Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • 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
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• This invention relates to novel triazolopyridazine derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals.
• This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
• HGF hepatocyte growth factor
• HGFR HGFR receptor tyrosine kinase
• RTK receptor tyrosine kinase
• c-MET can be activated through overexpression or mutations in various human cancers including small cell lung cancer (SCLC) (Ma, P.C., Kijima, T., Maulik, G., Fox, EA, Sattler, M., Griffin, J. D., Johnson, B.E. & Salgia, R. (2003a). Cancer Res, 63, 6272-6281 ).
• SCLC small cell lung cancer
• c-MET is a receptor tyrosine kinase that is encoded by the Met proto-oncogene and transduces the biological effects of hepatocyte growth factor (HGF), which is also referred to as scatter factor (SF).
• HGF hepatocyte growth factor
• SF scatter factor
• c-MET and HGF are expressed in numerous tissues, although their expression is normally confined predominantly to cells of epithelial and mesenchymal origin, respectively. c-MET and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation, and organization of 3-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.). In addition to its effects on epithelial cells, HGF/SF has been reported to be an angiogenic factor, and c-MET signaling in endothelial cells can induce many of the cellular responses necessary for angiogenesis (proliferation, motility, invasion).
• the c-MET receptor has been shown to be expressed in a number of human cancers.
• c-Met and its ligand, HGF have also been shown to be co-expressed at elevated levels in a variety of human cancers (particularly sarcomas).
• HGF histone growth factor
• c-MET signaling is most commonly regulated by tumor-stroma (tumor-host) interactions.
• c-MET gene amplification, mutation, and rearrangement have been observed in a subset of human cancers. Families with germline mutations that activate c-MET kinase are prone to multiple kidney tumors as well as tumors in other tissues.
• c-MET and/or HGF/SF have correlated the expression of c-MET and/or HGF/SF with the state of disease progression of different types of cancer (including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin, and bone cancers). Furthermore, the overexpression of c-MET or HGF have been shown to correlate with poor prognosis and disease outcome in a number of major human cancers including lung, liver, gastric, and breast. c-MET has also been directly implicated in cancers without a successful treatment regimen such as pancreatic cancer, glioma, and hepatocellular carcinoma.
• c-Met is an attractive target from a clinical perspective because: 1) c-Met has been implicated in the growth and metastases of most types of cancer; 2) growth at the secondary site appears to be the rate-limiting step in metastasis; and 3) by the time of diagnosis, R is likely that the disease has already spread.
• c-Met kinase inhibitors would be an effective treatment for primary tumors that are driven by c-Met, but more importantly, would prevent disseminated micrometastases from growing into life-threatening metastases. Therefore, the utility of a c-Met inhibitor extends to preventative and adjuvant therapy settings.
• certain cancers e.g., papillary renal cell carcinoma, some gastric and lung cancers
• various human cancers are the primary target indication for c- Met antagonists.
• cancers include major cancers such as breast, lung, colorectal, prostate; as well as pancreatic cancer, glioma, liver cancer, gastric cancer, head and neck cancers, melanoma, renal cancer, leukemias, myeloma, and sarcomas.
• c-Met has been directly implicated in cancers such as pancreatic cancer, glioma, and hepatocellular carcinoma. Accordingly, c-Met (HGFR) inhibitors and methods of using such inhibitors for the treatment of abnormal cell growth, such as cancer represent a substantial unmet medical need in the treatment of these and possibly other cancers.
• the present invention relates to a compound of the formula I:
• R 1 , R 2 and R 3 are independently selected from hydrogen, Br, Cl, F, -O(CH 2 )nCH 3 , -O(CH 2 ) n OR 6 ,
• R 4 is a 8-10 membered heterobicyclic optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, -(CH 2 ) n CH(OR 6 )CH 3 , -(CH 2 J n OR 6 , -(CH 2 J n C(CH 3 J 2 OR 6 , -(CH 2 ) n (3-8 membered heteroalicyclic), -C(O)R 6 , -C(O)OR 6 , -(CR 6 R 7 J n C(O)OR 6 , -C(O)NR 6 R 7 , -(CR 6 R 7 ) n C(O)NR 6 R 7 , - (CH 2 ) n NR 6 R 7 , -S(O) 2 R 6 , -S(O)R 6 , -S(O) 2 NR 6 R 7 , -CF 3 , -CF 2 H, -(CHz) n NR 6 C(
• R 5 is selected from the group consisting of hydrogen, F, -CF 3 , C 1 -C 6 alkyl and aryl;
• R 6 and R 7 are independently selected from H, -(CH 2 J n OR 8 , -(CH 2 J n C(CH 3 J 2 OR 8 , -CHR 8 (CH 2 ) n OR 9 , -(CH 2 J n CHR 8 OR 9 , -C(CH 3 J 2 (CH 2 J n OR 8 , -CH 2 CF 2 H, -(CH 2 J n C(CH 3 J 2 NR 8 R 9 , -(CH 2 J n NR 8 R 9 , -(CH 2 J n NR 8 R 9 , -(CH 2 ) n CHOR 8 (CH 2 ) n OR 9 , -(CH 2 ) n (NR 8 R 9 )C(O)NR 8 R 9 , -(CH 2 ) n S(O) 2 R 8 , -(CH 2 ) n C(O)NR 8 R 9 , -(CH 2 ) n C(O)R 8 ,
• R 8 and R 9 are independently selected from H, C 1 -C 6 alkyl, -C(O)CH 3 , C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 2 -C 6 alkenyl, 5-7 membered heteroaryl and C 2 -C 6 alkynyl, wherein said 5-7 membered heteroaryl is optionally substituted by one or more moieties selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -Ci 0 aryl.
