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

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.

Claims

1. A compound having a structure represented by formula (I): ##STR00130## wherein: Q.sup.1 is selected from N and CR.sup.1a; Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle; Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle; Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 are N; R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6) alkoxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkylamino, (C.sub.1-C.sub.6) haloalkyl-oxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) polyhaloalkyl-oxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) polyhaloalkyl-(C.sub.1-C.sub.6) alkoxy, and (C.sub.1-C.sub.6) dialkylamino; n is 0-5; X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or ##STR00131## wherein: Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and n is 0-5; R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3) polyhaloalkyl-oxy-(C.sub.1-C.sub.3) alkyl, and (C.sub.1-C.sub.3) haloalkyl-oxy-(C.sub.1-C.sub.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.sup.2 is hydrogen.

3. A compound of claim 1, wherein Q.sup.2 or Q.sup.3 is substituted with COCF.sub.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; ##STR00132## wherein: R.sup.3 is selected from OCH.sub.3, halogen, SCH.sub.3, hydrogen, or OCH.sub.2CH.sub.3.

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

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

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

10. A compound of claim 1 of the following formula: ##STR00133## wherein: X is CH.sub.2R.sup.4; R.sup.4 is substituted or unsubstituted phenyl, pyridinyl, phenyldihydrothiazolyl or phenylthiazolyl.

11. A compound of claim 1 of the following formula: ##STR00134##

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

13. A compound of claim 1, of the following formula: ##STR00135## ##STR00136##

14. A compound of claim 1, of the following formula: ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155##

15. A composition comprising a compound having a structure represented by formula (I): ##STR00156## wherein: Q.sup.1 is selected from N and CR.sup.1a; Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle; Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle; Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N; R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6) alkoxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkylamino, (C.sub.1-C.sub.6) haloalkyl-oxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) polyhaloalkyl-oxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) polyhaloalkyl-(C.sub.1-C.sub.6) alkoxy, and (C.sub.1-C.sub.6) dialkylamino; n is 0-5; X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or ##STR00157## wherein: Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and n is 0-5; R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3) polyhaloalkyl-oxy-(C.sub.1-C.sub.3) alkyl, and (C.sub.1-C.sub.3) haloalkyl-oxy-(C.sub.1-C.sub.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.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl.

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

18. The composition of claim 15, wherein Q.sup.2 is substituted with COCF.sub.3.

19. The composition of claim 15, wherein A is of the following formula; ##STR00158## wherein: R.sup.3 is selected from OCH.sub.3, halogen, SCH.sub.3, hydrogen, or OCH.sub.2CH.sub.3.

20. The composition of claim 15, (I), wherein Q.sup.2 cyclizes with Q.sup.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: ##STR00159## wherein: X is CH.sub.2R.sup.4; R.sup.4 is substituted or unsubstituted phenyl, pyridinyl, phenyldihydrothiazolyl or phenylthiazolyl.

23. The composition of claim 15, wherein the compound is of the following formula: ##STR00160##

24. The composition of claim 23, wherein Q.sup.4 is N; R.sup.5 is selected from hydrogen, Cl, Br, F, cyano, OCF.sub.3, OCH.sub.3, or CF.sub.3; and n is 0-2.

25. The composition of claim 23, wherein the compound is of the following formula: ##STR00161## ##STR00162##

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): ##STR00163## wherein: Q.sup.1 is selected from N and CR.sup.1a; Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle; Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle; Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N; R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6) alkoxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkylamino, (C.sub.1-C.sub.6) haloalkyl-oxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) polyhaloalkyl-oxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) polyhaloalkyl-(C.sub.1-C.sub.6) alkoxy, and (C.sub.1-C.sub.6) dialkylamino; n is 0-5; X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or ##STR00164## wherein: Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and n is 0-5; R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3) polyhaloalkyl-oxy-(C.sub.1-C.sub.3) alkyl, and (C.sub.1-C.sub.3) haloalkyl-oxy-(C.sub.1-C.sub.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): ##STR00165## wherein: Q.sup.1 is selected from N and CR.sup.1a; Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle; Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle; Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N; R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6) alkoxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkylamino, (C.sub.1-C.sub.6) haloalkyl-oxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) polyhaloalkyl-oxy-(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) polyhaloalkyl-(C.sub.1-C.sub.6) alkoxy, and (C.sub.1-C.sub.6) dialkylamino; n is 0-5; X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or ##STR00166## wherein: Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and n is 0-5; R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3) polyhaloalkyl-oxy-(C.sub.1-C.sub.3) alkyl, and (C.sub.1-C.sub.3) haloalkyl-oxy-(C.sub.1-C.sub.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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a graph that shows an example concentration response curve (CRC) measuring antagonism of PAR4 mediated .sub.IIB3 activation via PAC-1 binding using Example B9.

DETAILED DESCRIPTION

(2) The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

(3) Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

(4) All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which need to be independently confirmed.

(5) One embodiment of the present invention is indole compounds, stereoisomers, tautomers, salts, solvates, or prodrugs thereof, of formula (I), having the structure:

(6) ##STR00002##
wherein:

(7) Q.sup.1 is selected from N and CR.sup.1a;

(8) Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle;

(9) Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle;

(10) Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N;

(11) R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)dialkylamino; n is 0-5;

(12) X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or

(13) ##STR00003##

(14) wherein:

(15) Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and

(16) n is 0-5;

(17) R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3)polyhaloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and (C.sub.1-C.sub.3)haloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and

(18) A is optionally substituted and chosen from aryl or heteroaryl;

(19) or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

(20) Also disclosed are pharmaceutical compositions that comprise a compound described herein or pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier. In one embodiment, the composition includes a compound having a structure represented by formula (I):

(21) ##STR00004##
wherein:

(22) Q.sup.1 is selected from N and CR.sup.1a;

(23) Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle;

(24) Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle;

(25) Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N;

(26) R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)dialkylamino; n is 0-5;

(27) X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or

(28) ##STR00005##

(29) wherein:

(30) Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and

(31) n is 0-5;

(32) R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3)polyhaloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and (C.sub.1-C.sub.3)haloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and

(33) A is optionally substituted and chosen from aryl or heteroaryl;

(34) or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.

(35) Also disclosed are the pharmaceutical compositions described above, further comprising at least one additional drug or therapeutic agent. In certain embodiments of the preset invention, the at least one additional therapeutic agent(s) are an anti-platelet agent or a combination thereof. Examples of the anti-platelet agents include P2Y12 antagonists and/or aspirin. Preferably, the P2Y12 antagonists are clopidogrel, ticagrelor, or prasugrel. In another embodiment, the at least one additional therapeutic agent is an anticoagulant. Examples of the anticoagulant agent include FXa inhibitors or thrombin inhibitors. The FXa inhibitors may be, for example, apixaban or rivaroxaban. The thrombin inhibitor may be, for example, dabigatran.

(36) Also disclosed herein are methods for the treatment of a disease state associated with PAR4 activity in a mammal comprising the step of administering to the mammal at least one compound in a dosage and amount effective to treat the disease state, the compound having a structure represented by formula (I):

(37) ##STR00006##
wherein:

(38) Q.sup.1 is selected from N and CR.sup.1a;

(39) Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle;

(40) Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle;

(41) Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N;

(42) R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)dialkylamino; n is 0-5;

(43) X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or

(44) ##STR00007##

(45) wherein:

(46) Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and

(47) n is 0-5;

(48) R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3)polyhaloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and (C.sub.1-C.sub.3)haloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and

(49) A is optionally substituted and chosen from aryl or heteroaryl;

(50) or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

(51) Also disclosed are methods for making a compound comprising the steps of providing an indole compound having a structure represented by formula (I):

(52) ##STR00008##
as shown in the Examples below, and wherein the variable are defined herein.

