EP1109555A1 - Novel angiogenesis inhibitors - Google Patents

Novel angiogenesis inhibitors

Info

Publication number
EP1109555A1
EP1109555A1 EP99912408A EP99912408A EP1109555A1 EP 1109555 A1 EP1109555 A1 EP 1109555A1 EP 99912408 A EP99912408 A EP 99912408A EP 99912408 A EP99912408 A EP 99912408A EP 1109555 A1 EP1109555 A1 EP 1109555A1
Authority
EP
European Patent Office
Prior art keywords
benzoimidazol
alkyl
aryl
phenyl
heterocyclyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99912408A
Other languages
German (de)
French (fr)
Other versions
EP1109555A4 (en
Inventor
Mark T. Bilodeau
Randall W. Hungate
April M. Cunningham
Timothy J. Koester
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1109555A1 publication Critical patent/EP1109555A1/en
Publication of EP1109555A4 publication Critical patent/EP1109555A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/04—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic 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
    • C07D417/02—Heterocyclic 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
    • C07D417/04—Heterocyclic 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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphospate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Accordingly, inhibitors of these tyrosine kinases are useful for the prevention and treatment chemotherapy of proliferative diseases dependent on these enzymes. For example, a method of treatment described herein relates to neoangiogenesis. Neoangiogenesis occurs in conjunction with tumor growth and in certain diseases of the eye. It is characterized by excessive activity of vascular endothelial growth factor.
  • VEGF Vascular endothelial growth factor binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1.
  • KDR mediates the mitogenic function of VEGF
  • Flt-1 appears to modulate non- mitogenic functions such as those associated with cellular adhesion.
  • Inhibiting KDR thus modulates the level of mitogenic VEGF activity.
  • Vascular growth in the retina leads to visual degeneration culminating in blindness.
  • VEGF accounts for most of the angiogenic activity produced in or near the retina in diabetic retinopathy.
  • Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased p0 2 levels in mice that lead to neovascularization.
  • Intraocular injections of anti-VEGF monoclonal antibodies or VEGF receptor immunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease.
  • VEGF vascular endothelial growth factor
  • monoclonal anti-VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities.
  • These monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells.
  • VEGF-binding construct of Flk-1 Viral expression of a VEGF-binding construct of Flk-1, the mouse KDR receptor homologue, truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors.
  • Embryonic stem cells which normally grow as solid tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors.
  • KDR or Flt-1 are implicated in pathological neoangiogenesis, and these are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., diabetic retinal vascularization, as well as various forms of cancer.
  • Cancers which are treatable in accordance with the present invention demonstrate high levels of gene and protein expression.
  • cancers include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
  • Raf-activating oncogenes e.g., K-ras, erb-B
  • the present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, atherosclerosis, diabetic retinopathy or inflammatory diseases, in mammals.
  • X is N or C
  • Rj&R 3 are independently H, C 0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a :
  • R 2 is independently H, C,_ 6 alkyl, C 5 . 10 aryl, C3-.6 cycloalkyl,
  • R 4 &R 5 are independently H, C 0 alkyl, C3-6 cycloalkyl, C ⁇ 6 alkoxy C 2 . ⁇ o alkenyl, C 2-10 alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl,
  • C 1-6 alkoxyNR 7 R 8 halo, N0 2 , OH, -NH 2 or C 5 .
  • 10 heteroaryl said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a , or R4 and R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from R a .
  • R a is H, C 0 alkyl, halogen, N0 2 , R, NHC,. 6 alkylR ⁇ , OR, -NR
  • R is H, C j . 6 alkyl or C 1 -6 alkylR 9 ;
  • R 9 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R7&R8 are independently H, C,. 10 alkyl, C3-6 cycloalkyl, COR,
  • X is N or C
  • Rj is H, C 0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 . 10 heterocyclyl, or C . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H, C 6 alkyl, C 5 _ 10 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
  • R 4 is H, Cj., 0 alkyl, C3-6 cycloalkyl, C N6 alkoxy C 2 . 10 alkenyl, C 2 - ⁇ o alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, C ⁇ - 6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R is H, or C,. 6 alkyl, OR, halo, NH 2 or N0 2 ;
  • R is H, C J . JO alkyl, halogen, N0 2 , OR, -NR NR 7 R 8 , R 7 R 8) C 5 . 10 aryl, C 5 . 10 heteroaryl or C 3 . 10 heterocyclyl;
  • R is H, or C,_ 6 alkyl, C ⁇ -6 alkylR 9 ;
  • RQ is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl;
  • R7&R8 are independently H, C M0 alkyl, C3-6 cycloalkyl, COR, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • composition which is comprised of a compound represented by the formula I:
  • R,, R 2 , R 3 , R 4 and R 5 are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.
  • Also included is a method of treating or preventing a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof. Also included is a method of treating or preventing cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.
  • Also included in the present invention is a method of treating or preventing diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis.
  • a method of treating or preventing ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.
  • a method of treating or preventing retinal vascularization is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for treating retinal vascularization.
  • Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overall disease etiology.
  • a method of treating or preventing age-related macular degeneration is also included.
  • alkyl refers to a monovalent alkane
  • hydrocarbon (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic.
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl.
  • Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following:
  • the alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
  • substituted alkyl when substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups of R a , described herein.
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present.
  • Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted with one to three groups of R a , when a substituted alkenyl group is provided.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted with 1-3 groups of R a , when a substituted alkynyl group is provided.
  • Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
  • Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted with 1-3 groups of R a as defined herein.
  • Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
  • heterocycle, heteroaryl, heterocyclyl or heterocyclic represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • the heterocycle, heteroaryl or heterocyclic may be substituted with 1-3 groups of R a .
  • Examples of such heterocyclic elements, inclusive of all possible isomers, include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, iso
  • alkoxy refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
  • halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
  • prodrug refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process.
  • exemplary prodrugs include acyl amides of the amino compounds of this inventon such as amides of alkanoic(C ⁇ _ 6 )acids, amides of aryl acids (e.g., benzoic acid) and alkane(C. perennial 6 )dioic acids.
  • Tyrosine kinase dependent diseases or conditions refers to hyperproliferative disorders which are initiated/maintained by aberrant tyrosine kinase enzyme activity. Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (e.g. tumor growth, diabetic retinopathy), etc.
  • X is N or C
  • R,&R 3 are independently H, C M0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • Ro is independently H, C,_ 6 alkyl, C 5 . 10 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
  • R 4 &R 5 are independently H, C,_ 10 alkyl, C3-6 cycloalkyl, C,_ 6 alkoxy C 2- ⁇ o alkenyl, C 2- ⁇ o alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, C ⁇ -6 alkoxyNR 7 R 8 , halo, N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, .
  • alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a , or R4 a ⁇ j R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from R a .
  • R a is H, C 0 alkyl, halogen, N0 2 , R, NHC,. 6 alkylR 9 , OR, -NR,
  • R is H, C,. 6 alkyl or C ⁇ -6 alkylR 9 ;
  • R 9 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R7&R8 are independently H, C M o alkyl, C3-6 cycloalkyl, COR, C 5 _ ⁇ 0 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • Still another aspect of this invention is described wherein . is C 0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, C 5 . 10 heteroaryl, or C 3 . 10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Rj is C M0 alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • R a is H, C LI O alkyl, halogen, C 1-6 alkylR 9 , CN, R, OR, NR, RNR 7 R 8 , NR 7 R 8 , R 7 R 8 and all other variables are as described above.
  • R,&R 3 are independently H, C M0 alkyl, C 5 . 10 aiyl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 is independently H, C,. 6 alkyl, C 3-6 cycloalkyl, OH, or halogen;
  • R 4 &R 5 are independently H, C,. 10 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl, C ⁇ -6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ; and all other variables are as described above.
  • Another preferred subset of compounds of the present invention is realized when:
  • R 1 &R 3 are independently C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 is H or C,. 6 alkyl
  • R 4 is piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, is
  • X is N or C
  • R is H, C 0 alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H, C,. 6 alkyl, OH, N0 2 , -NH 2 , or halogen;
  • R 4 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, C 1-6 alkoxyNR 7 R 8 , or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 5 is H, C,. 6 alkyl, OR, halo, NH 2 or N0 2 ;
  • R a is H, C 0 alkyl, halogen, N0 2 , R, OR, -NR, NR 7 R 8j R 7 R 8 , C 5 . 10 aryl, C 5 . 10 heteroaryl or C 3 . 10 heterocyclyl,
  • R is H, or C,_ 6 alkyl, C ⁇ -6 alkylR 9 ;
  • R 9 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl;
  • R7&R8 are independently H, C M0 alkyl, C3-6 cycloalkyl, COR, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • R4 is C J . JO alkyl, C 3-6 cycloalkyl, C 5 .j 0 aryl, C 5 . 10 heteroaryl, or C 3 . 10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Rj is C J . JO alkyl, C 5 .j 0 aryl, C 3 .j 0 heterocyclyl, or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Rj is H, C J . J O alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H, C,_ 6 alkyl, C 3-6 cycloalkyl, OH, or halogen;
  • R 4 is H, C J . JO alkyl, C 3 . 6 cycloalkyl, C 5 ., 0 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl, Cj -6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ; and all other variables are as described above.
  • Rj is C 5 _i 0 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H or Cj. 6 alkyl
  • R 4 is C J . JO alkyl, C 5 ., 0 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from
  • X & W are independently N or C
  • R j &R 3 are independently H, C J . J0 alkyl, C 3-6 cycloalkyl, C 5 .j 0 aryl, halo, OH, C 3 _i 0 heterocyclyl, or C 5 .j 0 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 9 is independently H, Cj. 6 alkyl, C 5 ., 0 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
  • R is independently H, Cj. 10 alkyl, C3-6 cycloalkyl, Cj. 6 alkoxy C 2 _ ⁇ o alkenyl, C 2- ⁇ o alkynyl, C 5 .j 0 aryl, C 3 .j 0 heterocyclyl, Cj. 6 alkoxyNR 7 R 8 , halo, N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • Rio is H, or Cj. 6 alkyl, Cj. 6 alkylR 9 , C 5 . 10 aryl, C 3 . 10 heterocyclyl, NHC j . 6 alkylR 9; said alkyl (where R is C j . 6 alkyl), aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R is H, C J . JO alkyl, halogen, N0 2 , OR, -NR RNR 7 R 8 , NR 7 R 8 ,
  • R 7 R 8 CN, C 5 ., 0 aryl, C 5 . 10 heteroaryl or C 3 .j 0 heterocyclyl;
  • R is H, Cj. 6 alkyl or Cj. 6 alkylR 9 ;
  • R 9 is C 5 .jo aryl, C 3 .j 0 heterocyclyl, or C 5 .] 0 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R7&R8 are independently H, C 0 alkyl, C3-6 cycloalkyl, COR,
  • C 5 _jo aryl, C 3 .j 0 heterocyclyl, or C 5 .j 0 heteroaryl said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • R 10 is H, C,., 0 alkyl, Cj -6 alkylR 9 , C 5 .j 0 aryl, C 5 . 10 heteroaryl, or C 3 .j 0 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Examples of the compounds of this invention are:
  • the invention described herein includes a pharmaceutical composition which is comprised of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with a carrier.
  • pharmaceutically acceptable salts and “hydrates” refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, abso ⁇ tion, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which are also important in the selection are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
  • a counterion e.g., an alkali metal cation such as sodium or potassium.
  • suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
  • An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality.
  • the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.
  • salts also include acid addition salts.
  • the compound can be used in the form of salts derived from inorganic or organic acids or bases. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • any variable e.g., aryl, heterocyle, Rl, etc
  • the compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.
  • the compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
  • the carrier employed may be, for example, either a solid or liquid.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • the carrier for oral use may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
  • Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
  • oral solid dosage forms examples include tablets, capsules, troches, lozenges and the like. The size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500mg.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions. Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.
  • the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.
  • dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors.
  • An example of a suitable oral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided doses.
  • An example of a suitable parenteral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection.
  • An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day.
  • An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.
  • the compounds may be administered in conventional dosages as a single agent or in combination with other therapeutically active compounds.
  • the non-limiting examples that follow are illustrations of the compounds of the instant invention and are not meant to limit the invention in any way.
  • Nitroaniline 5 (0.213 g, 0.665 mmol) and palladium on carbon (10%, 100 mg) were stirred in 8 mL 3: 1 EtOH/AcOH. The reaction was put under a balloon of H 2 . After 2 h the reaction was filtered through a plug of celite and the filtrate was concentrated to dryness. The resulting residue was dissolved in 1.5 mL trimethylorthoformate and heated to 120 ° C for 30 min. The solution was cooled concentrated to dryness and purified by flash column chromatography (2 x 15 cm silica gel, 1 : 1 hexane/ethyl acetate) which provided 6.
  • Benzimidazole 7 (0.025g, 0.087 mmol) and N-(2- chloroethyl)piperidine hydrochloride (11 mg, 0.059 mmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL). Cesuim carbonate (0.085g, 0.26 mmol) was added and the resulting mixture was heated to 50 °C. After 2 h additional and N-(2-chloroethyl)pi ⁇ eridine hydrochloride (11 mg, 0.059 mmol) was added. After 1 h the reaction was allowed to cool, quenched with water and extracted with ethyl acetate (3x).
  • the bromochloronitropyridine was dissolved in 15mL of anhydrous l-methyl-2-pyrrolidinone.
  • Aniline (3.580 mL, 0.0393 mol) was added followed by the addition of N,N-diisopropylethylamine (13.69 mL, 0.0786 mol) and the solution was heated to 120 °C. After 1.5 hr., the solution was cooled to ambient temperature and diluted with water. The product was extracted using ethyl acetate and washed with brine. The organic layer was then dried over sodium sulfate, filtered, concentrated, and dried in vacuo.
  • Bromoaromatic 10 (30 mg, 0.102 mmol), 4- methoxyphenylboronic acid (17 mg, 0.112 mmol) was dissolved in 0.75 mL dioxane followed by the addition of 204 ⁇ L of 2M sodium carbonate.
  • the vessel was flushed with argon followed by the addition of tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) and 0.56 mL water.
  • the vessel was flushed again with argon and heated to 80 °C for 2.5 hr.
  • the solution was cooled to room temperature and diluted with water.
  • the product was extracted with ethyl acetate and washed with brine, followed by drying over sodium sulfate.
  • the organic layer was concentrated, and the product dried in vacuo.
  • the crude mixture was purified by flash column chromatography (2.5 x 8 cm silica gel, 8:2 hexane:ethyl
  • Nitroaniline 11 (1.333 g, 4.15 mmol), Zn dust(6.239 g, 95.40 mmol), and 10 mL acetic acid were mixed under argon. The solution was heated to 60 °C for 1 hr until the solution turned light green. The zinc was removed using vacuum filtration with celite and washed with acetic acid. The filtrate was concentrated and 20 mL of trimethylorthoformate was added. The solution was heated to 100 °C for 2 hr followed by cooling to ambient temperature. The solution was concentrated and the crude mixture was purified by flash column chromatography(5 x 16 cm silica gel, 6:4 ethylacetate:hexane) affording 12.
  • the aqueous layer was extracted a second time with dichloromethane w/ 3% 1-butanol.
  • the organic layers were washed with saturated sodium bicarbonate, and dried over sodium sulfate.
  • the organic layers were conentrated at aspirator pressure to remove ethyl acetate and methylene chloride; the 1-butanol and residual DMF were removed under high pressure.
  • the product was purified using flash column chromatography(silica gel 2.5 x 32.5 cm, 10:1 methylene chloride :methanol). Excess trifluoroacetic acid was added to the product to create the resulting salt, and the mixture was triturated using ether.
  • Bromoaromatic 4 (7.10 g, 24.1 mmol) and powdered zinc (36.2 g, 554 mmol, 23 equiv) were stirred in 80 mL glacial acetic acid. The mixture was heated to 60 °C. After lh the reaction was cooled and filtered through a plug of celite and concentrated to dryness. The resulting residue was dissolved in 60 mL of formic acid and heated to 100 °C overnight. The reaction was cooled and concentrated to dryness. Purification by flash column chromatography (6x25 cm silica, 55:45 hexanes/EtOAc) afforded 5.88 g benzimidazole 15 (89% yield). !
  • Benzimidazole 15 (2.91 g, 10.7 mmol), diboron pinacol ester (2.97 g, 11.7 mmol) and potassium acetate (3.14 g, 32.0 mmol) were stirred in 20 mL anhydrous DMF under Ar.
  • PdCl 2 (dppf) (0.26 g, 0.32 mmol) was added, solution was degassed and heated to 80 °C. After 20h the reaction was quenched with 125 mL of water and 50 mL of saturated aqueous NaCl and was extracted 3 x with EtOAc. The combined extracts were dried over Na 2 S0 4 , filtered and concentrated to afford 2.77 g of unpurified boronate.
  • l-Phenyl-5-pyridin-4-yl-lH-benzoimidazole (12) (8.82 g, 32.5 mmol) was dissolved in 120 mL of CH 2 C1 2 .
  • the resulting solution was cooled to 0°C and to it was added mCPBA (11.2 g, 65.0 mmol). After stirring for 2.5 days an additional portion of mCPBA (3.0 g, 17 mmol) was added. After an additional 24 h the reaction solution was loaded directly onto a column (8 x 20 cm) pre-wetted with CH 2 C1 2 .
  • N-3-chloropiperidine HC1 54 mg, .275 mmol
  • cesium carbonate 164 mg, .504 mmol
  • 4 mL anhydrous N,N- dimethylformamide 4 mL
  • the vessel was placed in 60 °C oil bath with stirring under argon.
  • the reaction was heated to 80 °C after 1 day, and was stopped after 4 days after no further progression.
  • the solvent was removed via high vacuum rotary evaporation, the residue was diluted with MeOH, and filtered through a 0.7 ⁇ M syringe filter.
  • VEGF RECEPTOR KINASE ASSAY VEGF receptor kinase activity is measured by incorporation of radio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY) substrate.
  • the phosphorylated pEY product is trapped onto a filter membrane and the incoporation of radio-labeled phosphate quantified by scintillation counting.
  • the intracellular tyrosine kinase domains of human KDR (Terman, B.I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519-524) were cloned as glutathione S-transferase (GST) gene fusion proteins. This was accomplished by cloning the cytoplasmic domain of the KDR kinase as an in frame fusion at the carboxy terminus of the GST gene.
  • GST glutathione S-transferase
  • Soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf 1) insect cells (Invitrogen) using a baculo virus expression vector (pAcG2T, Pharmingen).
  • EDTA 0.05% triton X-100, 10 % glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsulfonyl fluoride.
  • Millipore #MAFC NOB GF/C glass fiber 96 well plate.
  • reaction mix containing 5 ⁇ l of 10 X reaction buffer, 5 ⁇ l 25 mM ATP/10 ⁇ Ci [ 33 P]ATP (Amersham), and 5 ⁇ l 10 X substrate.
  • VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells.
  • Human umbilical vein endothelial cells (HUVECs) in culture proliferate in response to VEGF treatment and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation.
  • quiescent HUVEC monolayers are treated with vehicle or test compound 2 hours prior to addition of VEGF or basic fibroblast growth factor (bFGF).
  • the mitogenic response to VEGF or bFGF is determined by measuring the incorporation of [ 3 H]thymidine into cellular DNA.
  • HUVECs frozen as primary culture isolates are obtained from Clonetics Corp. Cells are maintained in Endothelial Growth Medium (EGM; Clonetics) and are used for mitogenic assays at passages
  • IPX Growth factors Solutions of human VEGF 165 (500 ng/ml; R&D Systems) and bFGF (10 ng/ml; R&D Systems) are prepared in Assay Medium.
  • HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4000 cells per 100 ul Assay Medium per well in 96-well plates. Cells are growth-arrested for 24 hours at 37°C in a humidified atmosphere containing 5% C0 2 .
  • Growth-arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% [v/v] DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37°C/5% C0 2 for 2 hours to allow test compounds to enter cells.
  • I are inhibitors of VEGF and thus are useful for the inhibition of neoangiogenesis, such as in the treatment of occular disease, e.g., diabetic retinopathy and in the treatment of cancers, e.g., solid tumors.
  • the instant compounds inhibit VEGF-stimulated mitogenesis of human vascular endothelial cells in culture with IC 50 values between 150-650 nM. These compounds also show selectivity over related tyrosine kinases (e.g. FGFR1 and the Src family).

Abstract

The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as angiogenesis, cancer, atherosclerosis, diabetic retinopathy or autoimmune diseases, in mammals.

Description

TITLE OF THE INVENTION
NOVEL ANGIOGENESIS INHIBITORS
BACKGROUND OF THE INVENTION Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphospate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Accordingly, inhibitors of these tyrosine kinases are useful for the prevention and treatment chemotherapy of proliferative diseases dependent on these enzymes. For example, a method of treatment described herein relates to neoangiogenesis. Neoangiogenesis occurs in conjunction with tumor growth and in certain diseases of the eye. It is characterized by excessive activity of vascular endothelial growth factor.
Vascular endothelial growth factor (VEGF) binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1. Cell culture and gene knockout experiments indicate that each receptor contributes to different aspects of angiogenesis. KDR mediates the mitogenic function of VEGF whereas Flt-1 appears to modulate non- mitogenic functions such as those associated with cellular adhesion. Inhibiting KDR thus modulates the level of mitogenic VEGF activity. Vascular growth in the retina leads to visual degeneration culminating in blindness. VEGF accounts for most of the angiogenic activity produced in or near the retina in diabetic retinopathy. Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased p02 levels in mice that lead to neovascularization. Intraocular injections of anti-VEGF monoclonal antibodies or VEGF receptor immunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease.
Expression of VEGF is also significantly increased in hypoxic regions of animal and human tumors adjacent to areas of necrosis. Monoclonal anti-VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities. These monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells. Viral expression of a VEGF-binding construct of Flk-1, the mouse KDR receptor homologue, truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors. Embryonic stem cells, which normally grow as solid tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors. Inhibition of KDR or Flt-1 is implicated in pathological neoangiogenesis, and these are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., diabetic retinal vascularization, as well as various forms of cancer.
Cancers which are treatable in accordance with the present invention demonstrate high levels of gene and protein expression. Examples of such cancers include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, atherosclerosis, diabetic retinopathy or inflammatory diseases, in mammals.
SUMMARY OF THE INVENTION
A compound is disclosed in accordance with formula la:
la
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
X is N or C;
Rj&R3 are independently H, C 0 alkyl, C3-6 cycloalkyl, C5.10 aryl, halo, OH, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra: R2 is independently H, C,_6 alkyl, C5.10 aryl, C3-.6 cycloalkyl,
OH, N02, -NH2, or halogen;
R4&R5 are independently H, C 0 alkyl, C3-6 cycloalkyl, Cμ6 alkoxy C2.ιo alkenyl, C2-10 alkynyl, C5.10 aryl, C3.10 heterocyclyl,
C1-6 alkoxyNR7R8, halo, N02, OH, -NH2 or C5.10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra, or R4 and R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from Ra.
Ra is H, C 0 alkyl, halogen, N02, R, NHC,.6 alkylRα, OR, -NR
RNR7R8, NR7R8, R7R8, CN, C5.10 aryl, C5.10 heteroaryl or C3.10 heterocyclyl;
R is H, C j .6 alkyl or C 1 -6 alkylR9;
R9 is C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and
R7&R8 are independently H, C,.10 alkyl, C3-6 cycloalkyl, COR,
C5-10 aryl> Q3-10 heterocyclyl, or C5.10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
Further compounds are disclosed in accordance with formula I:
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
X is N or C;
Rj is H, C 0 alkyl, C3-6 cycloalkyl, C5.10 aryl, halo, OH, C3.10 heterocyclyl, or C .10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2&R3 are independently H, C 6 alkyl, C5_10 aryl, C3-6 cycloalkyl, OH, N02, -NH2, or halogen;
R4 is H, Cj.,0 alkyl, C3-6 cycloalkyl, CN6 alkoxy C2.10 alkenyl, C2-ιo alkynyl, C5.10 aryl, C3.10 heterocyclyl, Cι-6 alkoxyNR7R8, N02, OH, -NH2 or C5.10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R is H, or C,.6 alkyl, OR, halo, NH2 or N02;
R is H, CJ.JO alkyl, halogen, N02, OR, -NR NR7R8, R7R8) C5.10 aryl, C5.10 heteroaryl or C3.10 heterocyclyl;
R is H, or C,_6 alkyl, Cι-6 alkylR9;
RQ is C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; and
R7&R8 are independently H, CM0 alkyl, C3-6 cycloalkyl, COR, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
Also disclosed is a pharmaceutical composition which is comprised of a compound represented by the formula I:
wherein R,, R2, R3, R4 and R5 are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.
Also included is a method of treating or preventing a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof. Also included is a method of treating or preventing cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof. Also included in the present invention is a method of treating or preventing diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis.
More particularly, a method of treating or preventing ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.
More particularly, a method of treating or preventing retinal vascularization is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for treating retinal vascularization. Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overall disease etiology. Also included is a method of treating or preventing age-related macular degeneration.
These and other aspects of the invention will be apparent from the teachings contained herein.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described herein in detail using the terms defined below unless otherwise specified. The term "alkyl" refers to a monovalent alkane
(hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic.
Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl.
Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following:
herein: x plus y = from 0-10; and w plus z = from 0-9.
The alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups of Ra, described herein.
The term "alkenyl" refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted with one to three groups of Ra, when a substituted alkenyl group is provided. The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted with 1-3 groups of Ra, when a substituted alkynyl group is provided.
Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like. Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted with 1-3 groups of Ra as defined herein. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
The term heterocycle, heteroaryl, heterocyclyl or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The heterocycle, heteroaryl or heterocyclic may be substituted with 1-3 groups of Ra. Examples of such heterocyclic elements, inclusive of all possible isomers, include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.
The term "alkoxy" refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
The term "halogen" is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
The term "prodrug" refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process. Exemplary prodrugs include acyl amides of the amino compounds of this inventon such as amides of alkanoic(Cι_6)acids, amides of aryl acids (e.g., benzoic acid) and alkane(C.„6)dioic acids.
Tyrosine kinase dependent diseases or conditions refers to hyperproliferative disorders which are initiated/maintained by aberrant tyrosine kinase enzyme activity. Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (e.g. tumor growth, diabetic retinopathy), etc.
One embodiment of the present invention is in accordance with formula la:
la or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
X is N or C;
R,&R3 are independently H, CM0 alkyl, C3-6 cycloalkyl, C5.10 aryl, halo, OH, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
Ro is independently H, C,_6 alkyl, C5.10 aryl, C3-6 cycloalkyl, OH, N02, -NH2, or halogen;
R4&R5 are independently H, C,_10 alkyl, C3-6 cycloalkyl, C,_6 alkoxy C2-ιo alkenyl, C2-ιo alkynyl, C5.10 aryl, C3.10 heterocyclyl, Cι-6 alkoxyNR7R8, halo, N02, OH, -NH2 or C5.10 heteroaryl, . said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra, or R4 aικj R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from Ra. Ra is H, C 0 alkyl, halogen, N02, R, NHC,.6 alkylR9, OR, -NR,
RNR7R8; NR7R8, R7R8, CN, C5.10 aryl, C5.10 heteroaryl or C3.10 heterocyclyl;
R is H, C,.6 alkyl or Cι-6 alkylR9;
R9 is C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and
R7&R8 are independently H, CMo alkyl, C3-6 cycloalkyl, COR, C5_ι0 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
An aspect of this invention is described wherein X is C and all other variables are as described above.
Another aspect of this invention is described wherein X is N and all other variables are as described above.
Still another aspect of this invention is described wherein . is C 0 alkyl, C3-6 cycloalkyl, C5.10 aryl, C5.10 heteroaryl, or C3.10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
In yet another aspect, the invention is described wherein Rj is CM0 alkyl, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
Another aspect of this invention is described wherein Ra is H, CLI O alkyl, halogen, C1-6 alkylR9, CN, R, OR, NR, RNR7R8, NR7R8, R7R8 and all other variables are as described above.
A preferred subset of compounds of the present invention is realized when: R,&R3 are independently H, CM0 alkyl, C5.10 aiyl, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2 is independently H, C,.6 alkyl, C3-6 cycloalkyl, OH, or halogen;
R4&R5 are independently H, C,.10 alkyl, C3-6 cycloalkyl, C5.10 aryl, C5.10 heteroaryl, C3.10 heterocyclyl, Cι-6 alkoxyNR7R8, N02, OH, -NH2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and all other variables are as described above. Another preferred subset of compounds of the present invention is realized when:
R1&R3 are independently C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2 is H or C,.6 alkyl;
R4 is piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
Another embodiment of the invention is a compound in accordance with formula I:
X is N or C;
R, is H, C 0 alkyl, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2&R3 are independently H, C,.6 alkyl, OH, N02, -NH2, or halogen; R4 is C5.10 aryl, C3.10 heterocyclyl, C1-6 alkoxyNR7R8, or C5.10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R5 is H, C,.6 alkyl, OR, halo, NH2 or N02;
Ra is H, C 0 alkyl, halogen, N02, R, OR, -NR, NR7R8j R7R8, C5.10 aryl, C5.10 heteroaryl or C3.10 heterocyclyl,
R is H, or C,_6 alkyl, Cι-6 alkylR9;
R9 is C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; and
R7&R8 are independently H, CM0 alkyl, C3-6 cycloalkyl, COR, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
An aspect of this invention is described wherein X is C and all other variables are as described above. Another aspect of this invention is described wherein X is N and all other variables are as described above.
Still another aspect of this invention is described wherein R4 is CJ.JO alkyl, C3-6 cycloalkyl, C5.j0 aryl, C5.10 heteroaryl, or C3.10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
In yet another aspect, the invention is described wherein Rj is CJ.JO alkyl, C5.j0 aryl, C3.j0 heterocyclyl, or C5.10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
A prefered embodiment of this invention is realized when: Rj is H, CJ.J O alkyl, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2&R3 are independently H, C,_6 alkyl, C3-6 cycloalkyl, OH, or halogen;
R4 is H, CJ.JO alkyl, C3.6 cycloalkyl, C5.,0 aryl, C5.10 heteroaryl, C3.10 heterocyclyl, Cj-6 alkoxyNR7R8, N02, OH, -NH2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
Another prefered embodiment of this invention is realized when: Rj is C5_i0 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2&R3 are independently H or Cj.6 alkyl;
R4 is CJ.JO alkyl, C5.,0 aryl, C5.10 heteroaryl, C3.10 heterocyclyl said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from
Ra; and all other variables are as described above.
Still another embodiment of the invention is a compound in accordance with formula Ila:
Ha or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
X & W are independently N or C;
Rj&R3 are independently H, CJ.J0 alkyl, C3-6 cycloalkyl, C5.j0 aryl, halo, OH, C3_i0 heterocyclyl, or C5.j0 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R9 is independently H, Cj.6 alkyl, C5.,0 aryl, C3-6 cycloalkyl, OH, N02, -NH2, or halogen;
R, is independently H, Cj.10 alkyl, C3-6 cycloalkyl, Cj.6 alkoxy C2_ιo alkenyl, C2-ιo alkynyl, C5.j0 aryl, C3.j0 heterocyclyl, Cj.6 alkoxyNR7R8, halo, N02, OH, -NH2 or C5.10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
Rio is H, or Cj.6 alkyl, Cj.6 alkylR9, C5.10 aryl, C3.10 heterocyclyl, NHCj.6 alkylR9; said alkyl (where R is Cj.6 alkyl), aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R is H, CJ.JO alkyl, halogen, N02, OR, -NR RNR7R8, NR7R8,
R7R8, CN, C5.,0 aryl, C5.10 heteroaryl or C3.j0 heterocyclyl;
R is H, Cj.6 alkyl or Cj.6 alkylR9;
R9 is C5.jo aryl, C3.j0 heterocyclyl, or C5.]0 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and
R7&R8 are independently H, C 0 alkyl, C3-6 cycloalkyl, COR,
C5_jo aryl, C3.j0 heterocyclyl, or C5.j0 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
An aspect of this invention is described wherein X or W independently are C and all other variables are as described above.
Another aspect of this invention is described wherein X or W are independently N and all other variables are as described above.
Still another aspect of this invention is described wherein R10 is H, C,.,0 alkyl, Cj-6 alkylR9, C5.j0 aryl, C5.10 heteroaryl, or C3.j0 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above. Examples of the compounds of this invention are:
1) 1 -phenyl-5 -(4-methoxyphenyl)benzimidazole, 2) 1 -phenyl-5-(4-(2-( 1 -piperidinyl)ethoxy)phenyl)benzimidazole, 3) 3-phenyl-6-(4-methoxylphenyl)imidazo[4,5-b]pyridine,
4) 3-phenyl-6-(4-(2-( 1 -piperidinyl)ethoxy)phenyl)imidazo[4,5-b]pyridine,
5) 3-phenyl-6-(4-(2-( 1 -piperidinyl)ethoxyphenyl)imidazo[4,5-b]pyridine,
6) 3-(2-thiazoyl)-6-(4-(3-(l-piperidinyl)propylphenyl)imidazo[4,5- b]pyridine, 7) 1 -(2-thiazoyl)-5-(4-(3-( 1 -piperidinyl)propyl)phenyl)benzimidazole,
8) l-(3-thiophenyl)-5-(4-(3-(l-piperidinyl)propyl)phenyl)imidazo[4,5- bjpyridine,
9) l-(3-thiophenyl)-5-(4-(3-(l-piperidinyl)propyl)phenyl)benzimidazole,
10) 3-(3-thiophenyl)-6-(4-(3-(l-piperidinyl)propylphenyl)imidazo[4,5- b]pyridine,
11) l-Phenyl-5-[5-(2-piperidin-l-yl-ethoxy)-pyridin-2-yl]-lH- benzimidazole,
12) l-(4-Cyanophenyl)-5-[6-(2-piperidin-l-yl-ethoxy)-pyridin-3-yl]-lH- benzimidazole, 13) l-Phenyl-5-[6-(2-piperidin-l-yl-ethoxy)-pyridin-3-yl]-lH- benzimidazole,
14) l-(3-Cyanophenyl)-5-[6-(2-piperidin-l-yl-ethoxy)-pyridin-3-yl]-lH- benzimidazole,
15) 1 -(3-Thiophene)-5-[6-(2-piperidin- 1 -yl-ethoxy)-pyridin-3-yl]- 1H- benzimidazole,
16) [5-( 1 -Phenyl- 1 H-benzoimidazol-5-yl)-pyridin-2-yl]-(2-piperidin- 1 -yl- ethyl)-amine,
17) [5-( 1 -Phenyl- lH-benzoimidazol-5-yl)-pyridin-2-yl]-(2-morpholin- 1 - yl-ethyl)-amine, 18) 1 -(3-Pyridyl)-5-(4-(2-( 1 -piperidinyl)ethoxy)phenyl)benzimidazole, 19)4-( 1 -phenyl- lH-benzoimidazol-5-yl)- 1 -(3-piperidin- 1 -yl-propyl)- 1 H- pyridin-2-one, 20) 4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 -(3-piperidin- 1 -yl-ethyl)- 1 H- pyridin-2-one, 21) 1 -(2-morpholin-4-yl-ethyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyridin-2-one, 22) 1 -(3-dimethylamino-propyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1H- pyridin-2-one, 23 ) 1 -( 1 -methyl-piperidin-3-ylmethyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5- yl)- 1 H-pyridin-2-one, 24) 1 - [3 -(4-methy lpiperazin- 1 -yl)-propyl)] -4-( 1 -phenyl- 1 H- benzoimidazol-5-yl)- 1 H-pyridin-2-one, 25) 1 -(2-dimethylamino-ρropyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyridin-2-one,
26) 1 -(3 -dimethylamino-2-methyl-propyl)-4-(l -phenyl- 1H- benzoimidazol-5-yl)-lH-pyridin-2-one, 27) 1- [2-(4-cyano-piperidin- 1 -yl)-ethyl]-4-( 1 -phenyl- 1 H-benzoimidazol-
5-yl)-lH-pyridin-2-one, 28) 1 -(3-piperidin- 1 -yl-propyl)-4-( 1 -thiophen-3-yl- 1 H-benzoimidazol-5 - yl)- 1 H-pyridin-2-one,
29) 1 -(3-piperidin- 1 -yl-ethyl)-4-(l -thiophen-3-yl- 1 H-benzoimidazol-5-yl)- lH-pyridin-2-one,
30) 1 -(2-moφholin-4-yl-ethyl)-4-( 1 -thiophen-3-yl- 1 H-benzoimidazol-5- yl)-lH-pyridin-2-one,
31) 1 -(3 -dimethylamino-propyl)-4-( 1 -thioρhen-3 -y 1- 1 H-benzoimidazol-5 - yl)- 1 H-pyridin-2-one,
32) l-(l-methyl-ρiperidin-3-ylmethyl)-4-(l-thioρhen-3-yl-lH- benzoimidazol-5-yl)- 1 H-pyridin-2-one, 33) l-[3-(4-methylρiperazin-l-yl)-propyl)]-4-(l-thioρhen-3-yl-lH- benzoimidazol-5-yl)- 1 H-pyridin-2-one, 34) l-(2-dimethylamino-propyl)-4-(l-thiophen-3-yl-l H-benzoimidazol-5 - yl)- 1 H-pyridin-2-one, 35) 1 -(3-dimethylamino-2-methyl-propyl)-4-( 1 -thiophen-3-yl- 1 H- benzoimidazol-5-yl)-lH-pyridin-2-one,
36) l-[2-(4-cyano-ρiperidin-l-yl)-ethyl]-4-(l-thiophen-3-yl-lH- benzoimidazol-5-yl)- 1 H-pyridin-2-one, 37) 5 -( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 -(3 -piperidin- 1 -yl-propyl)- 1 H- pyridin-2-one, 38) 5-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 -(3-piperidin- 1 -yl-ethyl)- 1H- pyridin-2-one,
39) l-(2-moφholin-4-yl-ethyl)-5-(l-phenyl-lH-benzoimidazol-5-yl)-lH- pyridin-2-one, 40) l-(3-dimethylamino-propyl)-5-(l-phenyl-lH-benzoimidazol-5-yl)-lH- pyridin-2-one,
41) 1 -( 1 -methyl-piperidin-3-ylmethyl)-5-( 1 -phenyl- 1 H-benzoimidazol-5 - yl)- 1 H-pyridin-2-one,
42) 1 -[3-(4-methylpiperazin- 1 -yl)-propyl)]-5-(l -phenyl- 1H- benzoimidazol-5-yl)-lH-pyridin-2-one,
43) 1 -(2-dimethylamino-propyl)-5-(l -phenyl- 1 H-benzoimidazol-5-yl)- 1H- pyridin-2-one,
44) 1 -(3-dimethylamino-2-methyl-propyl)-5-( 1 -phenyl- 1 H- benzoimidazol-5-yl)- 1 H-pyridin-2-one, 45) 1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl]-5-( 1 -phenyl- 1 H-benzoimidazol- 5-yl)- 1 H-pyridin-2-one,
46) 1 -(3-piperidin- 1 -yl-propyl)-5-( 1 -thiophen-3-yl- 1 H-benzoimidazol-5- yl)- 1 H-pyridin-2-one,
47) 1 -(3-piperidin- 1 -yl-ethyl)-5-( 1 -thiophen-3-yl- 1 H-benzoimidazol-5 -yl)- lH-pyridin-2-one,
48) l-(2-moφholin-4-yl-ethyl)-5-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyridin-2-one,
49) l-(3-dimethylamino-propyl)-5-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyridin-2-one, 50) l-(l-methyl-piperidin-3-ylmethyl)-5-(l-thiophen-3-yl-lH- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
51) 1 -[3-(4-methylpiperazin- 1 -yl)-propyl)]-5-( 1 -thiophen-3-yl- 1H- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
52) l-(2-dimethylamino-propyl)-5-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)-lH-pyridin-2-one,
53) l-(3-dimethylamino-2-methyl-propyl)-5-(l-thiophen-3-yl-lH- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
54) 1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl]-5-( 1 -thiophen-3-yl- 1 H- benzoimidazol-5-yl)- 1 H-pyridin-2-one, 55) 5-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 -(3-piperidin- 1 -yl-propyl)- 1 H- pyrimidin-2-one,
56) 5-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 -(3-piperidin- 1 -yl-ethyl)- 1H- pyrimidin-2-one, 57) 1 -(2-moφholin-4-yl-ethyl)-5-(l -phenyl-lH-benzoimidazol-5-yl)-lH- pyrimidin-2-one, 58) 1 -(3 -dimethylamino-propyl)-5 -( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 H- pyrimidin-2-one,
59) 1 -(1 -methyl-piperidin-3-ylmethyl)-5-(l -phenyl- lH-benzoimidazol-5- yl)-lH-pyrimidin-2-one,
60) 1 - [3 -(4-methylpiperazin- 1 -yl)-propyl)] -5-( 1 -phenyl- 1 H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
61) 1 -(2-dimethylamino-propyl)-5-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1H- pyrimidin-2-one, 62) l-(3-dimethylamino-2-methyl-propyl)-5-(l-phenyl-lH- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
63) 1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl]-5-( 1 -phenyl- 1 H-benzoimidazol- 5 -yl)- 1 H-pyrimidin-2-one,
64) 1 -(3-piperidin- 1 -yl-propyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5 - yl)-lH-pyrimidin-2-one,
65) 1 -(3 -piperidin- 1 -yl-ethyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
66) 1 -(2-moφholin-4-yl-ethyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one, 67) 1 -(3-dimethylamino-propyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
68) 1 -( 1 -methyl-piperidin-3 -ylmethyl)-5-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5 -yl)- 1 H-pyrimidin-2-one,
69) 1 -[3 -(4-methylpiperazin- 1 -yl)-propyl)]-5-( 1 -thiophen-3 -yl- 1H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
70) 1 -(2-dimethylamino-propyl)-5-(l -thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
71) 1 -(3-dimethylamino-2-methyl-propyl)-5-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)-lH-pyrimidin-2-one, 72) 1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl]-5-( 1 -thiophen-3 -yl-lH- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
73) 4-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 -(3 -piperidin- 1 -yl-propyl)- 1 H- pyrimidin-2-one, 74) 4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 -(3-piperidin- 1 -yl-ethyl)- 1 H- pyrimidin-2-one, 75) 1 -(2-moφholin-4-yl-ethyl)-4-( 1 -phenyl- lH-benzoimidazol-5-yl)- 1 H- pyrimidin-2-one,
76) 1 -(3 -dimethylamino-propyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyrimidin-2-one,
77) 1 -( 1 -methyl-piperidin-3-ylmethyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
78) 1 -[3 -(4-methylpiperazin- 1 -yl)-propyl)]-4-( 1 -phenyl- 1H- benzoimidazol-5-yl)-lH-pyrimidin-2-one, 79) 1 -(2-dimethylamino-propyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 H- pyrimidin-2-one,
80) 1 -(3 -dimethylamino-2-methyl-ρropyl)-4-( 1 -phenyl- 1 H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
81 ) 1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl] -4-( 1 -phenyl- 1 H-benzoimidazol- 5-yl)-lH-pyrimidin-2-one,
82) 1 -(3-piperidin- 1 -yl-propyl)-4-( 1 -thiophen-3-yl- 1 H-benzoimidazol-5 - yl)- 1 H-pyrimidin-2-one
83) l-(3-piperidin-l-yl-ethyl)-4-(l-thiophen-3-yl-lH-benzoimidazol-5-yl)- 1 H-pyrimidin-2-one, 84) l-(2-moφholin-4-yl-ethyl)-4-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one, 85) 1 -(3 -dimethylamino-propyl)-4-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5 - yl)- 1 H-pyrimidin-2-one,
86) 1 -( 1 -methyl-piperidin-3 -ylmethyl)-4-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
87) 1 -[3-(4-methylpiperazin- 1 -yl)-propyl)]-4-( 1 -thiophen-3 -yl- 1H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
88) l-(2-dimethylamino-propyl)-4-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one, 89) 1 -(3-dimethylamino-2-methyl-propyl)-4-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5 -yl)- 1 H-pyrimidin-2-one,
90) 1 -[2-(4-cyano-piρeridin- 1 -yl)-ethyl]-4-( 1 -thiophen-3 -yl- 1H- benzoimidazol-5 -yl)- 1 H-pyrimidin-2-one, 91) 1 -(4-Pyridyl)-5-(4-(2-( 1 -piperidinyl)ethoxy)ρhenyl)benzimidazole,
92) 1 -(3-Pyridyl)-5-[6-(2-piperidin- 1 -yl-ethoxy)-pyridin-3-yl]- 1 H- benzimidazole, and
93) l-(4-Pyridyl)-5-[6-(2-piperidin-l-yl-ethoxy)-ρyridin-3-yl]-lH- benzimidazole or a pharmaceutically acceptable salt, hydrate or prodrug thereof.
The invention described herein includes a pharmaceutical composition which is comprised of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with a carrier. As used herein the terms "pharmaceutically acceptable salts" and "hydrates" refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absoφtion, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
When a compound of formula I is present as a salt or hydrate which is non-pharmaceutically acceptable, this can be converted to a salt or hydrate form which is pharmaceutically acceptable in accordance with the present invention.
When the compound is negatively charged, it is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium. Other suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc. An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality. Likewise when the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.
Pharmaceutically acceptable salts also include acid addition salts. Thus, the compound can be used in the form of salts derived from inorganic or organic acids or bases. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
The compounds of the present invention, may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. When any variable (e.g., aryl, heterocyle, Rl, etc)occurs more than one time in any constituent or in Formula I, its definition on each occcurence is independent of its definition at every other occurrence, unless otherwise stated. The compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below. The compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
Thus, the carrier employed may be, for example, either a solid or liquid. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the carrier for oral use may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders. Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
Examples of oral solid dosage forms include tablets, capsules, troches, lozenges and the like. The size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500mg. Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like. Examples of injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions. Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.
In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.
For the methods of treatment disclosed herein, dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors. An example of a suitable oral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided doses. An example of a suitable parenteral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection. An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day. An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.
The examples which follow illustrate the compounds that can be synthesized but they are not limited by the compounds in the tables nor by any particular substituents employed in the schemes for illustrative puφoses.
The compounds may be administered in conventional dosages as a single agent or in combination with other therapeutically active compounds. The non-limiting examples that follow are illustrations of the compounds of the instant invention and are not meant to limit the invention in any way.
BrγγN02
l-Bromo-4-fluoro-3-nitrobenzene (3) (1.14 mL, 9.06 mmol) was dissolved in 5 mL of anhydrous l-methyl-2-pyrrolidinone under argon. Aniline (0.870 mL, 9.55 mmol) was added followed by the addition of ,N-diisopropylethylamine (1.90 mL, 10.9 mmol) and the resulting solution was heated to 120 °C. After 14 h additional aniline (0.082 mL, 0.90 mmol) was added and heating was continued for 8 h. The reaction solution was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (3x). The combined extracts was washed with brine, dried over Na2S04, filtered and concentrated in vacuo to provide 4.
Η NMR (CDC13) δ 9.46 (bs, 1H), 8.35 (d, 1H, J = 2.4 Hz), 7.45-7.40 (m, 3H), 7.29-7.25 (m, 3H), 7.10 (d, 1H, J = 9.2 Hz).
Bromoaromatic 4 (0.218 g, 0.744 mmol) and 4-methoxy- boronic acid (0.125 g, 0.823 mmol) were dissolved in a mixture of dioxane (4 mL) and water (3 mL). Sodium carbonate (0.60 g, 5.7 mmol) was added and the resulting mixture was degassed and put under argon. Tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.037 mmol) was added and the reaction was heated to 80 °C. After 14 h the reaction was cooled to ambient temperature, diluted with water and extracted with ethyl actetate (3 ). The combined extracts was dried with Na2S04, filtered and concentrated to dryness. Purification by flash column chromatography (2 x 16 cm silica gel, 6: 1 hexane/ethyl acetate) provided 5.
!H NMR (CDC13) d 9.48 (bs, 1H), 8.40 (d, 1H, J - 2.4 Hz), 7.58 (dd, 1H, J = 2.4, 9.2 Hz), 7.50 (d, 2H, 9.0 Hz), 7.43 (t, 2H, J = 9.0 Hz), 7.32-7.22 (m, 4H), 6.98 (d, 2H, J = 9.0 Hz), 3.83 (s, 3H).
l-phenyl-5-(4-methoxyphenyl)benzimidaole.
Nitroaniline 5 (0.213 g, 0.665 mmol) and palladium on carbon (10%, 100 mg) were stirred in 8 mL 3: 1 EtOH/AcOH. The reaction was put under a balloon of H2. After 2 h the reaction was filtered through a plug of celite and the filtrate was concentrated to dryness. The resulting residue was dissolved in 1.5 mL trimethylorthoformate and heated to 120 ° C for 30 min. The solution was cooled concentrated to dryness and purified by flash column chromatography (2 x 15 cm silica gel, 1 : 1 hexane/ethyl acetate) which provided 6.
'H NMR (CDC13) δ 8.14 (s, IH), 8.04 (d, IH, J = 0.9 Hz), 7.62-7.50 (m, 8H), 7.48 (t, IH, - 7.1 Hz), 7.01 (d, 2H, J = 8.8 Hz), 3.87 (s, 3H); FAB mass spectrometry [M+H]+ 301.1 ; Anal. Calcd. for C2oH16N20: C, 79.98; H, 5.37; N, 9.33. Found: C, 79.71 ; H, 5.48; N, 9.21.
An oven dried flask under argon was charged with benzimidazole 6 (0.039g, 0.13 mmol), aluminum chloride (0.175g, 1.31 mmol), and sodium iodide (0.200g, 1.33 mmol). Anhydrous acetonitrile (1 mL) and dichloromethane (0.5 mL) were added and reaction was heated to reflux. After 44 h the reaction was cooled to ambient temperature, quenched with water and extracted 3 x with ethyl acetate. The combined extracts was dried over Na2S04, filtered and concentrated to dryness. The resulting residue was triturated with ether, filtered and dried to provide phenol 7. !H NMR (CDCI3) δ 9.48 (s, IH), 8.58 (s, IH), 7.93 (s, IH), 7.73-7.71 (m, 2H), 7.67-7.63 (m, 3H), 7.57-7.49 (m, 4H), 6.86 (d, 2H, J = 8.6 Hz).
1 -phenyl-5-(4-(2-( 1 -piperidinyl)ethoxy)phenyl)benzimidazole
Benzimidazole 7 (0.025g, 0.087 mmol) and N-(2- chloroethyl)piperidine hydrochloride (11 mg, 0.059 mmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL). Cesuim carbonate (0.085g, 0.26 mmol) was added and the resulting mixture was heated to 50 °C. After 2 h additional and N-(2-chloroethyl)piρeridine hydrochloride (11 mg, 0.059 mmol) was added. After 1 h the reaction was allowed to cool, quenched with water and extracted with ethyl acetate (3x). The combined extracts was washed with brine, dried over Na2S04, filtered and concentrated to dryness. Purification by flash column chromatography (2 x 16 cm silica gel, 9:1 CH2Cl /MeOH) provided 8 as a colorless oil.
*H NMR (CDCI3) δ 8.14 (s, IH), 8.03 (d, IH, J - 0.9 Hz), 7.62-7.50 (m, 8H), 7.48 (t, IH, J = 7.2 Hz), 7.01 (d, 2H, J = 8.8 Hz), 4.21 (bt, 2H, J = 5.3 Hz), 2.87 (bs, 2H), 2.59 (bs, 4H), 1.66 (bs, 4H), 1.48 (bs, 2H); Mass spectrometry [M+H]+ 398.3.
5-Bromo-2-hydroxy-3-nitropyridine (9) (5.736 g, 0.0262 mol) and 15mL thionyl chloride were added under argon. N,N dimethylformamide (1 mL) was then added and the solution was heated to reflux for 1 hr. By the end of the reaction, the bromohydroxynitropyridine was completely dissolved in solution. After cooling to ambient temperature, 5 mL of toluene was added, and the solution was concentrated under vacuum. The product, 5-bromo-2- chloro-3-nitropyridine, was a yellow crystalline solid.
The bromochloronitropyridine was dissolved in 15mL of anhydrous l-methyl-2-pyrrolidinone. Aniline (3.580 mL, 0.0393 mol) was added followed by the addition of N,N-diisopropylethylamine (13.69 mL, 0.0786 mol) and the solution was heated to 120 °C. After 1.5 hr., the solution was cooled to ambient temperature and diluted with water. The product was extracted using ethyl acetate and washed with brine. The organic layer was then dried over sodium sulfate, filtered, concentrated, and dried in vacuo. The crude mixture was purified using flash column chromatography (7.5 x 16 cm silica gel, 10: 1 hexane:ethyl acetate) to afford 10 . lR NMR (CDC13) δ 10.04 (bs, IH), 8.65 (dd, IH, J= 2.2 Hz), 8.50(dd, IH, .7=2.4 Hz), 7.60 (d, 2H, J=8.6 Hz), 7.40(t, 2H, J =7.5 Hz), 7.21 (t, IH, .7=7.3 Hz).
Bromoaromatic 10 (30 mg, 0.102 mmol), 4- methoxyphenylboronic acid (17 mg, 0.112 mmol) was dissolved in 0.75 mL dioxane followed by the addition of 204 μL of 2M sodium carbonate. The vessel was flushed with argon followed by the addition of tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) and 0.56 mL water. The vessel was flushed again with argon and heated to 80 °C for 2.5 hr. The solution was cooled to room temperature and diluted with water. The product was extracted with ethyl acetate and washed with brine, followed by drying over sodium sulfate. The organic layer was concentrated, and the product dried in vacuo. The crude mixture was purified by flash column chromatography (2.5 x 8 cm silica gel, 8:2 hexane:ethyl acetate), affording 11.
!H NMR (CDC13) δ 10.09 (bs, IH), 8.71 (dd, IH, .7 =2.4 Hz), 8.66 (dd, IH, .7 =2.4), 7.67 (d, 2H, .7=7.9), 7.49 (d, 2H, J =8.8 Hz), 7.41 (t, 2H, J =1.1 Hz), 7.18 (t, IH, =7.3 Hz), 7.00 (d, 2H, J =8.6 Hz), 3.86 (s, 3H).
3-phenyl-6-(4-methoxylphenyl)imidazo[4,5-b]pyridine
Nitroaniline 11 (1.333 g, 4.15 mmol), Zn dust(6.239 g, 95.40 mmol), and 10 mL acetic acid were mixed under argon. The solution was heated to 60 °C for 1 hr until the solution turned light green. The zinc was removed using vacuum filtration with celite and washed with acetic acid. The filtrate was concentrated and 20 mL of trimethylorthoformate was added. The solution was heated to 100 °C for 2 hr followed by cooling to ambient temperature. The solution was concentrated and the crude mixture was purified by flash column chromatography(5 x 16 cm silica gel, 6:4 ethylacetate:hexane) affording 12.
!H NMR (CDCI3) δ 8.61 (dd, IH, .7 =2.0 Hz), 8.32 (s, IH), 8.22 (dd, IH, .7 =2.0), 7.74 (d, 2H, .7 =7.9 Hz), 7.55-7.50 (m, 4H), 7.39 (t, IH, J =7.3), 6.99 (d, 2H, J =8.8 Hz), 3.80 (s, 3H). Mass spectrometry [M+H]+ 302.3. EXAMPLE 3
To the imidazopyridine 12 (202 mg, 0.670 mmol) was added a mixture of 10 mL hydrobromic acid and 10 mL acetic acid. The solution was stirred a room temperature for 5 min., followed by heating at 100 °C for 17 hr. The solution was cooled to ambient temperature and concentrated. Toluene (15 mL) was added and the solution was concentrated a second time. The concentrate was placed in vacuo over heating at 40 °C for 40 min., followed by further drying in vacuo at ambient temperature. Purification was acheived by reverse phase column chromatography affording 13. Η NMR (CD3OD) δ 9.45 (s, IH), 8.82 (dd, IH, J =1.8 Hz), 8.37 (dd, IH, J =1.8 Hz), 7.91 (d, 2H, J =1.1 Hz), 7.68 (t, 2H, J =8.1 Hz), 7.63- 7.57 (m, 3H), 6.95 (d, 2H, J =8.6 Hz).
3-phenyl-6-(4-(2-( 1 -piperidinyl)ethoxy)phenyl)imidazo[4,5-b]pyridine
Cesium carbonate (296 mg, .908 mmol) and l-(2- chloroethyl)piperidine monochlorohyrdide (84 mg, .454 mmol) were added under argon to a flame dried round bottom flask. Imidazopyridine 13 (87 mg, .303 mmol) was dissolved in 1.5 mL of anhydrous N,N dimethyl formamide under argon. The vessel was heated at 50 °C for 16 hr. and cooled to ambient temperature. The solution was diluted to lOOmL with saturated sodium bicarbonate, and the product was extracted using ethyl acetate. The aqueous layer was extracted a second time with dichloromethane w/ 3% 1-butanol. The organic layers were washed with saturated sodium bicarbonate, and dried over sodium sulfate. The organic layers were conentrated at aspirator pressure to remove ethyl acetate and methylene chloride; the 1-butanol and residual DMF were removed under high pressure. The product was purified using flash column chromatography(silica gel 2.5 x 32.5 cm, 10:1 methylene chloride :methanol). Excess trifluoroacetic acid was added to the product to create the resulting salt, and the mixture was triturated using ether. The TFA salt was dried using phosphorous pentoxide in vacuo to yield 14 (1.10 TFA salt). 'H NMR (CD3OD) δ 8.66 (s, IH), 8.55 (dd, IH, J =2.0 Hz), 8.17 (dd, IH, J =2.0 Hz), 7.82 (d, 2H, J=8.6 Hz), 7.59-7.52 (m, 4H), 7.46 (t, IH, J =7.5 Hz), 7.01 (d, 2H, J =8.8 Hz), 4.85 (s, 2H), 4.15 (t, 2H, =5.5 Hz), 2.84 (t, 2H, =5.5 Hz), 2.62 (bs, 4H), 1.65 (m, 4H), 1.50 (m, 2H). Anal. Calcd. for CssHse^O'l.lO TFA: C, 62.35; H, 5.21; N, 10.69. Found: C, 62.32; H, 4.93; N, 10.53.
EXAMPLE 4
Bromoaromatic 4 (7.10 g, 24.1 mmol) and powdered zinc (36.2 g, 554 mmol, 23 equiv) were stirred in 80 mL glacial acetic acid. The mixture was heated to 60 °C. After lh the reaction was cooled and filtered through a plug of celite and concentrated to dryness. The resulting residue was dissolved in 60 mL of formic acid and heated to 100 °C overnight. The reaction was cooled and concentrated to dryness. Purification by flash column chromatography (6x25 cm silica, 55:45 hexanes/EtOAc) afforded 5.88 g benzimidazole 15 (89% yield). !H NMR(CDC13) δ 8.18 (s, IH), 8.05 (d, IH, 7=1.7 Hz), 7.60 (t, 2H, 7=7.1 Hz), 7.54-7.48 (m, 3H), 7.46 (dd, IH, 7= 1.8, 8.8 Hz), 7.40 (d, IH, 7=8.8 Hz).
16
1-Piperidineethanol (1.13 mL, 8.51 mmol) was dissolved in 10 mL anhydrous DMF under Ar. The solution was cooled to 0 °C and NaH (225 mg, 9.38 mmol) was added. After 10 min the mixture was allowed to warm to room temperature and 5-bromo-2-fluoropyridine (1.50 g, 8.52 mmol) was added. After lh the reaction was quenched with water and extracted 3x with EtOAc. The combined extracts were dried over Na2S04, filtered and concentrated to afford 2.20 g (91% yield) of the alkoxypyridine 16. JH NMR(CDC13) δ 8.17 (d, IH, 7=2.6 Hz), 7.62 (dd, IH, 7=2.6, 8.8 Hz), 6.67 (d, IH, 7=8.8 Hz), 4.40 (t, 2H, 7=6.0 Hz), 2.74 (t, 2H, 7=5.9 Hz), 2.49 (m, 4H), 1.60 (m, 4H), 1.44 (m, 2H).
1 -Phenyl-5- [6-(2-piperidin- 1 -yl-ethoxy)-pyridin-3 -yl] - 1 H-benzimidazole
Benzimidazole 15 (2.91 g, 10.7 mmol), diboron pinacol ester (2.97 g, 11.7 mmol) and potassium acetate (3.14 g, 32.0 mmol) were stirred in 20 mL anhydrous DMF under Ar. PdCl2(dppf) (0.26 g, 0.32 mmol) was added, solution was degassed and heated to 80 °C. After 20h the reaction was quenched with 125 mL of water and 50 mL of saturated aqueous NaCl and was extracted 3 x with EtOAc. The combined extracts were dried over Na2S04, filtered and concentrated to afford 2.77 g of unpurified boronate. The unpurified boronate (650 mg, 2.03 mmol), alkoxypyridine 16 (526 mg, 1.85 mmol), 2M Na2C03 (861 mg, 8.12 mmol), and 4 mL dioxane were added to a round bottom flask. After flushing three times with argon, Pd(PPh3)4 (117 mg, 10 mmol) was added, and the vessel was again flushed three times with argon. The vessel was heated to 80 °C under argon. After 22 hr., the reaction was cooled to room temperature followed by quenching with 25mL water. The mixture was extracted with 4x20 mL ethyl acetate, and the combined organic layers were washed with lx20mL brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification was performed using reverse phase column chromatography (Waters 2x40mm C-18 column, H20: acetonitrile mobile phase gradient). The resulting oil was triturated with ether, filtered and washed with ether, affording 16, a white TFA salt(150 mg, 16% yield). Mp: 160.5 - 162 °C. !H NMR(CDC13) δ 8.41 (d, IH, 7 =2.4 Hz), 8.19 (s, IH), 8.01 (d, IH, 7 =1.3 Hz), 7.90 (dd, IH, 7 =11.0 Hz), 7.61 (m, 3H, 7 =13.6), 7.52 (m, 4H, 7 =31.0 Hz), 6.86 (d, IH, 7 =8.4 Hz), 4.79 (t, 2H, 7 =9.9 Hz), 3.76 (bd, 2H, 7 =11.9 Hz), 3.51 (t, 2H, 7 =9.7 Hz), 2.80 (bt, 2H, 7 =23.1 Hz), 2.06 (m, 2H, 7 =26.2 Hz), 1.89 (s, 2H), 1.65 (s, 2H).
EXAMPLE 5
5 -Bromo-1 -phenyl- lH-benzoimidazole (11) (13.4 g, 49.1 mmol), 4- pyridylboronic acid (6.63 g, 54.0 mmol), palladium(II) acetate (551 mg, 2.45 mmol) and triphenylphosphine (1.93 g, 7.36 mmol) were stirred in 80 mL of n-PrOH in a flask equipped with a reflux condenser, under Ar. Sodium carbonate (6.24 g, 58.9 mmol) was dissolved in 30 mL of water and the resulting solution was added to the nPrOH mixture. The resulting mixture was degassed three times by alternating vacuum and argon atmoshphere. The reaction was then heated to reflux. After 18h the reaction as cooled, diluted with water and extracted three times with EtOAc. The combined extracts were washed with sat. NaCl (aq), dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography (95:5 CH2Cl2/MeOH) afforded 8.82 g of 1- phenyl-5-pyridin-4-yl-lH-benzoimidazole (66% yield).
IH NMR (CDC13) δ 8.68 (d, 7 = 6.0 Hz, 2H), 8.18 (s, IH), 8.17 (s, IH), 7.63-7.59 (m, 6H), 7.56-7.51 (m, 3H). Mass Spectrometry (for C18H13N3): [M+H]+ 272.1182, theoretical 272.1182.
l-Phenyl-5-pyridin-4-yl-lH-benzoimidazole (12) (8.82 g, 32.5 mmol) was dissolved in 120 mL of CH2C12. The resulting solution was cooled to 0°C and to it was added mCPBA (11.2 g, 65.0 mmol). After stirring for 2.5 days an additional portion of mCPBA (3.0 g, 17 mmol) was added. After an additional 24 h the reaction solution was loaded directly onto a column (8 x 20 cm) pre-wetted with CH2C12. The resulting flash column chromatography, eluting with 9: 1 CH2Cl2/MeOH, afforded 7.40 g of 5 -(l-oxy-pyridin-4-yl)-l -phenyl- lH-benzoimidazole (13) (79% yield). !H NMR (CDC13) δ 8.40 (d, 7 = 6.0 Hz, 2H), 8.18 (s, IH), 8.11 (d, J = 1.5 Hz, IH), 7.66-7.47 (m, 9H). Mass Spectrometry (for C,8Hi3N3): [M+HJ+ 288.1131, theoretical 288.1131.
5-( 1 -Oxy-pyridin-4-yl)- 1 -phenyl- 1 H-benzoimidazole (13)
(7.40 g, 25.8 mmol) was stirred in 48.6 mL of acetic anhydride (52.6 g, 515 mmol) and the resulting mixture was heated to reflux. After 8h the reaction was concentrate to dryness and the resulting residue was dissolved in 50 mL MeOH. Concentrated ammonium hydroxide (10 mL) was added and the solution was stirred for 16h. The solution was then concentrated to dryness and the residue was purified by flash column chromatography (elute with 95:5-90: 10 CH2Cl2/MeOH) to afford 4.57 g of 4-(l -phenyl- lH-benzoimidazol-5-yl)-lH-pyridin-2-one (14) (62% yield). H NMR (CDC13) δ 11.59 (bs, IH), 8.18 (s, IH), 8.13 (d, 7 = 0.9 Hz, IH), 7.64-7.60 (m, 4H), 7.55-7.51 (m, 3H), 7.42 (d, 7 = 7.0 Hz, IH), 6.88 (d, J = 1.3 Hz, IH), 6.65 (dd, J = 1.8, 7.0 Hz, IH). Elemental analysis (for 0.40 hydrate): Calc'd C, 73.40, H, 4.72, N, 14.27; Found C, 73.33, H, 5.00, N, 13.91.
4-(l -phenyl- lH-benzoimidazol-5-yl)-lH-pyridin-2-one (14)
(4.57 g, 15.9 mmol) was dissolved in 30 mL anhydrous DMF under Ar. Sodium iodide (2.86 g, 19.1 mmol), cesium carbonate (11.9 g, 36.6 mmol) and N-chloropropylpiperidine HC1 salt (3.78 g, 19.1 mmol) were added and the reaction was warmed to 40°C. After 3 days additional portions of N-chloropropylpiperidine HC1 salt (1.9 g, 9.6 mmol) and cesium carbonate (6.0 g, 18 mmol) were added. After an addtional 16 h the bulk of the DMF was removed in vacuo. The residue was diluted with water and extracted 3x with 5% n-BuOH in CH2C12. The combined organic phases was dried over Na2S0 , filtered and concentrated. The residue was purified in several batches by preperative reverse phase HPLC, dissolving sample in MeOH, eluting with 5:95 acetonitrile/water (0.1%) H3P04) to 50:50. Fractions containing pure product were concentrated to remove the bulk of the acetonitrile, basified to pH 8 w/ Na2C03 (s), and extracedt 3x with 5% BuOH in CH2C12. The combined organic phases were dried over Na2S04, filtered and concentrated to afford 3.70g of pure 4-(l-phenyl-lH-benzoimidazol-5-yl)-l-(3-piperidin- l-yl-propyl)-lH-pyridin-2-one (15). 'H NMR (CDC13) δ 8.17 (s, IH), 8.10 (s, IH), 7.63-7.50 (m, 7H), 7.45 (d, 7 = 7.1 Hz, IH), 6.85 (d, 7 = 1.6 Hz, IH), 6.52 (dd, 7 = 1.8, 7.1 Hz, IH), 4.05 (t, 7 = 6.8 Hz, 2H), 2.38-2.34 (m, 4H), 2.00 (t, 7 = 6.8 Hz, 2H), 1.65-1.58 (m, 6H), 1.45 (M, 2H). Elemental analysis: Calc'd C, 75.70, H, 6.84, N, 13.58; Found C, 75.32, H, 6.87, N, 13.37.
5-Bromo-l -phenyl- lH-benzoimidazole (11) (9.71 g, 35.6 mmol), diboron pinacol ester (9.93 g, 39.1 mmol), potassium acetate (10.5 g, 107 mmol) and dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.78 g, 1.1 mmol) were stirred in 40 mL anhydrous DMF under Ar. The solution was degassed three times by alternating vacuum and argon atmosphere. The reaction was heated to 80°C for 18h. After cooling the reaction was diluted with water and extracted 3x with EtOAc. The combined organic phases were dried over Na2S04, filtered and concentrated to afford 11.8 g l-phenyl-5-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-benzoimidazole (16) which was used without purification.
Sodium hydride (0.073 g, 3.0 mmol) was stirred in 4 mL anhydrous DMF under Ar. The solution was cooled to 0°C and 3-iodo-5- hydroxypyridine (0.305 g, 1.38 mmol) was added gradually. After bubbling had subsided N-chloropropylpiperidine hydrochloride (0.330 g, 1.67 mmol) was added slowly. The reaction was then allowed to warm to ambient temperature. After 40h the reaction was diluted with water and extracted 3x with EtOAc. The combined organic phases were washed was washed with saturated NaCl (aq), dried over Na2S04, filtered and concentrated. Purification by flash column chromatography (2 x 16 cm silica, 9:1 CH2C12/MeOH) afforded 192 mg 5-iodo-l-(3- piperidin- l-yl-propyl)-lH-pyridin-2-one (18) (40% yield). Η NMR
(CDC13) δ 7.72 (d, J = 2.6 Hz, IH), 7.40 (dd, J = 2.6, 9.5 Hz, IH), 6.37 (d, J = 9.5 Hz, IH), 3.96 (t, J = 6.6 Hz, 2H), 2.35 (bs, 4H), 2.26 (t, J = 6.6 Hz, 2H), 1.92 (t, 6.6 Hz, 2H), 1.60 (m, 4H), 1.46 (m, 2H).
5-iodo-l -(3 -piperidin- l-yl-propyl)-lH-pyridin-2-one (18) (0.096 g, 0.28 mmol), l-ρhenyl-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH- benzoimidazole (0.081 g, 0.25 mmol), palladium(II) acetate (0.003 g, 0.013 mmol), triphenylphosphine (0.010 g, 0.038 mmol) and sodium carbonate (0,080 g, 0.75 mmol) were stirred in 1.6 mL of a 3:1 mixture of dioxane/water. The mixture was degassed 3x by alternating vacuum and an argon atmosphere. The reaction was heated to 80°C for 18h, cooled and diluted with water. The aqueous phase was extracted 3x with EtOAc and the resulting organic phase was dried over Na2S04, filtered and concentrated. Purification by flash column chromatography (eluted with 85:15 CH2Cl2/MeOH) afforded 0.073 g 5-( 1 -phenyl- 1H- benzoimidazol-5-yl)-l-(3-piperidin-l-yl-propyl)-lH-pyridin-2-one (19) (71% yield). lH NMR (CDC13) δ 9.60 (s, IH), 7.90 (d, J = 1.3 Hz, IH), 7.74-7.67 (m, 2H), 7.64-7.48 (m, 6H), 7.39 (dd, J = 2.5, 9.5 Hz, IH), 6.68 (d, J = 9.5 Hz, IH), 4.13 (t, J = 6.5 Hz, 2H), 2.42 (bs, 6H), 2.10 (t, J = 6.5 Hz, 2H), 1.64 (m, 4H), 1.46 (m, 2H). Mass Spectrometry (for C26H28N4O): [M+H]+ 413.2334, theoretical 413.2336.
To a flame dried round bottom flask with stir bar was added l-phenyl-5- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-benzoimidazole (16) (2.00 g, 6.25 mmol), triphenylphosphine (147 mg, .562 mmol) ρalladium(II) acetate (42 mg, .187 mmol), 2M aqueous Na2C03 (9.37 mL, 18.7 mmol), 4-chloro-2-methylthiopyrimidine (1.00 g, 6.24 mmol), 3 mL water, and 14 mL of 1-propanol. Vessel was flushed three times with argon and placed in 80 °C oil bath with stirring. Reaction was complete after 1.7 hr by HPLC - cooled to RT and removed solvent under vacuum. Workup included dissolution into 150 mL ethyl acetate, adding 50 mL 1/2 saturated aqueous NaHC03, extracting, then extracting the aqueous layer again with 2 x 40 mL EtOAc. Washed combined organics with 1 x 50 mL 1/2 saturated brine, dried over Na2S04, filtered, and concentrated under vacuum. Performed purification via flash column chromatography (60 mm x 200 mm silica gel, 20:1 CH2Cl2:MeOH mobile phase) to afford 1.54 g of compound (21) (77% yield). *H NMR (CDC13) δ 8.64 (d, IH), 8.56 (d, IH) 8.20 (s, IH), 8.18 (dd, IH), 7.63 (m, 3H), 7.53 (m, 3H), 7.47 (d, IH), 2.68 (s, 3H).
To a stirred suspension of Oxone (potassium peroxymonosulfate, 11.87 g, 19.31 mmol) in water at 0 °C was added a suspension of the starting methyl sulfide benzimidazole (21) (1.54 g, 4.83 mmol) in MeOH. The reaction mixture was allowed to warm to RT and was monitored by HPLC. The starting methyl sulfide changed from the methyl sulfoxide to the methyl sulfone over the course of 12 hr . The MeOH was removed under vacuum after the reaction was complete. The reaction mixture was extracted with 3 x 40 mL CH2C12. The combined organic layers were washed with 40 mL brine, dried over Na2S04, filtered, and the solvent removed under vacuum to afford 1.5g (22) (90% crude yield). 'HNMR: (CDC13) δ 8.92 (d, IH, 7= 5.3 Hz), 8.66 (d, IH, 7= 1.6 Hz), 8.27 (dd, IH, 7= 1.6, 7.1 Hz), 8.23 (s, IH), 8.00 (d, IH, 7= 5.4 Hz), 7.65 (m, 3H), 7.54 (m, 3H), 3.47 (s, 3H).
To a flask containing the starting methyl sulfone (500 mg, 1.427 mmol) was added 56% LiOH hydrate (244 mg, 5.708 mmol). To this vessel was added 5 mL tetrahydrofuran and 5 mL water. The reaction mixture was cooled to 0 °C for 2 hr, then gradually was allowed to warm to RT. The reaction was stirred at RT overnight. The reaction was complete after 20 hr and the THF via low vacuum rotary evaporation and water by high vacuum rotary evaporation. The crude material was diluted in 15 mL MeOH, sonicated, and filtered through cotton and a 0.7 μM syringe filter into round bottom flask. The filtrate was concentrated to afford 480 mg of unpurified product (23). The solvent was again removed via rotary evaporation. ]H NMR: (CD3OD) δ 8.47 (s, IH), 8.40 (s, IH), 8.20 (d, IH, 7=5.2 Hz), 8.07 (dd, IH, 7= 1.4, 7.3 Hz), 7.65 (m, 5H), 7.55 (m, IH), 6.92 (d, IH, 7=5.3 Hz). High resolution mass spectometry: Measured mass = 289.1068 (289.1084 theoretical mass).
To a flask containing the starting benzimidazole (23) (66 mg, .229 mmol) was added N-3-chloropiperidine HC1 (54 mg, .275 mmol), cesium carbonate (164 mg, .504 mmol) and 4 mL anhydrous N,N- dimethylformamide. The vessel was placed in 60 °C oil bath with stirring under argon. The reaction was heated to 80 °C after 1 day, and was stopped after 4 days after no further progression. The solvent was removed via high vacuum rotary evaporation, the residue was diluted with MeOH, and filtered through a 0.7 μM syringe filter. Reverse phase column chromatography (Waters 2x40mm C-18 stationary phase, ACN:H20 mobile phase gradientcontaining 1% TFA). Concentrated appropriate HPLC fractions to afford two distinct products - confirmed to be N-alkylated and O-alkylated isomers by mass spectrometry (low res. M+ 1=414.3 ) and !H NMR. Yields of the TFA salts were: N- alkylated (24) (38.6 mg, 32% yield), O-alkylated (not shown) (6.2 mg, 5% yield). The 'HNMR for 4-(l-phenyl-lH-benzoimidazol-5-yl)-l-(3- piperidin-l-yl-propyl)-lH-pyrimidin-2-one is as follows: (CDC13) δ 8.63 (d, IH, 7= 7.9 Hz), 8.34 (d, IH, 7= 10.1Hz), 7.92 (d, IH, 7=6.9 Hz), 7.62 (m, 6H), 7.01 (d, IH, 7= 7.0 Hz), 4.11 (t, 2H, 7= 7.0 Hz), 3.64 (m, 2H), 3.17 (m, 2H), 2.68 (m, 2H), 2.39 (m, 2H), 1.92 (m, 6H).
The following compounds can be made by literature methods and/or in combination with methods disclosed herein.
Kinase inhibition is demonstrated in accordance with the following protocol.
VEGF RECEPTOR KINASE ASSAY VEGF receptor kinase activity is measured by incorporation of radio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY) substrate. The phosphorylated pEY product is trapped onto a filter membrane and the incoporation of radio-labeled phosphate quantified by scintillation counting. MATERIALS VEGF receptor kinase
The intracellular tyrosine kinase domains of human KDR (Terman, B.I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519-524) were cloned as glutathione S-transferase (GST) gene fusion proteins. This was accomplished by cloning the cytoplasmic domain of the KDR kinase as an in frame fusion at the carboxy terminus of the GST gene. Soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf 1) insect cells (Invitrogen) using a baculo virus expression vector (pAcG2T, Pharmingen).
Lysis buffer
50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.5% triton X-100, 10 % glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsulfonyl fluoride (all Sigma).
Wash buffer 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM
EDTA, 0.05% triton X-100, 10 % glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsulfonyl fluoride.
Dialysis buffer
50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% triton X-100, 50 % glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsuflonyl fluoride
10 X reaction buffer
200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl2, 10 mM
DTT and 5 mg/ml bovine serum albumin (Sigma). Enzyme dilution buffer
50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10 % glycerol, 100 mg/ml BSA.
10 X Substrate
750 μg/ml poly (glutamic acid, tyrosine; 4: 1) (Sigma).
Stop solution
30% trichloroacetic acid, 0.2 M sodium pyrophosphate (both Fisher).
Wash solution
15% trichloroacetic acid, 0.2 M sodium pyrophosphate.
Filter plates
Millipore #MAFC NOB, GF/C glass fiber 96 well plate.
METHOD
A. Protein purification 1. Sf21 cells were infected with recombinant vims at a multiplicity of infection of 5 vims particles/ cell and grown at 27 °C for
48 hours.
2. All steps were performed at 4°C. Infected cells were harvested by centrifugation at 1000 X g and lysed at 4 °C for 30 minutes with 1/10 volume of lysis buffer followed by centrifugation at
100,000Xg for 1 hour. The supernatant was then passed over a glutathione Sepharose column (Pharmacia) equilibrated in lysis buffer and washed with 5 volumes of the same buffer followed by 5 volumes of wash buffer. Recombinant GST-KDR protein was eluted with wash buffer/ 10 mM reduced glutathione (Sigma) and dialyzed against dialysis buffer. B. VEGF receptor kinase assay
1. Add 5 μl of inhibitor or control to the assay in 50% DMSO.
2. Add 35 μl of reaction mix containing 5 μl of 10 X reaction buffer, 5 μl 25 mM ATP/10 μCi [33P]ATP (Amersham), and 5 μl 10 X substrate.
3. Start the reaction by the addition of 10 μl of KDR (25 nM) in enzyme dilution buffer.
4. Mix and incubate at room temperature for 15 minutes. 5. Stop by the addition of 50 μl stop solution.
6. Incubate for 15 minutes at 4°C.
7. Transfer a 90 μl aliquot to filter plate.
8. Aspirate and wash 3 times with wash solution.
9. Add 30 μl of scintillation cocktail, seal plate and count in a Wallac Microbeta scintillation counter.
Human Umbilical Vein Endothelial Cell Mitogenesis Assay
Expression of VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells. Human umbilical vein endothelial cells (HUVECs) in culture proliferate in response to VEGF treatment and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation. In the assay described, quiescent HUVEC monolayers are treated with vehicle or test compound 2 hours prior to addition of VEGF or basic fibroblast growth factor (bFGF). The mitogenic response to VEGF or bFGF is determined by measuring the incorporation of [3H]thymidine into cellular DNA.
Materials
HUVECs
HUVECs frozen as primary culture isolates are obtained from Clonetics Corp. Cells are maintained in Endothelial Growth Medium (EGM; Clonetics) and are used for mitogenic assays at passages
3-7.
Culture Plates NUNCLON 96-well polystyrene tissue culture plates
(NUNC #167008).
Assay Medium
Dulbecco's modification of Eagle's medium containing 1 g/ml glucose (low-glucose DMEM; Mediatech) plus 10% (v/v) fetal bovine semm (Clonetics).
Test Compounds
Working stocks of test compounds are diluted serially in 100% dimethylsulfoxide (DMSO) to 400-fold greater than their desired final concentrations. Final dilutions to IX concentration are made directly into Assay Medium immediately prior to addition to cells.
IPX Growth factors Solutions of human VEGF165 (500 ng/ml; R&D Systems) and bFGF (10 ng/ml; R&D Systems) are prepared in Assay Medium.
IPX [3HlThvmidine
[Methyl-3H]Thymidine (20 Ci/mmol; Dupont-NEN) is diluted to 80 uCi/ml in low-glucose DMEM.
Cell Wash Medium
Hank's balanced salt solution (Mediatech) containing 1 mg/ml bovine semm albumin (Boehringer-Mannheim).
Cell Lysis Solution
1 N NaOH, 2% (w/v) Na2C03. Method
1. HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4000 cells per 100 ul Assay Medium per well in 96-well plates. Cells are growth-arrested for 24 hours at 37°C in a humidified atmosphere containing 5% C02.
2. Growth-arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% [v/v] DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37°C/5% C02 for 2 hours to allow test compounds to enter cells.
3. After the 2-hour pretreatment period, cells are stimulated by addition of 10 ul/well of either Assay Medium, 10X VEGF solution or 10X bFGF solution. Cells are then incubated at 37°C/5% C02. 4. After 24 hours in the presence of growth factors, 10X
[3H]Thymidine (10 ul/well) is added.
5. Three days after addition of [3H]thymidine, medium is removed by aspiration, and cells are washed twice with Cell Wash Medium (400 ul/well followed by 200 ul/well). The washed, adherent cells are then solubilized by addition of Cell Lysis Solution (100 ul/well) and warming to 37°C for 30 minutes. Cell lysates are transferred to 7-ml glass scintillation vials containing 150 ul of water. Scintillation cocktail (5 ml/vial) is added, and cell-associated radioactivity is determined by liquid scintillation spectroscopy. Based upon the foregoing assays the compounds of formula
I are inhibitors of VEGF and thus are useful for the inhibition of neoangiogenesis, such as in the treatment of occular disease, e.g., diabetic retinopathy and in the treatment of cancers, e.g., solid tumors. The instant compounds inhibit VEGF-stimulated mitogenesis of human vascular endothelial cells in culture with IC50 values between 150-650 nM. These compounds also show selectivity over related tyrosine kinases (e.g. FGFR1 and the Src family).

Claims

WHAT IS CLAIMED IS:
A compound in accordance with formula la:
la
or a pharmaceutically acceptable salt, hydrate or prodmg thereof,
wherein
X is N or C;
Rj&R3 are independently H, Cj.10 alkyl, C3-6 cycloalkyl, C5.10 aryl, halo, OH, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R7 is independently H, C╬╝6 alkyl, C5.10 aryl, C3-6 cycloalkyl, OH, N02, -NH2, or halogen;
R4&R5 are independently H, CJ.J0 alkyl, C3-6 cycloalkyl, Cj_6 alkoxy C2.JO alkenyl, C2-╬╣o alkynyl, C5.10 aryl, C3.10 heterocyclyl, Cj.6 alkoxyNR7R8, halo, N02, OH, -NH2 or C5.10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra, or R4 and R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from Ra.
Ra is H, CJ.JO alkyl, halogen, N02, R, NHCj.6 alkylR9, OR, -NR,
RNR7R8, NR7R8j R7R8? CN, C5.10 aryl, C5.10 heteroaryl or C3.10 heterocyclyl;
R is H, Cj.6 alkyl or Cj.6 alkylR9;
R9 is C5.,0 aryl, C3-10 heterocyclyl, or C5.j0 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and
R7&R8 are independently H, CJ.J0 alkyl, C3-6 cycloalkyl, COR, C5-10 aryl> C3.j0 heterocyclyl, or C5.10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
2. A compound in accordance with claim 1 wherein X is C and all other variables are as described above.
3. A compound in accordance with claim 1 wherein X is N and all other variables are as described above.
4. A compound in accordance with claim 1 wherein R4 is CJ.JO alkyl, C3.6 cycloalkyl, C5.10 aryl, C5.10 heteroaryl, or C3.10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
5. A compound in accordance with claim 1 wherein Rj is CJ.JO alkyl, C5_╬╣0 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
6. A compound in accordance with claim 1 wherein: R is H, CJ.JO alkyl, halogen, Cj.6 alkylR9, CN, R, OR, NR, RNR7R8, NR7R8, R R8 and all other variables are as described above.
7. A compound in accordance with claim 1 wherein Rj&R3 are independently H, Cj.,0 alkyl, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2 is independently H, Cj.6 alkyl, C3-6 cycloalkyl, OH, or halogen;
R4&R5 are independently H, CJ.J0 alkyl, C3.6 cycloalkyl, C5.10 aryl, C5_i0 heteroaryl, C3.10 heterocyclyl, Cj.6 alkoxyNR7R8, N02, OH, -NH2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
8. A compound in accordance with claim 7 wherein: Rj&R3 are independently C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R-, is H or Cj_6 alkyl;
R4 is piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
9. A compound of the structural formula
I or a pharmaceutically acceptable salt, hydrate or prodmg thereof, X is N or C;
Rj is H, CJ.JO alkyl, C3.6 cycloalkyl, C5.,0 aryl, halo, OH, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2&R3 are independently H, CU6 alkyl, C5.10 aryl, C3-6 cycloalkyl, OH, N02, -NH2, or halogen;
R4 is H, CJ.JO alkyl, C3-6 cycloalkyl, CU6 alkoxy C2.j0 alkenyl,
C2.JO alkynyl, C5.10 aryl, C3.10 heterocyclyl, Cj.6 alkoxyNR7R8, N02, OH, -NH2 or C5.10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R5 is H, or CN6 alkyl, OR, halo, NH2 or N02;
Ra is H, CJ.JO alkyl, halogen, N02, OR, -NR, NR7R8, R7Rs,
C5.10 aryl, C5.j0 heteroaryl or C3.10 heterocyclyl,
R is H, or Cj.6 alkyl, Cj.6 alkylR9;
R9 is C5.j0 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; and
R7&R8 are independently H, C 0 alkyl, C3-6 cycloalkyl, COR, C5.j0 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl or
NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
10. A compound in accordance with claim 9 wherein X is C and all other variables are as described above.
11. A compound in accordance with claim 9 wherein X is N and all other variables are as described above.
12. A compound in accordance with claim 9 wherein
R4 is CJ.JO alkyl, C3.6 cycloalkyl, C5.10 aryl, C5.10 heteroaryl, or C3.10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
13. A compound in accordance with claim 9 wherein Rj is CJ.JO alkyl, C .10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
14. A compound in accordance with claim 9 wherein:
R, is H, CJ.JO alkyl, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2&R3 are independently H, C,.6 alkyl, C3-6 cycloalkyl, OH, or halogen;
R4 is H, CJ.JO alkyl, C3.6 cycloalkyl, C5.10 aryl, C5.10 heteroaryl, C3.j0 heterocyclyl, Cj.6 alkoxyNR7R8, N02, OH, -NH2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
15. A compound in accordance with claim 9 wherein: Rj is C5-10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2&R3 are independently H or CN6 alkyl;
R4 is CJ.JO alkyl, C5.10 aryl, C5.10 heteroaryl, C3.10 heterocyclyl said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
16. A compound of the structural formula Ila
Ila or a pharmaceutically acceptable salt, hydrate or prodmg thereof,
wherein
X & W are independently N or C; Rj&R3 are independently H, CJ.J0 alkyl, C .6 cycloalkyl, C5.10 aryl, halo, OH, C3.j0 heterocyclyl, or C5.10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2 is independently H, Cj.6 alkyl, C5.10 aryl, C3-6 cycloalkyl,
OH, N02, -NH2, or halogen;
R5 is independently H, C,.10 alkyl, C3-6 cycloalkyl, C,.6 alkoxy
C2.JO alkenyl, C2-╬╣o alkynyl, C5.j0 aryl, C3.10 heterocyclyl, Cj.6 alkoxyNR7R8, halo, N02, OH, -NH2 or C5.10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
Rj0 is H, or Cj.6 alkyl, Cj.6 alkylR9, C5.10 aryl, C3.10 heterocyclyl, NHCj.6 alkylR9╬╣ said alkyl (where R is Cj.6 alkyl), aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from
Ra;
Ra is H, Cj.,0 alkyl, halogen, N02, OR, -NR, RNR7R8, NR7R8,
R7R8, CN, C5_╬╣o aryl, C5.j0 heteroaryl or C3.j0 heterocyclyl;
R is H, Cj.6 alkyl or Cj.6 alkylR9;
R9 is C5.j0 aryl, C3.10 heterocyclyl, or C5.j0 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and R7&R8 are independently H, CJ.J0 alkyl, C3-6 cycloalkyl, COR, C5.JO aryl, C3.10 heterocyclyl, or C5.j0 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substimted with from one to three members selected from Ra or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
17. A compound in accordance with claim 16 wherein X or W independently are CH and all other variables are as described above.
18. A compound in accordance with claim 16 wherein X or W are independently N and all other variables are as described above.
19. A compound in accordance with claim 16 wherein Rj0 is H, C 0 alkyl, C1-6 alkylR9, C5.,0 aryl, C .10 heteroaryl, or C3.10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
20. A compound in accordance with claim 1 which is:
l-phenyl-5-(4-methoxyphenyl)benzimidazole, 1 -phenyl-5-(4-(2-( 1 -piperidinyl)ethoxy)phenyl)benzimidazole, 3-phenyl-6-(4-methoxylphenyl)imidazo[4,5-b]pyridine, 3-phenyl-6-(4-(2-(l-piperidinyl)ethoxy)phenyl)imidazo[4,5-b]pyridine, 3-phenyl-6-(4-(2-(l-piperidinyl)ethoxyphenyl)imidazo[4,5-b]pyridine, 3-(2-thiazoyl)-6-(4-(3-(l-piρeridinyl)propylphenyl)imidazo[4,5- bjpyridine, 1 -(2-thiazoyl)-5-(4-(3-( 1 -piperidinyl)propyl)phenyl)benzimidazole, l-(3-thiophenyl)-5-(4-(3-(l-piperidinyl)proρyl)phenyl)imidazo[4,5- bjpyridine, l-(3-thiophenyl)-5-(4-(3-(l-piperidinyl)propyl)phenyl)benzimidazole,
3 -(3 -thiophenyl)-6-(4-(3 -( 1 -piperidinyl)propylphenyl)imidazo [4,5 - b]pyridine,
1 -Phenyl-5-[5-(2 -piperidin- 1 -yl-ethoxy)-pyridin-2-yl]- 1 H-benzimidazole,
1 -(4-Cyanophenyl)-5-[6-(2 -piperidin- 1 -yl-ethoxy)-pyridin-3-yl]- 1H- benzimidazole, l-Phenyl-5-[6-(2-piρeridin-l-yl-ethoxy)-ρyridin-3-yl]-lH-benzimidazole, l-(3-Cyanophenyl)-5-[6-(2-piperidin-l-yl-ethoxy)-pyridin-3-yl]-lH- benzimidazole, l-(3-Thiophene)-5-[6-(2-piperidin-l-yl-ethoxy)-pyridin-3-yl]-lH- benzimidazole,
[5-(l-Phenyl-lH-benzoimidazol-5-yl)-pyridin-2-yl]-(2-piperidin-l-yl- ethyl)-amine,
[5-( 1 -Phenyl- lH-benzoimidazol-5-yl)-pyridin-2-yl]-(2-mo holin- 1 -yl- ethyl)-amine,
4-( 1 -Phenyl- 1 H-benzoimidazol-5-yl)- 1 -(3 -piperidin- 1 -y 1-propyl)- 1 H- pyridin-2-one, 4-( 1 -Phenyl- 1 H-benzoimidazol-5-yl)- 1 -(3-piperidin- 1 -yl-ethyl)- 1 H- pyridin-2-one,
1 -(3-Pyridyl)-5-(4-(2-( 1 -piperidinyl)ethoxy)phenyl)benzimidazole,
1 -(4-Pyridyl)-5-(4-(2-( 1 -piperidinyl)ethoxy)phenyl)benzimidazole, l-(3-Pyridyl)-5-[6-(2-piperidin-l-yl-ethoxy)-pyridin-3-yl]-lH- benzimidazole, and l-(4-Pyridyl)-5-[6-(2-piperidin-l-yl-ethoxy)-pyridin-3-yl]-lH- benzimidazole or a pharmaceutically acceptable salt, hydrate or prodmg thereof.
21. A compound in accordance with claim 1 which is:
1 -(2-morpholin-4-yl-ethyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyridin-2-one, 1 -(3-dimethylamino-propyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyridin-2-one,
1 -( 1 -methyl-piperidin-3 -ylmethyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5 - yl)- 1 H-pyridin-2-one, 1 -[3 -(4-methylpiperazin- 1 -yl)-propyl)]-4-( 1 -phenyl- 1 H- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
1 -(2-dimethylamino-propyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyridin-2-one,
1 -(3-dimethylamino-2-methyl-propyl)-4-( 1 -phenyl- 1 H-benzoimidazol- 5-yl)-lH-pyridin-2-one,
1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl]-4-( 1 -phenyl- 1 H-benzoimidazol-5- yl)- 1 H-pyridin-2-one, l-(3-piperidin-l-yl-propyl)-4-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyridin-2-one, 1 -(3-piperidin- 1 -yl-ethyl)-4-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5-yl)-
1 H-pyridin-2-one, l-(2-morpholin-4-yl-ethyl)-4-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyridin-2-one, l-(3-dimethylamino-propyl)-4-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)-lH-pyridin-2-one, l-(l-methyl-piperidin-3-ylmethyl)-4-(l-thiophen-3-yl-lH- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
1 - [3 -(4-methylpiperazin- 1 -yl)-propyl)] -4-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)- 1 H-pyridin-2-one, l-(2-dimethylamino-propyl)-4-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyridin-2-one,
1 -(3-dimethylamino-2-methyl-propyl)-4-( 1 -thiophen-3 -yl- 1H- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
1 - [2-(4-cyano-piperidin- 1 -yl)-ethyl]-4-( 1 -thiophen-3-yl- 1 H- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
5-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 -(3 -piperidin- 1 -yl-propyl)- 1 H- pyridin-2-one,
5 -( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 -(3 -piperidin- 1 -yl-ethyl)- 1 H- pyridin-2-one, l-(2-morpholin-4-yl-ethyl)-5-(l-phenyl-lH-benzoimidazol-5-yl)-lH- pyridin-2-one,
1 -(3-dimethylamino-propyl)-5-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyridin-2-one, 1 -( 1 -methyl-piperidin-3-ylmethyl)-5-( 1 -phenyl- 1 H-benzoimidazol-5- yl)- 1 H-pyridin-2-one, l-[3-(4-methylpiperazin-l-yl)-propyl)]-5-(l-phenyl-lH- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
1 -(2-dimethylamino-propyl)-5-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 H- pyridin-2-one,
1 -(3-dimethylamino-2-methyl-propyl)-5-( 1 -phenyl- 1 H-benzoimidazol- 5-yl)-lH-pyridin-2-one, l-[2-(4-cyano-piρeridin-l-yl)-ethyl]-5-(l-ρhenyl-lH-benzoimidazol-5- yl)- 1 H-pyridin-2-one, 1 -(3-piperidin- 1 -yl-propyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5- yl)- 1 H-pyridin-2-one,
1 -(3-piperidin- 1 -yl-ethyl)-5-( 1 -thiophen-3-yl- 1 H-benzoimidazol-5 -yl)- 1 H-pyridin-2-one,
1 -(2-moφholin-4-yl-ethyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5 - yl)-lH-pyridin-2-one,
1 -(3-dimethylamino-propyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5- yl)- 1 H-pyridin-2-one,
1 -( 1 -methyl-piperidin-3-ylmethyl)-5-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)- 1 H-pyridin-2-one, l-[3-(4-methylpiperazin-l-yl)-propyl)]-5-(l-thiophen-3-yl-lH- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
1 -(2-dimethylamino-propyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5- yl)- 1 H-pyridin-2-one,
1 -(3-dimethylamino-2-methyl-propyl)-5-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl]-5-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)- 1 H-pyridin-2-one,
5-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 -(3 -piperidin- 1 -yl-propyl)- 1 H- pyrimidin-2-one, 5-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 -(3-piperidin- 1 -yl-ethyl)- 1 H- pyrimidin-2-one,
1 -(2-morpholin-4-yl-ethyl)-5-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyrimidin-2-one, 1 -(3-dimethylamino-proρyl)-5-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 H- pyrimidin-2-one, l-(l-methyl-piperidin-3-ylmethyl)-5-(l-phenyl-lH-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
1 -[3-(4-methylpiperazin- 1 -yl)-propyl)]-5-( 1 -phenyl-1 H- benzoimidazol-5 -y 1)- 1 H-pyrimidin-2-one,
1 -(2-dimethylamino-propyl)-5-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 H- pyrimidin-2-one,
1 -(3-dimethylamino-2-methyl-propyl)-5-( 1 -phenyl- 1 H-benzoimidazol- 5-yl)- lH-pyrimidin-2-one, l-[2-(4-cyano-piperidin-l-yl)-ethyl]-5-(l -phenyl- lH-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
1 -(3-piperidin- 1 -yl-propyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
1 -(3-piρeridin- 1 -yl-ethyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5 -yl)- lH-pyrimidin-2-one, l-(2-morpholin-4-yl-ethyl)-5-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
1 -(3 -dimethylamino-proρyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one, 1 -( 1 -methyl-piperidin-3 -ylmethyl)-5 -( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)-lH-pyrimidin-2-one,
1 - [3 -(4-methylpiperazin- 1 -yl)-propyl)] -5 -( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
1 -(2-dimethylamino-propyl)-5-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5- yl)-lH-pyrimidin-2-one,
1 -(3-dimethylamino-2-methyl-propyl)-5-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl]-5-( 1 -thiophen-3 -yl- 1H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one, 4-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 -(3 -piperidin- 1 -yl-propyl)- 1 H- pyrimidin-2-one,
4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 -(3-piperidin- 1 -yl-ethyl)- 1 H- pyrimidin-2-one, 1 -(2-morpholin-4-yl-ethyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyrimidin-2-one,
1 -(3-dimethylamino-propyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5-yl)- 1 H- pyrimidin-2-one,
1 -( 1 -methyl-piperidin-3-ylmethyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5 - yl)-lH-pyrimidin-2-one,
1 -[3 -(4-methylpiperazin- 1 -yl)-propyl)]-4-( 1 -phenyl- 1 H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
1 -(2-dimethylamino-propyl)-4-( 1 -phenyl- 1 H-benzoimidazol-5 -yl)- 1 H- pyrimidin-2-one, 1 -(3-dimethylamino-2-methyl-propyl)-4-( 1 -phenyl- 1 H-benzoimidazol-
5-yl)- 1 H-pyrimidin-2-one,
1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl]-4-( 1 -phenyl- 1 H-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
1 -(3-piperidin- 1 -yl-propyl)-4-( 1 -thiophen-3-yl- 1 H-benzoimidazol-5- yl)-lH-pyrimidin-2-one,
1 -(3-piρeridin- 1 -yl-ethyl)-4-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5-yl)- 1 H-pyrimidin-2-one, l-(2-morpholin-4-yl-ethyl)-4-(l -thiophen-3 -yl-1 H-benzoimidazol-5 - yl)- 1 H-pyrimidin-2-one, 1 -(3-dimethylamino-propyl)-4-( 1 -thiophen-3 -yl- 1 H-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
1 -( 1 -methyl-piperidin-3-ylmethyl)-4-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one,
1 -[3 -(4-methylpiperazin- 1 -yl)-propyl)]-4-(l -thiophen-3 -yl-1 H- benzoimidazol-5-yl)- 1 H-pyrimidin-2-one, l-(2-dimethylamino-propyl)-4-(l-thiophen-3-yl-lH-benzoimidazol-5- yl)- 1 H-pyrimidin-2-one,
1 -(3 -dimethylamino-2-methyl-propy l)-4-( 1 -thiophen-3 -yl- 1 H- benzoimidazol-5 -yl)- 1 H-pyrimidin-2-one, 1 -[2-(4-cyano-piperidin- 1 -yl)-ethyl]-4-( 1 -thiophen-3-yl- 1H- benzoimidazol-5-yl)-lH-pyrimidin-2-one or a pharmaceutically acceptable salt, hydrate or prodmg thereof.
22. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 or a pharmaceutically acceptable salt, prodmg or hydrate thereof in combination with a carrier.
23. A method of treating or preventing cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of claim 1.
24. A method of treating or preventing cancer in accordance with claim 23 wherein the cancer comprises cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung.
25. A method in accordance with claim 23 wherein the cancer comprises histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma.
26. A method of treating or preventing a disease in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of claim 1 or a pharmaceutically acceptable salt, prodmg or hydrate thereof in an amount which is effective for reducing neoangiogenesis.
27. A method in accordance with claim 26 wherein the disease is an ocular disease.
28. A method of treating or preventing retinal vascularization which is comprised of administering to a mammalian patient in need of such treatment a compound of claim 1 or a pharmaceutically acceptable salt, prodmg or hydrate thereof in an amount which is effective for treating retinal vascularization.
29. A method of treating or preventing diabetic retinopathy which is comprised of administering to a mammalian patient in need of such treatment a compound of claim 1 or a pharmaceutically acceptable salt, prodmg or hydrate thereof in an amount which is effective for treating diabetic retinopathy.
30. A method of treating or preventing age-related macular degeneration which is comprised of administering to a mammalian patient in need of such treatment a compound of claim 1 or a pharmaceutically acceptable salt, prodmg or hydrate thereof in an amount which is effective for inflammation.
31. A method of treating or preventing inflammatory diseases which is comprised of administering to a mammalian patient in need of such treatment a compound of claim 1 or a pharmaceutically acceptable salt, prodmg or hydrate thereof in an amount which is effective for inflammation.
32. A method according to claim 31 wherein the inflammatory disease comprises rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypertensitivity reactions.
33. A method for inhibiting tyrosine kinase which comprises administering to a mammalian patient in need of such treatment a therapeutically effective amount of a composition of claim 1.
EP99912408A 1998-08-31 1999-03-11 Novel angiogenesis inhibitors Withdrawn EP1109555A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14388198A 1998-08-31 1998-08-31
US143881 1998-08-31
PCT/US1999/005297 WO2000012089A1 (en) 1998-08-31 1999-03-11 Novel angiogenesis inhibitors