• R 1 , R 2 and R 3 are independently selected from hydrogen, Cl, -OR 10 , -O(CH 2 ) n CH 3 , -OCH 2 (CH 2 ) n OR 10 , -C(O)NR 10 R 11 , -NR 10 R 11 , C 1 -C 6 alkyl, 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C 6 -Ci 0 aryl and C 2 -C 6 alkenyl, wherein C 1 -C 6 alkyl, 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C 6 -C 10 aryl and C 2 -C 6 alkenyl are optionally substituted by one or more moie
• R 1 is selected from Cl, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 5-7 membered heteroaryl, and C 6 -C 10 aryl, wherein 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 5-7 membered heteroaryl and C 6 -Ci 0 aryl are optionally substituted by one or more moieties selected from the group consisting of -(CH 2 J n OR 10 , -C(O)OR 10 , -(CR 10 R 11 J n C(O)NR 10 R 11 , -
• R 2 and R 3 are H.
• R 5 is H.
• R 5 is C 1 -C 6 alkyl.
• R 5 is methyl.
• R 4 is selected from
• the present invention provides for a compound of the formula (I) selected from 6-(1 -methyl-1 H-pyrazol-4-yl)-3-[(S)-1 -(1 H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]- [1 ,2,4]triazolo[4,3-b]pyridazine, 7-methyl-6- ⁇ [6-(1 -methyl-1 H-pyrazol-4-yl)[1 ,2,4]triazolo[4,3-b]pyridazin-3- yl]methyl ⁇ quinoline, 6- ⁇ (S)-1-[6-(1 -methyl-1 H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-ethyl ⁇ - quinoline, 6-((6-(1 H-pyrazol-4-yl)-[1 ,2,4]triazolo[4,3--b]pyrid
• the present invention relates to a coumpound selected from any 10 compounds exemplified in Table 1.
• the present invention relates to any coumpound exemplified in Table 1.
• the present invention provides a pharmaceutical composition comprising a compound according to the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• the present invention provides for the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament to treat a c-Met related disorder in a mammal.
• the present invention provides for the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of medicament for the treatment of cancer in a mammal.
• the cancer is selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, glioma, liver cancer, gastric cancer, head cancer, neck cancer, melanoma, renal cancer, leukemia, myeloma, and sarcoma.
• the present invention provides a method of treating a mammal having a c-Met related disorder, comprising administering to the mammal an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating a mammal having cancer, comprising administering to the mammal an effective amount of a compound of the formula (I) as defined in any one of claims 1-9 or with a pharmaceutically acceptable salt thereof.
• the cancer is selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, glioma, liver cancer, gastric cancer, head cancer, neck cancer, melanoma, renal cancer, leukemia, myeloma, and sarcoma.
• the mammal is a human. In another embodiment, the mammal is a canine.
• “Pharmaceutically acceptable salt” refers to those salts, which retain the biological effectiveness and properties of the parent compound.
• Such salts include: acid addition salt which is obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic add, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic
• “Pharmaceutically acceptable excipient” or “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
• excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
• a “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients.
• the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
• a “physiologically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
• method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by, practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
• modulation refers to the ateration of the catalytic activity of c-Met.
• modulating refers to the activation of the catalytic activity of c-Met, preferably the activation or inhibition of the catalytic activity of c-Met, depending on the concentration of the compound or salt to which c-Met is exposed or, more preferably, the inhibition of the catalytic activity of c-Met.
• contacting refers to bringing a compound of this invention and c-Met together in such a manner that the compound can affect the catalytic activity of c-Met, either directly, i.e., by interacting with c-Met itself, or indirectly, i.e., by interacting with another molecule on which the catalytic activity of c-Met is dependent.
• Such "contacting” can be accomplished in vitro, i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and c-Met or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment.
• the ability of a particular compound to affect a c-Met related disorder i.e., the IC 50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted.
• IC 50 of the compound defined below
• multiple methods exist, and are well-known to those skilled in the art, to get c-Met in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmemtrane carrier techniques.
• In vitro refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium.
• isolated c- Met may be contacted with a modulator in an in vitro environment.
• an isolated cell may be contacted with a modulator in an in vitro environment.
• in vivo refers to procedures performed within a living organism such as, without limitation, a mouse, rat, rabbit, ungulate, bovine, equine, porcine, canine, feline, primate, or human.
• c-Met related disorder refers to a condition characterized by inappropriate, i.e., under-activity or, more commonly, over-activity of the c-Met catalytic activity.
• a “c-Met related disorder” also refers to a condition where there may be a mutation in the gene that produces c-Met, which, in turn, produces a c-Met that has an increased or decreased c-Met catalytic activity.
• Inappropriate catalytic activity can arise as the result of either: (1) c-Met expression in cells which normally do not express c-Met, (2) increased c-Met expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased c-Met expression leading to unwanted reductions in cell proliferation, differentiation and/or growth.
• Over-activity of a c-Met refers to either amplification of the gene encoding a c-Met or production of a level of c-Met activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the c-Met increases, the severity of one or more of the symptoms of the cellular disorder increases). Under-activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the c-Met activity decreases.
• the terms “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a c-Met mediated cellular disorder and/or its attendant symptoms. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
• organism refers to any living entity comprised of at least one cell.
• a living organism can be as simple as, for example, a single eukaryotic cell or as complex as a mammal.
• the organism is a mammal.
• the mammal is a human being.
• a therapeutically effective amount refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
• a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and/or, (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.
• monitoring is meant observing or detecting the effect of contacting a compound with a cell expressing a c-Met.
• the observed or detected effect can be a change in cell phenotype, in the catalytic activity of c-Met or a change in the interaction of c-Met with a natural binding partner.
• Techniques for observing or detecting such effects are well-known in the art.
• the catalytic activity of c-Met may be observed by determining the rate or amount of phosphorylation of a target molecule.
• Cell phenotype refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known in the art.
• a "natural binding partner” refers to a polypeptide that binds to a c-Met in a cell. Natural binding partners can play a role in propagating a signal in a c-Met-mediated signal transduction process.
• a change in the interaction of the natural binding partner with c-Met can manifest itself as an increased or decreased concentration of the c-Met/natural binding partner complex and, as a result, in an observable change in the ability of c-Met to mediate signal transduction.
• administer or “administration” refers to the delivery of a compound or salt of the present invention or of a pharmaceutical composition containing a compound or salt of this invention to an organism for the purpose of prevention or treatment of a c-Met-related disorder.
• abnormal cell growth and “hyperproliferative disorder” are used interchangeably in this application.
• Abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), including the abnormal growth of normal cells and the growth of abnormal cells. This includes, but is not limited to, the abnormal growth of: (1 ) tumor cells (tumors), both benign and malignant, expressing an activated Ras oncogene; (2) tumor cells, both benign and malignant, in which the Ras protein is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. Examples of such benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papilloma virus (HPV), and restinosis. “Abnormal cell growth” also refers to and includes the abnormal growth of cells, both benign and malignant, resulting from activity of the enzyme farnesyl protein transferase.
• Alkyl refers to a saturated aliphatic hydrocarbon including straight chain or branched chain.
• the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g., "1-20", is stated herein, it means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 6 carbon atoms.
• the alkyl group may be substituted or unsubstituted.
• each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR', -COOR', -OCOR', -CONRR', -RNCOR', -NRR', -CN, -NO 2 , -CF 3 -SR', -SOR', -SO 2 R', -SO 2 OR', -SO 2 NRR', thiocarbonyl, -RNSO 2 R', perfluoroalkyl, O- carbamyl, N-carbamyl, 0-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl.
• R and R' can be independently H, alkyl, or aryl, wherein alkyl or aryl may be further substituted with halogen, (CH 2 ) n N(R") 2 , (CH 2 ) n CO 2 R", (CH 2 ) n OR", (CH 2 ) n OC(O)R", alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, a heteroalicyclic ring, aryl, alkoxy, -OCF 3 , aryloxy, C(O)NH 2 or heteroaryl.
• R" can be H, alkyl or aryl.
• n is 0-3.
• alkenyl refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight chain, branched chain or cyclic groups having at least one carbon-carbon double bond.
• the alkenyl group has 2 to 20 carbon atoms (whenever a numerical range; e.g., "2-20", is stated herein, it means that the group, in this case the alkenyl group, may contain 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkenyl having 2 to 10 carbon atoms. Most preferably, it is a lower alkenyl having 2 to 6 carbon atoms.
• alkenyl groups examples include 1-propenyl, 1- and 2-butenyl, etc.
• the alkenyl group may be substituted or unsubstituted.
• each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR', -COOR', -OCOR', -CONRR", -RNCOR', -NRR', -CN, - NO 2 , -CF 3 , -SR 1 , -SOR", -SO 2 R', -SO 2 OR', -SO 2 NRR', thiocarbonyl, -RNSO 2 R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl
• Alkynyl refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight chain, branched chain or cyclic groups having at least one carbon-carbon triple bond.
• the.alkenyl group has 2 to 20 carbon atoms (whenever a numerical range; e.g., "2-20", is stated herein, it means that the group, in this case the alkynyl group, may contain 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkynyl having 2 to 10 carbon atoms.
• alkynyl having 2 to 6 carbon atoms.
• alkynyl groups include 1-propynyl, 1- and 2-butynyl, etc.
• the alkynyl group may be substituted or unsubstituted.
• each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR', -COOR', -OCOR', -CONRR', -RNCOR', -NRR 1 , -CN, - NO 2 , -CF 3 , -SR', -SOR', -SO 2 R', -SO 2 OR', -SO 2 NRR', thiocarbonyl, -RNSO 2 R", perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyi, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl.
• R and R' are defined herein.
• a “cycloalkyl” or an “alicyclic” group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi-electron system.
• the cycloalkyl group has from 3-8 carbon atoms in the ring(s). Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and, cycloheptatriene.
• a cycloalkyl group may be substituted or unsubstituted.
• each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR', -COOR', -OCOR', -CONRR', -RNCOR 1 , -NRR', -CN, -NO 2 , -CF 3 , -SR', -SOR 1 , -SO 2 R', -SO 2 OR 1 , -SO 2 NRR', thiocarbonyl, -RNSO 2 R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl.
• R and R' are defined herein.
• aryl group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system.
• the aryl group has from 6 to 12 carbon atoms in the riong(s). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl.
• the aryl group may be substituted or unsubstituted.
• each substituted group is preferably one or more selected halogen, hydroxy, alkoxy, aryloxy, - COR', -COOR', -OCOR', -CONRR 1 , -RNCOR', -NRR', -CN, -NO 2 , -CF 3 , -SR', -SOR 1 , -SO 2 R 1 , -SO 2 OR 1 , - SO 2 NRR', thiocarbonyl, -RNSO 2 R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl.
• R and R' are defined herein.
• heteroaryl group refers to a monocyclic group having in the ring one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur with the proviso that heteroaryl groups containing highly unstable heteroatom arrangements, such as O-O, 0-0-0 and the like, are not contemplated by the present invention.
• heteroaryl groups containing highly unstable heteroatom arrangements, such as O-O, 0-0-0 and the like, are not contemplated by the present invention.
• the heteroaryl group has a completely conjugated pi- electron system.