(53) Also disclosed are the products of the disclosed methods of making.

(54) Also disclosed are pharmaceutical compositions that comprise the products of the compounds disclosed herein.

(55) Also disclosed are methods for the manufacture of a medicament for antagonizing PAR4 activity in a mammal comprising combining a compound having a structure represented by formula (I):

(56) ##STR00009##
wherein:

(57) Q.sup.1 is selected from N and CR.sup.1a;

(58) Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle;

(59) Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle;

(60) Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N;

(61) R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)dialkylamino; n is 0-5;

(62) X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or

(63) ##STR00010##

(64) wherein:

(65) Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and

(66) n is 0-5;

(67) R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3)polyhaloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and (C.sub.1-C.sub.3)haloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and

(68) A is optionally substituted and chosen from aryl or heteroaryl;

(69) or a pharmaceutically acceptable salt, solvate, or polymorph thereof with a pharmaceutically acceptable carrier.

(70) Also disclosed is a use for a compound of formula (I):

(71) ##STR00011##
wherein:

(72) Q.sup.1 is selected from N and CR.sup.1a;

(73) Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle;

(74) Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle;

(75) Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N;

(76) R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)dialkylamino; n is 0-5;

(77) X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or

(78) ##STR00012##

(79) wherein:

(80) Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and

(81) n is 0-5;

(82) R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3)polyhaloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and (C.sub.1-C.sub.3)haloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and

(83) A is optionally substituted and chosen from aryl or heteroaryl;

(84) or a pharmaceutically acceptable salt, solvate, or polymorph thereof; in the manufacture of a medicament for use in the treatment of a thromboembolic disorder or the primary or secondary prophylaxis of a thromboembolic disorder.

(85) Also disclosed is the use of a compound of the following formula (I):

(86) ##STR00013##
wherein:

(87) Q.sup.1 is selected from N and CR.sup.1a;

(88) Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle;

(89) Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle;

(90) Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N;

(91) R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)dialkylamino; n is 0-5;

(92) X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or

(93) ##STR00014##

(94) wherein:

(95) Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and

(96) n is 0-5;

(97) R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3)polyhaloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and (C.sub.1-C.sub.3)haloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and

(98) A is optionally substituted and chosen from aryl or heteroaryl;

(99) or a pharmaceutically acceptable salt, solvate, or polymorph thereof; in the treatment of a thromboembolic disorder or the primary or secondary prophylaxis of a thromboembolic disorder.

A. Definitions

(100) As used in the specification and the appended claims, the singular forms a, an and the include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a functional group, an alkyl, or a residue includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

(101) Ranges can be expressed herein as from about one particular value, and/or to about another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent about, it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as about that particular value in addition to the value itself. For example, if the value 10 is disclosed, then about 10 is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

(102) As used herein, the terms optional or optionally means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

(103) As used herein, the term subject refers to a target of administration. The subject of the herein disclosed methods can be a mammal. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. A patient refers to a subject afflicted with a disease or disorder. The term patient includes human and veterinary subjects.

(104) In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more thromboembolic disorder and/or any other disease state associated with PAR4 prior to the administering step.

(105) As used herein, the term treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

(106) As used herein, the term prevent or preventing refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

(107) As used herein, the term diagnosed means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. For example, diagnosed with a disorder treatable by a reduction of PAR4 activity means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by a compound or composition that can antagonize PAR4 activity. Such a diagnosis can be in reference to a disorder, such as platelet aggregation, and the like, as discussed herein.

(108) As used herein, the terms administering and administration refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

(109) As used herein, the term effective amount refers to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a therapeutically effective amount refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a prophylactically effective amount; that is, an amount effective for prevention of a disease or condition.

(110) The term thrombotic disorders refers to disorders characterized by formation of a thrombus that obstructs vascular blood flow. Examples of thrombotic disorders include stroke, myocardial infarction, stable or unstable angina, peripheral vascular disease, abrupt closure following angioplasty or stent placement and thrombosis induced by vascular surgery. Thrombotic disorders also include disorders characterized by formation of a thrombus caused by atrial fibrillation or inflammation.

(111) The term platelet aggregation refers to the attachment of activated platelets one to another, which results in the formation of aggregates or clumps of activated platelets.

(112) As used herein, the term pharmaceutically acceptable carrier refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

(113) A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more OCH.sub.2CH.sub.2O units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more CO(CH.sub.2).sub.8CO moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

(114) As used herein, the term substituted is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms substitution or substituted with include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

(115) In defining various terms, A.sup.1, A.sup.2, A.sup.3, and A.sup.4 are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents. Unless otherwise specified, the substituents are all independent from one another.

(116) The term alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, thioether, sulfo-oxo, or thiol, as described herein. A lower alkyl group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.

(117) Throughout the specification alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term halogenated alkyl or haloalkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. The term alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term alkylamino specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like. When alkyl is used in one instance and a specific term such as alkylalcohol is used in another, it is not meant to imply that the term alkyl does not also refer to specific terms such as alkylalcohol and the like.

(118) This practice is also used for other groups described herein. That is, while a term such as cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an alkylcycloalkyl. Similarly, a substituted alkoxy can be specifically referred to as, e.g., a halogenated alkoxy, a particular substituted alkenyl can be, e.g., an alkenylalcohol, and the like. Again, the practice of using a general term, such as cycloalkyl, and a specific term, such as alkylcycloalkyl, is not meant to imply that the general term does not also include the specific term.

(119) The term cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term cycloalkyl, where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

(120) The terms alkoxy and alkoxyl as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an alkoxy group can be defined as OA.sup.1 where A.sup.1 is alkyl or cycloalkyl as defined above. Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as OA.sup.1-OA.sup.2 or OA.sup.1-(OA.sup.2).sub.a-OA.sup.3, where a is an integer of from 1 to 200 and A.sup.1, A.sup.2, and A.sup.3 are alkyl and/or cycloalkyl groups.

(121) The term aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term aryl also includes heteroaryl, which is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term non-heteroaryl, which is also included in the term aryl, defines a group that contains an aromatic group that does not contain a heteroatom. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term biaryl is a specific type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

(122) The term aldehyde as used herein is represented by a formula C(O)H. Throughout this specification C(O) is a short hand notation for a carbonyl group, i.e., CO.

(123) The terms amine or amino as used herein are represented by a formula NA.sup.1A.sup.2A.sup.3, where A.sup.1, A.sup.2, and A.sup.3 can be, independently, hydrogen or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

(124) The term heterocycle, as used herein refers to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Heterocycle includes pyridinde, pyrimidine, pyrazine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, oxadiazole including, for example, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, imidazothiadiazole, imidazooxadiazole, imidazothiazole, thiazolotriazole, and the like.

(125) The term hydroxyl as used herein is represented by a formula OH.

(126) The term thiol as used herein is represented by a formula SH.

(127) The term thioester as used herein is represented by a formula SCH.sub.3.

