EP2032578A2 - Triazolopyridazine derivatives - Google Patents

Triazolopyridazine derivatives

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Publication number
EP2032578A2
EP2032578A2 EP07734734A EP07734734A EP2032578A2 EP 2032578 A2 EP2032578 A2 EP 2032578A2 EP 07734734 A EP07734734 A EP 07734734A EP 07734734 A EP07734734 A EP 07734734A EP 2032578 A2 EP2032578 A2 EP 2032578A2
Authority
EP
European Patent Office
Prior art keywords
membered
compound
aryl
group
alkyl
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Withdrawn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
EP07734734A
Other languages
German (de)
French (fr)
Inventor
Hengmiao Cheng
Jingrong Jean Cui
Jacqui Elizabeth Hoffman
Lei Jia
Robert Steven Kania
Phuong Thi Quy Le
Mitchell David Nambu
Mason Alan Pairish
Hong Shen
Michelle Bich Tran-Dube
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.)
Pfizer Products Inc
Original Assignee
Pfizer Products Inc
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Filing date
Publication date
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of EP2032578A2 publication Critical patent/EP2032578A2/en
Withdrawn legal-status Critical Current

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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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Abstract

The invention relates to compounds of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and R3' are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula (I) and to methods of treating hyperproliferative disorders in a mammal by administering the compounds of formula (I).

Description

TRIAZOLOPYRIDAZINE DERIVATIVES
This application claims the benefit of U. S. Provisional Application No. 60/803,469 filed on May 30, 2006, the contents of which is hereby incorporated by reference in its entirety.
Introduction
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.
Background of the Invention
The hepatocyte growth factor (HGF) receptor (c-MET or HGFR) receptor tyrosine kinase (RTK) has been shown in many human cancers to be involved in oncogenesis, tumor progression with enhanced cell motility and invasion, as well as metastasis (see, e.g., Ma, P.C., Maulik, G., Christensen, J. & Salgia, R. (2003b). Cancer Metastasis Rev, 22, 309-25; Maulik, G., Shrikhande, A., Kijima, T., Ma, P.C., Morrison, PT. & Salgia, R. (2002b). Cytokine Growth Factor Rev, 13, 41-59). c-MET (HGFR) 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 ). 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). Jiang et al., Crit. Rev. Oncol. Hematol. 29: 209-248 (1999). 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). However, because the receptor and ligand are usually expressed by different cell types, c-MET signaling is most commonly regulated by tumor-stroma (tumor-host) interactions. Furthermore, 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. Numerous studies 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.
A family of novel compounds have been discovered which exhibit c-Met modulating ability and have an ameliorating effect against disorders related to abnormal c-Met activity. 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.
These observations suggest that 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. In addition, certain cancers (e.g., papillary renal cell carcinoma, some gastric and lung cancers) can be treated which are believed to be driven by c-Met mutation/genetic alteration and dependent on c-Met for growth and survival. These cancers are expected to be sensitive to treatment. Furthermore, various human cancers are the primary target indication for c- Met antagonists. These 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.
Summary of the Invention In one embodiment, the present invention relates to a compound of the formula I:
wherein: R1, R2 and R3 are independently selected from hydrogen, Br, Cl, F, -O(CH2)nCH3, -O(CH2)nOR6,
-(CHa)nOR6, -C(O)R6, -C(O)OR6, -C(O)NR6R7, -NR6R7, -S(O)2R6, -S(O)R6, -S(O)2NR6R7, -CF3, -CF2H, - NR6C(O)NR6R7, -NR6C(O)R7, -NR6S(O)2R7, -N(CH2)n(C3-C8 cycloalkyl), -CN, -NO2, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-Ci0 aryl, C2-C6 alkenyl, and C2-C6 alkynyl wherein C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalicyclic, 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10 aryl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, -(CH2)nCH(OR6)CH3, -(CH2)nOR6, - (CH2)nC(CH3)2OR6, -(CH2)n(3-8 membered heteroalicyclic), -C(O)R6, -C(O)OR6, -(CR6R7JnC(O)OR6, -C(O)NR6R7, -(CR6R7JnC(O)NR6R7, -(CH2JnNR6R7, -S(O)2R6, -S(O)R6, -S(O)2NR6R7, -CF3, -CF2H, -(CHz)nNR6C(O)NR6R7, -(CH2)nNR6C(O)OR7, -NR6C(O)R7, -NR6C(O)OR7, -NR6S(O)2R7, -CN, -NO2, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n(3-8 membered heteroalicyclic), -(CH2)n(5-7 membered heteroaryl), -(CH2Jn(C6-C10 aryl), C2-C6 alkenyl, and C2-C6 alkynyl;
R4 is a 8-10 membered heterobicyclic optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, -(CH2)nCH(OR6)CH3, -(CH2JnOR6, -(CH2JnC(CH3J2OR6, -(CH2)n(3-8 membered heteroalicyclic), -C(O)R6, -C(O)OR6, -(CR6R7JnC(O)OR6, -C(O)NR6R7, -(CR6R7)nC(O)NR6R7, - (CH2)nNR6R7, -S(O)2R6, -S(O)R6, -S(O)2NR6R7, -CF3, -CF2H, -(CHz)nNR6C(O)NR6R7, -(CH2JnNR6C(O)OR7, -NR6C(O)R7, -NR6C(O)OR7, -NR6S(O)2R7, -CN, -NO2, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n(3-8 membered heteroalicyclic), -(CH2)n(5-7 membered heteroaryl), -(CH2)π(C6-C10 aryl), C2-C6 alkenyl, and C2- C6 alkynyl;
R5 is selected from the group consisting of hydrogen, F, -CF3, C1-C6 alkyl and aryl;
R6 and R7 are independently selected from H, -(CH2JnOR8, -(CH2JnC(CH3J2OR8, -CHR8(CH2)nOR9, -(CH2JnCHR8OR9, -C(CH3J2(CH2JnOR8, -CH2CF2H, -(CH2JnC(CH3J2NR8R9, -(CH2JnNR8R9, -(CH2)nCHOR8(CH2)nOR9, -(CH2)n(NR8R9)C(O)NR8R9, -(CH2)nS(O)2R8, -(CH2)nC(O)NR8R9, -(CH2)nC(O)R8, -NR8(CH2)n(5-7 membered heteroaryl), -NR8(CH2)n(3-8 membered heterocycle), -(CH2)n(8-10 membered heterobicyclic), -(CH2)n(3-8 membered heteroalicyclic), C-I-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, C2-C6 alkenyl, 3-8 membered heteroalicyclic and C2-C6 alkynyl, wherein said 5-7 membered heteroaryl, 3-8 membered heterocycle and 8-10 membered heterobicyclic are optionally substituted by one or more moieties selected from the group consisting of -(CH2)nOR8, C1-C6 alkyl, C3-C8 cycloalkyl, C6-Ci0 aryl, C2- C6 alkenyl, 3-8 membered heteroalicyclic and C2-C6 alkynyl; or when R6 and R7 are attached to the same atom, R6 and R7 optionally combine to form a 3-8 membered heteroalicyclic ring;
R8 and R9 are independently selected from H, C1-C6 alkyl, -C(O)CH3, C3-C8 cycloalkyl, C6-C10 aryl, C2-C6 alkenyl, 5-7 membered heteroaryl and C2-C6 alkynyl, wherein said 5-7 membered heteroaryl is optionally substituted by one or more moieties selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C6-Ci0 aryl. C2-C6 alkenyl, and C2-C6 alkynyl; or when R12 and R13 are attached to the same atom, R12 and R13 optionally combine to form a 3-8 membered heteroalicyclic ring; and n is O, 1 , 2, 3 or 4; or a pharmaceutically acceptable salt thereof.
In another embodiment, R1, R2 and R3 are independently selected from hydrogen, Cl, -OR10, -O(CH2)nCH3, -OCH2(CH2)nOR10, -C(O)NR10R11, -NR10R11, C1-C6 alkyl, 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-Ci0 aryl and C2-C6 alkenyl, wherein C1-C6 alkyl, 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10 aryl and C2-C6 alkenyl are optionally substituted by one or more moieties selected from
,10 the group consisting of Br, Cl, F, -(CH2)nCH(OR1ϋ)CH3, -(CHz)nOR10, -(CH2)nC(CH3)2OR1u, -(CH2)n(3-8 membered heteroalicyclic), -C(O)R 10 -C(O)OR 10 -(CR10R11JnC(O)OR 10
-C(O)NR10R11,
-(CR10R1 1JnC(O)NR10R", -(CH2JnNR10R11, -S(O)2R10, -S(O)R10, -S(O)2NR10R11 -CF3, -CF2H, -(CH2JnNR10C(O)NR10R11, -(CH2)πNR10C(O)OR11, -NR10C(O)R11, -NR10C(O)OR11, -NR10S(O)2R11, -CN, - NO2, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n(3-8 membered heteroalicyclic), -(CH2)n(5-7 membered heteroaryl), -(CH2)n(C6-Ci0 aryl), C2-C6 alkenyl, and C2-C6 alkynyl.
