Fused ring compound having urea structure

Patent metadata

Field	Value
Publication number	US-11918568-B2
Application number	US-201917257262-A
Country	US
Kind code	B2
Filing date	Jul 3, 2019
Priority date	Jul 5, 2018
Publication date	Mar 5, 2024
Grant date	Mar 5, 2024

Abstract

The present invention relates to a novel fused ring compound having urea structure that exhibits excellent NAMPT activating effect, and a method using the same for treating/preventing metabolic disorder, cardiovascular and kidney disease, mitochondrial disease, neurodegenerative disease, ocular disease, and muscle wasting disorder. The present invention provides a compound represented by following formula (I) or a pharmacologically acceptable salt: Formula (I) wherein A, B, R, R 2 and R 3 represent the same meanings as in the claims.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

ring B is

R 1 is a hydrogen atom or a halogen atom;
R 2 is a hydrogen atom; a phenyl group or a heteroaryl group optionally substituted with one or more Y; or a C 1 -C 6 alkyl group optionally substituted with a C 3 -C 6 cycloalkyl group, or is absent;
R 3 is a hydrogen atom; a cyano group; a phenyl group or a heteroaryl group each optionally substituted with one or more Y; a C 1 -C 4 alkylcarbonyl group or a C 1 -C 4 alkyl group, each optionally substituted with one or more Z; or —C(═O)—Z;
each Y is independently selected from a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a phenyl group, a C 1 -C 3 alkylsulfonyl group, a C 1 -C 3 haloalkyl group, a halogen atom, and a C 1 -C 3 alkyl group or a C 1 -C 3 alkoxy group substituted with a C 1 -C 3 alkoxy group;
each Z is independently selected from a C 1 -C 3 alkoxy group, a dioxanyl group, an 8-oxa-3-azabicyclo[3.2.1]octyl group, a C 1 -C 4 alkoxycarbonyl group, and an amino group or a C 3 -C 6 cycloalkylamino group each optionally substituted with one or more W; and
each W is independently selected from a phenyl group, a heteroaryl group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkyl group substituted with phenyl, and a C 1 -C 3 alkyl group substituted with a heteroaryl group; and
at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1 , wherein A is

3. The pharmaceutical composition of claim 1 , wherein A is

4. The pharmaceutical composition of claim 1 , wherein A is

5. The pharmaceutical composition of claim 1 , wherein B is

6. The pharmaceutical composition of claim 1 , wherein R 1 is a hydrogen atom or a fluorine atom.

7. The pharmaceutical composition of claim 1 , wherein R 2 is a hydrogen atom; a phenyl group, a pyrazolyl group, a pyridinyl group, or a pyrrole group each optionally substituted with one Y; or a C 1 -C 3 alkyl group optionally substituted with a C 3 -C 6 cycloalkyl group; wherein Y is selected from a phenyl group, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 3 haloalkyl group, a C 1 -C 3 alkylsulfonyl group, a C 1 -C 3 alkoxy group, and a C 1 -C 3 alkyl group or a C 1 -C 3 alkoxy group substituted with a C 1 -C 3 alkoxy group.

8. The pharmaceutical composition of claim 1 , wherein R 2 is a hydrogen atom; a phenyl group, a pyrazolyl group, or a pyridinyl group each optionally substituted with one Y; or a C 1 -C 3 alkyl group; wherein Y is selected from a C 1 -C 4 alkyl group, a methanesulfonyl group, an ethanesulfonyl group, a methoxy group, an ethoxy group, a 2-methoxyethoxy group, a phenyl group, a trifluoromethyl group, a difluoromethyl group, a 2-methoxyethyl group, and a chlorine atom.

9. The pharmaceutical composition of claim 1 , wherein ring B is

R 3 is a hydrogen atom; a cyano group; a C 1 -C 4 alkyl group; a phenyl group or a heteroaryl group each optionally substituted with one or more Y; an ethylcarbonyl group or a methyl group each optionally substituted with one or more Z; or —C(═O)—Z; wherein each Y is independently selected from a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a phenyl group, and a halogen atom, a C 1 -C 3 alkylsulfonyl group, a C 1 -C 3 haloalkyl group, and a C 1 -C 3 alkyl group or a C 1 -C 3 alkoxy group each substituted with a C 1 -C 3 alkoxy group; wherein each Z is independently selected from a C 1 -C 2 alkoxy group, a dioxanyl group, an 8-oxa-3-azabicyclo[3.2.1]octyl group, and an amino group or a C 3 -C 6 cycloalkylamino group each optionally substituted with one or more W; and wherein each W is independently selected from a phenyl group, a heteroaryl group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkyl group substituted with phenyl, and a C 1 -C 3 alkyl group substituted with a heteroaryl group.

