US2008194580A1PendingUtilityA1
Inhibition Of Raf Kinase Using Quinolyl, Isoquinolyl Or Pyridyl Ureas
Est. expiryApr 20, 2021(expired)· nominal 20-yr term from priority
Inventors:Jacques DumasBernd RiedlUday KhireRobert SibleyHolia Hatoum-MokdadMary-Katherine MonahanDavid GunnTimotthy B. LowingerWilliam ScottRoger SmithJill Wood
C07D 213/40A61P 35/00
59
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Claims
Abstract
This invention relates to a group of quinolyl, isoquinolyl and pyridyl ureas, their the use in treating raf mediated diseases, and pharmaceutical compositions which contain these ureas for use in such therapy.
Claims
exact text as granted — not AI-modified1 - 20 . (canceled)
21 . A method for inhibiting raf kinase in a patient, comprising administering an effective amount of a compound of one of the following formulae
A-D-B (I) A′-D-B′ (II) and A″-D-B″ (III)
or a pharmaceutically acceptable salt thereof, wherein
D is —NH—C(O)—NH—,
A is selected from the group consisting of substituted t-butylpyridyl groups, unsubstituted t-butylpyridyl groups, substituted (trifluoromethyl)pyridyl groups, unsubstituted (trifluoromethyl) pyridyl groups, substituted isopropylpyridyl groups, unsubstituted isoproplpyridyl groups, substituted (2-methyl-2-butyl)pyridyl groups, unsubstituted (2-methyl-2-butyl pyridyl) groups, substituted (3-methyl-3-pentyl)pyridyl groups, and unsubstituted (3-methyl-3-pentyl)pyridyl groups, substituted (3-ethyl-3-pentyl)pyridyl groups and unsubstituted (3-ethyl-3-pentyl)pyridyl groups
A′ is a substituted isoquinolinyl group or unsubstituted isoquinolinyl group or an unsubstituted quinolinyl group,
A″ is a substituted quinolinyl group,
B, B′ and B″ are each, independently, a substituted or unsubstituted bridged cyclic structure of up to 30 carbon atoms of the formula -L-(ML 1 ) q wherein L comprises a cyclic moiety having at least 5 members and is bound directly to D, L 1 comprises a cyclic moiety having at least 5 members, M is a bridging group selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH—) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m , CHX a —, —CX a 2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3 X a is halogen, and R 7 is as defined below,
q is an integer of from 1-3, and each cyclic structure of L and L 1 contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur,
subject to the provisos that B is not
and B″ is not
wherein the substituents for A″ and the substituted isoquinolyl groups of A′ are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3 and each W is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, at least a five membered C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, at least a five-membered substituted C 3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O; —CN, up to per halo substituted C 6 -C 14 aryl, up to per halo substituted C 7 -C 24 alkaryl, up to per halo substituted C 7-4 aralkyl, up to per halo substituted C 3 -C 12 heteroaryl having at least 5 members and 1-3 heteratoms selected from O, N and S, up to per halo substituted C 4 -C 24 alkylheteroaryl having at least 5 members and 1-3 heteroatoms selected from O, N and S, C 6 -C 14 aryl, C 1 -C 24 alkaryl, C 1 -C 24 aralkyl, C 3 -C 12 heteroaryl having at least 5 cyclic members and 1-3 heteroatoms selected from O, N and S, C 4 -C 24 alkylheteroaryl having at least 5 cyclic members and 1-3 heteroatoms selected from O, N and S; —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, up to per halosubstituted C 1-10 alkyl, up to per halosubstituted C 1-10 alkoxy, up to per halosubstituted C 2-10 alkenyl and up to per halosubstituted C 1-10 alkenoyl;
wherein the substitutents for the substituted t-butyl pyridyl groups substituted trifluoromethyl pyridyl groups, substituted isopropyl pyridyl groups, substituted 2-methyl-2-butyl pyridyl groups and substituted 3-methyl-3-pentyl pyridyl groups of A are selected from the group consisting of halogen, up to per-halo, and Zn, where n is 0-3 and each Z is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W;
where B and B′ are substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Jn, where n is 0-3 and each J is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W, C 1-10 alkyl, C 1-10 alkoxy, at least a five-membered C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, C 6-12 aryl, at least a five-membered C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C 7-24 aralkyl, C 7-24 alkaryl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, at least a five-membered substituted C 3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C 6 -C 14 aryl, at least a five-membered substituted C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24 alkaryl and substituted C 7 -C 24 aralkyl,
where B″ is substituted, the substituents are selected from the group consisting of halogen, —CN, —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7″ independently as defined above for W, C 1-10 alkyl, at least a five-membered C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, C 6-12 aryl, at least a five-membered C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C 7-4 aralkyl, C 7-24 alkaryl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, at least a five-membered substituted C 3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C 6 -C 14 aryl, at least a five-membered substituted C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24 alkaryl and substituted C 7 -C 24 aralkyl,
subject to the proviso that where B, B′ or B″ is -L(ML 1 ) q , L 1 is not substituted by the substituents —C(O)R a , —C(NR a )R b , —C(O)NR a R b and —SO 2 R a wherein each R a and R b are independently hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O,
where J is a substituted group, it is substituted by halogen, up to per halo, or by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NO 2 , —NR 7 C(O)R 7′ and —NR 7 C(O)OR 7′ ; with each R 7 and R 7′ independently as defined above for W,
a patient in need thereof.
