1-(cyclopent-2-en-1-yl)-3-(2-hydroxy-3-(arylsulfonyl)phenyl)urea derivatives as CXCR2 inhibitors

Patent metadata

Field	Value
Publication number	US-10106515-B2
Application number	US-201515314124-A
Country	US
Kind code	B2
Filing date	May 27, 2015
Priority date	May 29, 2014
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

The invention relates to 1-(3-sulfonylphenyl)-3-(cyclopent-2-en-1-yl)urea derivatives, and their use in treating or preventing diseases and conditions mediated by the CXCR2 receptor In addition, the invention relates to compositions containing the derivatives and processes for their preparation.

First claim

The invention claimed is:

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

wherein
R 1 is H, C 1-3 alkyl, C 1-3 haloalkyl or halo;
R 2 is H, C 1-3 alkyl, C 1-3 haloalkyl or halo;
R 3 is fluoro, chloro or cyano; and
R 4 is selected from the group consisting of:
a) C 1-6 alkyl optionally substituted by one or more substituents independently selected from the group consisting of: fluoro, C 1-3 alkoxy, C 1-3 fluoroalkyl, C 1-3 fluoroalkoxy and hydroxy;
b) —(CH 2 ) n —N(R 4a )(R 4b ); wherein
n is 0, 1 or 2;
the —(CH 2 ) n — linker is optionally substituted by one or more groups independently selected from the group consisting of fluoro and methyl optionally substituted by one or more deuterium; and
wherein R 4a and R 4b are independently C 1-3 alkyl, or R 4a and R 4b , together with the nitrogen to which they are attached, form a 4, 5 or 6-membered ring, which ring
i) optionally contains one additional ring-heteroatom selected from nitrogen and oxygen;
ii) may be saturated, or when the ring is a 5 or 6-membered, be unsaturated or aromatic;
iii) is optionally substituted by one or more substituents independently selected from C 1-3 alkyl optionally substituted by one or more substituent independently selected from the group consisting of deuterium, fluoro, C 1-3 fluoroalkyl, hydroxy, C 1-3 alkoxy, C 1-3 alkoxyC 1-3 alkyl and C 1-3 fluoroalkoxy; or
iv) is ortho-fused to a further 5 or 6-membered ring which further ring is saturated, unsaturated or aromatic, which further ring optionally contains one additional ring-heteroatom selected from nitrogen and oxygen, and which further ring is optionally independently substituted by one or more fluoro or methyl substituents;

c) —(CH 2 ) p -heteroaryl; wherein
p is 1 or 2;
the —(CH 2 ) p — linker is optionally substituted by one or more groups independently selected from fluoro and methyl optionally substituted by one or more deuterium; the heteroaryl is 5 or 6-membered and is attached to the —(CH 2 ) p — via a ring carbon atom; and
wherein the heteroaryl is optionally substituted by one or more substituents independently selected from the group consisting of C 1-3 alkyl, fluoro, C 1-3 fluoroalkyl; C 1-3 alkoxy, C 1-3 alkoxyC 1-3 alkyl and C 1-3 fluoroalkoxy, or wherein two substituents on adjacent ring-atoms, together with the interconnecting atoms form a further 5 or 6-membered ring ortho-fused to the heteroaryl group; which further ring is saturated, unsaturated or aromatic, and which further ring contains one additional heteroatom selected from nitrogen and oxygen; and which further ring is independently substituted by one or more fluoro or methyl substituents;

d) —(CH 2 ) q -heterocyclyl; wherein
q is 0, 1 or 2;
the —(CH 2 ) q — linker is optionally substituted by one or more groups independently selected from fluoro and methyl optionally substituted by one or more deuterium;
the heterocyclyl group is 3, 4, 5, or 6-membered and is attached to the —(CH 2 ) q — via a ring carbon atom;
the heterocyclyl is saturated or unsaturated; and
wherein the heterocyclyl group is optionally substituted by one or more substituents independently selected from the group consisting of deuterium, C 1-3 alkyl optionally substituted by one or more deuterium, fluoro, C 1-3 fluoroalkyl, hydroxy, C 1-3 alkoxy, C 1-3 alkoxyC 1-3 alkyl, C 1-3 fluoroalkoxy, C 3-6 cycloalkyl and —(CH 2 ) S NR 4c R 4d ; or two substituents on the heterocyclyl group together with the interconnecting atom(s), foam a further 5 or 6-membered ring which further ring is saturated, unsaturated or aromatic when the further ring is ortho-fused; and which further ring optionally contains one additional heteroatom selected from nitrogen and oxygen, and which further ring is optionally independently substituted by one or more fluoro or methyl substituents; wherein s is 0 or 1, and wherein R 4c and R 4d are independently C 1-3 alkyl, or R 4c and R 4d , together with the nitrogen to which they are attached, form a 4, 5 or 6-membered saturated ring which ring is optionally substituted by one or more fluoro substituent; and

