Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain

Patent metadata

Field	Value
Publication number	US-10889589-B2
Application number	US-201916415575-A
Country	US
Kind code	B2
Filing date	May 17, 2019
Priority date	Nov 13, 2012
Publication date	Jan 12, 2021
Grant date	Jan 12, 2021

Abstract

Compounds of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

First claim

What is claimed is:

1. A compound of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
X is O;
Ring A is formula A-1

Y is H, halogen, or (1-3C alkoxy)(1-6C)alkyl;
R a , R b and R c are H, halogen, (1-3C)alkoxy;
B is NR 1 , a bond CRdRe;
D is NR 1 a bond or CR f R g ;
E is NR 1 , a bond or CR h R i ,
F is CR j R k ;
provided that the ring formed by B, D, E, and F together with the atoms to which they are attached contains at least five atoms;
R 1 is (1-6C)alkyl [optionally substituted with one to five fluoros], (1-6C)cycloalkyl [optionally substituted with one to five fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros], (1-6C)alkylC(═O)— or (1-6C alkoxy)C═O—;
R d , R e , R f , R g , R h , R i , R j and R k are independently H, OH, (1-6C)alkyl [optionally substituted with one to five fluoros](1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros], (1-6C)alkoxy [optionally substituted with one to five fluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionally substituted with one to five fluoros],
or one of a pair of R d and R e , or R f and R g , or R h and R i , or R j and R k , together with the carbon atom to which they are attached form a (3-6C)cycloalkyl ring,
and wherein only one of R d and R e can be OH and neither is OH if B is connected to a heteroatom, and only one of R h and R i can be OH and neither is OH if E is connected to a heteroatom;
Ring C is formula C-1

R 3 is Ar 2 ;
Ar 2 is phenyl;
R 4 is (1-6C)alkyl, hetCyc 2 (1-6C)alkoxy, hetAr 4 , aminocarbonyl, or hetAr 5 ;
hetCyc 2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-6C)alkyl;
hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from (1-6C)alkyl and (1-6C)alkoxy;
hetAr 5 is:

where R z is (1-3C)alkyl (optionally substituted with 1-3 fluoros), wherein said hetAr 5 group is optionally further substituted with o (1-3C)alkyl;
and
R 5 is (1-6C)alkyl.

2. The compound according to claim 1 , wherein zero to four of R d , R e , R f , R g , R h , R i , R j and R k are independently H, OH, or (1-6C)alkyl [optionally substituted with one to five fluoros],
or one of a pair of R d and R e , or R f and R g , or R h and R i , or R j and R k , together with the carbon atom to which they are attached form a (3-6C)cycloalkyl ring.

3. The compound according to claim 2 , wherein zero to two of R d , R e , R f , R g , R h , R i , R j and R k are independently H, OH, or (1-6C)alkyl [optionally substituted with one to five fluoros],
or one of a pair of R d and R e , or R f and R g , or R h and R i , or R j and R k , together with the carbon atom to which they are attached form a (3-6C)cycloalkyl ring.

4. The compound according to claim 3 , wherein zero to two of R d , R e , R f , R g , R h , R i , R j and R k are independently OH, methyl, methoxy, CH 3 OCH 2 CH 2 O—, or cyclopropyl, or one of a pair of R d and R e , or R f and R g , or R h and R i , or R j and R k , together with the carbon atom to which they are attached form a (3-6C)cycloalkylring.

5. The compound according to claim 4 , wherein B is a bond or CR d R e , D is a bond or CR f R g , E is a bond or CR h R i , and F is CR j R k , provided that the ring formed by B, D, E, and F together with the atoms to which they are attached contains at least five atoms.

6. The compound according to claim 4 , wherein B is a bond or CR d R e , D is NR 1 , a bond or CR f R g , E is NR 1 , a bond or CR h R i , and F is CR j R k , provided that the ring formed by B, D, E, and F together with the atoms to which they are attached contains at least five atoms.

7. The compound according to claim 4 , wherein B is a NR 1 , D is a bond or CR f R g , E is a bond or CR h R i , and F is CR j R k , provided that the ring formed by B, D, E, and F together with the atoms to which they are attached contains at least five atoms.

8. The compound according to claim 4 , wherein B is a bond or CR d R e , D is NR 1 , E is a bond or CR h R i , and F is CR j R k , provided that the ring formed by B, D, E, and F together with the atoms to which they are attached contains at least five atoms.

9. The compound according to claim 5 , wherein Y is H.

10. The compound according to claim 9 , wherein R 4 is hetAr 4 or hetAr 5 .

11. The compound according to claim 5 , wherein Y is (1-3C alkoxy)(1-6C)alkyl.

12. The compound according to claim 11 , wherein R 4 is hetAr 4 or hetAr 5 .

13. The compound according to claim 5 , wherein Y is halogen.

14. The compound according to claim 13 , wherein R 4 is hetAr 4 or hetAr 5 .

15. The compound according to claim 6 , wherein Y is H.

16. The compound according to claim 15 , wherein R 4 is hetAr 4 or hetAr 5 .

17. The compound according to claim 6 , wherein Y is (1-3C alkoxy)(1-6C)alkyl.

18. The compound according to claim 17 , wherein R 4 is hetAr 4 or hetAr 5 .

19. The compound according to claim 6 wherein Y is halogen.

20. The compound according to claim 19 , wherein R 4 is hetAr 4 or hetAr 5 .

21. The compound according to claim 7 , wherein Y is H.

22. The compound according to claim 21 , wherein R 4 is hetAr 4 or hetAr 5 .

23. The compound according to claim 7 , wherein Y is (1-3C alkoxy)(1-6C)alkyl.

24. The compound according to claim 23 , wherein R 4 is hetAr 4 or hetAr 5 .

25. The compound according to claim 7 , wherein Y is halogen.

26. The compound according to claim 25 , wherein R 4 is hetAr 4 or hetAr 5 .

27. The compound according to claim 8 , wherein Y is H.

28. The compound according to claim 27 , wherein R 4 is hetAr 4 or hetAr 5 .

29. The compound according to claim 8 , wherein Y is (1-3C alkoxy)(1-6C)alkyl.

30. The compound according to claim 29 , wherein R 4 is hetAr 4 or hetAr 5 .

31. The compound according to claim 8 , wherein Y is halogen.

32. The compound according to claim 31 , wherein R 4 is hetAr 4 or hetAr 5 .

33. The compound according to claim 1 , selected from

Ex. #
Structure

1

Assignees

• Array Biopharma Inc

Inventors

• Allen Shelley
• Andrews Steven Wade
• Blake James F
• Brandhuber Barbara J
• Haas Julia
• Jiang Yutong
• Kercher Timothy
• Kolakowski Gabrielle R
• Thomas Allen A
• Winski Shannon L

Classifications

• C07D491/048 Primary

  the oxygen-containing ring being five-membered · CPC title

• C07D453/02

  containing not further condensed quinuclidine ring systems · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title