Isoquinolinone potassium channel inhibitors

A compound of the structure:

• or a pharmaceutically acceptable salt, crystal form, or hydrate, wherein:
• A is
• a) an aryl ring, wherein any stable aryl ring atom is independently unsubstituted or substituted with
• 1) halogen,
• 2) NO2,
• 3) CN,
• 4) CR46═C(R47R48)2,
• 5) C≡C R46,
• 6) (CRiRj)rOR46,
• 7) (CRiRj)rN(R46R47),
• 8) (CRiRj)rC(O)R46,
• 9) (CRiRj)rC(O)R46,
• 10) (CRiRj)rR46,
• 11) (CRiRj)rS(O)0-2R61,
• 12) (CRiRj)rS(O)0-2N(R46R47),
• 13) OS(O)0-2R61,
• 14) N(R46)C(O)R47,
• 15) N(R46)S(O)0-2R61,
• 16) (CRiRj)rN(R46)R61,
• 17) (CRiRj)rN(R46)R61OR47,
• 18) (CRiRj)rN(R46)(CRkRl)sC(O)N(R47R48),
• 19) N(R46)(CRiRj)rR61,
• 20) N(R46)(CRiRj)rN(R47R48),
• 21) (CRiRj)rC(O)N(R47R48), or
• 22) oxo, or
• b) a heteroaryl ring selected from the group consisting of
• a 5-membered unsaturated monocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting or N, O or S,
• a 6-membered unsaturated monocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting N, O and S, and
• a 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting or N, O or S;
• wherein any stable S heteroaryl ring atom is unsubstituted or mono- or di-substituted with oxo, and any stable C or N heteroaryl ring atom is independently unsubstituted or substituted with
• 1) halogen,
• 2) NO2,
• 3) CN,
• 4) CR46═C(R47R48)2,
• 5) C≡CR46,
• 6) (CRiRj)rOR46,
• 7) (CRiRj)rN(R46R47),
• 8) (CRiRj)rC(O)R46,
• 9) (CRiRj)rC(O)OR46,
• 10) (CRiRj)rR46,
• 11) (CRiRj)rS(O)0-2R61,
• 12) (CRiRj)rS(O)O0-2N(R46R47),
• 13) OS(O)0-2R61,
• 14) N(R46)C(O)R47,
• 15) N(R46)S(O)0-2R61,
• 16) (CRiRj)rN(R46)R61,
• 17) (CRiRj)rN(R46)R61OR47,
• 18) (CRiRj)rN(R46)(CRkRl)sC(O)N(R47R48),
• 19) N(R46)(CRiRj)rR61,
• 20) N(R46)(CRiRj)rN(R47R48),
• 21) (CRiRj)rC(O)N(R47R48), or
• 22) oxo;
• R1 is selected from the group consisting of
• 1) hydrogen,
• 2) (CRaRb)nR40
• 3) (CRaRb)nR40,
• 4) (CRaRb)nN(R40R41),
• 5) (CRaRb)nN(R40)C(O)OR41,
• 7) C3-8 cycloalkyl,
• 8) (CRaRb)nC(O)OR40,
• 9) (CRaRb)nN(R40)(CRcRd)1-3R41,
• 10) (CRaRb)nS(O)0-2R6,
• 11) (CRaRb)nS(O)0-2N(R40R41),
• 12) (CRaRb)nN(R40)R6OR41,
• 13) (CRaRb)nN(R40)(CRcRd)0-6C(O)N(R41R42);
• R2, R8, R9 and R10 are independently selected from:
• 1) hydrogen,
• 2) halogen,
• 3) NO2,
• 4) CN,
• 5) CR43═C(R44R45),
• 6) C≡CR43,
• 7) (CReRf)pOR43,
• 8) (CReRf)pN(R43R44),
• 9) (CReRf)pC(O)R43,
• 10) (CReRf)pC(O)OR43,
• 11) (CReRf)pR43,
• 12) (CReRf)pS(O)0-2R60,
• 13) (CReRf)pS(O)0-2R43R44,
• 14) OS(O)0-2R60,
• 15) N(R43)C(O)R44,
• 16) N(R43)S(O)0-2R60,
• 17) (CReRf)pN(R43)R60,
• 18) (CReRf)pN(R43)R60OR44,
• 19) (CReRf)pN(R43)(CRgRh)qC(O)N(R44R45),
• 20) N(R43)(CReRf)pR60,
• 21) N(R43)(CReRf)pN(R44R45), and
• 22) (CReRf)pC(O)N(R43R44),
• or R2 and R8 are independently as defined above, and R9 and R10, together with the atoms to which they are attached, form the ring
• where Rm is C1-6alkyl;
• Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, and Rl are independently selected from the group consisting of:
• 1) hydrogen,
• 2) C1-C6 alkyl,
• 3) halogen,
• 4) aryl,
• 5) R80,
• 6) C3-C10 cycloalkyl, and
• 7) OR4,
• said alkyl, aryl, and cycloalkyl being unsubstituted, monosubstituted with R7, disubstituted with R7 and R15, trisubstituted with R7, R15 and R16, or tetrasubstituted with R7, R15, R16 and R17;
• R4, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R51, R52, R53 and R54 are independently selected from the group consisting of
• 1) hydrogen,
• 2) C1-C6 alkyl,
• 3) C3-C10cycloalkyl,
• 4) aryl,
• 5) R81,
• 6) CF3,
• 7) C2-C6alkenyl, and
• 8) C2-C6 alkynyl,
• said alkyl, aryl, and cycloalkyl is unsubstituted, mono-substituted with R18, di-substituted with R18 and R19, tri-substituted with R18, R19 and R20, or tetra-substituted with R18, R19, R20 and R21;
• R6, R60, R61, and R63 are independently selected from the group consisting of
• 1) C1-C6 alkyl,
• 2) aryl,
• 3) R83, and
• 4) C3-C10 cycloalkyl;
• said alkyl, aryl, and cycloalkyl is unsubstituted, mono-substituted with R26, di-substituted with R26 and R27, tri-substituted with R26, R27 and R28, or tetra-substituted with R26, R27, R28 and R29;
• R7, R15, R16, R17, R18, R19, R20, R21, R26, R27, R28, and R29 are independently selected from the group consisting of
• 1) C1-C6 alkyl,
• 2) halogen,
• 3) OR51,
• 4) CF3,
• 5) aryl,
• 6) C3-C10cylcoalkyl,
• 7) R84,
• 8) S(O)0-2N(R51R52),
• 9) C(O)OR51,
• 10) C(O)R51,
• 11) CN,
• 12) C(O)N(R51R52),
• 13) N(R51)C(O)R52,
• 14) S(O)0-2R63,
• 15) NO2,
• 16) N(R51R52), and
• 17) R82;
• R22 selected from the group consisting of
• 1) NHC(O)R88, and
• 2) N(R53R54);
• R88 is C1-C6 alkyl or C3-C6 cycloalkyl;
• R80, R81, R82, R83, R84 and R85 are independently selected from a group of unsubstituted or substituted heterocyclic rings consisting of a 3-6 membered unsaturated or saturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms selected from the group consisting N, O and S, and a 9- or 10-membered unsaturated or saturated bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting or N, O or S;
• and
• n, p, g, r, and s are independently 0, 1, 2, 3, 4, 5 or 6,
• wherein R5 is selected from the group consisting of —(CH2)2NH2, —(CH2)2NHC(O)CH3, —(CH2)2N(CH2CH3)2,