• the heteroaryl group has from 5 to 7 ring atoms.
• Examples of typical monocyclic heteroaryl groups include, but are not limited to: p ⁇ yrrole furan thi ⁇ ophene razole imidazole (pyrrolyl) (furanyl) (thiophenyl) (pyrazolyl) (imidazolyl)
• each substituted group is preferably one or more selected from halogen, hydroxy, -COR 1 , -COOR', -OCOR 1 , -CONRR', -RNCOR 1 , -NRR 1 , -CN, -NO 2 , -CF 3 , -SR', -SOR', -SO 2 R', - SO 2 OR', -SO 2 NRR', thiocarbonyl, -RNSO 2 R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl.
• a “heteroalicyclic ring” or “heteroalicycle” or “heterocyclic” or “heterocycle” group refers to a monocyclic group having in the ring one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur.
• the rings may be saturated and also have one or more double bonds (i.e. partially unsaturated). However, the rings may not have a completely conjugated pi-electron system.
• the heteroalicyclic ring contains from 3 to 8 ring atoms.
• saturated heteroalicyclic groups include, but are not limited to: oxirane thiarane aziridine oxetane thiatane azetidine tetrahydrofuran (oxiranyl) (thiaranyl) (aziridinyl) (oxetanyl) (thiatanyl) (azetidinyl) (tetrahydrofuranyl)
• piperazine 1 ,4-azathiane oxepane thiepane azepane piperazinyl (1 ,4-azathianyl) (oxepanyl) (thiepanyl) (azepanyl)
• Suitable partially unsaturated heteroalicyclic groups include, but are not limited to:
• a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
• the heteroalicyclic ring may be substituted or unsubstituted.
• the heteroalicydic ring may contain one or more oxo groups.
• the substituted group(s) is preferably one or more selected halogen, hydroxy, -COR", -COOR', OCOR', -CONRR', -RNCOR', -NRR', -CN, -NO 2 , -CZ 3 , - SR', -SOR', -SO 2 R', -SO 2 OR', -SO 2 NRR', thiocarbonyl, -RNSO 2 R', perfluoroalkyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alky], lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl.
• a "3-8 Membered heteroalicyclic-(3-8 membered heteroalicyclic)" group refers to a group having two 3-8 membered heteroalicyclic groups covalently bonded to each other through a single ring atom of each.
• the 3-8 membered heteroalicyclic rings may be any heteroalicyclic ring as defined above.
• the heteroalicyclic rings may be substituted or unsubstituted as defined above.
• Heterobicyclic or “heterobicycle” refers to a fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system (i.e.- aromatic heterobicyclic) or one or more double bonds that does not create a completely conjugated pi-electron system, with the proviso that heterobicyclic groups containing highly unstable heteroatom arrangements, such as 0-0, 0-0- O and the like, are not contemplated by the present invention.
• a fused ring i.e., rings which share an adjacent pair of atoms
• a completely conjugated pi-electron system i.e.- aromatic heterobicyclic
• heterobicyclic groups containing highly unstable heteroatom arrangements such as 0-0, 0-0- O and the like
• the heterobicyclic group contains from 8-10 ring atoms.
• the heterobicyclic ring may be substituted or unsubstituted.
• the heterobicyclic ring may contain one or more oxo groups. Examples of suitable fused ring aromatic heterobicyclic groups include, but are not limited to: benzofuran benzothiophene indole benzimidazole indazole
• pyrazolo[4,3-c]pyridine pyrazolo[3,4-c]pyridine pyrazolo[3,4-b]pyridine isoindole (pyrazolo[4,3-c]pyidinyl) (pyrazolo[3,4-c]pyidinyl) (pyrazolo[3,4-b]pyidinyl) (isoindolyl)
• fused ring aromatic heterobicyclic groups include, but are not limited to:
• the substituted group(s) is preferably one or more selected halogen, hydroxy, - COR', -COOR', OCOR 1 , -CONRR 1 , -RNCOR 1 , -NRR', -CN, -NO 2 , -CZ 3 , -SR 1 , -SOR 1 , -SO 2 R 1 , -SO 2 OR 1 , - SO 2 NRR 1 , thiocarbonyl, -RNSO 2 R 1 , perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl.
• R and R 1 are defined herein.
• the R groups on substitutents having two or more R groups on different atoms such as -(CH 2 ) n (NR B R a )C(O)NR B R a or -NR 0 C(O)NR ,6 0 O R7', may be the same or different.
• the two R 6 groups may be the same or different with respect to each other, likewise, the two R 6 groups may be the same or different with respect to the R 7 group.
• the two R 8 groups may be the same or different with respect to each other, and the two R 9 groups may be the same or different with respect to each other.
• the two R 8 groups may be the same or different with respect to the two R 9 groups.
• the groups on that atom may be the same or different. So, in -NR 6 C(O)NR 6 R 7 , the R 6 and R 7 on the same nitrogen may be the same or different from one another.
• oxo refers to a carbonyl moiety such that alkyl substituted by oxo refers ro a ketone group.
• a "hydroxy” group refers to an -OH group.
• An “alkoxy” group refers to both an -Oalkyl and an -Ocycloalkyl group, as defined herein.
• alkoxycarbonyl refers to a -C(O)OR.
• aminocarbonyl refers to a -C(O)NRR'.
• aryloxycarbonyl refers to -C(O)Oaryl.
• aryloxy refers to both an -Oaryl and an -Oheteroaryl group, as defined herein.
• arylalkyl refers to -alkylaryl, where alkyl and aryl are defined herein.
• arylsulfonyl refers to a -S0 2 aryl.
• alkylsulfonyl refer to a -SO 2 alkyl.
• heteroaryloxyl refers to a heteroaryl group with heteroaryl as defined herein.
• heteroalicycloxy refers to a heteroalicyclic-O group with heteroalicyclic as defined herein.
• aldehyde refers to a carbonyl group where R is hydrogen.
• a “trihalomethanecarbonyl” group refers to a Z 3 CC(O) group, where Z is halogen.
• a "C-carboxyl” group refers to a -C(O)OR groups.
• An "O-carboxyl” group refers to a RC(O)O group.
• a “carboxylic acid” group refers to a C-carboxyl group in which R is hydrogen.
• halo or halogen refers to fluorine, chlorine, bromine or iodine.
• trihalomethyl refers to a -CZ 3 group.
• a "trihalomethanesulfonyl” group refers to a Z 3 CS(O) 2 group.
• a "trihalomethanesulfonamido" group refers to a Z 3 CS(O) 2 NR-group.
• a “sulfinyl” group refers to a -S(O)R group.
• a “sulfonyl” group refers to a -S(O) 2 R group.
• An “S-sulfonamido” group refers to a -S(O) 2 NR-group.
• N-Sulfonamido refers to a -NR-S(O) 2 R group.
• O-carbamyl refers to a -OC(O)NRR' group.
• N-carbamyl refers to a ROC(O)NR-group.
• An "O-thiocarbamyl” group refers to a -OC(S)NRR' group.
• An "N-thiocarbamyl” group refers to a ROC(S)NR' group.
• amino refers to an -NH 2 or an -NRR'group.
• C-amido refers to a -C(O)NRR' group.
• N-amido refers to a R 1 C(O)NR group.
• a “nitro” group refers to a -NO 2 group.
• a “cyano” group refers to a -CN group.
• sil refers to a -Si(R) 3 group.
• aminoalkyl refers to an -alkylNRR' group.
• alkylaminoalkyl refers to an -alkyl-NR-alkyl group.
• dialkylamionalkyl refers to an -alkylN-(alkyl) 2 group.
• perfluoroalkyl group refers to an alkyl group where all of the hydrogen atoms have been replaced with fluorine atoms.
• isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or arrangements of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof.
• a mixture containing equal proportions of the enantiomers is called a "racemic mixture".
• the chemical formulae referred to herein may exhibit the phenomena of tautomerism and structural isomerism.
• This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which possess the ability to modulate c-Met activity and is not limited to any one tautomeric or structural isomeric form.
• This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which possess the ability to modulate c-Met activity and is not limited to any one tautomeric or structural isomeric form.
• the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)-or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
• the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).
• this invention also encompasses any stereoisomeric form, their corresponding enantiomers (d- and I- or (+) and (-) isomers) and diastereomers thereof, and mixtures thereof, which possess the ability to modulate c-Met activity and is not limited to any one stereoisomeric form.
• the compounds of the formula (I) may exhibit the phenomena of tautomerism and structural isomerism.
• the compounds described herein may adopt an E or a Z configuration about a double bond or they may be a mixture of E and Z.
• This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which possess the ability to modulate c-Met activity and is not limited to any one tautomeric or structural isomeric form.
• compounds of the formula (I) would be metabolized by enzymes in the body of the organism such as human being to generate a metabolite that can modulate the activity of c- Met. Such metabolites are within the scope of the present invention.
• Those compounds of the formula (I) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• Examples of such salts include the alkali metal or alkaline earth metal salts and particularly, the sodium and potassium salts.
• the compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
• This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
• the compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
• This invention also encompasses pharmaceutical compositions containing and methods of treating proliferative disorders or abnormal cell growth through administering prodrugs of compounds of the formula (I).
• Compounds of formula (I) having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
• Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula (I).
• the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3- methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
• Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
• Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
• acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
• Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
• Scheme 1 A general synthetic route to the compounds of the present invention is shown in Scheme 1.
• the groups R a , R b , R c and R d shown in Scheme 1 include but are not limited to those R 1 substituents described herein in connection with the present invention. Further exemplary methods for making the compounds of the invention are outlined in the non-limiting examples below.
• this invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. It is also an aspect of this invention that a compound described herein, or its salt, might be combined with other chemotherapeutic agents for the treatment of the diseases and disorders discussed above.
• a compound or salt of this invention might be combined with alkylating agents such as fluorouracil (5-FU) alone or in further combination with leukovorin; or other alkylating agents such as, without limitation, other pyrimidine analogs such as UFT, capecitabine, gemcitabine and cytarabine, the alkyl sulfonates, e.g., busulfan (used in the treatment of chronic granulocytic leukemia), improsulfan and piposulfan; aziridines, e.g., benzodepa, carboquone, meturedepa and uredepa; ethyleneimines and methylmelamines, e.g., altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphorami- de and trimethylolmelamine; and the nitrogen mustards, e.g., chlorambucil (used in the treatment of chronic lymphocytic leukemia, primary macroglobulinemia and
• a compound or salt of this invention might be expected to have a beneficial effect in combination with other antimetabolite chemotherapeutic agents such as, without limitation, folic acid analogs, e.g. methotrexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancer and osteogenic sarcoma) and pteropterin; and the purine analogs such as mercaptopurine and thioguanine which find use in the treatment of acute granulocytic, acute lymphocytic and chronic granulocytic leukemias.
• folic acid analogs e.g. methotrexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancer and osteogenic sarcoma) and pteropterin
• purine analogs such as mercaptopurine and thio
• a compound or salt of this invention might also be expected to prove efficacious in combination with natural product based chemotherapeutic agents such as, without limitation, the vinca alkaloids, e.g., vinblastin (used in the treatment of breast and testicular cancer), vincristine and vindesine; the epipodophylotoxins, e.g., etoposide and teniposide, both of which are useful in the treatment of testicular cancer and Kaposi's sarcoma; the antibiotic chemotherapeutic agents, e.g., daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat stomach, cervix, colon, breast, bladder and pancreatic cancer), dactinomycin, temozolomide, plicamycin, bleomycin (used in the treatment of skin, esophagus and genitourinary tract cancer); and the enzymatic chemotherapeutic agents such as L-asparaginase.
• a compound or salt of this invention might be expected to have a beneficial effect used in combination with the platinum coordination complexes (cisplatin, etc.); substituted ureas such as hydroxyurea; methylhydrazine derivatives, e.g., procarbazine; adrenocortical suppressants, e.g., mitotane, aminoglutethimide; and hormone and hormone antagonists such as the adrenocorticosteriods (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate); estrogens (e.g., diethylstilbesterol); antiestrogens such as tamoxifen; androgens, e.g., testosterone propionate; and aromatase inhibitors (such as anastrozole).
• substituted ureas such as hydroxyurea
• methylhydrazine derivatives e.g., procarbazine
• combination of a compound of this invention might be expected to be particularly effective in combination with mitoxantrone or paclitaxel for the treatment of solid tumor cancers or leukemias such as, without limitation, acute myelogenous (non-lymphocytic) leukemia.
• the above method can be carried out in combination with a chemotherapeutic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, antiangiogenic agents such as MMP-2, MMP-9 and COX-2 inhibitors, and anti-androgens.
• a chemotherapeutic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, antiangiogenic agents such as MMP-2, MMP-9 and COX-2 inhibitors, and anti-androgens.
• COX-II inhibitors include Vioxx.TM ' , CELEBREX.TM (alecoxib), valdecoxib, paracoxib, rofecoxib, and Cox 189.
• MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1.
• MMP-2 and/or MMP-9 are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix- metalloproteinase- s (i.e. MMP-1 , MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 ,
• MMP-12 MMP-12, and MMP-13.
• MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds recited in the following list:
• anti-angiogenesis agents including other COX-II inhibitors and other MMP inhibitors, can also be used in the present invention.
• Compounds of the formula (I) can also be used with signal transduction inhibitors, such as agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM. (Genentech, Inc. of South San Francisco, Calif., USA).
• EGFR inhibitors are described in, for example in WO 95/19970 (published JuI. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO 98/02434 (published Jan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5, 1998), and such substances can be used in the present invention as described herein.
• EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225 and anti- EGFR 22Mab (ImClone Systems Incorporated of New York, N.Y., USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, NJ. , USA), and OLX-103 (Merck & Co. of Whitehouse Station, N.J., USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Mass.).
• VEGF inhibitors can also be combined with a compounds of the Formulae (I).
• VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17,1995), WO 99/61422 (published Dec. 2,1999), U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 01/60814,WO 98/50356 (published Nov. 12,1998), U.S. Pat. No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issued Mar.
• VEGF inhibitors can be used in the present invention as described herein.
• ErbB2 receptor inhibitors such as GW-282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc.
• ErbB2 receptor inhibitors useful in the present invention are also described in U.S. Provisional Application No. 60/117,341 , filed Jan. 27,1999, and in U.S. Provisional Application No. 60/117,346, filed Jan. 27,1999, both of which are incorporated in their entireties herein by reference.
• the erbB2 receptor inhibitor compounds and substance described in the aforementioned PCT applications, U.S. patents, and U.S. provisional applications, as well as other compounds and substances that inhibit the erbB2 receptor can be used with compounds of the formula (I), in accordance with the present invention.
• Compounds of the formula (I) can also be used with other agents useful in treating cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and antiproliferative agents such as other famesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors described in the references cited in the "Background" section, of U.S. Pat. No, 6,258,824 Bl.
• CTLA4 antibodies that can be used in the present invention include those described in U.S. Provisional Application No. 60/113,647 (filed Dec. 23, 1998) which is incorporated by reference in its entirety, however other CTLA4 antibodies can be used in the present invention.
• the above method can be also be carried out in combination with radiation therapy, wherein the amount of a compound of the formula (I) in combination with the radiation therapy, is effective in treating the above diseases.
• the level of radiation therapy administered may be reduced to a sub-efficacy dose when administered in combination with the compounds of the preferred embodiments of the present invention.
• Another aspect of the invention is directed ot the use of compounds of the Formulae (I) in the preparation of a medicament, which is useful in the treatment of a disease mediated by abnormal Met kinase activity.
• this invention relates to a method for treating or preventing a c-Met related disorder by administering a therapeutically effective amount of a compound of this invention, or a salt thereof, to an organism.
• a pharmaceutical composition containing a compound of this invention, or a salt thereof is administered to an organism for the purpose of preventing or treating a c-Met related disorder.
• This invention is therefore directed to compounds that modulate PK signal transduction by affecting the enzymatic activity of c-Met, thereby interfering with the signal transduced by c-Met. More particularly, the present invention is directed to compounds which modulate c-Met mediated signal transduction pathways as a therapeutic approach to treat the many cancers described herein.
• a method for identifying a chemical compound that modulates the catalytic activity of c-Met is another aspect of this invention.
• the method involves contacting cells expressing c-Met with a compound of this invention (or its salt) and monitoring the cells for any effect that the compound has on them.
• the method can involve contacting the c-Met protein itself (i.e., not in a cell) with a chemical compound of the preferred embodiments of the present invention and monitoring the protein for any effect that the compound has on it.
• the effect may be observable, either to the naked eye or through the use of instrumentation.
• the effect may be, for example, a change or absence in a cell phenotype.
• the change or absence of change in the cell phenotype monitored for example, may be, without limitation, a change or absence of change in the catalytic activity of c-Met in the cells or a change or absence of change in the interaction of c-Met with a natural binding partner.
