WO2006108059A1 - C-met modulators and methods of use - Google Patents

C-met modulators and methods of use Download PDF

Info

Publication number
WO2006108059A1
WO2006108059A1 PCT/US2006/012709 US2006012709W WO2006108059A1 WO 2006108059 A1 WO2006108059 A1 WO 2006108059A1 US 2006012709 W US2006012709 W US 2006012709W WO 2006108059 A1 WO2006108059 A1 WO 2006108059A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound according
substituted lower
alkyl
ring system
Prior art date
Application number
PCT/US2006/012709
Other languages
French (fr)
Inventor
Timothy Patrick Forsyth
Morrison B. Mac
James William Leahy
John M. Nuss
Wei Xu
Original Assignee
Exelixis, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Exelixis, Inc. filed Critical Exelixis, Inc.
Priority to AU2006231646A priority Critical patent/AU2006231646A1/en
Priority to EP06749361A priority patent/EP1874759A4/en
Priority to US11/910,720 priority patent/US20080161305A1/en
Priority to JP2008505496A priority patent/JP2008537748A/en
Priority to CA002603748A priority patent/CA2603748A1/en
Publication of WO2006108059A1 publication Critical patent/WO2006108059A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Even more specifically, the invention relates to quinolines which inhibit, regulate and/or modulate kinase receptor signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, methods of using them to treat kinase-dependent diseases and conditions, synthesis of the compounds as well as processes for formulating the compounds for pharmaceutical purposes.
  • Protein kinases are enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy groups on tyrosine, serine and threonine residues of proteins.
  • the consequences of this seemingly simple activity are staggering; cell differentiation and proliferation; i.e., virtually all aspects of cell life in one-way or another depend on protein kinase activity.
  • abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
  • Protein kinases can be categorized as receptor type or non-receptor type.
  • Receptor- type tyrosine kinases have an extracellular, a transmembrane, and an intracellular portion, while non-receptor type tyrosine kinases are wholly intracellular.
  • Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified.
  • Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.
  • the insulin subfamily which includes INS-R, IGF- IR, and IR-R.
  • the PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-Kit and FLK-II.
  • the FLK family which is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-I), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1).
  • KDR kinase insert domain receptor
  • FLK-I fetal liver kinase-1
  • FLK-4 fetal liver kinase-4
  • flt-1 flt-1
  • the non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors.
  • the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, and Yrk.
  • the Src subfamily of enzymes has been linked to oncogenesis.
  • kinase modulation relates to oncological indications.
  • modulation of protein kinase activity for the treatment of cancer has been demonstrated successfully with the FDA approval of Gleevec® (imatmib mesylate, produced by Novartis Pharmaceutical Corporation of East Hanover, NJ) for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers (GIST).
  • Gleevec is a c-Kit and AbI kinase inhibitor.
  • c-Met One particularly attractive target for small-molecule modulation, with respect to antiangiogenic and antiproliferative activity is c-Met.
  • the kinase, c-Met is the prototypic member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) which include Met, Ron and Sea.
  • RTKs heterodimeric receptor tyrosine kinases
  • Expression of c-Met occurs in a wide variety of cell types including epithelial, endothelial and mesenchymal cells where activation of the receptor induces cell migration, invasion, proliferation and other biological activities associated with "invasive cell growth.”
  • signal transduction through c-Met receptor activation is responsible for many of the characteristics of tumor cells.
  • HGF hepatocyte growth factor
  • SF scatter factor
  • Binding of HGF to c-Met induces activation of the receptor via autophosphorylation resulting in an increase of receptor dependent signaling, which promotes cell growth and invasion.
  • Anti-HGF antibodies or HGF antagonists have been shown to inhibit tumor metastasis in vivo (See: Maulik et al Cytokine & Growth Factor Reviews 2002 13, 41-59).
  • Tumor growth progression requires the recruitment of new blood vessels into the tumor from preexisting vessels as well as invasion, adhesion and proliferation of malignant cells. Accordingly, c-Met overexpression has been demonstrated on a wide variety of tumor types including breast, colon, renal, lung, squamous cell myeloid leukemia, hemangiomas, melanomas, astrocytomas, and glioblastomas. Additionally activating mutations in the kinase domain of c-Met have been identified in hereditary and sporadic renal papilloma and squamous cell carcinoma.
  • Eph receptors comprise the largest family of receptor tyrosine kinases and are divided into two groups, EphA and EphB, based on their sequence homology.
  • the ligands for the Eph receptors are ephrin, which are membrane anchored. Ephrin A ligands bind preferentially to EphA receptors whilst ephrin B ligands bind to EphB receptors. Binding of ephrin to Eph receptors causes receptor autophosphorylation and typically requires a cell-cell interaction since both receptor and ligand are membrane bound.
  • Eph receptor tyrosine kinases and their ephrin ligands play important roles in a variety of processes during embryonic development and also in pathological angiogenesis and potentially metastasis. Therefore modulation of Eph receptor kinase activity should provide means to treat or prevent disease states associated with abnormal cell proliferation such as those described above.
  • EGF EGF
  • VEGF vascular endothelial growth factor
