IP Library › Granted Patent US 10,961,239
Granted Patent B2
US 10,961,239 · App. 16/475,413 · Granted Mar 30, 2021

TGF beta receptor antagonists

Inventors: Robert M. Borzilleri (Carversville, PA); Upender Velaparthi (Princeton Junction, NJ); Chetan Padmakar Darne (Ewing, NJ); Peiying Liu (Marlborough, MA); Manjunatha Narayana Rao Kamble (Bangalore, IN); Balaji Seshadri (Hosur, IN); Raju Mannoori (Bangalore, IN); Hasibur Rahaman (Bangalore, IN); Jayakumar Sankara Warrier (Bangalore, IN)
Assignee: Bristol-Myers Squibb Company
C07D471/04C07D401/14C07D487/04A61K45/06C07K16/2818
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Quick Facts
Patent No.
US 10,961,239
App. No.
16/475,413
Granted
Mar 30, 2021
Kind
B2
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.

Claims (48)

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 acceptable carriers, diluents or excipients.

Continuity (2)
Provisional Application 62442580 · Jan 5, 2017
Related Publication 20190337942A1 · Nov 7, 2019