undergoes ubiquitination, and is degraded by the proteasome pathway. However, under stress conditions, it dissociates from Keap1, avoids degradation, and translocates into the nucleus. Thereafter, Nrf2 forms a heterodimer with a small Maf group factor and binds to an antioxidant response element (ARE) to induce transcription of downstream molecules.

[0003] Activation of Nrf2 is thought to exert a wide range of pharmacological effects, such as anti-inflammatory, anti-fibrotic, and anti-apoptotic effects, in addition to its antioxidant effect, and to act protectively against various diseases. Specific examples of diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia, amyotrophic lateral sclerosis in neurodegenerative diseases; idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary arterial hypertension, asthma in lung diseases; chronic kidney disease, acute kidney injury in kidney diseases; uveitis, glaucoma, age-related macular degeneration in ophthalmic diseases; non-alcoholic steatohepatitis in liver diseases; multiple sclerosis, rheumatoid arthritis, ulcerative colitis in immune / inflammatory diseases, etc. (Non-Patent Documents 3 to 7). As compounds having an Nrf2 activation-inducing effect, clinical trials have been conducted on bardoxolone methyl (CDDO-Me, Patent Document 1) for various chronic kidney diseases and on RTA-408 (omaveloxolone, Patent Document 2) for Friedreich's ataxia, etc. Dimethyl fumarate (Patent Document 3) is used as a therapeutic agent for multiple sclerosis. However, these compounds are those that covalently bind to Keap1. A concern about the risk of heart failure due to the interaction of the covalent binding site of bardoxolone methyl with non-target proteins has been reported (Non-Patent Document 8).

[0004] So far, compounds such as those described in Patent Document 4 have been reported as Nrf2 activators. However, they have not yet reached clinical development, and the development of non-covalent Nrf2 activators in which the interaction with non-target proteins is reduced is desired (Non-Patent Documents 1 to 3).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Non-Patent Document

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Summary of the Invention

Problems to be Solved by the Invention

[0007] An object of the present invention is to provide a low-molecular compound having an ability to activate Nrf2, or a salt thereof or a solvate thereof, which reduces the interaction with non-target proteins caused by covalent bonding. Another object is to provide a prophylactic or therapeutic agent for various diseases, such as neurodegenerative diseases, lung diseases, and kidney diseases, containing them as an active ingredient.

Means for Solving the Problems

[0008] The inventors of the present invention conducted intensive studies to solve such problems, and as a result, they found that a compound having a basic skeleton represented by the formula (I), a pharmacologically acceptable salt thereof, or a solvate thereof, which has a significantly different chemical structure from known Nrf2 activators, has an excellent Nrf2 activation effect, and thus completed the present invention.

[0009] That is, in one aspect of the present invention, the following invention is provided. [1] Formula (1):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[10] When Y is the following formula (3):

Chemical formula

[11] Formula (4):

Chemical formula

Chemical formula

[10] , or a salt thereof or a solvate thereof.

[12] X b1 and X b2 are CH2, and X b3 is O, the compound according to any one of [1] to

[11] , or a salt thereof or a solvate thereof.

[13] R5 is hydroxy or C1-C6 alkylsulfonylamino, the compound according to any one of [1] to

[12] , or a salt thereof or a solvate thereof.

[14] X z is CR z5 and R z1 , R z2 and R z5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl and ethyl, the compound according to any one of [1] to

[13] , or a salt thereof or a solvate thereof.

[15] R z4is a 4- to 6-membered cyclic amino group which may have one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy, or is a 4- to 6-membered cyclic amino group having a crosslinking group selected from the group consisting of C1-C2 alkylene and C1-C2 alkylene containing one oxygen atom on the ring, a compound or a salt thereof or a solvate thereof as described in any one of [1] to

[14] .

[16] R z4 is C1-C3 alkyl (5- to 6-membered heteroaryl C1-C2 alkyl) amino which may have a substituent selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl, or is C1-C3 alkyl (4- to 6-membered heterocyclyl) amino which may have a substituent selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl, a compound or a salt thereof or a solvate thereof as described in any one of [1] to

[14] .

[17] R y1 is chlorine, X y1 is CR y3 is X y2 is CR y4 is X y3 is CR y5 is R y3 is a 4- to 10-membered saturated heterocyclic group which has a bond to the nitrogen atom on the ring and may have a substituent or a 5- to 10-membered heteroaryl which may have a substituent, R y2 , R y4 and R y5 is hydrogen, a compound or a salt thereof or a solvate thereof as described in any one of [1] to

[16] .

[18] R a1 is hydrogen or fluorine, R a2 is hydrogen or methoxy, R a3 is hydrogen or fluorine, a compound or a salt thereof or a solvate thereof as described in any one of [1] to

[17] .

[19] R z4is 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, morpholin-4-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, (2S,3S)-3-methoxy-2-methylazetidin-1-yl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, methyl(1,2-oxazol-3-ylmethyl)amino, methyl(oxetan-3-yl)amino, methyl-[(3R)-oxolan-3-yl]amino or methyl-(3-methyloxetan-3-yl)amino, a compound or a salt thereof or a solvate thereof as described in any one of [1] to

[18] . 〔20〕 R y3 is 1-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl, 4-methylpiperazin-1-yl, (2R)-2,4-dimethylpiperazin-1-yl, 6-methoxy-2-azaspiro[3.3]heptan-2-yl, 4-(2-methoxyethyl)piperazin-1-yl, 3-methoxyazetidin-1-yl, 4-(oxetan-3-yl)piperazin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, (2R,5R)-2,4,5-trimethylpiperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl or morpholin-4-yl, a compound or a salt thereof or a solvate thereof as described in any one of [1] to

[19] . 〔21〕 A compound selected from the following compounds or a salt thereof or a solvate thereof: Compound 17-1, Compound 17-2, Compound 17-3, Compound 17-4, Compound 17-5, Compound 17-8, Compound 17-9, Compound 17-10, Compound 17-15, Compound 17-16, Compound 17-23, Compound 1-1, Compound 1-2, Compound 1-3, Compound 1-4, Compound 1-5, Compound 1-6, Compound 1-7, Compound 1-8, Compound 1-9, Compound 1-10, Compound 1-11, Compound 1-12, Compound 1-13, Compound 1-14, Compound 1-15, Compound 1-16, Compound 1-17, Compound 1-18, Compound 1-19, Compound 1-20, Compound 1-21, Compound 1-22, Compound 1-23, Compound 1-24, Compound 1-25, Compound 1-26, Compound 1-27, Compound 1-30, Compound 1-31, Compound 1-32, Compound 1-33, Compound 1-34, Compound 1-35, Compound 1-36, Compound 1-37, Compound 1-38, Compound 1-39, Compound 1-40, Compound 1-41, Compound 1-42, Compound 1-43, Compound 1-44, Compound 1-45, Compound 1-46, Compound 1-47, Compound 1-48, Compound 1-49, Compound 1-50, Compound 1-51, Compound 1-52, Compound 1-53, Compound 1-54, Compound 1-55, Compound 1-56, Compound 1-57, Compound 1-58, Compound 1-59, Compound 1-60, Compound 1-61, Compound 1-62, Compound 1-63, Compound 1-64, Compound 1-65, Compound 1-66, Compound 1-67, Compound 1-68, Compound 1-69, Compound 1-70, Compound 1-71, Compound 1-72, Compound 1-73, Compound 1-74, Compound 1-75, Compound 1-76, Compound 1-77, Compound 1-78, Compound 1-79, Compound 1-80, Compound 1-81, Compound 1-82, Compound 1-83, Compound 1-84, Compound 1-85, Compound 1-86, Compound 1-87, Compound 1-88, Compound 2-1, Compound 2-2, Compound 2-3, Compound 2-4, Compound 2-5, Compound 2-6, Compound 3-1, Compound 3-2, Compound 3-3, Compound 3-4, Compound 3-5, Compound 3-6, Compound 3-7, Compound 3-8, Compound 3-9, Compound 3-10, Compound 3-11, Compound 3-12, Compound 3-13, Compound 3-14, Compound 3-15, Compound 3-16, Compound 3-17, Compound 3-18, Compound 3-19, Compound 3-20Compound 3-21, Compound 3-22, Compound 3-23, Compound 3-24, Compound 3-25, Compound 3-26, Compound 3-27, Compound 3-28, Compound 4-1, Compound 4-2, Compound 4-3, Compound 4-4, Compound 4-5, Compound 4-6, Compound 4-7, Compound 4-8, Compound 4-9, Compound 4-10, Compound 4-11, Compound 4-12, Compound 4-13, Compound 4-14, Compound 4-15, Compound 4-16, Compound 4-17, Compound 4-18, Compound 4-19, Compound 4-20, Compound 4-21, Compound 4-22, Compound 4-23, Compound 4-24, Compound 4-25, Compound 4-26, Compound 4-27, Compound 4-28, Compound 4-29, Compound 4-30, Compound 4-31, Compound 4-32, Compound 4-33, Compound 4-34, Compound 4-35, Compound 4-36, Compound 4-37, Compound 4-38, Compound 4-39, Compound 4-40, Compound 4-41, Compound 4-42, Compound 4-43, Compound 4-44, Compound 4-45, Compound 4-46, Compound 4-47, Compound 4-48, Compound 4-49, Compound 4-50, Compound 4-51, Compound 4-52, Compound 4-53, Compound 4-54, Compound 4-55, Compound 4-56, Compound 4-57, Compound 4-58, Compound 4-59, Compound 4-60, Compound 5-1, Compound 5-2, Compound 5-3, Compound 5-4, Compound 5-5, Compound 5-6, Compound 5-7, Compound 5-8, Compound 5-9, Compound 5-10, Compound 5-11, Compound 5-12, Compound 5-13, Compound 5-14, Compound 5-15, Compound 5-16, Compound 6-1, Compound 6-2, Compound 6-3, Compound 6-4, Compound 6-5, Compound 6-6, Compound 6-7, Compound 6-8, Compound 6-9, Compound 6-10, Compound 6-11, Compound 6-12, Compound 6-13, Compound 7-1, Compound 7-2, Compound 7-3, Compound 7-4, Compound 7-5, Compound 7-6, Compound 7-7, Compound 7-8, Compound 7-9, Compound 7-10, Compound 7-11, Compound 7-12, Compound 7-13, Compound 7-14, Compound 7-15, Compound 7-16, Compound 7-17, Compound 7-18, Compound 8-1, Compound 8-2, Compound 8-3, Compound 8-4, Compound 8-5, Compound 8-6, Compound 8-7, Compound 8-8, Compound 8-9, Compound 9-1, Compound 9-2, Compound 9-3, Compound 9-4, Compound 9-5, Compound 9-6, Compound 9-7Compound 9-8, Compound 9-9, Compound 9-10, Compound 9-11, Compound 9-12, Compound 9-13, Compound 9-14, Compound 9-15, Compound 9-16, Compound 9-17, Compound 9-18, Compound 9-19, Compound 9-20, Compound 9-21, Compound 9-22, Compound 9-23, Compound 9-24, Compound 9-25, Compound 10-1, Compound 10-2, Compound 10-3, Compound 10-4, Compound 10-5, Compound 10-6, Compound 10-7, Compound 10-8, Compound 10-9, Compound 10-10, Compound 10-11, Compound 10-12, Compound 10-13, Compound 11-1, Compound 11-2, Compound 11-3, Compound 11-4, Compound 11-5, Compound 11-6, Compound 11-7, Compound 11-8, Compound 11-9, Compound 11-10, Compound 12-1, Compound 12-2, Compound 12-3, Compound 12-4, Compound 13-1, Compound 13-2, Compound 13-3, Compound 13-4, Compound 13-5, Compound 13-6, Compound 13-7, Compound 13-8, Compound 13-9, Compound 13-10, Compound 13-11, Compound 13-12, Compound 13-13, Compound 13-14, Compound 13-15, Compound 13-16, Compound 13-17, Compound 13-18, Compound 13-19, Compound 13-20, Compound 13-21, Compound 14-1, Compound 14-2, Compound 14-3, Compound 14-4, Compound 14-5, Compound 14-6, Compound 14-7, Compound 14-8, Compound 14-9, Compound 15-1, Compound 15-2, Compound 15-3, Compound 15-4, Compound 16-1, Compound 16-2, Compound 16-3, Compound 16-4, Compound 16-5, Compound 16-6, Compound 16-7, Compound 16-8, Compound 16-9, Compound 16-10, Compound 16-11, Compound 16-12, Compound 16-13, Compound 16-14, Compound 16-15, Compound 16-16, Compound 16-17, Compound 17-18, Compound 17-21, Compound 18-1, Compound 18-2, Compound 18-3, Compound 18-4, Compound 18-5, Compound 18-6, Compound 18-7, Compound 18-8, Compound 18-9, Compound 18-10, Compound 18-11, Compound 18-12, Compound 19-2, Compound 19-3, Compound 19-4, Compound 19-5, Compound 19-6, Compound 19-7, Compound 19-8, Compound 19-9, Compound 19-10, Compound 19-11, Compound 19-12Compound 19-13, Compound 19-14, Compound 19-15, Compound 19-16, Compound 19-17, Compound 19-18, and Compound 19-19. 〔22〕 A compound selected from the following compounds, or a salt thereof, or a solvate thereof: Compound 1-4, Compound 1-18, Compound 1-21, Compound 1-33, Compound 1-54, Compound 1-83, Compound 1-88, Compound 2-2, Compound 4-8, Compound 4-37, Compound 5-1, Compound 5-2, Compound 5-7, Compound 5-9, Compound 5-10, Compound 5-16, Compound 7-2, Compound 13-16, Compound 13-21, Compound 14-1, Compound 19-9, and Compound 19-15. 〔23〕 A pharmaceutical composition comprising the compound according to any one of 〔1〕 to 〔22〕, or a salt thereof, or a solvate thereof. 〔24〕 The pharmaceutical composition according to 〔23〕 for the prevention and / or treatment of a neurodegenerative disease, a lung disease, or a kidney disease. 〔25〕 A method for preventing and / or treating a neurodegenerative disease, a lung disease, or a kidney disease, comprising administering to a subject an effective amount of the compound according to any one of 〔1〕 to 〔22〕, or a salt thereof, or a solvate thereof. 〔26〕 The compound according to any one of 〔1〕 to 〔22〕, or a salt thereof, or a solvate thereof, for use in the prevention and / or treatment of a neurodegenerative disease, a lung disease, or a kidney disease. 〔27〕 Use of the compound according to any one of 〔1〕 to 〔22〕, or a salt thereof, or a solvate thereof, for the manufacture of a pharmaceutical composition for the prevention and / or treatment of a neurodegenerative disease, a lung disease, or a kidney disease. 〔28〕 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, or a salt thereof, or a solvate thereof.

[29] 4-[3-[2,6-Dichloro-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[30] 4-[3-[2,6-Dichloro-4-[6-(difluoromethoxy)-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[31] 4-[3-[2,6-Dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[32] 4-[3-[2,6-Dichloro-4-[4-(2-methoxyethyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid or a salt thereof, or a solvate thereof.

[33] 4-[3-[2,6-Dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[34] 4-[3-[2-Chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, its salts, or their solvates. 〔35〕 4-[3-[2,6-Dichloro-4-(6-methoxypyridin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, its salts, or their solvates. 〔36〕 4-[3-[2,6-Dichloro-4-(4-ethylpiperazin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, its salts, or their solvates. 〔37〕 4-[3-[2,6-Dichloro-4-(2-methoxyethoxy)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, its salts, or their solvates. 〔38〕 4-[3-[2,6-Dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, its salts, or their solvates. 〔39〕 4-[3-[2,6-Dichloro-4-(5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, its salts, or their solvates. 〔40〕 4-[3-[2,6-Dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[41] 4-[3-[2,6-Dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[42] 4-[3-[2,6-Dichloro-4-(7,11-dioxa-2-azadispiro[3.1.56.14]dodecan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[43] 4-[3-[2,6-Dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[44] 4-[3-[2,6-Dichloro-4-[6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[44] 4-[3-[2,6-Dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof. 〔45〕 4-[3-[2-Chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof. 〔46〕 4-[3-[2,6-Dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid or a salt thereof, or a solvate thereof. 〔47〕 4-[3-[4-Chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof. 〔48〕 4-[3-[5-Chloro-7-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)-2,3-dimethylbenzimidazole-4-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof. 〔49〕 4-[3-[2,6-Dichloro-4-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔50〕 4-[3-[2,6-Dichloro-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔51〕 4-[3-[2,6-Dichloro-4-[6-(difluoromethoxy)-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔52〕 4-[3-[2,6-Dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔53〕 4-[3-[2,6-Dichloro-4-[4-(2-methoxyethyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid. 〔54〕 4-[3-[2,6-Dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔55〕 4-[3-[2-Chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔56〕 4-[3-[2,6-Dichloro-4-(6-methoxypyridin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔57〕 4-[3-[2,6-Dichloro-4-(4-ethylpiperazin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔58〕 4-[3-[2,6-Dichloro-4-(2-methoxyethoxy)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔59〕 4-[3-[2,6-Dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔60〕 4-[3-[2,6-Dichloro-4-(5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔61〕 4-[3-[2,6-Dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔62〕 4-[3-[2,6-Dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔63〕 4-[3-[2,6-Dichloro-4-(7,11-dioxa-2-azadispiro[3.1.56.14]dodecane-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔64〕 4-[3-[2,6-Dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔65〕 4-[3-[2,6-Dichloro-4-[6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔66〕 4-[3-[2,6-Dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔67〕 4-[3-[2-Chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔68〕 4-[3-[2,6-Dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid. 〔69〕 4-[3-[4-Chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔70〕 4-[3-[5-Chloro-7-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)-2,3-dimethylbenzimidazole-4-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔71〕 Hydrate of 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔72〕 Hydrate of 4-[3-[2,6-dichloro-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔73〕 Hydrate of 4-[3-[2,6-dichloro-4-[6-(difluoromethoxy)-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔74〕 Hydrate of 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔75〕 Hydrate of 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid. 〔76〕 Hydrate of 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔77〕 Hydrate of 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔78〕 Hydrate of 4-[3-[2,6-dichloro-4-(6-methoxypyridin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔79〕 Hydrate of 4-[3-[2,6-dichloro-4-(4-ethylpiperazin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔80〕 Hydrate of 4-[3-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔81〕 Hydrate of 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔82〕 Hydrate of 4-[3-[2,6-dichloro-4-(5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔83〕 Hydrate of 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔84〕 Hydrate of 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔85〕 Hydrate of 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azadispiro[3.1.5.6.14]dodecan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔86〕 Hydrate of 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔87〕 Hydrate of 4-[3-[2,6-dichloro-4-[6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔88〕 Hydrate of 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔89〕 Hydrate of 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. 〔90〕 Hydrate of 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid. 〔91〕 4-[3-[4-Chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a hydrate thereof. 〔92〕 Hydrate of 4-[3-[5-Chloro-7-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)-2,3-dimethylbenzimidazole-4-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

Advantages of the Invention

[0010] The compound according to the present invention, or a pharmacologically acceptable salt thereof, or a solvate thereof has an Nrf2 activation effect, and provides a preventive or therapeutic agent for various diseases, such as neurodegenerative diseases, lung diseases, and kidney diseases.

