KDM5 inhibitors

Patent metadata

Field	Value
Publication number	US-10975084-B2
Application number	US-201716341313-A
Country	US
Kind code	B2
Filing date	Oct 6, 2017
Priority date	Oct 12, 2016
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

The present invention provides a compound of Formula (I) (represented as tautomers Ia and Ib) or the pharmaceutically acceptable salts thereof, which are KDM5 inhibitors.

First claim

What is claimed is:

1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein
R 1 is
C 1 -C 6 alkyl, which is substituted with CF 3 ,
—(C 2 -C 3 alkylene)-C(O)—O—C 1 -C 6 alkyl,
or
a 6-membered unsaturated carbocycle;

R 2 is
halogen,
CF 3 ,
—C 2 -C 4 alkenylene-O—C 1 -C 3 alkyl,
C(O)—O—C 1 -C 6 alkyl,
C(═CH 2 )C 1 -C 4 alkyl,
—(C 2 -C 4 alkenylene)—C 6 H 5 ,
—(C 1 -C 4 alkylene)—C 6 H 5 ,
a 3-, 4-, 5- or 6 membered saturated carbocycle,
a 6-membered unsaturated carbocycle, unsubstituted or mono-substituted or independently di-substituted with R 3 ,
a 6-membered saturated heterocycle, unsubstituted, having 1 heteroatom which is O,
a 5-membered unsaturated heterocycle having 1 or 2 heteroatoms independently selected from N, O and S, unsubstituted or independently mono- or di-substituted with R 5 , or
a 6-membered unsaturated heterocycle, having 1 or 2 heteroatoms independently selected from N and O, unsubstituted or independently mono-, di-, tri- or tetra-substituted with R 4 , or
an 8-, 9-, or 10-membered unsaturated bicyclic heterocycle having 1, 2 or 3 heteroatoms independently selected from N or O, unsubstituted or substituted with R 6 ;

R 3 is
—C 1 -C 3 alkyl, unsubstituted or mono- or independently di-substituted with a 6-membered saturated heterocycle having 1 or 2 heteroatoms independently selected from N and O, —C(O)OC 1 -C 3 alkyl, —OH, —CF 3 , and CN,
C 1 -C 3 alkoxy,
halogen,
CN,
OH,
O—C 6 H 5 ,
OC 1 -C 3 alkyl,
C(O)OC 1 -C 3 alkyl,
CF 3 ,
C(O)N(CH 3 ) 2 ,
NH 2 ,
NHSO 2 C 1 -C 3 alkyl,
NH(C 1 -C 3 alkyl),
N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl),
NHSO 2 cC 3 H 5 ,
a 5- or 6-membered saturated heterocycle having 1 or 2 heteroatoms independently selected from N, O and S, wherein S is a dioxide, unsubstituted or substituted with C 1 -C 3 alkyl, or
a 5- or 6-membered unsaturated heterocycle, unsubstituted or substituted with C 1 -C 3 alkyl, having 1, 2 or 3 N atoms;

R 4 is
halogen,
C 1 -C 3 alkyl, unsubstituted or substituted with —OH,
CN,
CF 3 ,
cC 3 H 5 ,
CF 2 CH 2 OH,
a 6-membered saturated heterocycle having 1 or 2 heteroatoms independently selected from N and O, or
a 5-membered unsaturated heterocycle having 2 N atoms;

R 5 is
CF 3 ,
C 1 -C 5 alkyl, unsubstituted or substituted with a 6-membered saturated heterocycle having 1 or 2 heteroatoms independently selected from N and O, a 6-membered unsaturated carbocycle, a 6-membered unsaturated heterocycle having 1 N atom, —OC 1 -C 4 alkyl, —OH, —C(O)OH, a 5-membered unsaturated heterocycle having 1 S atom, cC 3 H 5 , —SO 2 C 1 -C 4 alkyl, —NHC 1 -C 4 alkyl, or a 3-5-membered saturated carbocycle unsubstituted or substituted with F,
a 3-, 4-, 5- or 6-membered saturated carbocycle,
a 6-membered unsaturated carbocycle unsubstituted or substituted with halogen,
a 6-membered saturated heterocycle having 1 or 2 heteroatoms independently selected from N and O, or
a 5-membered unsaturated unsubstituted heterocycle having 1 or 2 N heteroatoms; and

R 6 is C 1 -C 6 alkyl, cyclopropyl or ═O.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is
—CH 2 C(O)OCH 3 , CH 2 CF 3 ,

3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is
Cl, C(═CH 2 )CH 2 CH 2 CH 3 ,
CH═CHCH 2 OCH 3 ,
CF 3 , C(O)OCH 2 CH 3 , CH═CHC 6 H 5 ,

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is Cl, C(═CH 2 )CH 2 CH 2 CH 3 ,
CH═CHCH 2 OCH 3 ,
CF 3 , C(O)OCH 2 CH 3 , CH═CHC 6 H 5 ,

5. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is
—CH 2 C(O)OCH 3 , CH 2 CF 3 ,

and
R 2 is
Cl, C(═CH 2 )CH 2 CH 2 CH 3 ,
CH═CHCH 2 OCH 3 , CF 3 , C(O)OCH 2 CH 3 , CH═CHC 6 H 5 ,

6. A compound of or a pharmaceutically acceptable salt thereof, which is
6-bromo-5-(1-(tert-butyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(H)-one,
5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-propyl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
methyl (5-methyl-7-oxo-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate,
5-(4-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
ethyl 6-methyl-7-oxo-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-5-carboxylate,
5-(1-methyl-1H-pyrazol-3-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-methyl-6-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
6-cyclobutyl-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
6-ethyl-5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
6-fluoro-5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-[1-(1-methylethyl)-1H-pyrazol-4-yl][1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-furan-3-yl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-pyridin-4-yl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-pyridin-2-yl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-furan-2-yl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-(4-chlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)one,
5-(4-chlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-(2-chlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-(2-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-(3-chlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-(3-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
6-phenyl-5-propyl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
5-(1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one,
6-(1-methylethyl)-5-phenyl[1,2,4]triazolo[1,5-a]pyrimidi

Assignees

• Merck Sharp & Dohme
• Mansoor Umar Faruk
• Fischer Christian
• Siliphaivanh Phieng
• Torres Luis
• Gunaydin Hakan
• Sloman David L

Inventors

• Mansoor Umar Faruk
• Fischer Christian
• Siliphaivanh Phieng
• Torres Luis
• Gunaydin Hakan
• Sloman David L

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title