Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists

Patent metadata

Field	Value
Publication number	US-9572794-B2
Application number	US-201514820488-A
Country	US
Kind code	B2
Filing date	Aug 6, 2015
Priority date	Aug 6, 2014
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

Embodiments of the invention include substituted indole compounds and compositions thereof to inhibit protease activated receptor-4. Also described are methods of preparation of compositions and methods for treating diseases related to thrombotic disorders by administration of the composition.

First claim

We claim:

1. A compound having a structure represented by formula (I):

wherein:
Q 1 is selected from N and CR 1a ;
Q 2 is selected from N and CR 1b , or can optionally cyclize with Q 3 to form a C5 or C6 saturated heterocycle;
Q 3 is selected from N and CR 1c , or can optionally cyclize with Q 2 to form a C5 or C6 saturated heterocycle;
Q 4 is selected from N and CR 1d ; and wherein 0, 1, or 2 of Q 1 , Q 2 , Q 3 and Q 4 are N;
R 1a , R 1b , R 1c , and R 1d , when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1 -C 3 alkyl sulfone, C 1 -C 3 polyhaloalkyl sulfone, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 polyhaloalkyl, C 1 -C 6 alkoxy, (C 1 -C 6 ) alkoxy-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, (C 1 -C 6 ) haloalkyl-oxy-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) polyhaloalkyl-oxy-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) polyhaloalkyl-(C 1 -C 6 ) alkoxy, and (C 1 -C 6 ) dialkylamino; n is 0-5;
X is independently selected from optionally substituted CH 2 -aryl, CH 2 -heteroaryl, CH 2 -biaryl, or

wherein:
Q 5 is selected from N, CR 1a , and R 1a ; and
n is 0-5;
R 2 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 polyhaloalkyl, (C 1 -C 3 ) polyhaloalkyl-oxy-(C 1 -C 3 ) alkyl, and (C 1 -C 3 ) haloalkyl-oxy-(C 1 -C 3 ) alkyl, and
A is optionally substituted and chosen from imidazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl, imidazothiadiazolyl, imidazooxadiazole, imidazothiazole, thiazolotriazole, and triazolyl;
or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

2. A compound of claim 1 , wherein R 2 is hydrogen.

3. A compound of claim 1 , wherein Q 2 or Q 3 is substituted with C—O—CF 3 .

4. A compound of claim 1 , wherein A is pyridinyl, pyrimidinyl, or imadazothiadiazolyl, imidazooxadiazole, thiazolotriazole, imidazothiazole.

5. A compound of claim 1 , wherein A is pyridinyl.

6. A compound of claim 5 , wherein A is of the following formula;

wherein:
R 3 is selected from —O—CH 3 , halogen, —S—CH 3 , hydrogen, or —O—CH 2 CH 3 .

7. A compound of claim 1 , wherein A is substituted with alkoxy, thioether, or halogen.

8. A compound of claim 1 , wherein R 2 is selected from hydrogen or phenylthiazolymethyl.

9. A compound of claim 1 , (I), wherein Q 2 cyclizes with Q 3 to form dioxolane.

10. A compound of claim 1 of the following formula:

wherein:
X is CH 2 —R 4 ;
R 4 is substituted or unsubstituted phenyl, pyridinyl, phenyldihydrothiazolyl or phenylthiazolyl.

11. A compound of claim 1 of the following formula:

12. A compound of claim 11 wherein Q 4 is N;
R 5 is selected from hydrogen, Cl, Br, F, cyano, O—CF 3 , —O—CH 3 , or CF 3 ; and n is 0-2.

13. A compound of claim 1 , of the following formula:

14. A compound of claim 1 , of the following formula:

15. A composition comprising a compound having a structure represented by formula (I):

wherein:
Q 1 is selected from N and CR 1a ;
Q 2 is selected from N and CR 1b , or can optionally cyclize with Q 3 to form a C5 or C6 saturated heterocycle;
Q 3 is selected from N and CR 1c , or can optionally cyclize with Q 2 to form a C5 or C6 saturated heterocycle;
Q 4 is selected from N and CR 1d ; and wherein 0, 1, or 2 of Q 1 , Q 2 , Q 3 , and Q 4 are N;
R 1a , R 1b , R 1c , and R 1d , when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1 -C 3 alkyl sulfone, C 1 -C 3 polyhaloalkyl sulfone, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 polyhaloalkyl, C 1 -C 6 alkoxy, (C 1 -C 6 ) alkoxy-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, (C 1 -C 6 ) haloalkyl-oxy-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) polyhaloalkyl-oxy-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) polyhaloalkyl-(C 1 -C 6 ) alkoxy, and (C 1 -C 6 ) dialkylamino; n is 0-5;
X is independently selected from optionally substituted CH 2 -aryl, CH 2 -heteroaryl, CH 2 -biaryl, or

wherein:
Q 5 is selected from N, CR 1a , and R 1a ; and
n is 0-5;
R 2 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 polyhaloalkyl, (C 1 -C 3 ) polyhaloalkyl-oxy-(C 1 -C 3 ) alkyl, and (C 1 -C 3 ) haloalkyl-oxy-(C 1 -C 3 ) alkyl, and
A is optionally substituted and chosen from imidazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl, imidazothiadiazolyl, imidazooxadiazole, imidazothiazole, thiazolotriazole, and triazolyl;
or a pharmaceutically acceptable salt, solvate, or polymorph thereof; and
a pharmaceutically acceptable carrier.

16. The composition of claim 15 , wherein:
X is selected from substituted or unsubstituted CH 2 -aryl, CH 2 -heteroaryl, CH 2 -biaryl.

17. The composition of claim 15 , wherein R 2 ishydrogen.

18. The composition of cla

Assignees

• Univ Vanderbilt

Inventors

• Hamm Heidi E
• Stauffer Shaun R
• Lindsley Craig W
• Wen Wandong
• Young Summer E
• Duvernay Matthew T
• Temple Kayla J

Classifications

• C08K5/42

  Sulfonic acids; Derivatives thereof · CPC title

• C07D237/00

  Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings · CPC title

• C08L2205/02

  containing two or more polymers of the same C08L -group · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/407 Primary

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title