US 7,678,913 B2Granted

Ureas as factor Xa inhibitors

AssigneePortola Pharmaceuticals, Inc.

InventorsYonghong Song, Bing-Yan Zhu, Shumei Wang, Chhaya Bhakta, Robert M. Scarborough

Life of this patent

Estimating the term…

Abstract

The present invention is directed to compounds represented by Formula I and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof which are inhibitors of Factor Xa. The present invention is also directed to and intermediates used in making such compounds, pharmaceutical compositions containing such compounds, methods to prevent or treat a number of conditions characterized by undesired thrombosis and methods of inhibiting the coagulation of a blood sample.

Claims34

Dependent claims

A compound having the formula:

wherein:
R1 is hydrogen;
R2 is a member selected from the group consisting of:
aryl, and heteroaryl, optionally substituted with from 1 to 3 R2a substituents;
R3 is a member selected from the group consisting of:
hydrogen and —C0-6alky-aryl;
each R4 and R5 is a member independently selected from the group consisting of:
hydrogen,—C1-6alkyl,—C2-6alkenyl, —C2-6alkynyl,—C0-6alkyl-heteroaryl, —C0-6alkyl-heterocyclyl, —C0-6alkyl-CO—OR4a, —C0-6alkyl-C(O)—N(R4aR4b),—C0-6alkyl-C(O)R4a, and —C0-6alkyl-aryl;
or R4 and R5 can be taken together with the carbon atom to which they are attached to form a 3 to 8 membered cycloalkyl group;
and wherein 1 to 3 carbon or nitrogen atoms of aryl, heteroaryl and heterocyclyl are substituted with 1 to 3 R4d substituents;
D is a member selected from the group consisting of:
aryl, and heteromonocyclyl;
optionally substituted with 1 to 3 R9 substituents, wherein heterocyclyl comprises from 5 to 10 ring atoms, 1-4 of which are selected from the group consisting of N, O and S;
Q is selected from the group consisting of:
a direct bond, —C(R10aR10b)—, —C(O)—, —C(S)—, —C(═NR10a)—, —O—, —S—, —N(R10a)—, —N(R10a)CH2—, —CH2N(R10a)—, —C(O)N(R10a)—, —N(R10a)C(O)—, —SO—, —SO2N(R10a)—, and —N(R10a)—SO2—;
A is selected from the group consisting of:
—NR11cR11d, —C(═NR11c)NR11aR11b, —C(═NR11eR11f)NR11aR11b, —N(R11d)C(═NR11c)NR11aR11b, —N(R11d)C(═NR11c)R11a, —N(R11c)NR11aR11b, —N(R11c)OR11d, C1-6alkyl, C2-6alkenyl, pyridyl-oxide, pyridinyl, pyrrolidinyl, homopiperazinyl, piperazinyl and morpholinyl each optionally substituted with 1 to 3 R11g;
each R2a, R4d, R9 and R11g is a member independently selected from the group consisting of:
H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, —C1-4alkoxy, —O—C0-2alkyl-CF3, —C0-2alkyl-CF3, —C0-2alkyl-CN, —C0-2alkyl-NO2, —C0-2alkyl-NR12aR12b, —C0-2alkyl-SO2NR12aR12b, —C0-2alkyl-SO2R12a, —C0-2alkyl-SOR12a, —C0-2alkyl-CF3, —C0-2alkyl-OR12a, —C0-2alkyl-SR12a, —O—CH2—CH2—OR12a, —O—CH2—CO2R12a, —N(R12a)—CH2—CH2—OR12b, —C0-2alkyl-C(O)NR12aR12b, —C0-2alkyl-CO2R12a, —C0-2alkyl-N(R12a)—C(O)R12b, —C0-2alkyl-N(R12c)—C(O)NR12aR12b, —C0-2alkyl-C(═NR12c)NR12aR12b, —C0-2alkyl-C(═NR12a)R12b, —C0-2alkyl-N(R12d)C(═NR12c)NR12aR12b, —C0-2alkyl-N(R12a)—SO2—R12b, ═O, ═S, ═NR12a, 5- or 6-membered aryl, 5- or 6-membered heteroaryl and 5- to 7-membered heterocyclyl, each of which is optionally substituted with a member independently selected from the group consisting of halo, CF3, OCF3, SCF3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CONR12aR12b, ═O, ═S, —OH, —CN and —NO2;
