IP Library › Patent Application 15137327

Patent Application

App. No. 15/137,327

SUBSTITUTED XANTHINES AND METHODS OF USE THEREOF

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Patent No.: US None
App. No.: 15/137,327

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Abstract

Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.

Claims (64)

1 . A method of treating a TRPC5 mediated disorder in a subject, the method comprising administering to the subject a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1-4 R 5 ;

R 2 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, halo, C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyloxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 7 -C 16 arylalkoxy, amino, C 1 -C 6 akylamino, C 2 -C 12 dialkylamino, —S—, —S—C 1 -C 6 alkyl, —S(O)—, —S(O) 2 —, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, wherein each of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyloxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 7 -C 16 arylalkoxy, amino, C 1 -C 6 akylamino, C 2 -C 12 dialkylamino, —S—, —S—C 1 -C 6 alkyl, —S(O)—, —S(O) 2 —, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted with 1-3 R 6 ;

R 3 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 hydroxyalkyl, or C 1 -C 6 alkoxy, each of which is optionally substituted with 1-4 R 7 ;

R 4 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1-4 R 8 ;

R 5 , R 6 , R 7 , and R 8 are each independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, C 2 -C 12 dialkylamino, cyano, nitro, amido, C 1 -C 6 alkylamido, C 2 -C 12 dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, heterocycloalkyl, or heteroaryl, wherein each of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, C 2 -C 12 dialkylamino, amido, C 1 -C 6 alkylamido, C 2 -C 12 dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R 9 ; and

each R 9 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 4 -C 10 cycloalkylalkyl, heterocycloalkyl-C 1 -C 6 alkyl, C 7 -C 16 arylalkyl, heteroaryl-C 1 -C 6 alkyl, halo, hydroxyl, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, C 7 -C 16 arylalkoxy, C 2 -C 8 alkoxyalkoxyl, amino, C 1 -C 6 akylamino, C 2 -C 12 dialkylamino, C 1 -C 6 akyl-amino-C 1 -C 6 akyl, C 1 -C 6 akyl-amino-C 2 -C 12 dialkyl, —S—, —S—C 1 -C 6 alkyl, —S(O) 2 —C 1 -C 6 alkyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, —C(O)—C 6 -C 10 aryl, —NHC(O)—C 6 -C 10 aryl, —C(O)NH—C 6 -C 10 aryl, —C(O)OH, —C(O)O—C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkyl acyl, nitro, or cyano; to thereby treat the subject.

2 . The method of claim 1 , wherein the TRPC5 mediated disorder is selected from the group consisting of: a neuropsychiatric disorder, a neurodegenerative disorder, nephropathy, and seizure disorder.

3 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl.

4 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl and R 5 is independently C 6 -C 10 aryl or heteroaryl.

5 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 6 -C 10 aryl, C 6 -C 10 aryloxy or heteroaryloxy.

6 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 6 -C 10 aryloxy.

7 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 alkoxy.

8 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 alkyl.

9 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is or C 1 -C 6 akylamino.

10 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —S(O)— or —S(O) 2 —.

11 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1 -C 6 alkyl, C 2 -C 6 hydroxyalkyl, or C 1 -C 6 alkoxy.

12 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydroxypropyl.

13 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 6 alkyl.

14 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is independently C 6 -C 10 aryl, heteroaryl, C 3 -C 7 cycloalkyl, or heterocycloalkyl.

15 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, pyridyl, thiazolyl, pyrimidinyl, or oxazolyl.

16 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl.

17 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is pyridyl.

18 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is thiazolyl.

19 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or heterocycloalkyl.

20 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 6 -C 10 aryl or C 6 -C 10 aryloxy, and R 6 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 or haloalkoxy.

21 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 6 -C 10 aryloxy and R 6 is independently C 1 -C 6 haloalkyl or C 1 -C 6 or haloalkoxy.

22 . The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 6 -C 10 aryloxy and R 6 is —CF 3 or —OCF 3 .

23 . A compound of Formula I(a):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1-4 R 5 ;

R 3 is C 2 -C 6 hydroxyalkyl or C 1 -C 6 heteroalkyl;

R 4 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1-4 R 8 ;

R 5 , R 6 , and R 8 are each independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, C 2 -C 12 dialkylamino, cyano, nitro, amido, C 1 -C 6 alkylamido, C 2 -C 12 dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, heterocycloalkyl, or heteroaryl, each of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, C 2 -C 12 dialkylamino, amido, C 1 -C 6 alkylamido, C 2 -C 12 dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R 9 ; and

24 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl and R 5 is phenyl, pyridyl, thiazolyl, pyrimidinyl, or oxazolyl, e.g., phenyl, pyridiyl, or thiazolyl.

25 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 6 -C 10 aryl or C 6 -C 10 aryloxy, and R 6 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 or haloalkoxy.

26 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 2 -C 6 hydroxyalkyl.

27 . A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl, thiazolyl, pyrimidinyl, or oxazolyl;

R 3 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 hydroxyalkyl, or C 1 -C 6 alkoxy, each of which is optionally substituted with 1-4 R 7 ;

R 4 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1-4 R 8 ;

R 6 , R 7 , and R 8 are each independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, C 2 -C 12 dialkylamino, cyano, nitro, amido, C 1 -C 6 alkylamido, C 2 -C 12 dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, heterocycloalkyl, or heteroaryl, wherein each of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, C 2 -C 12 dialkylamino, amido, C 1 -C 6 alkylamido, C 2 -C 12 dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R 9 ;

each R a is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo;

n is 1 or 2; and

m is 1, 2, or 3.

28 . The compound of claim 27 , or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl or thiazolyl.

29 . The compound of claim 27 , wherein R 3 is hydroxypropyl.

30 . A compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R 2 is C 1 -C 6 alkoxy or C 6 -C 10 aryloxy substituted with 1-3 R 6 ;

R 3 is C 1 -C 6 heteroalkyl or C 2 -C 6 hydroxyalkyl;

R 4 is C 1 -C 6 alkyl;

R 6 is independently C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or C 1 -C 6 alkoxy;

each R a is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo;

n is 1 or 2; and

m is 1, 2, or 3.

31 . The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydroxypropyl.

32 . The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R a is independently chloro, fluoro, or methyl.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 26, 2016

From: CHENARD, BERTRAND L.; GALLASCHUN, RANDALL J.

To: HYDRA BIOSCIENCES, INC.

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