US 8,026,260 B2Granted

Histone deacetylase inhibitors with aryl-pyrazolyl-motifs

AssigneeMerck Sharp & Dohme Corp.

InventorsJoshua Close, Richard W. Heidebrecht, Jr., Solomon Kattar, Thomas A. Miller, David Sloman, Matthew G Stanton, Paul Tempest, David J. Witter

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Abstract

The present invention relates to a novel class of histone deacetylase inhibitors with aryl-pyrazolyl motifs. The compounds of this invention can be used to treat cancer. The compounds of this invention are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The present invention further provides pharmaceutical compositions comprising the compounds of this invention and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of the compounds of this invention in vivo.

Claims15

Dependent claims

A compound represented by the following structural Formula I:

wherein:
Ring B is heteroaryl or aryl;
R1 is selected from hydrogen, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 hydroxyalkyl, C1-C7 alkenyl, C1-C7 alkynyl, or L2-R2, wherein R2 is substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted C3-C8 cycloalkyl, L2 is selected from a bond or C1-C4 alkylene;
R3 is OH, SH or NH2;
R4 is selected from hydrogen, OH, NH2, nitro, CN, amide, carboxyl, C1-C7 alkoxy, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 haloalkyloxy, C1-C7 hydroxyalkyl, C1-C7 alkenyl, C1-C7 alkyl-C(═O)O—, C1-C7 alkyl-O—C(═O)—, C1-C7 alkyl-C(═O)—, C1-C7 alkynyl, halo group, hydroxyalkoxy, —NHSO2, —SO2NH, C1-C7 alkyl-NHSO2—, C1-C7 alkyl-SO2NH—, C1-C7 alkylsulfonyl, C1-C7 alkylamino, di(C1-C7)alkylamino, C1-C7 acylamino, amino-C1-C7 alkyl, C1-C7 alkylthio, perfluoro-C1-C7alkyl, perfluoro-C1-C7alkyloxy;
R5 is selected from hydrogen, C1-C10 alkyl, cycloalkyl, aryl or heterocyclyl, each of which is optionally substituted;
R13 is selected from hydrogen or halo;
L1 is a bond or (CH2)r, ethenyl or cyclopropyl, wherein r is 1 or 2;
X1 is selected from the group consisting of a covalent bond, L3-M1-L2-M1-L3, and L2-M2-L2 wherein:
L2 or L3, at each occurrence, is independently selected from the group consisting of a chemical bond, C1-C4-alkyl, C1-C4-alkyl-(NH)—C1-C4-alkyl, C1-C4-alkyl-(S)—C1-C4-alkyl, and C1-C4-alkyl-(O)—C1-C4-alkyl, each of the alkyl is optionally substituted, provided that L2 is not a chemical bond when X1 is L3-M1-L2-M1-L3;
M1, at each occurrence, is independently selected from the group consisting of —O—, —N(R11)—, —S—, —S(O)—, S(O)2—, —S(O)2N(R11)—, —N(R11)—S(O)2—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)—N(R11), —N(R11)—C(O)—, —C(S)—N(R11), —N(R11)—C(S)—, —N(R11)—C(O)—O—, —O—C(O)—N(R11)—, —N(R11)—C(O)—N(R11)—, —N(R11)—C(S)—O—, —O—C(S)—N(R11)—, —N(R11)—C(S)—N(R11)—, R11 is selected from the group consisting of hydrogen, C1-C6-alkyl, aryl, aralkyl, C(O)R12 or C0-C6 alkyl-heterocyclyl, wherein the alkyl moieties are optionally substituted with —OH, —NH2, —N(H)CH3, —N(CH3)2, or halo, wherein R12 is an optionally substituted C1-C4alkyl, perfluoro-C1-C4-alkyl, phenyl or heterocyclic;
M2 is selected from the group consisting of M1 or heterocyclic, either of which rings optionally is substituted;
Y is N or CR13;
t is 1, 2, 3 or 4;
and
Provided that when R3 is NH2, Y is CR13, R13 is H, L1 is CH2, Ring B is imidazolyl, X1 is a bond, R5 is hydrogen, t is 1, R4 is methyl, then R1 is not hydrogen;
or a stereoisomer or pharmaceutically acceptable salt thereof.

14 more elements

A compound selected from:

Pyridin-3-ylmethyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
4-(aminomethyl)-N-(4-amino-1-phenyl-1H-pyrazol-3-yl)benzamide;
4-(acetylamino)-N-(4-amino-1-phenyl-1H-pyrazol-3-yl)benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)nicotinamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-chlorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(4-methylphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(4-chlorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-methoxyphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl {4-[({4-amino-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}amino)carbonyl]benzyl}carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-fluorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(4-fluorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(2-fluorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-methylphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
4-(acetylamino)-N-[4-amino-1-(3-chlorophenyl)-1H-pyrazol-3-yl]benzamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(2-naphthyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
4-(acetylamino)-N-[4-amino-1-(3-methylphenyl)-1H-pyrazol-3-yl]benzamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-thienyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
4-(acetylamino)-N-[4-amino-1-(3-thienyl)-1H-pyrazol-3-yl]benzamide;
4-(acetylamino)-N-[4-amino-1-(2-naphthyl)-1H-pyrazol-3-yl]benzamide;
3-(acetylamino)-N-(4-amino-1-phenyl-1H-pyrazol-3-yl)benzamide;
N-[4-amino-1-(3-chlorophenyl)-1H-pyrazol-3-yl]-4-{[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(3,5-dichlorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-2-[methyl(2-phenylethyl)amino]-1,3-thiazole-5-carboxamide;
methyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)(1,3-benzoxazol-2-yl)acetate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-2-{[1-(4-methoxyphenyl)ethyl]amino}-1,3-thiazole-5-carboxamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{[5-(3-cyanophenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{fluoro[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(5-benzyl-1,3,4-oxadiazol-2-yl)methyl]benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(3,5-dimethylphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-1-benzothiophene-2-carboxamide;
2-naphthyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
benzyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
phenyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
2-naphthyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
isobutyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
(1,1-dioxido-1-benzothien-2-yl)methyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
2-chlorobenzyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
1-naphthyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{[methyl(pyridin-4-yl)amino]methyl}benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(pyridin-4-ylamino)methyl]benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-({[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]amino}methyl)benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-({methyl[3-(methylamino)propyl]amino}methyl)benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(isobutylamino)methyl]benzamide;
4-(acetylamino)-N-(4-amino-5-fluoro-1-phenyl-1H-pyrazol-3-yl)benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{difluoro[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
or
tert-butyl 4-(5-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}pyridin-2-yl)piperazine-1-carboxylate;
or a stereoisomer or a pharmaceutically acceptable salt thereof.

50 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/084,268Filed 30 Oct 2006 · us provisional application
Priority: 3 Nov 2005
Published: US 2009/0291965 A126 Nov 2009
Granted: 27 Sep 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 231/40
Nitrogen atoms: acylated on said nitrogen atom