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US 2008/0176857 A1Published application
4-Piperazinnylthieno[2,3-d]Pyrimidine Compounds as Platelet Aggregation Inhibitors
OwnerMichael Dalton Ennis, Steven Wade Kortum +1inventors
InventorsMichael Dalton Ennis, Steven Wade Kortum, Ruth Elizabeth Tenbrink
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Abstract
Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I: wherein A1, A2, A3, A4, A5, A6, A7, A8, X4, X6, R2, R4, R5, and R6 are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
Claims15
A compound, or a pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula I:
- wherein:
- A1, A2, A3, A4, A5, A6, A7 and A8 are independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
- R2 is selected from the group consisting of —S(O)R2a, —S(O)2R2a, —S(O)2NR2aR2b, —SC(O)R2a, and
- —SR2j;
- wherein:
- R2a and R2b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2a and R2b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, S, nitro, R2d, C(O)R2d —C(S)R2d, —C(O)OR2, —C(S)OR2d, —C(O)SR2d, C(O)NR2dR2e, —C(S)NR2dR2e, —OR2d, —OC(O)R2d OC(S)R2d, —OC(O)OR2d, —OC(O)NR2dR2e, —OC(S)NR2dR2e, —NR2dR2e, —NR2dC(O)R2e, —NR2dC(S)R2, —NR2dC(O)OR2e, —NR2dC(S)OR2e, —NR2dS(O)nR2e, —NR2dC(O)NR2eR2f, —S(O)nR2d, —S(O)nNR2dR2e, and —SC(O)R2d;
- n is 0, 1 or 2;
- R2d, R2e and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2d, R2e and R2f alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, ═S, nitro, —R2g, —C(O)R2g, —C(S)R2g, —C(O)OR2g, —C(S)OR2g, —C(O)SR2g, —C(O)NR2gR2h, —C(S)NR2gR2h, —OR2g, —OC(O)R2g, —OC(S)R2g, —OC(O)OR2g, —OC(O)NR2gR2h, —OC(S)NR2gR2h, —NR2gR2h, —NR2gC(O)R2h, —NR2gC(O)OR2h, —NR2gC(S)OR2h, —R2gS(O)pR2h, —NR2gC(O)NR2hR2i, —S(O)NR2gR2h and —SC(O)R2g;
- p is 0, 1 or 2;
- R2g, R2h and R2i are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2g, R2h and R2i alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, oxo, ═S, nitro, alkyl, haloalkyl, hydroxyalkyl, carboxy, and alkoxy;
- R2j is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein:
- (a) the R2j C7-C20 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen and —R2m;
- and
- (b) the R2j C1-C6 alkyl substituent is substituted with at least one substituent independently selected from the group consisting of chloro, bromo, iodo, and —R2m;
- R2m is selected from the group consisting of cyano, nitro, —NH2, oxo, ═S, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, —C(O)R2n, —C(S)R2n, —C(O)OR2n, —C(S)OR2n, —C(O)SR2n, —C(O)NR2nR2o, —C(S)NR2nR2o, —OR2n, —OC(O)R2n, —OC(S)R2n, —OC(O)OR2n, —OC(O)NR2nR2o, —OC(S)NR2nR2o, —NR2nR2o, —NR2nC(O)R2o, —NR2nC(S)R2o, —NR2nC(O)OR2o, —NR2nC(S)OR2o, —NR2nS(O)qR2o, —NR2nC(O)NR2oR2n, —S(O)qR2n, S(O)qNR2nR2o, and —SC(O)R2n;
- q is 0, 1 or 2;
- R2n, R2o and R2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2m, R2n, R2o and R2p alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, ═S, —R2q, —C(O)R2q, —C(S)R2q, —C(O)OR2q, —C(S)OR2q, —C(O)SR2q, —C(O)NR2qR2r, —C(S)NR2qR2r, —OR2q, —OC(O)R2r, —OC(S)R2q, —OC(O)OR2—OC(O)NR2qR2r, OC(S)NR2qR2r, —NR2qR2r, —NR2qC(O)R2r, —NR2qC(S)R2r, —NR2qC(O)OR2q, —C(S)OR2r, —NR2qS(O)rR2r, —NR2qC(O)NR2rR2s, —S(O)rR2q, —S(O)rNR2qR2r, and —SC(O)R2q;
- r is 0, 1 or 2;
- R2q, R2r and R2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2q, R2r and R2s alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, oxo, ═S, —SH, nitro, alkyl, haloalkyl, hydroxyalkyl, carboxy, and alkoxy;
- X4 is selected from the group consisting of —C(O)—, —C(S)—, —S(O)— and —S(O)2—;
- R4 is selected from the group consisting of —R4j, —OR4j, and —NR4jR4k;
- wherein R4j and R4k are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, and heterocyclylcarbonylaminoalkyl;
- wherein the R4j and R4k substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyalkyl, oxo, ═S, nitro, cyano, —R4l, —OR4l, —C(O)R4l, —C(O)OR4l, —C(O)NR4lR4m, —OC(O)R4l, —ONR4lR4m, —NR4lR4m, —NR4lC(O)R4m, —NR4lS(O)2R4m, —S(O)bR4l, —SC(O)R4l and —SC(O)NR4lR4m;
- b is 0, 1 or 2;
- R4l and R4m are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
- wherein the R4l and R4m alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, oxo, ═S, nitro, —SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl and alkylamino;
- R5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy and haloalkoxy;
- X6 represents a bond or is —C(O)—;
- wherein:
- (a) when X6 is —C(O)—, R6 is selected from the group consisting of —R6a and —OR6a;
- (b) when X6 represents a bond, R6 is selected from the group consisting of halogen, cyano, —R6a
- and —OR6a;
- R6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
- and
- wherein the R6a alkyl, cycloalkyl and aryl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, ═S, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, carboxy, aryl and heterocyclyl.