22 . A method as in claim 21 for inhibiting raf kinase in a patient, comprising administering an effective amount of a compound of one of the following formulae A-D-B, A′-D-B′, A″-D-B″,
R is selected from the group consisting of halogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , or a pharmaceutically acceptable salt thereof wherein D is —NH—C(O)—NH—
A is selected from the group consisting of substituted t-butylpyridyl groups, unsubstituted t-butylpyridyl group, substituted (trifluoromethyl)pyridyl group, unsubstituted (trifluoromethyl) pyridyl group, substituted isopropylpyridyl group, unsubstituted isopropylpyridyl group, substituted (2-methyl-2-butyl)pyridyl group, unsubstituted (2-methyl-2-butyl) pyridyl group, substituted (3-methyl-3-pentyl) pyridyl group, unsubstituted (3-methyl-3-pentyl) pyridyl group, substituted (3-ethyl-3-pentyl)pyridyl group, unsubstituted (3-ethyl-3-pentyl) pyridyl group,
A′ is a substituted isoquinolinyl group or unsubstituted isoquinolinyl group or an unsubstituted quinolinyl group,
A″ is a substituted quinolinyl group,
B, B′ and B″ are each independently of the formula -L-(ML 1 ) q , wherein L is phenyl or substituted phenyl and L 1 is phenyl, substituted phenyl, pyridinyl or substituted pyridinyl, q is an integer of from 1-2 and M is selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m , CHX a —, CX a 2 —, —S—(CH 2 )— and —N(R 7 )(CH 2 ) m —, where m=1-3, X a is halogen, and R 7 is as defined below;
subject to the provisos that B′ is not
B is not
wherein the substituents for the substituted t-butyl pyridyl groups, substituted trifluoromethyl pyridyl groups, substituted isopropyl pyridyl groups, substituted 2-methylbutyl pyridyl groups and 3-methylpentyl pyridyl groups, of A are selected from the group consisting of halogen, up to per-halo, and Zn, where n is 0-3 and each Z is independently selected from the group consisting of C 1-10 alkyl C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, up to per halosubstituted C 1-10 alkyl, up to per halosubstituted C 1-10 alkoxy, up to per halosubstituted C 2-10 and up to per halosubstituted C 1-10 alkenoyl;
wherein the substituents for A″ and the substituted isoquinolinyl groups of A′ are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3 and each W is independently selected from the group consisting. of C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, up to per halosubstituted C 1-10 alkyl, up to per halosubstituted C 1-10 alkoxy, up to per halosubstituted C 2-10 alkenyl and up to per halosubstituted C 1-10 alkenoyl;
wherein B and B′ are substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Jn, where n is 0-3 and each J is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, and substituted C 1-10 alkoxy, subject to the proviso that where B, B′ or B″ is -L(ML 1 ) q , L 1 is not substituted by the substituents —C(O)R a , —C(NR a )R b , —C(O)NR a R b and —SO 2 R a wherein R a and R b are each independently hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O,
wherein B″ is substituted, the substituents are selected from the group consisting of halogen, —CN, —C(O)NR 7 R 7′ , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, and substituted C 1-10 alkoxy, subject to the proviso that where B, B′ or B″ is -L(ML 1 ) q , L 1 is not substituted by the substituents —C(O)R a , —C(NR a )R b , C(O)NR a R b and —SO 2 R a wherein R a and R b are each independently, hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O to a patient in need thereof.
