US 2006/0189577 A1Published application

Tyrosine kinase inhibitors

AssigneeMerck & Co., Inc.

InventorsAnnette Kim, Xufang Zhang

Life of this patent

Estimating the term…

Abstract

The present invention relates to compounds that are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases. The compounds of the instant invention possess a core structure that comprises a substituted pyrrole moiety. The present invention is also related to the pharmaceutically acceptable salts, hydrates and stereoisomers of these compounds.

Claims30

Dependent claims

A compound of Formula I

wherein
R1 is selected from
1) hydrogen,
2) halogen,
3) substituted or unsubstituted C1-C10 alkyl,
4) substituted or unsubstituted C2-C10 alkenyl,
5) substituted or unsubstituted C2-C10 alkynyl,
6) substituted or unsubsituted aryl,
7) substituted or unsubstituted C3-C10 cycloalkyl,
8) substituted or unsubstituted heterocyclyl,
9) —CRa2)nOR4, and
10) —(CRa2)tC(O)OR4;
said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more of R7;
R2 is selected from
1) hydrogen,
2) substituted or unsubstituted aralkyl,
3) substituted or unsubstituted C1-C10 alkyl,
4) substituted or unsubstituted heterocyclyl,
5) substituted or unsubstituted aryl, and
6) substituted or unsubstituted C3-C10 cycloalkyl;
R3 is selected from
1) hydrogen,
2) halogen,
3) —C(O)R4,
4) substituted or unsubstituted C1-C10 alkyl,
5) substituted or unsubstituted aryl,
6) substituted or unsubstituted heterocyclyl,
7) substituted or unsubstituted C3-C10 cycloalkyl,
8) substituted or unsubstituted C2-C10 alkenyl, and
9) substituted or unsubstituted C2-C10 alkynyl;
R4 is independently selected from
1) hydrogen,
2) substituted or unsubstituted C1-C10 alkyl,
3) substituted or unsubstituted aryl,
4) substituted or unsubstituted heterocyclyl,
5) substituted or unsubstituted C3-C10 cycloalkyl,
6) substituted or unsubstituted C2-C10 alkenyl, and
7) substituted or unsubstituted C2-C10 alkynyl;
R6 is independently selected from
1) substituted or unsubstituted aryl,
2) substituted or unsubstituted heterocyclyl,
3) substituted or unsubstituted cycloalkyl, and
4) halogen;
R7 is independently selected from
1) hydrogen,
2) halogen,
3) substituted or unsubstituted C1-C10 alkyl,
4) substituted or unsubstituted C2-C10 alkenyl,
5) substituted or unsubstituted C2-C10 alkynyl,
6) substituted or unsubstituted C3-C10 cycloalkyl,
7) substituted or unsubstituted aryl,
8) substituted or unsubstituted heterocyclyl,
9) —NO2,
10) —NR4(CRa2)nC(O)R4,
11) —(CRa2)nNR42,
12) —(CRa2)nNR4(CRa2)nR6,
13) —CN,
14) —(CRa2)nC(O)R4,
15) —(CRa2)nC(O)(CRa2)nOR4,
16) —(CRa2)nOR4,
17) —(CRa2)nR6,
18) —(CRa2)nC(O)OR4, and
19) —(CRa2)nSi(R4)3;
Ra is independently selected from
1) hydrogen,
2) substituted or unsubstituted C1-C10 alkyl,
3) substituted or unsubstituted C2-C10 alkenyl,
4) substituted or unsubstitute C2-C10 alkynyl,
5) —OR4,
6) —C(O)OR4,
7) —NR42,
8) substituted or unsubstituted aryl,
9) substituted or unsubstituted heterocyclyl, and
10) substituted or unsubstituted C3-C10 cycloalkyl;
n is independently 0 to 6;
t is 1 to 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.