38 more elements
A compound, or a pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula I:
- wherein:
- R2 is selected from the group consisting of —S(O)R2a, —S(O)2R2a, —S(O)2NR2aR2b, —SC(O)R2a, and —SR2j;
- wherein:
- R2a and R2b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2a and R2b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, ═S, nitro, —R2d, —C(O)R2d, —C(S)R2d, —C(O)OR2d, —C(S)OR2d, —C(O)SR2d, —C(O)NR2dR2e, —C(S)NR2dR2e, —OR2d, —OC(O)R2d, —OC(S)R2d, —OC(O)OR2d OC(O)NR2dR2e, —OC(S)NR2dR2e, —NR2dR2e, —NR2dC(O)R2e, —NR2dC(S)R2e, —NR2dC(O)OR2e, —NR2dC(S)OR2e, —NR2dS(O)nR2e, —NR2dC(O)NR2eR2f, S(O)R2d, —S(O)nNR2dR2e, and —SC(O)R2d;
- n is 0, 1 or 2;
- R2d, R2e and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2d, R2e and R2f alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, ═S, nitro, —R2g, —C(O)R2g, —C(S)R2g, —C(O)OR2g, —C(S)OR2g, —C(O)SR2g, —C(O)NR2gR2h, —C(S)NR2gR2h, —OR2g, —OC(O)R2g, —OC(S)R2g—OC(O)OR2g, —OC(O)NR2gR2h, —OC(S)NR2gR2h, —NR2gR2h, —NR2gC(O)R2h, —NR2gC(S)R2h, —NR2gC(O)OR2h, —NR2gC(S)OR2h, —NR2gS(O)pR2h, —NR2gC(O)NR2hR2i, —S(O)pR2g, —S(O)NR2gR2h, and —SC(O)R2g;
- p is 0, 1 or 2;
- R2g, R2h and R2i are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2g, R2h and R2i alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, oxo, ═S, nitro, alkyl, haloalkyl, hydroxyalkyl, carboxy, and alkoxy;
- R2j is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein:
- (a) the R2j C7-C20 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen and —R2m;
- and
- (b) the R2j C1-C6 alkyl substituent is substituted with at least one substituent independently selected from the group consisting of chloro, bromo, iodo, and —R2m;
- R2m is selected from the group consisting of cyano, nitro, —NH2, oxo, ═S, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, —C(O)R2n, —C(S)R2n, —C(O)OR2n, —C(S)OR2n, —C(O)SR2n, —C(O)NR2R2o, —C(S)NR2nR2o, —OR2n, —OC(O)R2n, —OC(S)R2n, —OC(O)OR2n, —OC(O)NR2nR2o, —OC(S)NR2nR2o, —NR2nR2o, —NR2nC(O)R2o, —NR2nC(S)R2o, —NR2nC(O)OR2o, —NR2nC(S)OR2o, —NR2nS(O)qR2o, —NR2nC(O)NR2oR2p, —S(O)qR2n, —S(O)qNR2nR2o, and —SC(O)R2n;
- q is 0, 1 or 2;
- R2n, R2o and R2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2m, R2n, R2o and R2p alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, ═S, —R2q, —C(O)R2q, —C(S)R2q, —C(O)OR2q, —C(S)OR2q, —C(O)SR2q, —C(O)NR2qR2r, —C(S)NR2qR2r, —OR2q, —OC(O)R2r, —OC(S)R2q, —OC(O)OR2q, —OC(O)NR2qR2r, —OC(S)NR2qR2r, —NR2qR2r, —NR2qC(O)R2r, —NR2qC(S)R2r, —NR2qC(O)OR2r, —NR2qC(S)OR2r, —NR2qS(O)rR2r, —NR2qC(O)NR2rR2s, —S(O)R2q, —S(O)rNR2qR2r, and —SC(O)R2q;
- r is 0, 1 or 2;
- R2q, R2r and R2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
- wherein the R2q, R2r and R2s alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, oxo, ═S, —SH, nitro, alkyl, haloalkyl, hydroxyalkyl, carboxy, and alkoxy;
- R4 is selected from the group consisting of —R4j, —OR4j, and —NR4jR4k,
- wherein R4j and R4k are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, arylalkenyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, alkoxyaryl, alkoxyalkyl, heterocyclylcarbonylaminoalkyl, haloalkoxyaryl, alkoxycarbonylalkyl, alkoxycarbonylaryl, alkoxyheterocyclyl;
- wherein the R4j and R4k substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyalkyl, oxo, ═S, nitro, cyano, —R4l, —OR4l, —C(O)R4l, —C(O)OR4l, —C(O)NR4lR4m, —OC(O)R4l, —ONR4lR4m, —NR4lR4m, —NR4lC(O)R4m, —NR4lS(O)2R4m, —S(O)bR4l, —SC(O)R4l and —SC(O)NR4lR4m;
- b is 0, 1 or 2;
- R4l and R4m are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
- wherein the R4l and R4m alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, oxo, ═S, nitro, —SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl and alkylamino;
- R5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy and haloalkoxy;
- X6 represents a bond or is —C(O)—;
- wherein:
- (a) when X6 is —C(O)—, R6 is selected from the group consisting of —R6a and —OR6a;
- (b) when X6 represents a bond, R6 is selected from the group consisting of halogen, cyano, —R6a
- and —OR6a;
- R6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
- and
- wherein the R6a alkyl, cycloalkyl and aryl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, ═S, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl and heterocyclyl.
35 more elements
Dependencies are inferred from the claim text.