3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors

A compound of Formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• X1 is O;
• X2 and X4 are each independently CR1R2, C═O, S(O) or SO2;
• X3 is CR1′R2′;
• Y1 and Y4 are not bound to —C(O)NHOH and are each independently N or CR1;
• Y2 and Y3 are each independently N or CR1 when not bonded to —C(O)NHOH and Y2 and Y3 are C when bonded to —C(O)NHOH;
• L is selected from the group consisting of —C(O)—, —C(O)(CR1R2)m—, and —C(O)(CR1R2)mO—, wherein L is bound to the ring nitrogen through the carbonyl group;
• R is selected from the group consisting of —H, —C1-C6 alkyl, —C2-C6 alkenyl, —C4-C8 cycloalkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl, —C5-C12 spirocycle, heterocyclyl, spiroheterocyclyl, aryl, and heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, oxo, —NO2, —CN, —R1, —R2, —OR3, —NHR3, —NR3R4, —S(O)2NR3R4, —S(O)2R1, —C(O)R1, —CO2R1, —NR3S(O)2R1, —S(O)R1, —S(O)NR3R4, —NR3S(O)R1, heterocyclyl, aryl, and heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, with the proviso that R is not bound to L via a nitrogen atom;
• R1 and R2 are independently, at each occurrence, selected from the group consisting of —H, —R3, —R4, —C1-C6 alkyl, —C2-C6 alkenyl, —C3-C8 cycloalkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, —OH, halogen, —NO2, —CN, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, —S(O)2N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)2R5, —S(O)2(C1-C6 alkyl), —(C1-C6 alkyl)S(O)2R5, —C(O)C1-C6 alkyl, —CO2C1-C6 alkyl, —N(C1-C6 alkyl)S(O)2C1-C6 alkyl, and —(CHR5)nNR3R4, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO2, oxo, —CN, —R5, —OR3, —NHR3, —NR3R4, —S(O)2N(R3)2, —S(O)2R5, —C(O)R5, —CO2R5, —NR3S(O)2R5, —S(O)R5, —S(O)NR3R4, —NR3S(O)R5, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O;
• or R1 and R2 can combine with the carbon atom to which they are both attached to form a spirocycle, spiroheterocycle, or a spirocycloalkenyl;
• or R1 and R2, when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocycloalkyl;
• R1″ and R2′ are independently, at each occurrence, selected from the group consisting of —H, —C1-C6 alkyl, —C2-C6 alkenyl, —C3-C8 cycloalkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl, heterocyclyl, —OH, halogen, —NO2, —CN, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, —S(O)2N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)2R5, —S(O)2(C1-C6 alkyl), —(C1-C6 alkyl)S(O)2R5, —C(O)C1-C6 alkyl, —CO2C1-C6 alkyl, —N(C1-C6 alkyl)S(O)2C1-C6 alkyl, and —(CHR5)nNR3R4, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO2, oxo, —CN, —R5, —OR3, —NHR3, NR3R4, —S(O)2N(R3)2, —S(O)2R5, —C(O)R5, —CO2R5, —NR3S(O)2R5, —S(O)R5, —S(O)NR3R4, —NR3S(O)R5, heterocyclyl, aryl, and heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O;
• or R1′ and R2′ can combine with the carbon atom to which they are both attached to form a spirocycle, spiroheterocycle, or a spirocycloalkenyl;
• or R1′ and R2′ can combine with R1 or R2 on adjacent atoms to form a heterocycle, cycloalkyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or cycloalkenyl;
• or R1″ and R2′ can combine with R1 or R2 on non-adjacent atoms, to form a bridging cycloalkyl or heterocycloalkyl;
• R3 and R4 are independently, at each occurrence, selected from the group consisting of —H, —C1-C6 alkyl, —C2-C6 alkenyl, —C3-C8 cycloalkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, —S(O)2N(C1-C6 alkyl)2, —S(O)2(C1-C6 alkyl), —(C1-C6 alkyl)S(O)2R5, —C(O)C1-C6 alkyl, —CO2C1-C6 alkyl, and —(CHR5)nN(C1-C6 alkyl)2, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO2, oxo, —CN, —R5, —O(C1-C6alkyl), —NH(C1-C6 alkyl), N(C1-C6 alkyl)2, —S(O)2N(C1-C6 alkyl)2, —S(O)2NHC1-C6 alkyl, —C(O)C1-C6 alkyl, —CO2C1-C6 alkyl, —N(C1-C6 alkyl)S(O)2C1-C6 alkyl, —S(O)R5, —S(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)R5, heterocyclyl, aryl, and heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O;
• R5 is independently, at each occurrence, selected from the group consisting of —H, —C1-C6 alkyl, —C2-C6 alkenyl, —C3-C8 cycloalkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, —OH, halogen, —NO2, —CN, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —S(O)2NH(C1-C6 alkyl), —S(O)2N(C1-C6 alkyl)2, —S(O)2C1-C6 alkyl, —C(O)C1-C6 alkyl, —CO2C1-C6 alkyl, —N(C1-C6 alkyl)SO2C1-C6 alkyl, —S(O)(C1-C6 alkyl), —S(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)(C1-C6 alkyl) and —(CH2)nN(C1-C6 alkyl)2;
• n is independently and at each occurrence an integer from 0 to 6;
• and
• m is independently and at each occurrence an integer from 1 to 6.