US 2012/0071513 A1Published application

Compositions and Their Use as Anti-Tumor Agents

AssigneeCompass Pharmaceuticals LLC

InventorsDavid Kanne, John Ward, Gary Look, X. Michael Wang, Diva Chan, Tina Lee, Donald R. James, Richard Gless, John Schullek, Charles Vacin

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Abstract

The present invention provides novel compounds and pharmaceutical compositions thereof, as well as methods for using the compounds and pharmaceutical compositions for treating tumors. Examples of specific tumor types that the compounds may be used to treat include, but are not limited to sarcomas, melanomas, neuroblastomas, carcinomas (including but not limited to lung, renal cell, ovarian, liver, bladder, and pancreatic carcinomas), and mesotheliomas.

Claims35

Dependent claims

A compound of the formula:

or a pharmaceutically acceptable derivative thereof,
wherein
Y is C—R2 or N;
R1 is selected from hydrogen, lower alkyl or halo;
R2, R3 and R4 are independently selected from hydrogen or halo;
R6 is hydrogen, or
R6 is lower alkyl optionally substituted with one or two groups selected from amino, monoalkylamino or dialkylamino;
R10 is selected from aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, each of which is optionally substituted at the ring portion and/or alkyl portion with one to five groups selected from lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R, or
aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one to three groups selected from lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R, or
R6 and R10 together with the nitrogen atom to which they are attached form a 5-7 membered heteroaryl or heterocyclic ring optionally substituted with one to three groups independently selected from lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R;
Z is selected from
R12, R12′, R12″ and R12′″ are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R;
R13, R13′, R13″, R13′″ and R13″″ are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R;
X is halo;
R is selected from hydrogen and lower alkyl;
and
R′ is independently selected from hydrogen, lower alkyl, amino, monoalkylamino, dialkylamino, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl.

14 more elements

A compound according to claim selected from:

6-chloro-N-(tetrahydrofuran-2-ylmethyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(2-furylmethyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-chloropyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(4,5-dihydro-1,3-thiazol-2-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(2-pyrrolidin-1-ylethyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(5-chloropyrimidin-2-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(3-methylisoxazol-5-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-[6-(methylsulfonyl)-1,3-benzothiazol-2-yl]-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-1,2,4-triazin-3-yl-1,1′:4′,1″-terphenyl-3-carboxamide;
methyl 3-{[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]amino}benzoate;
6-chloro-N-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-[3-(2-methyl-1,3-dioxolan-2-yl)phenyl]-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(4-methoxyphenyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
(2aR,6R,9S,12S,12bS)-6,12b-bis(acetyloxy)-9-{[3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-4,11-dihydroxy-4-a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-yl benzoate;
6-chloro-N-quinolin-6-yl-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-pyrazin-2-yl-1,1′:4′,1″-terphenyl-3-carboxamide;
1-[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]pyrrolidin-3-amine;
N-(5-bromopyridin-2-yl)-6-chloro-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-fluoropyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(5-chloropyridin-2-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyridin-2-ylbiphenyl-3-carboxamide;
6-chloro-3′-fluoro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyridin-4-ylbiphenyl-3-carboxamide;
6-chloro-N-(4-methylphenyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(3-fluoro-4-methoxyphenyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyrimidin-5-ylbiphenyl-3-carboxamide;
6-chloro-N[2-(dimethylamino)ethyl]-N-pyridin-3-yl-1,1′:4′,1″-terphenyl-3-carboxamide;
N-(2-pyrrolidin-1-ylethyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-morpholin-4-ylpyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
4-chloro-N-(6-methoxypyridin-3-yl)-3-(6-phenylpyridin-3-yl)benzamide;
6-chloro-N-[6-(methylthio)pyridin-3-yl]-1,1′:4′,1″-terphenyl-3-carboxamide;
1,4-dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)anthra-9,10-quinone dihydrochloride;
6-chloro-N-(5-methoxypyrazin-2-yl)-1,1′:4′, 1″-terphenyl-3-carboxamide;
6-chloro-N-[2-(methylthio)pyrimidin-5-yl]-1,1′:4′,1″-terphenyl-3-carboxamide
6-chloro-N-(2-methoxypyrimidin-5-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
methyl [5-(2-thienylcarbonyl)-1H-benzimidazol-2-yl]carbamate;
6-chloro-N-(6-methylpyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-oxo-1,6-dihydropyridin-3-yl)-4′-pyridin-2-ylbiphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-(2-methyl-2H-tetrazol-5-yl)biphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-1,1′:3′, 1″-terphenyl-3-carboxamide;
N-(6-methoxypyridin-3-yl)-6-methyl-1,1′:4′,1″-terphenyl-3-carboxamide;
5-biphenyl-4-yl-6-chloro-N-(6-methoxypyridin-3-yl)nicotinamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyridin-2-ylbiphenyl-3-carboxamide;
6-chloro-3″-formyl-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-3″-[(dimethylamino)methyl]-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-3″-(hydroxymethyl)-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-4′-[(dimethylamino)methyl]-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-4″-[(dimethylamino)methyl]-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-4″-(hydroxymethyl)-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-3″-(methylsulfonyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyridin-3-ylbiphenyl-3-carboxamide;
4″-(aminomethyl)-6-chloro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-(methylsulfonyl)biphenyl-3-carboxamide;
4′-(benzyloxy)-6-chloro-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
4″-(benzyloxy)-6-chloro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
2′-chloro-5′-{[(6-methoxypyridin-3-yl)amino]carbonyl}biphenyl-3-carboxylic acid;
6-chloro-4′-[5-(hydroxymethyl)pyridin-3-yl]-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
4′-bromo-6-chloro-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
4′-bromo-6-chloro-N-pyrazin-2-ylbiphenyl-3-carboxamide;
6-chloro-N3-(6-methoxypyridin-3-yl)biphenyl-3,3′-dicarboxamide;
6-chloro-N3-(6-methoxypyridin-3-yl)-1,1′:4′, 1″-terphenyl-3,3″-dicarboxamide;
