Heterocyclo inhibitors of potassium channel function

A compound of formula I

• 1101
• enantiomers, diastereomers, salts and solvates thereof wherein
• m and p are independently 0, 1, 2 or 3 provided that the sum of m and p is at least 2;
• Q is NR1, O, S, S(O) or S(O)2;
• R1 is
• 1102
• —C(═NR8b)R8c, —SO2R8c, —OC(O)CCl3, —C(═S)R8c, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, perfluoroalkyl, cyano, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally subsituted alkenyl, or optionally subsituted alkynyl;
• R2 is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl or cycloalkyl, any of which may be optionally independently substituted with one or more groups T1, T2 or T3;
• J is a bond, C1-4 alkylene optionally independently substituted with one or more groups T1a, T2a or T3a, or C1-4 alkenylene optionally independently substituted with one or more groups T1a, T2a or T3a;
• R3 is
• 1103
• R4 is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl)alkyl or heteroaryl any of which may be optionally independently substituted with one or more groups T1b, T2b or T3b;
• R5 is
• (a) —NR6aR7a, cyano or
• (b) heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, or alkyl any of which may be optionally independently substituted with one or more groups T1c, T2c or T3c;
• R6 R6a, R7, R7a, R8, R8a, R8a1, R8a2, and R8a3 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R9, —CO2R9, —C(O)—NR9R10, or —NR9R10 any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
• or R6 and R7, or R6a and R7a together with the nitrogen atom to which they are attached may combine to form a 4 to 8 membered heterocyclo ring optionally independently substituted with one or more groups T1d, T2d or T3d;
• or one of R6 or R7, may combine with one of R8, R8a or R9 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T1d, T2d or T3d.
• or one of R6a or R7a, may combine with R8a1 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T1d, T2d or T3d
• R8b is H, alkyl, aryl, cyano, nitro, acyl or —SO2(alkyl) were the alkyl and aryl groups may be optionally independently substituted with one or more groups T1d, T2d or T3d;
• R8c is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocylco, heteroaryl, alkoxy or aryloxy any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
• R8d is R4, COR4, CO2R4, SO2R4, CONR6R7, or SO2NR6R7;
• R9 and R10 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T1f, T2f or T3f
• or R9 and R10 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T1f, T2f or T3f;
• W is ═NR8a1, ═N—CO2R8a1, ═N—COR8a1, ═N—CN, ═N—SO2R8a1, or
• 1104
• X1 is O, S, NR8a2 or CH2;
• Z, Z1 and Z2 are independently ═O, ═S, ═NR8a3 or ═N—CN;
• Rx is one or more optional substituents, attached to any available ring carbon atom, independently selected from T1g, T2g or T3g;
• T1-1g, T2-2g, and T3-3g are are each independently
• (1) hydrogen or T6, where T6 is
• (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl;
• aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
• (ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
• or
• (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T1-1g, T2-2g and T3-3g,
• (2) —OH or —OT6,
• (3) —SH or —ST6,
• (4) —C(O)tH, —C(O)tT6, or —O—C(O)T6, where t is 1 or 2;
• (5) —SO3H, —S(O)tT6, or S(O)tN(T9)T6,