Modes for Carrying Out the Invention

[0011] Hereinafter, the present invention will be described in detail by showing definitions of symbols, terms, etc. described in this specification, embodiments of the present invention, etc.

[0012] Examples of "halogen" in this specification include F, Cl, Br, or I.

[0013] As used herein, "alkyl" is a monovalent group derived by removing one arbitrary hydrogen atom from an aliphatic hydrocarbon, which does not contain a heteroatom (an atom other than a carbon and hydrogen atom) or an unsaturated carbon-carbon bond in the skeleton, and has a subset of a hydrocarbyl or hydrocarbon group structure containing hydrogen and carbon atoms. Alkyl includes not only linear ones but also branched ones. Preferably, alkyl has 1 to 20 carbon atoms (C1-C 20 , hereinafter "C p -C q"(which means having p to q carbon atoms) is an alkyl group, more preferably a C1-C 10 alkyl group, still more preferably a C1-C6 alkyl group. Specifically, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, and the like can be mentioned.

[0014] In this specification, "alkenyl" means a monovalent group having at least one double bond (two adjacent sp 2 carbon atoms). Depending on the arrangement of the double bond and the substituent (if present), the geometric form of the double bond can take an entgegen (E) or zusammen (Z), cis or trans configuration. Alkenyl includes not only linear ones but also branched ones. Preferably, the alkenyl is a C2-C 10 alkenyl group, more preferably a C2-C6 alkenyl group. Specifically, for example, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, and the like can be mentioned.

[0015] In this specification, "alkynyl" means a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only linear ones but also branched ones. Preferably, the alkynyl is a C2-C 10Alkynyl, more preferably C2-C6 alkynyl, is exemplified. Specifically, for example, ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, 3-methyl-(5-phenyl)-4-pentynyl, etc. are exemplified.

[0016] As used herein, "cycloalkyl" means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spiro rings. Preferably, C3-C8 cycloalkyl is exemplified as cycloalkyl. Specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, etc. are exemplified.

[0017] As used herein, "cycloalkylalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "cycloalkyl" as defined above. As cycloalkylalkyl, C3-C8 cycloalkyl C1-C6 alkyl is preferred, and C3-C6 cycloalkyl C1-C2 alkyl is more preferred. Specifically, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. are exemplified as cycloalkylalkyl.

[0018] As used herein, "aminoalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "amino" as defined below. As aminoalkyl, amino C1-C6 alkyl is preferred. Specifically, for example, 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, 4-aminobutyl, etc. are exemplified as aminoalkyl.

[0019] As used herein, "protected aminoalkyl" means a group in which the amino group contained in the "aminoalkyl" as defined above is protected by any protecting group. Specific examples of the protecting group for the amino group include, for example, Fmoc, Boc, Cbz, Alloc, Teoc, trifluoroacetyl, pentafluoropropionyl, phthaloyl, tosyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl and the like.

[0020] As used herein, "hydroxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with a hydroxyl group. Preferred examples of the hydroxyalkyl include hydroxy C1-C6 alkyl. Specific examples of the hydroxyalkyl include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 5-hydroxypentyl and the like.

[0021] As used herein, "haloalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with a halogen. Preferred examples of the haloalkyl include halo C1-C6 alkyl, and more preferred examples include C1-C6 fluoroalkyl. Specific examples of the haloalkyl include, for example, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5-difluoropentyl and the like.

[0022] As used herein, "carboxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with a carboxy group. Preferred examples of the carboxyalkyl include carboxy C1-C6 alkyl. Specific examples of the carboxyalkyl include, for example, carboxymethyl and the like.

[0023] As used herein, "aryl" means a monovalent aromatic hydrocarbon ring and an aromatic hydrocarbon ring group. Preferred examples of the aryl include C6-C 10Aryl is exemplified. Specifically, for example, phenyl, naphthyl (e.g., 1-naphthyl, 2-naphthyl), etc. are exemplified.

[0024] In this specification, "heterocyclyl" means a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. Heterocyclyl may have double and / or triple bonds in the ring, the carbon atoms in the ring may be oxidized to form carbonyls, and it may be a monocyclic or fused ring. In the case of a fused ring, it may form a fused ring with an aromatic ring such as a benzene ring, pyridine ring, pyrimidine ring, etc. It may also form a fused ring with a saturated alicyclic ring such as a cyclopentane ring, cyclohexane ring, etc., or a saturated heterocyclic ring such as a tetrahydropyran ring, dioxane ring, pyrrolidine ring, etc. The number of atoms constituting the heterocyclyl ring is preferably 4 to 10 (4- to 10-membered heterocyclyl), more preferably 4 to 7 (4- to 7-membered heterocyclyl). Specifically, as heterocyclyl, for example, azetidinyl, oxoazetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxopyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-thiadinane, thiadiazolidinyl, oxazolidonyl, benzodioxanyl, benzoxazolyl, dioxolanyl, dioxanyl, tetrahydropyrrolo[1,2-c]imidazole, thietanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2,4,5-trimethylpiperazin-1-yl, sultam, 2-oxaspiro[3.3]heptyl, 6,7-dihydro-pyrrolo[1,2-a]imidazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, azepanyl, dioxepanyl, 5,9-dioxaspiro[3.5]nonanyl, etc. are exemplified.

[0025] As used herein, "heteroaryl" means an aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms, and an aromatic heterocyclic group. The ring may be a monocyclic ring, a condensed ring with other rings, or may be partially saturated. The number of atoms constituting the heteroaryl ring is preferably 5 to 10 (5- to 10-membered heteroaryl), more preferably 5 to 7 (5- to 7-membered heteroaryl). Specific examples of heteroaryl include, for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, pyrrolopyrazinyl, furopyridyl, and the like.

[0026] As used herein, "aralkyl (arylalkyl)" means a group in which at least one hydrogen atom of "alkyl" as defined above is substituted with "aryl" as defined above. As aralkyl, C7-C 14 Aralkyl is preferred, C7-C 10 Aralkyl is more preferred. Specific examples of aralkyl include, for example, benzyl, phenethyl, 3-phenylpropyl, and the like.

[0027] As used herein, "heteroarylalkyl" means a group in which at least one hydrogen atom of "alkyl" as defined above is replaced by "heteroaryl" as defined above. As the heteroarylalkyl, 5- to 10-membered heteroaryl C1-C6 alkyl is preferred, and 5- to 10-membered heteroaryl C1-C2 alkyl is more preferred. Specific examples of the heteroarylalkyl include, for example, 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, 2-(5-benzofuranyl)ethyl, and the like.

[0028] As used herein, "heterocyclylalkyl" means a group in which one or more hydrogens of "alkyl" as defined above are replaced by "heterocyclyl" as defined above. As the heterocyclylalkyl, 4- to 7-membered heterocyclyl C1-C6 alkyl is preferred, and 4- to 7-membered heterocyclyl C1-C2 alkyl is more preferred. Specific examples of the heterocyclylalkyl include, for example, 2-(tetrahydro-2H-pyran-4-yl)ethyl, 2-(azetidin-3-yl)ethyl, 4-(oxolan-2-ylmethyl)piperazin-1-yl, and the like.

[0029] As used herein, the "saturated heterocyclic group" means a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The saturated heterocyclic group may have double and / or triple bonds in the ring, and the carbon atoms in the ring may be oxidized to form carbonyls. The saturated heterocyclic group may be monocyclic or may form a condensed ring with other rings, such as aromatic rings like benzene ring, pyridine ring, pyrimidine ring, etc., saturated alicyclic rings like cyclopentane ring, cyclohexane ring, etc., and saturated heterocyclic rings like tetrahydropyran ring, dioxane ring, pyrrolidine ring, etc. Preferably, the saturated heterocyclic group is a 4- to 10-membered saturated heterocyclic group. Specific examples of the saturated heterocyclic group include, for example, azetidinyl, oxoazetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 4-oxopyrrolidinyl, piperidinyl, 4-oxopiperidinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, oxazolidonyl, dioxolanyl, dioxanyl, thietanyl, octahydroindolyl, indolinyl, 5,9-dioxaspiro[3.5]nonanyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, morpholin-4-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 3-methoxy-2-methylazetidin-1-yl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 1-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl, 4-methylpiperazin-1-yl, 2,4-dimethylpiperazin-1-yl, 6-methoxy-2-azaspiro[3.3]heptan-2-yl, 4-(2-methoxyethyl)piperazin-1-yl, 3-methoxyazetidin-1-yl, 4-(oxetan-3-yl)piperazin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2,4,5-trimethylpiperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl, etc.

[0030] As used herein, "alkoxy" means an oxy group to which the "alkyl" as defined above is bonded. Preferred alkoxy groups include C1-C6 alkoxy groups. Specific examples of alkoxy groups include, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, 3-methylbutoxy, and the like.

[0031] As used herein, "haloalkoxy" means a group in which one or more hydrogens of the "alkoxy" as defined above are substituted with halogen. Preferred haloalkoxy groups include C1-C6 haloalkoxy groups, and more preferred are C1-C6 fluoroalkoxy groups. Specific examples of haloalkoxy groups include, for example, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, and the like.

[0032] As used herein, "cycloalkoxy" means an oxy group to which the "cycloalkyl" as defined above is bonded. Preferred cycloalkoxy groups include C3-C8 cycloalkoxy groups. Specific examples of cycloalkoxy groups include, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and the like.

[0033] As used herein, "alkoxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "alkoxy" as defined above. Preferred alkoxyalkyl groups include C1-C6 alkoxy C1-C6 alkyl groups, and more preferred are C1-C6 alkoxy C1-C2 alkyl groups. Specific examples of alkoxyalkyl groups include, for example, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, and the like.

[0034] As used herein, "cycloalkoxyalkyl" means a group in which one or more hydrogens of "alkyl" as defined above are replaced by "cycloalkoxy" as defined above. As the cycloalkoxyalkyl, C3-C8 cycloalkoxy C1-C6 alkyl is preferred, and C3-C6 cycloalkoxy C1-C2 alkyl is more preferred. Specific examples of the cycloalkoxyalkyl include, for example, cyclopropoxymethyl, cyclobutoxymethyl and the like.

[0035] As used herein, "aryloxy" means an oxy group to which "aryl" as defined above is bonded. As the aryloxy, preferably C6-C 10 aryloxy is exemplified. Specific examples of the aryloxy include, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

[0036] As used herein, "heterocyclyloxy" means an oxy group to which "heterocyclyl" as defined above is attached. The number of atoms constituting the ring of heterocyclyloxy is preferably 4 to 10 (4- to 10-membered heterocyclyloxy), more preferably 4 to 7 (4- to 7-membered heterocyclyloxy). Specific examples of heterocyclyloxy include, for example, azetidinyloxy, oxiranyloxy, oxetanyloxy, azetidinyloxy, dihydrofuranyloxy, tetrahydrofuranyloxy, dihydropyranyloxy, tetrahydropyranyloxy, tetrahydropyridyloxy, tetrahydropyrimidinyloxy, morpholinyl-oxy, thiomorpholinyl-oxy, pyrrolidinyloxy, piperidinyloxy, piperazinyl-oxy, pyrazolidinyloxy, imidazolinyl-oxy, imidazolidinyloxy, oxazolidinyloxy, isoxazolidinyloxy, thiazolidinyloxy, isothiazolidinyloxy, 1,2-thiadinanoxy, thiadiazolidinyloxy, oxazolidoneoxy, benzodioxanyl-oxy, benzoxazolyl-oxy, dioxolanyloxy, dioxanyloxy, tetrahydropyrrolo[1,2-c]imidazoleoxy, thietanyloxy, 3,6-diazabicyclo[3.1.1]heptanyloxy, 2,5-diazabicyclo[2.2.1]heptanyloxy, 3-oxa-8-azabicyclo[3.2.1]octanyloxy, sultamoxy, 2-oxaspiro[3.3]heptyloxy, and the like.

[0037] As used herein, "heteroaryloxy" means an oxy group to which the "heteroaryl" as defined above is attached. The number of atoms constituting the ring of the heteroaryloxy is preferably 5 to 10 (5- to 10-membered heteroaryloxy), more preferably 5 to 7 (5- to 7-membered heteroaryloxy). Specific examples of the heteroaryloxy include, for example, furyloxy, thienyloxy, pyrrolyloxy, imidazolyl oxy, pyrazolyloxy, thiazolyloxy, isothiazolyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, triazolyloxy, tetrazolyloxy, pyridyloxy, pyrimidyloxy, pyridazinilyloxy, pyrazinyloxy, triazinilyloxy, benzofuryloxy, benzothienyloxy, benzothiadiazolyloxy, benzothiazolyloxy, benzoxazolyloxy, benzoxadiazolyloxy, benzimidazolyl oxy, indryloxy, isoindryloxy, indazolyl oxy, quinolyl oxy, isoquinolyl oxy, cinnolinilyloxy, quinazolinilyloxy, quinoxalinilyloxy, benzodioxolyl oxy, indolizinilyloxy, imidazopyridyloxy and the like.

[0038] As used herein, "aralkoxy" means an oxy group to which the "aralkyl" as defined above is attached. As the aralkoxy, C7-C 14 Aralkoxy is preferred, and C7-C 10 Aralkoxy is more preferred. Specific examples of the aralkoxy include, for example, benzyloxy, phenethyloxy, 3-phenylpropoxy and the like.

[0039] As used herein, "heteroarylalkoxy" means an oxy group to which the "heteroarylalkyl" as defined above is attached. As the heteroarylalkoxy, 5- to 10-membered heteroaryl C1-C6 alkoxy is preferred, and 5- to 10-membered heteroaryl C1-C2 alkoxy is more preferred. Specific examples of the heteroarylalkoxy include, for example, 3-thienylmethoxy, 3-pyridylmethoxy and the like.

[0040] As used herein, "aralkyloxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by the "aralkyloxy" as defined above. As the aralkyloxyalkyl, C7-C 14 aralkyloxy C1-C6 alkyl is preferred, and C7-C 14 aralkyloxy C1-C2 alkyl is more preferred. Specific examples of the aralkyloxyalkyl include, for example, benzyloxymethyl, 1-(benzyloxy)ethyl, and the like.

[0041] As used herein, "heteroarylalkyloxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by the "heteroarylalkyloxy" as defined above. As the heteroarylalkyloxyalkyl, 5- to 10-membered heteroaryl C1-C6 alkoxy C1-C6 alkyl is preferred, and 5- to 10-membered heteroaryl C1-C2 alkoxy C1-C2 alkyl is more preferred. Specific examples of the heteroarylalkyloxyalkyl include, for example, 3-pyridylmethoxymethyl, and the like.

[0042] As used herein, "heterocyclylalkyloxy" means an oxy group in which "alkyl" is bonded to the "heterocyclyl" as defined above. The number of atoms constituting the ring of the heterocyclyl is preferably 4 to 10 (4- to 10-membered heterocyclyl), more preferably 4 to 7 (4- to 7-membered heterocyclyl), and the alkyl is preferably C1-C6 alkyl, more preferably C1-C4 alkyl. Preferred heterocyclylalkyloxy is 4- to 10-membered heterocyclyl C1-C6 alkoxy, more preferably 4- to 7-membered heterocyclyl C1-C2 alkoxy. Specific examples of the heterocyclylalkyloxy include, for example, oxolan-2-ylmethoxy, oxolan-3-ylmethoxy, oxan-4-ylmethoxy, 1,4-dioxan-2-ylmethoxy, (1-methylpiperidin-4-yl)methoxy, 3-morpholin-4-ylpropoxy, and the like.

[0043] As used herein, "hydroxyalkoxy" means a group in which "hydroxy" is bonded to the "alkoxy" as defined above. Preferably, the hydroxyalkoxy is hydroxy C2-C6 alkoxy, more preferably hydroxy C3-C6 alkoxy. Specific examples of the hydroxyalkoxy include 3-hydroxy-3-methylbutoxy, 4-hydroxybutoxy and the like.

[0044] As used herein, "alkoxyalkoxy" means a group in which "alkoxy" is bonded to the "alkoxy" as defined above. Preferably, the alkoxyalkoxy is C1-C6 alkoxy C1-C6 alkoxy, more preferably C1-C3 alkoxy C1-C2 alkoxy. Specific examples of the alkoxyalkoxy include 2-methoxyethoxy and the like.

[0045] As used herein, "alkylaminoalkoxy" means a group in which "alkylamino" is bonded to the "alkoxy" as defined above. Preferably, the alkylaminoalkoxy is bis(C1-C6 alkyl)amino C1-C6 alkoxy, more preferably bis(C1-C4 alkyl)amino C1-C3 alkoxy. Specific examples of the alkylaminoalkoxy include 2-(dimethylamino)ethoxy and the like.

[0046] As used herein, "aryloxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by the "aryloxy" as defined above. The aryloxyalkyl is preferably aryloxy C1-C6 alkyl, and more preferably aryloxy C1-C2 alkyl. Specific examples of the aryloxyalkyl include, for example, phenoxymethyl, 2-phenoxyethyl and the like. 10 aryloxy C1-C6 alkyl is preferred, and C6-C 10 aryloxy C1-C2 alkyl is more preferred. Specific examples of the aryloxyalkyl include, for example, phenoxymethyl, 2-phenoxyethyl and the like.

[0047] In the present specification, "amino" means -NH2 in a narrow sense, and -NRR' in a broad sense, where R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R and R' form a ring together with the nitrogen atom to which they are attached. Preferred examples of amino include -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, and 4- to 8-membered cyclic amino.

[0048] In the present specification, "monoalkylamino" refers to a group in which R is hydrogen and R' is an "alkyl" as defined above, among the "amino" as defined above. As the monoalkylamino, preferably, mono C1-C6 alkylamino can be mentioned. Specific examples of the monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, t-butylamino, etc.

[0049] In the present specification, "dialkylamino" refers to a group in which R and R' are independently "alkyl" as defined above among "amino" as defined above. Dialkylamino is preferably diC1-C6 alkylamino. Specific examples of dialkylamino include dimethylamino and diethylamino.

[0050] In the present specification, the term "cyclic amino" refers to a group in which R and R' form a ring together with the nitrogen atom to which they are bonded in the above-defined "amino". The cyclic amino is preferably a 4- to 8-membered cyclic amino. Specific examples of the cyclic amino include 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidethiomorpholinyl-4-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, and the like.

[0051] As used herein, "aminocarbonyl" means a carbonyl group to which the "amino" as defined above is attached. Preferred examples of the aminocarbonyl group include -CONH2, mono C1-C6 alkylaminocarbonyl, di C1-C6 alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl. Specific examples of the aminocarbonyl group include, for example, -CONH2, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidothiomorpholinyl-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, and the like.

[0052] As used herein, "aminocarbonylalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "aminocarbonyl" as defined above. Preferred examples of the aminocarbonylalkyl group include aminocarbonyl C1-C6 alkyl, and more preferred examples thereof include aminocarbonyl C1-C4 alkyl. Specific examples of the aminocarbonylalkyl group include, for example, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, t-butylaminocarbonylmethyl, 1-azetidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-morpholinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl)ethyl, 2-(4-morpholinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, 4-(dimethylaminocarbonyl)butyl, and the like.

[0053] As used herein, "alkylsulfonyl" means a sulfonyl group to which the "alkyl" as defined above is attached. Preferred examples of the alkylsulfonyl group include C1-C6 alkylsulfonyl. Specific examples of the alkylsulfonyl group include, for example, methylsulfonyl, ethylsulfonyl, and the like.