In a further embodiment, R1 is selected from Cl, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 5-7 membered heteroaryl, and C6-C10 aryl, wherein 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 5-7 membered heteroaryl and C6-Ci0 aryl are optionally substituted by one or more moieties selected from the group consisting of -(CH2JnOR10, -C(O)OR10, -(CR10R11JnC(O)NR10R11, -
(CH2JnNR10R11, -CF3, and -CN.
In another embodiment, R2 and R3 are H. In another embodiment, R5 is H. In another embodiment, R5 is C1-C6 alkyl. In another embodiment, R5 is methyl. In another embodiment, R4 is selected from
In still a further embodiment, 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]pyridazin-3-yl)methyl)quinoline, 4-(3-(quinolin-6- ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)benzonitrile, 3-[(7-methylquinolin-6-yl)methyl]-N- (tetrahydrofuran-3-yl)[1 ,2,4]triazolo[4,3-b]pyridazin-6-amine, N-cyclopentyl-3-[(7-methylquinolin-6- yl)methyl][1 ,2,4]triazolo[4,3-b]pyridazin-6-amine, 4-{3-[(S)-1 -(1 H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-
[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl}-benzonitrile, isopropyl-[3-((S)-1 -q u i nol in-6-yl-ethyl )-[1 ,2,4]triazolo[4,3- b]pyridazin-6-yl]-amine, ^-(i-quinolin-θ-yl-ethylJ-CI ^^Jtriazolo^.S-blpyridazin-β-ylJ^tetrahydro-furan-S- yl)-amine, 2-[3-(1-quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-ylamino]-ethanol, and 4-[3-((S)-1- quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-benzonitrile; or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a coumpound selected from any 10 compounds exemplified in Table 1.
In a further embodiment, the present invention relates to any coumpound exemplified in Table 1. In another embodiment, 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.
In another embodiment, 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. In another embodiment, 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. In another embodiment, 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.
In another embodiment, 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.
In another embodiment, 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.
In another embodiment, 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. In another embodiment, the mammal is a human. In another embodiment, the mammal is a canine.
It will be understood that each of the embodiments described herein may be combined with one or more other embodiments described herein, where reasonable, to form additional embodiments within the scope of the invention.
Definitions
"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 acid, pantothenic acid, succinic acid, tartaric acid, or malonic acid and the like, preferably hydrochloric acid or (L)-malic acid; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. "Pharmaceutically acceptable excipient" or "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of 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. As used herein, 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.
The term "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.
As used herein, the term "modulation" or "modulating" refers to the ateration of the catalytic activity of c-Met. In particular, 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.
The term "contacting" as used herein 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. In this context, the ability of a particular compound to affect a c-Met related disorder, i.e., the IC50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, 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. The skilled artisan will understand that, for example, isolated c- Met may be contacted with a modulator in an in vitro environment. Alternatively, an isolated cell may be contacted with a modulator in an in vitro environment.
As used herein, "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.
As used herein, "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.
As used herein, 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.
The term "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. In a preferred aspect, the organism is a mammal. In a particularly preferred aspect, the mammal is a human being.
The term "therapeutically effective amount" as used herein 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. In reference to the treatment of cancer, 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.
By "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. For example, 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. As used herein, "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.
The terms "abnormal cell growth" and "hyperproliferative disorder" are used interchangeably in this application.
"Abnormal cell growth", as used herein, 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. Preferably, 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. When substituted, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR', -COOR', -OCOR', -CONRR', -RNCOR', -NRR', -CN, -NO2, -CF3 -SR', -SOR', -SO2R', -SO2OR', -SO2NRR', thiocarbonyl, -RNSO2R', 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, (CH2)nN(R")2, (CH2)nCO2R", (CH2)nOR", (CH2)nOC(O)R", alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, a heteroalicyclic ring, aryl, alkoxy, -OCF3, aryloxy, C(O)NH2 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. Preferably, 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. Examples, without limitation, of alkenyl groups include 1-propenyl, 1- and 2-butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR', -COOR', -OCOR', -CONRR", -RNCOR', -NRR', -CN, - NO2, -CF3, -SR1, -SOR", -SO2R', -SO2OR', -SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl. Wherein R and R' are defined herein. "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. Preferably, 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. Most preferably, it is a lower alkynyl having 2 to 6 carbon atoms. Examples, without limitation, of alkynyl groups include 1-propynyl, 1- and 2-butynyl, etc. The alkynyl group may be substituted or unsubstituted. When substituted, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR', -COOR', -OCOR', -CONRR', -RNCOR', -NRR1, -CN, - NO2, -CF3, -SR', -SOR', -SO2R', -SO2OR', -SO2NRR', thiocarbonyl, -RNSO2R", perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyi, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl. Wherein 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. Preferably, 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. When substituted, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR', -COOR', -OCOR', -CONRR', -RNCOR1, -NRR', -CN, -NO2, -CF3, -SR', -SOR1, -SO2R', -SO2OR1, -SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl. Wherein R and R' are defined herein.
An "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. Preferably, 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. When substituted, each substituted group is preferably one or more selected halogen, hydroxy, alkoxy, aryloxy, - COR', -COOR', -OCOR', -CONRR1, -RNCOR', -NRR', -CN, -NO2, -CF3, -SR', -SOR1, -SO2R1, -SO2OR1, - SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl. Wherein R and R' are defined herein.
As used herein, a "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. One of ordinary skill in the art will recognize unstable groups that are not contemplated by the invention. In addition, the heteroaryl group has a completely conjugated pi- electron system. Preferably, the heteroaryl group has from 5 to 7 ring atoms. Examples of typical monocyclic heteroaryl groups include, but are not limited to: p ύyrrole furan thi ύophene razole imidazole (pyrrolyl) (furanyl) (thiophenyl) (pyrazolyl) (imidazolyl)
isoxazole oxazole isothiazole thiazolyl 1 ,2,3-triazole (isoxazolyl) (oxazolyl) (isothiazolyl) (thiazolyl) (1 ,2,3-triazolyl)
1 ,3,4-triazole 1-oxa-2,3-diazole 1-oxa-2,4-diazole 1-oxa-2,5-diazole (1,3,4-triazolyl) (1-oxa-2,3-diazolyl) (1-oxa-2,4-diazolyl) (1-oxa-2,5-diazolyl)
1-oxa-3,4-diazole 1-thia-2,3-diazole 1-thia-2,4-diazole 1-thia-2,5-diazole (1-oxa-3,4-diazolyl) (1-thia-2,3-diazo!yl) (1-thia-2,4-diazolyl) (1-thia-2,5-diazolyl)
1-thia-3,4-diazole tetrazole pyridine pyridazine pyrimidine (1-thia-3,4-diazolyl) (tetrazolyl) (pyridinyl) (pyridazinyl) (pyrimidinyl)
When substituted, each substituted group is preferably one or more selected from halogen, hydroxy, -COR1, -COOR', -OCOR1, -CONRR', -RNCOR1, -NRR1, -CN, -NO2, -CF3, -SR', -SOR', -SO2R', - SO2OR', -SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl. Wherein R and R1 are defined herein. 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. Preferably, the heteroalicyclic ring contains from 3 to 8 ring atoms. Examples of suitable saturated heteroalicyclic groups include, but are not limited to: oxirane thiarane aziridine oxetane thiatane azetidine tetrahydrofuran (oxiranyl) (thiaranyl) (aziridinyl) (oxetanyl) (thiatanyl) (azetidinyl) (tetrahydrofuranyl)
tetrahydrothiophene pyrrolidine tetrahydropyran tetrahydrothiopyran (tetrahydrothiophenyl) (pyrrolidinyl) (tetrahydropyranyl) (tetrahydrothiopyranyl)
piperidine 1 ,4-dioxane 1 ,4-oxathiane morpholine 1 ,4-dithiane (piperidinyl) (1 ,4-dioxanyl) (1 ,4-oxathianyl) (morpholinyl) (1 ,4-dithianyl)