e) —(CH 2 ) r —C 3-6 cycloalkyl; wherein
r is 0, 1 or 2;
the —(CH 2 ) r — linker is optionally substituted by one or more groups
independently selected from fluoro and methyl optionally substituted by one or mote deuterium; and
wherein the C 3-6 cycloalkyl group is optionally substituted by one or more substituents independently selected from the group consisting of C 1-3 alkyl optionally substituted by one or more deuterium, fluoro, C 1-3 fluoroalkyl, hydroxy, C 1-3 alkoxy, C 1-3 alkoxyC 1-3 alkyl, C 1-3 fluoroalkoxy and —(CH 2 ) t NR 4e R 4f , or wherein two substituents on the cycloalkyl group together with the interconnecting atom(s) form a further 5 or 6-membered ring which further ring is saturated, unsaturated or aromatic when the further ring is ortho-fused, and which further ring optionally contains one heteroatom selected from nitrogen and oxygen, and which further ring is optionally independently substituted by one or more fluoro or methyl substituents; wherein t is 0 or 1, and wherein R 4e and R 4f are independently C 1-3 alkyl, or R 4e and R 4f , together with the nitrogen to which they are attached, form a 4, 5 or 6-membered saturated ring which ring is optionally substituted by one or more fluoro substituent.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is methyl, fluoro or chloro.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is H, fluoro or chloro.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is chloro or cyano.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 4 is selected from the group consisting of:
a) C 1-6 alkyl optionally substituted by one or more substituents independently selected from the group consisting of: fluoro, C 1-3 alkoxy, C 1-3 fluoroalkyl, C 1-3 fluoroalkoxy and hydroxy;
d) —(CH 2 ) q -heterocyclyl; wherein
q is 0, 1 or 2;
the —(CH 2 ) q — linker is optionally substituted by one or more groups independently selected from fluoro and methyl optionally substituted by one or more deuterium;
the heterocyclyl group is 3, 4, 5 or 6-membered and is attached to the —(CH 2 ) q — via a ring carbon atom;
the heterocyclyl is saturated or unsaturated; and
wherein the heterocyclyl group is optionally substituted by one or more substituents independently selected from the group consisting of deuterium, C 1-3 alkyl optionally substituted by one or more deuterium, fluoro, C 1-3 fluoroalkyl, hydroxy, C 1-3 alkoxy, C 1-3 alkoxyC 1-3 alkyl, C 1-3 fluoroalkoxy, C 3-6 cycloalkyl and —(CH 2 ) S NR 4c R 4d , or two substituents on the heterocyclyl group together with the interconnecting atom(s), form a further 5 or 6-membered ring which further ring is saturated, unsaturated or aromatic when the further ring is ortho-fused, and which further ring optionally contains one additional heteroatom selected from nitrogen and oxygen, and which further ring is optionally independently substituted by one or more fluoro or methyl substituents, wherein s is 0 or 1, and wherein R 4c and R 4d are independently C 1-3 alkyl, or R 4c and R 4d , together with the nitrogen to which they are attached, form a 4, 5 or 6-membered saturated ring which ring is optionally substituted by one or more fluoro substituent; and

e) —(CH 2 ) r —C 3-6 cycloalkyl; wherein
r is 0, 1, or 2;
the —(CH 2 ) r — linker is optionally substituted by independently selected from fluoro and methyl optionally subtituted one or

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Chen Weichun
• Igboko Ebere F
• Lin Xichen
• Lu Hongfu
• Ren Feng
• Wren Paul Bryan
• Xu Zhongmiao
• Yang Ting
• Zhu Lingdong

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title