• a compound of the present invention or a physiologically acceptable salt thereof can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient(s).
• suitable carriers or excipient(s) suitable carriers or excipient(s).
• Suitable routes of administration may include, without limitation, oral, intraoral, rectal, transmucosal or intestinal administration or intramuscular, epicutaneous, parenteral, subcutaneous, transdermal, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, intramuscular, intradural, intrarespiratory, nasal inhalation or intraocular injections.
• the preferred routes of administration are oral and parenteral.
• the liposomes will be targeted to and taken up selectively by the tumor.
• compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
• compositions for use in the methods of the present invention may be prepared by any methods of pharmacy, but all methods include the step of bringing in association the active ingredient with the carrier which constitutes one or more necessary ingredients.
• pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
• Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, syrups, elixirs, gels, powders, magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs, suppositories, nasal or oral sprays, aerosols and the like.
• the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such buffers with or without a low concentration of surfactant or cosolvent, or physiological saline buffer.
• physiologically compatible buffers such buffers with or without a low concentration of surfactant or cosolvent, or physiological saline buffer.
• penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
• the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
• compositions for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries if desired, to obtain tablets or dragee cores.
• Useful excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, for example, maize starch, wheat starch, rice starch and potato starch and other materials such as gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
• disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid. A salt such as sodium alginate may also be used.
• Dragee cores are provided with suitable coatings.
• suitable coatings may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di-or triglycerides.
• Stabilizers may be added in these formulations, also.
• the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoroethane or carbon dioxide.
• a suitable propellant e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoroethane or carbon dioxide.
• the dosage unit may be controlled by providing a valve to deliver a metered amount.
• Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
• the compounds may also be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents.
• compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound.
• suspensions of the active compounds may be prepared in a lipophilic vehicle.
• Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.
• Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
• the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
• a suitable vehicle e.g., sterile, pyrogen-free water
• the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
• the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
• a compound of this invention may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
• a non-limiting example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer and an aqueous phase such as the VPD co-solvent system.
• VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
• the VPD co-solvent system (VPD:D5W) consists of VPD diluted 1 :1 with a 5% dextrose in water solution.
• This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
• the proportions of such a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
• identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80, the fraction size of polyethylene glycol may be varied, other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone, and other sugars or polysaccharides may substitute for dextrose.
• hydrophobic pharmaceutical compounds may be employed.
• Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
• certain organic solvents such as dimethylsulfoxide also may be employed, although often at the cost of greater toxicity.
• the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
• sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
• compositions herein also may comprise suitable solid or gel phase carriers or excipients.
• suitable solid or gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
• Many of the PK modulating compounds of the invention may be provided as physiologically acceptable salts wherein the claimed compound may form the negatively or the positively charged species.
• salts in which the compound forms the positively charged moiety include, without limitation, quaternary ammonium (defined elsewhere herein), salts such as the hydrochloride, sulfate, carbonate, lactate, tartrate, maleate, sucinate, malate, acetate and methylsulfonate (CH 3 SO 3 ), wherein the nitrogen atom of the quaternary ammonium group is a nitrogen of the selected compound of this invention which has reacted with the appropriate acid.
• Salts in which a compound of this invention forms the negatively charged species include, without limitation, the sodium, potassium, calcium and magnesium salts formed by the reaction of a carboxylic acid group in the compound with an appropriate base (e.g. sodium hydroxide (NaOH), potassium hydroxide (KOH), Calcium hydroxide (Ca(OH) 2 ), etc.).
• compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, i.e., the modulation of PK activity or the treatment or prevention of a PK-related disorder.
• a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
• the therapeutically effective amount or dose can be estimated initially from cell culture assays. Then, the dosage can be formulated for use in animal models so as to achieve a circulating concentration range that includes the IC 50 as determined in cell culture (i.e., the concentration of the test compound which achieves a half-maximal inhibition of c-Met activity). Such information can then be used to more accurately determine useful doses in humans.
• Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the IC 50 and the LD 50 (both of which are discussed elsewhere herein) for a subject compound.
• the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
• the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.1).
• Dosage amount and interval may be adjusted individually to provide plasma levels of the active species which are sufficient to maintain the kinase modulating effects. These plasma levels are referred to as minimal effective concentrations (MECs).
• MEC minimal effective concentrations
• the MEC will vary for each compound but can be estimated from in vitro data, e.g., the concentration necessary to achieve 50-90% inhibition of a kinase may be ascertained using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
• Compounds should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
• the therapeutically effective amounts of compounds of the Formulae (I)-(IV) may range from approximately 10 mg/m 2 to 1000 mg/m 2 perday. Even more preferably 25 mg/m 2 to 500 mg/m 2 .
• the effective local concentration of the drug may not be related to plasma concentration and other procedures known in the art may be employed to determine the correct dosage amount and interval.
• the amount of a composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
• compositions may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
• the pack may for example comprise metal or plastic foil, such as a blister pack.
• the pack or dispenser device may be accompanied by instructions for administration.
• the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or of human or veterinary administration.
• Such notice for example, may be of the labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
• compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
• Suitable conditions indicated on the label may include treatment of a tumor, inhibition of angiogenesis, treatment of fibrosis, diabetes, and the like.
• HPLC High-performance liquid chromatography (also known as high-pressure liquid chromatography)
• HATU 2-(7-Aza-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
• Step 3 To a solution of quinolin-6-yl-acetic acid methyl ester 3 (20.00 g, 99.54 mmol) in anhydrous tetrahydrofuran (200 mL) was added LDA (1.8 M THF solution, 61 mL, 109.5 mmol) drop wise at -78 0 C under nitrogen. The reaction mixture was stirred at at -78 0 C under nitrogen for half an hour. To the reaction mixture was added methyl iodide (6.20 mL, 99.54 mmol), and the mixture was stirred under nitrogen from -78 0 C to ambient temperature overnight. The reaction was quenched with the careful addition of water. The product was extracted with ethyl acetate.