piperazine 1 ,4-azathiane oxepane thiepane azepane (piperazinyl) (1 ,4-azathianyl) (oxepanyl) (thiepanyl) (azepanyl)
1 ,4-dioxepane 1 ,4-oxathiepane 1 ,4-oxaazepane 1 ,4-dithiepane (1 ,4-dioxepanyl) (1 ,4-oxathiepanyl) (1 ,4-oxaazepanyl) (1 ,4-dithiepanyl)
1 ,4-thieazepane 1 ,4-diazepane (1 ,4-thieazepanyl) (1 ,4-diazepanyl)
Examples of suitable partially unsaturated heteroalicyclic groups include, but are not limited to:
3,4-dihydro-2H-pyran 5,6-dihydro-2H-pyran 2H-pyran (3,4-dihydro-2H-pyranyl) (5,6-dihydro-2H-pyranyl) (2H-pyranyl)
1 ,2,3,4-tetrahydropyridine 1 ,2,5,6-tetrahydropyridine (1 ,2,3,4-tetrahydropyridinyl) (1 ,2,5,6-tetrahydropyridinyl)
The foregoing groups, as derived from the compounds listed above, may be C-attached or reattached where such is possible. For instance, 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. When substituted, the substituted group(s) is preferably one or more selected halogen, hydroxy, -COR", -COOR', OCOR', -CONRR', -RNCOR', -NRR', -CN, -NO2, -CZ3, - SR', -SOR', -SO2R', -SO2OR', -SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alky], lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl. Wherein R and R' are defined herein. 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. Furthermore, 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. One of ordinary skill in the art will recognize unstable groups that are not contemplated by the invention. Preferably, 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
(benzofuranyl) (benzothiophenyl) (indolyl) (benzimidazolyl) (indazolyl)
benzotriazole pyrrolo[2,3-b]pyridine pyrrolo[2,3-c]pyridine pyrrolo[3,2-c]pyridine (benzotriazolyl) (pyrrolo[2,3-b]pyridinyl) (pyrrolo[2,3-c]pyridinyl) (pyrrolo[3,2-c]pyridinyl)
pyrrolo[3,2-b]pyridine imidazo[4,5-b]pyridine imidazo[4,5-c]pyridine pyrazolo[4,3-d]pyridine (pyrrolo[3,2-b]pyridinyl) (imidazo[4,5-b]pyridinyl) (imidazo[4,5-c]pyridinyl) (pyrazolo[4,3-d]pyidinyl)
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)
indazole purine indolizine imidazo[1 ,2-a]pyridine imidazo[1 ,5-a]pyridine (indazolyl) (purinyl) (indolininyl) (imidazo[1 ,2-a]pyridinyl) (imidazo[1 ,5-a]pyridinyl)
pyrazolo[1 ,5-a]pyridine pyrrolo[1 ,2-b]pyridazine imidazo[1 ,2-c]pyrimidine (pyrazolo[1 ,5-a]pyridinyl) (pyrrolo[1 -2,b]pyridazinyl) (imidazo[1 ,2-c]pyrimidinyl)
Examples of suitable fused ring aromatic heterobicyclic groups include, but are not limited to:
3H-lndole lndoiine lsoindoline (3H-indolyl) (indolyl) (isoindolinyl)
2,3-Dihydrobenzofuran 1 ,3-Dihydroisobenzofuran 1/-/-lsoindole (2,3-dihydrobenzofuranyl) (1 ,3-dihydroisobenzofuranyl) (1H-isoindolyl)
1 ,2,3,4-Tetrahydroquinoxaline 1 ,2-Dihydroquinoxaline 1 ,2-Dihydroquinazoline (1 ,2,3,4-tetrahydroquinoxalinyl) (1 ,2-dihydroquinoxalinyl) (1 ,2-dihydroquinazolinyl)
3,4-Dihydroquinazoline 2,3-Dihydrobenzo[£>][1 ,4]dioxine 4/-/-Benzo[tf][1 ,3]dioxine (3,4-dihydroquinazolinyl) (2,3-dihydrobenzo[/b][1 ,4]dioxinyl) (4H-benzo[c/][1 ,3]dioxinyl)
3,4-Dihydro-2/-/-chromene 2/-/-Chromene 4/-/-Chromene (3,4-dihydro-2/-/-chromenyl) (2H-chromenyl) (4/-/-chromenyl)
When substituted, the substituted group(s) is preferably one or more selected halogen, hydroxy, - COR', -COOR', OCOR1, -CONRR1, -RNCOR1, -NRR', -CN, -NO2, -CZ3, -SR1, -SOR1, -SO2R1, -SO2OR1, - SO2NRR1, thiocarbonyl, -RNSO2R1, perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicycle, heteroaryl and aryl. Wherein R and R1 are defined herein.
When used herein, the R groups on substitutents having two or more R groups on different atoms, such as -(CH2)n(NRBRa)C(O)NRBRa or -NR0C(O)NR ,60 OR7', may be the same or different. Specifically, in the exemplary substituent -NR6C(O)NR6R7, the two R6 groups may be the same or different with respect to each other, likewise, the two R6 groups may be the same or different with respect to the R7 group. In, for example, -(CH2)n(NR8R9)C(O)NR8R9, the two R8 groups may be the same or different with respect to each other, and the two R9 groups may be the same or different with respect to each other.
Likewise, the two R8 groups may be the same or different with respect to the two R9 groups. In addition, where a single atom is substituted by more than one group, the groups on that atom may be the same or different. So, in -NR6C(O)NR6R7, the R6 and R7 on the same nitrogen may be the same or different from one another.
An "oxo" group 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.
An "alkoxycarbonyl" refers to a -C(O)OR.
An "aminocarbonyl" refers to a -C(O)NRR'.
An "aryloxycarbonyl" refers to -C(O)Oaryl. An "aryloxy" group refers to both an -Oaryl and an -Oheteroaryl group, as defined herein.
An "arylalkyl" group refers to -alkylaryl, where alkyl and aryl are defined herein.
An "arylsulfonyl" group refers to a -S02aryl.
An "alkylsulfonyl" group refer to a -SO2alkyl.
A "heteroaryloxyl" group refers to a heteroaryl group with heteroaryl as defined herein. A "heteroalicycloxy" group refers to a heteroalicyclic-O group with heteroalicyclic as defined herein.
A "carbonyl" group refers to a -C(=0)R.
An "aldehyde" group refers to a carbonyl group where R is hydrogen.
A "thiocarbonyl" group refers to a -C(=S)-R group. A "trihalomethanecarbonyl" group refers to a Z3CC(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.
A "halo" or "halogen" group refers to fluorine, chlorine, bromine or iodine. A "trihalomethyl" group refers to a -CZ3 group.
A "trihalomethanesulfonyl" group refers to a Z3CS(O)2 group.
A "trihalomethanesulfonamido" group refers to a Z3CS(O)2NR-group.
A "sulfinyl" group refers to a -S(O)R group.
A "sulfonyl" group refers to a -S(O)2R group. An "S-sulfonamido" group refers to a -S(O)2NR-group.
An "N-Sulfonamido" group refers to a -NR-S(O)2R group.
An "O-carbamyl" group refers to a -OC(O)NRR' group.
An "N-carbamyl" group 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.
An "amino" group refers to an -NH2 or an -NRR'group.
A "C-amido" group refers to a -C(O)NRR' group.
An "N-amido" group refers to a R1C(O)NR group.
A "nitro" group refers to a -NO2 group. A "cyano" group refers to a -CN group.
A "silyl" group refers to a -Si(R)3 group.
A "phosphonyl" group refers to a -P(=0)(0R)2 group.
An "aminoalkyl" group refers to an -alkylNRR' group.
An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group. A "dialkylamionalkyl" group refers to an -alkylN-(alkyl)2 group. A "perfluoroalkyl group" refers to an alkyl group where all of the hydrogen atoms have been replaced with fluorine atoms.
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). Thus, 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. For example, 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.
It is contemplated that 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. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the 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.
Detailed Description of the Invention
The compounds presented herein are exemplary and are not to be construed as limiting the scope of the invention.
A general synthetic route to the compounds of the present invention is shown in Scheme 1. One of skill in the art will recognize that this general scheme may be modified and yet still produce the compounds of the present invention. The groups Ra, Rb, Rc and Rd shown in Scheme 1 include but are not limited to those R1 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. Scheme 1
& Carbonyl
In one aspect, this invention is directed to 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. For instance, 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 non-Hodgkin's lymphoma), cyciophosphamide (used in the treatment of Hodgkin's disease, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilm's tumor and rhabdomyosarcoma), estramustine, ifosfamide, novembrichin, prednimustine and uracil mustard (used in the treatment of primary thrombocytosis, non-Hodgkin's lymphoma, Hodgkin's disease and ovarian cancer); and triazines, e.g., dacarbazine (used in the treatment of soft tissue sarcoma). Likewise 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.
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.
In addition to the above, 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).
Finally, the 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. Examples of useful COX-II inhibitors include Vioxx.™', CELEBREX.™ (alecoxib), valdecoxib, paracoxib, rofecoxib, and Cox 189. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Application No. 97304971.1 (filed JuI. 8, 1997), European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published JuI. 16, 1998), European Patent Publication 606,046 (published JuI. 13, 1994), European Patent Publication 931 ,788 (published JuI. 28, 1999), WO 90/05719 (published May 31 , 1990), WO 99/52910 (published Oct. 21 , 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filed JuI. 21 , 1998), European Patent Application No. 99302232.1 (filed Mar. 25, 1999), Great Britain patent application number 9912961.1 (filed Jun. 3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861 ,510 (issued Jan. 19, 1999), and European Patent Publication 780,386 (published Jun. 25, 1997), all of which are incorporated herein in their entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1.
