IP Library › Granted Patent US 10,702,498
Granted Patent B2
US 10,702,498 · App. 15/743,079 · Granted Jul 7, 2020

MU opioid receptor modulators

Inventors: Brian K. Shoichet (Kentfield, CA); Henry Lin (Dresher, PA); Peter Gmeiner (Buckenhof, DE); Aashish Manglik (Menlo Park, CA); Brian Kobilka (Palo Alto, CA); Bryan L. Roth (Durham, NC); Daniela Gisela Dengler (Erlangen, DE)
Assignees: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA; FRIEDRICH-ALEXANDER-UNIVERSITAT ERLANGEN-NÜRNBERG; THE BOARD OF TRUSTEES OFTHE LELAND STANFORD JUNIOR UNIVERSITY; THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
A61K31/381A61K31/165A61K31/17A61P25/36C07C275/24C07C275/26C07D207/452C07D233/16C07D249/04C07D295/125C07D333/16C07D333/20C07D333/58C07D401/12C07D409/12C07D471/04C07D495/04C07D498/18C07C2602/08
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Quick Facts
Patent No.
US 10,702,498
App. No.
15/743,079
Granted
Jul 7, 2020
Kind
B2
Abstract

Described herein, inter alia, are compositions and methods for modulating mu opioid receptor activity.

Claims (84)

1. A compound having the formula:

wherein,

W is O or S;

Ring A is independently R 3 -substituted or unsubstituted phenyl or R 3 -substituted or unsubstituted pyridinyl;

Ring B is independently R 4 -substituted or unsubstituted thienyl, R 4 -substituted or unsubstituted phenyl, R 4 -substituted or unsubstituted benzothienyl, R 4 -substituted or unsubstituted naphthyl, R 4 -substituted or unsubstituted benzofuranyl, R 4 -substituted or unsubstituted furanyl, R 4 -substituted or unsubstituted pyrrolyl-2,5-dione, or R 4 -substituted or unsubstituted 2,3-dihydro-1H-indenyl;

L 1 is independently a bond or an unsubstituted (C 1 -C 5 ) alkylene;

L 2 is an unsubstituted (C 1 -C 5 ) alkylene;

R 1 and R 2 are independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO2NH 2 , —NHNH 2 , —ONH 2 , NHC═(O)NHNH 2 , NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , substituted or unsubstituted (C 1 -C 5 ) alkyl, substituted or unsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted (C 3 -C 6 ) cycloalkyl, or substituted or unsubstituted 3 to 6 membered heterocycloalkyl; or R 1 and R 2 may optionally be joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl;

L 1 and R 1 may optionally be joined to form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl;

L 1 and R 2 may optionally be joined to form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl;

L 3 is —N(R 6 )—;

R 3 is independently hydrogen, —CX 3 , CHX 2 , CH 2 X, —CN, —SO n R 10 , —SO v NR 7 R 8 , —NHNR 7 R 8 , —ONR 7 R 8 , —NHC═(O)NHNR 7 R 8 , —NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O) —OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)OR 9 , —NR 7 OR 9 , —CHX 2 , —CH 2 X, —OCX 3 , —OCHX 2 , substituted or unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; or two adjacent R 3 substituents may optionally be joined to form an unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;

R 4 is independently hydrogen, halogen, —CX a 3 , —CN, —SO n1 R 14 , —SO v1 NR 11 R 12 , —NHNR 11 R 12 , —ONR 11 R 12 , —NHC═(O)NHNR 11 R 12 , —NHC═(O)NR 11 R 12 , —N(O) m1 , —NR 11 R 12 , —C(O)R 13 , —C(O) —OR 13 , α, —OR 14 , —NR 11 SO 2 R 14 , —NR 14 C═(O)R 13 , —NR 11 C(O)OR 13 , —NR 11 OR 13 , —CHX 2 , —CH 2 X, —OCX 3 , —OCHX 2 , oxo, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; or two adjacent R 4 substituents may optionally be joined to form an unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;

R 5 is independently hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CH 2 F, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl;

R 6 is hydrogen, —CF 3 , —CN, —COOH, —CONH 2 , —CHF 2 , —CH 2 F, substituted or unsubstituted (C 1 -C 5 ) alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl

R 10 is independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 7 and R 8 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R 7 and R 8 are independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted heteroaryl,

R 9 is independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 11 , R 12 , R 13 , and R 14 are independently hydrogen, halogen,

—CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 11 and R 12 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

m, m1, v, and v1 are independently 1 or 2;

n and n1 are independently an integer from 0 to 4; and

X and X a are independently —Cl, —Br, —I, or —F.

2. The compound of claim 1 , wherein Ring A is R 3 -substituted or unsubstituted phenyl.

3. The compound of claim 1 , wherein R 3 is independently hydrogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , substituted or unsubstituted (C 1 -C 5 ) alkyl, or unsubstituted 2 to 5 membered heteroalkyl.

4. The compound of claim 1 , having the formula:

wherein

R 3 is, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , or substituted or unsubstituted (C 1 -C 5 ) alkyl, or unsubstituted 2 to 5 membered heteroalkyl.

