TGF beta receptor antagonists

Patent metadata

Field	Value
Publication number	US-10961239-B2
Application number	US-201816475413-A
Country	US
Kind code	B2
Filing date	Jan 3, 2018
Priority date	Jan 5, 2017
Publication date	Mar 30, 2021
Grant date	Mar 30, 2021

Abstract

The invention relates generally to compounds of formula (I) that modulate the activity of TGFβR-1 and TGFβR-2, pharmaceutical compositions containing said compounds and methods of treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer, utilizing the compounds of the invention.

First claim

What is claimed is:

1. A compound of the formula

or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof;
wherein
Z is

each R 4 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, —NH 2 , —NO 2 , or —CN;
n is 0, 1 or 2,
each R Z is independently halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanol, —COO C 1 -C 6 alkyl, —CONR z1 R z2 , —NHC(O) C 1 -C 6 haloalkyl, —NHC(O) C 1 -C 6 alkyl, —NH C 1 -C 6 alkyl or a 5-8 membered heterocyclic ring substituted with 0-3 R 4 groups containing 1-4 heteroatoms selected from —O—, —S— or —N—;
each R z1 and R z2 is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkanol, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyl substituted with 0-2 R 4 groups, CONR 1a R 1b , —NHC(O) C 1 -C 6 alkyl, —COOH, —COO C 1 -C 6 alkyl or a 5-8 membered heterocyclic ring substituted with 0-3 R 4 groups containing 1-4 heteroatoms selected from —O—, —S— or —N—;
each R 1a and R 1b is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and
R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 3 -C 8 cycloalkyl or —NHC(O) C 1 -C 6 alkyl.

2. A compound of the formula

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,
wherein
each R 4 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, —NH 2 , —NO 2 , or —CN;
n is 0, 1 or 2;
R Z is independently halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanol, —COO C 1 -C 6 alkyl, —CONR z1 R z2 , —NHC(O) C 1 -C 6 haloalkyl, —NHC(O) C 1 -C 6 alkyl, —NH C 1 -C 6 alkyl or a 5-8 membered heterocyclic ring substituted with 0-3 R 4 groups containing 1-4 heteroatoms selected from —O—, —S— or —N—;
each R z1 and R z2 is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkanol, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyl substituted with 0-2 R 4 groups, CONR 1a R 1b , —NHC(O) C 1 -C 6 alkyl, —COOH, —COO C 1 -C 6 alkyl or a 5-8 membered heterocyclic ring substituted with 0-3 R 4 groups containing 1-4 heteroatoms selected from —O—, —S— or —N—;
each R 1a and R 1b is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and
R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 3 -C 8 cycloalkyl or —NHC(O) C 1 -C 6 alkyl.

3. A compound of the formula

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,
wherein
each R 4 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, —NH 2 , —NO 2 , or —CN;
n is 0, 1 or 2;
R Z is independently halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C2-C6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanol, —COO C 1 -C 6 alkyl, —CONR z1 R z2 , —NHC(O) C 1 -C 6 haloalkyl, —NHC(O) C 1 -C 6 alkyl, —NH C 1 -C 6 alkyl or a 5-8 membered heterocyclic ring substituted with 0-3 R 4 groups containing 1-4 heteroatoms selected from —O—, —S— or —N—;
each R z1 and R z2 is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C6 alkenyl, C 1 -C 6 alkanol, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyl substituted with 0-2 R 4 groups, CONR 1a R 1b , —NHC(O) C 1 -C 6 alkyl, —COOH, —COO C 1 -C 6 alkyl or a 5-8 membered heterocyclic ring substituted with 0-3 R 4 groups containing 1-4 heteroatoms selected from —O—, —S— or —N—;
each R 1a and R 1b is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and
R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 3 -C 8 cycloalkyl or —NHC(O) C 1 -C 6 alkyl.

4. A compound of the formula

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,
wherein
each R 4 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, —NH 2 , —NO 2 , or —CN;
n is 0, 1 or 2;
R Z is independently halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanol, —COO C 1 -C 6 alkyl, —CONR z1 R z2 , —NHC(O) C 1 -C 6 haloalkyl, —NHC(O) C 1 -C 6 alkyl, —NH C 1 -C 6 alkyl or a 5-8 membered heterocyclic ring substituted with 0-3 R 4 groups containing 1-4 heteroatoms selected from —O—, —S— or —N—;
each R z1 and R z2 is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkanol, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyl substituted with 0-2 R 4 groups, CONR 1a R 1b , —NHC(O) C 1 -C 6 alkyl, —COOH, —COO C 1 -C 6 alkyl or a 5-8 membered heterocyclic ring substituted with 0-3 R 4 groups containing 1-4 heteroatoms selected from —O—, —S— or —N—;
each R 1a and R 1b is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and
R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 3 -C 8 cycloalkyl or —NHC(O) C 1 -C 6 alkyl.

5. A pharmaceutical composition which comprises a compound according to claim 2 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

6. A combination pharmaceutical product comprising a compound according to claim 2 or a pharmaceutically acceptable salt thereof together with one or more therapeutically active agents.

7. A method of treating diseases or conditions for which a TGFßR antagonist is indicated in a subject in need thereof which comprises administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 wherein the disease or condition is cancer.

9. The method of claim 8 wherein the compound is administered in combination with a therapeutically effective amount of one or more chemotherapeutic agents.

10. A pharmaceutical composition which comprises a compound according to claim 3 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

11. A pharmaceutical composition which comprises a compound according to claim 4 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically accep

Assignees

• Bristol Myers Squibb Co

Inventors

• Borzilleri Robert M
• Velaparthi Upender
• Darne Chetan Padmakar
• Liu Peiying
• Kamble Manjunatha Narayana Rao
• Seshadri Balaji
• Mannoori Raju
• Rahaman Hasibur
• Warrier Jayakumar Sankara

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title