(128) The term pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

(129) As used herein, the term derivative refers to a compound having a structure derived from the structure of a parent compound (e.g., a compounds disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

(130) Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

(131) Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

(132) In some aspects, a structure of a compound can be represented by a formula:

(133) ##STR00015##
which is understood to be equivalent to a formula:

(134) ##STR00016##
wherein n is typically an integer. That is, R.sup.n is understood to represent five independent substituents, R.sup.n(a), R.sup.n(b), R.sup.n(c), R.sup.n(d), R.sup.n(e). By independent substituents, it is meant that each R substituent can be independently defined. For example, if in one instance R.sup.n(a) is halogen, then R.sup.n(b) is not necessarily halogen in that instance. Likewise, when a group R is defined as four substituents, R is understood to represent four independent substituents, R.sup.a, R.sup.b, R.sup.c, and R.sup.d. Unless indicated to the contrary, the substituents are not limited to any particular order or arrangement.

(135) It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

B. Compounds

(136) In one aspect, the invention relates to compounds, or pharmaceutically acceptable derivatives thereof, useful as antagonists of PAR4. In general, it is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.

(137) In one aspect, the invention relates to compounds having a structure represented by formula (I):

(138) ##STR00017##
wherein:

(139) Q.sup.1 is selected from N and CR.sup.1a;

(140) Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle;

(141) Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle;

(142) Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N;

(143) R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)dialkylamino; n is 0-5;

(144) X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or

(145) ##STR00018##

(146) wherein:

(147) Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and

(148) n is 0-5;

(149) R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3)polyhaloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and (C.sub.1-C.sub.3)haloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and

(150) A is optionally substituted and chosen from aryl or heteroaryl;

(151) or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

(152) Also disclosed are compounds wherein A is selected from imidazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl, imidazothiadiazolyl, imidazooxadiazole, imidazothiazole, thiazolotriazole, and triazolyl.

(153) Also disclosed are compounds of the following formula:

(154) ##STR00019##

(155) Also disclosed are compounds of formula (I), wherein A is substituted or unsubstituted pyridinyl. In another embodiment, A is substituted or unsubstituted 2-pyridinyl. In another embodiment, A is alkoxy substituted.

(156) Also disclosed are compounds of formula (I), wherein R.sup.1 is hydrogen, halogen, cyano, OCF.sub.3, alkoxy, or CF.sub.3.

(157) Also disclosed are compounds of formula (I), wherein Q.sup.2 and Q.sup.3 together form dioxolane.

(158) Also disclosed are compounds of formula (I), wherein Q.sup.2 is substituted with OCF.sub.3.

(159) Also disclosed are compounds where at least one of Q.sup.2-Q.sup.4 is substituted with cyano, C.sub.1-C.sub.3 thioester, or OCF.sub.3.

(160) Also disclosed are compounds of formula (I), wherein each Q.sup.5 is CR.sup.1a.

(161) Also disclosed are the following compounds:

(162) ##STR00020## ##STR00021##

(163) Also disclosed are the following compounds:

(164) ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040##

(165) The compounds disclosed herein can include all salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, carboxylic acids. The following are non-limiting examples of anions that can form salts with protonated basic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like. The following are non-limiting examples of cations that can form salts of acidic groups: ammonium, sodium, lithium, potassium, calcium, magnesium, bismuth, lysine, and the like.

(166) The analogs (compounds) of the present disclosure are arranged into several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.

(167) Some of the compounds of the instant invention have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to encompass all such isomeric forms of these compounds.

(168) The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

(169) If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

C. Pharmaceutical Compositions

(170) In one aspect, the invention relates to pharmaceutical compositions comprising the disclosed compounds. That is, a pharmaceutical composition can be provided comprising a therapeutically effective amount of at least one disclosed compound or at least one product of a disclosed method and a pharmaceutically acceptable carrier.

(171) In certain aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

(172) As used herein, the term pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium, manganese (-ic and -ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

(173) In practice, the compounds of the invention, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the invention, and/or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and/or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

(174) Thus, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

(175) In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques

(176) A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

(177) The pharmaceutical compositions of the present invention can comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

(178) Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

(179) Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

(180) Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.

(181) Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.

(182) In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

(183) It is understood that the specific dose level for any particular patient will depend upon a variety of factors. Such factors include the age, body weight, general health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, drug combination, and the type and severity of the particular disease undergoing therapy.

(184) The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological conditions.

(185) It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.

(186) Further disclosed herein are pharmaceutical compositions comprising one or more of the disclosed PAR4 antagonists and a pharmaceutically acceptable carrier.

(187) Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.

(188) The above combinations include combinations of a disclosed compound not only with one other active compound, but also with two or more other active compounds. Likewise, disclosed compounds may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which disclosed compounds are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

(189) The weight ratio of the compound of the present invention to the second active ingredient can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

(190) In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agent(s).

(191) Accordingly, the subject compounds can be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compound and the other agent may be coadministered, either in concomitant therapy or in a fixed combination.

(192) In one aspect, the compound can be employed in combination with at least one additional therapeutic agent. In one aspect of the invention the at least one additional therapeutic agent may be an anti-platelet agent. In one aspect, the anti-platelet agent(s) are P2Y12 antagonists and/or aspirin. The P2Y12 antagonists may be clopidogrel, ticagrelor, or prasugrel. In another aspect of the invention, the at least one additional therapeutic agent(s) may be an anticoagulant. The anticoagulant agent(s) may be FXa inhibitors or thrombin inhibitors. For example, the FXa inhibitors are apixaban or rivaroxaban. Additionally, the thrombin inhibitor may be dabigatran.

(193) In one aspect, the invention relates to pharmaceutical compositions comprising a compound having a structure represented by a formula (I):

(194) ##STR00041##
wherein:

(195) Q.sup.1 is selected from N and CR.sup.1a;

(196) Q.sup.2 is selected from N and CR.sup.1b, or can optionally cyclize with Q.sup.3 to form a C5 or C6 saturated heterocycle;

(197) Q.sup.3 is selected from N and CR.sup.1c, or can optionally cyclize with Q.sup.2 to form a C5 or C6 saturated heterocycle;

(198) Q.sup.4 is selected from N and CR.sup.1d; and wherein 0, 1, or 2 of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are N;

(199) R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d, when present, are each independently selected from hydrogen, halogen, hydroxyl, cyano, C.sub.1-C.sub.3 alkyl sulfone, C.sub.1-C.sub.3 polyhaloalkyl sulfone, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 polyhaloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-oxy-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)polyhaloalkyl-(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)dialkylamino; n is 0-5;

(200) X is independently selected from optionally substituted CH.sub.2-aryl, CH.sub.2-heteroaryl, CH.sub.2-biaryl, or

(201) ##STR00042##

(202) wherein:

(203) Q.sup.5 is selected from N, CR.sup.1a, and R.sup.1a; and

(204) n is 0-5;

(205) R.sup.2 is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 polyhaloalkyl, (C.sub.1-C.sub.3)polyhaloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and (C.sub.1-C.sub.3)haloalkyl-oxy-(C.sub.1-C.sub.3)alkyl, and

(206) A is optionally substituted and chosen from aryl or heteroaryl;

(207) or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.

D. Uses

(208) In some embodiments, the present invention provides methods for the treatment of a thromboembolic disorder or the primary or secondary prophylaxis of a thromboembolic disorder, which includes the steps of administering to a patient (for example, a human) in need thereof a therapeutically effective amount of a compound of Formula I or stereoisomers, tautomers, pharmaceutically acceptable salts, prodrug esters, or solvates thereof.