6-chloro-3′-hydroxy-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-3″-hydroxy-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-4″-hydroxy-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-4′-{5-[(dimethylamino)methyl]pyridin-3-yl}-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
5-fluoro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-{3-[(morpholin-4-ylacetyl)amino]phenyl}-1,1:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-1,1:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}-1,1′:4′,1″-terphenyl-3-carboxamide;
4′-acetyl-6-chloro-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-(methylsulfinyl)biphenyl-3-carboxamide;
6-chloro-4′-[hydroxy(oxido)amino]-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-4′-[(dimethylamino)sulfonyl]-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-N-[6-(hydroxymethyl)pyridin-3-yl]-1,1′:4′,1″-terphenyl-3-carboxamide;
2′-chloro-5′-{[(6-methoxypyridin-3-yl)amino]carbonyl}biphenyl-4-yl 4-methylpiperazine-1-carboxylate;
2″-chloro-5″-{[(6-methoxypyridin-3-yl)amino]carbonyl}-1,1′:4′,1″-terphenyl-4-yl 4-methylpiperazine-1-carboxylate;
6-chloro-4′-(methylsulfonyl)-N-pyrazin-2-ylbiphenyl-3-carboxamide;
(8S,10S)-10-((2R)-4-amino-tetrahydro-5-hydroxy-6-methyl-2H-pyran-2-yloxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxytetracene-5,12-dione;
2-{[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]amino}indane-2-carboxylic acid;
2-{[(2′,4′,6-trichlorobiphenyl-3-yl)carbonyl]amino}indane-2-carboxylic acid;
N-[4-chloro-3-(phenylethynyl)benzoyl]-3-(3a,7a-dihydro-1H-indol-3-yl)-L-alanine;
(2S)-2-{[4-chloro-3-(phenylethynyl)benzoyl]amino}-4-cyclohexa-2,4-dien-1-ylbutanoic acid;
N-[(4′,6-dichlorobiphenyl-3-yl)carbonyl]-3-(3a,7a-dihydro-1H-indol-3-yl)-L-alanine;
(4S)-3-[(4′,6-dichlorobiphenyl-3-yl)carbonyl]-1,3-thiazolidine-4-carboxylic acid;
3-cyclohexyl-N-[(5′,6-dichloro-2′-methoxybiphenyl-3-yl)carbonyl]-D-alanine;
3-cyclohexyl-N-[(2′,4′,6-trichlorobiphenyl-3-yl)carbonyl]-D-alanine;
2-{[4-chloro-3-(phenylethynyl)benzoyl]amino}indane-2-carboxylic acid;
N-[(6-chloro-4′-methoxybiphenyl-3-yl)carbonyl]-3-cyclohexyl-D-alanine;
(4S)-3-[4-chloro-3-(phenylethynyl)benzoyl]-1,3-thiazolidine-4-carboxylic acid;
N-[4-chloro-3-(phenylethynyl)benzoyl]-3-cyclopropyl-D-alanine;
3-cyclopropyl-N-[(4′,6-dichlorobiphenyl-3-yl)carbonyl]-D-alanine;
(4S)-3-[(6-chloro-1,1:4′,1″-terphenyl-3-yl)carbonyl]-1,3-thiazolidine-4-carboxylic acid;
N-[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]-D-methionine;
4-[4-(3-{1-[(5-bromo-6-chloropyridin-3-yl)sulfonyl]piperidin-4-yl}propyl)piperidin-1-yl]-3-chloro-N-(pyridin-2-ylmethyl)benzenesulfonamide;
2-[(2S)-2-amino-3-biphenyl-4-yl-1-oxopropyl]-N-(2-furylmethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(2S)-3-cyclohexyl-2-({(2S)-4-phenyl-2-[(quinolin-3-ylcarbonyl)amino]butanoyl}amino)propanoic acid;
N-[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]-3-cyclopropyl-D-alanine;
N-[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]-3-(7,7a-dihydro-1H-indol-3-yl)-D-alanine;
N-(4-{[2-(3-chlorophenyl)ethyl]amino}-2,5-difluorobenzoyl)-3-cyclohexylalanine;
N-(4-{[2-(4-bromophenyl)ethyl]amino}-2,5-difluorobenzoyl)-D-alanine;
N-(4-{[2-(4-bromophenyl)ethyl]amino}-2,5-difluorobenzoyl)-3-cyclohexylalanine;
4-{[2-(2-chlorophenyl)ethyl]amino}-N-[2-cyclohexyl-1-(hydroxymethyl)ethyl]-2,5-difluorobenzamide;
N-(4-{[2-(2,4-dichlorophenyl)ethyl]amino}-2,5-difluorobenzoyl)-D-alanine;
N-(2,5-difluoro-4-{[2-(1H-indol-3-yl)ethyl]amino}benzoyl)-D-alanine;
N-(4-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-2,5-difluorobenzoyl)-D-alanine;
and
N-(4-{[2-(4-aminophenyl)ethyl]amino}-2,5-difluorobenzoyl)-3-cyclohexylalanine.

106 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/305,103Filed 28 Nov 2011
Priority: 19 Oct 2004
Published: 22 Mar 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 213/75
Nitrogen atoms: amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
A61P 35/00
Antineoplastic agents
C07C 233/65
Having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings: having the nitrogen atoms of the carboxamide…
C07C 233/81
Having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings: having the nitrogen atom of at least one of the…

Family

Application60/620,042Us provisional application · filed 19 Oct 2004
Application11/664,900Continuation · filed 23 Jul 2008
Application13/076,127Continuation · filed 30 Mar 2011
Application13/305,103Continuation
US 2009/0018145 A1Published application
US 2011/0178087 A1Published application
US 2012/0071513 A1This patent

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