US 2003/0195230 A1 · Substituted amine derivatives and methods of use

Abstract

Selected amines are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

A compound of formula I

249
wherein each of A1 and A2 is independently C, CH or N;
wherein ring A is selected from
a) 5- or 6-membered partially saturated heterocyclyl,
b) 5- or 6-membered heteroaryl,
c) 9-, 10- or 11-membered fused partially saturated heterocyclyl,
d) 9-, 10- or 11-membered fused heteroaryl,
e) aryl, and
f) 4-, 5- or 6-membered cycloalkenyl;
wherein X is
250
wherein Z is oxygen or sulfur;
wherein R is selected from
a) substituted or unsubstituted 4-6 membered heterocyclyl,
b) substituted aryl, and
c) substituted or unsubstituted fused 9-14-membered bicyclic or tricyclic heterocyclyl;
wherein substituted R is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —SO2R3, —CO2R3, —CONR3R3, —COR3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted phenyl, nitro, alkylaminoalkoxyalkoxy, cyano, oxox, alkylaminoalkoxy, lower alkyl substituted with R2, lower alkenyl substituted with R2, and lower alkynyl substituted with R2;
wherein R1 is selected from
a) substituted or unsubstituted 6-10 membered aryl,
b) substituted or unsubstituted 4-6 membered heterocyclyl,
c) substituted or unsubstituted 9-14 membered bicyclic or tricyclic heterocyclyl,
d) cycloalkyl, and
e) cycloalkenyl,
wherein substituted R1 is substituted with one or more substituents independently selected from halo, —OR3, —SR3—CO2R3, —CONR3R3, —COR3, —NR3R3, —NH (C1-C4 alkylenylR14), —SO2R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, —NR3C(O)NR3R3, optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, halosulfonyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, lower alkyl substituted with R2, lower alkenyl substituted with R2, and lower alkynyl substituted with R2;
wherein R2 is one or more substituents independently selected from H, halo, —OR3, oxo, —SR3, —CO2R3, —COR3, —CONR3R3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, C1-6-alkoxy-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy-C1-6-alkoxy, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl;
wherein R3 is independently selected from H, lower alkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C3-C6-cycloalkyl, optionally substituted phenylalkyl, optionally substituted 3-6 membered heterocyclylalkyl, optionally substituted C3-C6 cycloalkylalkyl, and lower haloalkyl;
wherein R4 is selected from a direct bond, C2-4-alkylenyl, C2-4-alkenylenyl and C2-4-alkynylenyl, where one of the CH2 groups may be replaced with an oxygen atom or an —NH—, wherein R4 is optionally substituted with hydroxy;
wherein R5 is selected from H, lower alkyl, optionally substituted phenyl and optionally substituted lower aralkyl;
wherein R14 is selected from H, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl and optionally substituted C3-C6 cycloalkyl;
and pharmaceutically acceptable derivatives thereof;
provided A is not pyridyl when X is —C(O)NH— and when R1 is 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when R5 is methyl and when R is 4-methylpiperidyl;
further provided A is not pyridyl when X is —C(O)NH—, when R5 is H, when R2 is 6-methyl and when R is indazolyl;
further provided A is not phenyl when X is —C(O)NH—, when R1 is phenyl, 4-bromophenyl, 2-methylphenyl, 4-methoxyphenyl, when R5 is H and when R is 4-pyridyl;
further provided A is not phenyl when X is —C(O)NH—, when R1 is phenyl, when R5 is H and when R is 2-oxobenzopyan-4-yl;
further provided A is not phenyl when X is —C(O)NH—, when R1 is phenyl, 4-chlorophenyl, 3-nitrophenyl, 4-methoxyphenyl, when R5 is H and when R is 4-imidazolinyl;
further provided A is not phenyl when X is —C(O)NH—, when R5 is H, when R5a is substituted benzyl and when R is substituted triazinyl;
further provided A is not phenyl when X is —C(O)NH—, when R1 is phenyl or 2-chlorophenyl, when R5 is H and when R is 4-quinazolinyl;
further provided A is not phenyl when X is —C(O)NH—, when R1 is phenyl, when R5 is H and when R is isoquinolin-1-yl;
further provided A is not phenyl when X is —C(O)NH—, when R1 is 2-chlorophenyl or 4-chlorophenyl, when R5 is H and when R is 3-chloroisoquinolin-1-yl;
further provided A is not phenyl when X is —C(O)NH—, when R1 is 1-ethylpiperid-3-yl or 1-ethylpiperid-4-yl, when R5 is H and when R is 8-trifluoromethylquinolin-4-yl;
further provided A is not phenyl when X is —C(O)NH—, when R1 is 1-ethylpiperid-3-yl, when R5 is H and when R is 8-chloroquinolin-4-yl;
further provided A is not phenyl when X is —C(O)NH—, when R1 is halo substituted phenyl, 1-butylpiperid-4-yl, 1-ethylpiperid-3-yl or 1-ethylpiperid-4-yl, when R5 is H and when R is 7-chloroquinolin-4-yl;
and
further provided R is not unsubstituted 2-thienyl, unsubstituted 2-pyridyl or unsubstituted 3-pyridyl.

41 more elements

Substituted amine derivatives and methods of use

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Substituted amine derivatives and methods of use

Life of this patent

Abstract

Claims43