PIPERIDINE DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
First Claim
Patent Images
1. A compound of Formula (I):
- or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein;
Q is CH or N;
Z is O or S;
W is X is C(R8);
Y is CH(R1a), CH2, O, S, S(O), S(O)2, N(R8), C(═
O) or Z1 is CH(R7), CH2, O, S, N(R8), S(O) or S(O)2;
T is a bond, R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a;
provided that R1 is not unsubstituted phenyl when T is R1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
C(═
NR14)NR9R9, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R1b;
or any two R1a'"'"'s attached to the same carbon atom may form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;
R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
C(═
NR14)NR9R9, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;
R3, at each occurrence, is independently OH or alkyl;
or two R3'"'"'s together with the carbon atom to which they are attached may form a 3- to 6-membered ring;
R4 is hydrogen, F, OH, CN or —
NH2;
R5 is hydrogen, halo, —
CN or —
Oalkyl;
R5a is hydrogen, halo, —
CN or alkynyl;
R5b is hydrogen, halo, —
CN or —
Oalkyl;
R6, at each occurrence, is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R7b;
R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
C(═
NR14)NR9R9, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;
R8, at each occurrence, is independently hydrogen or alkyl;
R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-5 R9a, and the heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;
or any two R9'"'"'s may be taken to form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;
R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
C(═
NR14)NR14R14, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;
R10, at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3 R10a, and the heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;
R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
C(═
NR14)NR14R14, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;
R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl;
m is 0-2;
r is 0-5;
provided that;
(1) R5, R5a and R5b are not all H when T is a bond and R4 is H or OH; and
(2) R4 is not piperidin-4-yl, pyridine-4-yl, or pyrimidin-4-yl, when T is a bond and R4 is H.
1 Assignment
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Accused Products
Abstract
The present application describes modulators of MIP-1 of formula (I): or stereoisomers or pharmaceutically acceptable salts thereof, wherein m, Q, T, W, Z, R1, R3, R4, R5, R5a and R5b, are as set forth above. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis using the modulators are disclosed.
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Citations
15 Claims
-
1. A compound of Formula (I):
-
or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein; Q is CH or N; Z is O or S; W is X is C(R8); Y is CH(R1a), CH2, O, S, S(O), S(O)2, N(R8), C(═
O) orZ1 is CH(R7), CH2, O, S, N(R8), S(O) or S(O)2; T is a bond, R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a;
provided that R1 is not unsubstituted phenyl when T isR1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
C(═
NR14)NR9R9, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R1b;
or any two R1a'"'"'s attached to the same carbon atom may form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
C(═
NR14)NR9R9, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R3, at each occurrence, is independently OH or alkyl;
or two R3'"'"'s together with the carbon atom to which they are attached may form a 3- to 6-membered ring;R4 is hydrogen, F, OH, CN or —
NH2;R5 is hydrogen, halo, —
CN or —
Oalkyl;R5a is hydrogen, halo, —
CN or alkynyl;R5b is hydrogen, halo, —
CN or —
Oalkyl;R6, at each occurrence, is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R7b;R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
C(═
NR14)NR9R9, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-5 R9a, and the heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;
or any two R9'"'"'s may be taken to form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
C(═
NR14)NR14R14, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R10, at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3 R10a, and the heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
C(═
NR14)NR14R14, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; r is 0-5; provided that; (1) R5, R5a and R5b are not all H when T is a bond and R4 is H or OH; and (2) R4 is not piperidin-4-yl, pyridine-4-yl, or pyrimidin-4-yl, when T is a bond and R4 is H. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
-
-
3. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein:
-
Z is O or S; W is X is C(R8); Y is CH(R1a), CH2, O, S, S(O), S(O)2, N(R8), C(═
O) orZ1 is CH(R7), CH2, O, S, N(R8), S(O) or S(O)2; T is R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a;
provided that R1 is not unsubstituted phenyl when T isR1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R1b;
or any two R1a'"'"'s attached to the same carbon atom may form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R3, at each occurrence, is independently OH or alkyl;
or two R3'"'"'s together with the carbon atom to which they are attached may form a 3- to 6-membered ring;R4 is hydrogen, F, OH, CN or —
NH2;R5 is hydrogen, halo or —
CN;R5a is halo, —
CN or alkynyl;R5b is hydrogen, halo or —
CN;R6, at each occurrence, is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R7b;R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-5 R9a, and the heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;
or any two R9'"'"'s may be taken to form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R10, at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3 R10a, and the heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
NHC(═
NR14)NR14R14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O) NR14R14, aryloxy or arylalkyl;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; and r is 0-4.