[0054] As used herein, "alkylsulfonylamino" means a group in which sulfonyl is bonded to the "amino" as defined above. Preferably, C1-C6 alkylsulfonyl-NH-, (C1-C6 alkylsulfonyl-)2N-, etc. may be mentioned. Specific examples of aminoalkylsulfonyl include methylsulfonylamino, ethylsulfonylamino, bis(methylsulfonyl)amino, bis(ethylsulfonyl)amino, etc.

[0055] As used herein, "alkylsulfonylalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are substituted with the "alkylsulfonyl" as defined above. As alkylsulfonylalkyl, C1-C6 alkylsulfonyl C1-C6 alkyl is preferred, and C1-C6 alkylsulfonyl C1-C2 alkyl is more preferred. Specific examples of alkylsulfonylalkyl include methylsulfonylmethyl, 2-(methylsulfonyl)ethyl, etc.

[0056] As used herein, "alkylthio" means a thio group to which the "alkyl" as defined above is bonded, and preferably C1-C6 alkylthio may be mentioned. Specific examples of alkylthio include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, etc.

[0057] As used herein, "acyl (alkanoyl)" means a group in which a carbonyl group is bonded to hydrogen or the "alkyl" as defined above. As acyl, preferably C1-C6 acyl, more preferably C2-C4 acyl may be mentioned. Specific examples of acyl include formyl, acetyl, propionyl, butanoyl, etc.

[0058] As used herein, "haloacyl (haloalkanoyl)" means a group in which a carbonyl group is bonded to the above-mentioned "haloalkyl". Preferred haloacyls include C2-C6 haloacyls, more preferably C2-C4 haloacyls. Specific examples of haloacyls include trifluoroacetyl, trichloroacetyl, pentafluoropropionyl, 2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionyl, 3,3,3-trifluoro-2-(trifluoromethyl)propionyl, and the like.

[0059] As used herein, "alkylene" means a divalent group derived by further removing one arbitrary hydrogen atom from the above-mentioned "alkyl", preferably C1-C8 alkylene, more preferably C4-C8 alkylene. Specific examples of alkylene include -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)CH2-, -C(CH3)2-, -(CH2)4-, -CH(CH3)CH2CH2-, -C(CH3)2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2-, -CH2CH2CH(CH3)-, -CH2CH(CH2CH3)-, -(CH2)5-, -CH(CH3)CH(CH2CH3)-, -(CH2)6-, -(CH2)7-, -(CH2)8-, and the like.

[0060] As used herein, "arylene" means a divalent group derived by further removing one arbitrary hydrogen atom from the above-mentioned "aryl". The arylene may be a monocyclic or a condensed ring. The number of atoms constituting the arylene ring is not particularly limited, but is preferably 6 to 10 (C6-C 10 arylene). Specific examples of arylene include, for example, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, and the like.

[0061] As used herein, the "aromatic hydrocarbon ring" means a hydrocarbon ring composed of a monocyclic or condensed ring exhibiting aromaticity. Preferred examples of the aromatic hydrocarbon ring include 6- to 10-membered aromatic hydrocarbon rings. Specific examples of the aromatic hydrocarbon ring include, for example, a benzene ring, a naphthalene ring, and the like.

[0062] As used herein, the "aromatic heterocyclic ring" means a cyclic compound composed of a monocyclic or condensed ring containing one or more heteroatoms and exhibiting aromaticity. Preferred examples of the aromatic heterocyclic ring include 5- to 10-membered aromatic heterocyclic rings. Specific examples of the aromatic heterocyclic ring include, for example, a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a thiadiazole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a triazine ring, a benzofuran ring, a benzothiophene ring, a benzothiadiazoline ring, a benzothiazoline ring, a benzoxazoline ring, a benzoxadiazoline ring, a benzimidazole ring, a benzotriazole ring, an indole ring, an isoindole ring, an indazole ring, an azaindole ring, a quinoline ring, an isoquinoline ring, a cinnoline ring, a quinazoline ring, a quinoxaline ring, a benzodioxole ring, an indolizine ring, an imidazopyridine ring, a pyrazolopyridine ring, an imidazopyridine ring, a triazolopyridine ring, a pyrrolopyrazine ring, a furopyridine ring, and the like.

[0063] As used herein, the "alicyclic ring" means a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond in the ring and may be a polycyclic ring having two or more rings. Further, the carbon atoms constituting the ring may be oxidized to form a carbonyl group. Preferred examples of the alicyclic ring include 3- to 8-membered alicyclic rings. Specific examples of the alicyclic ring include, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a bicyclo[2.2.1]heptane ring, and the like.

[0064] As used herein, the term "saturated heterocyclic ring" means a non-aromatic heterocyclic ring that contains 1 to 5 heteroatoms in addition to carbon atoms and does not contain double bonds and / or triple bonds in the ring. The saturated heterocyclic ring may be a monocyclic ring or may form a condensed ring with other rings, such as an aromatic ring like a benzene ring. Preferably, the saturated heterocyclic ring is a 4- to 10-membered saturated heterocyclic ring. Specific examples of the saturated heterocyclic ring include, for example, azetidine ring, oxoazetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, pyrrolidine ring, 2-oxopyrrolidine ring, 4-oxopyrrolidine ring, piperidine ring, 4-oxopiperidine ring, piperazine ring, pyrazolidine ring, imidazolidine ring, oxazolidine ring, isoxazolidine ring, thiazolidine ring, isothiazolidine ring, thiadiazolidine ring, oxazolidone ring, dioxolane ring, dioxane ring, thietane ring, octahydroindole ring, indoline ring, azepane ring, dioxepane ring, 5,9-dioxaspiro[3.5]nonane ring, and the like.

[0065] As used herein, the “heterocyclic ring” refers to a non-aromatic heterocyclic ring containing preferably 1 to 5, more preferably 1 to 3 heteroatoms among the atoms constituting the ring. The heterocyclic ring may have double and / or triple bonds in the ring, the carbon atoms in the ring may be oxidized to form carbonyls, and it may be a monocyclic ring, a fused ring, or a spiro ring. The number of atoms constituting the ring of the heterocyclic ring is preferably 3 to 12 (3- to 12-membered heterocyclic ring), more preferably 4 to 10 (4- to 10-membered heterocyclic ring). Specific examples of the heterocyclic ring include, for example, azetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, pyrrolidine ring, 4-oxopyrrolidine ring, piperidine ring, 4-oxopiperidine ring, piperazine ring, pyrazolidine ring, imidazolidine ring, oxazolidine ring, isoxazolidine ring, thiazolidine ring, isothiazolidine ring, thiadiazolidine ring, oxazolidone ring, dioxolane ring, dioxane ring, thietane ring, octahydroindole ring, 6,7-dihydro-pyrrolo[1,2-a]imidazole ring, or azocane ring, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine ring, azepane ring, dioxepane ring, 5,9-dioxaspiro[3.5]nonane ring or a ring in which one or more single bonds in these saturated heterocyclic rings are replaced by double bonds or triple bonds, and the like.

[0066] As used herein, the “protecting group for carboxyl group” includes alkyl ester type protecting groups, benzyl ester type protecting groups, substituted alkyl ester type protecting groups, and the like.

[0067] As used herein, the “protecting group for amino group” includes carbamate type protecting groups, amide type protecting groups, arylsulfonamide type protecting groups, alkylamine type protecting groups, imide type protecting groups, and the like.

[0068] As used herein, the “protecting group for hydroxy” includes alkyl ether type protecting groups, aralkyl ether type protecting groups, silyl ether type protecting groups, carbonate ester type protecting groups, and the like.

[0069] Examples of the "substituent derived from halogen" in this specification include fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), etc.

[0070] Examples of the "substituent derived from an oxygen atom" in this specification include hydroxy (-OH), oxy (-OR), carbonyl (-C(=O)-R), carboxyl (-CO2H), oxycarbonyl (-C(=O)-OR), carbonyloxy (-O-C(=O)-R), thiocarbonyl (-C(=O)-SR), carbonylthio group (-S-C(=O)-R), aminocarbonyl (-C(=O)-NHR), carbonylamino (-NH-C(=O)-R), oxycarbonylamino (-NH-C(=O)-OR), sulfonylamino (-NH-SO2-R), aminosulfonyl (-SO2-NHR), sulfamoylamino (-NH-SO2-NHR), thiocarboxyl (-C(=O)-SH), carboxylcarbonyl (-C(=O)-CO2H).

[0071] Examples of the "substituent derived from a nitrogen atom" in this specification include azide (-N3, also referred to as "azide group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R), tertiary amino (-NR(R')), amidino (-C(=NH)-NH2), substituted amidino (-C(=NR)-NR'R''), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R''), aminocarbonylamino (-NR-CO-NR'R'').

[0072] Examples of the "substituent derived from a sulfur atom" in this specification include thiol (-SH), thio (-S-R), sulfinyl (-S(=O)-R), sulfonyl (-S(=O)2-R), sulfo (-SO3H), pentafluorothio (-SF5).

[0073] The "substituent derived from a boron atom" in this specification is exemplified by boryl (-BR(R')), dioxaborolyl (-B(OR)(OR')), and trifluoroborate salt (-BF3-), etc. Specifically, the "substituent derived from a boron atom" is such that these two substituents R and R' are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., or such that these two substituents R and R' together with the atoms to which R and R' are each bonded form a ring, that is, a cyclic boryl group is exemplified. Preferred "substituents derived from a boron atom" are exemplified by cyclic boryl groups. More specifically, examples of cyclic boryl groups include pinacolato boryl group, neopentanediolato boryl group, catecholato boryl group, 9-borabicyclo[3.3.1]nonan-9-yl group, etc.

[0074] The "group derived from zinc" in this specification is exemplified by an alkylzinc group (-Zn-(C1-C6 alkyl)) or a zinc halide group (-Zn-X). Preferred "groups derived from zinc" are exemplified by -ZnMe, -ZnEt, -ZnPr, -ZnCl, -ZnBr, -ZnI. The production of compounds having these "groups derived from zinc" can be carried out by referring to March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th Edition, John Wiley & Sons, Inc., 2019) and Comprehensive Organic Transformations by R. C. Laroch (3rd Edition, John Wiley & Sons, Inc., 2018).

[0075] As used herein, "optionally substituted" means that a group may be optionally substituted by any substituent. Further, each of these may optionally be substituted with a substituent, and these substituents are not limited, and may be freely selected independently from one or more of any substituents including, for example, a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom.

[0076] As used herein, "optionally protected" means that a group may be optionally protected by any protecting group.

[0077] As used herein, "one or more" means one or two or more. When "one or more" is used in the context related to the substituent of a group, this term means a number from one to the maximum number of substituents allowed for that group.

[0078] As used herein, "~" indicating a numerical range includes the values at both ends thereof. For example, "A~B" means a numerical range that is equal to or greater than A and equal to or less than B.

[0079] As used herein, the term "about", when used in combination with a numerical value, means a value range of +10% and -10% of that numerical value.

[0080] As used herein, the meaning of the term "and / or" includes any combination in which "and" and "or" are appropriately combined. Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.

[0081] One embodiment of the present invention is a compound represented by the general formula (1) (hereinafter also referred to as "compound (1)") or a salt thereof or a solvate thereof.

[0082] In compound (1), X a1 is CRa1 or N. X a1 is preferably CR a1 is.

[0083] In compound (1), X a3 is CR a3 or N. X a3 is preferably CR a3 is

[0084] In compound (1), R a1 is hydrogen, halogen or C1-C6 alkoxy. R a1 is preferably hydrogen or fluorine.

[0085] In compound (1), R a2 is hydrogen, halogen or C1-C6 alkoxy. R a2 is preferably hydrogen or methoxy.

[0086] In compound (1), R a3 is hydrogen, halogen or C1-C6 alkoxy. R a3 is preferably hydrogen or fluorine.

[0087] In compound (1), X b1 is CH2, O, NH, S or C=O. X b1 is preferably CH2.

[0088] In compound (1), X b2 is CH2, O, NH, S or C=O. X b2 is preferably CH2, O, NH or C=O, more preferably CH2.

[0089] In compound (1), X b3 is CH2, O, NH, S or C=O. X b3 is preferably CH2, O, NH, S or C=O, more preferably O.

[0090] Xb1 and X b2 and X b3 As a combination of X b1 is CH2, and X b2 is CH2, O, NH or C=O, and X b3 is preferably CH2, O, NH, S or C=O, and X b1 and X b2 is CH2, and X b3 is O, or X b1 and X b3 is CH2, Xb2 is O, or X b1 and X b2 is CH2, and X b3 is S, or Xb1 is CH2, and X b2 is NH, and X b3 is C=O, or X b1 and X b2 is CH2, and X b3 is NH, or X b1 is CH2, and X b2 is C=O, and X b3 is NH, or X b1 and X b3 is CH2, and X b2 is NH, or X b1 , X b2 and X b3 is more preferably CH2, and X b1 and X b2 is CH2, and X b3 is most preferably O.

[0091] In compound (1), Z is C6-C 10 aryl, 5- to 10-membered heteroaryl or C1-C6 alkyl, and the C6-C 10 aryl, 5- to 10-membered heteroaryl and C1-C6 alkyl are substituted with R z3 and may be further substituted with one or more groups selected from the group consisting of R z1 , R z2 , R z4 and R z5 . Preferably, Z is substituted with R z3 and may be further substituted with one or more groups selected from the group consisting of R z1, R z2 , R z4 and R z5 and is optionally substituted with one or more groups selected from the group consisting of phenyl, pyridyl or C2-C5 alkyl.

[0092] In compound (1), Z is preferably of formula (2):

Chemical formula

[0093] In compound (1), R z1 , R z2 and R z5 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, optionally substituted C1-C6 alkyl (5-10 membered heteroaryl C1-C6 alkyl) amino, optionally substituted C1-C6 alkyl (4-10 membered heterocyclyl) amino and optionally substituted 4-8 membered cyclic amino. R z1 , R z2 and R z5 are preferably each independently selected from the group consisting of hydrogen, halogen and C1-C6 alkyl, more preferably each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl and ethyl.

[0094] In compound (1), R z4 is hydrogen, halogen, C1-C6 alkyl, optionally substituted C1-C6 alkyl (5-10 membered heteroaryl C1-C6 alkyl) amino, optionally substituted C1-C6 alkyl (4-10 membered heterocyclyl) amino or optionally substituted 4-8 membered cyclic amino. R z4Preferably, it is C1-C6 alkyl (5-10 membered heteroaryl C1-C2 alkyl) amino which may have a substituent, C1-C6 alkyl (4-10 membered heterocyclyl) amino which may have a substituent or 4-8 membered cyclic amino which may have a substituent, more preferably, 4-6 membered cyclic amino which may have one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 alkoxy; 4-6 membered cyclic amino having a crosslinking group selected from the group consisting of C1-C2 alkylene and C1-C2 alkylene containing one oxygen atom on the ring; C1-C3 alkyl (5-6 membered heteroaryl C1-C2 alkyl) amino which may have a substituent selected from the group consisting of hydrogen, halogen and C1-C6 alkyl; C1-C3 alkyl (4-6 membered heterocyclyl) amino which may have a substituent selected from the group consisting of hydrogen, halogen and C1-C6 alkyl, particularly preferably, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, morpholin-4-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, (2S,3S)-3-methoxy-2-methylazetidin-1-yl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, methyl(1,2-oxazol-3-ylmethyl)amino, methyl(oxetan-3-yl)amino, methyl-[(3R)-oxolan-3-yl]amino or methyl-(3-methyloxetan-3-yl)amino.

[0095] In compound (1), R z3 is a carboxyl group or its biological equivalent. The biological equivalent refers to functional groups which have different chemical structures but can show similar biological effects as described by Matsuoka et al. (Pharmacia, 2010, 46(3), 215-222) and Thornber et al. (Chem. Soc. Rev., 1979, 8, 563-580). Examples of the equivalent of the carboxyl group are functional groups having an acidic proton. R z3It may also include compounds that can be converted into a carboxyl group or its biological equivalent after administration to a subject, such as these prodrugs.

[0096] In compound (1), R z3 is specifically the following substituent group A:

Chemical formula

Chemical formula

[0097] In compound (1), Y is C6-C 10 aryl or 5- to 10-membered heteroaryl, and the C6-C 10 aryl and 5- to 10-membered heteroaryl may be substituted with one or more groups selected from the group consisting of R y1 , R y2 , R y3 , R y4 and R y5 . Preferably, Y is phenyl or 6- to 10-membered heteroaryl, which may be substituted with one or more groups selected from the group consisting of R y1 , R y2 , R y3 , R y4 and R y5 , and more preferably, it is substituted with R y3 and Ry1 , R y2 , R y4 and R y5 It is phenyl or 6- to 10-membered heteroaryl, which may be substituted with one or more groups selected from the group consisting of

[0098] In compound (1), Y is preferably of formula (3):

Chemical formula

[0099] In compound (1), R y1 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, hydroxy C2-C6 alkoxy, 4- to 10-membered heterocyclyloxy, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 alkylamino C1-C6 alkoxy, 5- to 10-membered heteroaryloxy, C1-C6 alkylthio, a 4- to 10-membered saturated heterocyclic group having a bond and optionally having a substituent on a carbon atom of the ring, a 4- to 10-membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring, a 5- to 10-membered aromatic heterocyclic group optionally having a substituent or C1-C6 alkyl(C1-C6 alkoxy C1-C6 alkyl)amino. R y1is preferably hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, 5- to 6-membered heterocyclyl C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5- to 6-membered heterocyclyloxy, C1-C3 alkoxy-C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5- to 6-membered heteroaryloxy, C1-C4 alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond and optionally having a substituent on a carbon atom of the ring, a 4- to 10-membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring, a 5- to 10-membered aromatic heterocyclic group optionally having a substituent or C1-C3 alkyl(C1-C3 alkoxy C1-C2 alkyl)amino, more preferably hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl or C1-C3 alkoxy, still more preferably hydrogen, halogen, cyano or C1-C3 alkyl, and particularly preferably chlorine.

[0100] In the compound (1), R y2 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, hydroxy C2-C6 alkoxy, 4- to 10-membered heterocyclyloxy, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 alkylamino C1-C6 alkoxy, 5- to 10-membered heteroaryloxy, C1-C6 alkylthio, a 4- to 10-membered saturated heterocyclic group having a bond and optionally having a substituent on a carbon atom of the ring, a 4- to 10-membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring, a 5- to 10-membered aromatic heterocyclic group optionally having a substituent or C1-C6 alkyl(C1-C6 alkoxy C1-C6 alkyl)amino. R y2is preferably hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, 5-6 membered heterocyclyl C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 membered heterocyclyloxy, C1-C3 alkoxy-C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 membered heteroaryloxy, C1-C4 alkylthio, a 5-6 membered saturated heterocyclic group having a bond and optionally having a substituent on a carbon atom of the ring, a 4-10 membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring, a 5-10 membered aromatic heterocyclic group optionally having a substituent or C1-C3 alkyl(C1-C3 alkoxy C1-C2 alkyl)amino, more preferably hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl or C1-C3 alkoxy, still more preferably hydrogen.

[0101] In compound (1), R y3 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 4-10 membered heterocyclyl C1-C6 alkoxy, hydroxy C2-C6 alkoxy, 4-10 membered heterocyclyloxy, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 alkylamino C1-C6 alkoxy, 5-10 membered heteroaryloxy, C1-C6 alkylthio, a 4-10 membered saturated heterocyclic group having a bond and optionally having a substituent on a carbon atom of the ring, a 4-10 membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring, a 5-10 membered heteroaryl optionally having a substituent or C1-C6 alkyl(C1-C6 alkoxy C1-C6 alkyl)amino. R y3Preferably, it is hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, 5- to 6-membered heterocyclyl C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5- to 6-membered heterocyclyloxy, C1-C3 alkoxy-C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5- to 6-membered heteroaryloxy, C1-C4 alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond and optionally having a substituent on a carbon atom of the ring, a 4- to 10-membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring, a 5- to 10-membered heteroaryl optionally having a substituent or C1-C3 alkyl (C1-C3 alkoxy C1-C2 alkyl) amino, more preferably 5- to 6-membered heterocyclyl C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5- to 6-membered heterocyclyloxy, C1-C3 alkoxy C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5- to 6-membered heteroaryloxy, C1-C4 alkylthio, a 5- to 6-membered saturated heterocycle having a bond and optionally having a substituent on a carbon atom of the ring, a 4- to 10-membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring, a 5- to 10-membered heteroaryl optionally having a substituent or C1-C3 alkyl (C1-C3 alkoxy C1-C2 alkyl) amino, still more preferably a 4- to 10-membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring or a 5- to 10-membered heteroaryl optionally having a substituent, particularly preferably 1-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl, 4-methylpiperazin-1-yl, (2R)-2,4-dimethylpiperazin-1-yl, 6-methoxy-2-azaspiro[3.3]heptan-2-yl, 4-(2-methoxyethyl)piperazin-1-yl, 3-methoxyazetidin-1-yl, 4-(oxetan-3-yl)piperazin-1-yl, 2-oxa-6-azaspiro[3.3] heptan-6-yl, (2R,5R)-2,4,5-trimethylpiperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl or morpholin-4-yl.

[0102] In compound (1), R y4 and R y5 are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 4-10 membered heterocyclyl C1-C6 alkoxy, hydroxy C2-C6 alkoxy, 4-10 membered heterocyclyloxy, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkylamino C1-C6 alkoxy, 5-10 membered heteroaryloxy, C1-C6 alkylthio, a 4-10 membered saturated heterocyclic group having a bond and optionally having a substituent on a carbon atom of the ring, a 4-10 membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring, a 5-10 membered aromatic heterocyclic group optionally having a substituent, and C1-C6 alkyl(C1-C6 alkoxy C1-C6 alkyl)amino. R y4 and R y5Preferably, each independently, hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, 5-6 membered heterocyclyl C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 membered heterocyclyloxy, C1-C3 alkoxy-C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 membered heteroaryloxy, C1-C4 alkylthio, a 5-6 membered saturated heterocyclic group having a bond and optionally having a substituent on a carbon atom of the ring, a 4-10 membered saturated heterocyclic group having a bond and optionally having a substituent on a nitrogen atom of the ring, a 5-10 membered aromatic heterocyclic group optionally having a substituent, and C1-C3 alkyl (C1-C3 alkoxy C1-C2 alkyl) amino, more preferably each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl and C1-C3 alkoxy, even more preferably each independently selected from the group consisting of hydrogen, halogen, cyano and C1-C3 alkyl, and particularly preferably hydrogen.

[0103] In compound (1), X y1 is CR y3 When it is, R y2 and R y3 may combine with the carbon atom to which they are attached to form a 5- or 6-membered heteroaryl ring, X y1 is CR y3 and X y2 is CR y4 When it is, R y3 and R y4 may combine with the carbon atom to which they are attached to form a 5- or 6-membered heteroaryl ring, X y2 is CR y4 and X y3 is CR y5 When it is, R y4 and R y5 may combine with the carbon atom to which they are attached to form a 5- or 6-membered heteroaryl ring.

[0104] Another embodiment of the present invention is a compound represented by the general formula (4) (hereinafter, also referred to as "compound (4)"), a salt thereof, or a solvate thereof. X in compound (4) a3 , R a1 , R a2、 X b1 , X b2 , X b3 , R y1 , R y2 , X y1 , X y2 , X y3 , R z1 , R z2 , R z3 , R z4 and X z are synonymous with X a3 , R a1 , R a2、 X b1 , X b2 , X b3 , R y1 , R y2 , X y1 , X y2 , X y3 , R z1 , R z2 , R z3 , R z4 and X z in the above-described compound (1).

[0105] The compounds described in this specification can be their salts or their solvates. Examples of the salts of the compounds include hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonates such as methanesulfonate, p-toluenesulfonate, etc.; carboxylates such as acetate, citrate, malate, tartrate, succinate, salicylate, etc.; or alkali metal salts such as sodium salt, potassium salt, etc.; alkaline earth metal salts such as magnesium salt, calcium salt, etc.; ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc. These salts are produced, for example, by bringing the compound into contact with an acid or a base. In this specification, a solvate refers to a substance in which a compound forms a single molecular aggregate together with a solvent, and is not particularly limited as long as it is a solvate formed by a solvent that is acceptable for ingestion in association with the administration of the medicine. Examples thereof include not only solvates with a single solvent such as hydrate, alcohol solvate (ethanol solvate, methanol solvate, 1-propanol solvate, 2-propanol solvate, etc.), dimethyl sulfoxide, etc., but also those in which a plurality of solvents form solvates with one molecule of the compound, or those in which a plurality of types of solvents form solvates with one molecule of the compound. When the solvent is water, it is called a hydrate. As the solvate of the compound of the present invention, a hydrate is preferred, and specific examples of such hydrates include 1 to 10 hydrates, preferably 1 to 5 hydrates, and more preferably 1 to 3 hydrates.

[0106] When the compound according to the present invention is obtained as a free form, the compound can be converted into the state of a salt or their hydrates or solvates that the compound may form according to a conventional method. For example, hydrates, ethanol solvates, etc. of the compound represented by the formula (1) can be mentioned. Specifically, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate or 1-ethanol solvate of the compound represented by the formula (1), or hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate or 1-ethanol solvate of the sodium salt of the compound represented by the formula (1), or hydrates or ethanol solvates of the hydrochloride salt of the compound represented by the formula (1) etc. can be mentioned, but it is not limited to these. Hydrates or solvates may be produced in crystalline or amorphous form, and in the case of crystalline form, they may take crystal polymorphs. As a method for producing hydrates or solvates, for example, a solvent such as ethanol and / or water is added to the compound represented by the formula (1), and stirring, cooling, concentration, and / or drying are carried out, etc., and hydrates or solvates can be obtained by a conventional method.

[0107] Also, when the compound according to the present invention is obtained as a salt, hydrate, or solvate of the compound, the compound can be converted into its free form according to a conventional method.

[0108] The compounds described in this specification may contain isotope atoms in non-natural ratios in one or more atoms constituting such compounds. By substituting any atom in the compound with another isotope atom having the same atomic number (number of protons) but different mass number (sum of the number of protons and neutrons), a compound substituted with an isotope having an abundance ratio different from that of the isotopes in nature, that is, a compound labeled with an isotope atom is also included in the present invention. Examples of the isotope elements contained in the compounds of this specification include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, etc., respectively, 2 H, 3 H, 13 C, 14 C, 15N, 17 O, 18 O, 32 P, 35 S, 18 F, 36 Cl, etc. are included. Compounds labeled with isotope atoms are useful as therapeutic or prophylactic agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging diagnostic agents). Compounds of the present specification containing radioactive or non-radioactive isotope elements in all ratios are included within the scope of the present invention. Compounds labeled with isotope atoms can be produced by using reagents and solvents containing the corresponding isotope atoms in a manner similar to the production method of unlabeled compounds.

[0109] The compounds, salts thereof, or solvates thereof described in the present specification include all their stereoisomers (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of said isomers, and other mixtures. For example, the compounds of the present invention may have one or more asymmetric points, and the present invention includes racemic mixtures, diastereomer mixtures, and enantiomers of such compounds.

[0110] <General Production Method> Examples of the production method of the compound represented by the formula (1), its salt or their solvate will be described by the following reaction schemes. The compounds of the present invention can be synthesized by various methods, and the following production methods are illustrative, and the present invention is not limited only to the disclosed chemical reactions and conditions. In the following reaction schemes for the production methods, some substituents are excluded for clarity, but these are not intended to limit the disclosure of the reaction schemes. The representative compounds of the present invention can be synthesized using appropriate intermediates, known compounds, and reagents. In the formulas in the following general synthesis methods, the variable groups represented by R1, R2, etc. and the variables represented by n, etc. are synonymous with the variable groups represented by R1, R2, etc. and the variables represented by n, etc. in the compounds represented by the general formulas defined in this specification. In addition, when the starting material or the target product of a certain step undergoes an undesired chemical conversion under the reaction conditions of that step, for example, by performing functional group protection and deprotection, the target product of that step can be obtained. Regarding the selection of the protecting group and the selection of the methods for protection and deprotection, reference can be made to, for example, T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis (5th Edition, John Wiley & Sons 2014). Some aspects of functional group protection and deprotection are also described in the following reaction schemes.

[0111] The compounds of the present invention can be synthesized, for example, by the production methods shown below.

[0112] General Preparation Method A [Chemical formula] In the formula, PG1 represents a protecting group for amino, L1 and L2 each independently represent a leaving group, X a1 , X a3 , R a2 , X b1 , X b2 , X b3 , Y and Z are synonymous with the definitions in the above [1].

[0113] The amino protecting group (PG1) includes a formyl group, a C1-C6 alkylcarbonyl group (such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, etc.), a carbamoyl group, a C1-C6 alkoxycarbonyl group (such as a methoxycarbonyl group, an ethoxycarbonyl group, an isopropyloxycarbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonyl group, etc.), a substituted silyl group (such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, etc.), an aralkyloxycarbonyl group (such as a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, etc.), an allyl group, an aralkyl group (such as a benzyl group, a cumyl group, etc.).

[0114] The leaving groups (L1 and L2) in the general production method A include a halogen atom, a trifluoromethanesulfonyl group, a nonafluorobutanesulfonyl group, an acetyloxy group, a trifluoroacetyloxy group, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a group derived from a boron atom (such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 9-BBN, etc.), a group derived from zinc, etc.

[0115] Step 1 Compound (A-3) can be produced by subjecting a compound (A-1) having a leaving group L1 and a compound (A-2) having a leaving group L2 to a coupling reaction in the presence of a palladium catalyst, a ligand, and a base. Examples of the compound having a leaving group L1 and the compound having L2 include a compound having a halogen atom as a leaving group, a compound having a leaving group derived from a sulfonic acid, a compound having a leaving group derived from a boron atom, and a compound having a group derived from zinc. These can be produced by methods well known to those skilled in the art, for example, the methods described in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition, (by R.C. Larock), or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (by M.B. Smith, J. March), etc., and can be used in the coupling reaction. The coupling reaction can be carried out with reference to the method of Suzuki et al. (Chem. Rev. 1995, 95, 2457-2483) or the method of Negishi et al. (J. Org. Chem. 1977, 42, 1821-1823).

[0116] The palladium catalysts used in the coupling reaction can be those available from commercial suppliers. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex, bis(triphenylphosphine)palladium(II) dichloride, dichlorobis(tricyclohexylphosphine)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, or [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, or the catalysts of Buchwald et al. described in Org. Lett. 2014, 16, 4638-4641, or J.Am.Chem. Soc., 2014, 136, 14027-14030, such as SPhos Pd G3, XPhos Pd G3, CPhos Pd G3, or XantPhos Pd G3, etc. are exemplified. Also, palladium and a ligand can be used in combination. Palladium can be those available from commercial suppliers exemplified by palladium acetate, allylpalladium(II) chloride (dimer), or Pd2(dba)3, and the ligand can be those available from commercial suppliers exemplified by dppf, SPhos, or Xantphos, and they can be appropriately combined and used.

[0117] The bases used in the coupling reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), inorganic bases such as carbonates or phosphates (sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, etc.), or metal alkoxides (sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.). Preferably, inorganic bases such as cesium carbonate are exemplified.

[0118] The solvents used in the coupling reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), or acetonitrile. Preferably, 2-methyltetrahydrofuran and 1-methylpyrrolidin-2-one are exemplified.

[0119] The optimum reaction temperature when performing the coupling reaction is usually in the range of 0 °C to near the boiling point of the solvent, preferably in the range of 10 °C to 120 °C. The reaction time is usually in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The obtained target compound (A-3) can be isolated by general techniques and purified by crystallization or chromatography if necessary.

[0120] Step 2 Compound (A-4) can be produced by deprotecting the protecting group of compound (A-3). When the protecting group PG1 is a C1-C6 alkoxycarbonyl group such as t-butoxycarbonyl, it is preferable to carry out the deprotection reaction using an acid. Examples of the acid used in the deprotection reaction include inorganic acids (hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acids (formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.). Preferably, hydrogen chloride, methanesulfonic acid, trifluoroacetic acid, etc. are exemplified.

[0121] Examples of the solvent used in the deprotection reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), and ester solvents (ethyl acetate, isopropyl acetate, etc.). Preferably, 1,4-dioxane and ethyl acetate are exemplified.

[0122] The optimum reaction temperature for carrying out the deprotection reaction is usually in the range of 0°C to near the boiling point of the solvent, preferably in the range of 10°C to 100°C. The optimum reaction time for carrying out the deprotection reaction is usually in the range of 30 minutes to 12 hours, preferably in the range of 1 hour to 6 hours. The obtained compound (A-4) can be isolated by general techniques and purified by crystallization or chromatography if necessary. Note that compound (A-4) may be obtained as a salt with the acid used in the reaction, and such a salt can also be subjected to the next step.

[0123] Step 3 Compound (A-6) can be produced by converting compound (A-5) into an acid chloride and then performing an amidation reaction in the presence of compound (A-4) and a base. Examples of the reagent for converting compound (A-5) into an acid chloride include thionyl chloride, oxalyl chloride, and Ghosez reagent. Examples of the base used in the amidation reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), diamines (N,N,N’,N’-tetramethylethylenediamine, etc.), guanidines (guanidine, tetramethylguanidine, etc.), and pyridines (pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, etc.). Preferably, tertiary amines such as N,N-diisopropylethylamine and 4-methylmorpholine are exemplified.

[0124] Examples of the solvent used in the amidation reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), halogen solvents (dichloromethane, dichloroethane, chloroform, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), ester solvents (ethyl acetate, isopropyl acetate, etc.), acetonitrile, and water. Preferably, dichloromethane and acetonitrile are exemplified.

[0125] Examples of the optimal reaction temperature for performing the amidation reaction include the range from 0 °C to near the boiling point of the solvent, and preferably the range from 20 °C to 60 °C. Examples of the optimal reaction time for performing the deprotection reaction include the range from 10 minutes to 24 hours, and preferably the range from 30 minutes to 12 hours.

[0126] Compound (A-6) can be produced not only by the method via acid chloride but also, for example, by subjecting compound (A-4) and compound (A-5) to an amidation reaction using a condensing agent in the presence of a base. Examples of the condensing agent used in the amidation reaction include BOP-based condensing agents such as benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP (registered trademark)), PyAOP, BroP, PyCloP, PyBroP (registered trademark), DEPBT, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethylazanium hexafluorophosphate (HATU), ethyl (hydroxyimino)cyanoacetate (Oxyma), T3P, etc. Preferably, examples include HATU, etc.

[0127] Examples of the base used in the amidation reaction with the condensing agent include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), pyridines (pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, etc.). Preferably, examples include tertiary amines such as N,N-diisopropylethylamine and 4-methylmorpholine.

[0128] The solvents used in the amidation reaction with a condensing agent include ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), halogen solvents (dichloromethane, dichloroethane, chloroform, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), ester solvents (ethyl acetate, isopropyl acetate, etc.), and acetonitrile. Preferably, dichloromethane and N,N-dimethylformamide are exemplified.

[0129] The optimal reaction temperature for carrying out the amidation reaction with a condensing agent is in the range of 0 °C to near the boiling point of the solvent, preferably in the range of 20 °C to 60 °C. The optimal reaction time for carrying out the amidation reaction with a condensing agent is in the range of 1 minute to 24 hours, preferably in the range of 30 minutes to 12 hours. The obtained compound (A-6) may be isolated by general techniques and purified by crystallization or chromatography as necessary.

[0130] General Preparation Method B

Chemical formula

[0131] Step 1 Compound (B-2) can be produced by subjecting Compound (B-1) to a borylation reaction using various diborane reagents in the presence of an iridium catalyst and a ligand. The borylation reaction can be carried out with reference to, for example, Angew. Chem. Int. Ed., 2021, 60, 2796-2821, etc. Preferred examples of the iridium catalyst and ligand used in the borylation reaction include bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) and 4,4'-di-tert-butyl-2,2'-bipyridine.

[0132] Solvents used in the borylation reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.) and hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.). Preferred examples are tetrahydrofuran or hexane.

[0133] The optimum reaction temperature for carrying out the borylation reaction is generally in the range of 0 °C to near the boiling point of the solvent, and preferably in the range of 10 °C to 120 °C. The reaction time is generally in the range of 30 minutes to 48 hours, and preferably in the range of 1 hour to 24 hours. The obtained Compound (B-2) can be isolated by general techniques and purified by crystallization or chromatography as necessary.

[0134] Step 2 Compound (B-3) can be produced by subjecting Compound (B-2) to an oxidation reaction using an oxidizing agent exemplified by hydrogen peroxide.

[0135] The solvents used in the oxidation reaction include ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), alcohol solvents (methanol, ethanol, isopropanol, butanol, etc.), and methanol is preferably exemplified.

[0136] The optimal reaction temperature when performing the oxidation reaction is usually in the range of 0 °C to near the boiling point of the solvent, and preferably in the range of 10 °C to 60 °C. The reaction time is usually in the range of 30 minutes to 24 hours, and preferably in the range of 1 hour to 12 hours. The obtained compound (B-3) can be isolated by general techniques and purified by crystallization or chromatography if necessary.

[0137] Step 3 Compound (B-5) can be produced by subjecting compound (B-3) and compound (B-4) having a leaving group L3 to an etherification reaction in the presence of a base. The etherification reaction can be carried out with reference to the Williamson method (Liebigs Ann. Chem. 1851, 77, 37-49).

[0138] The bases used in the etherification reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), inorganic bases (sodium carbonate, potassium carbonate, cesium carbonate), etc., and inorganic bases such as potassium carbonate are preferably exemplified.

[0139] The solvents used in the etherification reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), ester solvents (ethyl acetate, isopropyl acetate, etc.), and acetonitrile. Preferably, amide solvents such as 1-methylpyrrolidin-2-one are exemplified.

[0140] The optimum reaction temperature when performing the etherification reaction is generally in the range of 0°C to near the boiling point of the solvent, preferably in the range of 10°C to 60°C. The optimum reaction time when performing the etherification reaction is generally in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The obtained compound (B-5) can be isolated by general techniques and purified by crystallization or chromatography as necessary.

