Small molecule inhibitors of voltage-gated sodium channel 1.7 and methods of using same

A method of treating a condition selected from the group consisting of itch, pain, and combinations thereof, the method comprising administering a therapeutically effective amount of a Nav1.7 inhibitor to a subject in need thereof, wherein the Nav1.7 inhibitor is an N-substituted indole, wherein the N-substituted indole is a compound according to Formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is -L1-R1a;
• -L1- is selected from the group consisting of —(CH2)n—, —NHS(O)2—, —NHC(O)—, and —S(O)2—, wherein subscript n is 1, 2, 3, 4, 5, or 6;
• R1a is selected from the group consisting of C6-14 aryl, C3-8 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, (C6-14 aryl) sulfonyl, (C1-8 alkyl) sulfonyl, (C3-8 cycloalkyl)sulfonyl, C2-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R1b;
• each R1b is independently selected from the group consisting of halogen, —CN, —NO2, —NHR1c, —N═C(OH)R1d, —N3, —OH, —SH, —SO3H, C1-8 alkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl, —COOR1c, —C(O)NHR1c, and —C(O)R1d, wherein each R1c is independently selected from the group consisting of H and C1-4 alkyl and each R1d is independently C1-4 alkyl;
• subscript x is 0, 1, 2, 3, or 4;
• each R2 is independently selected from the group consisting of halogen, —CN, —NO2, —NHR1c, —N3, —OH, —SH, —SO3H, C1-8 alkyl, C1-8 alkoxy, —COOR1c, —C(O)NHR1c, and —C(O)R1d;
• R3 is -L3-R3a;
• -L3- is selected from the group consisting of a bond, —O—, —O(CH2)n—, —(CH2)n—, —NHC(O)—, —NHS(O)2—, and —S(O)2—, wherein subscript n is 1,2, 3,4, 5, or 6;
• R3a is selected from the group consisting of C6-14 aryl, C3-8 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, (C6-14 aryl)sulfonyl, (C1-8 alkyl)sulfonyl, (C3-8 cycloalkyl)sulfonyl, C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R3b;
• each R3b is independently selected from the group consisting of halogen, —CN, —NO2, —NHR3c, —N3, —OH, —SH, —SO3H, C1-8 alkyl, C1-8 alkoxy, —COOR3c, —C(O)NHR3c, and —C(O)R3d, wherein each R3c is independently selected from the group consisting of H and C1-4 alkyl and each R3d is independently C1-4 alkyl;
• R4 is selected from the group consisting of H and C1-6 alkyl;
• subscript y is 2, 1, 3, 4, 5, or 6;
• subscript z is 0 or 1;
• R5 is selected from the group consisting of H and C1-6 alkyl;
• alternatively, R4 and R5 are taken together to form 4- to 10-membered heterocyclylene;
• R6 is selected from the group consisting of 5- to 10-membered heterocyclyl, 3- or 4-membered heterocyclyl, 5- to 10-membered heteroaryl, C3-8 cycloalkyl, C6-14 aryl, and C7-22 arylalkyl, each of which is optionally substituted with one or more R6a;
• and
• each R6a is independently selected from the group consisting of halogen, —CN, —NO2, —NHR6b, —N3, —OH, —SH, —SO3H, C1-8 alkyl, C1-8 alkoxy, —COOR6b, —C(O)NHR6b, and —C(O)R6c, wherein each R6b is independently selected from the group consisting of H and C1-4 alkyl and each R6c is independently C1-4 alkyl.