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms, independently selected from the group consisting of N, O and S,
each R3a,R3b,R4a,R4b,R12a,R12b,R12c and R12d are members independently selected from the group consisting of:
H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C0-4alkylaryl, C0-4alkyl-heteroaryl, —C0-6alkyl-COC1-4alkyl, —C0-6alkyl-CO2C1-4alkyl, —C0-6alkyl-SO2—C1-4alkyl, —C0-6alkyl-SO2—N(C1-4alkyl, C1-4alkyl), —C0-6alkyl-N(C1-4alkyl, C1-4alkyl) and —C1-6alkyl-O—C0-6alkyl, wherein 1-3 hydrogen atoms on the aryl or heteroaryl ring may be independently replaced with a member selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C4-alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl, C1-4alkyl), —OH, —CN and NO2;
or can be taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclyl group, comprising 1 to 4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with 1 to 4 R13 substituents selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl, C1-4 alkyyl), ═O, ═S, —OH, —CN and NO2;
each R6, R7, R8, R10a and R10b is a member independently selected from the group consisting of:
hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl and C0-4alkylC3-8cycloalkyl, —C0-6alkyl-aryl, heteraryl and —C0-6alkyl-heteroaryl, or R4 and R6 can be taken together with the atoms to which they are attached to form a 5 to 12 membered heterocyclyl group;
wherein each heterocyclyl is a 5 to 8 membered monocyclic ring or a 8-12 membered bicyclic ring, each comprising from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and wherein 1 to 3 carbon or nitrogen atoms of aryl, heteroaryl and heterocyclyl are substituted with 1 to 3 R4d substituents;
each R11a, R11b, R11c, R11d, R11e and R11f are members independently selected from the group consisting of:
H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C0-4alkylaryl, C0-4alkyl-heteroaryl, —C0-6alkyl-COC1-4alkyl, —C0-6alkyl-CO2C1-4alkyl, —C0-6alkyl-SO2—C1-4alkyl, —C0-6alkyl-SO2—NR12aR12b, —C0-6alkyl-NR12aR12b and —C1-6alkyl-O—C0-6alkyl, wherein 1-3 hydrogen atoms on the aryl or heteroaryl ring may be independently replaced with a member selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl, C1-4alkyl), —OH, —CN and NO2;
or each R11a and R11b can be taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclyl group, comprising 1 to 4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with 1 to 4 R13 substituents selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl, C1-4alkyl), ═O, ═S, —OH, —CN and NO2;
or each R11e and R11f can be taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclyl group, comprising 1 to 4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with 1 to 4 R13 substituents selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl , C1-4alkyl), ═O, ═S, —OH, —CN and NO2;
each subscript n1 and n2 is an integer of 0 to 1;
and
pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

30 more elements

A compound selected from the group consisting of:

