Compounds and methods which modulate feeding behavior and related diseases

A compound of formula

• or a pharmaceutically acceptable salt, ester, solvate or N-oxide thereof, wherein A is N—H or N—R4;
• R1 is a hydrogen, halo, —OH, —NO2, —NHOH, —CF3, —OCF3, (C1-C8)alkyl, (C3-C10)cycloalkyl, —Z((C1-C8)alkoxy), —Z(aryloxy), —Z(aryl), —Z(heteroaryl), —Z((C3-C10)cycloalkyl), —Z(NR5SO2R5), —Z(CON(R5)2), —Z(CO2R5), —Z(N(R5)2), —Z(NR5CON(R5)2), —Z(NR5(CO)R5), —Z(NR5CO2R5), —Z(COR5), —Z(S(O)pR5) or —Z(Q) radical;
• R2 is a hydrogen, halo, —OH, —NO2, —CF3, —OCF3, (C1-C8)alkyl, (C3-C10)cycloalkyl, —Z((C1-C8)alkoxy), —Z(aryloxy), —Z(aryl), —Z(heteroaryl), —Z((C3-C10)cycloalkyl), —Z(NR5SO2R5), —Z(CON(R5)2), —Z(CO2R5), —Z(N(R5)2), —Z(NR5CON(R5)2), —Z(NR5(CO)R5), —Z(NR5CO2R5), —Z(COR5), —Z(S(O)pR5) or —Z(Q) radical, provided that R2 is not an optionally substituted phenyl, thienyl, pyridyl, pyrazinyl, pyrimidyl or pyridazinyl radical;
• R3 is a (C3-C10)cycloalkyl, (C1-C8)alkyl, —((C1-C8)alkyl)OH, (C1-C8)alkoxy-(C1-C8)alkyl-, -((C1-C8)alkyl)N(R5)2, -((C1-C8)alkyl)S(O)p((C1-C8)alkyl), —(CH2)((C3-C10)cycloalkyl)k(CH2)mOH, —(CH2)m((C3-C10)cycloalkyl)(CH2)mOH, —(CH2)m((C3-C10)cycloalkyl)k(CH2)OH, —(CH2)((C3-C10)cycloalkyl)k(CH2)m(C1-C8)alkoxy, —(CH2)m((C3-C10)cycloalkyl)(CH2)m(C1-C8)alkoxy, —(CH2)m((C3-C10)cycloalkyl)k(CH2)(C1-C8)alkoxy, —(CH2)((C3-C10)cycloalkyl)k(CH2)mN(R5)2, —(CH2)m((C3-C10)cycloalkyl)(CH2)mN(R5)2, —(CH2)m((C3-C10)cycloalkyl)k(CH2)N(R5)2, —(CH2)m((C3-C10)cycloalkyl)(CH2)mS(O)pR5, —D′(S(O)qR5), —D′(aryloxy), —D′(aryl), —D′(heteroaryl), —D′((C3-C10)cycloalkyl), —D′(NR5SO2R5), —D′(CON(R5)2), —D′(CO2R5), —D′(NR5CON(R5)2), —D′(NR5(CO)R5), —D′(NR5CO2R5), —D′(COR5), —D′(Q), —D(aryloxy), —D(aryl), —D(heteroaryl), —D((C3-C10)cycloalkyl), —D(NR5SO2R5), —D(CON(R5)2), —D(CO2R5), —D(S(O)qR5), —D(NR5CON(R5)2), —D(NR5(CO)R5), —D(NR5CO2R5), —D(COR5) or —(NR5)k—D—Q radical;
• R4 is a (C1-C8)alkyl, (C3-C10)cycloalkyl, —Z((C1-C8)alkoxy), —Z(aryloxy), —Z(aryl), —Z(heteroaryl), —Z((C3-C10)cycloalkyl), —Z(NR5SO2R5), —Z(CON(R5)2), —Z(CO2R5), —Z(N(R5)2), —Z(NR5CON(R5)2), —Z(NR5(CO)R5), —Z(NR5CO2R5), —Z(COR5), —Z(S(O)pR5) or —Z(Q) radical;
• X is a (C1-C8)alkyl, (C3-C10)cycloalkyl, —(NR5)k((C1-C8)alkyl) (C1-C8)alkoxy, —(NR5)k((C1-C8)alkyl)aryloxy, —(NR5)((C1-C8)alkyl)kS(O)pR5, —(NR5)k((C1-C8)alkyl)S(O)pR5, —(NR5)D(C1-C8)alkoxy, —(NR5)(CH2)m((C3-C10)cycloalkyl)k(CH2)(C1-C8)alkoxy, —(NR5)k(CH2)((C3-C10)cycloalkyl)k(CH2)m(C1-C8)alkoxy, —(NR5)k(CH2)m((C3-C10)cycloalkyl)(CH2)m(C1-C8)alkoxy, —(NR5)(CH2)m((C3-C10)cycloalkyl)k(CH2)aryloxy, —(NR5)k(CH2)((C3-C10)cycloalkyl)k(CH2)maryloxy, —(NR5)k(CH2)m((C3-C10)cycloalkyl)(CH2)maryloxy, —Z(S(O)qR5), —Z(aryl), —Z(heteroaryl), —Z((C3-C10)cycloalkyl), —Z(NR5SO2R5), —Z(CON(R5)2), —Z(CO2R5), —Z(N(R5)2), —Z(NR5CON(R5)2), —Z(NR5(CO)R5), —Z(NR5CO2R5), —Z(COR5) or —Z(Q) radical;
• Q and Q′ are each independently a 4-membered to 10-membered heterocyclyl or heteroaryl radical;
