SUBSTITUTED 6,5-FUSED BICYCLIC HETEROARYL COMPOUNDS

1 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein

X is

A 1 is C or N and when A 1 is N, R 3 is absent;

A 2 is N, O, or S and when A 2 is O or S, R 3 is absent;

X 1 is NR 7 or CR 7 ;

X 2 is N, NR 8 , CR 8 , O, or S;

X 3 is Nits, CR 8 , O, or S;

X 4 is C or N;

Y 1 is N or CH;

Y 2 is N or CR 6 ;

Y 3 is N, or CR 11 ;

R 1 is -Q 0 -T 0 , in which Q 0 is NR 1a , O or S, R 1a being H, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl, and T 0 is H or R S0 , in which R S0 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R S0 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, C(O)OH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

each of R 2 , R 3 , and R 4 , independently, is -Q 1 -T 1 , in which Q 1 is a bond or C 1 -C 3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 1 is H, halo, hydroxyl, C(O)OH, cyano, azido, or R S1 , in which R S1 is C 1 -C 3 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 thioalkyl, C(O)O—C 1 -C 6 alkyl, CONH 2 , SO 2 NH 2 , —C(O)—NH(C 1 -C 6 alkyl), —C(O)—N(C 1 -C 6 alkyl) 2 , —SO 2 —NH(C 1 -C 6 alkyl), —SO 2 —N(C 1 -C 6 alkyl) 2 , C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R S1 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, C(O)OH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; or

neighboring R 1 and R 2 , together with the atoms to which they are attached, form a 5- or 6-membered heteroaryl having 0 to 2 additional heteroatoms or a 5 to 12-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms; or neighboring R 1 and R 4 , together with the atoms to which they are attached, form a 5- or 6-membered heteroaryl having 0 to 2 additional heteroatoms or a 5 to 12-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms; or neighboring R 2 and R 3 , together with the atoms to which they are attached, form C 5 -C 8 cycloalkyl, C 6 -C 10 aryl, or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, or a 5 to 12-membered heterocycloalkyl ring having 1 to 3 heteroatoms; or neighboring R 3 and R 4 , together with the atoms to which they are attached, form C 5 -C 8 cycloalkyl, C 6 -C 10 aryl, or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, or a 5 to 12-membered heterocycloalkyl ring having 1 to 3 heteroatoms; in which each of the ring structures formed by R 1 and R 2 , by R 1 and R 4 , by R 2 and R 3 , or by R 3 and R 4 , independently is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, C(O)O—C 1 -C 6 haloalkyl, cyano, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, amino, mono-C 1 -C 6 alkylamino, alkylamino, C 3 -C 8 cycloalkyl, aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

each of R 5 , R 9 , and R 10 , independently, is H or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

each R 6 independently is H, halo, OR a , —NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR b C(O)R a , —S(O) 2 R a , —S(O) 2 NR a R b , or R S2 , in which each of R a and R b , independently is H or R S3 and each of R S2 and R S3 , independently, is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl; or R a and R 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 each of R S2 , R S3 , and the 4 to 7-membered heterocycloalkyl ring containing R a and R b′ , is optionally substituted with one or more -Q 2 -T 2 , wherein Q 2 is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 2 is H, halo, cyano, —OR c , —NR c R d , —(NR c R d R d′ ) + A − , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —NR d C(O)R c , —NR d C(O)OR c , —S(O) 2 R c , —S(O) 2 NR c R d , or R S4 , in which each of R c , R d , and R d′ , independently is H or R S5 , A − is a pharmaceutically acceptable anion, each of R S4 and R S5 , independently, is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, or R c and R d , 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 each of R S4 , R S5 , and the 4 to 7-membered heterocycloalkyl ring containing R c and R d , is optionally substituted with one or more -Q 3 -T 3 , wherein Q 3 is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 3 is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, 5 to 6-membered heteroaryl, OR e , COOR e , —S(O) 2 R e , —NR e R f , and —C(O)NR e R f , each of R e and R f independently being H or C 1 -C 6 alkyl optionally substituted with OH, O—C 1 -C 6 alkyl, or NH—C 1 -C 6 alkyl; or -Q 3 -T 3 is oxo; or -Q 2 -T 2 is oxo; or any two neighboring -Q 2 -T 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 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, and 5 to 6-membered heteroaryl; provided that -Q 2 -T 2 is not H;

each R 7 independently is -Q 4 -T 4 , in which Q 4 is a bond, C 1 -C 4 alkyl linker, or C 2 -C 4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 4 is H, halo, cyano, NR g R h , —OR g , —C(O)R g , —C(O)OR g , —C(O)NR g R h , —C(O)NR g OR h , —NR g C(O)R h , —S(O) 2 R g , or R S6 , in which each of R g and R h , independently is H or R S7 , each of R S6 and R S7 , independently is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R S6 and R S7 is optionally substituted with one or more -Q 5 -T 5 , wherein Q 5 is a bond, C(O), C(O)NR k , NR k C(O), NR k , S(O) 2 , NR k S(O) 2 , or C 1 -C 3 alkyl linker, R k being H or C 1 -C 6 alkyl, and T 5 is H, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 1 -C 6 alkylene-C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkylene-C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, C 1 -C 6 alkylene-4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or C 1 -C 6 alkylene-5- or 6-membered heteroaryl, and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, O—C 1 -C 4 alkylene-C 1 -C 4 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo; provided that -Q 4 -T 4 is not H; and

each of R 8 and R 11 , independently, is H, halo, hydroxyl, COOH, cyano, R S8 , OR S8 , or COOR S8 , in which R S8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, amino, mono-C 1 -C 6 alkylamino, or di-C 1 -C 6 alkylamino, and R S8 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, and di-C 1 -C 6 alkylamino; and

n is 0, 1, 2, 3, 4, or 5;

provided that at most one of X 2 and X 3 is O or S, at least one of X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , and Y 3 is N or NR 7 , and X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , and Y 3 are assigned such that the

 moiety in Formula (I) is a bicyclic heteroaryl system.