23 . A method as in claim 21 for inhibiting raf kinase in a patient, comprising administering an effective amount of a compound which is
N-(4-tert-butylpyridinyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-phenoxyphenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-methylphenoxy)phenyl) or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-chlorophenoxy)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-4-tert-butylpyridinyl)-N′-(4-(4-pyridinylthio)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-3-(4-pyridinylthio)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(3-isoquinolinyl)-N′-(4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof;
N,N′-(bis(3-(2-methoxyquinolinyl)) urea) or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-pyridinylmethyl)phenyl)) urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-pyridinylcarbonyl)phenyl)) urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-methoxyphenyl)methylamino)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(3-(4-pyridinylthio)phenyl))urea or a pharmaceutically acceptable salt thereof; or
N-(1-(4-methylpiperazinyl)-3-isoquinolinyl)-N′ (4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof to a patient in need thereof.
24 - 40 . (canceled)
41 . A method for treating a solid tumor with cell growth mediated by raf kinase in a patient, comprising administering a therapeutically effective amount of
a compound of one of the following formulae
A-D-B (I)
A′-D-B′ (II) and
A″-D-B″ (III)
or a pharmaceutically acceptable salt thereof, wherein
D is —NH—C(O)—NH—,
A is selected from the group consisting of substituted t-butylpyridyl group, unsubstituted t-butylpyridyl group, substituted (trifluoromethyl)pyridyl group, unsubstituted (trifluoromethyl) pyridyl group, substituted isopropylpyridyl group, unsubstituted isopropylpyridyl group, substituted (2-methyl-2-butyl)pyridyl group, unsubstituted (2-methyl-2-butyl pyridyl) group, substituted (3-methyl-3-pentyl)pyridyl group, and unsubstituted(3-methyl-3-pentyl) pyridyl groups, substituted (3-ethyl-3-pentyl)pyridyl group and unsubstituted (3-ethyl-3-pentyl)pyridyl group,
A′ is a substituted isoquinolinyl group or unsubstituted isoquinolinyl group or an unsubstituted quinolinyl group,
A″ is a substituted quinolinyl group,
B, B′ and B″ are each, independently, a substituted or unsubstituted bridged cyclic structure of up to 30 carbon atoms of the formula -L-(ML 1 ) q wherein L comprises a cyclic moiety having at least 5 members and is bound directly to D, L 1 comprises a cyclic moiety having at least 5 members, M is a bridging group selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —C(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—,
—(CH 2 ) m N(R 7 )—, —O(CH 2 ) m , —CHX a —, —CX a 2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a is halogen, and R 7 is as defined below,
q is an integer of from 1-3, and each cyclic structure of L and L 1 contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur,
subject to the provisos that B is not
and B′ is not
wherein the substituents for A″ and the substituted isoquinolyl groups of A′ are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3 and each W is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, at least a five membered C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, at least a five-membered substituted C 3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O; —CN, up to per halo substituted C 6 -C 14 aryl, up to per halo substituted C 7 -C 24 alkaryl, up to per halo substituted C 7-4 aralkyl, up to per halo substituted C 3 -C 12 heteroaryl having at least 5 members and 1-3 heteratoms selected from O, N and S, up to per halo substituted C 4 -C 24 alkylheteroaryl having at least 5 members and 1-3 heteroatoms selected from O, N and S, C 6 -C 14 aryl, C 1 -C 24 alkaryl, C 1 -C 24 aralkyl, C 3 -C 12 heteroaryl having at least 5 cyclic members and 1-3 heteroatoms selected from O, N and S, C 4 -C 24 alkylheteroaryl having at least 5 cyclic members and 1-3 heteroatoms selected from O, N and S; —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, up to per halosubstituted C 1-10 alkyl, up to per halosubstituted C 1-10 alkoxy, up to per halosubstituted C 2-10 alkenyl and up to per halosubstituted C 1-10 alkenoyl;
wherein the substitutents for the substituted t-butyl pyridyl groups substituted trifluoromethyl pyridyl groups, substituted isopropyl pyridyl groups, substituted 2-methyl-2-butyl pyridyl groups and substituted 3-methyl-3-pentyl pyridyl groups of A are selected from the group consisting of halogen, up to per-halo, and Zn, where n is 0-3 and each Z is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W;