-
-
4. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein:
-
Z is O or S; W is X is C(R8); Y is CH(R1a), CH2, O, S, S(O)2, N(R8), C(═
O) orZ1 is CH(R7), CH2, O, S, N(R8) or S(O)2; T is R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a; R1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R1b;
or any two R1a'"'"'s attached to the same carbon atom may form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R3, at each occurrence, is independently OH or alkyl;
or two R3'"'"'s together with the carbon atom to which they are attached may form a 3- to 6-membered ring;R4 is hydrogen, F, OH, CN or —
NH2;R5 is hydrogen, halo or —
CN;R5a is halo, —
CN or alkynyl;R5b is hydrogen, halo or —
CN;R6, at each occurrence, is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R7b;R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-5 R9a, and the heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;
or any two R9'"'"'s may be taken to form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R10, at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3 R10a, and the heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
P(O)3H2, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; and r is 0-3.
-
-
5. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein:
-
Z is O; W is X is C(R8); Y is CH(R1a), CH2, O, S, S(O)2, N(R8) or C(═
O);Z1 is CH(R7), CH2, O, S or N(R8); T is R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a; R1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R1b;
or any two R1a'"'"'s attached to the same carbon atom may form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R3, at each occurrence, is independently OH or alkyl;
or two R3'"'"'s together with the carbon atom to which they are attached may form a 3- to 6-membered ring;R4 is hydrogen, F, OH, or —
NH2;R5 is hydrogen, halo or —
CN;R5a is halo, —
CN or alkynyl;R5b is hydrogen, halo or —
CN;R6, at each occurrence, is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R7b;R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
S(O)3H, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-5 R9a, and the heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;
or any two R9'"'"'s may be taken to form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R10, at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3 R10a, and the heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
S(O)3H, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; and r is 0-2.
-
-
6. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein:
-
Z is O; W is X is C(R8); Y is CH(R1a), CH2, O, S, S(O)2, N(R8), or C(═
O);Z1 is CH(R7), CH2, O or N(R8); T is R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a; R1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R1b;
or any two R1a'"'"'s attached to the same carbon atom may form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14;
—
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3;
—
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9;
—
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6;
—
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10;
—
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10;
—
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R3, at each occurrence, is independently OH or alkyl;
or two R3'"'"'s together with the carbon atom to which they are attached may form a 3- to 6-membered ring;R4 is hydrogen, F, OH, or —
NH2;R5 is hydrogen, halo or —
CN;R5a is halo or —
CN;R5b is hydrogen, halo or —
CN;R6, at each occurrence, is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3;
—
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R7b;R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-5 R9a, and the heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;
or any two R9'"'"'s may be taken to form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R10, at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3 R10a, and the heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)OH, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
)NR14H14, aryloxy or arylalkyl;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; and r is 0-2.
-
-
7. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein:
-
Z is O; W is X is C(R8); Y is CH(R1a), CH2, O, S or S(O)2; Z1 is CH(R7), CH2 or O; T is R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a; R1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R1b;
or any two R1a'"'"'s attached to the same carbon atom may form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R3, at each occurrence, is independently OH or alkyl;
or two R3'"'"'s together with the carbon atom to which they are attached may form a 3- to 6-membered ring;R4 is F, OH, or —
NH2;R5 is hydrogen, halo or —
CN;R5a is halo or —
CN;R5b is hydrogen, halo or —
CN;R6, at each occurrence, is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R7b;R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-5 R9a, and the heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;
or any two R9'"'"'s may be taken to form a 3- to 6-membered ring, wherein the carbon atoms of said ring may be optionally replaced with a heteroatom selected from N, O, and S and the N heteroatom of said ring may be optionally substituted with one or more of the following;
hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, —
C(═
O)O(CR8R8)rR10, —
OH, —
SH, —
C(═
O)NR14R14, —
S(O)2NR14R14, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10 or arylalkyl;R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
)NR14R14, aryloxy or arylalkyl;R10, at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3 R10a, and the heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; and r is 0-2.
-
-
8. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein:
-
Z is O; W is X is C(R8); Y is CH(R1a), CH2, O or S; Z1 is CH(R7) or CH2; T is R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a; R1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R1b;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R3, at each occurrence, is independently OH or alkyl;
or two R3'"'"'s together with the carbon atom to which they are attached may form a 3- to 6-membered ring;R4 is F or OH; R5 is hydrogen, halo or —
CN;R5a is halo or —
CN;R5b is hydrogen, halo or —
CN;R6, at each occurrence, is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R7b;R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-5 R9a, and the heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S; R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R10, at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3 R10a, and the heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; and r is 0-2.
