Claims for Patent: 9,090,562

Summary for Patent: 9,090,562

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 Wayne (Woburn, MA), Chesworth; Richard (Concord, MA), Duncan; Kenneth William (Norwood, MA), Keilhack; Heike (Belmont, MA), Warholic; Natalie (Brighton, MA), Klaus; Christine (Weymouth, MA), Knutson; Sarah Kathleen (Cambridge, MA), Wigle; Timothy James Nelson (Waltham, MA), Seki; Masashi (Tsukuba, JP), Shirotori; Syuji (Tsukuba, JP), Kawano; Satoshi (Tsukuba, JP)
Assignee:	Epizyme, Inc. (Cambridge, MA)
Application Number:	14/275,667
Patent Claims:	1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: ##STR00441## wherein X.sub.1 is N or CR.sub.11; X.sub.2 is N or CR.sub.13; Z is NR.sub.7R.sub.8, OR.sub.7, S(O).sub.nR.sub.7, or CR.sub.7R.sub.8R.sub.14, in which n is 0, 1, or 2; each of R.sub.1, R.sub.5, R.sub.9, and R.sub.10, independently, is H or C.sub.1-C.sub.6 alkyl 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; each of R.sub.2, R.sub.3, and R.sub.4, independently, is -Q.sub.1-T.sub.1, in which Q.sub.1 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.1 is H, halo, hydroxyl, COOH, cyano, or R.sub.S1, in which R.sub.S1 is C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxyl, C(O)O--C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R.sub.S1 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, 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.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; each of R.sub.8, R.sub.11, and R.sub.13, independently, 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 they are attached, form a 4 to 11-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, or R.sub.7 and R.sub.8, together with the C atom to which they are attached, form C.sub.3-C.sub.8 cycloalkyl or a 4 to 11-membered heterocycloalkyl ring having 1 to 3 heteroatoms, and each of the 4 to 11-membered heterocycloalkyl rings or C.sub.3-C.sub.8 cycloalkyl 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; R.sub.12 is 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; and R.sub.14 is absent, H, or C.sub.1-C.sub.6 alkyl 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. 2. The compound of claim 1, wherein R.sub.6 is phenyl substituted with one or more -Q.sub.2-T.sub.2. 3. The compound of claim 1, wherein R.sub.6 is 5- or 6-membered heteroaryl containing 1-3 additional heteroatoms selected from N, O, and S and optionally substituted with one or more -Q.sub.2-T.sub.2. 4. The compound of claim 1, wherein R.sub.7 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl or 4 to 12-membered heterocycloalkyl, each optionally substituted with one or more -Q.sub.5-T.sub.5. 5. The compound of claim 1, wherein each of R.sub.1 and R.sub.11 is H and each of R.sub.2 and R.sub.4, independently is H or C.sub.1-C.sub.6 alkyl optionally substituted with amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, or C.sub.6-C.sub.10 aryl. 6. The compound of claim 1, wherein R.sub.12 is methyl, ethyl, ethenyl, or halo; and R.sub.8 is H, methyl, or ethyl. 7. The compound of claim 1, wherein X.sub.1 is CR.sub.11 and X.sub.2 is CR.sub.13. 8. The compound of claim 1, wherein X.sub.1 is CR.sub.11 and X.sub.2 is N. 9. The compound of claim 1, wherein X.sub.1 is N and X.sub.2 is CR.sub.13. 10. The compound of claim 1, wherein X.sub.1 is N and X.sub.2 is N. 11. The compound of claim 1, wherein Z is NR.sub.7R.sub.8. 12. The compound of claim 1, wherein Z is CR.sub.7R.sub.8R.sub.14. 13. The compound of claim 1, wherein Z is OR.sub.7. 14. The compound of claim 1, wherein Z is SR.sub.7. 15. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 16. 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 unsubstituted or substituted with one or more -Q.sub.2-T.sub.2, in which Q.sub.2 is a bond or methyl or ethyl linker and T.sub.2 is H, halo, --OR.sub.a, --NR.sub.aR.sub.b, --(NR.sub.aR.sub.bR.sub.c).sup.+A.sup.-, --S(O).sub.2R.sub.a, or --S(O).sub.2NR.sub.aR.sub.b. 17. The compound of claim 1, wherein the compound is of Formula (Ig) or a pharmaceutically acceptable salt thereof: ##STR00442## in which R.sub.6 is phenyl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q.sub.2-T.sub.2, in which Q.sub.2 is a bond or C.sub.1-C.sub.3 alkyl linker optionally substituted with halo or hydroxyl, and T.sub.2 is H, halo, --OR.sub.a, --NR.sub.aR.sub.b, --(NR.sub.aR.sub.bR.sub.c).sup.+A.sup.-, --S(O).sub.2R.sub.a, or --S(O).sub.2NR.sub.aR.sub.b, and R.sub.7 is piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, each optionally substituted with one -Q.sub.5-T.sub.5. 18. The compound of claim 17, wherein R.sub.6 is phenyl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q.sub.2-T.sub.2, in which Q.sub.2 is a bond or methyl linker, and T.sub.2 is --OR.sub.a, --NR.sub.aR.sub.b, --(NR.sub.aR.sub.bR.sub.c).sup.+A.sup.-, or --S(O).sub.2R.sub.a. 19. The compound of claim 17, wherein Q.sub.5 is a bond and T.sub.5 is amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino. 20. The compound of claim 17, wherein R.sub.6 is phenyl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q.sub.2-T.sub.2, in which Q.sub.2 is a bond or methyl linker, and T.sub.2 is --OR.sub.a or --S(O).sub.2R.sub.a, in which R.sub.a is H or C.sub.1-C.sub.6 alkyl optionally substituted with one or more -Q.sub.3-T.sub.3.