where B and B′ are substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Jn, where n is 0-3 and each J is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W, C 1-10 alkyl, C 1-10 alkoxy, at least a five-membered C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, C 6-12 aryl, at least a five-membered C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C 7-24 aralkyl, C 7-24 alkaryl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, at least a five-membered substituted C 3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C 6 -C 14 aryl, at least a five-membered substituted C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24 alkaryl and substituted C 7 -C 24 aralkyl,
where B″ is substituted, the substituents are selected from the group consisting of halogen, —CN, —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7″ independently as defined above for W, C 1-10 alkyl, at least a five-membered C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, C 6-12 aryl, at least a five-membered C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C 7-24 aralkyl, C 7-24 alkaryl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, at least a five-membered substituted C 3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C 6 -C 14 aryl, at least a five-membered substituted C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24 alkaryl and substituted C 7 -C 24 aralkyl,
subject to the proviso that where B, B′ or B″ is -L(ML 1 ) q , L 1 is not substituted by the substituents —C(O)R a , —C(NR a )R b , —C(O)NR a R b and —SO 2 R a wherein each R a and R b are independently hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O,
where J is a substituted group, it is substituted by halogen, up to per halo, or by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NO 2 , —NR 7 C(O)R 7′ and —NR 7 C(O)OR 7′ ; with each R 7 and R 7′ independently as defined above for W, to treat said patient.
42 . A method for the treatment of carcinomas of the lungs, pancreas, thyroid, bladder or colon, myeloid leukemia or villous colon adenoma, comprising administering a therapeutically effective amount
of a compound of one of the following formulae
A-D-B (I)
A′-D-B′ (II) and
A″-D-B″ (III)
or a pharmaceutically acceptable salt thereof, wherein
D is —NH—C(O)—NH—,
A is selected from the group consisting of substituted t-butylpyridyl group, unsubstituted t-butylpyridyl group, substituted (trifluoromethyl)pyridyl group, unsubstituted (trifluoromethyl) pyridyl group, substituted isopropylpyridyl group, unsubstituted isopropylpyridyl group, substituted (2-methyl-2-butyl)pyridyl group, unsubstituted (2-methyl-2-butyl pyridyl) group, substituted (3-methyl-3-pentyl)pyridyl group, and unsubstituted (3-methyl-3-pentyl) pyridyl groups, substituted (3-ethyl-3-pentyl)pyridyl group and unsubstituted (3-ethyl-3-pentyl)pyridyl group,
A′ is a substituted isoquinolinyl group or unsubstituted isoquinolinyl group or an unsubstituted quinolinyl group,
A″ is a substituted quinolinyl group,
B, B′ and B″ are each, independently, a substituted or unsubstituted bridged cyclic structure of up to 30 carbon atoms of the formula -L-(ML 1 ) q wherein L comprises a cyclic moiety having at least 5 members and is bound directly to D, L 1 comprises a cyclic moiety having at least 5 members, M is a bridging group selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —C(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—,
—(CH 2 ) m N(R 7 )—, —O(CH 2 ) m , —CHX a —, —CX a 2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a is halogen, and R 7 is as defined below,
q is an integer of from 1-3, and each cyclic structure of L and L 1 contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur,
subject to the provisos that B is not
and B′ is not
wherein the substituents for A″ and the substituted isoquinolinyl groups of A′ are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3 and each W is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy. at least a five membered C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, at least a five-membered substituted C 3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O; —CN, up to per halo substituted C 6 -C 14 aryl, up to per halo substituted C 7 -C 24 alkaryl, up to per halo substituted C 7-4 aralkyl, up to per halo substituted C 3 -C 12 heteroaryl having at least 5 members and 1-3 heteratoms selected from O, N and S, up to per halo substituted C 4 -C 24 alkylheteroaryl having at least 5 members and 1-3 heteroatoms selected from O, N and S, C 6 -C 14 aryl, C 1 -C 24 alkaryl, C 1 -C 24 aralkyl, C 3 -C 12 heteroaryl having at least 5 cyclic members and 1-3 heteroatoms selected from O, N and S, C 4 -C 24 alkylheteroaryl having at least 5 cyclic members and 1-3 heteroatoms selected from O, N and S; —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, up to per halosubstituted C 1-10 alkyl, up to per halosubstituted C 1-10 alkoxy, up to per halosubstituted C 2-10 alkenyl and up to per halosubstituted C 1-10 alkenoyl;