N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-isopropyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(1,1-dimethylethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2,2-dimethylpropyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-benzyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-indol-3-ylmethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-imidazol-4-ylmethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(1-methyl-indol-3-ylmethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-pyridin-3-yl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(4-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-thienyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(3-thienyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2,2-diphenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-1-(4-chlorophenylaminocarbonylamino)-1-cyclopropanecarboxamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-thienyl)-2-(4-fluorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-thienyl)-2-(4-ethynylphenylaminocarbonylamino)-acetamide;
N-[4-(dimethylaminoimino)phenyl]-2-(2-thienyl)-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(N-methyl-N-ethylaminoimino)phenyl]-2-(2-thienyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(pyrrolidinylimino)phenyl]-2-(2-thienyl)-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(piperidinylimino)phenyl]-2-(2-thienyl)-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(dimethylaminoimino)phenyl]-2-phenyl-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(N-methyl-N-ethylaminoimino)phenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(methylaminoimino)phenyl]-2-phenyl-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(N-methyl-N-allylaminoimino)phenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-methyl-N-propargylaminoimino)phenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(azetidin-1-ylimino)phenyl]-2-phenyl-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(pyrrolidin-1-ylimino)phenyl]-2-phenyl-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-thienyl)-2-(4-bromophenylaminocarbonylamino)-acetamide;
(2S) N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2R) N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(dimethylaminoimino)-2-fluorophenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-methyl-N-ethylaminoimino)-2-fluorophenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-methyl-N-allylaminoimino)-2-fluorophenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-methyl-N-propargylaminoimino)-2-fluorophenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-(4-methylaminoimino-2-fluorophenyl)-2-phenyl-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(pyrrolidin-1-ylimino)-2-fluorophenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(azetidin-1-ylimino)-2-fluorophenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-fluorophenyl)-2-(4-bromophenylaminocarbonylamino)-acetamide;
N-[4-(pyrrolidin-1-ylimino)phenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(piperidin-1-ylimino)phenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(dimethylaminoimino)phenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(pyrrolidin-1-ylimino)phenyl]-2-(2-fluorophenyl)-2-(4-bromophenylaminocarbonylamino)-acetamide;
N-[4-(piperidin-1-ylimino)phenyl]-2-(2-fluorophenyl)-2-(4-bromophenylaminocarbonylamino)-acetamide;
N-[4-(dimethylaminoimino)phenyl]-2-(2-fluorophenyl)-2-(4-bromophenylaminocarbonylamino)-acetamide;
N-[4-(2,2-dimethylhydrazinoimino)-2-fluorophenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(pyridin-4-yl)phenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-4-yl)phenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-fluorophenyl)-2-(4-bromophenylaminocarbonylamino)-acetamide;
N-(piperidin-4-ylmethyl)-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[(N-acetimidyl-piperidin-4-yl)methyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(2-dimethylaminomethyl-phenyl)phenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(2-dimethylaminomethyl-phenyl)-2-fluorophenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(2-dimethylaminomethyl-phenyl)-2-fluorophenyl]-2-(2-fluorophenyl)-2-(4-bromophenylaminocarbonylamino)-acetamide;
N-[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluorophenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2S) N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-benzyloxy-carbonylmethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2S) N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-carboxymethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
2R) N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-benzyloxycarbonylmethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2R) N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-carboxymethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-dimethylaminocarbonylmethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(piperidin-1-ylcarbonylmethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(morpholin-4-ylcarbonylmethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(pyrrolidin-1-yl-carbonylmethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-[4-ethoxycarbonyl-piperidin-1-yl)carbonylmethyl]-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(homopiperidin-1-ylcarbonylmethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(benzylamino-carbonylmethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(methylamino-carbonylmethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(aminocarbonylmethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-3-(4-chlorophenylaminocarbonylamino)-succinimide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(phenylamino-carbonylmethyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(3-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(benzo-1,3-dioxl-5-yl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-4-yl)phenyl]-2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(dimethylaminoimino)phenyl]-2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(pyrrolidin-1-ylimino)phenyl]-2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-(1-isopropylpiperidin-4-yl)-2-(2-bromophenyl)-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluorophenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(dimethylaminoimino)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(pyrrolidin-1-ylimino)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(2-dimethylaminomethyl-phenyl)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-(1-isopropylpiperidin-4-yl)-2-(2-methylphenyl)-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(4-methyl-homopiperazinyl)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[1-(pyridin-4-yl)piperidin-4-yl]methyl-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(3-oxo-morpholin-4-yl)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-methyl-N-pyridin-4-yl-amino)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(thiazolidin-3-ylcarbonyl)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(oxazolidin-3-ylcarbonyl)phenyl]-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(dimethylaminoimino)phenyl]-2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(pyrrolidin-1-ylimino)phenyl]-2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(4-methyl-homopiperazinyl)phenyl]-2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-(1-isopropylpiperidin-4-yl)-2-(2-chlorophenyl)-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[1-(pyridin-4-yl)piperidin-4-yl]methyl-2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[1-(pyridin-4-yl)piperidin-4-yl]methyl-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-(1-isopropylpiperidin-4-yl)-2-(2-methoxyphenyl)-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(4-methyl-homopiperazinyl)phenyl]-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(dimethylaminoimino)phenyl]-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(pyrrolidin-1-ylimino)phenyl]-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-iodophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-iodophenyl)-2-(4-chlorophenylamino-carbonylamino)-acetamide;
N-[4-(dimethylaminoimino)phenyl]-2-(2-iodophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(pyrrlidin-1-ylimino)phenyl]-2-(2-iodophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-(2-iodophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(4-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-trifluoromethoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-trifluoromethoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-trifluoromethylthiophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-trifluoromethylthiophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(2-phenoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-phenoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(2-methythiophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-propargyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-(but-2-yn-1-yl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-(but-2-yn-1-yl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-allyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
N-[4-(N-oxo-pyridin-2-yl)phenyl]-2-allyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
1-[4-(dimethylaminoimino)phenyl]-3-(4-chlorophenylaminocarbonylamino)-3,4-dihydroquinolin-2-one;
1-[4-(pyrrolidinylimino)phenyl]-3-(4-chlorophenylaminocarbonylamino)-3,4-dihydroquinolin-2-one;
1-[4-(1-methyl-4,5-dihyrdo-1H-imidazol-2-yl)phenyl]-3-(4-chlorophenylaminocarbonylamino)-3,4-dihydroquinolin-2-one;
(2S) N-[4-(2-pyridon-1-yl)phenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2R) N-[4-(2-pyridon-1-yl)phenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2S) N-[4-(2-pyridon-1-yl)phenyl]-2-phenyl-2-(2-chlorothiophen-5-ylaminocarbonylamino)-acetamide;
(2R) N-[4-(2-pyridon-1-yl)-2-fluorophenyl]-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2R) 4-(2-piperidinon-1-yl)piperidin-1-yl-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2R) 4-(3-morpholinon-4-yl)piperidin-1-yl-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2R) 4-(2-pyridon-1-yl)piperidin-1-yl-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(3-morpholinon-4-yl)piperidin-1-yl-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(3-morpholinon-4-yl)piperidin-1-yl-2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(3-morpholinon-4-yl)piperidin-1-yl-2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(3-morpholinon-4-yl)piperidin-1-yl-2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(3-morpholinon-4-yl)piperidin-1-yl-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(2-piperidinon-1-yl)piperidin-1-yl-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(2-piperidinon-1-yl)piperidin-1-yl-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(4-methyl-2-piperazinon-1-yl)piperidin-1-yl-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(homopiperidin-4-yl)piperazin-1-yl-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
4-(1-methylhomopiperidin-4-yl)piperazin-1-yl-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2R) 4-(4-methylhomopiperazin-1-yl)piperidin-1-yl-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
(2R) 4-(1-methylpiperidin-4-yl)piperidin-1-yl-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide;
and (2R) 4-(1-methylpiperidin-4-yl)homopiperazin-1-yl-2-phenyl-2-(4-chlorophenylaminocarbonylamino)-acetamide.

