Muscarinic acetylcholine m1 receptor antagonists

A method of treating a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA):

• wherein:
• E is —CH2—, —CH2CH2—, —O—CH2—, or —CH2—O—;
• X is a bond,
• —C≡C—, —C(═O)— —CH2O—, —CH2CH2O—, —O—, —N(R7)—, —S(O)2—, —CH2N(R7)—, or —CH2CH2N(R7)—;
• Y is a bond, —O—, or —N(R8)—;
• R1 is
• wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, —CN, —N(R10)2, C1-6 alkyl, C1-6 alkyl-OH, C1-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkoxy;
• each R2 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• each R3 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• R4 is
• each R5 is independently selected from halogen, —CN, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
• each R6 is independently selected from deuterium, halogen, —CN, —N(R10)2, C1-6 alkyl, C1-6 alkyl-OH, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, —C(═O)(C1-6 alkyl), —(C(R10)2)g—O—(C1-6 alkyl) and —S(O)2R11;
• R7 is hydrogen or C1-6 alkyl;
• R8 is hydrogen or C1-6 alkyl;
• each R9 is independently C1-6 alkyl;
• each R10 is independently selected from H and C1-6 alkyl;
• R11 is C1-6 alkyl;
• each R12 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• each R13 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• a is 1, 2, 3, 4, or 5;
• m is 0, 1, 2, or 3;
• n is 1, 2, 3, 4, or 5;
• p is 0, 1, 2, or 3;
• and
• each q is independently 0, 1, 2, 3, or 4;
• or a pharmaceutically acceptable salt or solvate thereof.

A method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA):

• wherein:
• E is —CH2—, —CH2CH2—, —O—CH2—, or —CH2—O—;
• X is a bond,
• C≡C—, —C(═O)— —CH2O—, —CH2CH2O—, —O—, —N(R7)—, —S(O)2—, —CH2N(R7)—, or —CH2CH2N(R7)—;
• Y is a bond, —O—, or —N(R8)—;
• R1 is
• wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, —CN, —N(R10)2, C1-6 alkyl, C1-6 alkyl-OH, C1-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkoxy;
• each R2 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• each R3 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• R4 is
• each R5 is independently selected from halogen, —CN, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
• each R6 is independently selected from deuterium, halogen, —CN, —N(R10)2, C1-6 alkyl, C1-6 alkyl-OH, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, —C(═O)(C1-6 alkyl), —(C(R10)2)g—O—(C1-6 alkyl) and —S(O)2R11;
• R7 is hydrogen or C1-6 alkyl;
• R8 is hydrogen or C1-6 alkyl;
• each R9 is independently C1-6 alkyl;
• each R10 is independently selected from H and C1-6 alkyl;
• R11 is C1-6 alkyl;
• each R12 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• each R13 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• a is 1, 2, 3, 4, or 5;
• m is 0, 1, 2, or 3;
• n is 1, 2, 3, 4, or 5;
• p is 0, 1, 2, or 3;
• and
• each q is independently 0, 1, 2, 3, or 4;
• or a pharmaceutically acceptable salt or solvate thereof.

A method of treating a neuropathic disease, optionally a peripheral neuropathy, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA):

• wherein:
• E is —CH2—, —CH2CH2—, —O—CH2—, or —CH2—O—;
• X is a bond,
• —C≡C—, —C(═O)— —CH2O—, —CH2CH2O—, —O—, —N(R7)—, —S(O)2—, —CH2N(R7)—, or —CH2CH2N(R7)—;
• Y is a bond, —O—, or —N(R8)—;
• R1 is
• wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, —CN, —N(R10)2, C1-6 alkyl, C1-6 alkyl-OH, C1-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkoxy;
• each R2 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• each R3 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• R4 is
• each R5 is independently selected from halogen, —CN, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
• each R6 is independently selected from deuterium, halogen, —CN, —N(R10)2, C1-6 alkyl, C1-6 alkyl-OH, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, —C(═O)(C1-6 alkyl), —(C(R10)2)g—O—(C1-6 alkyl) and —S(O)2R11;
• R7 is hydrogen or C1-6 alkyl;
• R8 is hydrogen or C1-6 alkyl;
• each R9 is independently C1-6 alkyl;
• each R10 is independently selected from H and C1-6 alkyl;
• R11 is C1-6 alkyl;
• each R12 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• each R13 is independently selected from hydrogen, deuterium, halogen, —OH, and C1-6 alkyl;
• a is 1, 2, 3, 4, or 5;
• m is 0, 1, 2, or 3;
• n is 1, 2, 3, 4, or 5;
• p is 0, 1, 2, or 3;
• and
• each q is independently 0, 1, 2, 3, or 4;
• or a pharmaceutically acceptable salt or solvate thereof.