More preferred, 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, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds recited in the following list:
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclo-pentyl)-amino]propionic acid; 3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfon-ylamino]-8-oxa-bicyclo[3.2.1]-octane-3-carboxylic acid hydroxyamide; (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl- piperidine-2-carboxylic acid hydroxyamide; 4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]tetrahydro- pyran-4-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxy- carbamoylcyclobutyl)-amino]-propionic acid; 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro- pyran-4-carboxylic acid hydroxyamide; (R) 3-[4-(4-chloro-phenoxy)-benzenesulfonyl-amino]-tetrahydro- pyran-3-carboxylic acid hydroxyamide; (2R, 3R) 1-[4-(4-fluoro-2-methylbenzyloxy)-benzenesulfonyl]-3- hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 3-[[(4-(4-fluoro-phenoxy)-benzenesulfonyl]- (1 -hydroxycarbamoyl-1 -methylethyl)-amino]propionic acid; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4- hydroxycarbamoyl-tetrahydropyran-4-yl)-amino]-propionic acid; 3-exo-3-[4-(4-chloro-phenoxy)- benzenesulfonylamino]-8-oxa-bicyclo[3.2.1 ]octane-3-carboxylic acid hydroxy-amide; 3-endo-3-[4-(4- fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicylo[3.2.1]octane-3-carboxylic acid hydroxyamide; and (R) 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide; and pharmaceutically acceptable salts and solvates of said compounds.
Other 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, HERCEPTIN™. (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.).
These and other EGFR-inhibiting agents can be used in the present invention. 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. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar. 4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (published Jun.26, 1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998), all of which are incorporated herein in their entireties by reference. Other examples of some specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Wash., USA); anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, Calif.; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.). These and other 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. of TheWoodlands, Tex., USA) and 2B-1 (Chiron), can furthermore be combined with a compound of the formula (I) for example those indicated in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published JuI. 15, 1999), WO 99/35132 (published JuI. 15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published JuI. 27, 1995), U.S. Pat. No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2, 1999), which are all hereby incorporated herein in their entireties by reference. 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. Specific 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.
Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein. 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.
Indications
A precise understanding of the mechanism by which the compounds of the invention, in particular, the compounds generated in vivo from the compounds of the invention, inhibit c-Met is not required in order to practice the present invention. However, while not hereby being bound to any particular mechanism or theory, it is believed that the compounds interact with the amino acids in the catalytic region of c-Met. The compounds disclosed herein may thus have utility as in vitro assays for c-Met as well as exhibiting in vivo therapeutic effects through interaction with c-Met.
In another aspect, 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.
It is also an aspect of this invention that 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.
Alternatively, 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.
Pharmaceutical Compositions and Use
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). Techniques for formulation and administration of drugs may be found in "Remington's Pharmacological Sciences," Mack Publishing Co., Easton, Pa., latest edition. Routes of Administration
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.
Alternatively, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a solid tumor, often in a depot or sustained release formulation.
Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with tumor-specific antibody. The liposomes will be targeted to and taken up selectively by the tumor.
Composition/Formulation
Pharmaceutical 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.
Pharmaceutical 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. In particular, 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.
For injection, 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. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For oral administration, 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. Pharmaceutical preparations 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). If desired, 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. For this purpose, concentrated sugar solutions 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.
Pharmaceutical 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. In soft capsules, 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.
For administration by inhalation, 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. In the case of a pressurized aerosol, 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.
Pharmaceutical compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound. Additionally, 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. Optionally, 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.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. 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.
In addition to the formulations described previously, 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. Naturally, the proportions of such a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the 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.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. In addition, certain organic solvents such as dimethylsulfoxide also may be employed, although often at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various 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.
The pharmaceutical compositions herein also may comprise suitable solid or gel phase carriers or excipients. Examples of such 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. Examples of 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 (CH3SO3), 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.).
Pharmaceutical 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.
More specifically, 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.
Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any compound used in the methods of the invention, 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 IC50 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 IC50 and the LD50 (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). 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%. At present, the therapeutically effective amounts of compounds of the Formulae (I)-(IV) may range from approximately 10 mg/m2 to 1000 mg/m2 perday. Even more preferably 25 mg/m2 to 500 mg/m2. In cases of local administration or selective uptake, 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.
Packaging
The 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.
Examples
Compounds of the present invention can be made according to general Methods 1-13 described below. It will be understood by those skilled in the art that the following general methods are not limiting to the invention. It may be possible to alter exact solvents, conditions and reagents and quantities without deleterious effects. Specific embodiments of the present invention are summarized in Table 1 below.
Abbreviations:
TLC: thin layer chromatography aq.: aqueous
DMF: N,N-dimethylformamide
HPLC: High-performance liquid chromatography (also known as high-pressure liquid chromatography)
AcOH: Acetic acid
HATU: 2-(7-Aza-1 H-benzotriazole-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
DME: Dimethyl ether
EtOAc: Ethyl acetate ACN: Acetonitrile MeOH : Methanol
DMSO: Dimethylsulfoxide
THF: Tetrahydrofuran
LDA: Lithium diisopropylamide
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Method 1 :
Step L
A mixture of compound 1 (276 g, 1.8 mol), ferrous sulfate (63.6 g, 0.22 mol), glycerol (696 g, 7.56 mol), nitrobenzene (138 g, 1.12 mol) and cone, sulfuric acid (324 mL) was heated gently. After the first vigorous reaction, the mixture was refluxed for five hours and then was treated with aq. sodium hydroxide solution (2 N, 1320 mL), stirred with kieselguhr, and filtered. The filtrate was basified with aq. sodium hydroxide solution to pH 5~6, and a dark brown precipitate formed. The precipitate was filtered, washed with water, taken up with aq. sodium hydroxide solution (0.82 N, 3000 mL), then boiled with carbon (150 g). The mixture was filtered and the filtrate was treated with glacial acetic acid (240 mL), and the mixture was left standing overnight during which time dark-brown crystalline precipitate formed. The precipitate was collected and dried in vacuo to give crude compound 2 (60 g, 17.8%).
Step 2.
To a suspension of compound 2 (60 g, 0.32 mol) in MeOH (600 mL) cooled to 0~5°C, SOCI2 (30 mL, 0.35 mol) was added dropwise. After the mixture was heated to reflux for 2 h, the mixture was evaporated under reduced pressure, and the residue was taken up with EtOAc (600 mL). The mixture was washed with aq. NaHCO3 and brine, dried over Na2SO4 and concentrated to give crude product, which was purified via a silica column chromatography (EtOAc: Petroleum ether = 1 :5) to give pure compound 3 (50 g, 72.6%) as a yellow oil. 1H NMR (400 MHz, CDCI3): δ 8.898-8.878 (dd, 1 H), 8.130-8.055 (m, 2H), 7.718 (s, 1 H), 7.670-7.634 (dd, 1 H), 7.407-7.365 (q, 1 H), 4.207-4.135(q, 2 H), 3.799(s, 2H), 1.279-1.232 (t, 3H).
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 -780C under nitrogen. The reaction mixture was stirred at at -780C 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 -780C to ambient temperature overnight. The reaction was quenched with the careful addition of water. The product was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, and concentrated to provide 2-quinolin-6-yl-propionic acid methyl ester, 4 (21.49 g, -100% yield). MS m/e 216 [M+1]+; 1H NMR (400 MHz, DMSO-D6) δ 1.49 (d, J=7.07 Hz, 3 H), 3.60 (s, 3 H), 4.03 (q, J=7.07 Hz, 1 H), 7.51 (dd, J=8.34, 4.04 Hz, 1 H), 7.68 (dd, J=8.59, 2.02 Hz, 1 H), 7.86 (d, J=1.77 Hz, 1 H), 7.98 (d, J=8.59 Hz, 1 H), 8.33 (d, J=7.58 Hz, 1 H), 8.87 (dd, J=4Λ 7, 1.64 Hz, 1 H).
Step 4.
To a solution of 4 (21.17 g, 98.35 mmol) in methanol (200 mL) and water (50 mL) was added lithium hydroxide (12.02 g, 491.75 mmol). The reaction mixture was stirred at 650C oil bath for 4 hours, cooled to ambient temperature, and adjusted the acidity to pH ~7 with 6N HCI (65 mL). A lot of precipitate was formed. After filtration, the solid was washed with water, and the filtrate was concentrated to remove methanol. The solid was filtrated and washed with water. The combined solid product was dried under high vacuum to provide 2-quinolin-6-yl-propionic acid, 5 (19.09 g, 90% yield). MS m/e 202 [M+1]+;1H NMR
(400 MHz, DMSO-D6) δ 1.37 (d, J=7.07 Hz, 3 H), 3.54 (q, J=7.07 Hz, 1 H), 7.43 (dd, J=8.34, 4.04 Hz, 1 H), 7.72 - 7.80 (m, 2 H), 7.82 - 7.89 (m, 1 H), 8.20 - 8.26 (m, 1 H), 8.78 (dd, J=4.04, 1.77 Hz, 1 H).
Step 5.
To a solution of 5 (3.00 g, 14.9 mmol) in DMF (75 mL) was added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, 6 (3.14 g, 16.4 mmoi). The reaction mixture was stirred under nitrogen for half an hour and then (6-chloro-pyridazin-3-yl)-hydrazine (2.22 g, 14.9 mmol) was added. The reaction mixture was stirred under nitrogen for overnight, diluted with ethyl acetate, washed with water, dried over
Na2SO4, and concentrated to get the crude intermediate, which was dissolved in acetic acid (20 mL). The acetic acid solution was refluxed for 2 hours, and concentrated. The residue was purified on a silica gel column eluting with 5% methanol in ethyl acetate to provide 6-[1-(6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin- 3-yl)-ethyl]-quinoline, 7 (1.16 g, 25% yield). Method 2:
The 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).