wherein the substitutents for the substituted t-butyl pyridyl groups substituted trifluoromethyl pyridyl groups, substituted isopropyl pyridyl groups, substituted 2-methyl-2-butyl pyridyl groups and substituted 3-methyl-3-pentyl pyridyl groups of A are selected from the group consisting of halogen, up to per-halo, and Zn, where n is 0-3 and each Z is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W;
where B and B′ are substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Jn, where n is 0-3 and each J is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W, C 1-10 alkyl, C 1-10 alkoxy, at least a five-membered C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, C 6-12 aryl, at least a five-membered C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C 7-24 aralkyl, C 7-24 alkaryl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, at least a five-membered substituted C 3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C 6 -C 14 aryl, at least a five-membered substituted C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24 alkaryl and substituted C 7 -C 24 aralkyl,
where B″ is substituted, the substituents are selected from the group consisting of halogen, —CN, —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7″ independently as defined above for W, C 1-10 alkyl, at least a five-membered C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, C 6-12 aryl, at least a five-membered C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C 7-4 aralkyl, C 7-24 alkaryl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, at least a five-membered substituted C 3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C 6 -C 14 aryl, at least a five-membered substituted C 3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24 alkaryl and substituted C 7 -C 24 aralkyl,
subject to the proviso that where B, B′ or B″ is -L(ML 1 ) q , L 1 is not substituted by the substituents —C(O)R a , —C(NR a )R b , —C(O)NR a R b and —SO 2 R a wherein each R a and R b are independently hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O,
where J is a substituted group, it is substituted by halogen, up to per halo, or by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NO 2 , —NR 7 C(O)R 7′ and —NR 7 C(O)OR 7′ ; with each R 7 and R 7′ independently as defined above for W, to treat said patient.
43 . A method as in claim 41 for the treatment of a solid tumor with cell growth mediated by raf kinase in a patient, comprising administering a therapeutically effective amount of a compound of one of the following formulae A-D-B, A′-D-B′, A″-D-B″.
R is selected from the group consisting of halogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7″ , —NR 7 C(O)R 7′ , or a pharmaceutically acceptable salt thereof wherein D is —NH—C(O)—NH—
A is selected from the group consisting of substituted t-butylpyridyl groups, unsubstituted t-butylpyridyl group, substituted (trifluoromethyl)pyridyl group, unsubstituted (trifluoromethyl) pyridyl group, substituted isopropylpyridyl group, unsubstituted isopropylpyridyl group, substituted (2-methyl-2-butyl)pyridyl group, unsubstituted (2-methyl-2-butyl) pyridyl group, substituted (3-methyl-3-pentyl) pyridyl group, unsubstituted (3-methyl-3-pentyl) pyridyl group, substituted (3-ethyl-3-pentyl)pyridyl group, unsubstituted (3-ethyl-3-pentyl) pyridyl group,
A′ is a substituted isoquinolinyl group or unsubstituted isoquinolinyl group or an unsubstituted quinolinyl group,
A″ is a substituted quinolinyl group,
B, B′ and B″ are each independently of the formula -L-(ML 1 ) q , wherein L is phenyl or substituted phenyl and L 1 is phenyl, substituted phenyl, pyridinyl or substituted pyridinyl, q is an integer of from 1-2 and M is selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m , CHX a —, CX a 2 —, —S—(CH 2 )— and —N(R 7 )(CH 2 ) m —, where m=1-3, X a is halogen, and R 7 is as defined below;
subject to the provisos that B′ is not
B is not
wherein the substituents for the substituted t-butyl pyridyl groups, substituted trifluoromethyl pyridyl groups, substituted isopropyl pyridyl groups, substituted 2-methylbutyl pyridyl groups and 3-methylpentyl pyridyl groups, of A are selected from the group consisting of halogen, up to per-halo, and Zn, where n is 0-3 and each Z is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkenyl, C 1-10 alkenoyl, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, up to per halosubstituted C 1-10 alkyl, up to per halosubstituted C 1-10 alkoxy, up to per halosubstituted C 2-10 and up to per halosubstituted C 1-10 alkenoyl;
wherein the substituents for A″ and the substituted isoquinolinyl groups of A′ are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3 and each W is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, up to per halosubstituted C 1-10 alkyl, up to per halosubstituted C 1-10 alkoxy, up to per halosubstituted C 2-10 alkenyl and up to per halosubstituted C 1-10 alkenoyl;
