US RE49,517 E1Granted

Pyrazoles

AssigneeJanssen Pharmaceuticals, Inc.

InventorsRudolf Schindler, Hans-Joachim Lankau, Norbert Höfgen, Christian Grunwald, Ute Egerland, Barbara Langen, Rita Dost, Thorsten Hage, Simon Ward

Life of this patent

Estimating the term…

Abstract

The invention relates to pyrazole derivatives which are NMDA NR2B receptor inhibitors, useful in treating central nervous system diseases.

Claims32

Dependent claims

A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, polymorph, or N-oxide thereof;
wherein:
n is 1 or 2,
Het is selected from:
wherein
R1 and R2 are each independently selected from hydrogen;
a halogen selected from F, Cl, and Br;
C1-6 alkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkoxy, and C3-6 (halo)cycloalkyl;
C3-6 cycloalkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
C1-6 alkoxy, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkoxy and C3-6 (halo)cycloalkyl;
—O—C3-6 cycloalkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
—S—C1-3 alkyl, optionally substituted with at least one halogen atom;
—SO2—C1-3 alkyl, optionally substituted with at least one halogen atom;
and —SF5;
or
R1 and R2 together form a 5 to 7 member carbocycle, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
and a 5 to 7 member heterocycle containing one to three heteroatoms which can be O, S or N, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
R3 and R4 are each independently selected from hydrogen;
halogen;
C1-5 (halo)alkyl, optionally substituted with at least one halogen atom, provided that at least one of R3 and R4 is hydrogen;
R5 and R6 are each independently selected from hydrogen;
halogen;
amino;
C1-5 alkyl, optionally substituted with at least one substituent, selected from halogen, hydroxy, C1-3 (halo)alkoxy and C3-6 (halo)cycloalkyl;
C1-5 alkoxy, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkoxy, and C3-6 (halo)cycloalkyl, and C3-6 cycloalkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
and
R7 is hydrogen;
C1-5 alkyl, optionally substituted with at least one substituent, selected from halogen, hydroxy, C1-3 (halo)alkoxy and C3-6 (halo)cycloalkyl;
or C3-6 cycloalkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy,
wherein at least one of at least one of R1 and R2 is not hydrogen.

27 more elements

A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of:

4-[2-[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,
3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-methylpyrazole,
5-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,
4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,
4-[4-chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,
4-[4-chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazole,
3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-ethylpyrazole,
4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole,
4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[2-(1-ethylpyrazol-4-yl)ethyl]pyrazole,
3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-(1-ethylpropyl)-pyrazole,
3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-cyclopentyl-pyrazole,
4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole,
3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole,
3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole,
4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole,
4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,
4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,
4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-[(1methylpyrazol-4-yl)methyl]pyrazole,
4-[3-chloro-5-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,
1,3-dimethyl-5-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazole,
1-methyl-3-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazole,
3-[[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,
5-[[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
4-[4-chloro-3-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,
4-[2-[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,
4-[3-chloro-5-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,
5-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
3-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,
3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,
5-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,
4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,
4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole,
4-[2-[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,
4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole,
3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-ethyl-pyrazole,
4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole,
3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole,
3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole,
4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole,
4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,
4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole,
4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,
4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,
4-[3-(difluoromethyl)-5-fluoro-phenyl]-1-[2-(1H-pyrazol-3-ylmethyl]pyrazole,
1,3-dimethyl-5-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,
1-methyl-3-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,
1-methyl-3-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,
1,3-dimethyl-5-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,
5-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
5-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
5-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
3-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-yl]methyl]-1-methyl-pyrazole,
4-(4-fluoro-3-methyl-phenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,
5-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
3-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
3-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
5-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
3-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
5-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
3-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
5-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
5-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
3-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
3-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
5-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
4-(3-cyclopropylphenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,
4-(3-methylsulfonylphenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,
1-methyl-4-[[4-(3-methylsulfonylphenyl)pyrazol-1-yl]methyl]-pyrazole,
pentafluoro-[3-[1-(1H-pyrazol-3-ylmethyl)pyrazol-4-yl]]phenyl]-sulfane,
4-[2-[4-(4-chlorophenyl)-pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,
5-[[4-(4-chlorophenyl)-pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
3-[[4-(4-chlorophenyl)-pyrazol-1-yl]methyl]-1-methyl-pyrazole,
4-(4-chlorophenyl)-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,
4-(4-chlorophenyl)-1-(1H-pyrazol-3-ylmethyl)pyrazole,
4-(4-chlorophenyl)-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,
3-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
5-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
5-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
3-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
5-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,
3-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,
1-methyl-3-[(4-phenylpyrazol-1-yl)methyl]pyrazole,
1,3-dimethyl-5-[(4-phenylpyrazol-1-yl)methyl]pyrazole, and
1-methyl-5-[(4-phenylpyrazol-1-yl)methyl]pyrazole;
and
and pharmaceutically acceptable salt, solvate, polymorph, or N-oxide thereof, and at least one pharmaceutically acceptable excipient.