Method 3:
To a solution of 6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (1) (50 mg, 0.16 mmol) and the boronic acid (2) (26.4 mg, 0.18 mmol) in 1 ,2-dimethoxyethane (1.5 ml_) was added a freshly prepared solution of Cs2CO3 (186.3 mg, 0.528 mmol) in water (0.5 ml_), and the catalyst Pd(dppf)2CI2.CH2CI2 (6.5 mg, 0.008 mmol). The reaction mixture was degassed and charged with nitrogen for three times, and heated at 80°C oil bath for overnight. The 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).
Method 4:
A solution of 6-[1-(6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (50.0 mg, 0.16 mmol) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (60.0 mg, 0.32 mmol) in n-butanol (1.5 mL) was microwaved at 1250C for 50 minutes. After evaporation of solvents, the residue was suspended in methanol (2 mL) and HCI dioxane solution (4.0 N, 4 mL) until the de-protection was complete. The solvents were evaporated, and the residue was purified on a reverse-phase C-18 column eluting with acetonitrile-water system containing 0.1 % acetic acid to provide (R)-1-[3-(1-quinolin-6-yl-ethyl)- [1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-pyrrolidin-3-ylamine as an acetic acid salt (47.2 mg, 70% yield).
Method 5.
To a solution of 3-(1-quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-ylamine (30.0 mg, 0.103 mmol) in anhydrous pyridine (1 mL) was added acetyl chloride (0.015 mL, 0.207 mmol). The reaction mixture was stirred under nitrogen at ambient temperature for overnight. After evaporation of solvent, the residue was purified on a reverse-phase C-18 preparative HPLC eluting with acetonitrile-water containing 0.1 % acetic acid to provide N-[3-(1-quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-acetamide (27.1 mg, 79% yield).
Method 6:
To a solution of I H-imidazole-4-carboxylic acid methyl ester (83.1 mg, 0.646 mmol) in anhydrous DMF (3 mL) was added sodium hydride (60% oil suspension, 28.4 mg, 0.71 mmol). The reaction mixture was stirred at ambient temperature for one hour, and then 6-[1-(6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3- yl)-ethyl]-quinoline (200.0 mg, 0.646 mmol) was added. The reaction was heated in an 850C oil bath under nitrogen for overnight. LC-MS showed the reaction was not complete, and additional portions of sodium hydride (14.2 mg, 0.35 mmol) and 1 H-imidazole-4-carboxylic acid methyl ester (41.5 mg, 0.323 mmol) were added. The reaction was continued for another 2 hours at 850C under nitrogen. After cooling, the reaction was quenched with an addition of saturated aqueous ammonium chloride solution, and a lot of precipitate was observed. The solid was filtered, washed with water, methanol and ether to provide 1 -[3-(1 -quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-1 H-imidazole-4-carboxylic acid methyl ester (164.9 mg, 64% yield).
Method 7:
To a solution of 6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (50.0 mg, 0.16 mmol) in ACN (2 mL) was added Pd(PPh3)2CI2 (5.6 mg, 0.008 mmol), CuI (4.6 mg, 0.024 mmol), and 1- methyl-5-tributylstannyl-1 H-imidazole (74 mg, 0.194 mmol). The reaction solution was degassed and charged with nitrogen for three times, and heated at 850C oil bath under nitrogen for overnight. The 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).
Method 8:
To a solution of 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (5.0 g, 25.8 mmol) in DMF (52 mL) was added Cs2CO3 (8.396 g, 25.8 mmol) and bromo-acetic acid methyl ester (2.52 mL, 25.8 mmol). The reaction mixture was heated at 9O0C under nitrogen for overnight. After cooling, the reaction mixture was diluted with water, and extracted with ethyl acetate. The combined extracts were washed with water for three times and brine, dried over Na2SO4., and concentrated to provide 4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetic acid methyl ester (4.27 g, 62% yield).
To a solution of 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetic acid methyl ester (644.2 mg, 2.42 mmol) and 6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (500.0 mg, 1.61 mmol) in 1 ,2-dimethoxyethane were added a freshly prepared solution of Cs2CO3 (1.574 g, 4.83 mmol) in water (2.3 mL) and Pd(dppf)2CI2.CH2CI2 (40 mg, 0.048 mmol). The reaction mixture was degassed and charged with nitrogen for three times and then heated at 850C 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).
Method 9:
To a solution of {4-[3-(1-quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-pyrazol-1-yl}-acetic acid (50.0 mg, 0.13 mmol) in DMF (2 mL) was added HATU (52.4 mg, 0.138 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for half an hour, and then 2-pyrrolidin-1-yl-ethylamine (0.03 mL, 0.25 mmol) was added. The reaction was continued for overnight and purified on a reverse- phase C-18 preparative HPLC eluting with acetonitrile-water containing 0.1% acetic acid to provide N-(2- Pyrrolidin-1 -yl-ethyl)-2-{4-[3-(1 -quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-pyrazol-1 -yl}- acetamide (12 mg, 19% yield).
Method 10.
(1 H-Pyrrolo[2,3-b]pyridin-3-yl)-acetic acid (1 ) was prepared according to M. M. Robinson's method (J. Am. Chem. Soc. 78 (1956) 1247-1249). To a solution of (1 H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid (1) (283 mg, 1.61 mmoi) and (6-chloro-pyridazin-3-yl)-hydrazine (233 mg, 1.61 mmol) in DMF (8 mL) was added HATU (612 mg, 1.61 mmol). The reaction mixture was stirred at ambient temperature for one hour and then heated at 12O0C for two hours. After cooling, the reaction was concentrated and purified on a reverse-phase C-18 preparative HPLC eluting with acetonitrile-water containing 0.1% acetic acid to provide 6-chloro-3-[1-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-[1 ,2,4]triazolo[4,3-b]pyridazine (99 mg, 20% yield). Method 11.
Step 1.
To a solution of (1 H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (5.10 g, 28.78 mmol) and 4-dimethylaminopyridine (175.8 mg, 1.44 mmol) in anhydrous THF (100 ml.) was added di-tert-butyl dicarbonate (34.6 g, 34.54 mmol). The reaction mixture was stirred for overnight, diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated. The residue was suspended in hexane, and the solid was filtered and dried to provide a white solid of 3-methoxycarbonylmethyl- pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (6.07 g). The filtrate was concentrated and purified on a silica gel column eluting with hexane-ethyl acetate to provide additional product (1.71 g, total 7.78 g, 97% yield). 1 H NMR (400 MHz, CHLOROFORM-D) 51.60 (s, 9 H) 3.62 (s, 3 H) 3.83 (s, 2 H) 7.28 (dd, J=7.83, 4.80 Hz, 1 H) 7.73 (s, 1 H) 7.99 (dd, J=7.83, 1.52 Hz, 1 H) 8.38 (dd, J=4.55, 1.52 Hz, 1 H).
Step 2.
To a solution of S-methoxycarbonylmethyl-pyrroloP-.S-blpyridine-i-carboxylic acid tert-butyl ester (6.07 g, 20.9 mmol) in anhydrous THF (100 mL) was added LDA (1.8 M THF solution, 12.7 mL, 22.99 mmol) at-78°C under nitrogen. The reaction mixture was stirred at -780C under nitrogen for half an hour and then methyl iodide was added. The reaction mixture was stirred from -780C to ambient temperature overnight under nitrogen, quenched with an addition of saturated ammonium chloride, and diluted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, concentrated, and dried under high vacuum to provide 3-(1-methoxycarbonyl-ethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert- butyl ester (6.35 g, -100% yield). Step 3.
To a solution of 3-(1-methoxycarbonyl-ethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (6.35 g, 20.9 mmol) in dichloromethane (50 mL) was added HCI dioxane solution (4N, 20 ml_). The reaction mixture was stirred for overnight. After evaporation and high vacuum dry, the product was used directly for the next step.
Step 4.
To a solution of 2-(1 H-Pyrrolo[2,3-b]pyridin-3-yl)-propionic acid methyl ester (4.26 g, 20.9 mmol) in methanol (45 mL) and water (15 mL) was added LiOH (2.503 g, 104.5 mmol). The reaction mixture was stirred at 60oC oil bath for 2 hours. After cooling, the reaction mixture was neutralized to pH ~6 with 6N HCI solution. The solid was filtered and washed with water to provide 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)- propionic acid (2.45 g). The filtrate was concentrated and purified on a reverse-phase C-18 pad to provide addition portion of the product (1.05 g, total 3.50 g).
Step 5.
