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US 12,415,793 B2Granted
Modulators of TMEM16A for treating respiratory disease
AssigneeTMEM16A Limited
InventorsStephen Collingwood, Jonathan David Hargrave, Duncan Alexander Hay, Edward Walker
Life of this patent
Estimating the term…
Abstract
Compounds of general formula (I): wherein R1, R2, R3, R4, A, Z1, Z2 and Y are as defined herein are useful for treating respiratory disease and other diseases and conditions modulated by TMEM16A.
Claims13
A compound of formula (I):
- or a tautomer, a stereoisomer, an isotopic variant, a pharmaceutically acceptable salt, or solvate thereof, wherein
- A is
- where
- one of X1, X2, X3 is S and the other two of X1, X2 and X3 are CH;
- represents a single or a double bond such that the ring A is aromatic;
- *1 indicates the point of attachment to Z1 and *2 indicates the point of attachment to Z2;
- each of Z1 and Z2 is independently selected from *—C(O)NH— and *—NHC(O)—, where * indicates the point of attachment to the ring A;
- 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;
- R2 is H or C1-6 alkyl optionally substituted with OR12;
- and
- wherein each R12 and R13 is independently selected from H, C1-6 alkyl and C1-6 fluoroalkyl,
- R3 is:
- C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, any of which C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl groups are 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
- R3 is:
- 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 aryl, heteroaryl, carbocyclic or heterocyclic ring systems are 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;
- wherein 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 carbocyclic or heterocyclic ring systems or phenyl groups are 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;
- Y is —CH2— or —CH(CH3)—;
- 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)R6C(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 a 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which aryl, heteroaryl, carbocyclic or heterocyclic ring systems are 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 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 C1-4 alkyl, oxo and halo.
33 more elements
A compound selected from:
- N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]thiophene-2-carboxamide (Compound 1);
- N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]thiophene-3-carboxamide (Compound 1.2);
- N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]thiophene-2-carboxamide (Compound 1.3);
- 5-[[2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)thiophene-2-carboxamide (Compound 8);
- 5-[[2-[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl]thiophene-2-carboxamide (Compound 9);
- and
- pharmaceutically acceptable salts and solvates thereof.
4 more elements
A compound of formula (II), (X), (XVI), (XX), (XXV), (XXX) or (XXXV),
- wherein
- one of X1, X2, X3 is S and the other two of X1, X2 and X3 are CH;
- Y is —CH2— or —CH(CH3)—;
- 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)R6C(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 a 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which aryl, heteroaryl, carbocyclic or heterocyclic ring systems are 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 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 C1-4 alkyl, oxo and halo;
- wherein
- A is
- one of X1, X2, X3 is S and the other two of X1, X2 and X3 are CH;
- represents a single or a double bond such that the ring A is aromatic;
- *1 indicates the point of attachment to
- and *2 indicates the point of attachment to
- 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;
- R2 is H or C1-6 alkyl optionally substituted with OR12;
- and
- wherein each R12 and R13 is independently selected from H, C1-6 alkyl and C1-6 fluoroalkyl,
- R3 is:
- C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, any of which C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl groups are 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
- R3 is:
- 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 aryl, heteroaryl, carbocyclic or heterocyclic ring systems are 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;
- wherein 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(R)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 carbocyclic or heterocyclic ring systems or phenyl groups are 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(R)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;
- wherein
- A is
- one of X1, X2, X3 is S and the other two of X1, X2 and X3 are CH;
- represents a single or a double bond such that the ring A is aromatic;
- *1 indicates the point of attachment to
- and *2 indicates the point of attachment to
- Y is —CH2— or —CH(CH3)—;
- 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(R)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)R6C(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 a 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which aryl, heteroaryl, carbocyclic or heterocyclic ring systems are 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 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 C1-4 alkyl, oxo and halo;
- wherein
- A is
- one of X1, X2, X3 is S and the other two of X1, X2 and X3 are CH;
- represents a single or a double bond such that the ring A is aromatic;
- *1 indicates the point of attachment to
- and *2 indicates the point of attachment to
- Y is —CH2— or —CH(CH3)—;
- 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)R6C(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 a 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which aryl, heteroaryl, carbocyclic or heterocyclic ring systems are 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 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 C1-4 alkyl, oxo and halo;
- wherein
- A is
- one of X1, X2, X3 is S and the other two of X1, X2 and X3 are CH;
- represents a single or a double bond such that the ring A is aromatic;
- *1 indicates the point of attachment to
- and *2 indicates the point of attachment to
- 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;
- R2 is H or C1-6 alkyl optionally substituted with OR12;
- and
- wherein each R12 and R13 is independently selected from H, C1-6 alkyl and C1-6 fluoroalkyl,
- R3 is:
- C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, any of which C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl groups are 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
- R3 is:
- 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 aryl, heteroaryl, carbocyclic or heterocyclic ring systems are 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;
- wherein 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(R)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 carbocyclic or heterocyclic ring systems or phenyl groups are 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(R)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;
- wherein
- R32 is halo;
- A is
- one of X1, X2, X3 is S and the other two of X1, X2 and X3 are CH;
- represents a single or a double bond such that the ring A is aromatic;
- *1 indicates the point of attachment to R32 and *2 indicates the point of attachment to
- Y is —CH2— or —CH(CH3)—;
- 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(R)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)R6C(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 a 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which aryl, heteroaryl, carbocyclic or heterocyclic ring systems are 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 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 C1-4 alkyl, oxo and halo;
- wherein
- A is
- one of X1, X2, X3 is S and the other two of X1, X2 and X3 are CH;
- represents a single or a double bond such that the ring A is aromatic;
- *1 indicates the point of attachment to
- and *2 indicates the point of attachment to
- 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;
- R2 is H or C1-6 alkyl optionally substituted with OR12;
- and
- wherein each R12 and R13 is independently selected from H, C1-6 alkyl and C1-6 fluoroalkyl,
- R3 is:
- C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, any of which C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl groups are 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
- R3 is:
- 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 aryl, heteroaryl, carbocyclic or heterocyclic ring systems are 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;
- wherein 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 carbocyclic or heterocyclic ring systems or phenyl groups are 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(R)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.
132 more elements
Dependencies are inferred from the claim text.