Claims for Patent: 10,420,775

Summary for Patent: 10,420,775

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. (Westwood, MA), Keilhack; Heike (Belmont, MA), Warholic; Natalie (Brighton, MA), Klaus; Christine (Waban, MA), Knutson; Sarah K. (Cambridge, MA), Wigle; Timothy J. N. (Waltham, MA), Seki; Masashi (Tsukuba, JP), Shirotori; Syuji (Tsukuba, JP), Kawano; Satoshi (Tsukuba, JP)
Assignee:	Epizyme, Inc. (Cambridge, MA)
Application Number:	15/816,907
Patent Claims:	1. A method of treating a cell proliferative disorder comprising administering to a subject in need thereof a therapeutically effective amount of 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.S2and 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.aand 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.aand 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.dand R.sub.e independently being H or C.sub.1-C.sub.6 alkyl, or -Q.sub.3-T.sub.3is 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 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; 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 method of claim 1, wherein the cell proliferative disorder is cancer or a precancerous disorder. 3. The method of claim 2, wherein the cancer is a solid tumor. 4. The method of claim 2, wherein the cancer is lymphoma, leukemia, or melanoma. 5. The method of claim 2, wherein the cancer is melanoma. 6. The method of claim 2, wherein the precancerous condition is myelodysplastic syndrome. 7. The method of claim 1, wherein the cell proliferative disorder is a cell proliferative disorder of the lung. 8. The method of claim 7, wherein the cell proliferative disorder of the lung is asbestos-induced hyperplasia. 9. The method of claim 7, wherein the cell proliferative disorder of the lung is lung cancer. 10. The method of claim 9, wherein the lung cancer is mesothelioma. 11. The method of claim 9, wherein the lung cancer is malignant mesothelioma. 12. The method of claim 9, wherein the compound is ##STR00442## or a pharmaceutically acceptable salt thereof. 13. The method of claim 1, 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, SR.sub.7, or CR.sub.7R.sub.8R.sub.14; 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 7-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 7-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 7-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.S2and 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 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R.sub.aand 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.aand R.sub.b, is optionally substituted with one or more 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 7-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.dand R.sub.e independently being H or C.sub.1-C.sub.6 alkyl, or -Q.sub.3-T.sub.3is 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 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; provided that -Q.sub.2-T.sub.2is not H; 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; 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, 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 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 T6 is H, halo, hydroxyl, or cyano; or -Q.sub.6-T.sub.6 is oxo; R.sub.12 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; 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 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 14. The method of claim 1, wherein R.sub.6 is phenyl substituted with one or more -Q.sub.2-T.sub.2. 15. The method 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. 16. The method of claim 1, wherein each of R.sub.1 and R.sub.11 is H and each of R.sub.2and 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. 17. The method of claim 1, wherein R.sub.12 is methyl, ethyl, ethenyl, or halo; and R.sub.8is H, methyl or ethyl. 18. The method of claim 1, wherein X.sub.1 is CR.sub.11 and X.sub.2 is CR.sub.13. 19. The method of claim 1, wherein Z is NR.sub.7R.sub.8. 20. The method of claim 1, wherein the compound is ##STR00443## or a pharmaceutically acceptable salt thereof.