US 2020/0392144 A1Published application

Purine inhibitors of human phosphatidylinositol 3-kinase delta

AssigneeMerck Sharp & Dohme Corp.

InventorsMeredeth A. McGowan, Jason D. Katz, Matthew Christopher, Hua Zhou, David James Witter, Chaomin Li, John Lampe, Joey L. Methot, Abdelghani A. Achab, Xavier Fradera, Shimin Xu

Life of this patent

Estimating the term…

Abstract

The instant invention provides compounds of formulas Ia and Ib which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflammation, asthma, COPD and cancer.

Claims20

Dependent claims

A compound of Formula (Ia) or (Ib):

or a pharmaceutically acceptable salt thereof, wherein
n is 0, 1, 2 or 3;
A is selected from:
pyrazolyl, pyridinyl,
wherein A is substituted with 0, 1, 2, or 3 R2, each R2 is independently selected from C1-C6 alkyl, amino, C1-C6 haloalkyl, and cyano;
each R1 is independently selected from hydrogen, chloro, amino, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-12 heterocycloalkyl(C1-6 alkyl)0-1, C3-12 cycloalkyl(C1-6 alkyl)0-1, C1-6 alkyl(amino)0-1 carbonylamino, C1-6 haloalkyl(amino)0-1 carbonylamino, C3-12 cycloalkyl(amino)0-1 carbonylamino, C3-12 heterocycloalkyl(amino)0-1carbonylamino, C1-6 alkylamino, C1-6 haloalkylamino, C3-12 cycloalkyl(C1-6 alkyl)0-1 amino, C3-12 heterocycloalkyl(C1-6 alkyl)0-1amino, C5-7aryl (C1-6 alkyl)0-1amino, C1-6 alkyloxy(C0-6 alkyl), C1-6 haloalkyl oxy(C0-6 alkyl), C3-12 cycloalkyloxy(C0-6 alkyl), and C3-12 heterocycloalkyloxy(C0-6 alkyl), wherein R1 is independently substituted by 0, 1, 2, or 3 R8, each R8 is independently selected from amino, hydroxy, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkyloxy;
each R3 is independently selected from hydrogen, C1-6 alkyl, cyano, and amino;
each Z is independently selected from 2,5-diazabicyclo[2.2.1]hept-2-yl, piperazinyl, and 3,8-diazabicyclo[3.2.1]octyl, wherein each Z is substituted with 0, 1 or 2 R4, each R4 is independently selected from C1-C6 alkyl, and —(C1-C6 alkyl)OH;
each D is independently selected from phenyl, pyridinyl, cyclopropylcarbonyl, tert-butylcarbonyl, oxetanylcarbonyl, cyclobutylcarbonyl, thiophenylcarbonyl, cyclopentylsulfonyl, cyclopropylmethyl, propyl, ethylaminocarbonyl, oxazolylcarbonyl, oxetanylmethylcarbonyl, cyclopropylsulfonyl, isopropylsulfonyl, propylsulfonyl, ethylcarbonyl, cyclopentylcarbonyl, and spiro[2.4]heptylcarbonyl, wherein each D is independently substituted with 0, 1, 2, or 3 R5 each R5 is independently selected from cyano, C1-6 haloalkyl, fluoro, C1-6 alkyl, —(C1-6 alkyl)OH, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, pyrrolyl, nitro, C3-12cycloalkyl, C1-4 alkyl aminocarbonyl, and C1-4 alkylsufonyl and wherein each R5 is independently substituted with 0, 1, or 2, R6, each R6 is independently selected from fluoro, hydroxy, methyl, and methoxy;
and
each X is independently selected from cyano, chloro, hydrogen, propynol, 3-methylbutynyl, ethynyl, methylsulfanyl, difluoromethyl, ethylcarboxy, and oxazolyl;
wherein said propynol, 3-methylbutynyl, ethynyl, methylsulfanyl, difluoromethyl, ethylcarboxy, or oxazolyl is substituted with 0, 1 or 2 R7, each R7 independently selected from C1-4 alkyl, fluoro, hydroxy, and C1-6 alkoxy.

