US 2018/0008589 A1Published application

Tyrosine kinase inhibitors

AssigneeRigel Pharmaceuticals, Inc.

InventorsSacha Holland, Rajinder Singh, Somasekhar Bhamidipati, Pingyu Ding, Rao Kolluri, Ihab Darwish, Esteban Masuda, Jiaxin Yu

Life of this patent

Estimating the term…

Abstract

Disclosed are imidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein X, Y and Z are as described herein. In certain embodiments, a compound disclosed herein inhibits a cellular TAM receptor, and can be used to treat disease mediated by or involving the TAM receptor family.

Claims37

Dependent claims

A compound having the structure formula (I):

or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
X is hydrogen, Cak(C0-C6alkyl), Hca(C0-C6alkyl), Ar(C0-C6alkyl), Het(C0-C6alkyl), halogen or Hca(C1-C6alkyl)-O—, wherein Ar, Het, Cak, Hca and the alkyl group is optionally substituted by one to four —RX1 groups, wherein
each —RX1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2, —CH2—OP(O)(OR), Ar(C0-C6alkyl), Het(C0-C6alkyl), Cak(C0-C6alkyl) or Hca(C0-C6alkyl),
or two —RX1 groups taken together, when attached to adjacent atoms, form a Cak, Hca or Het, wherein the Cak Hca and the Het comprise a 3-8 membered ring optionally substituted with one or two —RX2 groups,
or two —RX1 groups taken together, when attached to the same carbon atom, form a Hca, wherein the Hca comprises a 3-8 membered ring optionally substituted with one or two —RX2 groups,
or two —RX1 groups taken together, when attached to non-adjacent atoms, and combined with X, form a bridged Hca optionally substituted with one or two —RX2 groups,
wherein each —RX2is independently halogen, cyano, nitro, oxo, —OR, —SR, —NR2, —C(O)OR, —C(O)NR2, —C(O)R, —S(O)R, —S(O)2R, —S(O)OR, —S(O)2OR, —S(O)NR2, —S(O)2NR2, —OC(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)R, —N(R)S(O)2R, C1-C6alkyl, or C1-C6haloalkyl;
Y is Cak(C0-C8alkyl) or Hca(C0-C6alkyl), each optionally substituted by one or two —RY1 groups;
wherein each —RY1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, N(R)C(NR2)NR2, —C(O)R, —C(O)OR, C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
Z is C1-C6alkyl or Cak(C0-C6alkyl), each optionally substituted by one to three —RZ1 groups;
wherein each —RZ1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
and
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, Hca(C0-C6alkyl), Cak(C0-C8alkyl), C1-C6alkyl-CN, —CH2C(O)NH2, wherein
Hca is a 3-15 membered ring or ring system comprising at least one ring, 1-4 O, S, or N atoms, provided no O or S is adjacent to another O or S;
Het is a 5-15 membered aromatic ring or ring system comprising at least one ring and 1-4 O, S, or N atoms, provided no O or S is adjacent to another O or S;
Cak is a 3-8 membered non-aromatic carbocyclic ring or ring system, which may be saturated or partially unsaturated;
and
Ar is a 6-16 membered aromatic ring or ring system having at least one carbocyclic aromatic ring optionally fused one or more aromatic or non-aromatic rings.
provided that the compound is not
3-(butylamino)-8-chloro-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one;
3-(butylamino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one;
3-(butylamino)-8-(2,6-difluorophenyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one;
or
3-(butylamino)-5-(4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one.

22 more elements

A compound that is:

