Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10251889-B2
Application number	US-201715724601-A
Country	US
Kind code	B2
Filing date	Oct 4, 2017
Priority date	Jul 9, 2009
Publication date	Apr 9, 2019
Grant date	Apr 9, 2019

Abstract

Compounds of Formula I:

and salts thereof in which R 1 , R 2 , R 3 , R 4 , X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

First claim

What is claimed is:

1. A compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein:
Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, —CF 3 —CHF 2 , —O(1-4C alkyl)hetCyc 3 , -(1-4C alkyl)hetCyc 3 , —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), or (ii) a 5-6 membered heteroaryl ring one ring nitrogen atom, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, —O(1-4C alkyl), (1-4C)alkyl and NH 2 , or (iii) a pyrid-2-on-3-yl ring optionally substituted with one or more substituents independently selected from halogen and (1-4C)alkyl;
hetCyc 3 is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-6C)alkyl;
X is —CH 2 — or —CH 2 CH 2 —;
R 3 is H or -(1-4C alkyl);
each R 4 is independently selected from halogen, -(1-4C)alkyl, —OH, -(1-4C)alkoxy, and —CH 2 OH; and
n is 0, 1, or 2.

2. The compound of claim 1 , wherein:
X is CH 2 ; and
Y is (i) fluorophenyl optionally substituted with a substituent selected from —O(1-4C alkyl)hetCyc 3 , -(1-4C alkyl)hetCyc 3 , —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), (ii) pyridyl substituted with one or more substituents independently selected from F, methyl and ethyl, or (iii) 5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl.

3. The compound of claim 1 , wherein R 3 is H.

4. A compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein:
Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, —CF 3 —CHF 2 , —O(1-4C alkyl)hetCyc 3 , -(1-4C alkyl)hetCyc 3 , —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), or (ii) a 5-6 membered heteroaryl ring one ring nitrogen atom, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, —O(1-4C alkyl), (1-4C)alkyl and NH 2 , or (iii) a pyrid-2-on-3-yl ring optionally substituted with one or more substituents independently selected from halogen and (1-4C)alkyl;
hetCyc 3 is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-6C)alkyl;
X is —CH 2 — or —CH 2 CH 2 —;
R 3 is H or -(1-4C alkyl);
each R 4 is independently selected from halogen, -(1-4C)alkyl, —OH, -(1-4C)alkoxy, and —CH 2 OH; and
n is 0, 1, or 2.

5. The compound of claim 4 , wherein:
X is CH 2 ; and
Y is (i) fluorophenyl optionally substituted with a substituent selected from —O(1-4C alkyl)hetCyc 3 , -(1-4C alkyl)hetCyc 3 , —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), (ii) pyridyl substituted with one or more substituents independently selected from F, methyl and ethyl, or (iii) 5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl.

6. The compound of claim 4 , wherein R 3 is H.

7. A compound of Formula IV

or a pharmaceutically acceptable salt thereof, wherein:
Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, —CF 3 —CHF 2 , —O(1-4C alkyl)hetCyc 3 , -(1-4C alkyl)hetCyc 3 , —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), or (ii) a 5-6 membered heteroaryl ring one ring nitrogen atom, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, —O(1-4C alkyl), (1-4C)alkyl and NH 2 , or (iii) a pyrid-2-on-3-yl ring optionally substituted with one or more substituents independently selected from halogen and (1-4C)alkyl;
hetCyc 3 is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-6C)alkyl;
X is —CH 2 — or —CH 2 CH 2 —;
R 3 is H or -(1-4C alkyl);
each R 4 is independently selected from halogen, -(1-4C)alkyl, —OH, -(1-4C)alkoxy, and —CH 2 OH; and
n is 0, 1, or 2.

8. The compound of claim 7 , wherein:
X is CH 2 ; and
Y is (i) fluorophenyl optionally substituted with a substituent selected from —O(1-4C alkyl)hetCyc 3 , -(1-4C alkyl)hetCyc 3 , —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), (ii) pyridyl substituted with one or more substituents independently selected from F, methyl and ethyl, or (iii) 5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl.

9. The compound of claim 7 , wherein R 3 is H.

10. A compound of Formula VIII

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H or (1-6C alkyl);
R 2 is H, (1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)difluoroalkyl, -(1-6C)trifluoroalkyl, -(1-6C)chloroalkyl, -(2-6C)chlorofluoroalkyl, -(2-6C)difluorochloroalkyl, -(2-6C)chlorohydroxyalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO 2 NH 2 , -(1-6C alkyl)NHSO 2 (1-3C alkyl), -(1-6C alkyl)NH 2 , -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl) 2 , -(1-6C alkyl)NHC(═O)O(1-4C alkyl), -(1-6C alkyl)hetCyc 1 , -(1-6C alkyl)hetAr 1 , hetAr 2 , hetCyc 2 , —O(1-6C alkyl) which is optionally substituted with halogen, OH or (1-4C)alkoxy, —O(3-6C cycloalkyl), Cyc 1 , -(1-6C alkyl)(3-6C cycloalkyl), -(1-6Calkyl)(1-4C alkoxy), -(1-6C hydroxyalkyl)(1-4C alkoxy), a bridged 7-membered cycloalkyl ring optionally substituted with (1-6C)hydroxyalkyl, or a bridged 8 membered heterocyclic ring having 1 ring nitrogen atom;
or NR 1 R 2 forms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, OH, CO 2 H, (1-3C alkyl)CO 2 H, —O(1-6C alkyl) and (1-6C)hydroxyalkyl;
hetCyc 1 is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc 1 is optionally substituted with oxo, OH, halogen or (1-6C)alkyl;
hetCyc 2 is a 6 membered carbon-linked heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc 2 is optionally substituted with F, SO 2 NH 2 , SO 2 (1-3C alkyl) or halogen;
hetAr 1 is a 5-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-4C)alkyl;
hetAr 2 is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C)alkyl, (3-6C)cycloalkyl, halogen and OH;
Cyc 1 is a 3-6 membered cycloalkyl ring which is optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —CO 2 H, -(1-4C alkyl)OH, halogen and CF 3 ;
X is —CH 2 — or —CH 2 CH 2 —;
R 3 is H or -(1-4C alkyl);
each R 4 is independently selected from halogen, -(1-4C)alkyl, —OH, -(1-4C)alkoxy, and —CH 2 OH; and
n is 0, 1, or 2.

11. The compound of claim 10 , wherein:
R 1 is H or -(1-6C alkyl);
R 2 is H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO 2 NH 2 , -(1-6C alkyl)NHSO 2 (1-3C alkyl), -(1-6C alkyl)NH 2 , -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl) 2 , -(1-6C alkyl)hetCyc 1 , -(1-6C alkyl)hetAr 1 , hetAr 2 , hetCyc 2 , —O(1-6C alkyl), —O(3-6C cycloalkyl), or Cyc 1 ;
or NR 1 R 2 for

Assignees

• Array Biopharma Inc
• Array Biopharm Inc

Inventors

• Allen Shelley
• Andrews Steven W
• Condroski Kevin Ronald
• Haas Julia
• Huang Lily
• Jiang Yutong
• Kercher Timothy
• Seo Jeongbeob

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title