(209) The thromboembolic disorder may be selected from the group consisting of acute coronary syndrome, unstable angina, stable angina, ST-elevated myocardial infarction, non-ST-elevated myocardial infarction, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebrovascular injury, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, cancer-related thrombosis, and thrombosis resulting from medical implants, devices, and procedures in which blood is exposed to an artificial surface that promotes thrombosis.

(210) In some embodiments, the present invention includes a method of inhibiting or preventing platelet aggregation, which includes the step of administering to a subject (such as a human) in need thereof a therapeutically effective amount of a PAR4 antagonist, which is a compound of Formula I.

(211) In some embodiments, the invention provides a method of treatment or prophylaxis of a thromboembolic disorder involving administering to a subject in need thereof (e.g., a human) a therapeutically effective amount of a compound that binds to PAR4 (such as a compound of Formula I of the invention) and inhibits PAR4 cleavage and/or signaling, wherein said subject has a dual PAR1/PAR4 platelet receptor repertoire.

(212) In some embodiments, the present invention provides a compound of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrug esters thereof, for use in therapy for the treatment or prophylaxis of a thromboembolic disorder.

(213) In some embodiments, the present invention also provides the use of a compound of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrug esters thereof, for the manufacture of a medicament for the treatment or prophylaxis of a thromboembolic disorder.

(214) In some embodiments, compounds of the present invention may be co-administered with at least one additional drug or therapeutic agent. In certain embodiments of the preset invention, the at least one additional therapeutic agent(s) are an anti-platelet agent or a combination thereof. Examples of the anti-platelet agents include P2Y12 antagonists and/or aspirin. Preferably, the P2Y12 antagonists are clopidogrel, ticagrelor, or prasugrel. In another embodiment, the at least one additional therapeutic agent is an anticoagulant. Examples of the anticoagulant agent include FXa inhibitors or thrombin inhibitors. The FXa inhibitors may be, for example, apixaban or rivaroxaban. The thrombin inhibitor may be, for example, dabigatran.

(215) Further examples include therapeutics such as a thrombolytic, anticoagulant or antiplatelet agent. Typically, the antithrombotic is aspirin, heparin, heparin sulfate, danaparoid sodium, clopidogrel, prasugrel, ticagrelor, cangrelor, elinogrel, cilostazol, abciximab, eptifibatide, tirofiban, dipyridamole, epoprostenol, abciximab, eptifibatide, tirofiban, beraprost, prostacyclin, iloprost, and treprostinil, aloxiprin, carbasalate calcium, indobufen, triflusal dipyridamole, picotamide, terutroban, triflusal cloricromen, ditazole, acenocoumarol, coumatetralyl, dicoumarol, ethyl biscoumacetate, phenprocoumon, warfarin, clorindione, diphenadione, phenindione, tioclomarol, defibrotide, ramatroban, antithrombin III, and/or protein C (drotrecogin alfa) or combinations thereof.

(216) The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

E. Examples/Experimental

(217) Some of the compounds of the instant invention have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to encompass all such isomeric forms of these compounds.

(218) The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

(219) If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

(220) 1. Preparation of Exemplary Compounds

(221) Several methods for preparing the compounds of this invention are illustrated in the Schemes and Examples herein. Starting materials are made according to procedures known in the art or as illustrated herein. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

(222) Example compounds of type 1.5 can be prepared according to Scheme 1 starting from an appropriate indole ester 1.1, bromination furnishes ester 1.2. Suzuki cross-coupling provides 1.3 followed by alkylation using 1.6 gives ester 1.4. Final reduction using LiBH4 or a related aluminium or boron reducing agent provides examples 1.5.

(223) ##STR00043##
Alternatively, novel indole ring systems 2.2 can be obtained using various 1,5-aryl and heteroaryl bromocarboxaldehydes of type 2.1 and ethyl isocyanoacetate in a highly efficient one-pot copper (I) catalyzed condensation/coupling/deformylation process to afford key intermediate indoles of type 2.2 in good yield (Cai, Q.; Li, Z.; Wei, J.; Ha, C.; Pei, C.; Ding, K. Chem. Commun. 2009, 7581-7583.) Subsequent bromination, Suzuki cross-coupling, alkylation, and ester reduction provides examples of type 2.5.

(224) ##STR00044##

(225) Intermediate benzyl alkylating agents of type 1.6 as described above are either commercially available or can be prepared according to Scheme 3. Beginning with acid or ester 3.1, reduction affords 3.2 which can be transformed to mesylate 3.3, bromide 1.6, or chloride 3.4 using known methods and used throughout to prepare final examples.

(226) ##STR00045##

(227) In addition, example compounds of type 4.2 can be prepared according to Scheme 4 starting from prior alcohol examples 4.1, as previously described. Alkylation using a functionalized alkyl halide reagent R.sub.2X in the presence of a base, such as sodium hydride, in an aprotic polar solvent, such as DMF, gives ethers of type 4.2.

(228) ##STR00046##

(229) The preparation of analogs bearing A groups with 5,5-bicycylic heterocycles, such as 2-methoxy-6-imidazo[2,1-b][1,3,4]thiadiazoles, can be prepared according to Scheme 5 starting from the desired 2-carboxy indole obtained from commercial sources, Scheme 2, or other indole methodologies familiar to those skilled in the art. Thus starting from indole 5.1, acylation using a Lewis acid, such as tin (IV) chloride, and acetic anhydride affords 5.2. Selective alpha-chlorination with benzyltrimethylammonium dichloroiodate (Kajigaeshi, S., et al., Synthesis Communications, 1988, 545.) affords intermediate chloro ketone 5.3. Displacement with sodium bromide followed by condensation with an aminothiadiazole affords intermediate 5.4. Displacement with alkoxide, followed by alkylation and reduction gives final examples of type 5.7.

(230) ##STR00047## ##STR00048##

(231) 2. Experimental

(232) Hereinafter, the term EtOAc means ethyl acetate, DCM means dichloromethane, DIPEA means N,N-diisopropylethylamine, DMF means N,N-dimethylformamide, THF means tetrahydrofuran, DTBAD means di-tert-butyl azodicarboxylate, HATU means 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, LCMS means liquid chromatography/mass spectrometry, MeOH means methanol, [M+H].sup.+ means the protonated mass of the free base of the compound, M. p. means melting point, NMR means nuclear magnetic resonance, R.sub.t means retention time (in minutes), THF means tetrahydrofuran, rt means room temperature.

(233) Microwave assisted reactions were performed in a single-mode reactor: Emrys Optimizer microwave reactor (Personal Chemistry A.B., currently Biotage).

(234) Hydrogenation reactions were performed in a continuous flow hydrogenator H-CUBE from ThalesNano Nanotechnology Inc. or using a Parr hydrogenation shaker apparatus.

(235) Analytical thin layer chromatography was performed on Analtech silica gel GF 250 micron plates using reagent grade solvents. Normal phase flash silica gel-based column chromatography was performed using ready-to-connect cartridges from ISCO, on irregular silica gel, particle size 15-40 m on a Combi-flash Companion chromatography system from ISCO.