[0141] General Preparation Method C [Chemical formula] In the formula, PG2 represents a protecting group for the carboxyl group, and Z1 represents a group selected from the group consisting of aryl, heteroaryl, and alkylene which may have any substituent, X a1 , X a3 , R a2 , X b1 , X b2 , X b3And Y is synonymous with the definition in the above [1]. Examples of the protecting group for the carboxyl group include C1-6 alkyl esters (such as methyl ester, ethyl ester, propyl ester, butyl ester, etc.), benzyl ester, aryl ester, etc. In addition to the protecting groups exemplified as such, the selection of the protecting group, as well as the methods of protection and deprotection, can be selected. For example, reference can be made to T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis (5th Edition, John Wiley & Sons 2014).

[0142] Step 1 Compound (C-2) can be produced by subjecting compound (C-1) to a deprotection reaction. When the protecting group PG2 is an alkyl ester such as a methyl ester, it is preferable to carry out deprotection using a base. Examples of the base used in the deprotection reaction include inorganic bases (such as sodium hydroxide, potassium hydroxide, barium hydroxide, potassium trimethylsiloxide, etc.) or metal alkoxides (such as sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.). Preferably, inorganic bases such as potassium hydroxide are exemplified. Examples of the solvent used in the deprotection reaction include ether solvents (such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), alcohol solvents (such as methanol, ethanol, isopropanol, butanol, etc.), amide solvents (such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), and water. Preferably, solvents such as tetrahydrofuran, methanol, or water, or solvents mixed with them in any ratio are exemplified.

[0143] When performing the deprotection reaction, the optimal reaction temperature is usually in the range of 0 °C to near the boiling point of the solvent, preferably in the range of 20 °C to 120 °C. The optimal reaction time when performing the deprotection reaction is usually in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 6 hours. The obtained compound (C-2) can be isolated by general techniques and purified by crystallization or chromatography if necessary.

[0144] General Preparation Method D

Chemical formula

[0145] Step 1 Compound (D-2) can be produced by subjecting compound (D-1) having a leaving group L4 and various nucleophiles to a coupling reaction in the presence of a palladium catalyst, a ligand, and a base. Examples of compound (D-1) having a leaving group L4 include a compound having a halogen atom as a leaving group and a compound having a leaving group derived from a sulfonic acid. These can be produced by methods well known to those skilled in the art, such as the methods described in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition, (by R.C. Larock), or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (by M.B. Smith, J. March), etc., and can be used in the coupling reaction. Examples of the nucleophiles used in the coupling reaction include an amine compound, an alcohol compound, and a compound having a group derived from a boron atom. The target product can be produced by forming a C-N bond, a C-O bond, and a C-C bond, respectively. These coupling reactions can be carried out with reference to the methods of Buchwald et al. (Org. Synth., 2002, 78, 23), the methods of Suzuki et al. (Chem. Rev. 1995, 95, 2457-2483), and the methods of Buchwald et al. (J. Am. Chem. Soc. 2001, 123, 12202-12206)).

[0146] The palladium catalyst and ligand used in the coupling reaction are combined and used by combining a palladium catalyst available from commercial suppliers exemplified by allylpalladium(II) chloride (dimer), palladium acetate, or Pd2(dba)3, and a ligand available from commercial suppliers exemplified by rac-BINAP, dppf, SPhos, or Xantphos, or a complex of palladium and ligand such as SPhos Pd G3 or rac-BINAP Pd G4 is preferably used. The base used in the coupling reaction is a tertiary amine (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), a carbonate, or an inorganic base such as a phosphate (sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, etc.), or a metal alkoxide (sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.), and preferably an inorganic base such as cesium carbonate is exemplified.

[0147] The solvent used in the coupling reaction is an ether solvent (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), an amide solvent (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), or acetonitrile, and preferably methyltetrahydrofuran or 1-methylpyrrolidin-2-one is exemplified.

[0148] The optimum reaction temperature when performing the coupling reaction is usually in the range of 0 °C to near the boiling point of the solvent, preferably in the range of 10 °C to 120 °C. The optimum reaction time when performing the coupling reaction is usually in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The obtained compound (D-2) may be isolated by general techniques and purified by crystallization or chromatography as necessary.

[0149] In addition, when the leaving group L4 of the compound (D-1) is a fluorine atom, the compound (D-2) can be produced by carrying out an SNAr reaction between the compound (D-1) and various nucleophiles in the presence of a base. Examples of the base used in the SNAr reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), inorganic bases (sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, etc.), and metal alkoxides (sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.). Preferably, DBU, sodium hydride, potassium carbonate, potassium tert-butoxide, etc. are exemplified.

[0150] Examples of the solvent used in the SNAr reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), hydrocarbon solvents (benzene, toluene, etc.), and amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.). Preferably, hydrocarbon solvents such as toluene, or amide solvents such as 1-methylpyrrolidin-2-one are exemplified.

[0151] The optimum reaction temperature for carrying out the SNAr reaction is generally in the range of 0 °C to near the boiling point of the solvent, preferably in the range of 20 °C to 120 °C. The optimum reaction time for carrying out the SNAr reaction is generally in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The obtained compound (D-2) can be isolated by general techniques and purified by crystallization or chromatography as necessary.

[0152] General Preparation Method E

Chemical formula

[0153] Step 1 Compound (E-3) can be produced by performing a coupling reaction on a compound (E-1) having a leaving group L5 and a compound (E-2) having a leaving group L6 in the presence of a palladium catalyst, a ligand, and a base. When the leaving group L5 of the compound (E-1) is a halogen atom, a coupling reaction can also be performed after converting L5 into another leaving group, for example, a group derived from a boron atom or a group derived from zinc. Compounds having these leaving groups can be produced by methods well known to those skilled in the art, for example, the methods described in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition, (authored by R.C. Larock), or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (authored by M.B. Smith, J. March), etc., and can be used in the coupling reaction. The coupling reaction can be carried out with reference to the methods of Suzuki et al. (Chem. Rev. 1995, 95, 2457-2483) or the methods of Negishi et al. (J. Org. Chem. 1977, 42, 1821-1823).

[0154] The palladium catalysts used in the coupling reaction can be those available from commercial suppliers. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex, bis(triphenylphosphine)palladium(II) dichloride, dichlorobis(tricyclohexylphosphine)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, or [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, or the catalysts of Buchwald et al. described in Org. Lett. 2014, 16, 4638-4641, or J. Am. Chem. Soc., 2014, 136, 14027-14030, such as SPhos Pd G3, XPhos Pd G3, CPhos Pd G3, or XantPhos Pd G3, etc. are exemplified. Also, palladium and a ligand can be used in combination. Palladium can be those available from commercial suppliers exemplified by palladium acetate, allylpalladium(II) chloride (dimer), or Pd2(dba)3, and the ligand can be those available from commercial suppliers exemplified by dppf, SPhos, or Xantphos, which can be appropriately combined and used.

[0155] The bases used in the coupling reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), inorganic bases such as carbonates or phosphates (sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, etc.), or metal alkoxides (sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.). Inorganic bases such as cesium carbonate are preferably exemplified.

[0156] The solvents used in the coupling reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), or acetonitrile. 2-Methyltetrahydrofuran and 1-methylpyrrolidin-2-one are preferably exemplified.

[0157] The optimal reaction temperature for carrying out the coupling reaction is generally in the range of 0 °C to near the boiling point of the solvent, preferably in the range of 10 °C to 120 °C. The reaction time is generally in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The obtained target compound (E-3) can be isolated by general techniques and purified by crystallization or chromatography if necessary.

[0158] <Pharmaceutical composition> The present invention provides a pharmaceutical composition containing the compound represented by the formula (1) of the present invention. The pharmaceutical composition of the present invention can be formulated by introducing a pharmaceutically acceptable carrier in addition to the compound represented by the formula (1) of the present invention, a salt of the compound represented by the formula (1), or a solvate thereof, and formulating it by a known method. Excipients, binders, lubricants, coloring agents, flavoring agents, and if necessary, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, etc., which are usually used in formulation, can be used, and components generally used as raw materials for pharmaceutical preparations are blended and formulated by a conventional method. Formulation can process the active ingredient used in pharmaceuticals by a known method into the optimal shape or property, that is, dosage form, according to the method of use and purpose of use. Examples of commonly used dosage forms include liquid pharmaceutical preparations (solutions) such as injections, suspensions, emulsions, eye drops, and solid pharmaceutical preparations (solid preparations) such as tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, troches, suppositories, etc., but are not limited thereto.

[0159] For example, to produce a solution, a pharmacologically acceptable carrier or medium, specifically, sterilized water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc., which are commonly used in the field of pharmaceutical preparations, are appropriately combined and added to the compound represented by the formula (1) of the present invention, or a salt thereof, or a solvate thereof, and then formulated by mixing in a unit dosage form required for generally recognized pharmaceutical practice. In addition, a solid preparation prepared for a solution can be added with an appropriate solvent, such as sterilized water or physiological saline, and dissolved as needed before administration, and then used for administration.

[0160] Such a liquid preparation can be used parenterally, for example, in the form of a sterile solution or suspension in water or other pharmaceutically acceptable liquids. For example, it can be formulated by appropriately combining a pharmacologically acceptable carrier or medium, specifically, sterile water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc., and mixing them in a unit dosage form required for generally recognized pharmaceutical practice. Specifically, examples of carriers include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, calcium carmellose, sodium carmellose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, gelatin, medium-chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethyl cellulose, corn starch, inorganic salts, etc. The amount of the active ingredient in these preparations is such that an appropriate volume within the indicated range can be obtained. A sterile composition for injection can be formulated according to ordinary pharmaceutical practice using a vehicle such as distilled water for injection.

[0161] Examples of aqueous solutions for injection include isotonic solutions containing physiological saline and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and may be used in combination with appropriate solubilizing agents, such as alcohol, specifically ethanol, polyalcohols, such as propylene glycol, polyethylene glycol, and nonionic surfactants, such as polysorbate 80 (registered trademark), HCO-50.

[0162] Examples of oily liquids include sesame oil and soybean oil, and may be used in combination with benzyl benzoate and benzyl alcohol as solubilizing agents. Also, it may be formulated with buffer agents, such as phosphate buffer solution and sodium acetate buffer solution, soothing agents, such as procaine hydrochloride, stabilizers, such as benzyl alcohol and phenol, and antioxidants. The prepared injection solution is usually filled into appropriate ampoules.

[0163] For example, to produce a solid preparation, an excipient, and, if necessary, a binder, a disintegrant, a lubricant, a colorant, a flavoring agent, and other pharmaceutically acceptable additives commonly used in the field of pharmaceutical preparations are appropriately combined and added to the compound represented by the formula (1) of the present invention, or a salt thereof, or a solvate thereof, and then tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, troches, suppositories, etc. are prepared by a conventional method.

[0164] Examples of pharmaceutically acceptable additives used in such solid preparations include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone, and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as lactose, lactose hydrate, fructose, and sucrose; inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate, and aluminum silicate; and purified water.

[0165] Examples of excipients include saccharides (e.g., lactose, lactose hydrate, fructose, sucrose, etc.), sugar alcohols (e.g., mannitol, etc.), starches (e.g., corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, etc.), celluloses (e.g., crystalline cellulose), inorganic salts (e.g., calcium silicate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc.).

[0166] Examples of the binder include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block polymer, and the like.

[0167] Examples of the disintegrant include croscarmellose sodium, carmellose sodium, hydroxypropyl cellulose, carmellose, carmellose calcium, methyl cellulose, crystalline cellulose, sodium lauryl sulfate, povidone, or polysorbate, and the like.

[0168] Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, hydrogenated oil, and the like.

[0169] Examples of the coloring agent are those permitted to be added to pharmaceuticals, and examples of the flavoring and deodorizing agent include cocoa powder, peppermint brain, aromatic powder, peppermint oil, borneol, cinnamon powder, and the like.

[0170] These tablets and granules may be appropriately coated with sugar coating or other coatings as necessary. Also, when producing liquid preparations such as syrups and injection preparations, a pH adjuster, a solubilizer, an isotonic agent, etc., and, if necessary, a solubilizing aid, a stabilizer, etc. are added to the compound according to the present invention or its pharmacologically acceptable salt, and formulated by a conventional method.

[0171] Administration is preferably parenteral administration, but the administration method is not limited to parenteral administration. Specific examples of parenteral administration include injection dosage forms, nasal administration dosage forms, pulmonary administration dosage forms, transdermal administration dosage forms, and the like. As an example of the injection dosage form, for example, it can be administered systemically or locally by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, or the like.

[0172] In addition, the administration method can be appropriately selected according to the age and symptoms of the patient. As the dosage of the pharmaceutical composition containing the compound represented by the formula (1) of the present invention, or a salt thereof, or a solvate thereof, produced by the method of the present invention, for example, it can be selected in the range of 0.0001 mg to 1000 mg per 1 kg of body weight per administration. Alternatively, for example, the dosage can be selected in the range of 0.001 to 100000 mg / body per patient, but these numerical values are not necessarily limiting. The dosage and administration method vary depending on the body weight, age, symptoms, etc. of the patient, but those skilled in the art can appropriately select them.

[0173] In one aspect, the compound of the present invention can be used for activating Nrf2 or for inhibiting Keap1 and activating Nrf2.

[0174] In one aspect, the pharmaceutical composition of the present invention can be used to treat or prevent, for example, diseases in a subject as described in Nature Reviews Drug Discovery, 2019, 18, p295-317, more specifically, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia, amyotrophic lateral sclerosis, pulmonary diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary arterial hypertension, asthma, kidney diseases such as chronic kidney disease, acute kidney injury, ophthalmic diseases such as uveitis, glaucoma, age-related macular degeneration, liver diseases such as non-alcoholic steatohepatitis, immune and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, ulcerative colitis, solid cancers such as head and neck cancers (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, gastric cancer, colorectal cancer (cecal cancer, colon cancer, rectal cancer, etc.), lung cancer (small cell cancer, non-small cell cancer, etc.), thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (endometrial cancer, cervical cancer, etc.), testicular cancer, renal cell cancer, bladder cancer, renal pelvis and ureteral cancer, malignant melanoma, skin cancer, blood and lymph cancers such as leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphoblastic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin lymphoma, etc.), multiple myeloma, myelodysplastic syndrome, and other proliferative diseases exemplified by such cancers.

[0175] As used herein, "subject" includes mammals, and preferably humans as mammals.

Examples

[0176] The content of the present invention will be further described with the following examples and reference examples. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. Room temperature (rt) refers to 5 - 35 °C. HPLC purification of the compounds was performed using an AutoPurification HPLC / MS System (manufactured by Waters) and Trilution (manufactured by Gilson). 1H-NMR spectra were measured using an MR400 OneNMR probe (400 MHz, Agilent technology), AVANCE III HD 400 SMART-BBFO probe (400 MHz, Bruker), ECP400 (400 MHz, JEOL), AVANCE III HD 400 SMART-BBFO probe (400 MHz, Bruker), MR400 OneNMR probe (400 MHz, Agilent technology), or AVANCE NEO 400 iProbe (400 MHz, Bruker) with or without using Me4Si as an internal standard substance (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double double doublet, dt = double triplet, td = triple doublet, m = multiplet). NMR data was shown in ppm (parts per million, δ). Mass spectrometry data was obtained using a single quadrupole mass spectrometer (LCMS-2020) equipped with a super high performance liquid chromatography (Nexera UC or Nexera) manufactured by Shimadzu Corporation or a single quadrupole mass spectrometer (SQD or SQD2) equipped with an Acquity super high performance liquid chromatography (UPLC or UPLC I-Class) manufactured by Waters. For those with two descriptions of the retention time, each indicates the retention time of the rotational isomer. Microwaves were irradiated using an InitiatorTM (manufactured by Biotage).

