NRF2 regulators

Patent metadata

Field	Value
Publication number	US-10272095-B2
Application number	US-201615735977-A
Country	US
Kind code	B2
Filing date	Jun 15, 2016
Priority date	Jun 15, 2015
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

Abstract

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators.

First claim

What is claimed is:

1. A compound of Formula (I)

wherein:
B is benzotriazolyl, phenyl, triazolopyridinyl, or —(CH 2 ) 2 triazolyl each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, —O—C 1-3 alkyl, CN, —(CH 2 ) 2 —O—(CH 2 ) 2 —OR 4 and halo;
D is —C(O)OH, —C(O)NHSO 2 CH 3 , —SO 2 NHC(O)CH 3 , 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl;
R 1 is independently hydrogen, C 1-3 alkyl, F, C 3-6 spirocycloalkyl, oxetane, or the two R 1 groups together with the carbon to which they are attached form a cyclopropyl group;
R 4 is hydrogen or C 1-3 alkyl;
A is tetrahydrobenzoxazepinyl, tetrahydrobenzazepinyl, tetrahydroimidazodiazepinyl, or tetrahydro-pyrido-oxazepinyl, each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, halo, CN, —OC 1-3 alkyl, —CH 2 —O—CH 3 , C 3-6 spirocycloalkyl, and OH;
n is 1 or 2;
or a pharmaceutically acceptable salt thereof.

2. A compound of Formula (II)

wherein:
B is benzotriazolyl, phenyl, triazolopyridinyl, or —(CH 2 ) 2 triazolyl each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, —O—C 1-3 alkyl, CN, —(CH 2 ) 2 —O—(CH 2 ) 2 —OR 4 and halo;
D is —C(O)OH, —C(O)NHSO 2 CH 3 , —SO 2 NHC(O)CH 3 , 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl;
R 1 is independently hydrogen, C 1-3 alkyl, F, C 3-6 spirocycloalkyl, oxetane, or the two R 1 groups together with the carbon to which they are attached form a cyclopropyl group;
R 2 is ═O or hydrogen;
R 4 is hydrogen or C 1-3 alkyl;
Linker is —CH 2 —, —O—C(O)—, —CH 2 —C(O)—, —C(O)—, —CH(CH 3 )—C(O)—, or —N(CH 3 )—C(O)—;
A is cyclohexyl, cyclopentyl, phenyl or decahydronapthalenyl; each of which is unsubstituted or independently substituted by 1, 2, or 3 substituents independently selected from C 1-3 alkyl, CN, and halo;
or A is C 4-5 alkyl which may be substituted by —OC 1-3 alkyl;
n is 1 or 2;
X is CH 2 or O;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein:
B is benzotriazolyl or —(CH 2 ) 2 triazolyl each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl and halo;
D is —C(O)OH;
R 1 is independently hydrogen or methyl or the two R 1 groups together with the carbon to which they are attached form a cyclopropyl group;
A is tetrahydrobenzoxazepinyl, tetrahydrobenzazepinyl, or tetrahydro-pyrido-oxazepinyl, each of which is unsubstituted or substituted by 1, 2, or 3 substituents chosen from: —C 1-3 alkyl, halo, CN, and —OC 1-3 alkyl; and
n is 1 or 2
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein
B is benzotriazolyl or phenyl each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, halo and CN;
D is —C(O)OH;
R 1 is independently hydrogen or C 1-3 alkyl;
A is tetrahydrobenzoxazepinyl, tetrahydrobenzazepinyl, tetrahydroimidazodiazepinyl, or tetrahydro-pyrido-oxazepinyl, each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, halo, CN, —OC 1-3 alkyl, —CH 2 —O—CH 3 , C 3-6 spirocycloalkyl, and OH; and
n is 1;
or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein
B is benzotriazolyl which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl;
D is —C(O)OH;
R 1 is independently hydrogen or C 1-3 alkyl;
A is tetrahydrobenzoxazepinyl which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, —OC 1-3 alkyl, CN and halo; and
n is 1;
or a pharmaceutically acceptable salt thereof.

