US 2006/0142301 A1 · Substituted 1-benzyl-4-substituted piperazine analogues

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein:
V is absent or —(C═O)—;
W is nitrogen, CH or C—OH;
Y1 is CH or nitrogen;
Y3 and Y4 are independently CR1 or nitrogen;
and Z is nitrogen or CR2;
such that at least one of Y3, Y4 and Z is nitrogen, and at least one of Y3, Y4 and Z is substituted carbon;
each R1 is independently:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, mono- or di-(C1-C6alkyl)aminoC0-C6alkyl, (C3-C7cycloalkyl)C0-C6alkyl or (4- to 7-membered heterocycloalkyl)C0-C6alkyl;
or
(ii) taken together with R2 to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
R2 is halogen, nitro, cyano, amino, acetyl, carboxamide, imino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6alkanoyl, C2-C6alkyloxime, C1-C6alkoxy, C1-C6alkoxyC1-C4alkyl, hydroxyC1-C6alkyl, C1-C6alkoxycarbonyl, mono- or di-alkylcarboxamide, C1-C6alkylthio, C1-C6alkylsulfonyl, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, mono- or di-(C1-C6alkyl)aminoC0-C6alkyl or (C3-C7cycloalkyl)C0-C6alkyl;
or
R2 is (4- to 7-membered heterocycloalkyl)C0-C6alkyl, phenylC0-C2alkyl, phenylC1-C2alkoxy or (5- or 6-membered heteroaryl)C0-C2alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, C1-C2alkoxy and C1-C2alkyl;
or
R2 is taken together with a R1 to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
n is 1 or 2;
R3 is:
(i) hydrogen, C1-C6alkyl, C2-C6alkenyl or haloC1-C6alkyl;
or
(ii) taken together with one or both of R6 and R10 to form a fused carbocycle or heterocycle having one or two rings, wherein each ring contains from 5 to 8 ring members and 0, 1 or 2 heteroatoms;
R4 is hydrogen, C1-C6alkyl or haloC1-C6alkyl;
each R5 is independently:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
or
(ii) taken together with R6 to form a fused 5- to 8-membered carbocycle or heterocycle or a methylene or ethylene bridge;
R6 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- and di-(C1-C6alkyl)amino and aminoC1-C6alkyl;
(ii) taken together with R3 taken together with to form a fused carbocycle or heterocycle;
or
(iii) taken together with R5 to form a fused carbocycle or heterocycle or a methylene or ethylene bridge;
P is N or CR7;
Q is N or CR8;
U is N or CR9;
T is N or CR10;
X is N or CR11;
R7 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R8 or R12 to form a fused 5- or 6-membered carbocycle or heterocycle;
R9 is:
(i) halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R7 to form a fused 5- or 6-membered carbocycle or heterocycle;
R9 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R10 or R11 to form a fused 5- to 10-membered carbocycle or heterocycle;
R10 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R3 or R9 to form a fused carbocycle or heterocycle;
R11 is:
(i) halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R9 to form a fused carbocycle or heterocycle;
R12 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
or
(ii) taken together with R7 to form a fused carbocycle or heterocycle;
each L is independently a single covalent bond, N(R13), O, C(═O), SO2, SO2NH, C(═O)N(R13) or N(R13)C(═O), wherein each R13 is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or haloC1-C6alkyl;
and
each M is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, aminoC1-C6alkyl or a 5- to 10-membered cycloalkyl or heterocycloalkyl;
such that if Y1 and Y3 are both nitrogen and R11 is trifluoromethyl, then R2 is not amino.