[0177] Analysis Condition A Apparatus: Nexera / 2020 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35°C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition B Equipment: Nexera UC / 2020 Column used: XSelect CSH C18 2.1mm I.D. × 50mm L, 2.5μm Column temperature: 35°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.75 min) → 100 / 0 (1.25 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition C Equipment: Nexera 2020 Column used: Meteoric Core C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35°C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition D Equipment: Acquity SQD / SQD2 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition E Equipment: Acquity SQD / SQD2 Column used: Ascentis Express C18 2.1 mm I.D. × 50 mm L, 2.7 μm Column temperature: 35 °C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 40 / 60 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition F Equipment: Acquity SQD / SQD2 Column used: Ascentis Express C18 2.1 mm I.D. × 50 mm L, 5 μm Column temperature: 35 °C Mobile phase and gradient: A) MeOH, B) 10 mM AA, H2O, A / B = 5 / 95 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 0.9 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition G Equipment: Nexera / 2020 Column used: Ascentis Express C18 2.1 mm I.D. × 50 mm L, 2.7 μm Column temperature: 35 °C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition H Equipment: Nexera / 2020 Column used: Meteoric Core C18 2.1mm I.D. ´ 50mm L, 2.7μm Column temperature: 35°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition I Equipment: Nexera / 2020 Column used: Ascentis Express C18 2.1mm I.D. ´ 50mm L, 2.7μm Column temperature: 35°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 50 / 50 → 100 / 0 (1.0 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition J Equipment: Nexera / 2020 Column used: Meteoric Core C18 2.1mm I.D. ´ 50mm L, 2.7μm Column temperature: 35°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 50 / 50 → 100 / 0 (1.0 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition K Instrument: Acquity SQD Column used: Ascentis Express C18 2.1 mm I.D. × 50 mm L, 2.7 μm Column temperature: 35°C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition L Instrument: Nexera / 2020 Column used: Ascentis Express C18 2.1 mm I.D. × 50 mm L, 2.7 μm Column temperature: 35°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.7 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition M Instrument: Nexera / 2020 Column used: Ascentis Express C18 2.1 mm I.D. × 50 mm L, 5 μm Column temperature: 35°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (4.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition N Equipment: Nexera / 2020 Column used: Speed Core C18 2.1 mm I.D. × 50 mm L, 2.7 μm Column temperature: 35 °C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition O Equipment: Acquity SQD Column used: Ascentis Express C18 2.1 mm I.D. × 50 mm L, 2.7 μm Column temperature: 35 °C Mobile phase and gradient: A) 0.05% FA, CH3CN, B) 0.05% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition P Equipment: Nexera / 2020 Column used: Ascentis Express C18 2.1 mm I.D. × 50 mm L, 2.7 μm Column temperature: 35 °C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 50 / 50 → 100 / 0 (1.0 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition Q Equipment: Nexera / 2020 Column used: Kinetex 1.7u C18 2.1 mm I.D. × 50 mm L, 1.7 μm Column temperature: 35 °C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 0 / 100 (1.5 min) → 0 / 100 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition R Equipment: Shimadzu LCMS - 2020 Column used: Shim - pack XR - ODS 3.0 mm.D ´ 50 mm.L, 2.2 μm Column temperature: 40 °C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 95 / 5 (2.0 min) → 95 / 5 (0.7 min) Flow rate: 1.2 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition S Equipment: Shimadzu LCMS - 2020 Column used: Shim - pack XR - ODS 2.1 mm.D ´ 50 mm.L, 2.6 μm Column temperature: 40 °C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 95 / 5 (2.0 min) → 95 / 5 (0.7 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition T Equipment: Shimadzu LCMS - 2020 Column used: Halo C18 2.1 mm.D ´ 30 mm.L, 2.0 μm Column temperature: 40 °C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (0.7 min) → 100 / 0 (0.25 min) Flow rate: 0.8 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition U Equipment: Shimadzu LCMS - 2020 Column used: InertCore C18 2.1mm.D ´ 50mm.L, 2.6μm Column temperature: 40°C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (L min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition V Equipment: Shimadzu LCMS - 2020 Column used: Shim - pack XR - ODS 3.0mm.D ´ 50mm.L, 2.2μm Column temperature: 40°C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (1.1 min) → 100 / 0 (0.6 min) Flow rate: 1.2 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition W Equipment: Shimadzu LCMS - 2020 Column used: XSelect HSS T3 3.0mm.D ´ 50mm.L, 2.5μm Column temperature: 40°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% TFA, H2O, A / B = 5 / 95 → 95 / 5 (1.1 min) → 95 / 5 (0.6 min) Flow rate: 1.2 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition X Instrument: Shimadzu LCMS - 2020 Column used: Shim - pack XR - ODS 3.0 mm.D × 50 mm.L, 2.2 μm Column temperature: 40°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 95 / 5 (1.1 min) → 95 / 5 (0.6 min) Flow rate: 1.2 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition Y Instrument: Shimadzu LCMS - 2020 Column used: CORTECS C18 2.1 mm.D × 50 mm.L, 2.7 μm Column temperature: 40°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.2 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition Z Instrument: Shimadzu LCMS - 2020 Column used: Kinetex EVO C18 2.1 mm.D × 50 mm.L, 2.6 μm Column temperature: 40°C Mobile phase and gradient: A) CH3CN, B) 6.5 mM NH4HCO3, H2O, A / B = 10 / 90 → 95 / 5 (1.1 min) → 95 / 5 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition AA Equipment: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 3.0mm.D × 50mm.L, 2.2μm Column temperature: 40°C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 30 / 70 → 80 / 20 (3.8 min) → 80 / 20 to 100 / 0 (0.3 min) → 100 / 0 (0.5 min) Flow rate: 1.2 mL / min Detection wavelength (PDA total): 190 - 400nm Analysis Condition AB Equipment: Shimadzu LCMS-2020 Column used: Waters T3 4.6mmD × 100mm.L, 3.0μm Column temperature: 40°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.2 min) → 100 / 0 (1.8 min) Flow rate: 1.2 mL / min Detection wavelength (PDA total): 190 - 400nm Analysis Condition AC Equipment: Shimadzu LCMS-2020 Column used: Kinetex XB-C18 3.0mmD × 30mm.L, 1.7μm Column temperature: 40°C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.2 min) → 100 / 0 (1.8 min) Flow rate: 1.2 mL / min Detection wavelength (PDA total): 190 - 400nm Analysis Condition AD Equipment: Shimadzu LCMS-2020 Column used: halo-C18 3.0mmD × 30mm.L, 2.0μm Column temperature: 40 °C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (1.5 min) Flow rate: 1.5 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition AE Equipment: Shimadzu LCMS - 2020 Column used: Halo 90A C18 3.0 mmD ´ 30 mm.L, 2.0 μm Column temperature: 40 °C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (1.5 min) Flow rate: 1.5 mL / min Detection wavelength (PDA total): 190 - 400 nm Analysis Condition AF Equipment: Nexera / 2020 Column used: Ascentis Express C18 2.1 mmI.D. ´ 50 mmL, 5 μm Column temperature: 35 °C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (4.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition AG Equipment: Acquity SQD / SQD2 Column used: Ascentis Express C18 2.1 mmI.D. ´ 50 mmL, 2.7 μm Column temperature: 35 °C Mobile phase and gradient: A) 0.1% FA, CH3CN, B) 0.1% FA, H2O, A / B = 5 / 95 → 100 / 0 (4.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210 - 400 nm Analysis Condition AH Equipment: Shimadzu LCMS - 2020 Column used: Shim - pack XR - ODS 3mm × 5cm, 2.2μm Column temperature: 40°C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (2.2 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 220 ± 4 nm Analysis Condition AI Equipment: Shimadzu LCMS - 2020 Column used: Shim - pack XR - ODS 2.2μm 3mm × 5cm Column temperature: 40°C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (1.2 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 254 ± 4 nm

[0178] Compounds 1 - 7 4-[3-[2,6-Dichloro-4-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound A9 tert-Butyl N-[(3-bromo-2-hydroxyphenyl)methyl]carbamate

Chemical formula

[0179] Second step Compound A10 tert-Butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chemical formula

[0180] Third step Compound A4 4-Bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [Chem.] A suspension of 4-bromo-2,5-difluorobenzoic acid (3.00 g, 12.7 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (2.46 g, 16.5 mmol) in tetrahydrofuran (6.00 mL) was added dropwise with a 1 M solution of lithium (bis(trimethylsilyl))amide in tetrahydrofuran (50.6 mL, 50.6 mmol) at room temperature over 12 minutes. The reaction mixture was stirred at room temperature for 5.5 hours and then allowed to stand at room temperature for 15 hours. 2 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the two organic layers were combined and washed with a 20% aqueous ammonium chloride solution and a 15% aqueous sodium chloride solution. The washed organic layer was concentrated to obtain the title compound as a crude product. LCMS: m / z 330 [M+H] + HPLC retention time: 0.61 minutes (analysis condition D)

[0181] Fourth step Compound A5 Methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [Chem.] To a solution of 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid (4.18 g, 12.7 mmol) in N,N-dimethylformamide (21.0 mL) were added potassium carbonate (2.10 g, 15.2 mmol) and iodomethane (1.58 mL, 25.3 mmol), and the mixture was stirred at room temperature for 30 minutes. 20% Aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 20% aqueous ammonium chloride solution and concentrated. Methanol was added to the obtained crude product, and the mixture was heated to 60 °C, then cooled to room temperature and stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was stirred for 1 hour, then further water was added and the mixture was stirred for 30 minutes. After filtering the reaction mixture, the obtained solid was washed with methanol / water (1 / 1) and dried under reduced pressure to obtain the title compound (55%, 2.38 g). LCMS: m / z 344 [M+H] + HPLC retention time: 1.18 minutes (Analysis condition G)

[0182] Fifth step Compound A6 tert-Butyl 8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate [Chemical formula] A solution of methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (1.21 g, 3.50 mmol) in tetrahydrofuran (5.30 mL) was cooled to -10 °C. 2M Isopropylmagnesium chloride - tetrahydrofuran solution (1.91 mL, 3.82 mmol) was added and stirred for 1 hour. 2M Zinc(II) chloride - 2-methyltetrahydrofuran solution (0.955 mL, 1.91 mmol) was added to the reaction solution. tert-Butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate (1.00 g, 3.18 mmol) and SPhos Pd G3 (0.0250 g, 0.0320 mmol) were added to the reaction solution, the temperature was raised to 45 °C, and stirred for 90 minutes. The reaction solution was cooled to room temperature, ethyl acetate and aqueous ammonium chloride solution were added, and extracted with ethyl acetate. The organic layer was washed with aqueous N-acetylcysteine solution and aqueous sodium chloride solution, and concentrated to obtain a crude product. Ethanol was added to the obtained crude product, heated to 80 °C to dissolve, and then cooled to room temperature. Heptane was added to the obtained solution and cooled to 0 °C. The solid obtained by filtration was washed with ethanol / heptane (1 / 2) and dried under reduced pressure to obtain the title compound (73%, 1.16 g). LCMS: m / z 499 [M+H] + HPLC retention time: 1.40 minutes (Analysis condition G)

[0183] Sixth step Compound A7 Methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride [Chemical formula] tert-Butyl 8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate (10.0 g, 20.1 mmol) was added to acetonitrile (100 mL), and 4M hydrochloric acid ethyl acetate solution (25.1 mL, 100 mmol) was added thereto. The mixture was stirred at room temperature for 2 hours. The resulting solid was collected by filtration to obtain the title compound (76%, 7.16 g) as crystals. LCMS: m / z 399 [M+H] + HPLC retention time: 0.75 minutes (Analysis condition G)

[0184] Seventh step Compound A2 4-Bromo-2,6-dichlorobenzoyl chloride

Chemical formula

[0185] Eighth step Compound A Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chemical formula

[0186] The ninth step Compound 1-7 4-[3-[2,6-Dichloro-4-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0187] Compound 1-33 4-[3-[2,6-Dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound CP5 Methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0188] Second step Compound 1-33 4-[3-[2,6-Dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0189] Using the amines and Compound A shown in Table 1-2, which are known from the literature or commercially available, the compounds shown in Table 1-1 were synthesized in the same manner as in the ninth step of Compounds 1-7. However, in the synthesis of Compounds 1-1, 1-5, 1-34, 1-41, and 1-42, a toluene solution was used instead of a 1,4-dioxane solution, in the synthesis of Compounds 1-6, 1-16, 1-17, 1-43, and 1-45, a 1-methylpyrrolidin-2-one solution was used, and in the synthesis of 1-19, 1-20, and Compound 1-44, a 1-methylpyrrolidin-2-one:water = 10:1 solution was used. Also, in the synthesis of Compounds 1-32 and 1-46, Xantphos Pd G4 was used instead of rac-BINAP Pd G4.

[0190]

Table 1-1

[0191]

Table 1-2

[0192] Compounds 1-4 4-[3-[2,6-Dichloro-4-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The first step Compound a1 Benzyl (2R,3R)-3-methoxy-2-methylazetidine-1-carboxylate

Chem.

[0193] The second step Compounds 1-4 4-[3-[2,6-Dichloro-4-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0194] Compound 1-9 4-[3-[2,6-Dichloro-4-(3-methoxy-2,2-dimethylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound b1 1-Benzhydryl-3-methoxy-2,2-dimethylazetidine

Chemical formula

[0195] Second step Compound 1-9 4-[3-[2,6-Dichloro-4-(3-methoxy-2,2-dimethylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0196] Compound 1-84 4-[3-[2,6-Dichloro-4-[(2R,3S)-2-methyl-3-morpholin-4-ylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound c1 Benzyl (2R,3S)-2-methyl-3-morpholin-4-ylazetidine-1-carboxylate

Chemical formula

[0197] Second step Compound 1-84 4-[3-[2,6-Dichloro-4-[(2R,3S)-2-methyl-3-morpholin-4-ylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0198] Compound 1-85 4-[3-[2,6-Dichloro-4-[(2R,3R)-2-methyl-3-morpholin-4-ylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound c2 Benzyl (2R,3R)-2-methyl-3-morpholin-4-ylazetidine-1-carboxylate

Chem.

[0199] Second step Compound 1-85 4-[3-[2,6-Dichloro-4-[(2R,3R)-2-methyl-3-morpholin-4-ylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0200] Compound 1-22 4-[3-[2,6-Dichloro-4-[(7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0201] Compound 1-23 4-[3-[2,6-Dichloro-4-[(7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0202] Compound 1-31 4-[3-[2,6-Dichloro-4-[(8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound e1 tert-Butyl (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [Chemical formula] Compound e2 tert-Butyl (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [Chemical formula] To a solution of tert-butyl 8-methoxy-5-oxa-2-azaspiro[3.4]oct-7-ene-2-carboxylate (33.8 mg, 0.140 mmol) in methanol (2.8 mL) was added 10% palladium / carbon (6.76 mg, 0.0640 mmol). The mixture was stirred at room temperature for 15 h under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl 8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate as a racemic mixture. The obtained racemic mixture was purified by SFC (CHIRALPAK IG, supercritical carbon dioxide / ethanol / tert-butyl methyl ether) to obtain tert-butyl (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (31%, 10.7 mg) and tert-butyl (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (25%, 8.40 mg).

[0203] Compound e1 tert-Butyl (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [Chemical formula] LCMS: m / z 244 [M+H] + SFC retention time: 4.72 minutes (analysis conditions: CHIRALPAK IG 4.6 mm I.D. x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether = 1 / 1] = 90 / 10 (10 minutes), 40 °C, 210 nm)

[0204] Compound e2 tert-Butyl (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

Chemical formula

[0205] Second step Compound 1-31 4-[3-[2,6-Dichloro-4-[(8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0206] Compounds 1 - 30 4-[3-[2,6-Dichloro-4-[(8R)-8-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0207] Compound 1 - 24 4-[3-[2,6-Dichloro-4-[(1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound f1 O-tert-Butyl 6-methoxy-2-azaspiro[3.3]heptane-2-carbothioate

Chem.

[0208] Second step Compound f2 O-tert-Butyl (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chem.] Compound f3 O-tert-Butyl (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chem.] A solution of O-tert-butyl 6-methoxy-2-azaspiro[3.3]heptane-2-carbothioate (63.3 mg, 0.260 mmol) in tetrahydrofuran (1.30 mL) was cooled to -78 °C. Tetramethylethylenediamine (0.118 mL, 0.780 mmol) and 1.05 M sec-butyllithium cyclohexane hexane solution (0.495 mL, 0.520 mmol) were added, and the mixture was stirred at -78 °C for 35 minutes. Iodomethane (0.0650 mL, 1.04 mmol) was added, and the mixture was stirred at -78 °C for 10 minutes and then at room temperature for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether and passed through a phase separator. After concentration of the organic layer, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give O-tert-butyl 6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (61%, 40.7 mg) as a diastereomeric mixture. The diastereomeric mixture (40.7 mg, 0.158 mmol) was purified by HPLC (CHIRALPAK IE, hexane / 2-propanol) to give O-tert-butyl (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (47%, 19.0 mg) and O-tert-butyl (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (34%, 14.0 mg) as racemic mixtures.

[0209] Compound f2 O-tert-Butyl (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chemical formula] LCMS: m / z 202 [M - tBu + H] + SFC retention time: 4.16 minutes, 5.18 minutes (Analysis conditions: CHIRALPAK IC 4.6 mm I.D. x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether = 1 / 1] = 90 / 10 (10 minutes), 40°C, 254 nm)

[0210] Compound f3 O-tert-butyl (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chemical formula] LCMS: m / z 202 [M - tBu + H] + SFC retention time: 4.79 minutes, 5.88 minutes (Analysis conditions: CHIRALPAK IC 4.6 mm I.D. x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether = 1 / 1] = 90 / 10 (10 minutes), 40°C, 254 nm)

[0211] Third step Compound f4 O-tert-butyl (1S,4s,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chemical formula] Compound f5 O-tert-butyl (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chemical formula] Compound f6 O-tert-butyl (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chemical formula] Compound f7 O-tert-butyl (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chemical] A racemic mixture of O-tert-butyl (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (19.0 mg, 0.0740 mmol) was purified by HPLC (CHIRALPAK IC, hexane / 2-propanol) to obtain O-tert-butyl (1S,4s,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (41%, 7.70 mg) and O-tert-butyl (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (39%, 7.40 mg).

[0212] Compound f4 O-tert-butyl (1S,4s,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chemical] LCMS: m / z 202 [M-tBu+H]+ SFC retention time: 4.09 minutes (analysis conditions: CHIRALPAK IC 4.6 mm I.D. x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether = 1 / 1] = 90 / 10 (10 minutes), 40 °C, 254 nm)

[0213] Compound f5 O-tert-butyl (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chemical] LCMS: m / z 202 [M-tBu+H] + SFC retention time: 5.09 minutes (analysis conditions: CHIRALPAK IC 4.6 mm I.D. x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether = 1 / 1] = 90 / 10 (10 minutes), 40 °C, 254 nm)

[0214] A racemic mixture of O-tert-butyl (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (14.0 mg, 0.0540 mmol) was purified by HPLC (CHIRALPAK IC, hexane / 2-propanol) to give O-tert-butyl (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (36%, 5.10 mg) and O-tert-butyl (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (40%, 5.60 mg).

[0215] Compound f6 O-tert-butyl (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate

Chemical Structure

[0216] Compound f7 O-tert-butyl (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate

Chemical Structure

[0217] Fourth Step Compound 1-24 4-[3-[2,6-dichloro-4-[(1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [Chemical formula] To a solution of O-tert-butyl (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (5.60 mg, 0.0220 mmol) in dichloromethane (0.218 mL) was added trifluoroacetic acid (0.00335 mL, 0.0440 mmol), and the mixture was stirred at room temperature overnight. Trifluoroacetic acid (0.0335 mL, 0.0440 mmol) was added and the mixture was stirred at room temperature for an additional 1 hour. The reaction solution was concentrated, and using the obtained crude product and Compound A, the title compound was obtained by the same procedure as in the ninth step of Compound 1-7. LCMS: m / z 696 [M+H] + HPLC retention time: 1.75 min, 1.78 min (Analysis condition B)

[0218] Compound 1-25 4-[3-[2,6-dichloro-4-[(1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [Chemical formula] Using O-tert-butyl (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate, the title compound was obtained by the same procedure as in the fourth step of Compound 1-24. LCMS: m / z 696 [M+H] + HPLC retention time: 1.75 min, 1.78 min (Analysis condition B)

[0219] Compound 1-26 4-[3-[2,6-dichloro-4-[(1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [Chemical formula] Using O-tert-butyl (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate, the title compound was obtained by the same procedure as in the fourth step of Compound 1-24. LCMS: m / z 696 [M+H] + HPLC retention time: 1.75 min, 1.78 min (Analysis condition B)

[0220] Compound 1-27 4-[3-[2,6-Dichloro-4-[(1S,4S,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0221] Compound 1-86 4-[3-[2,6-Dichloro-4-[rel-(6R,7R)-6-methoxy-7-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound g1 tert-Butyl 6-(dimethylhydrazinylidene)-2-azaspiro[3.3]heptane-2-carboxylate

Chem.

[0222] Second step Compound g2 rac-tert-Butyl (5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate

Chem.

Chem.

[0223] Compound g2 rac-tert-Butyl (5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate [Chemical formula] LCMS: m / z 228 [M+H] + 1 1H-NMR (400 MHz, CDCl3) δ: 4.03 (1H, d, J = 8.7 Hz), 3.83 (2H, d, J = 8.9 Hz), 3.79 (2H, d, J = 8.9 Hz), 3.64 - 3.56 (1H, m), 3.63 (1H, d, J = 8.7 Hz), 2.49 (1H, dd, J = 11.5, 6.9 Hz), 2.13 - 2.06 (1H, m), 1.92 (1H, dd, J = 11.5, 8.1 Hz), 1.43 (9H, s), 1.14 (3H, d, J = 6.9 Hz).

[0224] Compound g3 rac-tert-Butyl (5R,6S)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate [Chemical formula] LCMS: m / z 228 [M+H] + 1H-NMR (400 MHz, CDCl3) δ: 4.32 - 4.25 (1H, m), 4.01 (1H, d, J = 9.0 Hz), 3.88 (1H, d, J = 8.6 Hz), 3.84 (1H, d, J = 8.6 Hz), 3.66 (1H, d, J = 9.0 Hz), 2.56 - 2.46 (2H, m), 2.11 (1H, dd, J = 13.10, 6.92 Hz), 1.43 (9H, s), 1.07 (3H, d, J = 7.25 Hz).