(236) Low resolution mass spectra were obtained on an Agilent 1200 series 6130 mass spectrometer. High resolution mass spectra were recorded on a Waters Q-TOF API-US. Analytical HPLC was performed on an HP 1100 with UV detection at 214 and 254 nm along with ELSD detection, LC/MS (J-Sphere80-C18, 3.050 mm, 4.1 min gradient, 5% [0.05% TFA/CH.sub.3CN]:95% [0.05% TFA/H.sub.2O] to 100% [0.05% TFA/CH.sub.3CN]. Preparative RP-HPLC purification was performed on a custom HP 1100 automated purification system with collection triggered by mass detection or using a Gilson Inc. preparative UV-based system using a Phenomenex Luna C18 column (5030 mm I.D., 5 m) with an acetonitrile (unmodified)-water (0.1% TFA) custom gradient.

(237) For LC-MS-characterization of the compounds of the present invention, the following methods were used:

(238) Method 1: The HPLC measurement was performed using an Agilent 1200 system comprising a binary pump with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a SQ mass spectrometer and Polymer Labs ELSD. The MS detector was configured with an ES ionization source. Nitrogen was used as the nebulizer gas. The source temperature was maintained at 350 C. Data acquisition was performed with Agilent Chemstation software. Reversed phase HPLC was carried out on a Kinetex C18 column (2.6 m, 2.130 m) from Phenomenex, with a flow rate of 1.5 mL/min, at 45 C. The gradient conditions used are: 93% A (water+0.1% TFA), 7% B (acetonitrile), to 95% B in 1.1 minutes, returning to initial conditions at 1.11 minutes. Injection volume 1 L. Low-resolution mass spectra (single quadruple MSD detector) were acquired in electrospray mode by scanning from 100 to 700 in 0.25 seconds, step size of 0.1 and peak width of 0.03 minutes. The capillary needle voltage was 3.0 kV and the fragmentor voltage was 100V. Method 2: Using method 1 instrument and column conditions. The gradient conditions used are: 93% A (water+0.1% TFA), 7% B (acetonitrile), to 95% B in 2.0 minutes, returning to initial conditions at 2.11 minutes. Injection volume 1 L. Low-resolution mass spectra (single quadruple MSD detector) were acquired in electrospray mode by scanning from 100 to 700 in 0.25 seconds, step size of 0.1 and peak width of 0.03 minutes. The capillary needle voltage was 3.0 kV and the fragmentor voltage was 100V.

(239) Chiral purification of racemic mixtures was readily accomplished using a supercritical fluid chromatography (SFC) instrument from Thar Scientific Instruments. Chiral analytical and semi-prep SFC purification columns were from Chiral Technologies.

(240) .sup.1H and .sup.13C NMR spectra were recorded either on a Bruker DPX-400 or on a Bruker AV-500 spectrometer with standard pulse sequences, operating at 400 MHz and 500 MHz respectively. Chemical shifts (6) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which was used as internal standard.

(241) a. Preparation of Intermediates

Intermediate A1. Ethyl 3-bromo-5-(trifluoromethoxy)-1H-indole-2-carboxylate

(242) ##STR00049##

(243) To a THF solution (3 mL) of commercially available ethyl 5-(trifluoromethoxy)-1H-indole-2-carboxylate (300 mg, 1.098 mmol, 1 eq.) was added dropwise the THF (5 mL) solution of N-bromosuccinimide (214.7 mg, 1.206 mmol, 1.1 eq.). The mixture was stirred at rt for 2 h. THF was removed under reduced pressure to afford crude ethyl 3-bromo-5-(trifluoromethoxy)-1H-indole-2-carboxylate. The product was purified via automated flash chromatography (0-10% EtOAc/hexanes, 382 mg, 99%): LC-MS, >98% (215, 254 nm), Rt=1.276, m/z=351.8 [M+H]; .sup.1H NMR(400 MHz, CDCl.sub.3) 1.46 (t, J=7.1, 3H), 4.44-4.50 (q, J=7.1, 2H), 7.23 (d, J=1.4, 1H), 7.38-7.42 (dd, J=4.7, 8.9, 1H), 7.53 (d, J=16.1, 1H), 9.12 (s, 1H).

Intermediate A2. Ethyl 3-bromo-5-(trifluoromethyl)-1H-indole-2-carboxylate

(244) ##STR00050##

Step 1

(245) To a dry and argon-filled vial was added 2-bromo-5-(trifluoromethyl)benzaldehyde (500 mg, 1.82 mmol), ethyl 2-isocyanoacetate (226 mg, 230 L, 2.00 mmol), CsCO.sub.3 (1186 mg, 3.64 mmol), CuI (35 mg, 0.182 mmol) and DMSO (10 mL). The mixture was allowed to stir overnight at 50 C. Upon completion, the solution was passed through Celite and was concentrated under reduced pressure. The crude product was purified by RP-HPLC to afford ethyl 5-(trifluoromethyl)-1H-indole-2-carboxylate (332 mg, 71%): LC-MS, >98% (215, 254 nm), Rt=1.157, m/z=257.9 [M+H]; .sup.1H NMR (400 MHz, CDCl.sub.3) 1.44 (t, J=7.1, 3H), 4.42-4.47 (q, J=7.1, 2H), 7.29-7.30 (dd, J=0.5, 1.9, 1H), 7.50-7.55 (m, 2H), 8.00 (d, J=0.7, 1H), 9.28 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) 14.5, 61.6, 109.3, 112.5, 120.6 (q, J=4.3), 121.9 (q, J=3.2), 123.5 (q, J=31.8), 125.0 (q, J=271.6), 126.8, 129.4, 138.0, 161.8.

Step 2

(246) To a THF solution (3 mL) of ethyl 5-(trifluoromethyl)-1H-indole-2-carboxylate (310 mg, 1.205 mmol) was added dropwise a THF (5 mL) solution of N-bromosuccinimide (321 mg, 1.807 mmol). The mixture was stirred at rt for 2 h. THF was removed under reduced pressure to afford the crude ethyl 3-bromo-5-(trifluoromethyl)-1H-indole-2-carboxylate. Purification using automated flash chromatography (SiO.sub.2 0-10% EtOAc/hexanes) afforded title product (401 mg, 99%): LC-MS, >98% (215, 254 nm), Rt=1.248, m/z=373.0 [M+2H.sub.2O+H], 335.7 [M+H]; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.37 (d, J=7.1, 3H), 4.36-4.42 (q, J=7.1, 2H), 7.60-7.62 (dd, J=1.6, 8.8, 1H), 7.67 (d, J=8.7, 1H), 7.83 (s, 1H).

(247) b. Preparation of Representative Compounds

Example 1

(Table 1, B13) (1-(3-methoxybenzyl)-3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-indol-2-yl)methanol

(248) ##STR00051##

Step 1

(249) To a microwave vial was added ethyl 3-bromo-5-(trifluoromethyl)-1H-indole-2-carboxylate (Intermediate A2) (100 mg, 0.30 mmol), 6-methoxy-3-pyridinyl-boronic acid (70.8 mg, 0.48 mmol), Pd(PPh.sub.3).sub.4 (8.4 mg, 0.006 mmol), DMF (3 mL) and water (0.75 mL). The vial was sealed and put in microwave reactor and heated for 15 min. at 120 C. Upon completion, the solvent was passed through Celite. The filtrate was concentrated under reduced pressure and the crude product purified by RP-HPLC to afford 109 mg of ethyl 3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-indole-2-carboxylate (79%): LC-MS>98% (214, 254 nm), Rt=1.190 min, m/z=364.8 [M+H]; .sup.1H NMR (400 MHz, CDCl.sub.3) 1.27 (t, J=7.1, 3H) 4.02 (s, 3H), 4.30-4.36 (q, J=7.1, 2H), 6.86-6.88 (dd, J=0.6, 8.5, 1H), 7.53-7.59 (m, 2H), 7.75-7.78 (dd, J=2.4, 8.5, 1H), 7.89 (d, J=0.6, 1H), 8.33-8.33 (dd, J=0.6, 2.4, 1H), 9.47 (s, 1H); .sup.13C NMR (100.6 MHz, CDCl.sub.3) 14.2, 53.7, 61.5, 110.3, 112.5, 119.4 (q, J=4.3), 121.2, 121.7, 122.5 (q, J=3.2), 123.8 (q, J=32.1), 125.0, 124.9 (q, J=271.0), 127.3, 136.9, 141.0, 147.9, 161.6, 163.7.

