Multicyclic compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9351954-B2
Application number	US-201414205859-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Dec 4, 2009
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

Provided herein are multicyclic compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. For example, disclosed herein are compounds having formula (IIa) shown below, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the variables are defined herein. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.

First claim

What is claimed:

1. A compound of formula (IIa):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
(i) R 1 and R 3 together with the atoms to which they are attached form 5-membered heterocyclyl, and R 4 is hydrogen or C 1 -C 6 alkyl; or (ii) R 3 and R 4 together form a double bond and together with R 1 and the atoms to which they are attached form a 5-membered heteroaryl;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 5 is hydrogen or C 1 -C 6 alkyl;
R 6 and R 7 are each independently (i) hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl C 1 -C 6 alkyl, 6- to 10-membered aryl, or 6- to 10-membered C 1 -C 6 aralkyl; or (ii) —(CH 2 ) p —R 11 , wherein R 11 is CF 3 , CN, nitro, amino, hydroxyl, C 3 -C 7 cycloalkoxyl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl;
m is 0, 1, or 2;
n is 0, 1, or 2; and
each occurrence of p is independently 0, 1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0.

3. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, CF 3 , ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

5. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is hydrogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 and R 3 together with the atoms to which they are attached form a pyrrolidinyl; and R 4 is hydrogen or C 1 -C 6 alkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 4 together form a double bond and together with R 1 and the atoms to which they are attached form an imidazoyl, pyrazolyl, or thiazolyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 and R 3 together with the atoms to which they are attached form a 5-membered heterocyclyl; and R 4 is hydrogen or C 1 -C 6 alkyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is hydrogen.

10. The compound of claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is hydrogen.

11. The compound of claim 10 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is hydrogen or methyl.

12. The compound of claim 11 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is hydrogen.

13. The compound of claim 11 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, CF 3 , ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

14. The compound of claim 13 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, or CF 3 .

15. The compound of claim 14 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0.

16. The compound of claim 15 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.

17. The compound of claim 16 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 1 together with the atoms to which they are attached form a pyrrolidinyl.

18. The compound of claim 8 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 8 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 8 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 8 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 4 together form a double bond and together with R 1 and the atoms to which they are attached form a 5-membered heteroaryl.

23. The compound of claim 22 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is hydrogen.

24. The compound of claim 23 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is hydrogen or methyl.

25. The compound of claim 24 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, CF 3 , ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

26. The compound of claim 25 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, or CF 3 .

27. The compound of claim 26 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0.

28. The compound of claim 27 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.

29. The compound of claim 28 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 4 together form a double bond and together with R 1 and the atoms to which they are attached form an imidazoyl, pyrazolyl, or thiazolyl.

30. The compound of claim 22 , wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

31. The compound of claim 22 , wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

32. The compound of claim 22 , wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

33. The compound of claim 22 , wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

34. The compound of claim 22 , wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

Assignees

• Sunovion Pharmaceuticals Inc
• Pgi Drug Discovery Llc

Inventors

• Shao Liming
• Campbell John Emmerson
• Hewitt Michael Charles
• Campbell Una
• Hanania Taleen G

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title