Trpm8 agonists as cooling agents and for the treatment of disease

A compound having the structure of Formula (I):

• wherein:
• R1 and R2 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 R6;
• or R1 and R2, together with the nitrogen atom to which they are attached, are combined to form a C2-C9heterocycloalkyl optionally substituted by 1, 2, 3, or 4 R6;
• each R3 is independently selected from halogen, —OR9, —N(R9)(R10), —CN, —C(O)OR9, —C(O)N(R9)(R10), —C(O)R11, —S(O)2R11, —S(O)2N(R9)(R10), C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 R7;
• or an R3 and R1, together with the atoms to which they are attached, are combined to form a C2-C9heterocycloalkyl optionally substituted by 1, 2, 3, or 4 R7;
• R4a, R4b, and R5 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl optionally substituted by 1, 2, 3, or 4 R8;
• each R6, each R7, and each R8 are each independently selected from halogen, oxo, —OR9, —N(R9)(R10), —CN, —C(O)OR9, —C(O)N(R9)(R10), —C(O)R11, C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl;
• each R9 is independently selected from hydrogen, C1-6alkyl, —C1-6alkyl-NH2, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, —CH2—C3-6cycloalkyl, C2-9heterocycloalkyl, —CH2—C2-9heterocycloalkyl, C6-10aryl, —CH2—C6-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, —CH2—C3-6cycloalkyl, C2-9heterocycloalkyl, —CH2—C2-9heterocycloalkyl, C6-10aryl, —CH2—C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• each R10 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
• or R9 and R10, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• each R11 is independently selected C1-6alkyl, —C1-6alkyl-NH2, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• X is a bond or C1-6alkylene;
• n is 0 or 1;
• and
• p is 0, 1, 2, 3, or 4;
• or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.