Publications (2)

Publication Number Publication Date
EP1109555A1 true EP1109555A1 (en) 2001-06-27
EP1109555A4 EP1109555A4 (en) 2001-11-21

Family

ID=22506085

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99912408A Withdrawn EP1109555A4 (en) 1998-08-31 1999-03-11 Novel angiogenesis inhibitors

Country Status (5)

Country Link
EP (1) EP1109555A4 (en)
JP (1) JP2002523459A (en)
AU (1) AU760020B2 (en)
CA (1) CA2341409A1 (en)
WO (1) WO2000012089A1 (en)

Families Citing this family (127)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1132381A1 (en) * 2000-03-08 2001-09-12 Cermol S.A. Ester derivatives of dimethylpropionic acid and pharmaceutical compositions containing them
DE10021246A1 (en) * 2000-04-25 2001-10-31 Schering Ag New N-substituted benzamide derivatives are tyrosine kinase KDR and FLT inhibitors useful e.g. for treating tumors, psoriasis, rheumatoid arthritis, diabetic retinopathy or liver sclerosis
AU2001293233A1 (en) * 2000-09-01 2002-03-13 Chiron Corporation Aza heterocyclic derivatives and their therapeutic use
PL214667B1 (en) 2000-12-21 2013-08-30 Glaxo Group Ltd Pyrimidineamines as angiogenesis modulators
US7081454B2 (en) 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
RU2259825C9 (en) 2001-06-18 2006-04-10 БиоДием Лимитед Substances of antimicrobial, antifungoid and antiprotozoan activities
WO2003074515A1 (en) * 2002-03-01 2003-09-12 Smithkline Beecham Corporation Diamino-pyrimidines and their use as angiogenesis inhibitors
BR0313160A (en) * 2002-08-08 2005-07-12 Smithkline Beecham Corp Compound, pharmaceutical composition, methods for treating a condition and a susceptible neoplasm in an animal in an animal, process for preparing a compound and use of a compound.
JP2006513162A (en) * 2002-11-01 2006-04-20 パラテック ファーマシューティカルズ インコーポレイテッド Transcription factor modulating compounds and methods of use thereof
FR2846656B1 (en) 2002-11-05 2004-12-24 Servier Lab NOVEL IMIDAZOPYRIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
MEP31408A (en) 2003-07-18 2010-10-10 Abgenix Inc Specific binding agents to hepatocyte growth factor
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
US7442709B2 (en) 2003-08-21 2008-10-28 Osi Pharmaceuticals, Inc. N3-substituted imidazopyridine c-Kit inhibitors
AU2004268948A1 (en) 2003-08-21 2005-03-10 Osi Pharmaceuticals, Inc. N-substituted pyrazolyl-amidyl-benzimidazolyl c-kit inhibitors
WO2005037827A1 (en) 2003-10-16 2005-04-28 Smithkline Beecham Corporation Process for preparing benzimidazole thiophenes
US20050107374A1 (en) * 2003-10-21 2005-05-19 Amgen Inc. Substituted heterocyclic compounds and methods of use
WO2005075470A1 (en) 2004-01-28 2005-08-18 Smithkline Beecham Corporation Thiazole compounds
GB0402137D0 (en) * 2004-01-30 2004-03-03 Smithkline Beecham Corp Novel compounds
GB0402809D0 (en) * 2004-02-09 2004-03-10 Glaxo Group Ltd Chemical compounds
US20060160799A1 (en) 2004-04-23 2006-07-20 Alekshun Michael N Transcription factor modulating compounds and methods of use thereof
BRPI0512261A (en) 2004-06-17 2008-02-26 Wyeth Corp Gonadotropin-releasing hormone receptor antagonists
JP2008503470A (en) 2004-06-17 2008-02-07 ワイス Method for producing gonadotropin releasing hormone receptor antagonist
MX2007006230A (en) 2004-11-30 2007-07-25 Amgen Inc Quinolines and quinazoline analogs and their use as medicaments for treating cancer.
US7534796B2 (en) 2005-02-18 2009-05-19 Wyeth Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor
US7538113B2 (en) 2005-02-18 2009-05-26 Wyeth 4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7582634B2 (en) 2005-02-18 2009-09-01 Wyeth 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
NZ562468A (en) * 2005-04-05 2009-10-30 Pharmacopeia Inc Purine and imidazopyridine derivatives for immunosuppression
US7884109B2 (en) 2005-04-05 2011-02-08 Wyeth Llc Purine and imidazopyridine derivatives for immunosuppression
US7531542B2 (en) 2005-05-18 2009-05-12 Wyeth Benzooxazole and benzothiazole antagonists of gonadotropin releasing hormone receptor
US7582636B2 (en) 2005-05-26 2009-09-01 Wyeth Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor
US7595330B2 (en) 2005-09-06 2009-09-29 Smithkline Beecham Corporation Benzimidazole thiophene compounds
US20080108664A1 (en) 2005-12-23 2008-05-08 Liu Belle B Solid-state form of AMG 706 and pharmaceutical compositions thereof
AR059066A1 (en) 2006-01-27 2008-03-12 Amgen Inc COMBINATIONS OF THE ANGIOPOYETINE INHIBITOR -2 (ANG2) AND THE VASCULAR ENDOTELIAL GROWTH FACTOR INHIBITOR (VEGF)
WO2007092178A1 (en) 2006-02-10 2007-08-16 Amgen Inc. Hydrate forms of amg706
US7989459B2 (en) 2006-02-17 2011-08-02 Pharmacopeia, Llc Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
AR059898A1 (en) 2006-03-15 2008-05-07 Janssen Pharmaceutica Nv DERIVATIVES OF 3-CIANO-PIRIDONA 1,4-DISUSTITUTED AND ITS USE AS ALLOSTERIC MODULATORS OF MGLUR2 RECEIVERS
US7615643B2 (en) 2006-06-02 2009-11-10 Smithkline Beecham Corporation Benzimidazole thiophene compounds
US8217177B2 (en) 2006-07-14 2012-07-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
PE20080403A1 (en) 2006-07-14 2008-04-25 Amgen Inc FUSED HETEROCYCLIC DERIVATIVES AND METHODS OF USE
AR063141A1 (en) 2006-10-04 2008-12-30 Pharmacopeia Inc DERIVATIVES OF 2- (BENZIMIDAZOLIL) PURINA 8- REPLACED FOR IMMUNOSUPPRESSION
WO2008043031A1 (en) 2006-10-04 2008-04-10 Pharmacopeia, Inc. 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7902187B2 (en) 2006-10-04 2011-03-08 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
WO2008067644A1 (en) * 2006-12-04 2008-06-12 Boehringer Ingelheim International Gmbh Inhibitors of hiv replication
AU2007338792B2 (en) 2006-12-20 2012-05-31 Amgen Inc. Substituted heterocycles and methods of use
MX2009006706A (en) 2006-12-22 2009-07-02 Astex Therapeutics Ltd Bicyclic heterocyclic compounds as fgfr inhibitors.
JP5442449B2 (en) 2006-12-22 2014-03-12 アステックス、セラピューティックス、リミテッド New compounds
US8131527B1 (en) 2006-12-22 2012-03-06 Astex Therapeutics Ltd. FGFR pharmacophore compounds
US7759344B2 (en) 2007-01-09 2010-07-20 Amgen Inc. Bis-aryl amide derivatives and methods of use
CA2676173A1 (en) 2007-02-16 2008-08-28 Amgen Inc. Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
ES2650224T3 (en) 2007-08-21 2018-01-17 Amgen, Inc. Human C-FMS antigen binding proteins
KR101533440B1 (en) 2007-09-14 2015-07-03 얀센 파마슈티칼스 인코포레이티드 1',3'-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1'H-[1,4']bipyridinyl-2'-ones
GB0720041D0 (en) 2007-10-12 2007-11-21 Astex Therapeutics Ltd New Compounds
GB0720038D0 (en) 2007-10-12 2007-11-21 Astex Therapeutics Ltd New compounds
GB0810902D0 (en) 2008-06-13 2008-07-23 Astex Therapeutics Ltd New compounds
ES2439291T3 (en) 2008-09-02 2014-01-22 Janssen Pharmaceuticals, Inc. 3-Azabicyclo [3.1.0] hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
GB0906472D0 (en) 2009-04-15 2009-05-20 Astex Therapeutics Ltd New compounds
GB0906470D0 (en) 2009-04-15 2009-05-20 Astex Therapeutics Ltd New compounds
MY161325A (en) 2009-05-12 2017-04-14 Janssen Pharmaceuticals Inc 1, 2, 4-triazolo[4,3-a]pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
EA020671B1 (en) 2009-05-12 2014-12-30 Янссен Фармасьютикалз, Инк. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF mGluR2 RECEPTORS
WO2011161217A2 (en) 2010-06-23 2011-12-29 Palacký University in Olomouc Targeting of vegfr2
PT2649069E (en) 2010-11-08 2015-11-20 Janssen Pharmaceuticals Inc 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
JP5852666B2 (en) 2010-11-08 2016-02-03 ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド 1,2,4-Triazolo [4,3-a] pyridine derivatives and their use as positive allosteric modulators of the mGluR2 receptor
CA2814998C (en) 2010-11-08 2019-10-29 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
ES2543569T3 (en) 2011-03-23 2015-08-20 Amgen Inc. Dual condensed tricyclic inhibitors of CDK 4/6 and FLT3
WO2013025939A2 (en) 2011-08-16 2013-02-21 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
AR090263A1 (en) 2012-03-08 2014-10-29 Hoffmann La Roche COMBINED ANTIBODY THERAPY AGAINST HUMAN CSF-1R AND USES OF THE SAME
WO2014036022A1 (en) 2012-08-29 2014-03-06 Amgen Inc. Quinazolinone compounds and derivatives thereof
JO3368B1 (en) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JO3367B1 (en) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv 1,2,4-TRIAZOLO[4,3-a]PYRIDINE COMPOUNDS AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
KR20220039824A (en) 2014-01-21 2022-03-29 얀센 파마슈티카 엔.브이. Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
IL279202B2 (en) 2014-01-21 2023-09-01 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
WO2016112111A1 (en) 2015-01-08 2016-07-14 The Board Of Trustees Of The Leland Stanford Junior University Factors and cells that provide for induction of bone, bone marrow, and cartilage
JP2018527340A (en) 2015-08-11 2018-09-20 ネオメド インスティテュートＮｅｏｍｅｄ Ｉｎｓｔｉｔｕｔｅ Aryl-substituted dihydroquinolinones, their preparation and their use as pharmaceuticals
US10836742B2 (en) 2015-08-11 2020-11-17 Neomed Institute N-substituted bicyclic lactams, their preparation and their use as pharmaceuticals
EP3334719B1 (en) 2015-08-12 2021-09-15 Neomed Institute Substituted benzimidazoles, their preparation and their use as pharmaceuticals
US10501459B2 (en) 2015-10-21 2019-12-10 Neomed Institute Substituted imidazo[1,2-a]pyridines as bromodomain inhibitors
