Claims for Patent: 8,410,088

Summary for Patent: 8,410,088

Title:	Aryl- or heteroaryl-substituted benzene compounds
Abstract:	The present invention relates to aryl- or heteroaryl-substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.
Inventor(s):	Kuntz; Kevin W. (Woburn, MA), Chesworth; Richard (Concord, MA), Duncan; Kenneth W. (Norwood, MA), Seki; Masashi (Tsukuba, JP), Shirotori; Syuji (Tsukuba, JP)
Assignee:	Epizyme, Inc. (Cambridge, MA) Eisai R&D Management Co., Ltd. (Tokyo, JP)
Application Number:	13/447,007
Patent Claims:	1. A compound of Formula (Ig) or a pharmaceutically acceptable salt thereof: ##STR00440## wherein R.sub.2, R.sub.4 and R.sub.12 are each, independently C.sub.1-6 alkyl; R.sub.6 is C.sub.6-C.sub.10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more -Q.sub.2-T.sub.2, wherein Q.sub.2 is a bond or C.sub.1-C.sub.3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C.sub.1-C.sub.6 alkoxy, and T.sub.2 is H, halo, cyano, --OR.sub.a, --NR.sub.aR.sub.b, --(NR.sub.aR.sub.bR.sub.c).sup.+A.sup.-, --C(O)R.sub.a, --C(O)OR.sub.a, --C(O)NR.sub.aR.sub.b, --NR.sub.bC(O)R.sub.a, --NR.sub.bC(O)OR.sub.a, --S(O).sub.2R.sub.a, --S(O).sub.2NR.sub.aR.sub.b, or R.sub.S2, in which each of R.sub.a, R.sub.b and R.sub.c, independently is H or R.sub.S3, A.sup.- is a pharmaceutically acceptable anion, each of R.sub.S2 and R.sub.S3, independently, is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R.sub.a and R.sub.b, together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R.sub.S2, R.sub.S3, and the 4 to 12-membered heterocycloalkyl ring formed by R.sub.a and R.sub.b, is optionally substituted with one or more -Q.sub.3-T.sub.3, wherein Q.sub.3 is a bond or C.sub.1-C.sub.3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C.sub.1-C.sub.6 alkoxy, and T.sub.3 is selected from the group consisting of halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR.sub.d, COOR.sub.d, --S(O).sub.2R.sub.d, --NR.sub.dR.sub.e, and --C(O)NR.sub.dR.sub.e, each of R.sub.d and R.sub.e independently being H or C.sub.1-C.sub.6 alkyl, or -Q.sub.3-T.sub.3 is oxo; or any two neighboring -Q.sub.2-T.sub.2, together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O--C.sub.1-C.sub.6 alkyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; R.sub.7 is -Q.sub.4-T.sub.4, in which Q.sub.4 is a bond, C.sub.1-C.sub.4 alkyl linker, or C.sub.2-C.sub.4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C.sub.1-C.sub.6 alkoxy, and T.sub.4 is H, halo, cyano, NR.sub.fR.sub.g, --OR.sub.f, --C(O)R.sub.f, --C(O)OR.sub.f, --C(O)NR.sub.fR.sub.g, --C(O)NR.sub.fOR.sub.g, --NR.sub.fC(O)R.sub.g, --S(O).sub.2R.sub.f, or R.sub.S4, in which each of R.sub.f and R.sub.g, independently is H or R.sub.S5, each of R.sub.S4 and R.sub.S5, independently is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R.sub.S4 and R.sub.S5 is optionally substituted with one or more -Q.sub.5-T.sub.5, wherein Q.sub.5 is a bond, C(O), C(O)NR.sub.k, NR.sub.kC(O), S(O).sub.2, or C.sub.1-C.sub.3 alkyl linker, R.sub.k being H or C.sub.1-C.sub.6 alkyl, and T.sub.5 is H, halo, C.sub.1-C.sub.6 alkyl, hydroxyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O).sub.qR.sub.q in which q is 0, 1, or 2 and R.sub.q is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T.sub.5 is optionally substituted with one or more substituents selected from the group consisting of halo, C.sub.1-C.sub.6 alkyl, hydroxyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T.sub.5 is H, halo, hydroxyl, or cyano; or -Q.sub.5-T.sub.5 is oxo; and R.sub.8 is H, halo, hydroxyl, COOH, cyano, R.sub.S6, OR.sub.S6, or COOR.sub.S6, in which R.sub.S6 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-C.sub.1-C.sub.6 alkylamino, or di-C.sub.1-C.sub.6 alkylamino, and R.sub.S6 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O--C.sub.1-C.sub.6 alkyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, and di-C.sub.1-C.sub.6 alkylamino; or R.sub.7 and R.sub.8, together with the N atom to which the are attached, form a 4 to 11-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, and the 4 to 11-membered heterocycloalkyl ring formed by R.sub.7 and R.sub.8 is