Claims for Patent: 10,155,002

Summary for Patent: 10,155,002

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 (Waban, 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:	15/346,677
Patent Claims:	1. A method of treating soft tissue sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof: ##STR00440## 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.c, 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, R.sub.12, 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; 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: 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.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 7-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 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 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.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 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; provided that -Q.sub.2-T.sub.2 is 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 Ts 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, R.sub.12, 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 T.sub.6 is H, halo, hydroxyl, or cyano; or -Q.sub.6-T.sub.6 is oxo; 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. 3. The method of claim 2, wherein the compound is of Formula (II): ##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. The method of claim 1, wherein the compound is of Formula (Ia): ##STR00442## 5. The method of claim 1, wherein R.sub.6 is phenyl substituted with one or more -Q.sub.2-T.sub.2. 6. The method 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. 7. The method of claim 6, wherein R.sub.6 is pyridinyl, pyrazolyl, pyrimidinyl, quinolinyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, or thienyl, each of which is optionally substituted with one or more -Q.sub.2-T.sub.2. 8. The method of claim 1, wherein T.sub.2 is --NR.sub.aR.sub.b or --C(O)NR.sub.aR.sub.b, in which each of R.sub.a and R.sub.b, independently is H or 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 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, the C.sub.1-C.sub.6 alkyl and the 4 to 12-membered heterocycloalkyl ring being optionally substituted with one or more -Q.sub.3-T.sub.3. 9. The method of claim 1, wherein Q.sub.2 is C.sub.1-C.sub.3 alkyl linker optionally substituted with halo or hydroxyl. 10. 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. 11. The method of claim 10, wherein R.sub.7 is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more -Q.sub.5-T.sub.5. 12. The method of claim 1, wherein one or more -Q.sub.5-T.sub.5 are oxo; or when Q.sub.5 is a bond, T.sub.5 is amino, mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, or 4 to 12-membered heterocycloalkyl; or when Q.sub.5 is CO, S(O).sub.2, or NHC(O), T.sub.5 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl, C.sub.3-C.sub.8 cycloalkyl, or 4 to 12-membered heterocycloalkyl; or when Q.sub.5 is C.sub.1-C.sub.3 alkyl linker, T.sub.5 is H, C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl, 4 to 12-membered heterocycloalkyl, or S(O).sub.qR.sub.q. 13. The method of claim 1, wherein R.sub.11 is H. 14. The method of claim 1, wherein 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. 15. The method of claim 1, wherein R.sub.1 is H. 16. The method of claim 1, wherein R.sub.12 is H, methyl, ethyl, ethenyl, or halo. 17. The method of claim 1, wherein R.sub.8 is H, methyl, or ethyl. 18. The method of claim 1, wherein Z is NR.sub.7R.sub.8 or CR.sub.7R.sub.8R.sub.14 wherein R.sub.7 and R.sub.8, together with the atom to which they are attached, form a ring selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, and cyclohexenyl, each optionally substituted with one -Q.sub.6-T.sub.6. 19. The method of claim 1, wherein R.sub.13 is H or methyl. 20. The method of claim 1, wherein the compound is of Formula (Ie): ##STR00443## 21. The method of claim 1, wherein the compound is of Formula (Ig): ##STR00444## wherein R.sub.2, R.sub.4 and R.sub.12 are each, independently C.sub.1-6 alkyl. 22. The method of claim 21, 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. 23. The method of claim 21, wherein the compound is of Formula (IIa): ##STR00445## 24. The method of claim 23, 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, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, or morpholinyl. 25. The method of claim 24, 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. 26. The method of claim 25, 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. 27. The method of claim 26, 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. 28. The method of claim 1, wherein the compound is selected from Compounds 13, 1, 2, 11, 12, 17, 20, 21, 36, 42, 43, 44, 59, 65, 67, 68, 69, 73, 75, 76, 78, 80, 82, 83, 87, 88, 89, 90, 91, 94, 97, 103, 105, 138 and 141, and their pharmaceutically acceptable salts thereof. 29. A method of treating soft tissue sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of ##STR00446## or a pharmaceutically acceptable salt thereof.