• each R5 is independently a hydrogen, —OH, (C1-C8)alkoxy, aryl, —NH2, —NH((C1-C8)alkyl), —N((C1-C8)alkyl)2, (C1-C8)alkyl or (C3-C10)cycloalkyl radical;
• D is —(CH2)m((C3-C10)cycloalkyl)k(CH2)m— and D′ is -((C1-C8)alkyl)k—;
• Z is D(NR5)k, D′(NR5)k, (NR5)kD or (NR5)kD′;
• each k is independently 0 or 1;
• each m is independently an integer between 0 and 6;
• each p is independently an integer between 0 and 2;
• and
• each q is independently 1 or 2;
• and
• wherein each alkyl, aryl, heteroaryl, cycloalkyl, Q, alkoxy or aryloxy moiety of any of X, R1, R2, R3, R4 and R5 is optionally substituted with 1-3 radicals of halo and 1-2 radicals of —CF3, —OCF3, —Z(COOH), —Z(OH), —Z(NO2), —Z(SH), -(C1-C8)alkyl, -(C1-C8)acyloxy, -(C3-C10)cycloalkyl, —S-((C1-C8)alkyl)k-aryl, ((C1-C8)alkyl)k—SO2NH-aryl, —S-(C1-C8)alkyl, —Z((C1-C8)alkoxy), —Z(aryloxy), —Z(aryl), —Z(heteroaryl), —Z((C3-C10)cycloalkyl), —Z(NR9SO2R9), —Z(CON(R9)2), —Z(CO2R9), —Z(N(R9)2), —Z(NR9CON(R9)2), —Z(NR9(CO)R9), —Z(NR9CO2R9), —Z(COR9), —Z(S(O)pR9) or —Z(Q′), wherein such aryl, heteroaryl, cycloalkyl and Q′ substituents are optionally substituted with 1-3 radicals of halo, —NO2, —CF3, —OCF3, —N(R9)2, —C(O)R9, —CO2R9, —OR9, —SR9 or (C1-C8)alkyl;
• and wherein each R9 is independently a hydrogen or (C1-C8)alkyl radical;
• and
• provided that the total number of aryl, heteroaryl, cycloalkyl, heterocyclyl, Q and Q′ moieties in A, X, R1, R2 and R3 is 0-4;
• and
• provided that:
• (a) when A is NH, R1 is H, methyl or phenyl, and R3 is methyl, ethyl or phenyl, then (1) when R2 is H, X is not —NH2, —N(CH2CH3)2, —NHCH2CH2N(CH2CH2)2, —NHCH2CH2CH2CO2H, —NHCH2CH2OH, —NH-phenyl, —NHCH2CH2-phenyl, —NH—CH(CH3)CH2-phenyl, —NH-(methoxyphenyl), —NHCH2CH2-(dimethoxyphenyl), —NHCH2CH2-imidazolyl, —NHCH2CH2-(methylthioimidazolyl), —NHCH2CH2-cyclohexyl, —NH-cyclohexyl, piperidinyl, morpholinyl, —NHNH2, —NHCH(CH3)2, —NH-butyl, —NH—CH(CH3)(CH2)4CH3, —NH(CH2)2cyclohexenyl, —NH—(CH2)5CH3, —NHCH2CH═CH2, —NH—CH2-phenyl, 4-methylpiperazine, —NHSO2(4-aminophenyl) or —NH-(4-methylpiperazine);
• (2) when R2 is —CH2N(CH2CH3)2, —CH2NH-butyl, —CH2NHCH2CH2-cyclohexenyl or —CH2NHCH2CH2COOH, X is not —NH(CH2)2cyclohexenyl;
• and (3) when R2 is methyl, acetyl or —COOCH2CH3, X is not —NH2 or —NH(C(O)CH3);
• (b) when R1 is ethoxy, R2 is H, R3 is —COOCH2CH3 and A is NH, then X is not —NH2;
• (c) when A is N-C1-C6 alkyl, R1 and R3 are hydrogen, halo, alkyl, alkoxy or alkylthio, then R2 is not thienyl optionally substituted with 1-3 halo, hydroxy, alkyl or alkoxy radicals;
• (f) when A is N—H or N—R4 and R3 is aryl or heteroaryl, then R2 is not aryl or heteroaryl;
• (g) when A is N—R4, R1 is H and R3 is alkyl, then X is not —NH2;
• and
• (h) when A is N—H or N—R4 and R2 is H, then R3 is not optionally substituted phenyl which is substituted by —N(R5)-(C2-C6 alkyl)—N(R5)2 or —N(R5)-(C2-C6 alkyl)-Q.