wherein B and B′ are substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Jn, where n is 0-3 and each J is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, and substituted C 1-10 alkoxy, subject to the proviso that where B, B′ or B″ is -L(ML 1 ) q , L 1 is not substituted by the substituents —C(O)R a , —C(NR a )R b , —C(O)NR a R b and —SO 2 R a wherein R a and R b are each independently hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O,
wherein B″ is substituted, the substituents are selected from the group consisting of halogen, —CN, —C(O)NR 7 R 7′ , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, and substituted C 1-10 alkoxy, subject to the proviso that where B, B′ or B″ is -L(ML 1 ) q , L 1 is not substituted by the substituents —C(O)R a , —C(NR a )R b , C(O)NR a R b and —SO 2 R a wherein R a and R b are each independently, hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O to a patient in need thereof.
44 . (canceled)
45 . A method as in claim 42 for the treatment of carcinomas of the lungs, pancreas, thyroid, bladder or colon, myeloid leukemia or villous colon adenoma in a patient mediated by raf kinase, comprising administering a therapeutically effective amount of
a compound of one of the following formulae A-D-B, A′-D-B′, A″-D-B″,
R is selected from the group consisting of halogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7″ , —NR 7 C(O)R 7′ , or a pharmaceutically acceptable salt thereof wherein D is —NH—C(O)—NH—
A is selected from the group consisting of substituted t-butylpyridyl groups, unsubstituted t-butylpyridyl group, substituted (trifluoromethyl)pyridyl group, unsubstituted (trifluoromethyl) pyridyl group, substituted isopropylpyridyl group, unsubstituted isopropylpyridyl group, substituted (2-methyl-2-butyl)pyridyl group, unsubstituted (2-methyl-2-butyl) pyridyl group, substituted (3-methyl-3-pentyl) pyridyl group, unsubstituted (3-methyl-3-pentyl) pyridyl group, substituted (3-ethyl-3-pentyl)pyridyl group, unsubstituted (3-ethyl-3-pentyl) pyridyl group,
A′ is a substituted isoquinolinyl group or unsubstituted isoquinolinyl group or an unsubstituted quinolinyl group,
A″ is a substituted quinolinyl group,
B, B′ and B″ are each independently of the formula -L-(ML 1 ) q , wherein L is phenyl or substituted phenyl and L 1 is phenyl, substituted phenyl, pyridinyl or substituted pyridinyl, q is an integer of from 1-2 and M is selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m , CHX a —, CX a 2 —, —S—(CH 2 )— and —N(R 7 )(CH 2 ) m —, where m=1-3, X a is halogen, and R 7 is as defined below;
subject to the provisos that B′ is not
B is not
wherein the substituents for the substituted t-butyl pyridyl groups, substituted trifluoromethyl pyridyl groups, substituted isopropyl pyridyl groups, substituted 2-methylbutyl pyridyl groups and 3-methylpentyl pyridyl groups, of A are selected from the group consisting of halogen, up to per-halo, and Zn, where n is 0-3 and each Z is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, up to per halosubstituted C 1-10 alkyl, up to per halosubstituted C 1-10 alkoxy, up to per halosubstituted C 2-10 and up to per halosubstituted C 1-10 alkenoyl;
wherein the substituents for A″ and the substituted isoquinolinyl groups of A′ are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3 and each W is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, up to per halosubstituted C 1-10 alkyl, up to per halosubstituted C 1-10 alkoxy, up to per halosubstituted C 2-10 alkenyl and up to per halosubstituted C 1-10 alkenoyl;
wherein B and B′ are substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Jn, where n is 0-3 and each J is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7′ , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, and substituted C 1-10 alkoxy, subject to the proviso that where B, B′ or B″ is -L(ML 1 ) q , L 1 is not substituted by the substituents —C(O)R a , —C(NR a )R b , —C(O)NR a R b and —SO 2 R a wherein R a and R b are each independently hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O,
wherein B″ is substituted, the substituents are selected from the group consisting of halogen, —CN, —C(O)NR 7 R 7′ , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7′ , —NR 7 C(O)OR 7′ , —NR 7 C(O)R 7′ , with each R 7 and R 7′ independently as defined above for W, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkenoyl, substituted C 1-10 alkyl, and substituted C 1-10 alkoxy, subject to the proviso that where B, B′ or B″ is -L(ML 1 ) q , L 1 is not substituted by the substituents —C(O)R a , —C(NR a )R b , C(O)NR a R b and —SO 2 R a wherein R a and R b are each independently, hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O to treat said patient.
