SELECTIVE NaV1.7 INHIBITORS FOR THE TREATMENT OF DIABETES

A method for treating or preventing diabetes comprising administering to a subject in need thereof a therapeutically effective amount of a compound selectively inhibiting NaV1.7, wherein compound is a compound of Formula (I′):

• or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof,
• wherein:
• Z is —O— or —S—;
• Y is —X—C(═O)NR4R5, —(CH2)3—NR9R10, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-(2-yl or 3-yl);
• X is (C6-C10)aryl or 5- or 6-membered heteroaryl;
• R1 is a partially unsaturated or aromatic 5- or 6-membered heterocycle;
• R2 is independently at each occurrence —F, —Cl, —Br, —CH3 or —CN;
• R3 is independently at each occurrence —H, —F, —Cl, —Br, —CF3, —OCF3, —CN, (C1-C12)alkyl, or (C1-C12)alkoxy;
• R4 and R5 are each independently H, (C1-C9)alkyl, (C4-C12)cycloalkyl, or R4 and R5 together form a 5- to 7-membered heterocycloalkyl ring;
• with the proviso that:
• R4 and R5 are not both H;
• and
• at least one of R4 and R5 independently or said heterocycloalkyl ring formed by R4 and R5 together is substituted with 1 or 2 substituents selected from the group consisting of —CO2H, —CO2R6, —CN, —OH, —CONR7R8, and —NR7R8;
• wherein:
• R6 is (C1-C12)alkyl;
• R7 and R8 are each independently H, (C1-C12)alkyl, or R7 and R8 together form a 4- to 7-membered heterocycloalkyl ring;
• R9 is (C1-C6)alkyl, (C3-C8)cycloalkyl, pyrazolyl or pyridinyl;
• wherein R9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of —COOH, —COOR11, —CONR11R12, —SO2R11, —SO2NR11R12, —OH, —CN, —OR11, and —NR11R12;
• wherein R11 and R12 may form a 6 membered heterocycloalkyl ring
• R10 is R11, (C3-C6)alkynyl, (C3-C6)alkenyl, —COR11, —COOR11, —SO2R11, 5-methyl-2-oxo-1,3-dioxol-4-yl,
• —COO—CH(CH3)OCOCH(CH3)2;
• or R9 and R10 together form a piperazinone or a 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 substituents selected from the group consisting of —COOH, —COOR11, —CH2—COOR11, —OH, —NH2, —CN, and (C1-C8)alkoxy;
• or R9 and R10 together form a unsubstituted 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused with a 5-membered heteroaryl;
• and
• R11 and R12 are independently H or (C1-C6)alkyl, optionally substituted with 4- to 8-membered heterocycloalkyl ring;
• and
• m and n are each independently 1, 2, 3, or 4.

A method for maintaining or lowering blood or plasma glucose levels in a subject in need thereof comprising administering to the subject, a therapeutically effective amount of a compound selectively inhibiting NaV1.7, wherein compound is a compound of Formula (I′):

• or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof,
• wherein:
• Z is —O— or —S—;
• Y is —X—C(═O)NR4R5, —(CH2)3—NR9R10, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-(2-yl or 3-yl);
• X is (C6-C10)aryl or 5- or 6-membered heteroaryl;
• R1 is a partially unsaturated or aromatic 5- or 6-membered heterocycle;
• R2 is independently at each occurrence —F, —Cl, —Br, —CH3 or —CN;
• R3 is independently at each occurrence —H, —F, —Cl, —Br, —CF3, —OCF3, —CN, (C1-C12)alkyl, or (C1-C12)alkoxy;
• R4 and R5 are each independently H, (C1-C9)alkyl, (C4-C12)cycloalkyl, or R4 and R5 together form a 5- to 7-membered heterocycloalkyl ring;
• with the proviso that:
• R4 and R5 are not both H;
• and
• at least one of R4 and R5 independently or said heterocycloalkyl ring formed by R4 and R5 together is substituted with 1 or 2 substituents selected from the group consisting of —CO2H, —CO2R6, —CN, —OH, —CONR7R8, and —NR7R8;
• wherein:
• R6 is (C1-C12)alkyl;
• R7 and R8 are each independently H, (C1-C12)alkyl, or R7 and R8 together form a 4- to 7-membered heterocycloalkyl ring;
• R9 is (C1-C6)alkyl, (C3-C8)cycloalkyl, pyrazolyl or pyridinyl;
• wherein R9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of —COOH, —COOR11, —CONR11R12, —SO2R11, —SO2NR11R12, —OH, —CN, —OR11, and —NR11R12;
• wherein R11 and R12 may form a 6 membered heterocycloalkyl ring
• R10 is R11, (C3-C6)alkynyl, (C3-C6)alkenyl, —COR11, —COOR11, —SO2R11, 5-methyl-2-oxo-1,3-dioxol-4-yl,
• —COO—CH(CH3)OCOCH(CH3)2 or R9 and R10 together form a piperazinone or a 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 substituents selected from the group consisting of —COOH, —COOR11, —CH2—COOR11, —OH, —NH2, —CN, and (C1-C8)alkoxy;
• or R9 and R10 together form a unsubstituted 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused with a 5-membered heteroaryl;
• and
• R11 and R12 are independently H or (C1-C6)alkyl, optionally substituted with 4- to 8-membered heterocycloalkyl ring;
• and
• m and n are each independently 1, 2, 3, or 4.