152 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/298,317Filed 7 Dec 2005 · us provisional application
Priority: 7 Dec 2004
Published: US 2006/0160821 A120 Jul 2006
Granted: 16 Mar 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07D 213/40
Radicals substituted by singly-bound nitrogen atoms: acylated substituent nitrogen atom
C07C 275/30
Having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton: being further substituted by…
C07D 211/26
With substituted hydrocarbon radicals attached to ring carbon atoms: with hydrocarbon radicals, substituted by nitrogen atoms
C07D 211/58
Nitrogen atoms: attached in position 4

Family

Application60/634,201Us provisional application · filed 7 Dec 2004
US 2006/0160821 A1Pre-grant publication · published 20 Jul 2006
US 7,678,913 B2This patent

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

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Abstract

A compound having the formula:

wherein:
R1 is hydrogen;
R2 is a member selected from the group consisting of:
aryl, and heteroaryl, optionally substituted with from 1 to 3 R2a substituents;
R3 is a member selected from the group consisting of:
hydrogen and —C0-6alky-aryl;
each R4 and R5 is a member independently selected from the group consisting of:
hydrogen,—C1-6alkyl,—C2-6alkenyl, —C2-6alkynyl,—C0-6alkyl-heteroaryl, —C0-6alkyl-heterocyclyl, —C0-6alkyl-CO—OR4a, —C0-6alkyl-C(O)—N(R4aR4b),—C0-6alkyl-C(O)R4a, and —C0-6alkyl-aryl;
or R4 and R5 can be taken together with the carbon atom to which they are attached to form a 3 to 8 membered cycloalkyl group;
and wherein 1 to 3 carbon or nitrogen atoms of aryl, heteroaryl and heterocyclyl are substituted with 1 to 3 R4d substituents;
D is a member selected from the group consisting of:
aryl, and heteromonocyclyl;
optionally substituted with 1 to 3 R9 substituents, wherein heterocyclyl comprises from 5 to 10 ring atoms, 1-4 of which are selected from the group consisting of N, O and S;
Q is selected from the group consisting of:
a direct bond, —C(R10aR10b)—, —C(O)—, —C(S)—, —C(═NR10a)—, —O—, —S—, —N(R10a)—, —N(R10a)CH2—, —CH2N(R10a)—, —C(O)N(R10a)—, —N(R10a)C(O)—, —SO—, —SO2N(R10a)—, and —N(R10a)—SO2—;
A is selected from the group consisting of:
—NR11cR11d, —C(═NR11c)NR11aR11b, —C(═NR11eR11f)NR11aR11b, —N(R11d)C(═NR11c)NR11aR11b, —N(R11d)C(═NR11c)R11a, —N(R11c)NR11aR11b, —N(R11c)OR11d, C1-6alkyl, C2-6alkenyl, pyridyl-oxide, pyridinyl, pyrrolidinyl, homopiperazinyl, piperazinyl and morpholinyl each optionally substituted with 1 to 3 R11g;
each R2a, R4d, R9 and R11g is a member independently selected from the group consisting of:
H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, —C1-4alkoxy, —O—C0-2alkyl-CF3, —C0-2alkyl-CF3, —C0-2alkyl-CN, —C0-2alkyl-NO2, —C0-2alkyl-NR12aR12b, —C0-2alkyl-SO2NR12aR12b, —C0-2alkyl-SO2R12a, —C0-2alkyl-SOR12a, —C0-2alkyl-CF3, —C0-2alkyl-OR12a, —C0-2alkyl-SR12a, —O—CH2—CH2—OR12a, —O—CH2—CO2R12a, —N(R12a)—CH2—CH2—OR12b, —C0-2alkyl-C(O)NR12aR12b, —C0-2alkyl-CO2R12a, —C0-2alkyl-N(R12a)—C(O)R12b, —C0-2alkyl-N(R12c)—C(O)NR12aR12b, —C0-2alkyl-C(═NR12c)NR12aR12b, —C0-2alkyl-C(═NR12a)R12b, —C0-2alkyl-N(R12d)C(═NR12c)NR12aR12b, —C0-2alkyl-N(R12a)—SO2—R12b, ═O, ═S, ═NR12a, 5- or 6-membered aryl, 5- or 6-membered heteroaryl and 5- to 7-membered heterocyclyl, each of which is optionally substituted with a member independently selected from the group consisting of halo, CF3, OCF3, SCF3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CONR12aR12b, ═O, ═S, —OH, —CN and —NO2;