-
-
9. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein:
-
Z is O; W is X is C(R8); Y is CH(R1a), CH2 or O; Z1 is CH(R7) or CH2; T is R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a; R1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R1b;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R3, at each occurrence, is alkyl; R4 is OH; R5 is hydrogen or halo; R5a is halo or —
CN;R5b is hydrogen or halo; R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl; R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, aryloxy or arylalkyl, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, aryloxy and arylalkyl may be optionally substituted with 0-3 R7b;R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, aryloxy, arylalkyl or arylalkyloxyalkyl;R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with 0-5 R9a, and the heteroaryl or heterocyclyl contain 1-4 heteroatoms selected from N, O, and S; R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R10, at each occurrence, is independently selected from alkyl, aryl or heterocyclyl, wherein the aryl or heterocyclyl may be optionally substituted with 0-3 R10a, and the heterocyclyl contains 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, aryloxy or arylalkyl;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; and r is 0-2.
-
-
10. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein:
-
Z is O; W is X is C(R8); Y is CH(R1a) or CH2; Z1 is CH(R7) or CH2; T is R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, all of which may be optionally substituted with 0-5 R1a; R1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9, or aryloxy, wherein the alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl and aryloxy may be optionally substituted with 0-3 R1b;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, or aryloxy;R3, at each occurrence, is alkyl; R4 is OH; R5 is hydrogen or halo; R5a is halo; R5b is hydrogen or halo; R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl; R7, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, ═
O, —
OC(═
O)NR9R9 or aryloxy, wherein the alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl and aryloxy may be optionally substituted with 0-3 R7b;R7b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6 or aryloxy;R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with 0-5 R9a, and the heteroaryl or heterocyclyl contain 1-4 heteroatoms selected from N, O, and S; R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, or aryloxy;R10, at each occurrence, is independently selected from alkyl, aryl or heterocyclyl, wherein the aryl or heterocyclyl may be optionally substituted with 0-3 R10a, and the heterocyclyl contains 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14 or aryloxy;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; and r is 0-2.
-
-
11. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein:
-
Z is O; W is X is CH; Y is CH2; Z1 is CH2; T is R1 is alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with 0-5 R1a; R1a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, —
OC(═
O)NR9R9, or aryloxy, wherein the alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl and aryloxy may be optionally substituted with 0-3 R1b;R1b, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR10, —
O(CF2)rCF3, —
O(CR8R8)rR10, —
OH, —
SH, —
S(CR8R8)rR10, —
C(═
O)NR9R9, —
NR9R9, —
S(O)2NR9R9, —
NR9S(O)2(CF2)rCF3, —
C(═
O)NR9S(O)2R6, —
S(O)2NR9C(═
O)OR6, —
S(O)2NR9C(═
O)NR9R9, —
C(═
O)NR9S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR10, —
NR9C(═
O)H, —
NR9C(═
O)(CR8R8)rR10, —
OC(═
O)(CR8R8)rR10, —
S(═
O)(CR8R8)rR10, —
S(O)2(CR8R8)rR10, —
NR9C(═
O)OR6, —
NR9S(O2)R6, or aryloxy;R3, at each occurrence, is alkyl; R4 is OH; R5 is hydrogen or halo; R5a is chloro; R5b is hydrogen or halo; R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl; R8, at each occurrence, is independently hydrogen or alkyl; R9, at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with 0-5 R9a, and the heteroaryl or heterocyclyl contain 1-4 heteroatoms selected from N, O, and S; R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14, or aryloxy;R10, at each occurrence, is independently selected from alkyl, aryl or heterocyclyl, wherein the aryl or heterocyclyl may be optionally substituted with 0-3 R10a, and the heterocyclyl contains 1-4 heteroatoms selected from N, O, and S; R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —
CN, —
NO2, —
C(═
O)O(CR8R8)rR14, —
O(CF2)rCF3, —
O(CR8R8)rR14, —
OH, —
SH, —
S(CR8R8)rR14, —
C(═
O)NR14R14, —
NR14R14, —
S(O)2NR14R14, —
NR14S(O)2(CF2)rCF3, —
C(═
O)NR14S(O)2R6, —
S(O)2NR14C(═
O)OR6, —
S(O)2NR14C(═
O)NR14R14, —
C(═
O)NR14S(O)2(CF2)rCF3, —
C(═
O)(CR8R8)rR14, —
NR14C(═
O)H, —
NR14C(═
O)(CR8R8)rR14, —
OC(═
O)(CR8R8)rR14, —
S(═
O)(CR8R8)rR14, —
S(O)2(CR8R8)rR14, —
NR14C(═
O)OR6, —
NR14S(O2)R6, —
OC(═
O)NR14R14 or aryloxy;R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or phenyl; m is 0-2; and r is 0-2.
-
-
12. A pharmaceutical composition comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.
-
13. A method for modulation of chemokine or chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 1.
-
14. A method for treating a disorder comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 1;
- wherein said disorder is selected from osteoarthritis, aneurysm, fever, cardiovascular effects, Crohn'"'"'s disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, inflammatory bowel disease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, artherosclerosis, rheumatoid arthritis, restinosis, organ transplantation, and cancer.
-
15. A method for treating inflammatory diseases comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 1.
Specification