10. The pharmaceutical composition of claim 1 , wherein ring B is

R 3 is a hydrogen atom, a cyano group, a N-methylpyrazolyl group, a phenyl group, a methyl group, a 2-methoxyethyl group, a dioxanylmethyl group, or —C(═O)—Z; wherein Z is selected from an 8-oxa-3-azabicyclo[3.2.1]octyl group and an amino group optionally substituted with one or more W; and wherein each W is independently selected from a C 1 -C 3 alkyl group, a methylphenyl group, and a C 1 -C 3 alkyl group substituted with a heteroaryl group.

11. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of:
N-(2-phenyl-1,3-benzoxazol-5-yl)-N′-[(pyridin-4-yl)methyl]urea,
N-(2-phenyl-1,3-benzoxazol-6-yl)-N′-[(pyridin-4-yl)methyl]urea,
N-[2-(2-methylphenyl)-1,3-benzoxazol-6-yl]-N′-[(pyridin-4-yl)methyl]urea,
N-[(1,3-oxazol-5-yl)methyl]-N-(2-phenyl-1,3-benzoxazol-6-yl)urea,
N-[2-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazol-6-yl]-NL[(pyridin-4-yl)methyl]urea,
N-(5-fluoro-2-phenyl-1,3-benzoxazol-6-yl)-N′-[(pyridin-4-yl)methyl]urea,
N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-N′-[(pyridin-4-yl)methyl]urea,
N-(2-phenyl-1H-indol-5-yl)-N′-[(pyridin-4-yl)methyl]urea,
methyl[2-phenyl-5-({[(pyridin-4-yl)methyl]carbamoyl}amino)-1H-indol-1-yl]acetate,
N-{2-[3-(methanesulfonyl)phenyl]-1-methyl-1H-indol-5-yl}-N′-[(pyridin-4-yl)methyl]urea,
N-{2-[3-(2-methoxyethoxy)phenyl]-1-methyl-1H-indol-5-yl}-N′-[(pyridin-4-yl)methyl]urea,
N-[1-(2-methoxyethyl)-2-phenyl-1H-indol-5-yl]-N′-[(pyridin-4-yl)methyl]urea,
N-[1-methyl-2-(pyridin-2-yl)-1H-indol-5-yl]-N′-[(pyridin-4-yl)methyl]urea,
N-(1-methyl-2-phenyl-1H-indol-5-yl)-N′-[(pyridin-4-yl)methyl]urea,
N-{1-[(1,4-dioxan-2-yl)methyl]-2-phenyl-1H-indol-5-yl}-N′-[(pyridin-4-yl)methyl]urea,
N,N-dimethyl-2-phenyl-5-({[(pyridin-4-yl)methyl]carbamoyl}amino)-1H-indole-1-carboxamide,
N-[1-(2-methylpropyl)-1H-indazol-5-yl]-N′-[(pyridin-4-yl)methyl]urea,
N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N′-[(pyridin-4-yl)methyl]urea,
N-[(1,3-oxazol-5-yl)methyl]-N′-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea,
N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N′-[(1H-pyrazol-4-yl)methyl]urea,
N-[2-(2-butylphenyl) [1,2,4]triazolo[1,5-a]pyridin-6-yl]-N′-[(pyridin-4-yl)methyl]urea,
N-[2-(1-phenyl-TH-pyrrol-2-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]-N′-[(pyridin-4-yl)methyl]urea,
N-[2-(1-methyl-1H-pyrazol-5-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]-N′-[(pyridin-4-yl)methyl]urea,
N-[(pyridin-4-yl)methyl]-N′-{2-[2-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-6-yl}urea,
N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N′-[(pyridin-4-yl)methyl]urea,
N-(2-phenylpyrazolo[1,5-a]pyridin-6-yl)-N′-[(pyridin-4-yl)methyl]urea,
N-(2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)-N′-[(pyridin-4-yl)methyl]urea,
N-(3-methyl-2-phenylpyra

Assignees

• Daiichi Sankyo Co Ltd
• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Nakamura Tsuyoshi
• Akiu Mayuko
• Tsuji Takashi
• Tanaka Jun
• Terayama Koji
• Yokoyama Mika
• Pinkerton Anthony B
• Sessions Edward Hampton

Classifications

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/423

  condensed with carbocyclic rings · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/443

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title