Soluble Epoxide Hydrolase Inhibitors and Use Thereof

A method of preventing, delaying or reducing the occurrence of, or treating Alzheimer's disease in a subject in need thereof, the method comprising administering to the subject at least one compound or pharmaceutically acceptable salt corresponding in structure to Formula I

• or a pharmaceutically acceptable salt thereof, wherein:
• R0 is A, B, C or D,
• R1 is selected from the group consisting of H, halo, —OCF3, —OCF2H, —CF3, C1-C6-alkyl, —CF(CF3)2, —SF5, —CHF2, and —OCF2;
• R2 is halo;
• R3 is selected from the group consisting of —CO-alkyl, —CO-aryl, —CO—O-alkyl, —CO—O-alkylaryl, —CO-fluoroalkyl, aryl, and C1-C6-alkyl;
• R3′ is selected from the group consisting of —NHCO-alkyl, —NHCO-aryl, —NHCO—O-alkyl, —NHCO-fluoroalkyl, —NCH3CO—O-alkyl, —NCH3CO-alkyl, —NH-aryl, —NH-alkyl, —NH2, and C1-C6-alkoxy;
• R4 and R4′ are independently selected from the group consisting of H, halo, and C1-C6-alkyl;
• or R4 and R4′ can together form a 3-6 membered ring;
• or R4 or R4′ can form a 3-6 membered ring with X;
• or R4 or R4′ can form a 3-6 membered ring with R3′;
• or R4 or R4′ can form a 3-6 membered ring with R5 or R5′
• X is selected from the group consisting of —C(R7)(R7);
• or X can form a 3-6 membered ring with R4 or R4′;
• Z is NH or O;
• R5 and R5′ are independently selected from the group consisting of H, halo, and C1-C6-alkyl;
• or R5 and R5′ can together form a 3-6 membered ring;
• or R5 or R5′ can form a 3-6 membered ring with R4 or R4′;
• R6 and R6′ are independently selected from the group consisting of H, halo, and C1-C6-alkyl;
• or R6 or R6′ and can form a 3-6 membered ring with R4, R4′, R5, or R5′;
• or R6 and R6′ can together form a 3-6 membered ring;
• R7 and R7′ are independently selected from the group consisting of H, C1-C6-alkyl, and substituted C1-C6-alkyl;
• or R7 and RT can together form a 3-6 membered ring;
• R8 is H, halo, C1-C6-alkyl, C1-C6-alkoxy;
• or R8 can form a 3-6 membered ring with X;
• or R8 can form a 4-6 membered ring with X and R3′;
• R9 and R9′ are independently H, C1-C6-alkyl, and aryl;
• R10 and R10′ are independently selected from the group consisting of H, halo, and C1-C6-alkyl or R10 or R10′ and can form a 3-6 membered ring with R4, R4′, R5 or R5′;
• or R10 or R10′ can together form a 3-6 membered ring;
• R11 is selected from the group consisting of H, halo, C1-C6-alkyl, and C1-C6-alkoxy;
• m is zero, 1 or 2;
• n is zero, 1 or 2;
• p is zero, 1, 2, or 3;
• q is zero, 1 or 2;
• s is zero or 1;
• t is zero or 1;
• u is zero or 1;
• v is zero, 1, or 2;
• and
• wherein the compound is not 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU).

A method of treating brain injury inflammation, the method comprising administering to the subject at least one compound or pharmaceutically acceptable salt corresponding in structure to Formula I

• or a pharmaceutically acceptable salt thereof, wherein:
• R0 is A, B, C or D,
• R1 is selected from the group consisting of H, halo, —OCF3, —OCF2H, —CF3, C1-C6-alkyl, —CF(CF3)2, —SF5, —CHF2, and —OCF2;
• R2 is halo;
• R3 is selected from the group consisting of —CO-alkyl, —CO-aryl, —CO—O-alkyl, —CO—O-alkylaryl, —CO-fluoroalkyl, aryl, and C1-C6-alkyl;
• R3′ is selected from the group consisting of —NHCO-alkyl, —NHCO-aryl, —NHCO—O-alkyl, —NHCO-fluoroalkyl, —NCH3CO—O-alkyl, —NCH3CO-alkyl, —NH-aryl, —NH-alkyl, —NH2, and C1-C6-alkoxy;
• R4 and R4′ are independently selected from the group consisting of H, halo, and C1-C6-alkyl;
• or R4 and R4′ can together form a 3-6 membered ring;
• or R4 or R4′ can form a 3-6 membered ring with X;
• or R4 or R4′ can form a 3-6 membered ring with R3′;
• or R4 or R4′ can form a 3-6 membered ring with R5 or R5′;
• X is selected from the group consisting of —C(R7)(R7);
• or X can form a 3-6 membered ring with R4 or R4′;
• Z is NH or O;
• R5 and R5′ are independently selected from the group consisting of H, halo, and C1-C6-alkyl;
• or R5 and R5′ can together form a 3-6 membered ring;
• or R5 or R5′ can form a 3-6 membered ring with R4 or R4′;
• R6 and R6′ are independently selected from the group consisting of H, halo, and
• C1-C6-alkyl;
• or R6 or R6′ and can form a 3-6 membered ring with R4, R4′, R5, or
• R5′;
• or R6 and R6′ can together form a 3-6 membered ring;
• R7 and RT are independently selected from the group consisting of H, C1-C6-alkyl, and substituted C1-C6-alkyl;
• or R7 and R7′ can together form a 3-6 membered ring;
• R8 is H, halo, C1-C6-alkyl, C1-C6-alkoxy;
• or R8 can form a 3-6 membered ring with X;
• or R8 can form a 4-6 membered ring with X and R3′;
• R9 and R9′ are independently H, C1-C6-alkyl, and aryl;
• R10 and R10′ are independently selected from the group consisting of H, halo, and C1-C6-alkyl or R10 or R10′ and can form a 3-6 membered ring with R4, R4′, R5, or R5′;
• or R10 or R10′ can together form a 3-6 membered ring;
• R11 is selected from the group consisting of H, halo, C1-C6-alkyl, and C1-C6-alkoxy;
• m is zero, 1 or 2;
• n is zero, 1 or 2;
• p is zero, 1, 2, or 3;
• g is zero, 1 or 2;
• s is zero or 1;
• t is zero or 1;
• u is zero or 1;
• v is zero, 1, or 2;
• and
• wherein the compound is not 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU).