Pyrazolo pyrimidine derivatives and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016168151-A1
Application number	US-201514864655-A
Country	US
Kind code	A1
Filing date	Sep 24, 2015
Priority date	Jun 20, 2003
Publication date	Jun 16, 2016
Grant date	—

Abstract

This invention generally relates to pyrazolo pyrimidine derivatives useful as, inter alia, inhibitors of short chain dehydrogenase/reductase (SDR) family of NAD(P)(H) dependent oxido-reductases. More specifically, the invention relates to pyrazolo pyrimidine derivatives, including derivatives and analogs of SDR inhibitors, pharmaceutical compositions containing derivatives and analogs of SDR inhibitors, methods of making derivatives and analogs of SDR inhibitors and methods of use thereof.

First claim

1 . A compound of Formula I:

or a pharmaceutically-acceptable salt thereof;
wherein:
Y is N;
Z is NR 3 R 4 , halo, H, OH, alkyl, alkyloxy, or haloalkyl;
R 1a is benzyl or phenyl, wherein said benzyl or phenyl is optionally substituted with one or two OH, —NR 3 R 4 , —C(═O)NR 6 R 7 , —CN, NO 2 —C(═O)OH, —C(═O)O-alkyl, (C 1 -C 4 )alkyl, haloalkyl or haloaryl;
R 2 is C 1 -C 6 alkyl or C 4 -C 7 cycloalkyl, wherein said alkyl or said cycloalkyl is optionally substituted with mono- or di-alkoxy, mono- or di-halophenyl, mono- or di-(C 1-4 )alkoxy phenyl, mono- or di-(C 1-4 )alkyl phenyl, perhalo(C 1-4 )alkyl phenyl, carboxyl, tert-butyl carboxyl, phosphoryl, (C 1-6 )alkyl, (C 4-7 )cycloalkyl, indolyl, isoindolyl, pyridyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, or alkylmorpholino;
R 3 and R 4 are independently H, C 1 -C 6 alkyl, tert-butyloxycarbonyl, morpholino(C 1 -C 4 )alkyl, carboxy(C 1 -C 3 )alkyl, (C 1 -C 4 )alkoxycarbonyl(C 1 -C 3 )alkyl, aryl, heteroaryl, aryloxy, heterocycle, cycloalkyl, alkenyl with the proviso that the double bond of the alkenyl is not present at the carbon atom that is directly linked to N, alkynyl with the proviso that the triple bond of the alkynyl is not present at the carbon atom that is directly linked to N, perfluoroalkyl, —S(O) 2 alkyl, —S(O) 2 aryl, —(C═O)heteroaryl, —(C═O)aryl, —(C═O)(C 1 -C 6 ) alkyl, —(C═O)cycloalkyl, —(C═O)heterocycle, alkyl-heterocycle, aralkyl, arylalkenyl, —CON R 6 R 7 , —SO 2 R 6 R 7 , arylalkoxyalkyl, arylalkylalkoxy, heteroarylalkylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, aryloxyaryl, aryloxyheteroaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl, alkylaryloxyalkyamine, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl;
R 6 and R 7 are independently H, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, or alkylheteroaryl;
provided the compound is not 1-tert-butyl-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine.

2 . A compound according to claim 1 , wherein R 1a is benzyl optionally substituted with mono, di or tri —OH.

3 . A compound according to claim 1 , wherein R 1a is phenyl optionally substituted with mono, di or tri-OH.

4 . (canceled)

5 . (canceled)

6 . A compound according to claim 1 , wherein R 2 is C 1 -C 6 alkyl.

7 . A compound according to claim 1 , wherein Z is NR 3 R 4 ; and R 3 and R 4 are H.

8 . A compound according to claim 1 , wherein R 2 is C 1 -C 6 alkyl optionally substituted with alkoxy.

9 . A compound according to claim 1 , wherein R 6 is H and R 7 is methyl.

10 . A compound according to claim 1 , wherein, R 1a is phenyl optionally substituted with —CH 3 .

11 . A compound according to claim 1 , wherein R 1a is phenyl substituted with —NH 2 .

12 .- 14 . (canceled)

15 . A compound or pharmaceutically-acceptable salt according to claim 1 , wherein said compound has the formula:

wherein R 2 is isopropyl, tert-butyl, or ethoxyethyl.

16 . A compound or pharmaceutically-acceptable salt according to claim 15 , wherein said compound has the formula:

17 . (canceled)

18 .- 19 . (canceled)

20 . A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and a compound or pharmaceutically-acceptable salt according to claim 1 .

21 .- 44 . (canceled)

45 . A compound or pharmaceutically-acceptable salt according to claim 1 , wherein said compound has the formula:

wherein R 2 is isopropyl, tert-butyl, or ethoxyethyl.

46 . A compound or pharmaceutically-acceptable salt according to claim 45 , wherein said compound has the formula:

47 . A compound or pharmaceutically-acceptable salt according to claim 1 , wherein said compound has the formula:

wherein R 2 is isopropyl, tert-butyl, or ethoxyethyl.

48 . A compound or pharmaceutically-acceptable salt according to claim 47 , wherein said compound has the formula:

49 . A compound or pharmaceutically-acceptable salt according to claim 1 , wherein said compound has the formula:

Assignees

• Univ California

Inventors

• Tanaka Masahiro
• Zhang Chao
• Shokat Kevan M
• Burlingame Alma L
• Hansen Kirk
• Bateman Raynard L
• Dimagno Stephen G

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title