The suspension of 2-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid (542 mg, 2.85 mmol) in thionyl chloride (6 mL) was stirred at ambient temperature for two hours, and then thionyl chloride was removed in vacuum. To the residue was added a solution of (6-chloro-pyridazin-3-yl)-hydrazine (412 mg, 2.85 mmol) in anhydrous DMF (5 mL). The reaction solution was stirred for 5 minutes at ambient temperature and then heated at. 1000C oil bath for 30 minutes. After cooling, DMF was removed with vacuum. The residue was dissolved in water, washed with ethyl acetate, and the water layer was lyophilized to provide 6-chloro-3-[1-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-[1 ,2,4]triazolo[4,3-b]pyridazine (610 mg, 71.5% yield).
Method 12:
Synthesis of 7-methyl-6-{[6-(1-methyl-1 H-pyrazol-4-yl)[1 ,2,4]triazolo[4,3-b]pyridazin-3- yl]methyl}quinoline (11 )
Step i
To a solution of compound A (321 g, 3 mol) in CH2CI2 (3.5 L) cooled to 0-10 0C was added dropwise AcCI (259 g, 3.3 mol) while keeping the temperature at 0-100C. During the addition, white solid deposited. After the addition was complete, the resulting mixture was stirred at room temperature overnight. TLC (EtOAc: Petroleum ether = 1 :2) indicated the reaction was complete, the solvent and excessive AcCI were removed under reduced pressure to give crude compound B (500 g, 100%), which was used directly in next step.
Step 2
To a suspension of compound B (500 g, 3 mol in theory) in CH2CI2 (6 L) cooled to 0-10 0C was added AICI3 (1400 g, 10.5 mol) portionwise. The mixture turned clear and a few minutes later turned cloudy. AcCI (282.6 g, 3.6 mol) was added dropwise while keeping the temperature below 20 0C. Then the resulting mixture was stirred at room temperature overnight. TLC (EtOAc: Petroleum ether = 1 :2) indicated the reaction was complete. The mixture was poured carefully into a mixture of cone. HCI (1 L) and ice (2 Kg) with strong stirring. The solid was collected via filtration to give compound C (100 g). The organic layer was separated from the filtrate, washed with water (1.5 L) and brine, dried over Na2SO4 and concentrated until about 150 mL of CH2CI2 was left. The mixture was filtered to give compound C (180 g). The total yield is 48.8%.
Step 3
A mixture of compound C (96 g, 0.5 mol), morpholine (48.5 g, 0.558 mol) and sulfur (17.9 g, 0.558 mol) was heated to 110-13O0C and stirred overnight. TLC (EtOAc: Petroleum ether = 1 :2) indicated the reaction was complete, the mixture was powered into hot water (70-80 0C, 1 L) with strong stirring. A few minutes later, some solid deposited. The solid was colleted via filtration to give crude compound D, which was re-crystallized from EtOH (150 ml) at 70~80°C to give compound D (66 g, 45.2%). 1H NMR (400 MHz, CDCI3): δ 7.443 (s, 1 H), 7.254-7.131 (m, 2H), 7.131-7.080 (d, 1 H), 4.440- 4.340 (t, 2H), 4.179 (s, 2H), 3.818-3.786 (t, 2H), 3.497 (s, 4H), 2.231 (s, 3H), 2.187 (s, 3H).
Step 4
A suspension of compound D (151 g, 0.517 mol) in cone. HCI (500 ml_) and water (1 L) was heated to 100-1100C and stirred for 2 days. The solvent was removed under reduce pressure. 900 mL of hot water (50~60°C) was added and filtered. The filtrate was adjusted pH 9-10 with 20% aq. NaOH, and there was solid deposited. EtOAc (250 mL) was added and the mixture was filtered. The aqueous layer was separated from the filtrate, acidified with 10% aq. HCI to pH 5. The solid was filtered and dried to give compound E (60 g, 70.3%).
1H NMR (400 MHz, DMSO): δ 6.945-6.868 (d, 1 H), 6.519 (s, 1 H), 6.490-6.464 (dd, 1 H), 3.391 (s, 2H), 2.098 (s, 3H).
Step 5
A mixture of compound E (60 g, 0.364 mol), ferrous sulfate (13 g, 0.047 mol), glycerol (140 g, 1.52 mol), nitrobenzene (27.5 g, 0.22 mol) and concentrated sulfuric acid (65 mL) was heated gently. After the first vigorous reaction, the mixture was refluxed for five hours and then treated with aq. sodium hydroxide solution (2 N, 250 mL) and 4 N aq. sodium hydroxide solution until pH = 5-6. A dark brown precipitate formed. The precipitate was filtered, washed with water and taken up with aq. sodium hydroxide solution (4 N, 250 mL). The mixture was adjusted to pH 5-6 with glacial acetic acid. A dark- brown precipitate formed. The precipitate was collected and dried in vacuo to give crude compound F & FI (100 g, 100%).
Step 6
To a suspension of compound F & £1 (100 g, 0.364 mol in theory) in EtOH (600 mL) cooled to 0~5°C was added dropwise SOCI2 (37 mL, 0.437 mol). After the mixture was heated to reflux for 2 h, the mixture was evaporated under reduced pressure, and the residue was taken up with EtOAc (300 mL) and aq. NaHCO3 (300 mL). (If there was solid appeared, filtered). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to give crude product, which was purified via a silica column chromatography (EtOAc: Petroleum ether = 1:10 -1 :5) to give compound G & GI. (50 g, 60%) as a red oil. 1H NMR (400 MHz, CDCI3): δ 8.896-8.886 (d, 0.45H), 8.858-8.848 (d, 1H), 8.416-8.394 (d,
0.45H), 8.098-8.078 (d, 1 H), 7.958-7.923 (m, 1.4H), 7.658 (s, 1 H), 7.585-7.563 (d, 0.45H), 7.448-7.414 (q, 0.45H), 7.351-7.320 (q, 1H), 4.206-4.106 (m, 3.1 H), 3.860 (s, 0.9H), 3.812 (s, 2H), 2.641 (s, 1.3H), 2.520 (s, 3H), 1.276-1.231 (m, 4.8H). Step 7
A mixture of compound G & GI- (14 g, 0.06 mol) and sodium hydroxide solution (20%, 160 mL) was heated at 9O0C for 3 hours. The mixture was diluted with water (160 mL), and adjusted to pH = 6 with 15% aq. HCI. The white precipitate was collected, washed with water and dried in vacuo to give compound H & HI, (11.7 g, 97%) as a white solid.
1H NMR (400 MHz, DMSO): δ 12.510- (s, 1.2H), 8.863-8.844 (dd, 0.3H), 8.820-8.800 (dd, 1 H), 8.560-8.505 (d, 0.3H), 8.258-8.233 (d, 1 H)1 7.812 (s, 1 H), 7.793-7.762 (d, 0.3H), 7.697 (s, 1 H), 7.608- 7.579 (d, 0.3H), 7.550-7.508 (q, 0.3H), 7.452-7.411 (q, 1 H), 3.844 (s, 0.6H), 3.799 (s, 1H), 2.550 (s, 0.9H), 2.433 (s, 3H).
Step 8
To a suspension of compound H & HI. (11.7 g, 0.058 mol) and (6-chloro-pyridazin-3-yl)-hydrazine (8.4 g, 0.058 mol) in DMF (150 mL) was added EDCI (16.7 g, 0.087 mol) at room temperature. The mixture turned clear and stirred for 2 days. TLC (CH2CI2: MeOH = 10:1) showed the reaction was complete. DMF was removed under reduced pressure, and water (100 mL) and EtOAc (20 mL) were added to the mixture and filtered. (If there was no solid separated, the mixture was evaporated under reduced pressure for a while and solid would appear). The cake was washed with water and dried in vacuum to give compound I & H (17 g, 89.5%) as a yellow solid.
1H NMR (400 MHz, DMSO): δ 10.289 (s, 1.2H), 9.179 (s, 1.2H), 8.844-8.816 (m, 0.36H), 8.803- 8.797 (m, 1H), 8.570-8.490 (d, 0.36H), 8.254-8.228 (d, 1H), 7.852-7.806 (m, 2.2H), 7.679 (m, 0.38H), 7.558-7.515 (m, 1.7H), 7.458-7.417 (q, 1 H), 7.035-6.975 (m, 1.3H), 3.836 (s, 0.7H), 3.780 (s, 2H), 2.638(s, 0.96H), 2.509 (s, 3H).
Step 9
A suspension of compound i & H (17 g, 0.052 mol) in AcOH (150 mL) was heated to reflux and stirred overnight. After most of the solvent was removed in vacuum, water (300 mL) was added to the residue and stirred strongly. The mixture was filtered, and the cake was washed with water and dried in vacuum to give J (6 g, 37.4%) as a grey solid.
1H NMR (400 MHz, DMSO): δ 8.816-8.797 (q, 1 H), 8.485-8.453 (d, 1 H), 8.210-8.182 (d, 1 H), 7.859 (s, 1 H), 7.645 (s, 1 H), 7.510-7.478 (d, 1 H), 7.430-7.388(q, 1 H), 4.638 (s, 2H), 2.544 (s, 3H).
