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US 7,005,436 B2Granted
Heterocyclo inhibitors of potassium channel function
AssigneesBristol-Myers Squibb Company, Icagen, Inc.
InventorsJohn Lloyd, Yoon T. Jeon, Heather Finlay, Lin Yan, Michael F. Gross, Serge Beaudoin
Life of this patent
Estimating the term…
Abstract
Novel heterocyclo compounds useful as inhibitors of potassium channel function (especially inhibitors of the Kv1 subfamily of voltage gated K+ channels, especially inhibitors Kv1.5 which has been linked to the ultra-rapidly activating delayed rectifier K+ current IKur), methods of using such compounds in the prevention and treatment of arrhythmia and IKur-associated conditions, and pharmaceutical compositions containing such compounds.
Claims15
A compound of formula I
- including enantiomers, diastereomers, salts and solvates thereof wherein
- mn and p are independently 0, 1, or 2, provided that the sum of m and p is 2;
- Q is NR1;
- J is a bond or C1-4 alkylene optionally substituted with one or more groups T1a, T2a or T3a;
- R1 is selected from
- R2 is aryl, which may be optionally independently substituted with one or more groups T1, T2 or T3;
- R3 is
- R5 is optionally substituted heteroaryl or (heteroaryl)alkyl wherein the hetero is pyrazine or pyridine, and either of these may be optionally independently substituted with one or more groups T1c, T2c or T3c;
- R6, R7, R8 and R8a are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)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;
- R8b is H, alkyl, aryl, cyano, nitro, acyl or —SO2(alkyl) wherein 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, alkoxy or aryloxy, any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
- R9 and R10 are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl (alkoxy)alkyl, (aryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or (aryl)alkyl, any of which may be optionally independently substituted with one or more groups T1f, T2f or T3f;
- Z1 is ═O;
- Rx is one or more optional substituents attached to any available ring carbon atom, each of which is independently selected from T1g, T2g or T3g;
- T1-1g, T2-2g, and T3-3g are independently
- (1) hydrogen or T6, where T6 is
- (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, or (aryl)alkyl;
- (ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
- or
- (iii) B group (i) or (ii) which is independently substituted by one or more of the following groups (2) to (13);
- (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-NT7T6,
- (10) -T4-N(T9)-T5-NT7T8,
- (11) -T4-N(T10)-T5-T6,
- (12) -T4-N(T10)-T5-H,
- (13) oxo;
- T4 and T5 are 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 independently hydrogen or a group provided in the definition of T6;
- and
- T11 and T12 are independently
- (1) a single bond,
- (2) alkylene,
- (3) alkenylene, or
- (4) alkynylene.
48 more elements
A compound having the structure:
- wherein
- R8c is selected from H or alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, aryloxy, any of which may be optionally independently substituted with one or more groups T1b, T2d or T3d as defined hereinabove;
- T1, T2 and T3 may each be present or absent and each may be selected from halo or —CN;
- and
- T10 is selected from H or —NH2.
2 more elements
A method of treating arrhythmia comprising administering to a patient in need thereof an effective amount of a compound of the formula I:
- including enantiomers, diastereomers, salts and solvates thereof wherein
- m and p are independently 0, 1, or 2, provided that the sum of m and p is 2;
- Q is NRt;
- J is a bond or C1-4 alkylene optionally substituted with one or more groups T1a, T2a or T3a;
- R1 is selected from
- R2 is aryl, which may be optionally independently substituted with one or more groups T1, T2 or T3;
- R3 is
- R5 is optionally substituted heteroaryl or (heteroaryl)alkyl wherein the hetero is pyrazine or pyridine, and either of these may be optionally independently substituted with one or more groups T1c, T2c or T3c;
- R6, R7, R8 and R8a are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)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;
- R8b is H, alkyl, aryl, cyano, nitro, acyl or —SO2(alkyl) wherein 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, alkoxy or aryloxy, any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
- R9 and R10 are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or (aryl)alkyl, any of which may be optionally independently substituted with one or more groups T1f, T2f or T3f;
- Z1 is ═O;
- Rx is one or more optional substituents attached to any available ring carbon atom, each of which is independently selected from T1g, T2g or T3g;
- T1-1g, T2-2g, and T3-3g are independently
- (1) hydrogen or T6, where T6 is
- (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, or (aryl)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 of the following groups (2) to (13);
- (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)-T6-NT7T8,
- (11) -T4-N(T10)-T5-T6,
- (12) -T4-N(T10)-T5-H,
- (13) oxo;
- T4 and T5 are 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 independently hydrogen or a group provided in the definition of T6;
- and
- T11 and T12 are independently
- (1) a single bond,
- (2) alkylene,
- (3) alkenylene, or
- (4) alkynylene.
48 more elements
Dependencies are inferred from the claim text.