46 . A method as in claim 41 for the treatment of a solid tumor with cell growth mediated by raf kinase in a patient, comprising administering a therapeutically effective amount of a compound which is
N-(4-tert-butylpyridinyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-phenoxyphenyl)urea or a pharmaceutically acceptable salt thereof:
N-(4-tert-butylpyridinyl)-N′-(4-(4-methylphenoxy)phenyl) or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-chlorophenoxy)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-pyridinylthio)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(3-(4-pyridinylthio)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(3-isoquinolinyl)-N′-(4-(4-pyridinyloxy)phenyl) urea or a pharmaceutically acceptable salt thereof;
N,N′-(bis(3-(2-methoxyquinolinyl)) urea) or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-pyridinylmethyl)phenyl)) urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-pyridinylcarbonyl)phenyl)) urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-pyridinyloxy)phenyl))urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-((4-methoxyphenyl)methylamino)phenyl) urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(3-(4-pyridinylthio)phenyl)) urea or a pharmaceutically acceptable salt thereof; or
N-(1-(4-methylpiperazinyl)-3-isoquinolinyl)-N′ (4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof,
to treat said patient.
47 . A method as in claim 42 for the treatment of carcinomas of the lungs, pancreas, thyroid, bladder or colon, myeloid leukemia or villous colon adenoma, comprising administering a therapeutically effective amount of a compound which is
N-(4-tert-butylpyridinyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-phenoxyphenyl) urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-methylphenoxy)phenyl) or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-chlorophenoxy)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(4-(4-pyridinylthio)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(4-tert-butylpyridinyl)-N′-(3-(4-pyridinylthio)phenyl)urea or a pharmaceutically acceptable salt thereof;
N-(3-isoquinolinyl)-N′-(4-(4-pyridinyloxy phenyl)urea or a pharmaceutically acceptable salt thereof;
N,N′-(bis(3-(2-methoxy-quinolinyl))urea) or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-pyridinylmethyl)-phenyl)) urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-pyridinylcarbonyl)phenyl)) urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-(4-pyridinyloxy)phenyl)) urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(4-((4-methoxyphenyl)methylamino)phenyl)) urea or a pharmaceutically acceptable salt thereof;
N-(3-(2-methoxyquinolinyl)-N′-(3-(4-pyridinylthio)phenyl)) urea or a pharmaceutically acceptable salt thereof; or
N-(1-(4-methylpiperazinyl)-3-isoquinolinyl)-N′ (4-(4-pyridinyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof to treat said patient.
48 . A method as in claim 47 for the treatment of carcinomas of the lungs.
49 . A method as in claim 47 for the treatment of carcinomas of the pancreas.
50 . A method as in claim 47 for the treatment of carcinomas of the thyroid.
51 . A method as in claim 47 for the treatment of carcinomas of the bladder.
52 . A method as in claim 47 for the treatment of carcinomas of the colon.
53 . A method as in claim 47 for the treatment of myeloid leukemia.
54 . A method as in claim 47 for the treatment of villous colon adenoma.Cited by (0)
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