optionally substituted with one or more -Q.sub.6-T.sub.6, wherein Q.sub.6 is a bond, C(O), C(O)NR.sub.m, NR.sub.mC(O), S(O).sub.2, or C.sub.1-C.sub.3 alkyl linker, R.sub.m being H or C.sub.1-C.sub.6 alkyl, and T.sub.6 is H, halo, C.sub.1-C.sub.6 alkyl, hydroxyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O).sub.pR.sub.p in which p is 0, 1, or 2 and R.sub.p is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T.sub.6 is optionally substituted with one or more substituents selected from the group consisting of halo, C.sub.1-C.sub.6 alkyl, hydroxyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T.sub.6 is H, halo, hydroxyl, or cyano; or -Q.sub.6-T.sub.6 is oxo. 2. The compound of claim 1, wherein R.sub.6 is C.sub.6-C.sub.10 aryl or 5- or 6-membered heteroaryl, each of which is optionally, independently substituted with one or more -Q.sub.2-T.sub.2, wherein Q.sub.2 is a bond or C.sub.1-C.sub.3 alkyl linker, and T.sub.2 is H, halo, cyano, --OR.sub.a, --NR.sub.aR.sub.b, --(NR.sub.aR.sub.bR.sub.c).sup.+A.sup.-, C(O)NR.sub.aR.sub.b, --NR.sub.bC(O)R.sub.a, --S(O).sub.2R.sub.a, or R.sub.S2, in which each of R.sub.a and R.sub.b, independently is H or R.sub.S3, each of R.sub.S2 and R.sub.S3, independently, is C.sub.1-C.sub.6 alkyl, or R.sub.a and R.sub.b, together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R.sub.S2, R.sub.S3, and the 4 to 7-membered heterocycloalkyl ring formed by R.sub.a and R.sub.b, is optionally, independently substituted with one or more -Q.sub.3-T.sub.3, wherein Q.sub.3 is a bond or C.sub.1-C.sub.3 alkyl linker and T.sub.3 is selected from the group consisting of halo, C.sub.1-C.sub.6 alkyl, 4 to 7-membered heterocycloalkyl, OR.sub.d, --S(O).sub.2R.sub.d, and --NR.sub.dR.sub.e, each of R.sub.d and R.sub.e independently being H or C.sub.1-C.sub.6 alkyl, or -Q.sub.3-T.sub.3 is oxo; or any two neighboring -Q.sub.2-T.sub.2, together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S. 3. The compound of claim 1, wherein the compound is of Formula (II) or a pharmaceutically acceptable salt thereof: ##STR00441## wherein Q.sub.2 is a bond or methyl linker, T.sub.2 is H, halo, --OR.sub.a, --NR.sub.aR.sub.b, --(NR.sub.aR.sub.bR.sub.c).sup.+A.sup.-, or --S(O).sub.2NR.sub.aR.sub.b, R.sub.7 is piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, each optionally substituted with one -Q.sub.5-T.sub.5 and R.sub.8 is ethyl. 4. A compound of Formula (IIa) or a pharmaceutically acceptable salt thereof: ##STR00442## wherein each of R.sub.a and R.sub.b, independently is H or R.sub.S3, R.sub.S3 being C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R.sub.a and R.sub.b, together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R.sub.S3 and the 4 to 12-membered heterocycloalkyl ring formed by R.sub.a and R.sub.b, is optionally substituted with one or more -Q.sub.3-T.sub.3, wherein Q.sub.3 is a bond or C.sub.1-C.sub.3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C.sub.1-C.sub.6 alkoxy, and T.sub.3 is selected from the group consisting of halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR.sub.d, COOR.sub.d, --S(O).sub.2R.sub.d, --NR.sub.dR.sub.e, and --C(O)NR.sub.dR.sub.e, each of R.sub.d and R.sub.e independently being H or C.sub.1-C.sub.6 alkyl, or -Q.sub.3-T.sub.3 is oxo; R.sub.7 is -Q.sub.4-T.sub.4, in which Q.sub.4 is a bond, C.sub.1-C.sub.4 alkyl linker, or C.sub.2-C.sub.4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C.sub.1-C.sub.6 alkoxy, and T.sub.4 is H, halo, cyano, NR.sub.fR.sub.g, --OR.sub.f, --C(O)R.sub.f, --C(O)OR.sub.f, --C(O)NR.sub.fR.sub.g, --C(O)NR.sub.fOR.sub.g, --NR.sub.fC(O)R.sub.g, --S(O).sub.2R.sub.f, or R.sub.S4, in which each of R.sub.f and R.sub.g, independently is H or R.sub.S5, each of R.sub.S4 and R.sub.S5, independently is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R.sub.S4 and R.sub.S5 is optionally substituted with one or more -Q.sub.5-T.sub.5, wherein Q.sub.5 is a bond, C(O), C(O)NR.sub.k, NR.sub.kC(O), S(O).sub.2, or C.sub.1-C.sub.3 alkyl linker, R.sub.k being H or C.sub.1-C.sub.6 alkyl, and T.sub.5 is H, halo, C.sub.1-C.sub.6 alkyl, hydroxyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O).sub.qR.sub.q