85 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/124,879Filed 17 Dec 2020 · reissue
Priority: 15 Aug 2014
Granted: 2 May 2023
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
A61K 31/03
Carbocyclic: aromatic
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
C07D 403/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms

Family

Application62/037,815Us provisional application · filed 15 Aug 2014
Application62/146,629Us provisional application · filed 13 Apr 2015
Application15/503,875Reissue · filed 14 Aug 2015
US 10,155,727 B2Reissue · filed 18 Dec 2018
US 2017/0275254 A1Published application
US RE49,517 E1This patent

From the US filing history. Foreign family members aren’t listed.

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A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, polymorph, or N-oxide thereof;
wherein:
n is 1 or 2,
Het is selected from:
wherein
R1 and R2 are each independently selected from hydrogen;
a halogen selected from F, Cl, and Br;
C1-6 alkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkoxy, and C3-6 (halo)cycloalkyl;
C3-6 cycloalkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
C1-6 alkoxy, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkoxy and C3-6 (halo)cycloalkyl;
—O—C3-6 cycloalkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
—S—C1-3 alkyl, optionally substituted with at least one halogen atom;
—SO2—C1-3 alkyl, optionally substituted with at least one halogen atom;
and —SF5;
or
R1 and R2 together form a 5 to 7 member carbocycle, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
and a 5 to 7 member heterocycle containing one to three heteroatoms which can be O, S or N, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
R3 and R4 are each independently selected from hydrogen;
halogen;
C1-5 (halo)alkyl, optionally substituted with at least one halogen atom, provided that at least one of R3 and R4 is hydrogen;
R5 and R6 are each independently selected from hydrogen;
halogen;
amino;
C1-5 alkyl, optionally substituted with at least one substituent, selected from halogen, hydroxy, C1-3 (halo)alkoxy and C3-6 (halo)cycloalkyl;
C1-5 alkoxy, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkoxy, and C3-6 (halo)cycloalkyl, and C3-6 cycloalkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy;
and
R7 is hydrogen;
C1-5 alkyl, optionally substituted with at least one substituent, selected from halogen, hydroxy, C1-3 (halo)alkoxy and C3-6 (halo)cycloalkyl;
or C3-6 cycloalkyl, optionally substituted with at least one substituent, selected from hydroxy, halogen, C1-3 (halo)alkyl and C1-3 (halo)alkoxy,
wherein at least one of at least one of R1 and R2 is not hydrogen.

27 more elements

Facts

Application

17/124,879Filed 17 Dec 2020 · reissue

Priority

15 Aug 2014

Granted

2 May 2023

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
A61K 31/03
Carbocyclic: aromatic
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
C07D 403/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms

Family

Application62/037,815Us provisional application · filed 15 Aug 2014

Application62/146,629Us provisional application · filed 13 Apr 2015

Application15/503,875Reissue · filed 14 Aug 2015

US 10,155,727 B2Reissue · filed 18 Dec 2018

US 2017/0275254 A1Published application

US RE49,517 E1This patent

From the US filing history. Foreign family members aren’t listed.