trans-3-((2,2-Difluorobutyl)amino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
cis-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
cis-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-((4-hydroxycyclohexyl)methyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
tert-Butyl (4-((3-(butylamino)-8-(morpholinomethyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)methyl)cyclohexyl)carbamate
tert-Butyl (4-((3-(butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)methyl)cyclohexyl)carbamate
5-((4-Aminocyclohexyl)methyl)-3-(butylamino)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
5-((4-Aminocyclohexyl)methyl)-3-(butylamino)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-Amino-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((3,3-Difluorocyclobutyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((3-Fluorocyclobutyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-(6-hydroxyspiro[3.3]heptan-2-yl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
cis-3-(Butylamino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(((1-Ethylcyclobutyl)methyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(((1-Ethylcyclobutyl)methyl)amino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(((1-Ethylcyclobutyl)methyl)amino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclobutylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(((1-Ethylcyclopropyl)methyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(((1-Ethylcyclopropyl)methyl)amino)-5-((4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2,2-Difluorobutyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)-3-((4,4,4-trifluorobutyl)amino)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2-Cyclopropylethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2-Cyclopropylethyl)amino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2-Cyclopropylethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-isopropylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-isopropylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2-Cyclopropylethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-isopropylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-34(Cyclobutylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-isopropylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclobutylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(oxetan-3-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-(oxetan-3-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-(3-(butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclohexane-1-carbonitrile
trans-5-(4-hydroxycyclohexyl)-3-(isopentylamino)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(piperazin-1-ylmethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-(((S)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-(((R)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-((1,1-dioxidothiomorpholino)methyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-Ethyl 1-((3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-6-oxo-5,6-dihydropyrimido[4,5-c]isoquinolin-8-yl)methyl)piperidine-4-carboxylate
trans-4-((3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-6-oxo-5,6-dihydropyrimido[4,5-c]isoquinolin-8-yl)methyl)-1,4-diazabicyclo[3.2.2]nonane 1-oxide
trans-3-((cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((1-oxidothiomorpholino)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(thiomorpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(piperazin-1-ylmethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-(((R)-3,4-dimethylpiperazin-1-yl)methyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-5-(4-Hydroxycyclohexyl)-3-(isobutylamino)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-((1S,4S)-4-hydroxycycloheptyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-((1,4-Diazabicyclo[3.2.2]nonan-4-yl)methyl)-3-((cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-4-(3-((Cyclopropylmethyl)amino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclohexyl carbamate
trans-8-((4-(tert-butyl)piperazin-1-yl)methyl)-3-((cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-morpholinopyrimido[4,5-c]isoquinolin-6(5H)-one
cis-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
tert-Butyl (4-((3-(Butylamino)-8-(4-methylpiperazin-1-yl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)methyl)cyclohexyl)carbamate
5-((4-Aminocyclohexyl)methyl)-3-(butylamino)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((3,3-Difluorocyclobutyl)amino)-5-(4-hydroxycyclohexyl)-8-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((3,3-difluorocyclobutypamino)-5-(4-hydroxycyclohexyl)-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(4-isopropylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-8-(4-isopropylpiperazin-1-yl)-5-(4-oxocyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimido[4, 5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-(4-oxocyclohexyl)-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-8-((S)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-((1r,4S)-4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((3-Fluorocyclobutyl)amino)-5-(4-hydroxycyclohexyl)-8-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((3-Fluorocyclobutyl)amino)-5-(4-hydroxycyclohexyl)-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-8-((R)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(4-(oxetan-3-yl)piperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-((2S,5R)-2,4,5-trimethylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-(4-oxocyclohexyl)-8-((2S,5R)-2,4,5-trimethylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-8-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-3-(butylamino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
8-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-3-(butylamino)-5-(4-oxocyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxycyclohexyl)-8-(piperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-(4-oxocyclohexyl)-8-(piperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((3,3-Difluorocyclobutyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxy-4-methylcyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-(6-hydroxyspiro[3.3]heptan-2-yl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
cis-3-(Butylamino)-5-(4-hydroxy-4-methylcyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-8-((R)-3,4-dimethylpiperazin-1-yl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(((1-Ethylcyclobutyl)methyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclobutylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2,2-Difluorobutyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(((1-Ethylcyclopropyl)methyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-5-(4-Hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)-3-((4,4,4-trifluorobutyl)amino)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2-Cyclopropylethyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2-Cyclopropylethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-(4-methylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-3-((cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-((S)-hexahydropyrrolopyrazin-2(1H)-yl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-((R)-hexahydropyrrolopyrazin-2(1H)-yl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-(4-(2,2-difluoroethyl)piperazin-1-yl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-((R)-3,4-dimethylpiperazin-1-yl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((2S,5R)-2,4,5-trimethylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(piperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-isopropylpiperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-(4-cyclopropylpiperazin-1-yl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(4-(oxetan-3-yl)piperazin-1-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-(6-hydroxyspiro[3.3]heptan-2-yl)pyrimido[4, 5-c]isoquinolin-6(5H)-one
