M4 activators/modulators and uses thereof

A compound having a structure of Formula (I):

• or a pharmaceutically acceptable salt of the compound, wherein:
• A is a 6-8 membered heterocycle comprising 1 or 2 ring nitrogen atoms and optionally substituted with 1 to 3 substituents independently selected from halogen, OH, and C1-3alkyl;
• Y is a bond, O, S, CH2, CHF, CF2, or C(OH)H;
• m is 1 or 2;
• n is 1 or 2;
• p is 1 or 2;
• R1 is H, halogen, CN, OH, —N(R6)(R7), C1-6alkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, —[O]0-1—C3-6cycloalkyl, —[O]0-1—C6-10aryl, —[O]0-1-4-8 membered heterocycle or —[O]0-1-5-10 membered heteroaryl, wherein the heterocycle and heteroaryl each comprises 1, 2, or 3 ring heteroatoms selected from N, O, and S, and when R1 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, —[O]0-1—C3-6cycloalkyl, —[O]0-1—C6-10aryl, —[O]0-1-4-8 membered heterocycle, —[O]0-1-5-10 membered heteroaryl, —NH—C3-6cycloalkyl, —NH—C6-10aryl, —NH-4-8 membered heterocycle, —NH-5-10 membered heteroaryl, —N(C1-6alkyl)-C3-6cycloalkyl, —N(C1-6alkyl)-C6-10aryl, —N(C1-6alkyl)-4-8 membered heterocycle, or —N(C1-6alkyl)-5-10 membered heteroaryl, R1 is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ═O, SO2, and C1-3alkyl,
• R2 is H, halogen, CN, OH, —N(R6)(R7), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6heteroalkyl, C3-6cycloalkyl, or 4-8 membered heterocycle comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S;
• R3 is halogen, CN, OH, —N(R6)(R7), C1-6alkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, —[O]0-1—C3-6cycloalkyl, —[O]0-1—C6-10aryl, —[O]0-1-4-8 membered heterocycle, or —[O]0-1-5-10 membered heteroaryl, —NH—C3-6cycloalkyl, —NH—C6-10aryl, —NH-4-8 membered heterocycle, —NH-5-10 membered heteroaryl, —N(C1-6alkyl)-C3-6cycloalkyl, —N(C1-6alkyl)-C6-10aryl, —N(C1-6alkyl)-4-8 membered heterocycle, or —N(C1-6alkyl)-5-10 membered heteroaryl, wherein the heterocycle and heteroaryl each comprises 1, 2, or 3 ring heteroatoms selected from N, O, and S, and the C3-6cycloalkyl, —C6-10aryl, 4-8 membered heterocycle, or 5-10 membered heteroaryl is substituted with 0, 1, 2, or 3 R3a substituents;
• each R3a is independently selected from halogen, CN, OH, ═O, ═N(C1-3alkly), SO2, C1-6alkyl, C2-10alkene, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkylene-O—C1-6alkyl, C0-6alkylene-NH2, C0-6alkylene-NH(C1-6alkyl), C0-6alkylene-N(C1-6alkyl)2, —S—C1-6alkyl, C0-6alkylene-SO2C1-6alkyl, C0-6alkylene-C(O)NH2, C0-6alkylene-C(O)NH(C1-6alkyl), C0-6alkylene-C(O)N(C1-6alkyl)2, C0-6alkylene-NHC(O)C1-6alkyl, C0-6alkylene-COOH, C0-6alkylene-C3-6cycloalkyl, C1-6alkylene-O—C1-6alklyeneSi(C1-3alkyl)3, and C0-6alkylene-3-6 membered heterocycle comprising 1, 2, or 3 heteroatoms selected from N, O, and S;
• R4 is H, halogen, CN, or OH;
• R5 is —CO2—Z, or a bioisostere thereof;
• each R6 and R7 is independently H, C1-6alkyl, C(O)—C1-6alkyl, spiro or bicyclic C8-14cycloalkyl, 8-14 membered heterocycle comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S, and when R6 or R7 is other than H, it can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, =O, SO2, OH, C0-6alkylene-NH2, C0-6alkylene-NH(C1-6alkyl), C0-6alkylene-N(C1-6alkyl)2, C0-6alkylene-SO2C1-6alkyl, C1-6alkyl and C1-6alkoxy, or
• R6 and R7, together with the nitrogen to which they are attached, form a 4-10 membered heterocycle comprising 0-2 additional ring heteroatoms independently selected from N, O, and S;
• and
• Z is C1-7alkyl, C1-7haloalkyl, C3-6cycloalkyl, or C2-6alkyne, and Z is optionally substituted with C1-6alkoxy or C3-6cycloalkyl;
• with the proviso that when R1, R2, and R4 are each H, Y is CH2, m, n, and p are each 1, A is
• and R3 is trifluoroethoxy, trifluoromethoxy, difluoromethoxy, methoxy, or
• then R5 is not CO2CH2CH3.