6. The compound of claim 2 wherein:
B is benzotriazolyl or —(CH 2 ) 2 triazolyl each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl and halo;
D is —C(O)OH;
R 1 is independently hydrogen or methyl or the two R 1 groups together with the carbon to which they are attached form a cyclopropyl group;
R 2 is ═O or hydrogen;
Linker is —CH 2 —, —O—C(O)—, —CH(CH 3 )—C(O)—, or —N(CH 3 )—C(O)—;
A is cyclohexyl or cyclopentyl, each of which is unsubstituted or independently substituted by 1, 2, or 3 substituents independently selected from C 1-3 alkyl, CN, and halo;
n is 1; and
X is CH 2 or O;
or a pharmaceutically acceptable salt thereof.

7. The compound of claim 2 , wherein
B is benzotriazolyl or —(CH 2 ) 2 triazolyl each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl and —O—C 1-3 alkyl;
D is —C(O)OH;
R 1 is independently hydrogen;
R 2 is hydrogen;
Linker is —CH 2 —, —O—C(O)—, or —CH 2 —C(O)—;
A is cyclohexyl, phenyl or decahydronapthalenyl; each of which is unsubstituted or independently substituted by 1, 2, or 3 substituents independently selected from C 1-3 alkyl, CN, and halo;
or A is C 4-5 alkyl which is unsubstituted or substituted by —OC 1-3 alkyl;
n is 1; and
X is CH 2 ;
or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 , wherein
B is benzotriazolyl or —(CH 2 ) 2 triazolyl each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl and —O—C 1-3 alkyl;
D is —C(O)OH;
R 1 is independently hydrogen;
R 2 is ═O;
Linker is —CH 2 —, —O—C(O)—, or —CH 2 —C(O)—;
A is cyclohexyl, phenyl or decahydronapthalenyl; each of which is unsubstituted or independently substituted by 1, 2, or 3 substituents independently selected from C 1-3 alkyl, CN, and halo;
or A is C 4-5 alkyl which is unsubstituted or substituted by —OC 1-3 alkyl;
n is 1; and
X is CH 2 or O;
or a pharmaceutically acceptable salt thereof.

9. A compound which is:
3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-[1-(3,3-3-[(3aR,8bS)-1-(cyclohexyl)methyl)-2-oxo-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl]-3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;
3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-{1-[(4-ethylcyclohexyl)methyl]-2-oxo-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl}propanoic acid;
3-[(3aR,8bS)-1-(cyclohexylmethyl)-2-oxo-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl]-5-(1-ethyl-1H-1,2,3-triazol-4-yl)pentanoic acid;
3-[1-(decahydronaphthalen-2-ylmethyl)-2-oxo-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl]-3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;
3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-{2-oxo-1-[(4-propylcyclohexyl)methyl]-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl}propanoic acid;
3-{1-[(tert-butoxy)carbonyl]-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl}-3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;
3-[1-(2-cyclohexylacetyl)-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl]-3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;
3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-[1-(2-phenylpropanoyl)-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl]propanoic acid;
3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-[1-(2-phenylpropanoyl)-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl]propanoic acid;
3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-[1-(2-methylpentanoyl)-1H,2H,3H,3aH,4H,8bH-indeno[1,2-b]pyrrol-7-yl]propanoic acid;
3-{1-[2-(2

Assignees

• Glaxosmithkline Ip Dev Ltd
• Astex Therapeutics Ltd
• Glaxosmithkline Intellectual Propert Development Ltd

Inventors

• Kerns Jeffrey K
• Callahan James Francis
• Yan Hongxing
• Heightman Thomas Daniel
• Boehm Jeffrey Charles
• Woolford Alison Jo-Anne

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D403/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title