IP Library › Granted Patent US 11,053,251
Granted Patent B2
US 11,053,251 · App. 16/751,092 · Granted Jul 6, 2021

GPR35 modulators

Inventor: Robert Higuchi (Solana Beach, CA)
Assignee: Prometheus Biosciences, Inc.
C07D487/04A61P1/00
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Quick Facts
Patent No.
US 11,053,251
App. No.
16/751,092
Granted
Jul 6, 2021
Kind
B2
Abstract

Described herein are GPR35 modulators and methods of using these compounds in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

Claims (40)

1. A compound having the structure of Formula (I″):

wherein:

R 1 is —CH 2 R 4 , —CN, —B(OH) 2 , —N(R 10 ) 2 , —NR 10 C(O)R 9 , —C(O)OH, —CH 2 C(O)OH, —C(O)N(R 10 ) 2 , —C(O)NHS(O) 2 N(R 10 ) 2 , —C 1-6 alkyl-OH, C 3-8 cycloalkyl,

or a 5- or 6-membered heteroaryl optionally substituted with one, two, or three R 8 groups;

R 2 is H, —OH, —N(R 10 ) 2 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —O—C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl;

each R 3 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —NO 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

R 4 is R 6

each R 5 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)NHS(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-R 9 , —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , —C 1-6 alkyl-C(O)OR 10 , C 2-6 alkenyl, —C 2-6 alkenyl-C(O)OR 10 , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkyl-OH, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, and C 2-9 heteroaryl; wherein C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, —C(O)OR 10 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and C 2-9 heterocycloalkyl; and wherein C 2-9 heterocycloalkyl and —C 1-6 alkyl-C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups independently selected from halogen, —C(O)OR 10 , C 1-6 alkyl, C 1-6 haloalkyl, and oxo;

R 6 is —C(O)OR 7 , —C(O)NHS(O) 2 N(R 10 ) 2 ,

R 7 is independently selected from H and C 1-6 alkyl;

each R 8 is independently selected from halogen, —OH, —OR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)NHS(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , —C 1-6 alkyl-C(O)OR 10 , C 1-6 haloalkyl, C 1-6 haloalkyl-OH, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, and C 1-9 heteroaryl; wherein phenyl, —C 1-6 alkyl-phenyl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and C 2-9 heterocycloalkyl; and wherein C 2-9 heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and oxo;

each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —N(R 11 )C(O)R 12 , —C(O)R 12 , and —C(O)OR 12 ;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, —N(R 11 ) 2 , and —C(O)OR 12 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl;

each R 13 is independently selected from C 1-6 alkyl;

m is 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

p is 0, 1, 2, 3, 4, or 5; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is

3. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2.

4. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 5 is independently selected from halogen, —OH, —OR 9 , —N(R 10 ) 2 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)NHS(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , —C 1-6 alkyl-C(O)OR 10 , C 1-6 haloalkyl, C 1-6 haloalkyl-OH, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, and C 1-9 heteroaryl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 5 is independently selected from halogen, —OH, —OR 9 , —N(R 10 ) 2 , —C(O)NHS(O) 2 N(R 10 ) 2 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , C 1-6 alkyl, —C 1-6 alkyl-C(O)OR 10 , and C 1-6 heteroaryl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 5 is independently selected from halogen, —OH, —OR 9 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , C 1-6 alkyl, —C 1-6 alkyl-C(O)OR 10 , and

7. The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 5 is independently selected from halogen, —OH, —C(O)OR 10 .

8. The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 5 is independently selected from halogen, —OH, —OR 9 and —C 1-6 alkyl-C(O)OR 10 .

9. The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is C 1-6 alkyl optionally substituted with —C(O)OR 12 .

10. The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 10 is independently selected from H and C 1-6 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a 5- or 6-membered heteroaryl optionally substituted with one, two, or three R 8 groups.

12. The compound of claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a 5-membered heteroaryl optionally substituted with one or two R 8 groups, wherein the 5-membered heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, tetrazolyl, and isoxazolyl.

13. The compound of claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a 6-membered heteroaryl optionally substituted with one or two R 8 groups, wherein the 6-membered heteroaryl is selected from pyridinyl and pyrimidinyl.

14. The compound of claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is independently selected from halogen, —C(O)OR 10 , C 1-6 alkyl, and —C 1-6 alkyl-C(O)OR 10 .

15. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H, —OH, —N(R 10 ) 2 , or —O—C 1-6 alkyl.

16. The compound of claim 15 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is —OCH 2 CH 3 .

17. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

18. A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 1, 2020
From: HIGUCHI, ROBERT
To: PROMETHEUS BIOSCIENCES, INC.
Reel/Frame 053665/0506 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 4, 2020
From: HIGUCHI, ROBERT
To: PROMETHEUS BIOSCIENCES, INC.
Reel/Frame 054511/0584 →