[0225] The third step Compound 1 - 86 4-[3-[2,6-Dichloro-4-[rac-(6R,7R)-6-methoxy-7-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0226] Compound 1 - 87 4-[3-[2,6-Dichloro-4-[rac-(6R,7S)-6-methoxy-7-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0227] Compound 1 - 47 4-[3-[2,6-Dichloro-4-(6-cyano-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound CP1 Methyl 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0228] Second step Compound 1-47 4-[3-[2,6-Dichloro-4-(6-cyano-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0229] Compound 1-15 4-[3-[2,6-Dichloro-4-(3-cyano-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound CP2 Methyl 4-[3-[2,6-dichloro-4-(3-cyano-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0230] Second step Compound 1-15 4-[3-[2,6-Dichloro-4-(3-cyano-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0231] In the following synthesis, the intermediates shown in Table 1-3 were used.

[0232]

Table 1-3

[0233] Compound B Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate First Step Compound B1 4-Bromo-5-fluoro-2-morpholin-4-ylbenzoic acid

Chem.

[0234] Second Step Compound B2 Methyl 4-bromo-5-fluoro-2-morpholin-4-ylbenzoate

Chem.

[0235] Third step Compound B3 tert-Butyl 8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chem.

[0236] Fourth step Compound B4 Methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride

Chem.

[0237] Fifth step Compound B Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chemical formula

[0238] Compound C 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chemical formula

[0239] Compound D Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate First step Compound D2 4-Bromo-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0240] Second step Compound D3 Methyl 4-bromo-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chemical formula

[0241] Third step Compound D4 tert-Butyl 8-[4-methoxycarbonyl-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chemical formula

[0242] Fourth step Compound D5 Methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride

Chemical formula

[0243] Fifth step Compound D Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [Chemical formula] Using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride, the title compound was obtained by the same operation as in the fifth step of Compound B. LCMS: m / z 631 [M+H] + HPLC retention time: 1.00 minutes (Analysis condition D)

[0244] Compound E Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate First step Compound E1 4-Bromo-2-morpholin-4-ylbenzoic acid [Chemical formula] To a solution of 4-bromo-2-fluorobenzoic acid (672 mg, 3.07 mmol) in 1-methylpyrrolidin-2-one (3.07 mL) was added morpholine (5.76 mL, 66.1 mmol), and the mixture was stirred at 150 °C for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (77%, 672 mg). LCMS: m / z 286 [M+H] + HPLC retention time: 0.75 minutes (Analysis condition G)

[0245] Second step Compound E2 Methyl 4-bromo-2-morpholin-4-ylbenzoate [Chemical formula] Using 4-bromo-2-morpholin-4-ylbenzoic acid, the title compound was obtained by the same operation as in the second step of Compound B. LCMS: m / z 300 [M+H] + HPLC retention time: 1.10 min (Analysis condition G)

[0246] The third step Compound E3 tert-Butyl 8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chem.

[0247] The fourth step Compound E4 Methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate dihydrochloride

Chem.

[0248] The fifth step Compound E Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate

Chem.

[0249] Compound F 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid

Chem.

[0250] Compound G Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzothiazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate First step Compound G2 2-Ethylhexyl 3-(2-bromo-6-cyanophenyl)sulfanylpropanoate

Chem.

[0251] Second step Compound G4 2-Ethylhexyl 3-[2-bromo-6-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]sulfanylpropanoate

Chem.

[0252] Third step Compound G5 tert-Butyl N-[(3-bromo-2-sulfanylphenyl)methyl]carbamate

Chemical formula

[0253] Fourth step Compound G6 tert-Butyl 8-bromo-2,4-dihydro-1,3-benzothiazine-3-carboxylate [ka] A solution of tert-butyl N-[(3-bromo-2-sulfanylphenyl)methyl]carbamate (602 mg, 1.89 mmol), paraformaldehyde (568 mg, 18.9 mmol) and p-toluenesulfonic acid (3.60 mg, 0.0190 mmol) in toluene (0.200 mL) was stirred at 90° C. for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, passed through a phase separator, and the organic layer was concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (99%, 620 mg). LCMS: m / z 274 [M-tBu+H] + HPLC retention time: 1.37 minutes (analysis condition G)

[0254] Fifth step Compound G7 tert-Butyl 8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzothiazine-3-carboxylate [ka] The title compound was obtained by the same procedure as in the third step of Compound B using tert-butyl 8-bromo-2,4-dihydro-1,3-benzothiazine-3-carboxylate and methyl 4-bromo-5-fluoro-2-morpholin-4-ylbenzoate. LCMS: m / z 489[M+H] + HPLC retention time: 1.34 minutes (analysis condition G)

[0255] Sixth step Compound G8 Methyl 4-(3,4-dihydro-2H-1,3-benzothiazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride [Chemical formula] Using tert-butyl 8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzothiazine-3-carboxylate, the title compound was synthesized in the same manner as in the fourth step of Compound B. LCMS: m / z 389 [M+H] + HPLC retention time: 0.69 minutes (Analysis condition G)

[0256] Seventh step Compound G Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzothiazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate [Chemical formula] Using methyl 4-(3,4-dihydro-2H-1,3-benzothiazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride, the title compound was obtained in the same manner as in the fifth step of Compound B. However, triethylamine was used instead of N,N-diisopropylethylamine. LCMS: m / z 639 [M+H] + HPLC retention time: 1.37 minutes, 1.39 minutes (Analysis condition G)

[0257] Compound H Methyl 4-[3-(4-bromo-2-chlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [Chemical formula] Using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride and 4-bromo-2-chlorobenzoyl chloride, the title compound was obtained by the same procedure as in the fifth step of Compound B. LCMS: m / z 615 [M+H] + HPLC retention time: 0.97 min (Analysis condition N)

[0258] Compound I Methyl 4-[3-(4-bromo-2-chlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chem.

[0259] Compound J Methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate First step Compound J2 Methyl 4-bromo-2-chloro-5-methylbenzoate

Chem.

[0260] Second step Compound J3 4-Bromo-2-chloro-5-methylbenzoic acid

Chem.

[0261] The third step Compound J4 4-Bromo-2-chloro-5-methylbenzoyl chloride

Chem.

[0262] The fourth step Compound J Methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chem.

[0263] Compound K Methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate First step Compound K2 Methyl 4-bromo-2-chloro-5-methoxybenzoate

Chemical formula

[0264] Second step Compound K3 4-Bromo-2-chloro-5-methoxybenzoic acid

Chemical formula

[0265] Third step Compound K4 4-Bromo-2-chloro-5-methoxybenzoyl chloride

Chemical formula

[0266] Fourth step Compound K Methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chem.

[0267] Compound L Methyl 4-[2-(4-bromo-2,6-dichlorobenzoyl)-4-oxo-1,3-dihydrophthalazin-5-yl]-2-morpholin-4-ylbenzoate First step Compound L4 Methyl 2-bromo-6-[[(2-methylpropan-2-yl)oxycarbonyl-[(2-methylpropan-2-yl)oxycarbonylamino]amino]methyl]benzoate

Chem.

[0268] Second step Compound L5 tert-Butyl 5-bromo-4-oxo-1,3-dihydrophthalazine-2-carboxylate

Chemical formula

[0269] Third step Compound L6 tert-Butyl 5-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-4-oxo-1,3-dihydrophthalazine-2-carboxylate

Chemical formula

[0270] Fourth step Compound L Methyl 4-[2-(4-bromo-2,6-dichlorobenzoyl)-4-oxo-1,3-dihydrophthalazin-5-yl]-2-morpholin-4-ylbenzoate

Chem.

[0271] Compound M Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-5-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate First step Compound M2 tert-Butyl N-[(2-fluoro-6-hydroxyphenyl)methyl]carbamate

Chem.

[0272] Second step Compound M3 tert-Butyl N-[(3-bromo-6-fluoro-2-hydroxyphenyl)methyl]carbamate

Chemical formula

[0273] Third step Compound M4 tert-Butyl 8-bromo-5-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chemical formula

[0274] Fourth step Compound Z6 (2-Fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)boronic acid

Chem.

[0275] Fifth step Compound M5 tert-Butyl 5-fluoro-8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chem.

[0276] Sixth step Compound M6 Methyl 5-fluoro-4-(5-fluoro-3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate dihydrochloride

Chemical formula

[0277] The seventh project Compound M Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-5-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chem.

[0278] Compound N Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate The first step Compound N3 tert-Butyl N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate

Chem.

[0279] Second step Compound N4 tert-Butyl 8-bromo-7-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chemical formula

[0280] Third step Compound N7 Methyl 2-morpholin-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Chem.

[0281] Fourth step Compound N5 tert-Butyl 7-fluoro-8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chem.

[0282] Fifth step Compound N Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate

Chemical formula

[0283] Compound O Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate First step Compound O1 2,6-Dichloro-4-fluorobenzoyl chloride

Chem.

[0284] Second step Compound O Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0285] Compound P 4-[3-(2,6-Dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0286] Compound Q Ethyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate First step Compound Q1 Ethyl 4-bromo-2-morpholin-4-ylbenzoate

Chemical formula

[0287] Second step Compound Q4 tert-Butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chem.

[0288] Third step Compound Q2 tert-Butyl 8-(4-ethoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chem.

[0289] Fourth Step Compound Q3 Ethyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate hydrochloride

Chemical Structure

[0290] Fifth Step Compound Q Ethyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate

Chemical Structure

[0291] Compound R Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate

Chemical formula

[0292] Compound S Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chemical formula

[0293] Compound T Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-methyl-6-morpholin-4-ylbenzoate First step Compound T1 4-Bromo-2-methyl-6-morpholin-4-ylbenzoic acid

Chem.

[0294] Second step Compound T2 Methyl 4-bromo-2-methyl-6-morpholin-4-ylbenzoate

Chem.

[0295] Third step Compound T3 tert-Butyl 8-(4-methoxycarbonyl-3-methyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chem.

[0296] Fourth step Compound T4 Methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-methyl-6-morpholin-4-ylbenzoate dihydrochloride

Chem.

[0297] Fifth step Compound T Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-methyl-6-morpholin-4-ylbenzoate

Chem.

[0298] Compound U Methyl 4-[3-(2-chloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate First step Compound U2 2-Chloro-4-fluorobenzoyl chloride

Chem.

[0299] Second step Compound U Methyl 4-[3-(2-chloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chem.

[0300] Compound V 4-[3-(2-Chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid First step Compound V2 Methyl 2-chloro-4-fluoro-5-methoxybenzoate

Chem.

[0301] Second step Compound V3 2-Chloro-4-fluoro-5-methoxybenzoic acid

Chem.

[0302] The third step Compound V4 2-Chloro-4-fluoro-5-methoxybenzoyl chloride

Chemical formula

[0303] The fourth step Compound V5 Methyl 4-[3-(2-chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chemical formula

[0304] The fifth step Compound V 4-[3-(2-Chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chem.

[0305] Compound W Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzoate First step Compound X7 2-(Aminomethyl)-6-bromophenol hydrochloride

Chem.

[0306] Second step Compound W1 N-[(3-Bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-fluorobenzamide

Chem.

[0307] Third step Compound W2 (8-Bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-(2,6-dichloro-4-fluorophenyl)methanone

Chemical formula

[0308] Fourth Project Compound W9 Methyl 5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Chem.

[0309] Fifth Project Compound W3 Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-hydroxybenzoate

Chem.

[0310] Sixth step Compound W4 Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate

Chem.

[0311] Seventh step Compound W5 Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Chem.

[0312] Eighth step Compound W6 Methyl 2-bromo-4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluorobenzoate

Chemical formula

[0313] Ninth step Compound W Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzoate

Chem.

[0314] Compound X Methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate First step Compound X2 Methyl 2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoate

Chem.

[0315] Second step Compound X3 2,6-Dichloro-4-(1-methylpyrazol-4-yl)benzoic acid

Chemical formula

[0316] Third step Compound X4 N-[(3-Bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-(1-methylpyrazol-4-yl)benzamide

Chemical formula

[0317] Fourth step Compound X5 (8-Bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl]methanone

Chemical Structure

[0318] Fifth step Compound X6 Methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-hydroxybenzoate

Chemical Structure

[0319] Sixth step Compound X Methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate

Chemical formula

[0320] Compound Y Methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate First step Compound Y1 (8-Bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]phenyl]methanone

Chemical formula

[0321] Second step Compound Y2 Methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-hydroxybenzoate

Chemical formula

[0322] Third step Compound Y Methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate

Chemical formula

[0323] Compound Z Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate First step Compound Z2 tert-Butyl N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate

Chemical formula

[0324] Second step Compound Z3 tert-Butyl 8-bromo-7-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chem.

[0325] Third step Compound Z4 tert-Butyl 7-fluoro-8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate

Chem.

[0326] Fourth step Compound Z5 Methyl 5-fluoro-4-(7-fluoro-3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate hydrochloride

Chem.

[0327] Fifth step Compound Z Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chemical formula

[0328] Compound 1-61 4-[3-[2,6-Dichloro-4-(5-oxa-2-azaspiro[3.4]octan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0329] Compound 1-71 4-[3-[2-Chloro-4-(3-methoxyazetidin-1-yl)-5-methylbenzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound CP8 Methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0330] Second step Compound 1-71 4-[3-[2-Chloro-4-(3-methoxyazetidin-1-yl)-5-methylbenzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0331] Compound 1-74 4-[3-[2-Chloro-5-methoxy-4-(3-methoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound CP9 Methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0332] Second Step Compound 1-74 4-[3-[2-Chloro-5-methoxy-4-(3-methoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical Structure

[0333] Compound 1-55 4-[3-[2,6-Dichloro-4-[4-(oxetan-3-yl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chemical Structure

[0334] Compound 1-54 4-[3-[2,6-Dichloro-4-[4-(2-methoxyethyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chemical Structure

[0335] Compound 1-88 4-[3-[2-Chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound CP6 Methyl 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0336] Second step Compound 1-88 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0337] Compound 1-83 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound CP7 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0338] Second step Compound 1-83 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0339] The compounds shown in Table 1-4 were obtained by the same procedure as the preparation method of Compounds 1-55 using the corresponding intermediates and the commercially available amine reagents shown in Table 1-5. However, in the synthesis of Compound 1-59, a 1,4-dioxane solution was used instead of a toluene solution.

[0340]

Table 1-4

[0341]

Table 1-5

[0342] Compound 1-73 4-[3-[2-chloro-5-methoxy-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chem.

[0343] The compounds shown in Table 1-6 were obtained by the same procedure as the preparation method of Compound 1-73 using the corresponding intermediates and the amine reagents shown in Table 1-7. However, palladium(II) acetate was used instead of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct in Compounds 1-57, 1-67, and 1-76. In addition, toluene solvent was used instead of 1-methylpyrrolidin-2-one solvent in Compounds 1-57, 1-60, 1-65, 1-66, 1-67, 1-76, 1-79, 1-80, 1-81, 1-82, and 1-35.

[0344]

Table 1-6

[0345]

Table 1-7

[0346] Compound 1-64 4-[3-[2,6-dichloro-4-(4-methylpiperazin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid

Chem.

[0347] Compound 1-51 4-[3-[2,6-dichloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chem.

[0348] Compound 1-52 4-[3-[2,6-dichloro-4-(2-oxopyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid First step Compound CP3 Methyl 4-[3-[2,6-dichloro-4-(2-oxopyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chemical Structure

[0349] Second step Compound 1-52 4-[3-[2,6-Dichloro-4-(2-oxopyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chemical formula

[0350] Compound 1-50 4-[3-[2,6-Dichloro-4-(2-oxoazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chem.

[0351] Compound 2-6 4-[3-[2-Chloro-5-methoxy-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chem.

[0352] Using various boronic acids or boronic acid esters known in the literature or commercially available, or the boronic acids or boronic acid esters shown in Table 2-2, the compounds shown in Table 2-1 were synthesized by the same procedure as the preparation method of Compound 2-6. However, in the synthesis of Compound 2-4, tetrakis(triphenylphosphine)palladium was used instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and in the synthesis of Compound 2-5, toluene was used instead of 1,4-dioxane / water.

[0353]

Table 2-1

[0354]

Table 2-2

[0355] Compound 3-2 4-[3-[2,6-Dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound BRO4 [3,5-Dichloro-4-[8-[2-Fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid

Chem.

[0356] Second step Compound 3-2a Methyl 4-[3-[2,6-dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0357] Third step Compound 3-2 4-[3-[2,6-Dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0358] Compound 3-6 4-[3-[2,6-Dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound h6 7-Bromo-2-methylpyrazolo[4,3-c]pyridine

Chem.

[0359] Second step Compound 3-6a Methyl 4-[3-[2,6-dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0360] The third step Compound 3-6 4-[3-[2,6-Dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0361] Compound 3-10 4-[3-[2,6-Dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The first step Compound h10 7-Bromo-2-methyltriazolo[4,5-c]pyridine

Chemical formula

[0362] Second step Compound 3-10a Methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0363] Third step Compound 3-10 4-[3-[2,6-Dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0364] Compound 3-17 4-[3-[2,6-Dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound 3-17a Methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [Chemistry] Compound 3-19a Methyl 4-[3-[2,6-dichloro-4-(3-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [Chemistry] To a solution of 7-bromo-3H-triazolo[4,5-b]pyridine (100 mg, 0.502 mmol) in tetrahydrofuran (2.51 mL) were added 1M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (0.754 mL, 0.754 mmol) and iodomethane (0.0940 mL, 1.51 mmol), and the mixture was stirred at room temperature for 18 h. 1M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (0.754 mL, 0.754 mmol) was added, and the mixture was stirred at room temperature for 1 h. 1M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (0.754 mL, 0.754 mmol) and iodomethane (0.094 mL, 1.51 mmol) were added, and the mixture was stirred at room temperature for 1 h. An aqueous formic acid solution was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (methanol / water, 0.01M ammonium acetate) to obtain a mixture of 7-bromo-2-methyltriazolo[4,5-b]pyridine and 7-bromo-3-methyltriazolo[4,5-b]pyridine (25%, 27.0 mg). Using the obtained mixture and [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid, the title compound 3-17a and the title compound 3-19a were obtained by the same procedure as in the second step of Compound 3-2. However, for purification, reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) was followed by SFC (ACQUITY UPC2 Torus 1-AA, supercritical carbon dioxide / methanol). Compound 3-17a LCMS: m / z 703 [M+H] + SFC retention time: 3.18 minutes (analysis conditions: ACQUITY UPC2 Torus 1-AA 4.6 mm I.D. x 50 mm, 5 μm, supercritical carbon dioxide / methanol = 70 / 30 (10 minutes), 40 °C, 270 nm) Compound 3-19a LCMS: m / z 703 [M+H] + SFC retention time: 2.44 minutes (analysis conditions: ACQUITY UPC2 Torus 1-AA 4.6 mm I.D. x 50 mm, 5 μm, supercritical carbon dioxide / methanol = 70 / 30 (10 minutes), 40 °C, 270 nm)

[0365] Second step Compound 3-17 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0366] Compound 3-19 4-[3-[2,6-dichloro-4-(3-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0367] Compound 3-26 4-[3-[2,6-dichloro-4-(4-methoxy-2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound h26 7-Bromo-4-methoxy-2-methyltriazolo[4,5-c]pyridine

Chemical formula

Chemical formula

[0368] Second step Compound 3-26a Methyl 4-[3-[2,6-dichloro-4-(4-methoxy-2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chemical formula

[0369] Third step Compound 3-26 4-[3-[2,6-dichloro-4-(4-methoxy-2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0370] Compound 3-27 4-[3-[2,6-Dichloro-4-(4-methoxy-3-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The first step Compound 3-27a Methyl 4-[3-[2,6-dichloro-4-(4-methoxy-3-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate

Chem.