2 . (canceled)

3 . The method of claim 1 , wherein the compound is of Formula (IIa):

wherein R 7 is -Q 4 -T 4 , wherein Q 4 is a bond or methyl linker, T 4 is C 1 -C 6 alkyl optionally substituted with one or more -Q 5 -T 5 , C 3 -C 8 cycloalkyl optionally substituted with one or more -Q 5 -T 5 , or 4- to 14-membered heterocycloalkyl optionally substituted with one or more -Q 5 -T 5 .

4 . The method of claim 1 , wherein R 7 is tetrahydropyranyl, piperidine substituted by 1, 2, or 3 C 1-4 alkyl groups, or cyclohexyl substituted by N(C 1-4 alkyl) 2 wherein one or both of the C 1-4 alkyl is optionally substituted with C 1-6 alkoxyl.

5 . The method of claim 4 , wherein R 7 is sec-butyl, cyclopentyl, or iso-propyl.

6 . The method of claim 1 , wherein R 6 is selected from the group consisting of Br, Cl, CH 3 , OCH 3 ,

7 . The method of claim 6 , wherein R 6 is

8 . The method of claim 1 , wherein X is

wherein

Q 0 is NH or O;

between A 3 and A 4 is a single or double bond,

each of A 3 and A 4 , independently, is CR 15 R 16 , NR 15 , O, or S;

each of R 15 and R 16 , independently is absent, H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, C(O)O—C 1 -C 6 haloalkyl, cyano, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; and

(i) when Q 0 is NH and is a single bond, each of A 3 and A 4 independently is CR 15 R 16 , NR 15 , O, or S;

(ii) when Q 0 is NH and is a double bond, each of A 3 and A 4 independently is CR 15 or N;

(iii) when Q 0 is O and is a single bond, each of A 3 and A 4 independently is CR 15 R 16 or NR 15 ; or

(iv) when Q 0 is O and is a double bond, each of A 3 and A 4 independently is CR 15 or N.

9 . The method of claim 1 , wherein X is

wherein

Q 0 is NH or O;

between A 3 and A 4 is a single or double bond,

each of A 3 and A 4 , independently, is CR 15 R 16 , NR 15 , O, or S;

each of R 15 and R 16 , independently is absent, H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, C(O)O—C 1 -C 6 haloalkyl, cyano, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; and

(v) when Q 0 is NH and is a single bond, each of A 3 and A 4 independently is CR 15 R 16 , NR 15 , O, or S;

(vi) when Q 0 is NH and is a double bond, each of A 3 and A 4 independently is CR 15 or N;

(vii) when Q 0 is O and is a single bond, each of A 3 and A 4 independently is CR 15 R 16 or NR 15 ; or

(viii) when Q 0 is O and is a double bond, each of A 3 and A 4 independently is CR 15 or N.

10 . The method of claim 1 , wherein X is

wherein

A 2 is N or O, and when A 2 is O, R 3 is absent;

each of R 2 , R 3 , and R 4 , independently, is -Q 1 -T 1 , in which Q 1 is a bond or C 1 -C 3 alkyl linker optionally substituted with halo, and T 1 is H, halo, hydroxyl, C(O)OH, cyano, azido, or R S1 , in which R S1 is C 1 -C 3 alkyl, C 1 -C 6 alkoxyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R S1 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; or

neighboring R 2 and R 3 , together with the atoms to which they are attached, form a 6 to 12-membered heterocycloalkyl ring having 2 to 3 heteroatoms; or neighboring R 3 and R 4 , together with the atoms to which they are attached, form a 6-membered heteroaryl having 1 to 3 heteroatoms, or a 6 to 12-membered heterocycloalkyl ring having 1 to 3 heteroatoms; in which each of the ring structures formed by R 2 and R 3 , or by R 3 and R 4 , independently is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, amino, mono-C 1 -C 6 alkylamino, or di-C 1 -C 6 alkylamino.

11 . The method of claim 1 , wherein n is 0, 1, or 2.

12 . The method of claim 11 , wherein n is 1.

13 . The method of claim 1 , wherein the compound is selected from those in Table 1A and Tables 1-3 and pharmaceutically acceptable salts thereof.

14 - 15 . (canceled)

16 . The method of claim 1 , wherein the cancer is lymphoma, leukemia, or melanoma.

17 . The method of claim 1 , wherein the cancer is diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), follicular lymphoma, diffuse large B-cell lymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, mixed lineage leukemia, or myelodysplastic syndromes (MDS).

18 . The method of claim 1 , wherein the cancer is malignant rhabdoid tumor or INI1-deficient tumor.

19 . The method of claim 1 , wherein the cancer is with aberrant H3-K27 methylation.

20 . The method of claim 1 , wherein the cancer overexpresses EZH2 or other PRC2 subunits, contains loss-of-function mutations in H3-K27 demethylases such as UTX, or overexpresses accessory proteins such as PHF19/PCL3 capable of increasing and or mislocalizing EZH2 activity.

21 . The method of claim 1 , wherein the cancer expresses a mutant EZH2.

22 . The method of claim 1 , wherein the cancer is selected from the group consisting of brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, and prostate cancer.

23 . The method of claim 1 , wherein the cancer is selected from the group consisting of medulloblastoma, oligodendroglioma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, ovarian serous adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic endocrine tumor, malignant rhabdoid tumor, astrocytoma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, pineoblastoma, carcinosarcoma, chordoma, extragonadal germ cell tumor, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma.