CA2516627A1 - Substituted pyridine derivatives useful in the treatment of cancer and other disorders - Google Patents

Substituted pyridine derivatives useful in the treatment of cancer and other disorders

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Publication number
CA2516627A1
CA2516627A1 CA 2516627 CA2516627A CA2516627A1 CA 2516627 A1 CA2516627 A1 CA 2516627A1 CA 2516627 CA2516627 CA 2516627 CA 2516627 A CA2516627 A CA 2516627A CA 2516627 A1 CA2516627 A1 CA 2516627A1
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Prior art keywords
yl
phenyl
amino
cndot
linear
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Abandoned
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CA 2516627
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French (fr)
Inventor
Jacques Dumas
Wendy Lee
Yuanwei Chen
Lila Adnane
William J. Scott
Sharad Verma
Jianqing Chen
Zhi Chen
Lin Yi
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Bayer HealthCare LLC
Original Assignee
Bayer Pharmaceuticals Corporation
Jacques Dumas
Wendy Lee
Yuanwei Chen
Lila Adnane
William J. Scott
Sharad Verma
Jianqing Chen
Zhi Chen
Lin Yi
Bayer Healthcare Llc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals
    • C07D213/83Thioacids; Thioesters; Thioamides; Thioimides
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    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals
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    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/38Medical treatment of vector-borne diseases characterised by the agent
    • Y02A50/398Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a bacteria
    • Y02A50/399Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a bacteria of the genus Borrellia
    • Y02A50/401Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a bacteria of the genus Borrellia the bacteria being Borrelia burgdorferi, i.e. Lyme disease or Lyme borreliosis
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/38Medical treatment of vector-borne diseases characterised by the agent
    • Y02A50/408Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa
    • Y02A50/413Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa of the genus Trypanosoma
    • Y02A50/414Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa of the genus Trypanosoma the protozoa being Trypanosoma cruzi i.e. Chagas disease or American trypanosomiasis
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/46Medical treatment of waterborne diseases characterized by the agent
    • Y02A50/468The waterborne disease being caused by a bacteria
    • Y02A50/473The waterborne disease being caused by a bacteria the bacteria being Escherichia coli, i.e. E. coli Infection

Abstract

This invention relates to novel diaryl ureas of formula I wherein A is phenyl, naphthyl, mono- or bi-cyclic heteroaryl, or a group of the formula B is phenyl, naphthyl, or pyridyl, L is a bridging group Q is: (1) C(S)NR4R5; (2) C(O)NR7-NR4R5; (3) tetrazolyl; (4) imidazolyl; (5) imidazoline-2-yl; (6) 1,3,4-oxadiazoline-2-yl; (7) 1,3-thiazoline-2-yl; (8) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl; (9) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or (10) a group of the formula and, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and angiogenesis disorders, as a sole agent or in combination with cytotoxic therapies.

Claims (25)

1) ~A compound of formula (I) ~
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein A is phenyl, naphthyl, mono- or bi-cyclic heteroaryl, or a group of the formula optionally substituted with 1-4 substituents which are independently R1, OR1, S(O)p R1, C(O)R1, C(O)OR1, C(O)NR1R2, halogen, hydroxy, amino, cyano, or nitro;

B is phenyl, naphthyl, or pyridyl, optionally substituted with 1-4 substituents which are independently C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, or nitro;

L is (a) -(CH2)m-O-(CH2)l-(b) -(CH2)m-(CH2)l-, (c) -(CH2)m-C(O)-(CH2)l-, (d) -(CH2)m-NR3-(CH2)l-, (e) -(CH2)m-NR3C(O)-(CH2)l-, (f) -(CH2)m-S-(CH2)l-, (g) -(CH2)m -C(O)NR3-(CH2)l-, or (h) a single bond;

m and l are integers independently selected from 0-4;

M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, or nitro;

Q is:

(1) C(S)NR4R5;
(2) C(O)NR7-NR4R5;
(3) tetrazolyl;
(4) imidazolyl;
(5) imidazoline-2-yl;
(6) 1,3,4-oxadiazoline-2-yl;
(7) 1,3-thiazoline-2-yl;
(8) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl;
(9) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or (10) a group of the formula wherein each of R1, R2, R3, R4 and R5 is independently (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) phenyl, (d) C1-C3 phenyl-alkyl, (e) up to per-halo substituted C1-C5 linear or branched alkyl, or (f) -(CH2)q -X, where X is a 5 or 6 membered heterocyclic ring, containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or a 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S;

R4 and R5 may additionally be taken together to form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, optionally substituted with 1-3 substituents which are independently C1-C5 linear or branched alkyl, up to perhalo substituted C1-C5 linear or branched alkyl, C1-C3 alkoxy, hydroxy, oxo, carboxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, or nitro;

R6 is independently (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) cyano, (d) nitro, (e) up to per-halo substituted C1-C5 linear or branched alkyl. or (f) -C(O)R7, where R7 is C1-C5 linear, branched, or cyclic alkyl;

R7 is hydrogen or linear, branched, or cyclic C1-C5 alkyl;

q is an integer 0, 1, 2, 3, or 4 and p is an integer 0, 1, or 2.
2) A compound of claim 1 wherein B is phenyl or pyridinyl, optionally substituted with 1-4 halogen.
3) A compound of claim 1 wherein L is -O- and B is phenyl or pyridinyl, optionally substituted with 1-4 halogen.
4) A compound of claim 1 wherein A is phenyl, naphthyl, indazolyl, quinolinyl, pyridyl, benzo[1,3]dioxolan-5-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl or 4H-benzo[1,3]dioxin-6-yl, optionally substituted with 1-4 substituents which are independently R1 and halogen, L is -O- and B is phenyl, optionally substituted with 1-4 halogen.
5) A compound of claim 1 wherein A and B follow one of the following combinations:

A= phenyl and B= phenyl, A= indazolyl and B= phenyl, A= quinolinyl and B= phenyl, A= 4H-benzo[1,3]dioxin-6-yl and B= phenyl;

A= phenyl and B= pyridyl, A= indazolyl and B= pyridyl, A= quinolinyl and B= pyridyl, or A= 4H-benzo[1,3]dioxin-6-yl and B= pyridyl.
6) A compound which is .cndot. N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-f[2-(hydrazinocarbonyl)pyridin-4-yl]oxy}phenyl)urea .cndot. ~N-(4-{[2-(hydrazinocarbonyl)pyridin-4-yl]oxy}phenyl)-N'-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)urea .cndot.~N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[3-({2-[(2,2-dimethylhydrazino)carbonyl]pyridin-4-yl}oxy)phenyl]urea .cndot.~4-{3-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-piperidin-1-ylpyridine-2-carboxamide .cndot. ~N-piperidin-1-yl-4-[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxamide .cndot. ~4-{3-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-morpholin-4-ylpyridine-2-carboxamide .cndot. ~N-morpholin-4-yl-4-[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxamide .cndot. ~4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]-N-morpholin-4-ylpyridine-2-carboxamide .cndot. ~N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(1H-tetrazol-5-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. ~N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. ~N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea .cndot.~N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(4-methyl-1,3-thiazol-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. ~N-quinolin-6-yl-N'-(4-([2-(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. ~N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. ~N-(4-{[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)-N'-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)urea .cndot. ~4-{4-{({j4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboximidamide .cndot. 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridine-2-carboximidamide .cndot. N-methyl-4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboximidamide .cndot. N-methyl-4-(4-{[(quinolin-6-ylamino)carbonyl]amino}phenoxy)pyridine-2-carboximidamide .cndot. 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridine-2-carbothioamide .cndot. 4-(4-{[(quinolin-6-ylamino)carbonyl]amino}phenoxy)pyridine-2-carbothioamide or .cndot. 4-[4-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carbothioamide
7) A pharmaceutical composition which comprises an effective amount of at least one compound of claim 1 and a physiologically acceptable carrier.
8) A method for treating or preventing a hyper-proliferative disorder in a human or other mammal comprising administering to a human or other mammal in need thereof a compound of claim 1.
9) A method for treating or preventing a hyper-proliferative disorder in a human or other mammal comprising administering to a human or other mammal in need thereof a compound of claim 1 and an additional anti-proliferative agent.
10) A method for treating or preventing cancer in a human or other mammal comprising administering to a human or other mammal in need thereof a compound of claim 1 and a cytotoxic agent or cytostatic chemotherapeutic agent.
11) A method for treating or preventing a disease in a human or other mammal regulated by tyrosine kinase, associated with an aberration in the tyrosine kinase signal transduction pathway, comprising administering to a human or other mammal in need thereof a compound of claim 1.
12) A method for treating or preventing a disease in a human or other mammal mediated by the VEGF-induced signal transduction pathway, comprising administering to a human or other mammal in need thereof a compound of claim 1.
13) A method for treating or preventing a disease in a human or other mammal characterized by abnormal angiogenesis or hyperpermeability processes, comprising administering to a human or other mammal in need thereof a compound of claim 1.
14) A method for treating or preventing a disease in a human or other mammal characterized by abnormal angiogenesis or hyperpermeability processes, comprising administering to a human or other mammal in need thereof a compound of claim 1 simultaneously with another angiogenesis inhibiting agent in the same formulation or in separate formulations.
15) A method for treating or preventing one or more of the following conditions in humans and/or other mammals: tumor growth, retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration;
rheumatoid arthritis, psoriasis, a bolos disorder associated with subepidermal blister formation, including bullous pemphigoid, erythema multiforme, or dermatitis herpetiformis, comprising administering to a human or other mammal in need thereof a compound of claim 1.
16) A method for treating or preventing one or more of the following conditions in humans and/or other mammals: tumor growth, retinopathy, diabetic retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age related macular degeneration; rheumatoid arthritis, psoriasis, bullous disorder associated with subepidermal blister formation, bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis, in combination with an infectious disease selected from the group consisting of: tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga's disease resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin resulting from E. coli infection, effects of enterotoxin A
resulting from Staphylococcus infection, meningococcal infection, and infections from Borrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV), said method comprising administering to a human or other mammal in need thereof a compound of claim 1.
17) A method for treating or preventing diseases mediated by the VEGF-induced signal transduction pathway comprising administering a compound selected from the group consisting of:
.cndot. 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-carbothioic acid amide;
.cndot. 4-{3-[3-(2,2,4,4-Tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-ureido]-phenoxy}-pyridine-2-carboxylic acid (1-piperidyl)-amide;
.cndot. 4-{3-[3-(2,2,4,4-Tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-ureido]-phenoxy}-pyridine-2-carboxylic acid (4-morpholino)-amide;
.cndot. 4-(3-[3-(1-Methyl-1H-indazol-5-yl)-ureido]-phenoxy}-pyridine-2-carboxylic acid (4-morpholino)-amide;
.cndot. 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-carboxamidine;
.cndot. 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-{4-[2-(1H-tetrazol-5-yl)-pyridinyl-4-oxy]-phenyl}-urea;
.cndot. 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-{4-[2-(4,5-dihydro-1H-imidazol-2-yl)-pyridinyl-4-oxy]-phenyl}-urea;

.cndot. 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-N-methyl-pyridine-2-carboxamidine;
or a salt form, prodrug or metabolite thereof.
18) A method for treating or preventing cancer comprising administering a compound selected from the group consisting of:
.cndot. N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(hydrazinocarbonyl)pyridin-4-yl]oxy}phenyl)urea .cndot. N-(4-{[2-(hydrazinocarbonyl)pyridin-4-yl]oxy}phenyl)-N'-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)urea .cndot. N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[3-({2-[(2,2-dimethylhydrazino)carbonyl]pyridin-4-yl}oxy)phenyl]urea .cndot. 4-{3-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-piperidin-1-ylpyridine-2-carboxamide .cndot. N-piperidin-1-yl-4-[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxamide .cndot. 4-{3-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-morpholin-4-ylpyridine-2-carboxamide .cndot. N-morpholin-4-yl-4-[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxamide .cndot. 4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]-N-morpholin-4-ylpyridine-2-carboxamide .cndot. N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(1H-tetrazol-5-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(4-methyl-1,3-thiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. N-quinolin-6-yl-N'-(4-{[2-(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)urea .cndot. N-(4-{[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-4-yl]oxy}phenyl)-N'-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)urea .cndot. 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboximidamide .cndot. 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino)carbonyl)amino]phenoxy}pyridine-2-carboximidamide .cndot. N-methyl-4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboximidamide .cndot. N-methyl-4-(4-{[(quinolin-6-ylamino)carbonyl]amino}phenoxy)pyridine-2-carboximidamide .cndot. 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridine-2-carbothioamide .cndot. 4-(4-{[(quinolin-6-ylamino)carbonyl]amino}phenoxy)pyridine-2-carbothioamide .cndot. 4-[4-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carbothioamide, or a salt form, prodrug or metabolite thereof.
19) A compound of formula (I) or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein A is wherein A is optionally substituted with 1-4 substituents which are independently R1, OR1, S(O)p R1, C(O)R1, C(O)OR1, C(O)NR1R2, halogen, hydroxy, amino, cyano, or nitro;
B is phenyl, naphthyl, or pyridyl, optionally substituted with 1-4 substituents which are independently C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, or nitro;
L is (a) -(CH2)m-O-(CH2)l-, (b) -(CH2)m-(CH2)l-, (c) -(CH2)m-C(O)-(CH2)l-, (d) -(CH2)m-NR3-(CH2)l-, (e) -(CH2)m- NR3C(O)-(CH2)l-, (f) -(CH2)m-S-(CH2)l-, (g) -(CH2)m-C(O)NR3-(CH2)l-, or (h) a single bond;
m and l are integers independently selected from 0-4;
M is a pyridine ring, optionally substituted with 1-3 substituents which are independently C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, or nitro;
Q is:
(1) C(S)NR4R5;
(2) C(O)NR7-NR4R5;
(3) tetrazolyl;
(4) imidazolyl;
(5) imidazoline-2-yl;
(6) 1,3,4-oxadiazoline-2-yl;
(7) 1,3-thiazoline-2-yl;
(8) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl;
(9) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or (10) a group of the formula wherein each of R1, R2, R3, R4 and R5 is independently (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) phenyl, (d) C1-C3 phenyl-alkyl, (e) up to per-halo substituted C1-C5 linear or branched alkyl, or (f) -(CH2)q-X, where X is a 5 or 6 membered heterocyclic ring, containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or a 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S;
R4 and R5 may additionally be taken together to form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, optionally substituted with 1-3 substituents which are independently C1-C5 linear or branched alkyl, up to perhalo substituted C1-C5 linear or branched alkyl, C1-C3 alkoxy, hydroxy, oxo, carboxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, or nitro;
R6 is independently (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) cyano, (d) nitro, (e) up to per-halo substituted C1-C5 linear or branched alkyl. or (f) -C(O)R7, where R7 is C1-C5 linear, branched, or cyclic alkyl;
R7 is hydrogen or linear, branched, or cyclic C1-C5 alkyl;
q is an integer 0, 1, 2, 3, or 4 and p is an integer 0, 1, or 2.
20) A compound of claim 19 wherein B is phenyl or pyridinyl, optionally substituted with 1-4 halogen.
21) A compound of claim 19 wherein L is -O- and B is phenyl or pyridinyl, optionally substituted with 1-4 halogen.
22) A compound as in claim 19 wherein B is phenyl or pyridyl, L is -O-, M a pyridine ring substituted only by Q, and Q is C(S)NR4R5;
C(O)NR7-NR4R5;
or a group of the formula with each of R4 and R5, independently:
(a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) phenyl, (d) C1-C3 phenyl-alkyl, (e) up to per-halo substituted C1-C5 linear or branched alkyl, or (f) -(CH2)q-X, where the substituent X is pyridinyl and the variable q is preferably an integer 0 or 1, and R6 is:

