Substituted pyrazolopyrimidines as glucocerebrosidase activators

Patent metadata

Field	Value
Publication number	US-9353117-B2
Application number	US-201113991816-A
Country	US
Kind code	B2
Filing date	Dec 8, 2011
Priority date	Dec 8, 2010
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

Substituted pyrazolopyrimidines and dihydropyrazolopyrimidines and related compounds, their methods of manufacture, compositions containing these compounds, and methods of use of these compounds in treating lysosomal storage disorders such as Gaucher disease are described herein. The compounds are of general Formula (I)

in which variables R 1 -R 7 and X are described in the application.

First claim

What is claimed is:

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier wherein
the ring

is a ring system of the formula
(i)

in which R 5 is an optionally substituted alkylidene group and R 6 and R 7 carry the definitions set forth below, or
(ii)

in which R 5 , R 6 , and R 7 carry the definitions set forth below;
R 1 is phenyl, naphthyl, tetrahydronaphthyl, cyclohexyl, or dihydroindenyl, each of which R 1 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, (mono- or di- C 1 -C 6 alkylamino)C 0 -C 4 alkyl, mono- or di-C 1 -C 6 alkylcarboxamide, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and with 0 or 1 substituents chosen from Y-Z- where Z is a covalent bond, C 1 -C 4 alkylene, C 2 -C 4 alkenylene, C 2 -C 4 alkynylene, -S-, -0-, -NR-, -C(0)-, -NHC(0)-, or -C(0)NH-, where R is hydrogen or C 1 -C 4 alkyl, and Y is phenyl, pyrimidinyl, 5- or 6-membered heterocycloalkyl, or pyridyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di- C 1 -C 4 alkylamino, trifluoromethyl, difluoromethyl, trifluoromethoxy, and phenyl; and
R 2 is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or (phenyl)C o -C 2 alkyl;
R 3 is hydrogen;
R 5 is halogen, hydroxyl, amino, cyano, vinyl, cyclopropyl, cyclopropylidenyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, difluoromethyl, or trifluoromethyl;
R 6 is hydrogen, halogen, hydroxyl, or C 1 -C 4 alkoxy; and
R 7 is halogen, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, difluoromethyl, or trifluoromethyl, or
R 7 is phenyl or a 5- to 7-membered heterocycloalkyl ring having 1 or 2 heteroatoms chosen from N, O and S, each of which R 7 is directly attached via a covalent bond or attached via a C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 alkylamino group, and each of which R 7 is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, C i -C 4 alkyl, C i -C 4 alkoxy, (mono- and di-C 1 -C 2 alkylamino)C o -C 4 alkyl, C i -C 2 haloalkyl, and C i -C 2 haloalkoxy; or
R 6 and R 7 are taken together to form a 5- or 6-membered carbocyclic ring with no additional points of unsaturation, which ring is unsubstituted or substituted with 1 to 3 substituents independently chosen from C 1 -C 2 alkyl and C 1 -C 2 alkoxy;
wherein R 1 is not unsubstituted phenyl, dihydroindenyl, cyclohexyl, or phenyl substituted with 1 or 2 substituents independently chosen from chloro, fluoro, C 1 -C 4 alkyl, acetyl, and trifluoromethyl, when R 6 is hydrogen, and R 5 and R 7 are both methyl, or when R 6 is hydrogen and one of R 5 and R 7 is methyl and the other is phenyl.

2. The pharmaceutical composition of claim 1 , wherein R 6 is hydrogen.

3. The pharmaceutical composition of claim 1 of the formula

4. The pharmaceutical composition of claim 1 of the formula

where R 5a is hydrogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, or 4- to 7-membered carbon-attached heterocycloalkyl, having 1 or 2 heteroatoms independently chosen from N, S, and O.

5. The pharmaceutical composition of claim 3 , wherein
R 2 is hydrogen or methyl; and
R 5 is C 1 -C 4 alkyl or difluoromethyl; and
R 7 is C 1 -C 4 difluoromethyl, or phenyl.

6. The pharmaceutical composition of claim 5 , wherein R 5 and R 7 are both methyl; or R 5 is methyl and R 7 is phenyl; or one of R 5 and R 7 is methyl and the other is difluoromethyl.

7. The pharmaceutical composition of claim 6 , wherein R 1 is phenyl, cyclohexyl, naphthyl, tetrahydronaphthyl, or dihydroindenyl, each of which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, mono- or di- C 1 -C 6 alkylamino, mono- or di-C 1 -C 6 alkylcarboxamide, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and with 0 or 1 substituents chosen from Y-Z- where Z is a covalent bond, C 1 -C 4 alkylene, -S-, -0-, -NR-, -C(0)-, -NHC(0)-, or -C(0)NH-, where R is hydrogen or C 1 -C 4 alkyl, and Y is phenyl or pyridyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy.

8. The pharmaceutical composition of claim 6 , wherein
R 1 is phenyl, substituted with at least one substituent chosen from cyano, trifluoromethyl, and CH 3 C(0)NH-, or
R 1 is cyclohexyl, substituted with at least one trifluoromethyl, or C 3 -C 6 alkyl; or
R 1 is dihydroindenyl, substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, mono- or di- C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

9. The pharmaceutical composition of claim 4 , wherein R 5a is hydrogen or cyclopropyl.

10. The pharmaceutical composition of claim 4 , wherein
R 2 is hydrogen or methyl; and
R 7 is C 1 -C 4 alkyl, difluoromethyl, or phenyl.

11. The pharmaceutical composition of claim 10 , wherein R 7 is difluoromethyl.

12. The pharmaceutical composition of claim 4 , wherein R 1 is phenyl, cyclohexyl, naphthyl, tetrahydronaphthyl, or dihydroindenyl, each of which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, mono- and di- C 1 -C 6 alkylamino, mono- and di-C 1 -C 6 alkylcarboxamide, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and with 0 or 1 substituents chosen from Y-Z- where Z is a covalent bond, C 1 -C 4 alkylene, -S-, -0-, -NR-, -C(0)-, -NHC(0)-, or -C(0)NH-, where R is hydrogen or C 1 -C 4 alkyl, and Y is phenyl or pyridyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy.

13. The pharmaceutical composition of claim 4 , wherein
R 2 is hydrogen or methyl; and
R 7 is methyl or difluoromethyl; and
R 1 is phenyl, cyclohexyl, naphthyl, tetrahydronaphthyl, or dihydroindenyl, each of which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, mono- or di- C 1 -C 4 alkylamino, mono- or di-C 1 -C 4 alkylcarboxamide, C 1 -C 2 alkylsulfonyl, trifluoromethyl, trifluoromethoxy, and difluoromethyl, and with 0 or 1 substituents chosen from Y-Z- where Z is a covalent bond, C 1 -C 4 alkylene, -S-, -0-, -NR-, -C(0)-, -NHC(0)-, or -C(0)NH-, where R is hydrogen or C 1 -C 4 alkyl, and Y is phenyl or pyridyl, each

Assignees

• Marugan Juan Jose
• Southall Noel
• Goldin Ehud
• Zheng Wei
• Patnaik Samarjit
• Sidransky Ellen
• Motabar Omid
• Westbroek Wendy
• Us Health

Inventors

• Marugan Juan Jose
• Southall Noel
• Goldin Ehud
• Zheng Wei
• Patnaik Samarjit
• Sidransky Ellen
• Motabar Omid
• Westbroek Wendy

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519 Primary

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title