2,3-disubstituted pyridine compounds as TGF-beta inhibitors and methods of use

1. A compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein

Cy 1 is phenyl substituted with 2, 3, or 4 moieties independently selected from halo, C 1-3 alkyl optionally substituted with 1, 2, or 3 halo, ethynyl, or (trimethylsilyl)ethynyl, and —O—C 1-3 alkyl optionally substituted with 1-3 halo; benzofuranyl; 2,3-dihydrobenzofuranyl; or phenylethenyl; or Cy 1 is phenyl substituted with a single substituent selected from halo, C 1-3 alkyl optionally substituted with 1, 2, or 3 halo, ethynyl, or (trimethylsilyl)ethynyl, —O—C 1-3 alkyl optionally substituted with 1-3 halo, —O—(C 0-3 alkyl)R IIIe , and —C(O)N(R x ) 2 ,

wherein R IIIe is phenyl, heteroaryl or heterocycloalkyl and each R x is independently H or C 1-3 alkyl;

Cy 2 is pyrazolo[1,5-a]pyrimidinyl; benzo[d]thiazolyl; imidazo[1,2-a]pyridinyl optionally substituted with phenyl-S(O) 2 —; [1,2,4]triazolo[1,5-a]pyridinyl; pyridinyl; quinazolinyl; 1H-pyrrolo[2,3-b]pyridinyl; pyrido[3,2-d]pyrimidinyl optionally substituted with amino, methylamino, or methoxy; or pyrido[3,2-d]pyrimidin-4(3H)-one,

wherein the quinazolinyl is optionally substituted with 1 or 2 substituents independently selected from —N(R IIIa ) 2 ; R IIId ; C 1-3 alkyl optionally substituted with 1-3 halo; halo; methoxy; and —N(H)(C 1-3 alkyl)R IV

each R IIIa is independently H; C 1-6 alkyl optionally substituted with —C(O)OH, —C(O)O(C 1-3 alkyl), or —CONH 2 ; or heteroaryl optionally substituted with C 1-3 alkyl;

R IIId is H or C 1-3 alkyl optionally substituted with 1-3 halo;

R IV is H, C 1-3 alkyl, -pyrrolidonyl, 4-methylpiperzinyl, —N(C 1-2 alkyl)(C 1-2 alkyl), or morpholinyl;

and

R IIIc is H, halo, —OH, C 1-3 alkyl optionally substituted with 1-3 halo, or —O—C 1-3 alkyl optionally substituted with 1-3 halo

provided the compound is not one of compounds 1-974:

2. A compound according of formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein

each R IIIa is independently H; C 1-6 alkyl optionally substituted with —C(O)OH, —C(O)O(C 1-3 alkyl), or —CONH 2 ; or heteroaryl optionally substituted with C 1-3 alkyl;

x is 0, 1, 2, or 3;

each R IIIb is independently selected from halo, —OH, C 1-3 alkyl optionally substituted with 1-3 halo, —O—C 1-3 alkyl optionally substituted with 1-3 halo, or, when x is 1, R IIIb also selected from —O—(C 0-3 alkyl)RI IIe and —C(O)N(R x ) 2

wherein R IIIb is phenyl, heteroaryl, or heterocycloalkyl, and each R x is independently H or C 1-3 alkyl;

R IIIc is H, halo, —OH, C 1-3 alkyl optionally substituted with 1-3 halo, or —O—C 1-3 alkyl optionally substituted with 1-3 halo; and

R IIId is H or C 1-3 alkyl optionally substituted with 1-3 halo,

provided the compound is not one of compounds 1-974:

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof,

wherein

a) both R IIIa are H,

b) R IIId and R IIIc are each H,

c) x is 1, 2, or 3 and each R IIIb is independently selected from halo, methyl, methoxy, and hydroxy,

d) both R IIIa are H and R IIId and R IIIc are each H,

e) both R IIIa are H, R IIId and R IIIc are each H, and x is 1, 2, or 3 and each R IIIb is independently selected from halo, methyl, methoxy, -difluoromethyl, and hydroxy; or

f) x is 1, 2, or 3 and at least one R IIIb is difluoromethyl.

4. The compound according to claim 2 selected from

#

Structure

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990

991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

and

1036

or a pharmaceutically acceptable salt thereof.

5. A compound of formula,

or a pharmaceutically acceptable salt thereof, wherein

X is CH and each R Z is independently —OH, —C 1-3 alkyl optionally substituted with one or more halo, or C 1-3 alkyloxy optionally substituted with one or more halo, or

X is N and each R Z is independently halo, —OH, —C 1-3 alkyl optionally substituted with one or more halo, or C 1-3 alkyloxy optionally substituted with one or more halo, and

a is 1, 2, or 3,

provided the compound is not one of the following compounds:

6. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable carrier, excipient, or diluent.