(a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, or (c) cyano.
23) A compound of formula (I) or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein A is wherein A is optionally substituted with 1-4 substituents which are independently R1, OR1, or halogen;
B is phenyl or pyridinyl, optionally substituted with 1-4 substituents which are independently C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, or nitro, L is -O-, M is a pyridine ring, Q is:

(1) C(S)NR4R5;
(2) C(O)NR7-NR4R5;
(3) tetrazolyl;
(4) imidazolyl;
(5) imidazoline-2-yl;
(6) 1,3,4-oxadiazoline-2-yl;
(7) 1,3-thiazoline-2-yl;
(8) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl;
(9) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or (10) a group of the formula wherein each of R1, R4 and R5 is independently (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) phenyl, (d) C1-C3 phenyl-alkyl, (e) up to per-halo substituted C1-C5 linear or branched alkyl, or (f) -(CH2)q- X, where X is a 5 or 6 membered heterocyclic ring, containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or a 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S;

R4 and R5 may additionally be taken together to form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom selected from N, O or S, optionally substituted with 1-3 substituents which are independently C1-C5 linear or branched alkyl, up to perhalo substituted C1-C5 linear or branched alkyl, C1-C3 alkoxy, hydroxy, oxo, carboxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, or nitro;

R6 is independently (a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) cyano, (d) nitro, (e) up to per-halo substituted C1-C5 linear or branched alkyl. or (f) -C(O)R7, where R7 is C1-C5 linear, branched, or cyclic alkyl;

R7 is hydrogen or linear, branched, or cyclic C1-C5 alkyl;
q is an integer 0, 1, 2, 3, or 4 and p is an integer 0, 1, or 2.
24) A compound of claim 23 wherein B is phenyl or pyridinyl, substituted with 1-4 halogen.
25) A compound as in claim 23 wherein M a pyridine ring substituted only by Q, and Q is C(S)NR4R5;
C(O)NR7-NR4R5;
or a group of the formula with each of R4 and R5, independently:

(a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, (c) phenyl, {d) C1-C3 phenyl-alkyl, (e) up to per-halo substituted C1-C5 linear or branched alkyl, or (f) -(CH2)q- X, where the substituent X is pyridinyl and the variable q is preferably an integer 0 or 1, and R6 is:

(a) hydrogen, (b) C1-C5 linear, branched, or cyclic alkyl, or (c) cyano.

95~
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