Step 2

(250) To a vial was added ethyl 3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-indole-2-carboxylate (2 0 mg, 0.055 mmol), 3-methoxybenzyl bromide (14 mg, 0.082 mmol) and K.sub.2CO.sub.3 (15.2 mg, 0.110 mmol) and DMF (1.5 mL). The mixture was stirred for 6-8 h at 60 C. Upon completion, the desired indole ester was purified by the RP-HPLC to afford ethyl 1-(3-methoxybenzyl)-3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-indole-2-carboxylate (17 mg, 65%): LC-MS>95% (214, 254 nm), m/z=485.1 [M+H].

Step 3

(251) To a solution of ethyl 1-(3-methoxybenzyl)-3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-indole-2-carboxylate (17 mg, 0.035 mmol) in THF was added lithium aluminum hydride (LAH) (1.0 M in THF) (70 L, 0.07 mmol) at 0 C. The solution was allowed to warm to rt and stir for 45 min. Upon completion, 10 L 2N HCl was added to consume the remaining LAH, followed by the addition of 10 L saturated aq. NaHCO.sub.3. The solvent was concentrated on a heated air-blowing block. The residue was purified by RP-HPLC to afford title example compound (Example B13) (10.2 mg, 65%): LC-MS>98% (214, 254 nm), Rt=1.232 min, m/z=442.8 [M+H].

Example 2

(Table 1, B75) (1-(2-chlorobenzyl)-3-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanol

(252) ##STR00052##

Step 1. Preparation of ethyl 3-acetyl-5-(trifluoromethoxy)-1H-indole-2-carboxylate (2)

(253) To an oven dried round bottom flask cooled under an Argon atmosphere was added a magnetic stirring bar and a solution of ethyl 5-(trifluoromethoxy)-1H-indole-2-carboxylate (1)(0.55 mmol) in 1,2-dichloroethane (2.2 mL). The solution was cooled to 0 C. where SnCl.sub.4 (0.66 mmol) was added in a single portion via syringe. After the ice bath was removed, the mixture was stirred at ambient temperature for 30 minutes after which acetic anhydride (0.55 mmol) was added in small portions to the suspension followed by nitromethane (1.6 mL). The mixture was stirred for 48 hr at room temperature and then the reaction mixture was quenched with ice cooled water. The mixture was filtered to remove inorganic precipitates and the organic material was extracted with ethyl acetate (25 mL). The organic phase was dried over magnesium sulfate, concentrated, and purified via silica chromatography (hexanes-20% EtOAc/Hexanes) to afford title compound in 92% yield. M+H=316, RT 1.004.

(254) .sup.1H NMR (400 MHz, chloroform-d) 9.32 (s, 1H), 8.01 (s, 1H), 7.41-7.43 (d, J=8.92 Hz, 1H), 7.23-7.26 (m, 1H), 4.47-4.52 (q, J=7.15 Hz, 3H), 2.75 (s, 3H), 1.44-1.47 (t, J=7.14, 4H).

Step 2. Preparation of ethyl 3-|(2-chloroacetyl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (3)

(255) Benzyltrimethylammonium dichloroiodate (0.81 mmol) was added to a solution of ethyl 3-acetyl-5-(trifluoromethoxy)-1H-indole-2-carboxylate (2) (0.54 mmol) in THF (1.8 mL) and the mixture was stirred at 50 C. for 3-5 hrs. Mixture was cooled to 0 C. and quenched with a 10% NaHCO.sub.3 solution. The mixture is extracted with EtOAc (25 mL), washed with 5% Na.sub.2S.sub.2O.sub.3(aq), brine, and the organic layer was dried with MgSO.sub.4, filtered and evaporated at reduced pressure. Purification by silica chromatography (5% EtOAc/Hexanes-30% EtOAc/Hexanes) to afford the title compound in 83% yield. M+H=350, RT=1.217.

(256) .sup.1H NMR (400 MHz, chloroform-d) 9.31 (s, 1H), 8.06 (s, 1H), 7.44-7.46 (m, 1H), 7.27-7.7.30 (m, 1H), 4.91 (s, 2H), 4.49-4.54 (q, J=7.16 Hz, 3H), 1.46-1.50 (t, J=7.16, 4H).

Step 3. Preparation of ethyl 3-(2-bromoimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (4)

(257) Ethyl 3-(2-chloroacetyl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (3) was dissolve|d in acetone (5.4 mmol) and NaBr (1.08 mmol) was added to the solution and the reaction mixture was stirred at 50 C. for 16 hr. Upon completion, the reaction was filtered, concentrated under reduced pressure and used directly in the next reaction. A mixture of ethyl 3-(2-bromoacetyl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (0.45 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (0.68 mmol) were dissolved in ACN/IPA (1:1; 5.6 mL) in a microwave vial that was sealed and heated to 80 C. for 18 hr. Next, the vial was placed in a Microwave for 30 minutes at 150 C. The reaction was diluted with DCM, washed with saturated sodium bicarb. (10 mL), brine, and dried over magnesium sulfate. Purification by silica chromatography (Hexanes30% EtOAc/Hexanes-80% EtOAc/Hexanes) afforded the title compound in 62% yield. M+H=476, RT=1.338.

(258) .sup.1H NMR (400 MHz, chloroform-d) 9.21 (s, 1H), 8.62 (s, 1H), 8.43-8.44 (m, 1H), 7.37-7.40 (d, J=8.92 Hz, 1H), 7.22-7.25 (m, 1H), 4.41-4.46 (q, J=7.14 Hz, 3H), 1.41-1.44 (t, J=7.14, 4H).

Step 4. Preparation of methyl 3-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (5)

(259) A solution of ethyl 3-(2-bromoimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (4) (0.28 mmol) in a mixture of DCM/MeOH (4:1; 12.5 mL) was treated at 22 C. with a 25 wt. % solution of NaOMe (1.1 mmol) in MeOH. Next, an additional 2.5 mL of MeOH was added and the reaction was stirred fir 1 hr. Upon completion, the reaction mixture was quenched by addition of 1% HCl (5 mL) followed by addition of sat. NaHCO.sub.3 (5 mL). Solvent was evaporated and the residue was diluted with DCM, washed with brine, dried with magnesium sulfate and evaporated. Column chromatography on silica (100% DCM-5% EtOAc/DCM-30% EtOAc/DCM) afforded title compound in 38% yield. M+H=413, RT=1.131.

(260) .sup.1H NMR (400 MHz, chloroform-d) 9.08 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 7.36-7.39 (d, J=8.88 Hz, 1H), 7.22-7.24 (d, J=8.76 Hz, 1H), 4.2165 (s, 1H), 3.96 (s, 1H).