• LDA 1.8 M THF solution, 61 mL, 109.5 mmol
• racemic 6-[1-(6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline was resolved with a chiral column (Chiralcel AD-H) eluting with 45% methanol in liquid carbon dioxide (100 bar, 2.5 mL/min).
• 6-[(S)-1-(6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline had an optical rotation of -0.125° in methanol (5.22 mg/mL), and 6-[(R)-1-(6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline had an optical rotation of +0.157° in methanol (5.53 mg/mL).
• reaction solution was diluted with methanol, and filtered through a celite pad.
• the filtrate was concentrated and purified on a reverse-phase C-18 preparative HPLC eluting with acetonitrile-water containing 0.1 % acetic acid to provide 4-[3-(1- quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-benzonitrile (27 mg, 45% yield).
• reaction was evaporated and purified on a reverse-phase C-18 preparative HPLC eluting with acetonitrile- water containing 0.1 % acetic acid to provide 6- ⁇ 1-[6-(3-methyl-3H-imidazol-4-yl)-[1 ,2,4]triazolo[4,3- b]pyridazin-3-yl]-ethyl ⁇ -quinoline (22 mg, 38% yield).
• reaction mixture was degassed and charged with nitrogen for three times and then heated at 85 0 C oil bath for overnight. After cooling, the residue was dissolved in methanol and filtered through a celite pad. The filtrate was concentrated and purified on a reverse-phase preparative HPLC eluting with acetonitrile-water containing 0.1% acetic acid to provide ⁇ 4-[3-(1-quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-pyrazol-1-yl ⁇ - acetic acid (193 mg, 30% yield).
• the concentrated reaction mixtures were combined and purified by flash chromatography using a Horizon purification system on a 4OS column eluting with chloroform/7 N ammonia in methanol (0.5-10%), followed by a second column on a 25S column eluting with chloroform/methanol (0.1-10%), then chloroform/7 N methanolic ammonia (0-8%), followed by preparative TLC eluting (2x) with chloroform/7 N ammonia in methanol (7%).
• the peak of interest was scraped and the silica gel was slurried in chloroform/7 N ammonia in methanol (10%), filtered and concentrated to afford the title compound (29 mg, 9%).
• 6-((6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (0.50 g, 1.7 mmol) and Cs 2 CO 3 (1.64 g, 5.0 mmol) were dissolved in 5 mL of DMF and 2.5 mL of water. The resulting solution was degassed three times. Then catalytic amount of Pd(PPh 3 ) 2 CI 2 and compound N,N-dimethyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-1 -sulfonamide (0.60 g, 2.0 mmol) were added.
• N,N-dimethyl-4-(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)-1 H-pyrazole-1- sulfonamide (0.19 g, 0.437 mmol) was added to 1 mL of ice-cold CF 3 COOH. The resulting mixture was stirred at room temperature for 3 h. Then CF 3 COOH was removed in vacuum. 10 mL of saturated aqueous NaHCO 3 was added carefully.
• In vitro assays may be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed along the same lines for any PK using techniques well known in the art. See for example, michova-Dobrova Z, Sardanelli AM, Papa S FEBS Lett. 1991 Nov 4; 292: 69-72.
• a general procedure is as follows: compounds and kinase assay reagents are introduced into test wells. The assay is initiated by addition of the kinase enzyme. Enzyme inhibitors reduce the measured activity of the enzyme.
• the continuous-coupled spectrophotometry assay was used to determine the level of activity and effect of the different compounds of the present invention on the tyrosine kinase activity of HGFR on the Met-2 substrate peptide.
• the time- dependent production of ADP by the kinase is determined by analysis of the rate of consumption of NADH by measurement of the decrease in absorbance at 340 nm.
• PK As the PK produces ADP it is re-converted to ATP by reaction with phosphoenol pyruvate and pyruvate kinase. Pyruvate is also produced in this reaction. Pyruvate is subsequently converted to lactate by reaction with lactate dehydrogenase, which simultaneously converts NADH to NAD. NADH has a measurable absorbance at 340 nm whereas NAD does not.
• lactate dehydrogenase which simultaneously converts NADH to NAD. NADH has a measurable absorbance at 340 nm whereas NAD does not.
• the presently preferred protocol for conducting the continuous-coupled spectrophotometric experiments for specific PKs is provided below. However, adaptation of this protocol for determining the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art.
• HGFR Continuous-coupled Spectrophotometric Assay This assay was used to analyze the tyrosine kinase activity of HGFR on the Met-2 substrate peptide, a peptide derived from the activation loop of the HGFR. Assay results in the form of Ki values ( ⁇ M) are summarized in Table 2. Materials and Reagents:
• NADH B-Nicotinamide Adenine Dinucleotide, Reduced Form
• DB Prep Dilution Buffer (DB) for Enzyme (For 30 mL prep) 1.
• DB final concentration is 2 mM DTT, 25 mM NaCI 2 , 5 mM MgCI 2 , 0.01% Tween-20, and 50 mM
• HEPES buffer pH 7.5.
• reaction buffer add 10 ⁇ L of 1M PEP, 33 ⁇ L of 100 mM NADH, 50 ⁇ L of 4M MgCI 2 , 20 ⁇ L of 1 M DTT, 6 ⁇ L of 500 mM ATP, and 500 ⁇ L of 10 mM Met-2 peptide into 100 mM HEPES buffer pH 7.5 and vortex/mix.

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