US 2025/0084093 A1Published application

Nitrogen-containing heterocyclic compound having nrf2 activation effect

OwnerAtsushi KIMBARA, Takeo HARADA +5inventors

InventorsAtsushi KIMBARA, Takeo HARADA, Susumu KOMIYAMA, Mizuki OKUYAMA, Yoshihito OHTAKE, Yoshihisa MURATA, Rie SAITO

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Abstract

Provided is a low-molecular compound or a salt thereof, or a solvate thereof which has the ability to activate Nrf2. The present invention provides a compound represented by the formula (1) or a salt thereof, or a solvate thereof, wherein 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 C6-C10 aryl optionally having a substituent or 5- to 10-membered heteroaryl optionally having a substituent, and Z is C6-C10 aryl optionally having a substituent, 5- to 10-membered heteroaryl optionally having a substituent or C1-C6 alkyl optionally having a substituent.

Claims26

Dependent claims

A compound represented by the formula (1) or a salt thereof, or a solvate thereof:

wherein
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 C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl and the 5- to 10-membered heteroaryl are each optionally substituted by one or more groups selected from the group consisting of Ry1, Ry2, Ry3, Ry4 and Ry5,
Ry1, Ry2, Ry3, Ry4 and Ry5 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- to 10-membered heterocyclyl C1-C6 alkoxy, hydroxy C2-C6 alkoxy, 4- to 10-membered heterocyclyloxy, 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 in a carbon atom on a ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond in a nitrogen atom on a ring and optionally having a substituent, 5- to 10-membered heteroaryl optionally having a substituent and C1-C6 alkyl(C1-C6 alkoxy C1-C6 alkyl)amino,
Z is C6-C10 aryl, 5- to 10-membered heteroaryl or C1-C6 alkyl, wherein the C6-C10 aryl, the 5- to 10-membered heteroaryl and the C1-C6 alkyl are each substituted by Rz3 and optionally substituted by one or more groups selected from the group consisting of Rz1, Rz2, Rz4 and Rz5,
Rz3 is a group selected from the following substituent group A:
wherein
the wavy line represents a binding point with the C6-C10 aryl, the 5- to 10-membered heteroaryl or the C1-C6 alkyl,
R5 is hydroxy, C1-C6 alkoxy, mono- or di-C1-C6 alkylamino or C1-C6 alkylsulfonylamino, and
n is 1 or 2, and
Rz1, Rz2, Rz4 and Rz5 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl(5- to 10-membered heteroaryl C1-C6 alkyl)amino optionally having a substituent, C1-C6 alkyl(4- to 10-membered heterocyclyl)amino optionally having a substituent and 4- to 8-membered cyclic amino optionally having a substituent.

11 more elements

A compound selected from the following compounds or a salt thereof, or a solvate thereof:

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 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.

Dependencies are inferred from the claim text.