9 more elements

The compound or a pharmaceutically acceptable salt, wherein the compound is

4-[(1S,4R)-5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile;
2-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-4-[(1S,4R)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[6-(difluoromethyl)pyridin-3-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[3-(1-hydroxy-1-methylethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-pyridin-3-yl-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-[(1S,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[3-(2-fluoroethoxy)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-{(1S,4R)-5-[3-(1H-pyrrol-1-yl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(3-nitrophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[3-(1-methylcyclopropyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
3-{(1R,4S)-5-[5-cyano-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-methylbenzamide;
4-[(1S,4R)-5-(3-methoxyphenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-{(1S,4R)-5-[3-(methylsulfonyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}pyrimidine-5-carbonitrile;
4-[(1S,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(5-methylpyridin-3-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1H-indazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-isoquinolin-5-ylpyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-morpholin-4-ylpyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclopropylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclopropylsulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclopropylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
(1R,4S)-5-[5-cyano-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]-N-ethyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide;
4-[(1S,4R)-5-(2,2-dimethylpropanoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-fluoro-2,2-dimethylpropanoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[(3-methyloxetan-3-yl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-{[1-(methoxymethyl)cyclopropyl]carbonyl}-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclobutylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(thiophen-2-ylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(1,3-oxazol-4-ylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(oxetan-3-ylacetyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[(1-methylethyl)sulfonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(propylsulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclopentylsulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-fluoropropyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[4-(3-fluorophenyl)-3,3-dimethylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[4-(3-fluorophenyl)piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(3-fluorophenyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[8-(3-fluorophenyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-3-methyl-4-propanoylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclobutylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(3R)-3-methyl-4-[(1-methylcyclopropyl)carbonyl]piperazin-1-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(3R)-4-[(2,2-difluorocyclobutyl)carbonyl]-3-methylpiperazin-1-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopentylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(3R)-3-methyl-4-(spiro[2.4]hept-1-ylcarbonyl)piperazin-1-yl]pyrimidine-5-carbonitrile;
4-[(3R)-3-methyl-4-{[(1R,2R)-2-methylcyclopropyl]carbonyl}piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-3-methyl-4-{[(1S,2R)-2-methylcyclopropyl]carbonyl}piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(3-fluorophenyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-3-methyl-4-(3-nitrophenyl)piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(3-cyanophenyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(3R)-3-methyl-4-[3-(methylsulfonyl)phenyl]piperazin-1-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
3-{2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl}prop-2-yn-1-ol;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carbonitrile;
6-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carbonitrile;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-5-[5-(1-methylethyl)-1,3-oxazol-2-yl]-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine;
4-[(3R)-4-(cyclopropylcarbonyl)-3-(2-methylpropyl)piperazin-1-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3S)-4-(cyclopropylcarbonyl)-3-(hydroxymethyl)piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-5-(3-methylbut-1-yn-1-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-5-ethynyl-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-4-(1-methyl-1H-pyrazol-4-yl)-5-(methylsulfanyl)pyrimidine;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-5-(difluoromethyl)-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine;
ethyl 2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate;
5-chloro-4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine;
4-amino-6-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
1-{5-cyano-6-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl}-3-(1-methylethyl)urea;
N-{5-cyano-6-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl}acetamide;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-6-[(2,2,2-trifluoroethyl)amino]pyrimidine-5-carbonitrile;
4-chloro-6-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-6-ethyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-(cyclobutylamino)-6-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-6-(phenylamino)pyrimidine-5-carbonitrile;
4-chloro-2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-[1-methyl-5-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]pyrimidine-5-carbonitrile;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-4-(2-methoxyethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]pyrimidine-5-carbonitrile;
4-(3-amino-1-methyl-1H-pyrazol-4-yl)-2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidine-5-carbonitrile;
1-{5-cyano-6-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl}-3-(2,2,2-trifluoroethyl)urea;
1-{5-cyano-6-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl}-3-cyclobutylurea;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-6-[(oxetan-3-ylmethyl)amino]pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-6-[(3,3,3-trifluoropropyl)amino]pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-6-[(1-methylethyl)amino]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-6-[(2-methylpropyl)amino]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-6-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-6-[3-(trifluoromethyl)azetidin-1-yl]pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-6-propylpyrimidine-5-carbonitrile;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-4-(1-methyl-1H-pyrazol-4-yl)-6-propylpyrimidine-5-carbonitrile;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-4-(1-methyl-1H-pyrazol-4-yl)-6-(3,3,3-trifluoropropyl)pyrimidine-5-carbonitrile;
4-cyclopropyl-2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
or
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]pyrimidine-5-carbonitrile.

97 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/764,448Filed 12 Dec 2018
Priority: CN PCT/CN2017/11691718 Dec 2017
Published: 17 Dec 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

A61P 35/00
Antineoplastic agents
C07D 487/08
In which the condensed system contains two hetero rings: bridged systems
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…

Family

US 11,230,547 B2Related patent
US 2020/0392144 A1This patent

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

Timeline

Citations

Open elsewhere

Building an agent or pulling many patents? Use the API or MCP server instead of scraping pages. Get an API key

patentgrep

Loading patent…

Abstract

A compound of Formula (Ia) or (Ib):

or a pharmaceutically acceptable salt thereof, wherein
n is 0, 1, 2 or 3;
A is selected from:
pyrazolyl, pyridinyl,
wherein A is substituted with 0, 1, 2, or 3 R2, each R2 is independently selected from C1-C6 alkyl, amino, C1-C6 haloalkyl, and cyano;
each R1 is independently selected from hydrogen, chloro, amino, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-12 heterocycloalkyl(C1-6 alkyl)0-1, C3-12 cycloalkyl(C1-6 alkyl)0-1, C1-6 alkyl(amino)0-1 carbonylamino, C1-6 haloalkyl(amino)0-1 carbonylamino, C3-12 cycloalkyl(amino)0-1 carbonylamino, C3-12 heterocycloalkyl(amino)0-1carbonylamino, C1-6 alkylamino, C1-6 haloalkylamino, C3-12 cycloalkyl(C1-6 alkyl)0-1 amino, C3-12 heterocycloalkyl(C1-6 alkyl)0-1amino, C5-7aryl (C1-6 alkyl)0-1amino, C1-6 alkyloxy(C0-6 alkyl), C1-6 haloalkyl oxy(C0-6 alkyl), C3-12 cycloalkyloxy(C0-6 alkyl), and C3-12 heterocycloalkyloxy(C0-6 alkyl), wherein R1 is independently substituted by 0, 1, 2, or 3 R8, each R8 is independently selected from amino, hydroxy, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkyloxy;
each R3 is independently selected from hydrogen, C1-6 alkyl, cyano, and amino;
each Z is independently selected from 2,5-diazabicyclo[2.2.1]hept-2-yl, piperazinyl, and 3,8-diazabicyclo[3.2.1]octyl, wherein each Z is substituted with 0, 1 or 2 R4, each R4 is independently selected from C1-C6 alkyl, and —(C1-C6 alkyl)OH;
each D is independently selected from phenyl, pyridinyl, cyclopropylcarbonyl, tert-butylcarbonyl, oxetanylcarbonyl, cyclobutylcarbonyl, thiophenylcarbonyl, cyclopentylsulfonyl, cyclopropylmethyl, propyl, ethylaminocarbonyl, oxazolylcarbonyl, oxetanylmethylcarbonyl, cyclopropylsulfonyl, isopropylsulfonyl, propylsulfonyl, ethylcarbonyl, cyclopentylcarbonyl, and spiro[2.4]heptylcarbonyl, wherein each D is independently substituted with 0, 1, 2, or 3 R5 each R5 is independently selected from cyano, C1-6 haloalkyl, fluoro, C1-6 alkyl, —(C1-6 alkyl)OH, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, pyrrolyl, nitro, C3-12cycloalkyl, C1-4 alkyl aminocarbonyl, and C1-4 alkylsufonyl and wherein each R5 is independently substituted with 0, 1, or 2, R6, each R6 is independently selected from fluoro, hydroxy, methyl, and methoxy;
and
each X is independently selected from cyano, chloro, hydrogen, propynol, 3-methylbutynyl, ethynyl, methylsulfanyl, difluoromethyl, ethylcarboxy, and oxazolyl;
wherein said propynol, 3-methylbutynyl, ethynyl, methylsulfanyl, difluoromethyl, ethylcarboxy, or oxazolyl is substituted with 0, 1 or 2 R7, each R7 independently selected from C1-4 alkyl, fluoro, hydroxy, and C1-6 alkoxy.

9 more elements

Facts

Application

16/764,448Filed 12 Dec 2018

Priority

CN PCT/CN2017/11691718 Dec 2017

Published

17 Dec 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

A61P 35/00
Antineoplastic agents
C07D 487/08
In which the condensed system contains two hetero rings: bridged systems
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…