• (6) halo,
• (7) cyano,
• (8) nitro,
• (9) —T4—NT7T8,
• (10) —T4—N(T9)—T5—NT7T8,
• (11) —T4—N(T10)—T5—T6,
• (12) —T4—N(T10)—T5—H,
• (13) oxo,
• T4 and T5 are each independently
• (1) a single bond,
• (2) —T11—S(O)t—T12—,
• (3) —T11—C(O)—T12—,
• (4) —T11—C(S)—T12—,
• (5) —T11—O—T12—,
• (6) —T11—S—T12—,
• (7) —T11—O—C(O)—T12—,
• (8) —T11—C(O)—O—T12—,
• (9) —T11—C(═NT9a)—T12—, or
• (10) —T11—C(O)—C(O)—T12—
• T7, T8, T9, T9a and T10
• (1) are each independently hydrogen or a group provided in the definition of T6, or
• (2) T7 and T8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1-1g, T2-2g and T3-3g, or
• (3) T7 or T8, together with T9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1-1g, T2-2g and T3-3g, or
• (4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT13T14 where T13 and T14 are each independently H or a group provided in the definition of T6;
• and
• T11 and T12 are each independently
• (1) a single bond,
• (2) alkylene,
• (3) alkenylene, or
• (4) alkynylene;
• provided said compound is other than
• (i) a compound of formula I
• 1105
• where
• R1i is H, alkyl, aralkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)alkylene—CO2alkyl, —CO2alkyl, —CO2alkenyl, —CO2aralkyl, or —SO2alkyl;
• and
• R8i is H, or alkyl;
• (ii) a compound of formula iia, iib or iic
• 1106
• where
• q is 0, 1 or 2;
• and
• R1iib is H or —C(O)2alkyl;
• 1107
• where
• R1iic is H or alkyl;
• and
• R8iic is H or alkyl;
• (iii) a compound of formula iii
• 1108
• where
• R1iii is -alkylene-C(O)—Ar where Ar is phenyl, alkylphenyl, xylyl, halophenyl, methoxyphenyl or thienyl;
• and
• R2iii is thienyl, phenyl, halophenyl, methoxyphenyl, alkylphenyl, xylyl, or trifluoromethylphenyl;
• (iv) a compound of formula iv
• 1109
• where
• R1iv is
• 1110
• where
• T1h is alkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, (cycloalkyl)alkyl, -alkylene-M-alkyl, -alkylene-M-alkylene-aryl, -alkylene-M-alkylene-heteroaryl, -alkylene-M-alkylene-cycloalkyl
• where alkyl and alkylene groups may be optionally substituted with 1 to 5 halo, S(O)qH, —S(O)qalkyl, or 1 to 3 hydroxy, alkoxy, carboxyl or —C(O)Oalkyl, and where the aryl and heteroaryl groups may be optionally substituted with phenyl, phenoxy,(aryl)alkoxy, (heteroaryl)alkoxy, halophenyl, 1 to 3 halo or alkyl, 1 to 3 methoxy, alkoxy, or cycloalkoxy, 1 to 3 trifluoromethyl or trifluoromethoxy, 1 to 2 methylenedioxy, S(O)qR5b, nitro, —NR5bR5b, —NR5bC(O)R5b, —C(O)OR5b, —C(O)NR5bR5b, —SO2NR5bR5b, —NR5bSO2aryl, —NR5bSO2heteroaryl, or —NR5bSO2R5b;
• M is O, SOq, NR5bC(O), C(O)NR5b, OC(O), C(O)O, —CR5b═CR5b—, or —c≡c—;
• T2h is H, alkyl, or cycloalkyl;
• or T1h and T2h combine to form a 3 to 8-membered ring optionally including heteroatoms;
• T3h is —LC(O)ANR6dR7d;
• L is NR5c, O or CH2,
• R5c is H, alkyl or R5c combines with T2h to form a 3 to 8-membered ring;
• R6d and R7d are independently H, alkyl, or substituted alkyl where the subtituents are selected from phenyl, phenoxy, 2-furyl, —C(O)Oalkyl, —S(O)qalkyl, 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 —OC(O)alkyl, or 1 to 3 alkoxy, or R6d and R7d may combine to form an unsaturated ring optionally containing additional heteroatoms;
• A is a bond or
• 1111
• where r and s are independently 0-3;
• Q1 is a bond, NR5b or O;