[0371] The second step Compound 3-27 4-[3-[2,6-Dichloro-4-(4-methoxy-3-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chem.

[0372] The first step The compounds shown in Table 3-1 were synthesized by the same operation as in the second step of Compound 3-2 using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and the aryl bromides described in Table 3-1. However, in the synthesis of Compound Nos. 3-14a, 3-15a, and 3-18a, tetrakis(triphenylphosphine)palladium(0) was used instead of APhos Pd G3, and sodium carbonate was used instead of potassium carbonate.

[0373]

Table 3-1

[0374] Second step The compounds shown in Table 3-2 were synthesized by the same operation as in the second step of Compound 3-2 using the esters described in Table 3-1 obtained in the first step.

[0375]

Table 3-2

[0376] Compound 3-1 4-[3-[2,6-Dichloro-4-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid First step Compound BRO1 [3,5-Dichloro-4-[8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid

Chemical formula

[0377] Second step Compound 3-1a Methyl 4-[3-[2,6-dichloro-4-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate

Chemical Structure

[0378] Third Step Compound 3-1 4-[3-[2,6-Dichloro-4-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid

Chem.

[0379] Compound 3-28 4-[3-[2,6-Dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid First Step Compound BRO2 [3,5-Dichloro-4-[8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid

Chem.

[0380] Second Step Compound 3-28a Methyl 4-[3-[2,6-dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate [Chemical formula] [3,5-Dichloro-4-[8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and 4-bromo-1-(2-methoxyethyl)pyrazole were used to obtain the title compound by the same method as in the second step for Compound 3-1. LCMS: m / z 651 [M+H] + HPLC retention time: 1.22 min, 1.24 min (Analysis condition G)

[0381] The third step Compound 3-28 4-[3-[2,6-Dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid [Chemical formula] Using methyl 4-[3-[2,6-dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate, the title compound was obtained by the same operation as in the third step of Compound 3-2. LCMS: m / z 637 [M+H] + HPLC retention time: 1.01 min, 1.04 min (Analysis condition A)

[0382] Compound 4-2 4-[3-[2,6-Dichloro-4-(3-ethoxy-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [Chemical formula] 3-Ethoxy-3-methylazetidine hydrochloride (27.0 mg, 0.178 mmol), potassium carbonate (23.0 mg, 0.166 mmol) were added to 1-methylpyrrolidin-2-one (0.600 mL), and the mixture was stirred at room temperature for 10 minutes. Compound O (35.0 mg, 0.0590 mmol) was added to the reaction solution, and the mixture was stirred at 100 °C for 14 hours. After cooling the reaction solution, 8M aqueous potassium hydroxide solution (0.0742 mL, 0.594 mmol) was added and the mixture was stirred at 60 °C for 1 hour. After neutralizing the reaction solution with aqueous formic acid, the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (82%, 32.7 mg). LCMS: m / z 670 [M+H] + HPLC retention time: 1.62 minutes, 1.66 minutes (analysis condition B)

[0383] Using the amines shown in Table 4-2, which are known from the literature or commercially available, the compounds shown in Table 4-1 were synthesized by the same procedure as for the preparation of Compound 4-2. However, in the synthesis of Compound 4-18, Compound 4-7, and Compound 4-17, potassium tert-butoxide was used instead of potassium carbonate, and in the synthesis of Compound 4-20, Compound 4-22, Compound 4-23, Compound 4-24, Compound 4-25, Compound 4-27, Compound 4-28, and Compound 4-29, triethylamine was used.

[0384]

Table 4-1

[0385]

Table 4-2

[0386] Compound 4-12 4-[3-[2,6-Dichloro-4-(4-cyclopropylpiperazin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [Chemistry] In 1 - methylpyrrolidin - 2 - one (0.106 mL), compound O (25.0 mg, 0.0420 mmol) and 1 - cyclopropylpiperazine (16.1 mg, 0.127 mmol) were stirred at 130 °C for 6 hours. After cooling the reaction mixture, 8 M aqueous potassium hydroxide solution (0.0265 mL, 0.212 mmol) was added and the mixture was stirred at 60 °C for 30 minutes. The reaction mixture was neutralized with aqueous formic acid, and then the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (73%, 21.1 mg). LCMS: m / z 681 [M + H] + HPLC retention time: 1.03, 1.06 minutes (analysis condition B)

[0387] Using the amines shown in Table 4 - 4, which are either known from the literature or commercially available, the compounds shown in Table 4 - 3 were synthesized by the same procedure as the preparation method of compound 4 - 12.

[0388]

Table 4 - 3

[0389]

Table 4 - 4

[0390] Compound 4 - 13 4-[3-[4-[(9aS)-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2,6-dichlorobenzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [Chemistry] (9aS)-1,3,4,6,7,8,9,9a-Octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (37.4 mg, 0.174 mmol) in 1-methylpyrrolidin-2-one (0.0870 mL) was added with potassium tert-butoxide (42 mg, 0.375 mmol), and the mixture was stirred at room temperature for 5 minutes. Compound P (20.0 mg, 0.0350 mmol) was added to the reaction solution, and the mixture was stirred at 130 °C for 4 hours. The reaction solution was cooled, diluted with methanol, and then neutralized with aqueous formic acid. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (40%, 9.70 mg). LCMS: m / z 697 [M+H] + HPLC retention time: 1.03 min, 1.06 min (analysis condition B)

[0391] Compound 4-14 4-[3-[4-[(9aR)-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2,6-dichlorobenzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0392] Compound 4-15 4-[3-[2,6-Dichloro-4-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical formula

[0393] Compound 4-19 4-[3-(2,6-Dichloro-4-morpholin-4-ylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid

Chemical Structure

[0394] Using the amines shown in Table 4-6 which are known from the literature or commercially available, the compounds shown in Table 4-5 were synthesized by the same operation as the production method of compound 4-19.

[0395]

Table 4-5

[0396]

Table 4-6

[0397] Compound 4-42 4-[3-[2,6-Dichloro-4-[[(2S)-1,4-dioxan-2-yl]methoxy]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [Chem.] [(2R)-1,4-Dioxan-2-yl]methanol (0.0273 mL, 0.254 mmol), potassium tert-butoxide (27.4 mg, 0.244 mmol) were added to 1-methylpyrrolidin-2-one (0.254 mL), and the mixture was stirred at room temperature for 10 minutes. Compound O (30.0 mg, 0.0510 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After neutralizing the reaction solution with aqueous formic acid, the reaction mixture was purified by HPLC (acetonitrile / wa...

Claims

1. Formula (1): 【Chemistry 1】 [In the formula, X ａ１ is CR ａ１ or N, X ａ３ is CR ａ３ or N, R ａ１ , R ａ２ and R ａ３ are each independently hydrogen, halogen, and C １ -C ６ alkoxy; X ｂ１ , X ｂ２ and X ｂ３ are each independently CH ２ , O, NH, S and C═O; Y is C ６ -C １０ aryl or 5- to 10-membered heteroaryl, ６ -C １０ Aryl and 5- to 10-membered heteroaryl are R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ and optionally substituted with one or more groups selected from the group consisting of The R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, hydroxy C ２ -C ６ Alkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Alkoxy, C １ -C ６ Alkylamino C １ -C ６ Alkoxy, 5-10 membered heteroaryloxy, C １ -C ６ alkylthio, a 4- to 10-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, and C １ -C ６ Alkyl (C １ -C ６ Alkoxy C １ -C ６ is selected from the group consisting of (alkyl)amino; Z is C ６ -C １０ Aryl, 5- to 10-membered heteroaryl or C １ -C ６ alkyl, ６ -C １０ Aryl, 5- to 10-membered heteroaryl and C １ -C ６ Alkyl is R ｚ３ and R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ and optionally substituted with one or more groups selected from the group consisting of R ｚ３ is the following substituent group A: 【Chemistry 2】 A group selected from (In the formula, The wavy line is the C ６ -C １０ Aryl, 5- to 10-membered heteroaryl or C １ -C ６ represents the point of attachment to the alkyl, R ５ is hydroxy, C １ -C ６ Alkoxy, mono or di C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino, n is 1 or 2; R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ are each independently hydrogen, halogen, or C １ -C ６ alkyl, optionally substituted C １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ６ alkyl)amino, optionally substituted C １ -C ６ It is selected from the group consisting of alkyl(4- to 10-membered heterocyclyl)amino and optionally substituted 4- to 8-membered cyclic amino. However, the following compounds: 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[6-(difluoromethoxy)-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid, 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(6-methoxypyridin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(4-ethylpiperazin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azadispiro[3.1.56.14]dodecan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid, 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, and Excluding 4-[3-[5-chloro-7-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)-2,3-dimethylbenzimidazole-4-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.] A compound represented by the formula (I), a salt thereof, or a solvate thereof.

2. X ｂ１ is CH ２ and X ｂ２ is CH ２ , O, NH or C═O, and X ｂ３ is CH ２ , O, NH, S or C═O, or a salt thereof, or a solvate thereof, according to claim 1 .

3. X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is O or X ｂ１ and X ｂ３ is CH ２ and X ｂ２ is O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is S or X ｂ１ is CH ２ and X ｂ２ is NH, and X ｂ３ is C=O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is NH or X ｂ１ is CH ２ and X ｂ２ is C=O, and X ｂ３ is NH or X ｂ１ and X ｂ３ is CH ２ and X ｂ２ is NH or X ｂ１ , X ｂ２ and X ｂ３ is CH ２ The compound according to claim 1, or a salt thereof, or a solvate thereof,

4. X ａ１ is CR ａ１ and X ａ３ is CR ａ３ or N, or a salt thereof, or a solvate thereof according to claim 1 .

5. Z is phenyl, pyridyl or C ２ -C ５ alkyl, and the phenyl, pyridyl and C ２ -C ５ Alkyl is R ｚ３ and R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ and optionally substituted with one or more groups selected from the group consisting of R ｚ３ The following substituent group B: 【Transformation 3】 A group selected from (In the formula, The wavy line indicates the phenyl, pyridyl or C ２ -C ５ represents the point of attachment to the alkyl, R ５ is hydroxy, C １ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino, R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ are each independently hydrogen, halogen, C １ -C ６ alkyl, optionally substituted C １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ６ alkyl)amino, optionally substituted C １ -C ６ is selected from the group consisting of alkyl(4- to 10-membered heterocyclyl)amino and optionally substituted 4- to 8-membered cyclic amino. That is, The compound according to claim 1, or a salt thereof, or a solvate thereof.

6. R ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, and C １ -C ６ is selected from the group consisting of alkyl, R ｚ４ C which may have a substituent １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ２ alkyl)amino, optionally substituted C １ -C ６ alkyl(4- to 10-membered heterocyclyl)amino or optionally substituted 4- to 8-membered cyclic amino; The compound according to claim 1, or a salt thereof, or a solvate thereof.

7. Y is phenyl or 6- to 10-membered heteroaryl, and the phenyl and 6- to 10-membered heteroaryl are R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ and optionally substituted with one or more groups selected from the group consisting of The R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl, C １ -C ３ Alkoxy, 5- to 6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, and C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ selected from the group consisting of: The compound according to claim 1, or a salt thereof, or a solvate thereof.

8. Y is phenyl or 6- to 10-membered heteroaryl, and the phenyl and 6- to 10-membered heteroaryl are R ｙ３ is substituted with a group other than hydrogen, and R ｙ１ , R ｙ２ , R ｙ４ and R ｙ５ and optionally substituted with one or more groups selected from the group consisting of The R ｙ１ , R ｙ２ , R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy; The R ｙ３ 5-6 membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ alkyl)amino; The compound according to claim 1, or a salt thereof, or a solvate thereof.

9. Z is the following formula (2): 【Chemistry 4】 [In the formula, The wavy line represents the attachment point of Z, R ｚ３ is the following substituent group B: 【Transformation 5】 A group selected from (In the formula, The wavy lines represent the attachment points, R ５ is hydroxy, C １ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino.) X ｚ is CR ｚ５ or N, R ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, and C １ -C ６ is selected from the group consisting of alkyl, R ｚ４ C which may have a substituent １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ２ alkyl)amino, optionally substituted C １ -C ６ alkyl(4- to 10-membered heterocyclyl)amino or an optionally substituted 4- to 8-membered cyclic amino.] is a group represented by The compound according to claim 1, or a salt thereof, or a solvate thereof.

10. Y is the following formula (3): 【Transformation 6】 [In the formula, The wavy line represents the attachment point of Y; X ｙ１ is CR ｙ３ or N, X ｙ２ is CR ｙ４ or N, X ｙ３ is CR ｙ５ or N, R ｙ１ and R ｙ５ are each independently hydrogen, halogen, cyano, and C １ -C ３ is selected from the group consisting of alkyl, R ｙ２ and R ｙ４ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy; R ｙ３ 5-6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ alkyl)amino, X ｙ１ is CR ｙ３ If R ｙ２ and R ｙ３ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring; X ｙ１ is CR ｙ３ and X ｙ２ is CR ｙ４ If R ｙ３ and R ｙ４ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring; X ｙ２ is CR ｙ４ and X ｙ３ is CR ｙ５ If R ｙ４ and R ｙ５ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring. is a group represented by The compound according to claim 1, or a salt thereof, or a solvate thereof.

11. Formula (4): 【Transformation 7】 [In the formula, X ａ３ is CR ａ３ or N, R ａ１ , R ａ２、 and R ａ３ are each independently hydrogen, halogen, and C １ -C ６ alkoxy; X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is O or X ｂ１ and X ｂ３ is CH ２ and X ｂ２ is O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is S or X ｂ１ is CH ２ and X ｂ２ is NH, and X ｂ３ is C=O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is NH or X ｂ１ is CH ２ and X ｂ２ is C=O, and X ｂ３ is NH or X ｂ１ and X ｂ３ is CH ２ and X ｂ２ is NH or X ｂ１ , X ｂ２ and X ｂ３ is CH ２ and X ｙ１ is CR ｙ３ or N, X ｙ２ is CR ｙ４ or N, X ｙ３ is CR ｙ５ or N, R ｙ１ and R ｙ５ are each independently hydrogen, halogen, cyano, and C １ -C ３ is selected from the group consisting of alkyl, R ｙ２ and R ｙ４ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy; R ｙ３ 5-6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic ring having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic ring having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl group optionally having a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ is selected from the group consisting of (alkyl)amino; X ｙ１ is CR ｙ３ If R ｙ２ and R ｙ３ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring; X ｙ１ is CR ｙ３ and X ｙ２ is CR ｙ４ If R ｙ３ and R ｙ４ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring; X ｙ２ is CR ｙ４ and X ｙ３ is CR ｙ５ If R ｙ４ and R ｙ５ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring; R ｚ３ is the following substituent group B: 【Transformation 8】 (In the formula, The wavy line indicates the R ｚ３ and R ｚ３ represents the point of attachment to the ring to which it is attached, R ５ is hydroxy, C １ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino.) X ｚ is CR ｚ５ or N, R ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, and C １ -C ６ is selected from the group consisting of alkyl, R ｚ４ C which may have a substituent １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ２ alkyl)amino, optionally substituted C １ -C ６ alkyl(4- to 10-membered heterocyclyl)amino or an optionally substituted 4- to 8-membered cyclic amino.] is a group represented by The compound according to claim 1, or a salt thereof, or a solvate thereof.

12. X ｂ１ and X ｂ２ is CH ２ and X ｂ３ The compound according to claim 1 , or a salt thereof, or a solvate thereof, wherein

13. R ５ is hydroxy or C １ -C ６ The compound according to claim 1, or a salt thereof, or a solvate thereof, which is alkylsulfonylamino.

14. X ｚ is CR ｚ５ and R ｚ１ , R ｚ２ and R ｚ５ The compound or salt thereof, or a solvate thereof according to claim 11, wherein each of is independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl and ethyl.

15. R ｚ４ is hydrogen, halogen, C １ -C ６ Alkyl and C １ -C ６ 4- to 6-membered cyclic amino optionally having one or more substituents selected from the group consisting of alkoxy, or C １ -C ２ Alkylene and C containing one oxygen atom １ -C ２ The compound according to claim 1, or a salt thereof, or a solvate thereof, which is a 4- to 6-membered cyclic amino having a bridging group selected from the group consisting of alkylene.

16. R ｚ４ is hydrogen, halogen and C １ -C ６ C optionally having a substituent selected from the group consisting of alkyl １ -C ３ Alkyl (5-6 membered heteroaryl C １ -C ２ alkyl)amino or hydrogen, halogen and C １ -C ６ C optionally having a substituent selected from the group consisting of alkyl １ -C ３ The compound according to claim 1, which is alkyl(4- to 6-membered heterocyclyl)amino, or a salt thereof, or a solvate thereof.

17. R ｙ１ is chlorine, and X ｙ１ is CR ｙ３ and X ｙ２ is CR ｙ４ and X ｙ３ is CR ｙ５ and R ｙ３ is a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, or a 5- to 10-membered heteroaryl having an optionally substituted group, and R ｙ２ , R ｙ４ and R ｙ５ The compound according to claim 11, or a salt thereof, or a solvate thereof, wherein is hydrogen.

18. R ａ１ is hydrogen or fluorine, and R ａ２ is hydrogen or methoxy, and R ａ３ The compound according to claim 1, or a salt thereof, or a solvate thereof, wherein is hydrogen or fluorine.

19. R ｚ４ is 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, morpholin-4-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, (2S,3S)-3-methoxy-2-methylazetidin-1-yl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, methyl(1,2-oxazol-3-ylmethyl)amino, methyl(oxetan-3-yl)amino, methyl-[(3R)-oxolan-3-yl]amino, or methyl-(3-methyloxetan-3-yl)amino, or a salt thereof, or a solvate thereof according to claim 1.

20. R ｙ３ is 1-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl, 4-methylpiperazin-1-yl, (2R)-2,4-dimethylpiperazin-1-yl, 6-methoxy-2-azaspiro[3.3]heptan-2-yl, 4-(2-methoxyethyl)piperazin-1-yl, 3-methoxyazetidin-1-yl, 4-(oxetan-3-yl)piperazin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, (2R,5R)-2,4,5-trimethylpiperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl, or morpholin-4-yl, or a salt thereof, or a solvate thereof according to claim 1.

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20, or a salt thereof, or a solvate thereof.

22. 22. The pharmaceutical composition according to claim 21 for the prevention and / or treatment of a neurodegenerative disease, a pulmonary disease, a renal disease, or an immune-inflammatory disease.

23. Use of the compound according to any one of claims 1 to 20, or a salt thereof, or a solvate thereof, for the manufacture of a pharmaceutical composition for the prevention and / or treatment of a neurodegenerative disease, a pulmonary disease, a renal disease, or an immune / inflammatory disease.

24. A pharmaceutical composition comprising 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate of the same, for the prevention and / or treatment of an immune / inflammatory disease.

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