Step 10
Compound J (200mg, 0.646mmol), pyrazole boronic ester (162mg, 0.779mmol), and sodium carbonate (205mg, 1.94 mmol) were mixed in DME (8mL) and H2O (2mL), after degassed three times, Pd catalyst (22.7mg, 0.0323mmol) was added, and the reaction mixture was stirred at 800C for 3h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (50ml) and water (20ml). The aqueous layer was extracted with EtOAc (25ml). The combined organic layers were dried over MgS04, and evaporated in vacuo to afford the crude product. The crude product was purified by Flash column chromatography eluting with 70:25:5 CH2CI2:EtOAc:MeOH first and then 70:20:10 CH2CI2:Et0Ac:Me0H to afford 83m g of compound K.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3 H) 3.93 (s, 3 H) 4.70 (s, 2 H) 7.42 (dd, J=8.21 , 4.17 Hz, 1 H) 7.68 (d, J=9.60 Hz, 1 H) 7.85 (s, 1 H) 7.88 (s, 1 H) 8.16 (s, 1 H) 8.27 (d, J=8.08 Hz, 1 H) 8.34 (d, J=9.60 Hz, 1 H) 8.53 (s, 1 H) 8.80 (dd, J=4.17, 1.64 Hz, 1 H).
Method 13
To a flask containing 6-[(6-chloro[1 ,2,4]triazolo[4,3-6]pyridazin-3-yl)methyl]quinoline (75 mg, 0.25 mmol), (4-aminomethylphenyl) boronic acid hydrochloride (52 mg, 0.28 mmol), and cesium carbonate (284 mg, 0.761 mmol) was added 1 :3 wateπdimethoxyethane (2.0 ml_, degassed by bubbling with nitrogen gas for 15 minutes) followed by 1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1 :1 with dichloromethane, 8 mg, 0.01 mmol). The resulting mixture was then heated to 7O0C overnight. The reaction was cooled to room temperature, filtered and the filtrate was concentrated.
A mixture of 6-[(6-chloro[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]quinoline (100 mg, 0.338 mmol), (4-aminomethylphenyl) boronic acid hydrochloride (70 mg, 0.37 mmol), and cesium fluoride (154 mg, 1.01 mmol) in water (1.0 mL) and dimethoxyethane (3.4 ml_) was degassed by alternating between vacuum and nitrogen (5x), then bis(triphenylphosphine)palladium(ll)chloride (7 mg, 0.01 mmol) was added and the mixture was heated to 800C. After 1 hour, sodium carbonate (1 M in water, 1 mL) was added and the reaction mixture continued to heat overnight. The mixture was cooled to room temperature diluted with dichloromethane and concentrated. To a microwave vial containing 6-[(6-chloro[1 ,2,4]triazolo[4,3-ιb]pyridazin-3-yl)methyl]quinoline (75 mg, 0.25 mmol), (4-aminomethylphenyl) boronic acid hydrochloride (52 mg, 0.28 mmol), and sodium carbonate (1 M in water, 761 μL) was added dimethoxyethane (2.0 mL, degassed by bubbling with nitrogen gas for 15 minutes) followed by 1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1 :1 with dichloromethane 8 mg, 0.01 mmol). The resulting mixture was heated in the microwave for 20 minutes at 8O0C, 20 minutes at 12O0C, then 30 minutes at 16O0C. The reaction mixture was diluted with dichloromethane, filtered and the filtrate was concentrated.
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%).
Method 14:
A mixture of 3 ml. of DMF, Cs2CO3 (0.98 g, 0.003 mol) and 1 mL of water was degassed for 5 minutes. 6-((6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (0.30 g, 0.001 mol) and cyanophenyl boronic acid (0.164 g, 0.001 mol) were added. A catalytic amount of PdCI2(PPh3)2 was added. The mixture was heated to 8O0C and stirred overnight. The mixture was diluted with CH2CI2 (10 mL), and then filtered. The organic phase was separated, dried over Na2SO4 and evaporated in vacuum. The residue was washed with DMF and EtOAc to give 4-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazin-6-yl)benzonitrile (90.0 mg, 25.0%) as a white solid.
Method 15:
6-((6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (0.50 g, 1.7 mmol) and Cs2CO3 (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(PPh3)2CI2 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. The reaction mixture was heated to 8O0C and stirred overnight. The mixture was diluted with CH2CI2, and then filtered. The organic phase was separated and concentrated to dryness in vacuum. The residue was washed with DMF and EtOAc to give N,N-dimethyl-4-(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3- b]pyridazin-6-yl)-1 H-pyrazole-1 -sulfonamide (190 mg, 25.0%) as a white solid.
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 CF3COOH. The resulting mixture was stirred at room temperature for 3 h. Then CF3COOH was removed in vacuum. 10 mL of saturated aqueous NaHCO3 was added carefully. A lot of white solid was formed, which was filtered and dried to give 6-((6-(1 H-pyrazol-4-yl)-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (80 mg, 60.0%) as a white solid. Table 1
H)
1
Hz,
(s, 3
2
δ
H)
H)
- -
2
Hz,
1
1
-
11
Biological Assays
General
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, Technikova-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. Presently, 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. In the continuous-coupled spectrophotometric assay 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. 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. 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 (μM) are summarized in Table 2. Materials and Reagents:
1. HGFR enzyme from Upstate (Met, active) Cat. # 14-526 2. Met-2 Peptide (HGFR Activation Loop) Ac-ARDMYDKEYYSVHNK (MW = 1960). Dissolve up in
200 mM HEPES, pH 7.5 at 10 mM stock.
3. 1 M PEP (phospho-enol-pyruvate) in 200 mM HEPES, pH 7.5
4. 100 mM NADH (B-Nicotinamide Adenine Dinucleotide, Reduced Form) in 20OmM HEPES, pH 7.5
5. 4 M MgCI2 (Magnesium Chloride) in ddH2O 6. 1 M DTT (Dithiothreitol) in 200 mM HEPES, pH 7.5
7. 15 Units/mL LDH (Lactic Dehydrogenase)
8. 15 Units/mL PK (Pyruvate Kinase)
9. 5M NaCI dissolved in ddH2O
10. Tween-20 (Protein Grade) 10% Solution 11. 1 M HEPES buffer: (N-[2-Hydroxethyl]piperazine-N-[2-ethanesulfonic acid]) Sodium Salt.
Dissolve in ddH2O, adjust pH to 7.5, bring volume to 1 L. Filter at 0.1 μm.
12. HPLC Grade Water; Burdick and Jackson #365-4, 1 X 4 liters (or equivalent)
13. 100% DMSO (SIGMA)
14. Costar # 3880 - black clear flat bottom half area plates for Kj determination and % inhibition 15. Costar # 3359 - 96 well polypropylene plates, round bottom for serial dilutions
16. Costar # 3635 - UV-plate clear flat bottom plates for % inhibition
17. Beckman DU-650 w/ micro cell holders
18. Beckman 4-position micro cell cuvette Procedure:
Prep Dilution Buffer (DB) for Enzyme (For 30 mL prep) 1. DB final concentration is 2 mM DTT, 25 mM NaCI2, 5 mM MgCI2, 0.01% Tween-20, and 50 mM
HEPES buffer, pH 7.5.
2. Make up 50 mM HEPES by adding 1.5 mL 1 M HEPES into 28.1 mL of ddH2O. Add rest of the reagents. Into 50 mL conical vial, add 60 μL of 1 M DTT, 150 μL 5M NaCI2, 150 μL 1M MgCI2, and 30 μL of 10% Tween-20 to give total volume of 30 mL. 3. Vortex for 5-10 seconds.
4. Aliquot out DB at 1 mL/tube and label tubes as "DB HGFR"
5. Note: This can be prepared and stored ahead of time.
6. Freeze un-used aliquots in microcentrifuge tubes at -200C freezer.
Prep Compounds
1. For compound dilution plate, add 4 μL of 10 mM stock into column 1 of plate, and bring volume to
100 μL with 100% DMSO.
2. Set up the Precision 2000 dilution method. A final concentration of 200 μM compound in 50% DMSO, 100 mM HEPES (1 :2 serial dilution). Prep Coupled Enzymatic Buffer:
1. Final concentration in assay:
Reagent (Stock Cone.) Final Cone. In Assay a. PEP (1 M) 1 mM b. NADH (IOO mM) 300 μM c. MgCI2 (4 M) 20 mM d. DTT (I M) 2 mM e. ATP (50O mM) 300 μM f. HEPES 200 mM (pH 7.5) 10O mM g. Pyruvate Kinase (PK) 15 units/mL h. Lactic Dehydrogenase (LDH) 15 units/mL i. Met-2 peptide (1O mM) 0.50O mM j. HGFR 50 nM
2. For a 10 mL reaction buffer add 10 μL of 1M PEP, 33 μL of 100 mM NADH, 50 μL of 4M MgCI2, 20 μL of 1 M DTT, 6 μL of 500 mM ATP, and 500 μL of 10 mM Met-2 peptide into 100 mM HEPES buffer pH 7.5 and vortex/mix.
