US 12,377,105 B2 · Compounds

Abstract

Compounds of general formula (I): wherein R1, R2, R3, R4, R5a, R5b X1, X2, Z and Y are as defined herein are positive modulators of the calcium-activated chloride channel (CaCC), TMEM16A. The compounds are useful for treating diseases and conditions affected by modulation of TMEM16A, particularly respiratory diseases and conditions.

A method for the treatment or prophylaxis of diseases and conditions affected by modulation of TMEM16A, the method comprising administering to a patient an effective amount of a compound according to formula (I):

wherein:
R1 is H, CN, C(O)OR12, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl, any of which alkyl, alkenyl or alkynyl groups are optionally substituted with one or more substituents selected from fluoro, OR12, N(R12)2, C(O)OR12, C(O)N(R12)2, C(O)R12 and N(R13)C(O)R12;
wherein each R12 and R13 is independently selected from H, C1-6 alkyl and C1-6 fluoroalkyl
R2 is H or C1-6 alkyl optionally substituted with OR12;
R3 is:
C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, any of which is optionally substituted with one or more substituents selected from fluoro, CN, R14 OR14, OR15, N(R15)2, C(O)OR15, C(O)N(R15)2, N(R16)C(O)R15, N(R15)S(O)2R14, N(R15)S(O)2R16 and N(R15) C(O)OR16;
or
a 3- to 7-membered carbocyclic or heterocyclic ring system or a 6- to 10 membered aryl or 5- to 10-membered heteroaryl ring system, either of which is optionally substituted with one or more substituents selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, OR17 and N(R17)2;
wherein R14 is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halo, C1-4 alkyl, C1-4 haloalkyl, OR17 and N(R17)2;
wherein each R17 is independently H, C1-4 alkyl or C1-4 haloalkyl;
each R15 and R16 is independently H, C1-6 alkyl or C1-6 haloalkyl;
or
R2 and R3 together with the carbon atom to which they are attached combine to form a 3- to 10-membered carbocyclic or heterocyclic ring system optionally substituted with one or more substituents selected from halo, CN, OR9, N(R9)2, C(O)OR9, C(O)N(R9)2, C(O)R9, N(R9)C(O)R9 and C1-4 alkyl optionally substituted with halo, OR9 or N(R9)2;
or
R1, R2 and R3 together with the carbon atom to which they are attached combine to form a bridged 5- to 10-membered carbocyclic or heterocyclic ring system or phenyl, any of which is optionally substituted with one or more substituents selected from halo, CN, OR9, N(R9)2, C(O)OR9, C(O)N(R9)2, C(O)R9,N(R9)C(O)R9 and C1-4 alkyl optionally substituted with halo, OR9 or N(R9)2;
each R9 is independently selected from H, C1-6 alkyl or C1-6 haloalkyl;
X1 is N;
X2 is CR8
R8 is H, halo, OH, O(C1-4 alkyl), CN or NH2;
Y is a bond or a straight C1-6 alkylene chain which is optionally substituted with one or more substituents R18, wherein two substituents R18 may be attached to the same or to different carbon atoms;
wherein each R18 is independently C1-3 alkyl or C1-3 haloalkyl in which a —CH2— is optionally replaced with —NH— or —O— and wherein two R18 groups may combine with the atom or atoms to which they are attached to form a 3- to 6-membered carbocyclic or heterocyclic ring system;
Z is —C(O)— or —C(O)NH—;
R4 is a 6- to 14-membered aryl, 5- to 14-membered heteroaryl or a 5- to 10-membered carbocyclic ring system, any of which is optionally substituted with one or more substituents selected from:
halo, CN, nitro, R19, OR19, OR6, SR6, NR6R7, C(O)R6, C(O)R19, C(O)OR6, C(O)N(R6) (R7), N(R7)C(O)R6;
C1-6 alkyl or O(C1-6 alkyl), either of which is optionally substituted with one or more substituents selected from halo, CN, nitro, R19, OR6, SR6, NR6R7, C(O)R6 C(O)OR6, C(O)N(R6) (R7) and N(R7)C(O)R6, and
when R4 is not fully aromatic in character, oxo;
wherein R19 is 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halo, C1-4 alkyl, C1-4 haloalkyl, OH, O(C1-4 alkyl), O(C1-4 haloalkyl);
R6 is H, C1-6 alkyl, C1-6 haloalkyl, benzyl, 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl;
R7 is H, C1-6 alkyl or C1-6 haloalkyl;
or
R6 and R7 together with the nitrogen atom to which they are attached may form a 4 to 7-membered heterocyclic ring optionally containing one or more further heteroatoms and optionally substituted with one or more substituents selected from oxo and halo;
and
each of R5a and R5b is independently H, C1-4 alkyl or halo.

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Compounds

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Compounds

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Abstract

Claims14