Mitotic kinesin inhibitors

A compound of Formula I:

• or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
• a is 0 or 1;
• b is 0 or 1;
• m is 0, 1, or 2;
• n is 0 or 1;
• r is 0 or 1;
• s is 0 or 1;
• u is 2, 3, 4 or 5;
• a dashed line represents an optional double bond, provided that one and only one double bond is present in the ring;
• X is selected from —CH2—, —CH2CH2—, —SO2— and —C(═O)—;
• Y is selected from:
• O, N(Rc), S, —C(═O)—, —CH(R8)—, —N(Rc)C(═O)— and —N(Rc)CH(R8)—;
• or
• X and Y are combined to form —C(R8)═C(R8)—;
• Z is selected from:
• —C(═O)—, —C(═S)—, —SO2— and —C(R8)(R9)—,
• R1 and R5 are independently selected from:
• 1) aryl,
• 2) C1-C6 aralkyl,
• 3) C3-C8 cycloalkyl, and
• 4) heterocyclyl,
• said aryl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R10;
• R2, R3, R4, R6 and R7 are independently selected from:
• 1) H,
• 2) C1-C10 alkyl,
• 3) aryl,
• 4) C2-C10 alkenyl,
• 5) C2-C10 alkynyl,
• 6) C1-C6 perfluoroalkyl,
• 7) C1-C6 aralkyl,
• 8) C3-C8 cycloalkyl, and
• 9) heterocyclyl,
• said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R10;
• or
• R3 and R4 attached to the same carbon atom are combined to form —(CH2)u— wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O)m,
• —N(Ra)C(O)—, —N(Rb)— and —N(CORa)—;
• R8 and R9 is independently selected from:
• 1) H,
• 2) (C═O)aObC1-C10 alkyl,
• 3) (C═O)aObaryl,
• 4) C2-C10 alkenyl,
• 5) C2-C10 alkynyl,
• 6) (C═O)aOb heterocyclyl,
• 7) CO2H,
• 8) halo,
• 9) CN,
• 10) OH,
• 11) ObC1-C6 perfluoroalkyl,
• 12) Oa(C═O)bNR12R13,
• 13) S(O)mRa,
• 14) S(O)2NR12R13,
• 15) CHO,
• 16) (N═O)R12R13, and
• 17) (C═O)aObC3-C8 cycloalkyl,
• said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R11;
• R10 is independently selected from:
• 1) (C═O)aObC1-C10 alkyl,
• 2) (C═O)aObaryl,
• 3) C2-C10 alkenyl,
• 4) C2-C10 alkynyl,
• 5) (C═O)aOb heterocyclyl,
• 6) CO2H,
• 7) halo,
• 8) CN,
• 9) OH,
• 10) ObC1-C6 perfluoroalkyl,
• 11) Oa(C═O)bNR12R13,
• 12) S(O)mRa,
• 13) S(O)2NR12R13,
• 14) oxo,
• 15) CHO,
• 16) (N═O)R12R13,
• 17) (C═O)aObC3-C8 cycloalkyl, and
• 18) —OPO(OH)2;
• said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R11;
• R11 is selected from:
• 1) (C═O)rOs(C1-C10)alkyl,
• 2) Or(C1-C3)perfluoroalkyl,
• 3) (C0-C6)alkylene-S(O)mRa,
• 4) oxo,
• 5) OH,
• 6) halo,
• 7) CN,
• 8) (C═O)rOs(C2-C10)alkenyl,
• 9) (C═O)rOs(C2-C10)alkynyl,
• 10) (C═O)rOs(C3-C6)cycloalkyl,
• 11) (C═O)rOs(C0-C6)alkylene-aryl,
• 12) (C═O)rOs(C0-C6)alkylene-heterocyclyl,
• 13) (C═O)rOs(C0-C6)alkylene-N(Rb)2,
• 14) C(O)Ra,
• 15) (C0-C6)alkylene-CO2Ra,
• 16) C(O)H,
• 17) (C0-C6)alkylene-CO2H,
• 18) C(O)N(Rb)2,
• 19) S(O)mRa,
• 20) S(O)2N(Rb)2 and
• 21) —OPO(OH)2;
• said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (C1-C6)alkoxy, halogen, CO2H, CN, O(C═O)C1-C6 alkyl, oxo, and N(Rb)2;
• R12 and R13 are independently selected from:
• 1) H,
• 2) (C═O)ObC1-C10 alkyl,
• 3) (C═O)ObC3-C8 cycloalkyl,
• 4) (C═O)Obaryl,
• 5) (C═O)Obheterocyclyl,
• 6) C1-C10 alkyl,
• 7) aryl,
• 8) C2-C10 alkenyl,
• 9) C2-C10 alkynyl,
• 10) heterocyclyl,
• 11) C3-C8 cycloalkyl,
• 12) SO2Ra, and
• 13) (C═O)NRb2,
• said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R11, or
• R12 and R13 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R11;
• R14 is independently selected from:
• 1) (C═O)aObC1-C10 alkyl,
• 2) (C═O)aObaryl,
• 3) C2-C10 alkenyl,
• 4) C2-C10 alkynyl,
• 5) (C═O)aOb heterocyclyl,
• 6) CO2H,
• 7) halo,
• 8) CN,
• 9) OH,
• 10) ObC1-C6 perfluoroalkyl,
• 11) Oa(C═O)bNR12R13,
• 12) S(O)mRa,
• 13) S(O)2NR12R13,
• 14) oxo,
• 15) CHO,
• 16) (N═O)R12R13,
• 17) (C═O)aObC3-C8 cycloalkyl, and
• 18) —OPO(OH)2;
• said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R11;
• Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl, optionally substituted with one to three substituents selected from R14;
• Rb is H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C═O)OC1-C6 alkyl, (C═O)C1-C6 alkyl or S(O)2Ra, optionally substituted with one to three substituents selected from R14;
• Rc and Rc′ are independently selected from:
• H, (C1-C6)alkyl, aryl, heterocyclyl and (C3-C6)cycloalkyl, optionally substituted with one, two or three substituents selected from R10, or
• Rc and Rc′ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R11;
• Rd and Rd′ are independently selected from:
• (C1-C6)alkyl, (C1-C6)alkoxy and NRb2, or
• Rd and Rd′ can be taken together with the phosphorous to which they are attached to form a monocyclic heterocycle with 5-7 members the ring and optionally containing, in addition to the phosphorous, one or two additional heteroatoms selected from NRe, O and S, said monocyclic heterocycle optionally substituted with one, two or three substituents selected from R11;
• and
• Re is selected from:
• H and (C1-C6)alkyl.