2,3-Disubstituted pyridine compounds as TGF-β inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-10858335-B2
Application number	US-201916249458-A
Country	US
Kind code	B2
Filing date	Jan 16, 2019
Priority date	Apr 8, 2014
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

The invention described herein comprises compounds and a method of treating cancer comprising administering to a subject having cancer one of the compounds in conjunction with another therapeutic treatment of cancer. The compounds inhibit signaling by a member of the TGF-β superfamily such as Nodal or Activin.

First claim

We claim:

1. A method of inhibiting GDF8 in a cell, the method comprising contacting the cell with 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:

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Singh Rajinder
• Bhamidipati Somasekhar
• Ding Pingyu
• Payan Donald
• Gelman Marina
• Kinsella Todd

Classifications

• A61K39/39541

  against normal tissues, cells · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title