61 more elements

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
W is nitrogen, CH, C—CN or C—OH;
Y1, Y3 and Y4 are independently CR1 or nitrogen, and Z is nitrogen or CR2, such that at least one of Y3, Y4 and Z is nitrogen;
each R1 is independently:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, mono- or di-(C1-C6alkyl)aminoC0-C6alkyl, (C3-C7cycloalkyl)C0-C6alkyl or (4- to 7-membered heterocycloalkyl)C0-C6alkyl;
or
(ii) taken together with R2 to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
R2 is hydrogen, halogen, nitro, cyano, amino, acetyl, carboxamide, imino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6alkanoyl, C2-C6alkyloxime, C1-C6alkoxy, C1-C6alkoxyC1-C4alkyl, hydroxyC1-C6alkyl, C1-C6alkoxycarbonyl, mono- or di-alkylcarboxamide, C1-C6alkylthio, C1-C6alkylsulfonyl, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, mono- or di-(C1-C6alkyl)aminoC0-C6alkyl or (C3-C7cycloalkyl)C0-C6alkyl;
or
R2 is (4- to 7-membered heterocycloalkyl)C0-C6alkyl, phenylC0-C2alkyl, phenylC1-C2alkoxy or (5- or 6-membered heteroaryl)C0-C2alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
or
R2 is taken together with a R1 to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
n is 1 or 2;
each R5 is independently:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
or
(ii) taken together with R6 to form a carbocyclic or heterocyclic ring having from 5 to 8 ring members or a methylene or ethylene bridge;
R6 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
or
(ii) taken together with R5 to form a fused carbocycle or heterocycle or a bridge;
P is N or CR7;
Q is N or CR8;
U is N or CR9;
T is N or CR10;
X is N or CR11;
R7 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R8 or R12 to form a fused 5- or 6-membered carbocycle or heterocycle;
R8 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R7 to form a fused 5- or 6-membered carbocycle or heterocycle;
R9 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R10 or R11 to form a fused 5- to 10-membered carbocycle or heterocycle;
R10 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R3 or R9 to form a fused carbocycle or heterocycle;
R11 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R9 to form a fused carbocycle or heterocycle;
R12 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
or
(ii) taken together with R7 to form a fused carbocycle or heterocycle;
each L is independently a single covalent bond, N(R13), O, C(═O), SO2, SO2NH, C(═O)N(R13) or N(R13)C(═O), wherein each R13 is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or haloC1-C6alkyl;
and
each M is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, aminoC1-C6alkyl or a 5- to 10-membered cycloalkyl or heterocycloalkyl.

50 more elements

A method for treating a disease or disorder associated with MCH receptor activation, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
V is a absent or —(C═O)—;
W is nitrogen, CH, C—CN or C—OH;
Y1, Y3 and Y4 are independently CR1 or nitrogen, and Z is nitrogen or CR2, such that at least one of Y3, Y4 and Z is nitrogen;
each R1 is independently:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, mono- or di-(C1-C6alkyl)aminoC0-C6alkyl, (C3-C7cycloalkyl)C0-C6alkyl or (4- to 7-membered heterocycloalkyl)C0-C6alkyl;
or
(ii) taken together with R2 to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
R2 is hydrogen, halogen, nitro, cyano, amino, acetyl, carboxamide, imino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6alkanoyl, C2-C6alkyloxime, C1-C6alkoxy, C1-C6alkoxyC1-C4alkyl, hydroxyC1-C6alkyl, C1-C6alkoxycarbonyl, mono- or di-alkylcarboxamide, C1-C6alkylthio, C1-C6alkylsulfonyl, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, mono- or di-(C1-C6alkyl)aminoC0-C6alkyl or (C3-C7cycloalkyl)C0-C6alkyl;
or
R2 is (4- to 7-membered heterocycloalkyl)C0-C6alkyl, phenylC0-C2alkyl, phenylC1-C2alkoxy or (5- or 6-membered heteroaryl)C0-C2alkyl each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
or
R2 is taken together with a R1 to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
n is 1 or 2;
R3 is:
(i) hydrogen, C1-C6alkyl, C2-C6alkenyl or haloC1-C6alkyl;
or
(ii) taken together with one or both of R6 and R10 to form a fused carbocycle or heterocycle having one or two rings, wherein each ring contains from 5 to 8 ring members and 0, 1 or 2 heteroatoms;
R4 is hydrogen, C1-C6alkyl or haloC1-C6alkyl;
each R5 is independently:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
or
(ii) taken together with R6 to form a 5- to 8-membered carbocycle or heterocycle or a methylene or ethylene bridge;
R6 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
(ii) taken together with R3 form a fused carbocycle or heterocycle;
(iii) taken together with R5 to form a fused carbocycle or heterocycle or a methylene or ethylene bridge;
P is N or CR7;
Q is N or CR8;
U is N or CR9;
T is N or CR10;
X is N or CR11;
R7 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R8 or R12 to form a fused 5- or 6-membered carbocycle or heterocycle;
R8 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R7 to form a fused 5- or 6-membered carbocycle or heterocycle;
R9 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R10 or R11 to form a fused 5- to 10-membered carbocycle or heterocycle;
R10 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R3 or R9 to form a fused carbocycle or heterocycle;
R11 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or
(ii) taken together with R9 to form a fused carbocycle or heterocycle;
R12 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
or
(ii) taken together with R7 to form a fused carbocycle or heterocycle;
each L is independently a single covalent bond, N(R13), O, C(═O), SO2, SO2NH, C(═O)N(R13) or N(R13)C(═O), wherein each R13 is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or haloC1-C6alkyl;
and
each M is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, aminoC1-C6alkyl or a 5- to 10-membered cycloalkyl or heterocycloalkyl.

56 more elements

Substituted 1-benzyl-4-substituted piperazine analogues

Life of this patent

Substituted 1-benzyl-4-substituted piperazine analogues

Life of this patent

Abstract

Claims35