US 8,076,488 B2 · Bicyclic urea derivatives useful in the treatment of cancer and other disorders

Abstract

This invention relates to novel diaryl ureas, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and angiogenesis disorders, as a sole agent or in combination with cytotoxic therapies.

A compound of formula (I):

wherein
A is a bicyclic heterocycle which is:
(1) benzimidazolyl
(2) 1,3-benzothiazolyl
(3) 1,2,3-benzotriazolyl
(4) 1,3-benzoxazolyl
(5) 2,3-dihydro-1H-indolyl
(6) 2,3-dihydro-1H-indenyl
(7) 1,1-dioxido-2,3-dihydro-1-benzothienyl
(8) 1H-indazolyl
(9) 2H-indazolyl
(10) 1H-indolyl
(11) 2H-chromenyl
(12) quinoxalinyl or
(13) one of the formulae
optionally substituted with 1-4 substituents which are independently R1, OR1, S(O)pR1, C(O)R1, C(O)OR1, C(O)NR1R2, halogen, oxo, cyano, or nitro;
B is phenyl, naphthyl, or pyridyl, optionally substituted with 1-4 substituents which are independently C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, carboxyamide, halogen, cyano, nitro or S(O)pR7;
L is:
(a) —(CH2)m—O—(CH2)l—,
(b) —(CH2)m—(CH2)l—,
(c) —(CH2)m—C(O)—(CH2)l—,
(d) —(CH2)m—NR3—(CH2)l—,
(e) —(CH2)m—NR3C(O)—(CH2)l—,
(f) —(CH2)m—S—(CH2)l—,
(g) —(CH2)m—C(O)NR3—(CH2)l—, or
(h) a single bond;
m and l are integers independently selected from 0-4;
M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, or nitro;
Q is C(O)R4, C(O)OR4 or C(O)NR4R5;
each of R1, R2, R3, R4 and R5 is independently:
(a) hydrogen,
(b) C1-C5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C1-C3 alkyl-phenyl,
(e) up to per-halo substituted C1-C5 linear or branched alkyl,
(f) —(CH2)q—X, wherein X is a 5 or 6 membered heterocyclic ring, containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or a 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms which are O, N or S, or
(g) —(CH2)q—Y, where Y is C(O)R6, C(O)OR6 and C(O)NR6R7;
each of R6-R7 is independently:
(a) hydrogen,
(b) C1-C5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C1-C3 alkyl-phenyl, or
(e) up to per-halo substituted C1-C5 linear or branched alkyl;
each of R1, R2, R3, R4, R5, R6 and R7, other than per-halo substituted C1-C5 linear or branched alkyl, is optionally substituted with 1-3 substituents which are independently C1-C5 linear or branched alkyl, up to perhalo substituted C1-C5 linear or branched alkyl, C1-C3 alkoxy, hydroxy, carboxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, or nitro;
p is an integer selected from 0, 1, or 2;
and
q is an integer selected from 1, 2, 3, or 4,
or a pharmaceutically acceptable salt of formula I or an oxidized derivative of formula I wherein one or more urea nitrogens are substituted with a hydroxyl group, or an oxidized derivative of formula I wherein the nitrogen atom of pyridine ring M is in the oxide form, or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl ester or phenyl C1-C5 alkyl ester of formula I at a carboxylic acid group or amide group.

45 more elements

Bicyclic urea derivatives useful in the treatment of cancer and other disorders

Life of this patent

Bicyclic urea derivatives useful in the treatment of cancer and other disorders

Life of this patent

Abstract

Claims32