• R15 and R15a are independently H, alkyl, trifluoromethyl, phenyl or optionally substituted alkyl where the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR5b, S(O)qR5b, C(O)OR5b, cycloalkyl, NR5bR5b, C(O)NR5bR5b, or R15 and R15a can independently be joined to one or both of R6d and R7d to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R15 and R15a group, or R15 and R15a may combine to form a 3 to 7-membered ring;
• R2iv is alkyl, cycloalkyl, aryl or heteroaryl, each optionally substitued with one to three halo, methyl, methoxy or trifluoromethyl,;
• —Jiv—R3iv is —OR5b, —C(O)OR5c, —NR6bR7b,
• 1112
• or —Jiva—R3iva, where
• Jiva is a bond or alkylene optionally substituted with one or more halo or hydroxy;
• R3iva is a 5 or 6-membered cycloalkyl or heterocyclo ring to which is fused an optionally substituted 5 or 6-membered aryl or heteroaryl ring where the optional substituents are selected from halo, methyl, methoxy or trifluoromethyl;
• R5b is H, alkyl or cycloalkyl;
• R5c is H, alkyl, haloalkyl, cycloalkyl, aryl, hetoraryl, (aryl)alkyl, or (heteroaryl)alkyl where the aryl and heteoraryl groups are optionally substituted with 1 to 3 halo, methyl, methoxy or trifluoromethyl;
• R6b is —C(O)—R12a or —SO2—R12a;
• R7b is aryl or heteroaryl, each optionally substituted with 1 to 3 halo, methyl, methoxy or trifluoromethyl;
• R6c is H, alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl each optionally substituted with 1 to 3 halo, methyl, methoxy, trifluoromethyl or triflourmethoxy;
• R7c is H or alkyl optionally substitued with phenyl, phenoxy, —C(O)Oalkyl, —SOqalkyl, 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 alkoxy, or 1 to 3 —OC(O)alkyl
• or R6c and R7c may cobmine to form a cycloalkyl or heterocyclo ring optionally subtituted with alkyl or cycloalkyl;
• R12a is 4-morpholinyl, 4-(1-methylpiperazinyl), cycloalkyl or alkyl, each optionally substituted with 1 to 3 fluorine, hydroxy, methoxy, trifluoromethoxy, trifluoromethyl or cycloalkyl;
• (v) a compound of formula v
• 1113
• where
• R1v is H, (alkoxy)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (hetercyclo)alkyl, cycloalkyl, or (cycloalkyl)alkyl wherein the alkyl moieties may be optionally substituted with 1 to 7 fluroines, and wherein the aryl, heteroaryl and heterocyclo moieties may be optionally independenlty substituted with 1 to 3 halo, alkyl, fluoralkyl, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, alkoxy, (alkyl)amino and (dialkyl)amino
• T1 is hydroxy, (hydroxy)alkyl, (alkoxy)alkyl, NHSO2R16, C(OH)R16R17, halo, heteroaryl, or C(O)NHR16;
• T2 is H, halo or alkyl
• R16 and R17 are independently H, alkyl, alkoxy and (alkoxy)alkyl wherein the alkyl moieties are optionally substituted with 1 to 7 florine atoms;
• n is 0 or 1;
• E and F are independently O, N, S or CH provided E and F cannot both be either O or S;
• and
• T1c is H, aryl, halo, heteroaryl, heterocylo, —SO2R18, —C(O)R18, —C(O)NR18R19, —COOR18, or —C(OH)R18R19;
• R18 and R19 are independently H, (alkoxy)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (hetercyclo)alkyl, cycloalkyl, or (cycloalkyl)alkyl wherein the alkyl moieties may be optionally substituted with 1 to 7 fluroines, and wherein the aryl, heteroaryl and heterocyclo moieties may be optionally independently substituted with 1 to 3 halo, alkyl, fluoralkyl, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, alkoxy, (alkyl)amino and (dialkyl)amino;