WO2017127930A1 (en) 2016-01-28 2017-08-03 Neomed Institute Substituted [1,2,4]triazolo[4,3-a]pyridines, their preparation and their use as pharmaceuticals
ES2894255T3 (en) 2016-12-22 2022-02-14 Amgen Inc Benzoisothiazole derivatives, isothiazolo[3,4-b]pyridine, quinazoline, phthalazine, pyrido[2,3-d]pyridazine and pyrido[2,3-d]pyrimidine derivatives as KRAS G12C inhibitors to treat lung cancer pancreatic or colorectal
JOP20190272A1 (en) 2017-05-22 2019-11-21 Amgen Inc Kras g12c inhibitors and methods of using the same
UY37870A (en) 2017-09-08 2019-03-29 Amgen Inc KRAS G12C INHIBITORS AND METHODS TO USE THEM FIELD OF THE INVENTION
CA3099118A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11090304B2 (en) 2018-05-04 2021-08-17 Amgen Inc. KRAS G12C inhibitors and methods of using the same
AU2019265822A1 (en) 2018-05-10 2020-11-19 Amgen Inc. KRAS G12C inhibitors for the treatment of cancer
MA52765A (en) 2018-06-01 2021-04-14 Amgen Inc KRAS G12C INHIBITORS AND THEIR PROCEDURES FOR USE
MA52780A (en) 2018-06-11 2021-04-14 Amgen Inc KRAS G12C INHIBITORS FOR CANCER TREATMENT
AU2019336588B2 (en) 2018-06-12 2022-07-28 Amgen Inc. KRAS G12C inhibitors encompassing a piperazine ring and use thereof in the treatment of cancer
JP2020090482A (en) 2018-11-16 2020-06-11 アムジエン・インコーポレーテツド Improved synthesis of key intermediate of kras g12c inhibitor compound
MX2021005700A (en) 2018-11-19 2021-07-07 Amgen Inc Kras g12c inhibitors and methods of using the same.
JP7377679B2 (en) 2018-11-19 2023-11-10 アムジエン・インコーポレーテツド Combination therapy comprising a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancer
MX2021007158A (en) 2018-12-20 2021-08-16 Amgen Inc Heteroaryl amides useful as kif18a inhibitors.
WO2020132653A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
MX2021007156A (en) 2018-12-20 2021-08-16 Amgen Inc Kif18a inhibitors.
EP3897855B1 (en) 2018-12-20 2023-06-07 Amgen Inc. Kif18a inhibitors
AU2020232616A1 (en) 2019-03-01 2021-09-09 Revolution Medicines, Inc. Bicyclic heterocyclyl compounds and uses thereof
SG11202109036WA (en) 2019-03-01 2021-09-29 Revolution Medicines Inc Bicyclic heteroaryl compounds and uses thereof
US11465998B2 (en) 2019-04-25 2022-10-11 Regents Of The University Of Minnesota Therapeutic compounds and methods of use thereof
EP3738593A1 (en) 2019-05-14 2020-11-18 Amgen, Inc Dosing of kras inhibitor for treatment of cancers
CN114144414A (en) 2019-05-21 2022-03-04 美国安进公司 Solid state form
EP4007638A1 (en) 2019-08-02 2022-06-08 Amgen Inc. Pyridine derivatives as kif18a inhibitors
MX2022001296A (en) 2019-08-02 2022-02-22 Amgen Inc Kif18a inhibitors.
MX2022001295A (en) 2019-08-02 2022-02-22 Amgen Inc Kif18a inhibitors.
AU2020324963A1 (en) 2019-08-02 2022-02-24 Amgen Inc. KIF18A inhibitors
WO2021081212A1 (en) 2019-10-24 2021-04-29 Amgen Inc. Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer
JP2022553858A (en) 2019-11-04 2022-12-26 レボリューション メディシンズ インコーポレイテッド RAS inhibitor
TW202132314A (en) 2019-11-04 2021-09-01 美商銳新醫藥公司 Ras inhibitors
CR20220240A (en) 2019-11-04 2022-08-03 Revolution Medicines Inc Ras inhibitors
CA3156359A1 (en) 2019-11-08 2021-05-14 Adrian Liam Gill Bicyclic heteroaryl compounds and uses thereof
US20230192681A1 (en) 2019-11-14 2023-06-22 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
WO2021097207A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
EP4065231A1 (en) 2019-11-27 2022-10-05 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
TW202140011A (en) 2020-01-07 2021-11-01 美商銳新醫藥公司 Shp2 inhibitor dosing and methods of treating cancer
KR20230042600A (en) 2020-06-18 2023-03-28 레볼루션 메디슨즈, 인크. Methods of Delaying, Preventing, and Treating Acquired Resistance to RAS Inhibitors
AU2021344830A1 (en) 2020-09-03 2023-04-06 Revolution Medicines, Inc. Use of SOS1 inhibitors to treat malignancies with SHP2 mutations
IL301298A (en) 2020-09-15 2023-05-01 Revolution Medicines Inc Indole derivatives as ras inhibitors in the treatment of cancer
JP2024501280A (en) 2020-12-22 2024-01-11 キル・レガー・セラピューティクス・インコーポレーテッド SOS1 inhibitors and their uses
CN117500811A (en) 2021-05-05 2024-02-02 锐新医药公司 Covalent RAS inhibitors and uses thereof
CR20230570A (en) 2021-05-05 2024-01-22 Revolution Medicines Inc Ras inhibitors
AR125787A1 (en) 2021-05-05 2023-08-16 Revolution Medicines Inc RAS INHIBITORS
AR127308A1 (en) 2021-10-08 2024-01-10 Revolution Medicines Inc RAS INHIBITORS
TW202340214A (en) 2021-12-17 2023-10-16 美商健臻公司 Pyrazolopyrazine compounds as shp2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5593997A (en) * 1995-05-23 1997-01-14 Pfizer Inc. 4-aminopyrazolo(3-,4-D)pyrimidine and 4-aminopyrazolo-(3,4-D)pyridine tyrosine kinase inhibitors
WO1998041525A1 (en) * 1997-03-19 1998-09-24 Basf Aktiengesellschaft Pyrrolo[2,3d]pyrimidines and their use as tyrosine kinase inhibitors
WO1998054093A1 (en) * 1997-05-30 1998-12-03 Merck & Co., Inc. Novel angiogenesis inhibitors

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2637731A (en) * 1949-06-02 1953-05-05 American Cyanamid Co Imidazopyridines
US3819640A (en) * 1972-08-07 1974-06-25 Degussa Aza-benzimidazoles and process for their production
SE422799B (en) * 1975-05-28 1982-03-29 Merck & Co Inc ANALOGY PROCEDURE FOR PREPARATION OF 1,3-DIHYDROIMIDAZO (4,5-B) PYRIDIN-2-ONER
US4859672A (en) * 1986-10-29 1989-08-22 Rorer Pharmaceutical Corporation Pyrido[2,3-d]pyrimidinone and imidazo[4,5-b]pyrimidinone
FR2643903A1 (en) * 1989-03-03 1990-09-07 Union Pharma Scient Appl NOVEL BENZIMIDAZOLE DERIVATIVES, PROCESSES FOR PREPARING SAME, SYNTHESIS INTERMEDIATES, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME, IN PARTICULAR FOR THE TREATMENT OF CARDIOVASCULAR DISEASES, AND DUODENIAL ULCERS
US5010086A (en) * 1990-02-28 1991-04-23 Sterling Drug Inc. Imidazopyridines, compositions and use
US5248672A (en) * 1990-11-01 1993-09-28 The Regents Of The University Of Michigan Polysubstituted benzimidazole nucleosides as antiviral agents
WO1993015712A1 (en) * 1992-02-13 1993-08-19 Merck Patent Gmbh Use of benzimidazole derivatives as protective light filters
DK40192D0 (en) * 1992-03-26 1992-03-26 Neurosearch As IMIDAZOLE COMPOUNDS, THEIR PREPARATION AND USE
GB9210400D0 (en) * 1992-05-15 1992-07-01 Merck Sharp & Dohme Therapeutic agents
CA2131134A1 (en) * 1993-09-17 1995-03-18 Gerhard Stucky Process for preparing imidazopyridine derivatives
US5637724A (en) * 1995-06-05 1997-06-10 Neurogen Corporation Substituted aryl and cycloalkyl imidazolones; a new class of GABA brain receptor ligands

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5593997A (en) * 1995-05-23 1997-01-14 Pfizer Inc. 4-aminopyrazolo(3-,4-D)pyrimidine and 4-aminopyrazolo-(3,4-D)pyridine tyrosine kinase inhibitors
WO1998041525A1 (en) * 1997-03-19 1998-09-24 Basf Aktiengesellschaft Pyrrolo[2,3d]pyrimidines and their use as tyrosine kinase inhibitors
WO1998054093A1 (en) * 1997-05-30 1998-12-03 Merck & Co., Inc. Novel angiogenesis inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0012089A1 *

Also Published As

Publication number Publication date
AU760020B2 (en) 2003-05-08
AU3078999A (en) 2000-03-21
JP2002523459A (en) 2002-07-30
WO2000012089A1 (en) 2000-03-09
EP1109555A4 (en) 2001-11-21
CA2341409A1 (en) 2000-03-09

Similar Documents

Publication Publication Date Title
US6465484B1 (en) Angiogenesis inhibitors
US6162804A (en) Tyrosine kinase inhibitors
AU760020B2 (en) Novel angiogenesis inhibitors
AU744939B2 (en) Novel angiogenesis inhibitors
US6235741B1 (en) Angiogenesis inhibitors
AU734009B2 (en) Novel angiogenesis inhibitors
US7696223B2 (en) Pyrrolo- and Thiazolo-pyridine compounds, and methods of use thereof
EP2328871B1 (en) Hedgehog pathway modulators
US6180643B1 (en) Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
AU2006223070B2 (en) Benzazole derivatives, compositions, and methods of use as B-secretase inhibitors
EP1097147A1 (en) Novel angiogenesis inhibitors
JP5255438B2 (en) Benzimidazoles useful as protein kinase inhibitors
KR20160135283A (en) 5-substituted indazole-3-carboxamides and preparation and use thereof
WO2000043393A1 (en) Novel angiogenesis inhibitors
WO2003051366A2 (en) 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
EA019507B1 (en) Fused nitrogen containing heterocycles and compounds thereof as kinase inhibitors
WO1998022457A9 (en) Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
US20050075334A1 (en) Novel compounds
US6380203B1 (en) Angiogenesis inhibitors
EP1463505A2 (en) 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
US6228871B1 (en) Angiogenesis inhibitors
AU2011244844A1 (en) Benzazole derivatives, compositions, and methods of use as B-secretase inhibitors

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010402

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20010402;LT PAYMENT 20010402;LV PAYMENT 20010402;MK PAYMENT 20010402;RO PAYMENT 20010402;SI PAYMENT 20010402

A4 Supplementary search report drawn up and despatched

Effective date: 20011009

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 61K 31/44 A, 7A 61K 31/415 B, 7A 61K 31/445 B, 7A 61K 31/495 B, 7A 61K 31/505 B, 7A 61K 31/535 B, 7C 07D 235/10 B, 7C 07D 235/12 B, 7C 07D 235/14 B, 7C 07D 235/16 B, 7C 07D 235/06 B, 7C 07D 471/04 B, 7C 07D 401/04 B, 7A 61K 31/435 B

17Q First examination report despatched

Effective date: 20020207

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20031203