OMEGA-AMINO ACID DERIVATIVES OF BENZENE, PYRIDINE, AND PYRIDAZINE COMPOUNDS

摘要

Disclosed are compounds and pharmaceutically acceptable salts of Formula I;;wherein R1, R2, R3, R4, R5, R6, R7, n, Q1, Q2, Q3, Y, and X1-X4 are as defined herein. Compounds of Formula I are useful in the treatment of diseases and/or conditions related to cell proliferation, such as cancer, inflammation, arthritis, angiogenesis, or the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.

主权项

1. A compound of the formula, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently
(a) H,(b) halo, or(c) a C1-C15 alkyl group where up to six of the carbon atoms in said alkyl group are optionally replaced independently by R22, carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO2, or SO, with the proviso that two O atoms, two S atoms, or an O and S atom are not immediately adjacent each other, wherein
R22 is
(i) heteroaryl,(ii) aryl,(iii) saturated or unsaturated C3-C10 cycloalkyl, or(iv) saturated or unsaturated C2-C10 heterocycloalkyl, wherein each aryl, heteroaryl, saturated or unsaturated cycloalkyl, or saturated or unsaturated heterocycloalkyl, independently, is optionally substituted with at least one group, which independently is hydroxy, halo, amino, cyano, carboxy, carboxamido, nitro, oxo, —S-(C1-C6)alkyl, —SO2-(C1-C6)alkyl, —SO2-aryl, —SO-(C1-C6)alkyl, —SO-aryl, —SO2NH2, —SO2NH-(C1-C6)alkyl, —SO2NH-aryl, (C1-C6)alkoxy, or mono- or di-(C1-C10)alkylamino; andeach R22 is optionally fused to a C6-C10 aryl group, C5-C8 saturated cyclic group, or a C5-C10 heterocycloalkyl group;wherein each (c) moiety is optionally substituted at any available position with C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro, —SH, —S-(C1-C6)alkyl, —SO2-(C1-C6)alkyl, —SO2NH2, —SO2N -(C1-C6)alkyl, —SO2NH-aryl, —SO2-aryl, -SO-(C1-C6)alkyl, —SO2-aryl, C1-C6 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, mono- or di-(C1-C10)alkylamino, —OC1-C10 alkyl-Z, or R23, wherein
Z is OR0 or —N(R30)2, wherein
each R30 is independently —H or C1-C6 alkyl, or N(R3o)2 represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1,3- or 1,4-diazepanyl, or morpholinyl, each of which is optionally substituted with hydroxy, amino, aminoalkyl, C1-C6 alkyl, mono- or di(C1-C6)alkylamino, C1-C6 alkoxy, or halogen;Ro is —H, -C1-C10 alkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, heteroaryl, or -C1-C6 acyl;R23 is
(1) heteroaryl,(2) aryl,(3) saturated or unsaturated C5-C10 cycloalkyl, or(4) saturated or unsaturated C5-C10 heterocycloalkyl, and the R23 groups are optionally substituted with at least one group which independently is hydroxy, oxo, halo, amino, cyano, nitro, —SH, —S-(C1-C6)alkyl, —SO2-(C1-C6)alkyl, —SO2-aryl, —SO-(C1-C6)alkyl, —SO-aryl, —SO2NH2, —SO2NH-(C1-C6)alkyl, —SO2NH-aryl, (C1-C6)alkoxy, or mono- or di-(C1-C10)alkylamino; and wherein at least one of R3 and R4 is substituted with a group R50 where R50 is: wherein
d and k are integers independently selected from 1 and 2;R201 is (C1-C6)alkyl where the alkyl is optionally substituted with (C3-C7)cycloalkyl, (C2-C6) alkenyl, (C2-C6)alkynyl, hydroxy, halogen, nitro, or cyano; andT is O or NR202 where R202 is hydrogen or (C1-C6)alkyl; andR301 and R302 are independently hydrogen or (C1-C6)alkyl, and R303 is absent, hydrogen, or (C1-C6)alkyl; R7 is O, S, NH, N—OH, N—NH2, N—NHR22, N—NH-(C1-C6 alkyl), N-O-(C0-C6)alkyl-R22, N-(C1-C6 alkenoxy);or N-(01-C6 alkoxy optionally substituted with carboxy); Y is N or CRS, wherein
each RC independently is hydrogen, halogen, cyano, nitro, —C(O)RC′, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-Cio haloalkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C10)alkyl, heterocycloalkyl, aryl, or heteroaryl, wherein
each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(C1-C6) alkylamino, cyano, nitro, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, carboxamide, heterocycloalkyl, aryl, or heteroaryl,wherein
the aryl and heteroaryl groups are optionally substituted with from 1-4 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(C1-C6) alkylamino, halo(C1-C6)alkyl, or carboxamide;RC′ is -C1-C6 alkyl, —ORC″, or —N(RCN)2, wherein
RC″ is —H, C1-C10 alkyl, C1-C10 haloalkyl, C3-C7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each RCN is independently —H, -C1-C10 alkyl, -C1-C10 -aloalkyl, -C3-C7 cycloalkyl, -heterocycloalkyl, -C1-C6 acyl, -aryl, or -heteroaryl, wherein
each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(C1-C6) alkylamino, nitro, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, or carboxamide; X1 is N or CRC; Q1, Q2, and Q3 are independently N or CRQ , wherein one and only one of Q1, Q2, and Q3 is C-R21, and wherein
each RQ is independently hydrogen, halogen, —N(RCN)2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, aryl, or heteroaryl, or R21, wherein each alkyl, cycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(C1-C6) alkylamino, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, or carboxamide;R21 is cyano, —C(O)OH, —C(O)—O(C1-C6 alkyl), or a group of the formula  wherein
R1 and R2 are independently H, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, C3-C8 cycloalkyl, heterocycloalkyl, wherein
each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(C1-C6) alkylamino, nitro, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, or carboxamide;or R1 and R2 together with the nitrogen to which they are both attached, form a heterocycloalkyl which optionally contains one or more additional heteroatoms which are, independently, O, N, S, or N(RCN);andX4 is O, S, NH, NOH, N—NH2, N—NHaryl, N—NH-(C1-C6 alkyl), or N-(C1-C6 alkoxy);X2 and X3 are independently C, O, N, or S(O)p wherein
p is 0, 1, or 2; andn is 0, 1, 2, 3, or 4;provided that when
(i) X2 is C, then
R5 and R6 are independently H, C1-C6 alkyl, or aryl, wherein the aryl is optionally substituted with from 1-4 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(C1-C6) alkylamino, nitro, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, or carboxamide,
wherein any two adjacent substituted aryl positions, together with the carbon atoms to which they are attached, form an unsaturated cycloalkyl or heterocycloalkyl; orR5 and R6 together with the carbon to which they are attached form a 3-8 membered ring; (ii) X2 is N, then
R6 is absent and R5 is H or C1-C6 alkyl; (iii) X3 is C, then
it is substituted with two groups that are independently H, C1-C6 alkyl, or mono- or di-(C1-C6)alkylamino(C1-C6)alkyl; and (iv) X2 is 0 or S(O)p, then R6 and R5 are absent.