3. Add coupling enzymes, LDH and PK, into reaction mix. Mix by gentle inversion. Running samples 1. Spectrophotometer settings: i. Absorbance wavelength (λ): 340 nm ii. Incubation time: 10 min iii. Run time: 10 min iv. Temperature: 370C
2. Add 85 μl_ of CE reaction mix into each well of assay plate.
3. Add 5 μl_ of diluted compound into a well of the assay plate.
4. Add 5 μl_ of 50% DMSO for negative control into last column of assay plate.
5. Mix with multi-channel pipettor or orbital shaker.
6. Pre-incubate for 10 minutes at 370C.
7. Add 10 μL of 500 nM HGFR to each well of assay plate; the final HGFR concentration is 50 nM in a total final volume of 100 μL.
8. Measure activity for 10 minutes at λ = 340 nm and 370C.
Table 2

Claims

What is claimed:
1. A compound of the formula I:
I
wherein:
R1, R2 and R3 are independently selected from hydrogen, Br, Cl, F, -0(CHz)nCH3, -O(CH2)nOR6, -(CH2)nOR6, -C(O)R6, -C(O)OR6, -C(O)NR6R7, -NR6R7, -S(O)2R6, -S(O)R6, -S(O)2NR6R7, -CF3, -CF2H, - NR6C(O)NR6R7, -NR6C(O)R7, -NR6S(O)2R7, -N(CH2)n(C3-C8 cycloalkyl), -CN, -NO2, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10 aryl, C2-C6 alkenyl, and C2-C6 alkynyl wherein C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalicyclic, 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10 aryl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, -(CH2)nCH(OR6)CH3, -(CH2JnOR6, - (CH2)nC(CH3)2OR6, -(CH2)n(3-8 membered heteroalicyclic), -C(O)R6, -C(O)OR6, -(CR6R7)nC(O)OR6, -C(O)NR6R7, -(CR6R7)nC(O)NR6R7, -(CH2)nNR6R7, -S(O)2R6, -S(O)R6, -S(O)2NR6R7, -CF3, -CF2H, -(CHz)nNR6C(O)NR6R7, -(CH2JnNR6C(O)OR7, -NR6C(O)R7, -NR6C(O)OR7, -NR6S(O)2R7, -CN, -NO2, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n(3-8 membered heteroalicyclic), -(CH2)n(5-7 membered heteroaryl), -(CH2UC6-C10 aryl), C2-C6 alkenyl, and C2-C6 alkynyl;
R4 is a 8-10 membered heterobicyclic optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, -(CH2)nCH(OR6)CH3, -(CH2)nOR6, -(CH2)nC(CH3)2OR6, -(CH2)n(3-8 membered heteroalicyclic), -C(O)R6, -C(O)OR6, -(CR6R7)nC(O)OR6, -C(O)NR6R7, -(CR6R7JnC(O)NR6R7, - (CHz)nNR6R7, -S(O)2R6, -S(O)R6, -S(O)2NR6R7, -CF3, -CF2H, -(CHz)nNR6C(O)NR6R7, -(CH2)nNR6C(O)OR7, -NR6C(O)R7, -NR6C(O)OR7, -NR6S(O)2R7, -CN, -NO2, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n(3-8 membered heteroalicyclic), -(CH2)n(5-7 membered heteroaryl), -(CH2)n(C6-C10 aryl), C2-C6 alkenyl, and C2- C6 alkynyl;
R5 is selected from the group consisting of hydrogen, F, -CF3, C1-C6 alkyl and aryl;
R6 and R7 are independently selected from H, -(CH2JnOR8, -(CH2)nC(CH3)2OR8, -CHR8(CH2)nOR9,
,8r-,θ -(CH2JnCHROR9, -C(CH3J2(CH2JnOR*, -CH2CF2H, -(CH2JnC(CH3J2N RBRS, -(CH2JnNR ,80Rn9",
-.8^,9
-(CH2)nCHOR8(CH2)nOR9, -(CH2Jn(NR8R9JC(O)NR8R9, -(CH2JnS(O)2R8, -(CH2)nC(O)NRBRb, -(CH2)nC(0)Rδ, -NR8(CH2)n(5-7 membered heteroaryl), -NR8(CH2)n(3-8 membered heterocycle), -(CH2)n(8-10 membered heterobicyclic), -(CH2)n(3-8 membered heteroalicyciic), C1-C6 alkyl, C3-C8 cycloalkyl, C6-Ci0 aryl, C2-C6 alkenyl, 3-8 membered heteroalicyciic and C2-C6 alkynyl, wherein said 5-7 membered heteroaryl, 3-8 membered heterocycle and 8-10 membered heterobicyclic are optionally substituted by one or more moieties selected from the group consisting of -(CH2)nOR8, C1-C6 alkyl, C3-C8 cycloalkyl, C6-Ci0 aryl, C2- C6 alkenyl, 3-8 membered heteroalicyciic and C2-C6 alkynyl; or when R6 and R7 are attached to the same atom, R6 and R7 optionally combine to form a 3-8 membered heteroalicyciic ring;
R8 and R9 are independently selected from H, C1-C6 alkyl, -C(O)CH3, C3-C8 cycloalkyl, C6-C10 aryl,
C2-C6 alkenyl, 5-7 membered heteroaryl and C2-C6 alkynyl, wherein said 5-7 membered heteroaryl is optionally substituted by one or more moieties selected from the group consisting of CrC6 alkyl, C3-C8 cycloalkyl, C6-Ci0 aryl, C2-C6 alkenyl, and C2-C6 alkynyl; or when R12 and R13 are attached to the same atom, R12 and R13 optionally combine to form a 3-8 membered heteroalicyciic ring; and n is 0, 1 , 2, 3 or 4; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R1, R2 and R3 are independently selected from hydrogen, Cl,
-OR6, -0(CHa)nCH3, -OCH2(CH2)nOR6, -C(O)NR6R7, -NR6R7, C1-C6 alkyl, 3-8 membered heteroalicyciic, 3- 8 membered heteroalicyclic-(3-8 membered heteroalicyciic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10 aryl and C2-C6 alkenyl, wherein C1-C6 alkyl, 3-8 membered heteroalicyciic, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyciic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-Ci0 aryl and C2-C6 alkenyl are optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, -(CH2)nCH(OR6)CH3, -(CH2)nOR6, -(CH2)nC(CH3)2OR6, - (CH2)n(3-8 membered heteroalicyciic), -C(O)R6, -C(O)OR6, -(CR6R7JnC(O)OR6, • -C(O)NR6R7, -(CR6R7JnC(O)NR6R7, -(CHa)nNR6R7, -S(O)2R10, -S(O)R10, -S(O)2NR10R11, -CF3, -CF2H, -(CHz)nNR10C(O)NR10R11, -(CH2JnNR10C(O)OR11, -NR10C(O)R11, -NR10C(O)OR11, -NR10S(O)2R11, -CN, - NO2, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, -(CH2)n(3-8 membered heteroalicyciic), -(CH2)n(5-7 membered heteroaryl), -(CH2)n(C6-C10 aryl), C2-C6 alkenyl, and C2-C6 alkynyl.
3. The compound of claim 1 , wherein R1 is selected from Cl, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyciic), 5-7 membered heteroaryl, and C6-C10 aryl, wherein 3-8 membered heteroalicyclic-(3-8 membered heteroalicyciic), 5-7 membered heteroaryl and C6-C10 aryl are optionally substituted by one or more moieties selected from the group consisting of -(CH2JnOR10, -C(O)OR10, -(CR10R11JnC(O)NR10R11, -(CH2JnNR10R11, -CF3, and -CN.
4. The compound according to any one of claims 1-3, wherein R2 and R3 are H.
5. The compound according to any one of claims 1-4, wherein R5 is H.
6. The compound according to any one of claims 1-4, wherein R5 is Ci-C6 alkyl.
7. The compound according to any one of claims 1-4, wherein R5 is methyl.
8. The compound according to any one of claims 1-7, wherein R is selected from
9. The compound of claim 1 , wherein said compound is selected from θ-CI-methyl-I H-pyrazol^-yO-S-KSJ-I^I H-pyrrolop.S-bJpyridin-S-yO-ethylJ-Ci ^.^triazoloμ.S- bjpyridazine,
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]pyridazin-3-yl)methyl)quinoline,
4-(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)benzonitrile,
S-^T-methylquinolin-θ-ylJmethyO-N-^etrahydrofuran^-yOfi ^^Jtriazolo^.S-blpyridazin-β-amine,
N-cyclopentyl-S-^T-methylquinolin-θ-yOmethyOCI ^^ltriazolo^.S-blpyridazin-δ-amine,
4-{3-[(S)-1-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl}-benzonitrile, isopropyl-[3-((S)-1-quinolin-6-yl-ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-amine,
[3-(1-quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-(tetrahydro-furan-3-yl)-amine,
2-[3-(1-quinolin-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-ylamino]-ethanol, and
4-[3-((S)-1 -q u inol in-6-yl-ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]-benzonitrile; or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound according to the formula (I) as defined in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
11. The use of a compound of the formula (I) as defined in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament to treat a c-Met related disorder in a mammal.
12. The use of a compound of the formula (I) as defined in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, for the manufacture of medicament for the treatment of cancer in a mammal.
13. The use of claim 12, wherein 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.
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