Step 5. Preparation of methyl 1-(2-chlorobenzyl)-3-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (6)

(261) To a vial containing a magnetic stir bar were added methyl 3-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (5) (0.02 mmol), potassium carbonate (0.05 mmol), and DMF (0.5 mL). Next, 2-chlorobenzyl bromide (0.05 mmol) was added and the reaction was stirred at ambient temperature for 16 hr. The reaction was then diluted with EtOAc (3 mL) and washed successively with 5% LiCl (25 mL) and brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica (Hexanes-25% EtOAc/Hexanes) afforded title compound in 30% yield. M+H=536, RT=1.268

Step 6. Preparation of (1-(2-chlorobenzyl)-3-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanol (7)

(262) To vial were added methyl 1-(2-chlorobenzyl)-3-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxylate (6) (0.006 mmol) in THF (1.5 mL) followed by LiBH.sub.4 (0.014 mmol) at room temperature. The mixture was allowed to stir for 16 hr and then quenched by addition of Glauber's salt, filtered, and concentrated. Column chromatography on silica (10% EtOAc/Hexanes-25% EtOAc/Hexanes-50% EtOAc/Hexanes) afforded title compound in 43% yield. M+H=454; RT=1.093

(263) .sup.1H NMR (400 MHz, chloroform-d) 7.92 (s, 1H), 7.65 (s, 1H), 7.42-7.44 (dd, J.sub.1=0.98 Hz, J.sub.2=7.94 Hz, 1H), 7.18-7.23 (m, 2H), 7.04-7.10 (m, 2H), 6.43-6.45 (d, J=7.40 Hz, 1H), 5.73 (s, 1H), 5.56 (s, 2H), 4.76 (s, 2H), 4.24 (s, 3H).

(264) TABLE-US-00001 TABLE 1 I. Synthetic LC-MS Retention Example/ No. Compound [M + H] time Scheme* B1 447 1.034 Intermediate A1/Ex. 1/ Scheme 1 B2 465 1.075 Intermediate A1/Ex. 1/ Scheme 1 B3 497 1.105 Intermediate A1/Ex. 1/ Scheme 1 B4 429 1.095 Intermediate A1/Ex. 1/ Scheme 1 B5 465 1.145 Intermediate A1/Ex. 1/ Scheme 1 B6 447 1.136 Intermediate A1/Ex. 1/ Scheme 1 B7 0 507 1.272 Intermediate A1/Ex. 1/ Scheme 1 B8 353 1.095 Intermediate A1/Ex. 1/ Scheme 1 B9 463 1.205 Intermediate A1/Ex. 1/ Scheme 1 B10 489 1.255 Intermediate A1/Ex. 1/ Scheme 1 B11 459 1.191 Intermediate A1/Ex. 1/ Scheme 1 B12 463 1.216 Intermediate A1/Ex. 1/ Scheme 1 B13 443 1.132 Intermediate A2/Ex. 1/ Scheme 2 B14 414 1.055 Intermediate A2/Ex. 1/ Scheme 2 B15 346 0.980 Intermediate A2/Ex. 1/ Scheme 2 B16 376 0.988 Intermediate A2/Ex. 1/ Scheme 2 B17 0 426 0.995 Intermediate A2/Ex. 1/ Scheme 2 B18 380 0.959 Intermediate A2/Ex. 1/ Scheme 2 B19 430 1.050 Intermediate A2/Ex. 1/ Scheme 2 B20 364 0.985 Intermediate A2/Ex. 1/ Scheme 2 B21 503 0.989 Intermediate A1/Ex. 1/ Scheme 1 B22 507 0.923 Intermediate A1/Ex. 1/ Scheme 1 B23 441 1.005 Intermediate A1/Ex. 1/ Scheme 1 B24 370 1.215 Intermediate A1/Ex. 1/ Scheme 1 B25 453 0.985 Intermediate A1/Ex. 1/ Scheme 1 B26 371 0.866 Intermediate A1/Ex. 1/ Scheme 1 B27 0 424 0.82 Intermediate A1/Ex. 1/ Scheme 1 B28 400 1.055 Intermediate A1/Ex. 1/ Scheme 1 B29 491 1.152 Intermediate A1/Ex. 1/ Scheme 1 B30 457 1.205 Intermediate A1/Ex. 1/ Scheme 1 B31 448 1.178 Intermediate A1/Ex. 1/ Scheme 1 B32 454 1.213 Intermediate A1/Ex. 1/ Scheme 1 B33 406 1.142 Intermediate A1/Ex. 1/ Scheme 1 B34 404 1.161 Intermediate A1/Ex. 1/ Scheme 1 B35 438 1.19 Intermediate A1/Ex. 1/ Scheme 1 B36 413 1.086 Intermediate A1/Ex. 1/ Scheme 1 B37 0 389 1.049 Intermediate A2/Ex. 1/ Scheme 2 B38 390 0.833 Intermediate A2/Ex. 1/ Scheme 2 B39 423 1.17 Intermediate A2/Ex. 1/ Scheme 2 B40 432 1.049 Intermediate A2/Ex. 1/ Scheme 2 B41 407 1.119 Intermediate A2/Ex. 1/ Scheme 2 B42 457 1.139 Intermediate A2/Ex. 1/ Scheme 2 B43 423 1.711 Intermediate A2/Ex. 1/ Scheme 2 B44 469 1.159 Intermediate A2/Ex. 1/ Scheme 2 B45 419 1.059 Intermediate A2/Ex. 1/ Scheme 2 B46 425 1.147 Intermediate A2/Ex. 1/ Scheme 2 B47 00 433 1.057 Intermediate A1/Ex. 1/ Scheme 1 B48 01 466 (MOH) 1.306 Intermediate A1/Ex. 1/ Scheme 1 B49 02 420 (MOH) 1.297 Intermediate A1/Ex. 1/ Scheme 1 B50 03 480 1.037 Intermediate A1/Ex. 1/ Scheme 1 B51 04 464 (MOH) 1.428 Intermediate A1/Ex. 1/ Scheme 1 B52 05 478 1.042 Intermediate A1/Ex. 1/ Scheme 1 B53 06 453 1.332 Intermediate A1/Ex. 1/ Scheme 1 B54 07 464 1.027 Intermediate A1/Ex. 1/ Scheme 1 B55 08 434 1.016 Intermediate A1/Ex. 1/ Scheme 1 B56 09 450 (MOH) 1.384 Intermediate A1/Ex. 1/ Scheme 1 B57 0 451 1.342 Intermediate A1/Ex. 1/ Scheme 1 B58 435 1.068 Intermediate A1/Ex. 1/ Scheme 1 B59 409 1.100 Intermediate A2/Ex. 1/ Scheme 2 B60 426 1.118 Intermediate A2/Ex. 1/ Scheme 2 B61 423 1.135 Intermediate A2/Ex. 1/ Scheme 2 B62 429 1.187 Intermediate A2/Ex. 1/ Scheme 2 B63 440 1.197 Intermediate A2/Ex. 1/ Scheme 2 B64 454 1.184 Intermediate A2/Ex. 1/ Scheme 2 B65 463 1.191 Intermediate A2/Ex. 1/ Scheme 2 B66 437 1.13 Intermediate A2/Ex. 1/ Scheme 2 B67 0 339 1.011 B68 514 1.225 Intermediate A1/Ex. 1/ Scheme 1 B69 512 1.218 Intermediate A1/Ex. 1/ Scheme 1 B70 511.7 (loss of methyl-2- phenylthiazole) 1.1213 Intermediate A1/Ex. 1/ Scheme 1, 3-4 B71 480 1.216 Intermediate A2/Ex. 1/ Scheme 2 B72 403 1.079 Intermediate A2/Ex. 1/ Scheme 2 B73 460 1.100 (non-polar method) Intermediate A2/Ex. 1/ Scheme 2 B74 435 0.926 Intermediate A2/Ex. 2/ Scheme 4-5 B75 590 0.948 Intermediate A2/Ex. 2/ Scheme 4-5 B76 480 1.396 Intermediate A2/Ex. 1/ Scheme 2