in which q is 0, 1, or 2 and R.sub.q is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T.sub.5 is optionally substituted with one or more substituents selected from the group consisting of halo, C.sub.1-C.sub.6 alkyl, hydroxyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T.sub.5 is H, halo, hydroxyl, or cyano; or -Q.sub.5-T.sub.5 is oxo; provided that R.sub.7 is not H; and R.sub.8 is H, halo, hydroxyl, COOH, cyano, R.sub.S6, OR.sub.S6, or COOR.sub.S6, in which R.sub.S6 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, amino, mono-C.sub.1-C.sub.6 alkylamino, or di-C.sub.1-C.sub.6 alkylamino, and R.sub.S6 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O--C.sub.1-C.sub.6 alkyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, and di-C.sub.1-C.sub.6 alkylamino; or R.sub.7 and R.sub.8, together with the N atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring which has 0 to 2 additional heteroatoms and is optionally substituted with one or more -Q.sub.6-T.sub.6, wherein Q.sub.6 is a bond, C(O), C(O)NR.sub.m, NR.sub.mC(O), S(O).sub.2, or C.sub.1-C.sub.3 alkyl linker, R.sub.m being H or C.sub.1-C.sub.6 alkyl, and T.sub.6 is H, halo, C.sub.1-C.sub.6 alkyl, hydroxyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O).sub.pR.sub.p in which p is 0, 1, or 2 and R.sub.p is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T.sub.6 is optionally substituted with one or more substituents selected from the group consisting of halo, C.sub.1-C.sub.6 alkyl, hydroxyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4 to 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T.sub.6 is H, halo, hydroxyl, or cyano; or -Q.sub.6-T.sub.6 is oxo. 5. The compound of claim 4, wherein R.sub.a and R.sub.b, together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom and the ring is optionally substituted with one or more -Q.sub.3-T.sub.3, wherein the heterocycloalkyl is azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, or morpholinyl. 6. The compound of claim 5, wherein R.sub.7 is C.sub.3-C.sub.8 cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q.sub.5-T.sub.5. 7. The compound of claim 6, wherein R.sub.7 is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl, each optionally substituted with one or more -Q.sub.5-T.sub.5. 8. The compound of claim 7, R.sub.8 is H or C.sub.1-C.sub.6 alkyl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O--C.sub.1-C.sub.6 alkyl, cyano, C.sub.1-C.sub.6 alkoxyl, amino, mono-C.sub.1-C.sub.6 alkylamino, and di-C.sub.1-C.sub.6 alkylamino. 9. The compound of claim 1, wherein the compound is selected from ##STR00443## ##STR00444## ##STR00445## ##STR00446## ##STR00447## ##STR00448## ##STR00449## ##STR00450## ##STR00451## and pharmaceutically acceptable salts thereof. 10. A pharmaceutical composition comprising a compound of Formula (Ig) of claim 1 and a pharmaceutically acceptable carrier. 11. A compound, which is ##STR00452## 12. A pharmaceutically acceptable salt of ##STR00453## 13. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable carrier. 14. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 12 and a pharmaceutically acceptable carrier. 15. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (Ig) of claim 1 and a pharmaceutically acceptable carrier. 16. A pharmaceutical composition comprising a compound of Formula (IIa) of claim 4 and a pharmaceutically acceptable carrier. 17. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (IIa) of claim 4 and a pharmaceutically acceptable carrier. 18. A pharmaceutical composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier. 19. A pharmaceutical composition comprising a compound of Formula (II) of claim 3 and a pharmaceutically acceptable carrier. 20. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (II) of claim 3 and a pharmaceutically acceptable carrier. 21. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier. 22. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier. 23. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier. 24. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier. 25. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier.