[6,6] fused bicyclic HDAC8 inhibitors

A compound of Formula (I):

• or pharmaceutically acceptable salts thereof,
• wherein:
• Y1, Y2, Y3, and Y4 are each independently C or CR3, provided that when bonded to —C(O)NHOH any of Y1, Y2, Y3, or Y4 is C;
• X is selected from the group consisting C(═O) and C(R4)(R5);
• W is C(R4)(R5);
• R1 is C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, —(CH2)n—Ra, —(CH2)n—O—(CH2)p—Ra, or —C(O)N(Ra)(Rb), wherein each alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more of —OH, halogen, oxo, —NO2, —NH2, —CN, —C1-C6 alkyl, —C1-C6 alkoxy, heterocycle, aryl, heteroaryl, or R4;
• Ra is, independently at each occurrence, halogen, OH, NH2, C2-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, or —C(O)N(R10)(R11), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycle is optionally substituted with one or more of —OH, R4′, R5′, halogen, oxo, (CH2)nOR6, —NO2, —OR6, —N(R6)(R7), C(O)OR6, —C(O)N(R6)(R7), —S(O)2R6, —S(O)R6, —S(R6), —C(O)R6, —S(O)2N(R6)(R7), —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl, and wherein each aryl is optionally substituted with one or more of —OH, R4′, R5′, halogen, oxo, (CH2)nOR6, —OR6, —N(R6)(R7), C(O)OR6, —C(O)N(R6)(R7), —S(O)2R6, —S(O)R6, —S(R6), —C(O)R6, —S(O)2N(R6)(R7), —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl;
• Rb is at each occurrence, hydrogen, halogen, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, or —C(O)N(R10)(R11), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more —OH, R4′, R5′, halogen, oxo, (CH2)nOR6, —NO2, —OR6, —N(R6)(R7), C(O)OR6, —C(O)N(R6)(R7), —S(O)2R6, —S(O)R6, —S(R6), —C(O)R6, —S(O)2N(R6)(R7), —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl;
• or Ra and Rb can combine with the carbon or nitrogen to which they are attached to form a C3-C8 cycloalkyl, or 3- to 8-membered heterocycle optionally substituted with one or more substituents selected from R4′ and R5′, wherein R4′ and R5′ independently at each occurrence are H or —C1-C6 alkyl;
• R2 and R2′ are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, —OH, halogen, —NO2, —NH2, —CN, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aryl, heteroaryl, or 3- to 8-membered heterocycle, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more —OH, halogen, oxo, —NO2, —NH2, —CN, —C1-C6 alkyl, or —C1-C6 alkoxy;
• or
• R2 and R2′ can combine with the carbon to which they are attached to form an oxo group, C3-C8 cycloalkyl, or 3- to 8-membered heterocycle;
• R3 is independently, at each occurrence, hydrogen, halogen, —OH, —CN, —NO2, —NH2, C1-C3 alkyl, or C1-C3 alkoxy;
• each R4 or R5 is each independently, at each occurrence, hydrogen, halogen, —OH, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, or —C(O)N(R10)(R11), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycle is optionally substituted with one or more —OH, R4′, R5′, halogen, oxo, (CH2)nOR6, —NO2, —OR6, —N(R6)(R7), C(O)OR6, —C(O)N(R6)(R7), —S(O)R6, —S(R6), S(O)2N(R6)(R7), —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl, and wherein aryl is optionally substituted with one or more —OH, R4′, R5′, halogen, oxo, (CH2)nOR6, —OR6, —N(R6)(R7), C(O)OR6, —C(O)N(R6)(R7), —S(O)2R6, —S(O)R6, —S(R6), —C(O)R6, —S(O)2N(R6)(R7), —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl;
• or
• R4 and R5 can combine with the carbon or nitrogen to which they are attached to form an oxo group, C3-C8 cycloalkyl, or 3- to 8-membered heterocycle optionally substituted with one or more substituents selected from R4′ and R5′;
• R4′ and R5′ are, independently at each occurrence, H or —C1-C6 alkyl;
• or
• R4′ and R5′ together when attached to the same atom form a C3-C8 spirocycloalkyl ring;
• or
• R4′ and R5′ together when attached to the same atom form a C3-C8 spiroheterocycloalkyl ring;
• or
• R4′ and R5′ together when attached to adjacent atoms form an aryl ring, a heteroaryl ring, a C3-C8 cycloalkyl, or a 3- to 8-membered heterocycle, wherein the spirocycloalkyl, spiroheterocycloalkyl, heteroaryl, cycloalkyl or heterocycle is optionally substituted with one or more groups selected from OH, halogen, —C1-C6 alkyl and C(O)OR6;
• R6 and R7 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocycle, —S(O)2NR8R9, —S(O)2R8, —C(O)R8, —CO2R8, —S(O)R8, and —S(O)NR8R9, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more —OH, halogen, oxo, —NO2, —NH2, —CN, —C1-C6 alkyl, —C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 hydroxyalkyl, heterocycle, aryl, or heteroaryl;
• or
• R6 and R7 together with the atom to which they are attached form a C3-C8 cycloalkyl or a 3- to 8-membered heterocycle, wherein the cycloalkyl or the heterocycle is optionally substituted with one or more groups selected from halogen, oxo and C1-C6 alkyl;
• R8 and R9 are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heteroaryl, or 3- to 8-membered heterocycle, wherein each is optionally substituted with one or more —OH, halogen, oxo, —NO2, —NH2, —CN, —C1-C6 alkyl, —C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 hydroxyalkyl, heterocycle, aryl, or heteroaryl;
• R10 and R11 are each independently hydrogen, C1-C6 alkyl, aryl, C1-C6 alkylaryl or 3- to 8-membered heterocycle, wherein aryl, alkylaryl and heterocycle are optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy;
• or
• R10 and R11 can combine to form a 3- to 8-membered heterocycle optionally substituted with one or more R12;
• R12 is H or C1-C6 alkyl or two adjacent R12 can combine to form an aryl or heteroaryl group;
• n is an integer from 1 to 6;
• and
• p is an integer from 0 to 2.