5. The compound of claim 1 , having the formula:

wherein

R 3A , R 3B , and R 3C are independently

CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, OCF 3 , —OCHF 2 , substituted or unsubstituted (C 1 -C 5 ) alkyl, or unsubstituted 2 to 5 membered heteroalkyl;

R 3D is hydrogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , substituted or unsubstituted (C 1 -C 5 ) alkyl, or unsubstituted 2 to 5 membered heteroalkyl; and

R 3E is hydrogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, OCF 3 , —OCHF 2 , substituted or unsubstituted (C 1 -C 5 ) alkyl, or unsubstituted 2 to 5 membered heteroalkyl.

6. The compound of claim 5 , wherein R 3D and R 3E are independently unsubstituted (C 1 -C 3 ) alkyl.

7. The compound of claim 5 , wherein R 3D and R 3E are independently unsubstituted methyl.

8. The compound of claim 5 , having the formula:

9. The compound of claim 1 , wherein

Ring A is unsubstituted phenyl and Ring B is unsubstituted thienyl;

Ring A is para-hydroxy substituted phenyl and Ring B is unsubstituted thienyl;

Ring A is para-hydroxy substituted phenyl and Ring B is unsubstituted phenyl;

Ring A is para-hydroxy substituted phenyl and Ring B is unsubstituted benzothienyl;

Ring A is para-hydroxy substituted phenyl and Ring B is para-methyl substituted phenyl;

Ring A is 2-hydroxy pyridin-4-yl and Ring B is unsubstituted thienyl;

Ring A is 2-hydroxy pyridin-5-yl and Ring B is unsubstituted thienyl;

Ring A is para-hydroxy substituted phenyl and Ring B is unsubstituted napththyl; or

Ring A is para-hydroxy substituted phenyl and Ring B is unsubstituted 2,3-dihydro-1H-indenyl.

10. The compound of claim 1 , wherein Ring B is unsubstituted phenyl.

11. The compound of claim 1 , wherein R 1 is unsubstituted (C 1 -C 2 ) alkyl.

12. The compound of claim 1 , wherein R 1 is independently hydrogen, substituted or unsubstituted (C 1 -C 5 ) alkyl, substituted or unsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted (C 3 -C 6 ) cycloalkyl, or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

13. The compound of claim 1 , wherein R 2 is unsubstituted (C 1 -C 2 ) alkyl.

14. The compound of claim 1 , wherein R 2 is independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , substituted or unsubstituted (C 1 -C 5 ) alkyl, substituted or unsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted (C 3 -C 6 ) cycloalkyl, or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

15. The compound of claim 1 , wherein R 5 is hydrogen, substituted or unsubstituted (C 1 -C 5 ) alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl.

16. The compound of claim 1 , wherein W is O.

17. The compound of claim 1 , wherein R 6 is hydrogen, substituted B or unsubstituted (C 1 -C 5 ) alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl.

18. The compound of claim 1 , wherein L 2 is unsubstituted (C 1 -C 3 ) alkylene.

19. The compound of claim 1 , having the formula:

wherein d is an integer between 0 and 3.

20. The compound of claim 1 , having the formula:

wherein d is an integer between 0 and 3.

21. The compound of claim 1 , having the formula:

wherein:

Ring B is a substituted or unsubstituted phenyl or substituted or unsubstituted thienyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl-2,5-dione, substituted or unsubstituted 2,3-dihydro-1H-indenyl, substituted or unsubstituted 1H-1,2,3-triazolyl, or substituted or unsubstituted pyrazolo[1,5-a]pyridinyl;

R 3 is —OH, or —NH 2 ;

R 99a is substituted or unsubstituted (C 1 -C 3 ) alkyl; and

R 99b is hydrogen or substituted or unsubstituted (C 1 -C 3 ) alkyl.

22. The compound of claim 21 , wherein Ring B is an unsubstituted 3-thienyl.

23. The compound of claim 1 , having the formula:

wherein:

Ring B is a substituted or unsubstituted phenyl or substituted or unsubstituted thienyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl-2,5-dione, substituted or unsubstituted 2,3-dihydro-1H-indenyl, substituted or unsubstituted 1H-1,2,3-triazolyl, or substituted or unsubstituted pyrazolo[1,5-a]pyridinyl;

R 3A is —OH, or —NH 2 ;

R 3D is unsubstituted (C 1 -C 2 ) alkyl;

R 3E is unsubstituted (CL-C2) alkyl;

R 99a is hydrogen or substituted or unsubstituted (C 1 -C 3 ) alkyl; and

R 99b is substituted or unsubstituted (C 1 -C 3 ) alkyl.

24. The compound of claim 1 , having the formula:

25. The compound of claim 1 , having the formula:

26. A compound of claim 1 , having a higher binding affinity for the mu opioid receptor than for the kappa opioid receptor, wherein ring A is a substituted or unsubstituted phenyl.

27. A compound of claim 1 , having a higher binding affinity for the mu opioid receptor than for the delta opioid receptor, wherein ring A is a substituted or unsubstituted phenyl.

28. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .

Assignments (1)
CONFIRMATORY LICENSE Recorded Feb 1, 2019
From: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 048228/0730 →
Continuity (2)
Provisional Application 62190390 · Jul 9, 2015
Related Publication 20190076398A1 · Mar 14, 2019