Melanin concentrating hormone receptor ligands: substituted 2-(4-benzyl-piperazin-1-ylmethyl)- and 2-(4-benzyl-diazepan-1-ylmethyl)-1H-benzoimidazole analogues

A compound of the formula:

• 114
• or a pharmaceutically acceptable salt thereof, wherein:
• A, B, E, D and X each independently represent CH or N, with the proviso that not more than two of A, B, E and D represent N;
• R1 is:
• (i) hydrogen, —C(═O)—NH2, —SO2NH2, or —COOH;
• or
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkyl ether, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- or di-(C1-C8alkyl)amino, C1-C8carbamate, mono- or di-(C1-C8alkyl)sulfonamido, or mono- or di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• R2 is:
• (i) hydrogen, halogen, hydroxy, —C(═O)—NH2, —SO2NH2, or —COOH;
• or
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkyl ether, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- or di-(C1-C8alkyl)amino, C1-C8carbamate, mono- or di-(C1-C8alkyl)sulfonamido or mono- or di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• R3 represents 0 to 4 substituents, each of which is linked to a carbon atom at A, B, E or D, and each of which is independently selected from:
• (i) halogen, hydroxy, amino, cyano, nitro, —C(═O)—NH2, —SO2NH2 and —COOH;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di-(C1-C8alkyl)amino, C1-C8carbamate, mono- and di-(C1-C8alkyl)sulfonamido, and mono- and di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 secondary substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• L is C1-C6alkyl;
• RA is a 5- to 7-membered carbocyclic or heterocyclic ring, unsubstituted or substituted with from 1 to 4 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy, C1-C8alkanoyl, C1-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di(C1-C8alkyl)amino, C1-C8carbamate and 5- to 10-membered carbocyclic and heterocyclic groups;
• R5 represents from 0 to 3 substituents, each of which is independently selected from:
• (i) halogen, hydroxy, amino, cyano, nitro, —C(═O)—NH2, —SO2NH2, and —COOH;
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di-(C1-C8alkyl)amino, C1-C8carbamate, mono- and di-(C1-C8alkyl)sulfonamido, m6no- and di-(C1-C8alkyl)carboxamido, and fused and pendant 3- to 10-membered carbocyclic and heterocyclic groups, each of which is unsubstituted or substituted with from 1 to 9 secondary substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• and
• (iii) substituents that are joined to R8 to form a 5- or 6-membered heterocyclic ring;
• R6 and R7 are independently:
• (i) hydrogen, amino, cyano, nitro, —C(═O)—NH2, —SO2NH2, or —COOH;
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkyl ether, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- or di-(C1-C8alkyl)amino, C1-C8carbamate, mono- or di-(C1-C8alkyl)sulfonamido, or mono- or di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• or
• (iii) joined to form, with XCH2CH2N, a 5- to 7-member heterocyclic ring, wherein the ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1C8alkyl;
• and
• R8 is hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkanoyl, C2-C8alkyl ether, haloC1-C8alkyl, haloC1-C8alkoxy or a substituent that is joined to R5 to form a 5- or 6-member heterocyclic ring.

A compound of the formula:

• 115
• or a pharmaceutically acceptable salt thereof, wherein:
• A, B, E, D and X each independently represent CH or N, with the proviso that not more than two of A, B, E and D represent N;
• R1 is:
• (i) hydrogen, —C(═O)—NH2, —SO2NH2, or —COOH;
• or
• (ii) (C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkyl ether, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- or di-(C1-C8alkyl)amino, C1-C8carbamate, mono- or di-(C1-C8alkyl)sulfonamido, or mono- or di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• R2 is:
• (i) hydrogen, halogen, hydroxy, —C(═O)—NH2, —SO2NH2, or —COOH;
• or
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkyl ether, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- or di-(C1-C8alkyl)amino, C1-C8carbamate, mono- or di-(C1-C8alkyl)sulfonamido or mono- or di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• R3 represents 0 to 4 substituents, each of which is linked to a carbon atom at A, B, E or D, and each substituent is independently selected from:
• (i) halogen, hydroxy, amino, cyano, nitro, —C(═O)—NH2, —SO2NH2 and —COOH;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di-(C1-C8alkyl)amino, C1-C8carbamate, mono- and di-(C1-C8alkyl)sulfonamido, and mono- and di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 secondary substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• L is C1-C6alkyl;
• 116
• is a 5- to 7-membered carbocyclic or heterocyclic ring, unsubstituted or substituted with from 1 to 4 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy, C2-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di-(C1-C8alkyl)amino, C1-C8carbamate and 5- to 10-membered carbocyclic and heterocyclic groups;
• R5 represents from 0 to 3 substituents, each of which is independently selected from:
• (i) halogen, hydroxy, amino, cyano, nitro, —C(═O)—NH2, —SO2NH2, or —COOH;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di-(C1-C8alkyl)amino, C1-C8carbamate, mono- and di-(C1-C8alkyl)sulfonamido, mono- and di-(C1-C8alkyl)carboxamido, and fused and pendant 3- to 10-membered carbocyclic and heterocyclic groups, each of which is unsubstituted or substituted with from 1 to 9 secondary substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• R6 and R7 are independently:
• (i) hydrogen, amino, cyano, nitro, —C(═O)—NH2, —SO2NH2 or —COOH;
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkyl ether, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- or di-(C1-C8alkyl)amino, C1-C8carbamate, mono- or di-(C1-C8alkyl)sulfonamido, or mono- or di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• or
• (iii) joined to form, with XCH2CH2N, a 5- to 7-membered heterocyclic ring, wherein the ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• and
• R9 is hydroxy, C1-C8alkoxy, haloC1-C8alkoxy, C2-C8alkanoyloxy or haloC2-C8alkanoyloxy.