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms, independently selected from the group consisting of N, O and S,
each R3a,R3b,R4a,R4b,R12a,R12b,R12c and R12d are members independently selected from the group consisting of:
H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C0-4alkylaryl, C0-4alkyl-heteroaryl, —C0-6alkyl-COC1-4alkyl, —C0-6alkyl-CO2C1-4alkyl, —C0-6alkyl-SO2—C1-4alkyl, —C0-6alkyl-SO2—N(C1-4alkyl, C1-4alkyl), —C0-6alkyl-N(C1-4alkyl, C1-4alkyl) and —C1-6alkyl-O—C0-6alkyl, wherein 1-3 hydrogen atoms on the aryl or heteroaryl ring may be independently replaced with a member selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C4-alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl, C1-4alkyl), —OH, —CN and NO2;
or can be taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclyl group, comprising 1 to 4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with 1 to 4 R13 substituents selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl, C1-4 alkyyl), ═O, ═S, —OH, —CN and NO2;
each R6, R7, R8, R10a and R10b is a member independently selected from the group consisting of:
hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl and C0-4alkylC3-8cycloalkyl, —C0-6alkyl-aryl, heteraryl and —C0-6alkyl-heteroaryl, or R4 and R6 can be taken together with the atoms to which they are attached to form a 5 to 12 membered heterocyclyl group;
wherein each heterocyclyl is a 5 to 8 membered monocyclic ring or a 8-12 membered bicyclic ring, each comprising from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and wherein 1 to 3 carbon or nitrogen atoms of aryl, heteroaryl and heterocyclyl are substituted with 1 to 3 R4d substituents;
each R11a, R11b, R11c, R11d, R11e and R11f are members independently selected from the group consisting of:
H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C0-4alkylaryl, C0-4alkyl-heteroaryl, —C0-6alkyl-COC1-4alkyl, —C0-6alkyl-CO2C1-4alkyl, —C0-6alkyl-SO2—C1-4alkyl, —C0-6alkyl-SO2—NR12aR12b, —C0-6alkyl-NR12aR12b and —C1-6alkyl-O—C0-6alkyl, wherein 1-3 hydrogen atoms on the aryl or heteroaryl ring may be independently replaced with a member selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl, C1-4alkyl), —OH, —CN and NO2;
or each R11a and R11b can be taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclyl group, comprising 1 to 4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with 1 to 4 R13 substituents selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl, C1-4alkyl), ═O, ═S, —OH, —CN and NO2;
or each R11e and R11f can be taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclyl group, comprising 1 to 4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with 1 to 4 R13 substituents selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-4alkylC3-8cycloalkyl, C1-4alkoxy, —CO2H, —CO2C1-4alkyl, —CON(C1-4alkyl , C1-4alkyl), ═O, ═S, —OH, —CN and NO2;
each subscript n1 and n2 is an integer of 0 to 1;
and
pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

30 more elements

Facts

Application

11/298,317Filed 7 Dec 2005 · us provisional application

Priority

7 Dec 2004

Published

US 2006/0160821 A120 Jul 2006

Granted

16 Mar 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07D 213/40
Radicals substituted by singly-bound nitrogen atoms: acylated substituent nitrogen atom
C07C 275/30
Having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton: being further substituted by…
C07D 211/26
With substituted hydrocarbon radicals attached to ring carbon atoms: with hydrocarbon radicals, substituted by nitrogen atoms
C07D 211/58
Nitrogen atoms: attached in position 4