74 more elements

A compound of Formula II

wherein
R1 is selected from
1) hydrogen,
2) halogen,
3) substituted or unsubstituted C1-C6 alkyl,
4) substituted or unsubstituted C2-C10 alkynyl,
5) substituted or unsubstituted aryl,
6) substituted or unsubstituted C3-C10 cycloalkyl, and
7) substituted or unsubstituted heterocyclyl;
said alkyl, alkynyl, aryl, cycloalkyl and heterocyclyl is optionally substituted with one or more of R7;
R2 is selected from
1) substituted or unsubstituted aralkyl, and
2) substituted or unsubstituted C1-C6 alkyl;
R4 is independently selected from
1) hydrogen,
2) substituted or unsubstituted C1-C10 alkyl,
3) substituted or unsubstituted aryl,
4) substituted or unsubstituted heterocyclyl,
5) substituted or unsubstituted C3-C10 cycloalkyl,
6) substituted or unsubstituted C2-C10 alkenyl, and
7) substituted or unsubstituted C2-C10 alkynyl;
R6 is independently selected from
1) substituted or unsubsituted aryl,
2) substituted or unsubstituted heterocyclyl,
3) substituted or unsubstituted C3-C10 cycloalkyl, and
4) halogen;
R7 is independently selected from
1) hydrogen,
2) halogen,
3) substituted or unsubstituted C1-C10 alkyl,
4) substituted or unsubstituted C2-C10 alkenyl,
5) substituted or unsubstituted C2-C10 alkynyl,
6) substituted or unsubstituted C3-C10 cycloalkyl,
7) substituted or unsubstituted aryl,
8) substituted or unsubstituted heterocyclyl,
9) —NO2,
10) —NR4(CRa2)nC(O)R4,
11) —(CRa2)nNR42,
12) —(CRa2)nNR4(CRa2)nR6,
13) —CN,
14) —(CRa2)nC(O)R4,
15) —(CRa2)nC(O)(CRa2)nOR4,
16) —(CRa2)nOR4,
17) —(CRa2)nR6,
18) —(CRa2)nC(O)OR4, and
19) —(CRa2)nSi(R4)3;
Ra is independently selected from
1) hydrogen,
2) substituted or unsubstituted C1-C10 alkyl,
3) substituted or unsubstituted C1-C10 alkenyl,
4) substituted or unsubstitute C1-C10 alkynyl,
5) —OR4,
6) —C(O)OR4,
7) —NR42,
8) substituted or unsubstituted aryl,
9) substituted or unsubstituted heterocyclyl, and
10) substituted or unsubstituted C3-C10 cycloalkyl;
n is independently 0 to 6;
t is 1 to 4;
or a pharmaceutically acceptable salt or stereisomer thereof.

57 more elements

A compound selected from:

benzyl 4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2,5-diiodo-1H-pyrrole-3-carboxylate;
methyl 5-(4-fluorophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-thien-2-yl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-[3-(trimethylsilyl)prop-1-ynyl]-1H-pyrrole-3-carboxylate;
4′-benzyl 1-tert-butyl 3′-ethyl-5′-formyl-1H,1′H-2,2′-bipyrrole-1,4′-dicarboxylate;
benzyl 5-(3,5-dimethylisoxazol4-yl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
benzyl 5-(1-benzofuran-2-yl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-(3-nitrophenyl)-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-(5-methyl-2-furyl)-1H-pyrrole-3-carboxylate;
benzyl 5-[3-(acetylamino)phenyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-pyridin4-yl-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-phenyl-1H-pyrrole-3-carboxylate;
benzyl 5-(3-cyanophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-(3-methoxyphenyl)-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-(5-formyl-2-furyl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(phenylethynyl)-1H-pyrrole-3-carboxylate;
methyl 5-{3-[benzyl(methyl)amino]prop-1-ynyl}4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
benzyl 5-(2-cyanophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
benzyl 5-(4-cyanophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-(4-nitrophenyl)-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate;
benzyl 4-ethyl-2-formyl-5-(3-methylphenyl)-1H-pyrrole-3-carboxylate;
benzyl 5-(2-chlorophenyl)4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
benzyl 5-(3-chlorophenyl)4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-[1-(3-hydroxypropyl)vinyl]-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(5-hydroxypent-1-ynyl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-[(1-hydroxycyclohexyl)ethynyl]-1H-pyrrole-3-carboxylate;
methyl 5-[3-(dimethylamino)prop-1-ynyl]4ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 5-(3,3dimethylbut-1-ynyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(pyridin-2-ylethynyl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(6-methoxypyridin-2-yl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(3-methoxyprop-1-ynyl)-1H-pyrrole-3-carboxylate;
methyl 5-[(2-bromophenyl)ethynyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 5-[3-(1H-1,2,3-benzotriazol-1-yl)prop-1-ynyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-5-(2-ethylbutyl)-2-formyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(4-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(6-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate;
methyl 5-(4-tert-butylphenyl)4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 5-(2,4-difluorophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-[3-(methoxycarbonyl)phenyl]-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-[4-(methoxycarbonyl)phenyl]-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-[(1-hydroxycyclopentyl)ethynyl]-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(3-hydroxy-3-methylbut-1-ynyl)-1H-pyrrole-3-carboxylate
methyl 4-ethyl-2-formyl-5-(1-hexylvinyl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-1,3-thiazol-2-yl)-1H-pyrrole-3-carboxylate;
methyl 5-[1-(3-chloropropyl)vinyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 5-(5-chloropent-1-ynyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(3-hydroxy-3-phenylbut-1-ynyl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-isopentyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(3-methylthien-2-yl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-isobutyl-1H-pyrrole-3-carboxylate;
methyl 5-cyclohexyl-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 5-butyl-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 5-cyclopentyl-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 5-(cyclohexylmethyl)4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 5-sec-butyl-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(3-methoxy-2-methyl-3-oxopropyl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-phenyl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-pyridin-4-yl-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(4-nitrophenyl)-1H-pyrrole-3-carboxylate;
methyl 4-ethyl-2-formyl-5-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate;
or a pharmaceutically acceptable salt or stereoisomer thereof.