A method for treating a disease or disorder associated with pathogenic melanin concentrating hormone receptor activation, comprising administering to a patient in need of such treatment an effective amount of a compound having the formula:

• 117
• or a pharmaceutically acceptable salt thereof, wherein:
• A, B, E, D and X each independently represent CH or N, with the proviso that not more than two of A, B, E and D represent N;
• R1 is:
• (i) hydrogen, —C(═O)—NH2, —SO2NH2 or —COOH;
• or
• (ii) (C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkyl ether, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- or di-(C1-C8alkyl)amino, C1-C8carbamate, mono- or di-(C1-C8alkyl)sulfonamido, or mono- or di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• R2 is:
• (i) hydrogen, halogen, hydroxy, —C(═O)—NH2, —SO2NH2 or —COOH;
• or
• (ii) C1-C8alkyl, C2-C8a]kenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkyl ether, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- or di-(C1-C8alkyl)amino, C1-C8carbamate, mono- or di-(C1-C8alkyl)sulfonamido or mono- or di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• R3 represents 0 to 4 substituents, each of which is linked to a carbon atom at A, B, E or D, and each substituent is independently selected from:
• (i) halogen, hydroxy, amino, cyano, nitro, —C(═O)—NH2, —SO2NH2 and —COOH;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di-(C1-C8alkyl)amino, C1-C8carbamate, mono- and di-(C1-C8alkyl)sulfonamido, and mono- and di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 secondary substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• R4 is:
• (i) hydrogen, —C(═O)—NH2, —SO2NH2 or —COOH;
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di-(C1-C8alkyl)amino, C1-C8carbamate, mono- and di-(C1-C8alkyl)sulfonamido, and mono- and di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 secondary substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• or
• (iii) L-RA, wherein L is C1-C6alkyl;
• and RA is a 5- to 7-membered carbocyclic or heterocyclic ring, unsubstituted or substituted with from 1 to 4 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy, C2-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di-(C1-C8alkyl)amino, C1-C8carbamate and 5- to 10-membered carbocyclic and heterocyclic groups;
• R5 represents from 0 to 3 substituents, each of which is independently selected from:
• (i) halogen, hydroxy, amino, cyano, nitro, —C(═O)—NH2, —SO2NH2 and —COOH;
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- and di-(C1-C8alkyl)amino, C1-C8carbamate, mono- and di-(C1-C8alkyl)sulfonamido, mono- and di-(C1-C8alkyl)carboxamido, and fused and pendant 3- to 10-membered carbocyclic and heterocyclic groups, each of which is unsubstituted or substituted with from 1 to 9 secondary substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• and
• (iii) substituents that join with a second substituent to form a 5- to 7-membered carbocyclic or heterocyclic ring;
• and
• R6 and R7 are independently:
• (i) hydrogen, amino, cyano, nitro, —C(═O)—NH2, —SO2NH2 or —COOH;
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C2-C8alkanoyl, C2-C8alkyl ether, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8carbonate, C1-C8alkylthio, mono- or di-(C1-C8alkyl)amino, C1-C8carbamate, mono- or di-(C1-C8alkyl)sulfonamido, or mono- or di-(C1-C8alkyl)carboxamido, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl;
• or
• (iii) joined to form, with XCH2CH2N, a 5- to 7-member heterocyclic ring, wherein the ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C8alkyl and haloC1-C8alkyl.