Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists
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.
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 claim 15 , wherein Q 2 is substituted with C—O—CF 3 .
19. The composition of claim 15 , 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 .
20. The composition of claim 15 , (I), wherein Q 2 cyclizes with Q 3 to form dioxolane.
21. The composition of claim 15 , wherein X is optionally substituted benzyl or optionally substituted pyridinyl.
22. The composition of claim 15 , wherein the compound is of the following formula:
wherein:
X is CH 2 —R 4 ;
R 4 is substituted or unsubstituted phenyl, pyridinyl, phenyldihydrothiazolyl or phenylthiazolyl.
23. The composition of claim 15 , wherein the compound is of the following formula:
24. The composition of claim 23 , 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.
25. The composition of claim 23 , wherein the compound is of the following formula:
26. A method of preventing or treating thromboembolic disorder, comprising administering to a patient in need thereof an effective amount of a composition that includes 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 aryl or heteroaryl;
or a pharmaceutically acceptable salt, solvate, or polymorph thereof; and
a pharmaceutically acceptable carrier.
27. A method of inhibiting PAR-4 activity, comprising administering to a patient in need thereof an effective amount of a composition that includes 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 aryl or heteroaryl;
or a pharmaceutically acceptable salt, solvate, or polymorph thereof; and
a pharmaceutically acceptable carrier.