• (vi) a compound of formula vi
• 1114
• where
• R1vi is alkyl optionally substituted with hydroxy or —OC(O)alkyl;
• and
• R20 is H or —C(O)alkyl;
• (vii) a compound of formula vii
• 1115
• where
• R1vii is (aryl)alkyl, (aryl)alkenyl, (alkoxy)alkyl, (aryloxy)alkyl, (arylalkoxy)alkyl, (cycloalkyloxy)alkyl, (heterocyclo)alkyl, or —X—CH2—Y-phenyl, where X is —CH2— or —C(O)—, and Y is —C(O)—, —C(═NOH)— or —CH2— optionally substituted with hydroxy;
• R21 is —C(O)alkyl, —C(O)aryl, —C(O)Oalkyl, —O—C(O)alkyl, or —C(O)NR6eR7e, where R6e and R7e are independently alkyl or combine to form an alkylene chain;
• and
• T1vii is H, hydroxy or alkoxy;
• (viii) a compound of formula viii
• 1116
• where
• R1viii is SO2R23 or a group
• 1117
• R22 is H, alkyl, phenyl, benzyl or biphenyl, wherein alkyl is optionally substituted with biphenyl, carboxy, alkoxy, —C(O)alkyl, or —C(O)N(H)alkyl, and wherein benzyl is optionally substituted with hydroxy, alkoxy or halo;
• R23 is alkyl or phenyl, wherein phenyl is optionally substituted with 1 or 2 halo, methoxy, halomethoxy, —N(H)C(O)methyl, CF3, alkyl or CN;
• Xvii is a bond, CH2 or CHMe;
• R24 is H or —N(H)R25;
• and
• R25 is
• 1118
• (ix) a compound of formula ixa or ixb
• 1119
• where
• R1ix is H or alkyl;
• R2ixa is heteroaryl or (heteroaryl)alklyl;
• R2ixb is alkyl optionally substituted with C(O)tH or C(O)talkyl where t is 1 or 2;
• R26a is is alkyl optionally substituted with C(O)tH or C(O)talkyl;
• R26b is optionally substituted heteroaryl, —NHR27, or —OR27;
• and
• R27 is optionally substituted heteroaryl;
• (x) a compound of formula x
• 1120
• where
• R1x is —C(O)—(CHR28)—NHR29;
• R2x is phenyl, (phenyl)alkyl, tetrahydropyranyl, piperidyl, alkyl, cycloalkyl or (cycloalkyl)alkyl;
• R26c is —C(O)R30, —C(O)2alkyl, —CH2—R31, or —NR32R33;
• R28 is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, aryloxy, (aryloxy)alkyl, aralkoxy or (aralkoxy)alkyl, any of which may be optionally substituted;
• R29 is H or —C(O)—(CR34R34)s-het* where s is 0-2;
• R34 is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, heteroaryl or (heteroaryl)alkyl;
• and het* is an optionally substituted N-containing heterocylo ring fused to an optionally substituted aryl, heteroaryl, heteroclo or cycloalkyl ring;
• R30 is alkyl, heterocyclo, —NR35R36, where R35 and R36 are independently H, alkyl, cycloalkyl or (cycloalkyl)alkyl;
• R31 is —S-alkyl, —S(O)-alkyl, —S(O)2-alkyl, —O-alkyl, —NR32R33, or triazolyl;
• R32 and R33 are independently H, alkyl, —S(O)2alkyl, or —C(O)alkyl;
• (xi) a compound of formula xi
• 1121
• where
• R1xi is
• 1122
• R2xi is
• 1123
• R3xi is
• 1124
• R34 is phenyl or naphthyl optionally substituted with cyano or —C(O)NH2;
• R35 is H or alkyl;
• R36 is phenyl optionally substituted with alkoxy;
• R37 is H, alkyl, or —C(O)NH2;
• T1xi is H, alkyl, alkoxy, haloalkoxy, cyano, nitro, —CH2NH2, —CH2N(H)(—C(O)OCH2-phenyl), or —NH—SO2alkyl;
• T1axi is H, alkyl, halo, alkoxy, haloalkoxy, or cyano;
• T1bxi is H, alkyl, halo alkoxy or hydroxy;
• T1cxi is H or alkyl;
• (xii) a compound of formula xii
• 1125
• where
• R38 is H or methyl;
• R39 is
• 1126
• R40 is H or Cl;
• and
• v is 0 or 1.