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US 7,202,253 B2Granted
Cycloalkyl 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 cycloalkyl 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.
Claims9
A compound of Formula I
- enantiomers, diastereomers, solvates or salts thereof wherein
- the dashed line represents an optional double bond, provided that R1a is absent when a double bond is present;
- m and p are independently 0, 1, 2 or 3;
- R1 is
- —N(R8)R14, —N(R8)C(O)R14, —SO2R8c, —OC(O)CCl3, —NR6R7, —OC(O)NR6R7, —N3, nitro, or hydroxy;
- R1a is H;
- R2 is aryl, which may be optionally independently substituted with one or more groups T1, T2, or T3;
- J is a C1-4 alkylene optionally independently substituted with one or more groups T1a, T2a or T3a;
- R3 is—R5 ;
- R4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T1b, T2b or T3b ;
- R4a is R4 or OR4;
- R5 is —NR6aR7a;
- R6, R7, R8, R8a, R8a2, R8a4, and R8a5 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)R12, —CO2R12, —C(O)—NR12R13, or —NR12R13 any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
- or R6 and R7, together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered 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 or R8a to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T1d, T2d or T3d;
- R6a is H;
- R7a is heteroaryl, which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
- R8b is independently H, alkyl, aryl, cyano, nitro, acyl or —SO2(alkyl);
- R8c is independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
- R8d is R4, COR4, CO2R4, CONR6R7, or SO2—NR6R7;
- R12 and R13 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)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 R12 and R13 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 ═NR8a2, ═N—CO2R8a2, ═N—COR8a2, ═N—CN, or ═N—SO2R8a2;
- Z and Z2 are independently ═O, ═S, ═NR8a4 or ═N—CN;
- R14 is independently
- where q is 1, 2 or 3;
- RY is an optional oxo substituent attached to any available ring carbon atom;
- X1 is O, S, NR8a5 or CH2;
- and
- X2 is NR8a5 or CH2;
- 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 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, (heterocyclo)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 definition 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 definition 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;
- T11 and T12 are each independently
- (1) a single bond,
- (2) alkylene,
- (3) alkenylene, or
- (4) alkynylene.
67 more elements
A compound of Formula I
- enantiomers, diastereomers or salts thereof wherein
- the dashed line represents an optional double bond, provided that R1a is absent when a double bond is present;
- m and p are independently 0, 1, 2 or 3;
- R1 is
- —N(R8)R14, —N(R8)C(O)R14, —SO2R8c, —OC(O)CCl3, —NR6R7, —OC(O)NR6R7, —N3, nitro, or hydroxy;
- R1a is H;
- R2 is aryl, which may be optionally independently substituted with one or more groups T1, T2 or T3;
- J is C1-4 alkylene optionally independently substituted with one or more groups T1a, T2a or T3a;
- R3 is —R5;
- R4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T1b, T2b or T3b;
- R4a is R4 or OR4;
- R5 is —NR6aR7a;
- R6, R7, R8, R8a, R8a2, R8a4, and R8a5 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)R12, —C2R12, —C(O)—NR12R13, or —NR12R13 any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
- or R6 and R7 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered 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;
- R6a is H;
- R7a is heteroaryl, which may be optionally independently substituted with one or more groups T1d, T2d or T3d;
- R8b is independently H, alkyl, aryl, cyano, nitro, acyl or —SO2(alkyl);
- R8c is independently H, alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
- R8d is R4, COR4, CO2R4, SO2R4, CONR6R7, or SO2—NR6R7;
- R12 and R13 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)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 R12 and R13 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 ═NR8a2, ═N—CO2R8a2, ═N—COR8a2, ═N—CN, or ═N—SO2R8a2;
- Z and Z2 are independently ═O, ═S, ═NR8a4 or ═N—CN;
- R14 is independently
- where q is 1, 2 or 3;
- RY is an optional oxo substituent attached to any available ring carbon atom;
- X1 is O, S, NR8a5 or CH2;
- and
- X2 is NR8a5 or CH2;
- T1-1g, T2-2g and T3-3g 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, (heterocyclo)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 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 definition 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 definition 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;
- T11 and T12 are each independently
- (1) a single bond,
- (2) alkylene,
- (3) alkenylene, or
- (4) alkynylene.
66 more elements
Dependencies are inferred from the claim text.