(265) 3. Assay Descriptions

(266) PAC-1 Binding assay: 60 L of washed platelets (Tyrodes buffer containing 0.1% BSA) at a concentration of 0.1510.sup.8 platelets/mL were added to 5 mL round bottom polystyrene tubes (BD, Franklin Lakes, N.J.). FITC conjugated PAC-1 (BD Biosciences, San Jose, Calif.) antibody was diluted (to the manufacturers recommended concentration) in Tyrode's buffer containing 0.1% BSA. 40 L of diluted antibody was added to the platelets and allowed to incubate for 5 minutes. Platelets were pre-treated with indicated concentrations of antagonist or DMSO control for 5 minutes followed by addition of PAR1-AP (GL Biochem, Shanghai, China) or PAR4-AP for 10 minutes. Platelet activity was quenched by the addition of ice cold 1.5% paraformaldehyde followed by dilution in 1 phosphate buffered saline. The final DMSO concentration was 0.5%. Platelets were stored up to 18 hours at 4 C. before flow cytometric analysis. Analysis was carried out on a BD FACS Canto II (Franklin Lakes, N.J.). Fluorescent intensity was determined for 100,000 events within the platelet gate. Data was collected and analyzed via FACS DiVa software. Flow cytometric data analysis was conducted by the following method. The DMSO-vehicle treated control was subtracted from each data point. 100% response for PAR4-AP was determined for each individual as the DMSO treated control stimulated with either 200 M PAR4-AP, or 20 M PAR1-AP. Data was plotted in GraphPad PRISM v.5.0. For compounds with a notable reduction in PAC-1 binding response, dose response curves and IC.sub.50 values were generated using the inhibitory sigmoidal dose response variable slope parameter. PAR4 results are plotted as mean values.

(267) 4. In Vitro Activity of Representative PAR4 Antagonists.

(268) TABLE-US-00002 TABLE 2 % Max PAC-1/IC.sub.50 Example [M] B1 80.6 B2 19.7/8.23E07 B3 59.7 B4 53.4 B5 36.5 B6 89.0 B7 27.2 B8 93.9 B9 21.4/6.58E07 B10 110.6 B11 40.9 B12 27.8 B13 108.5 B14 49.5 B15 109.0 B16 69.0 B17 76.2 B18 80.6 B19 42.9/1.0E05 B20 97.5 B21 74.3 B22 87.4 B23 84.6 B24 83.9 B25 77.5 B26 113.7 B27 100.1 B28 82.3 B29 88.6 B30 77.7 B31 109.1 B32 114.3 B33 105.0 B34 85.4 B35 90.5 B36 108.8 B37 80.7 B38 107.2 B39 100.1 B40 98.6 B41 61.9 B42 71.3 B43 83.6 B44 96.5 B45 129.1 B46 94.7 B47 101.7 B48 14.5/1.98E06 B49 96.0 B50 4.68/5.51E07 B51 48.5 B52 24.0 B53 48.2 B54 2.01/2.9E06 B55 101.8 B56 53.7/>1.0E05 B57 21.05/1.29E06 B58 102.2 B59 4.31/1.35E06 B60 21.33/4.30E06 B61 19.78/3.84E06 B62 34.32/3.71E06 B63 14.77/2.15E06 B64 18.53/1.38E06 B65 12.25/9.66E07 B66 59.45 B67 116.1 B68 61.98 B69 89.19 B70 61.82 B71 5.57/1.62E07 B72 81.76 B73 107.63 B74 38.32 B75 8.40/1.84E07 B76 79.22

F. REFERENCES

(269) 1. Ruggeri, Z. M. Platelets in atherothrombosis. Nat. Med. 2002, 8, 1227-1234. 2. Adams, M. N.; Ramachandran, R.; Yau, M.-K.; Suen, J. Y.; Fairlie, D. P.; Hollenberg, M. D.; Hooper, J. D. Pharm. Therap. 2011, 130, 248-282. 3. Coughlin, S. Nature 2000, 407, 258-322. 4. Kahn, M. L.; Zheng, Y. W.; Huang, W.; Bigornia, V.; Zeng, D.; Moff, S.; Farese, R. V., Jr.; Tam, C.; Coughlin, S. R. Nature 1998, 394, 690-694. 5. Mao, Y.; Zhang, M.; Tuma, R.; Kunapuli, S. Journal of cerebral blood flow and metabolism 2010, 30, 1044-1096. 6. Vandendries, E. R.; Hamilton, J. R.; Coughlin, S. R.; Furie, B.; Furie, B. C. Proc. Nat. Acad. Sci. USA 2007, 104, 288-292. 7. Cornelissen, I.; Palmer, D.; David, T.; Wilsbacher, L.; Concengco, C.; Conley, P.; Pandey, A.; Coughlin, S. R. Proc. Nat. Acad. Sci. USA 2010, 107, 18605-18615. 8. Sambrano, G.; Weiss, E.; Zheng, Y.; Huang, W.; Coughlin, S. Nature 2001, 413, 7 4-82. 9. Henrih-Noack, P.; Riek-Burchardt, M.; Baldauf, K.; Reiser, G.; Reymann, K. Brain Research 2006, 1070, 232-273. 10. See http://www.mercknewsroom.com and http://www.fda.gov for May 2014 Zontivity press releases. 11. For information on the MLPCN and information on how to request probe compounds, such as ML354, see: http://mli.nih.gov/mli/mlpcn/. 12. Lee, F.-Y.; Lien, J.-C.; Huang, L.-J.; Huang, T.-M.; Tsai, S.-C.; Teng, C.-M.; Wu, C.-C.; Cheng, F.-C.; Kuo, S.-C. J. Med. Chem. 2001, 44, 3746-3755. 13. Chen, H.-S.; Kuo, S.-C.; Teng, C.-M.; Lee, F.-Y.; Want, J.-P.; Lee, Y.-C.; Kuo, C.-W.; Huang, C.-C.; Wu, C.-C.; Huang, L.-J. Bioorg. Med. Chem. 2008, 16, 1262-1340. 14. Young, S. E.; Duvernay, M. T.; Schulte, M. L.; Lindsley, C. W.; Hamm, H. E. PLoS One 2013, 8, e65528. 15. Smith, G. F. Progress in Medicinal Chemistry 2011, 50, 1-47. 16. Kou-San, J. Microbiology and Molecular Biology Reviews 2012, 74, 250-272. 17. Cai, Q.; Li, Z.; Wei, J.; Ha, C.; Pei, C.; Ding, K. Chem. Commun. 2009, 7581-7583. 18. Meanwell, N. A. J. Med. Chem. 2011, 54, 2529-2591.