TGF-Beta Inhibitors

Patent metadata

Field	Value
Publication number	US-2016257690-A1
Application number	US-201615054895-A
Country	US
Kind code	A1
Filing date	Feb 26, 2016
Priority date	Mar 2, 2015
Publication date	Sep 8, 2016
Grant date	—

Abstract

Disclosed are imidazole and thiazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein X, A, Z, R 1 and R′ are as described herein. In certain embodiments, a compound disclosed herein inhibits TGF-β, and can be used to treat disease by blocking TGF-β signaling.

First claim

1 . A compound having the structure of formula (I°):

or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
X is —S— or —N(R′)—;
R′ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, —(C 0 -C 12 alkyl)-Cak or —(C 0 -C 6 alkyl)-Hca, each optionally substituted with 1 to 3 moieties that are each independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, —OR S0 , C 1 -C 6 alkyl-OR S0′ , —C(O)OR S0 , —C(O)R S0 , —C(O)NR S0 2 , —R S0 or cyano;
wherein each R S0 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, —OR, —NR S1 2 , —SR S1 or —N(R S1 )C(O)R S1 , each optionally substituted with 1 to 3 moieties that are each independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;
wherein each R S1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

or R′ and R 1 combined with the atoms to which they are attached form a five- to eight-membered ring;
A is phenyl optionally substituted with one to five R 2 groups, wherein
each R 2 is independently halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —NO 2 , —N(R S2 )C(O)R S2 , —OR S2 , —C(O)NR S2 2 , —N(R S2 )S(O) 2 R S2 , —S(O) 2 R S2 , —(C 0 -C 6 alkyl)-Ar or —CN, wherein each alkyl, haloalkyl and alkoxy are optionally substituted with 1, 2, 3, or 4 groups that are each independently halogen, cyano, nitro, —OR S2 , —SR S2 , —NR S2 2 , —C(O)OR S2 , —C(O)NR S2 2 , —C(O)R S2 , —S(O)R S2 , —S(O) 2 R S2 , —S(O)OR S2 , —S(O) 2 OR S2 , —S(O)NR S2 2 , —S(O) 2 NR S2 2 , —OC(O)R S2 , —OC(O)OR S2 , —OC(O)NR S2 2 , —N(R S2 )C(O)R S2 , —N(R S2 )C(O)OR S2 , —N(R S2 )C(O)NR S2 2 , —N(R S2 )S(O)R S2 , —N(R S2 )S(O) 2 R S2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
wherein each R S2 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

Z is
a fused bicyclic ring of the formula,

 wherein
ring A is Ar or 5- or 6-membered Het,
ring B is 5- or 6-membered Het,

wherein
Z is optionally substituted by one or two —R Z groups that are each independently halogen, cyano, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Hca, —OR S3 , —SR, —NR S3 2 , —C(O)R S3 , —C(O)OR S3 , —C(O)NR S3 2 , —C(NR S3 )NR S3 OR S3 , —S(O) 2 NR S3 2 , —S(O) 2 R S3 , —OC(O)R S3 , —N(R S3 )C(O)R S3 , —OC(O)OR S3 , —OC(O)NR S3 2 , —N(R S3 )C(O)OR S3 , —N(R S3 )C(O)NR S3 2 , —N(R S3f )S(O) 2 R S3 , —OP(O)(OR S3 ) 2 or —CH 2 —OP(O)(OR S3 ), wherein each alkyl, haloalkyl and alkoxy is optionally substituted by one or two —R Z2 groups;
wherein each R S3 is independently hydrogen, —NR S3 2 , —OR S3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, —C(O)NR S4 2 or cyano; and
each —R Z2 is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR S4 , —SR S4 , —NR S4 2 , —C(O)R S4 , —C(O)OR S4 , —C(O)NR S4 2 , —S(O) 2 NR S4 2 , —S(O) 2 R S4 , —OC(O)R S4 , —N(R S4 )C(O)R S4 , —OC(O)OR S4 , —OC(O)NR S4 2 , —N(R S4 )C(O)OR S4 , —N(R S4 )C(O)NR S4 2 , —N(R S4 )S(O) 2 R S4 , —OP(O)(OR S4 ) 2 or —CH 2 —OP(O)(OR S4 ); and
wherein each R S4 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with one or two C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

provided that
(a) when ring A is Ar, ring B is not triazolyl or imidazolidin-2-onyl; and
(b) Z is not

2 . A compound according to claim 1 having the structure of formula (I):

or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
X is —S— or —N(R′)—;
R′ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, each optionally substituted with 1 to 3 moieties that are each independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, —OR S1 , —NR S1 2 , —SR S1 , each optionally substituted with 1 to 3 moieties that are each independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;
wherein each R S1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

A is phenyl optionally substituted with one to five R 2 groups, wherein
each R 2 is independently halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —NO 2 or —CN, wherein each alkyl, haloalkyl and alkoxy are optionally substituted with 1, 2, 3, or 4 groups that are each independently halogen, cyano, nitro, —OR S2 , —SR S2 , —NR S2 2 , —C(O)OR S2 , —C(O)NR S2 2 , —C(O)R S2 , —S(O)R S2 , —S(O) 2 R S2 , —S(O)OR S2 , —S(O) 2 OR S2 , —S(O)NR S2 2 , —S(O) 2 NR S2 2 , —OC(O)R S2 , —OC(O)OR S2 , —OC(O)NR S2 2 , —N(R S2 )C(O)R S2 , —N(R S2 )C(O)OR S2 , —N(R S2 )C(O)NR S2 2 , —N(R S2 )S(O)R S2 , —N(R S2 )S(O) 2 R S2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
wherein each R S2 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

Z is
a fused bicyclic ring of the formula,

 wherein
ring A is Ar or 5- or 6-membered Het,
ring B is 5- or 6-membered Het,

wherein
Z is optionally substituted by one or two —R Z groups that are each independently halogen, cyano, C 1 -6alkyl, C 1 -6haloalkyl, —C 1 -C 6 alkoxy, —OR S3 , —SR S3 , —NR S3 2 , —C(O)R S3 , —C(O)OR S3 , —C(O)NR S3 2 , —S(O) 2 NR S3 2 , —S(O) 2 R S3 , —OC(O)R S3 , —N(R S3 )C(O)R S3 , —OC(O)OR S3 , —OC(O)NR S3 2 , —N(R S3 )C(O)OR S3 , —N(R S3 )C(O)NR S3 2 , —N(R S3 )S(O) 2 R S3 , —OP(O)(OR S3 ) 2 or —CH 2 —OP(O)(OR S3 ), wherein each alkyl, haloalkyl and alkoxy is optionally substituted by one or two —R Z2 groups;
wherein each

Assignees

• Rigel Pharmaceuticals Inc
• Bristol Myers Squibb Co

Inventors

• Kinsella Todd
• Gelman Marina
• Hong Hui
• Darwish Ihab S
• Singh Rajinder
• Yu Jiaxin
• Borzilleri Robert M
• Velaparthi Upender
• Liu Peiying
• Darne Chetan
• Rahaman Hasibur
• Warrier Jayakumar Sankara

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title