trans-3-(Butylamino)-5-(4-hydroxy-4-methylcyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
cis-3-(Butylamino)-5-(4-hydroxy-4-methylcyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(((1-Ethylcyclobutyl)methyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclobutylmethyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(((1-Ethyl cyclopropyl)methyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2,2-difluorobutyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2-Cyclopropylethyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2-Cyclopropylethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclobutylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-((1r,5r)-5-((tert-butyldimethylsilyl)oxy)cyclooctyl)-8-chloropyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-((1r,5r)-5-((tert-butyldimethylsilyl)oxy)cyclooctyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(Butylamino)-5-((1r,5r)-5-hydroxycyclooctyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-5-(4-hydroxycyclohexyl)-3-(isobutylamino)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-4-(3-(Butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclohexane-1-carboxamide
trans-4-(3-(Butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclohexane-1-carboxylic acid
trans-4-(3-((Cyclopropylmethyl)amino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclohexane-1-carboxamide
trans-4-(3-((Cyclopropylmethyl)amino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclohexane-1-carboxylic acid
trans-3-(cyclobutylamino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-4-(3-(Butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5 (6H)-yl)-N-methyl cyclohexane-1-carboxamide
trans-4-(3-(Butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)-N-(2,2,2-trifluoroethyl)cyclohexane-1-carboxamide
trans-4-(3-(Butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)-N-(oxetan-3-yl)cyclohexane-1-carboxamide
trans-4-(3-(Butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)-N-(cyclopropylmethyl)cyclohexane-1-carboxamide
trans-4-(3-(Butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)-N,N-dimethylcyclohexane-1-carboxamide
8-((4-(1H-tetrazol-5-yl)piperidin-1-yl)methyl)-3-((cyclopropylmethyl)amino)-5-((1s,4s)-4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-((cyclopropylmethyl)amino)-8-((4-ethoxypiperidin-1-yl)methyl)-5-((1s,4s)-4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-((cyclopropylmethyl)amino)-8-((4-hydroxy-4-methylpiperidin-1-yl)methyl)-5-((1s,4s)-4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-tert-Butyl (4-(3-((cyclopropylmethyl)amino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclohexyl)carbamate
trans-5-(4-aminocyclohexyl)-3-((cyclopropylmethyl)amino)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-((2-Oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-3-((cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((1-methylpiperidin-4-yl)amino)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-2-Cyano-N-(4-(3-((cyclopropylmethyl)amino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclohexyl)acetamide
trans-5-(4-Hydroxycyclohexyl)-3-(isopropylamino)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Cyclopropylamino)-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-((2-Oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-3-((2,2-difluorobutyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-((4-(tert-Butyl)piperazin-1-yl)methyl)-3-((2,2-difluorobutyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-((4-(tert-Butyl)piperazin-1-yl)methyl)-3-((3,3-difluorocyclobutyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-1-((3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-6-oxo-5,6-dihydropyrimido[4,5-c]isoquinolin-8-yl)methyl)piperidine-4-carboxylic acid
trans-tert-Butyl 1-((3-((cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-6-oxo-5,6-dihydropyrimido[4,5-c]isoquinolin-8-yl)methyl)piperidine-4-carboxylate
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(piperidin-1-ylmethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-1-((3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-6-oxo-5,6-dihydropyrimido[4,5-c]isoquinolin-8-yl)methyl)piperidine-4-carboxamide
trans-1-((3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-6-oxo-5,6-dihydropyrimido[4,5-c]isoquinolin-8-yl)methyl)piperidine-4-carbonitrile
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(piperidin-4-ylmethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-(3-morpholinopropoxy)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-((2-Oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-3-(cyclobutylamino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-((2-Oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-3-((3,3-difluorocyclobutyl)amino)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((3,3-Difluorocyclobutyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-5-(4-hydroxycyclohexyl)-8-((4-methylpiperazin-1-yl)methyl)-3-(((S)-pentan-2-yl)amino)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-5-(4-hydroxycyclohexyl)-3-(((S)-pentan-2-yl)amino)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-8-((4-(tert-Butyl)piperazin-1-yl)methyl)-5-(4-hydroxycyclohexyl)-34(S)-pentan-2-yl)amino)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(pyrimidin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(pyridin-4-yl)piperidin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((1-(pyridin-4-yl)piperidin-4-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-5-(4-Hydroxycyclohexyl)-3-(((S)-pentan-2-yl)amino)-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclobutylmethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2,2-Difluorobutyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((2-Cyclopropylethyl)amino)-5-(4-hydroxycyclohexyl)-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-5-(4-Hydroxycyclohexyl)-3-(isopentylamino)-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-5-(4-hydroxy-4-methylcyclohexyl)-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Cyclobutylamino)-5-(4-hydroxycyclohexyl)-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Cyclobutylamino)-5-(4-hydroxycyclohexyl)-8-((4-(pyrimidin-4-yl)piperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-(Cyclobutylamino)-5-(4-hydroxycyclohexyl)-8-((4-(pyridin-4-yl)piperidin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
trans-3-((Cyclopropylmethyl)amino)-8-((4-hydroxy-4-(pyridin-4-yl)piperidin-1-yl)methyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(butylamino)-5-((1S,4S)-4-hydroxycycloheptyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-((cyclopropylmethyl)amino)-5-((1S,4S)-4-hydroxycycloheptyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
tert-butyl ((1S,3S)-3-(3-(butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclopentyl)carbamate
5-((1S,3S)-3-aminocyclopentyl)-3-(butylamino)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
N-((1S,3S)-3-(3-(butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclopentyl)acetamide
3-(butylamino)-8-chloro-5-((1R,3R)-3-hydroxycyclopentyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(butylamino)-5-((1R,3R)-3-hydroxycyclopentyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
3-(butylamino)-5-((1S,3S)-3-(dimethylamino)cyclopentyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
2-(((1S,3S)-3-(3-(butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclopentyl)amino)acetamide
3-(butylamino)-5-((1S,3S)-3-((2-hydroxyethyl)amino)cyclopentyl)-8-((4-methylpiperazin-1-yl)methyl)pyrimido[4,5-c]isoquinolin-6(5H)-one
1-((1S,3S)-3-(3-(butylamino)-8-((4-methylpiperazin-1-yl)methyl)-6-oxopyrimido[4,5-c]isoquinolin-5(6H)-yl)cyclopentyl)guanidine
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof.

186 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/645,775Filed 10 Jul 2017
Priority: 8 Jul 2016
Published: 11 Jan 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61P 35/00
Antineoplastic agents
A61P 35/02
Antineoplastic agents: specific for leukemia

Family

Application62/360,297Us provisional application · filed 8 Jul 2016
US 10,130,623 B2Related patent
US 2018/0008589 A1This patent

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

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Abstract

A compound having the structure formula (I):

or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
X is hydrogen, Cak(C0-C6alkyl), Hca(C0-C6alkyl), Ar(C0-C6alkyl), Het(C0-C6alkyl), halogen or Hca(C1-C6alkyl)-O—, wherein Ar, Het, Cak, Hca and the alkyl group is optionally substituted by one to four —RX1 groups, wherein
each —RX1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2, —CH2—OP(O)(OR), Ar(C0-C6alkyl), Het(C0-C6alkyl), Cak(C0-C6alkyl) or Hca(C0-C6alkyl),
or two —RX1 groups taken together, when attached to adjacent atoms, form a Cak, Hca or Het, wherein the Cak Hca and the Het comprise a 3-8 membered ring optionally substituted with one or two —RX2 groups,
or two —RX1 groups taken together, when attached to the same carbon atom, form a Hca, wherein the Hca comprises a 3-8 membered ring optionally substituted with one or two —RX2 groups,
or two —RX1 groups taken together, when attached to non-adjacent atoms, and combined with X, form a bridged Hca optionally substituted with one or two —RX2 groups,
wherein each —RX2is independently halogen, cyano, nitro, oxo, —OR, —SR, —NR2, —C(O)OR, —C(O)NR2, —C(O)R, —S(O)R, —S(O)2R, —S(O)OR, —S(O)2OR, —S(O)NR2, —S(O)2NR2, —OC(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)R, —N(R)S(O)2R, C1-C6alkyl, or C1-C6haloalkyl;
Y is Cak(C0-C8alkyl) or Hca(C0-C6alkyl), each optionally substituted by one or two —RY1 groups;
wherein each —RY1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, N(R)C(NR2)NR2, —C(O)R, —C(O)OR, C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
Z is C1-C6alkyl or Cak(C0-C6alkyl), each optionally substituted by one to three —RZ1 groups;
wherein each —RZ1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
and
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, Hca(C0-C6alkyl), Cak(C0-C8alkyl), C1-C6alkyl-CN, —CH2C(O)NH2, wherein
Hca is a 3-15 membered ring or ring system comprising at least one ring, 1-4 O, S, or N atoms, provided no O or S is adjacent to another O or S;
Het is a 5-15 membered aromatic ring or ring system comprising at least one ring and 1-4 O, S, or N atoms, provided no O or S is adjacent to another O or S;
Cak is a 3-8 membered non-aromatic carbocyclic ring or ring system, which may be saturated or partially unsaturated;
and
Ar is a 6-16 membered aromatic ring or ring system having at least one carbocyclic aromatic ring optionally fused one or more aromatic or non-aromatic rings.
provided that the compound is not
3-(butylamino)-8-chloro-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one;
3-(butylamino)-5-(4-hydroxycyclohexyl)-8-(morpholinomethyl)pyrimido[4,5-c]isoquinolin-6(5H)-one;
3-(butylamino)-8-(2,6-difluorophenyl)-5-(4-hydroxycyclohexyl)pyrimido[4,5-c]isoquinolin-6(5H)-one;
or
3-(butylamino)-5-(4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrimido[4,5-c]isoquinolin-6(5H)-one.

22 more elements

Facts

Application

15/645,775Filed 10 Jul 2017

Priority

8 Jul 2016

Published

11 Jan 2018

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61P 35/00
Antineoplastic agents
A61P 35/02
Antineoplastic agents: specific for leukemia