65 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/564,347Filed 20 Jul 2004
Priority: US 6048963024 Jul 2003
Published: 24 Aug 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/40
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with one nitrogen as the only ring hetero atom,…
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…

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Abstract

A compound of Formula I

wherein
R1 is selected from
1) hydrogen,
2) halogen,
3) substituted or unsubstituted C1-C10 alkyl,
4) substituted or unsubstituted C2-C10 alkenyl,
5) substituted or unsubstituted C2-C10 alkynyl,
6) substituted or unsubsituted aryl,
7) substituted or unsubstituted C3-C10 cycloalkyl,
8) substituted or unsubstituted heterocyclyl,
9) —CRa2)nOR4, and
10) —(CRa2)tC(O)OR4;
said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more of R7;
R2 is selected from
1) hydrogen,
2) substituted or unsubstituted aralkyl,
3) substituted or unsubstituted C1-C10 alkyl,
4) substituted or unsubstituted heterocyclyl,
5) substituted or unsubstituted aryl, and
6) substituted or unsubstituted C3-C10 cycloalkyl;
R3 is selected from
1) hydrogen,
2) halogen,
3) —C(O)R4,
4) substituted or unsubstituted C1-C10 alkyl,
5) substituted or unsubstituted aryl,
6) substituted or unsubstituted heterocyclyl,
7) substituted or unsubstituted C3-C10 cycloalkyl,
8) substituted or unsubstituted C2-C10 alkenyl, and
9) substituted or unsubstituted C2-C10 alkynyl;
R4 is independently selected from
1) hydrogen,
2) substituted or unsubstituted C1-C10 alkyl,
3) substituted or unsubstituted aryl,
4) substituted or unsubstituted heterocyclyl,
5) substituted or unsubstituted C3-C10 cycloalkyl,
6) substituted or unsubstituted C2-C10 alkenyl, and
7) substituted or unsubstituted C2-C10 alkynyl;
R6 is independently selected from
1) substituted or unsubstituted aryl,
2) substituted or unsubstituted heterocyclyl,
3) substituted or unsubstituted cycloalkyl, and
4) halogen;
R7 is independently selected from
1) hydrogen,
2) halogen,
3) substituted or unsubstituted C1-C10 alkyl,
4) substituted or unsubstituted C2-C10 alkenyl,
5) substituted or unsubstituted C2-C10 alkynyl,
6) substituted or unsubstituted C3-C10 cycloalkyl,
7) substituted or unsubstituted aryl,
8) substituted or unsubstituted heterocyclyl,
9) —NO2,
10) —NR4(CRa2)nC(O)R4,
11) —(CRa2)nNR42,
12) —(CRa2)nNR4(CRa2)nR6,
13) —CN,
14) —(CRa2)nC(O)R4,
15) —(CRa2)nC(O)(CRa2)nOR4,
16) —(CRa2)nOR4,
17) —(CRa2)nR6,
18) —(CRa2)nC(O)OR4, and
19) —(CRa2)nSi(R4)3;
Ra is independently selected from
1) hydrogen,
2) substituted or unsubstituted C1-C10 alkyl,
3) substituted or unsubstituted C2-C10 alkenyl,
4) substituted or unsubstitute C2-C10 alkynyl,
5) —OR4,
6) —C(O)OR4,
7) —NR42,
8) substituted or unsubstituted aryl,
9) substituted or unsubstituted heterocyclyl, and
10) substituted or unsubstituted C3-C10 cycloalkyl;
n is independently 0 to 6;
t is 1 to 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.

74 more elements

Facts

Application

10/564,347Filed 20 Jul 2004

Priority

US 6048963024 Jul 2003

Published

24 Aug 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/40
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with one nitrogen as the only ring hetero atom,…
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…