  • ephrin signal transduction will prevent cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. Drug Disc. Technol. 2001 6, 1005-1024).
  • EGF and VEGF receptors are previously described targets for small molecule inhibition.
  • KDR and flt-4 are both VEGF receptors
  • c-Kit One particularly attractive target for small-molecule modulation is c-Kit.
  • the proto-oncogene c-Kit was first identified as the oncogenic component of the acutely transforming Hardy-Zuckerman 4-feline sarcoma virus (Besmer et al Nature 1986 320:415-421).
  • c-Kit also called stem cell factor receptor or steel factor receptor
  • RTK type 3 receptor tyrosine kinase
  • c-Kit binds the ligand stem cell factor (SCF), and triggers its multiple signal transduction pathways including Src family kinases, phosphatidyl-inositol 3 kinase, the Ras-Raf-Map kinase cascade, and phospholipase C (Broudy et al Blood 1999 94: 1979- 1986; Lennartsson et al Oncogene 1999 18: 5546-5553 ; Timokhina et al EMBO J 1998 17;6250-6262; Chian et al Blood 2001 98(5)1365-1373; Blume-Jensen et al Curr Biol
  • c-Kit is required for normal hematopoiesis, melanonogenesis, and gametogenesis. c-Kit is expressed in mast cells, immature myeloid cells, melanocytes, epithelial breast cells and the interstitial cells of Cajal (ICC). In mast cells, it is required not only for the differentiation, maturation, chemotaxis, and haptotaxis but also for the promotion of survival and proliferation.
  • Mutations in c-Kit have been implicated in human disease. Mutations in the juxtamembrane domain are found in many human gastrointestinal stromal tumors, and mutations in the kinase domain are found in mastocytosis, germ cell tumors, acute myeloid leukemia (AML), NK lymphoma, and other hematologic disorders (Hirota et al Science 1998 279:577-580; Singer et al J Clin Oncol 2002 203898-3905; Longley et al Proc Natl Aca Sci USA 1999: 1609-1614; Tian et al Am J Pathol 1999 154: 1643-1647; Beghini et al Blood 2000 95:726-727; Hongyo et al Cancer Res 2000 60:2345-2347).
  • c-Kit and c-Kit ligand have also been described in other tumors including small-cell lung cancer, neuroblastomas, gynecological tumors, and colon carcinoma, which might result in autocrine or paracrine c-Kit activation.
  • NFl neurofibromatosis type 1
  • Mutations in the tumor suppressor gene NFl lead to a deficiency in neurofibromin, a GTPase-activating protein for Ras.
  • This deficiency results in abnormal proliferation of Schwann cells in the peripheral nervous system, and predisposes affected individuals to peripheral nerve sheath tumors (neurofibromas), astrocytomas (optic pathway gliomas), learning disabilities, seizures, strokes, macrocephaly, vascular abnormalities, and juvenile myelomonocytic leukemia (Lynch & Gutmann Neurol Clin 2002 20:841-865).
  • c-Kit inhibitors may be effective chemotherapeutic agents for treating patients with NF-I.
  • GISTs are the most common mesenchymal tumors of the gastrointestinal tract, and they are generally resistant to chemotherapy and radiation therapy.
  • c-Kit/BCR-Abl inhibitor STI571 indicate that targeting c-Kit may be an effective therapeutic strategy for this disease (Eisenberg & Mehren Expert Opin Pharmacother 2003 4:869-874).
  • Malignant mast cell disease often suggests an extremely poor prognosis, and no reliable effective chemotherapeutic agents have been identified (Marone et al Leuk Res 2001 25:583-594).
  • activated c-Kit might serve as a therapeutic target in GISTs and mast cell disease, as well as other disorders associated with activated c-Kit.
  • Flt-3 is normally expressed on hematopoietic progenitor cells and a subset of mature myeloid and lymphoid cells, where it modulates cell survival and proliferation.
  • Flt-3 is constitutively activated via mutation, either in the juxtamembrane region or in the activation loop of the kinase domain, in a large proportion of patients with AML (Reilly Leuk Lymphoma 2003 44: 1-7). Also, mutations in flt-3 are significantly correlated with poor prognosis in AML patients (Sawyers Cancer Cell 2002 1: 413-415).
  • the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of kinases is desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis, and is an object of this invention.
  • the present invention provides compounds for modulating kinase activity and methods of treating diseases mediated by kinase activity utilizing the compounds and pharmaceutical compositions thereof.
  • Diseases mediated by kinase activity include, but are not limited to, diseases characterized in part by migration, invasion, proliferation and other biological activities associated with invasive cell growth.
  • the invention provides methods of screening for modulators of c- Met, KDR, c-Kit, flt-3, and flt-4 activity.
  • the methods comprise combining a composition of the invention, a kinase, e.g. c-Met, KDR, c-Kit, flt-3, or flt-4, and at least one candidate agent and determining the effect of the candidate agent on the c-Met, KDR, c-Kit, flt-3, or flt-4, activity.
  • kits comprising one or more containers filled with one or more of the ingredients of pharmaceutical compounds and/or compositions of the present invention, including, one or more kinase, e.g. c-Met, KDR, c-Kit, flt-3, or flt-4, enzyme activity modulators as described herein.
  • kinase e.g. c-Met, KDR, c-Kit, flt-3, or flt-4, enzyme activity modulators as described herein.
  • kits can also include, for example, other compounds and/or compositions (e.g., diluents, permeation enhancers, lubricants, and the like), a device(s) for administering the compounds and/or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflects approval by the agency of manufacture, use or sale for human administration.
  • other compounds and/or compositions e.g., diluents, permeation enhancers, lubricants, and the like
  • a device(s) for administering the compounds and/or compositions e.g., a device(s) for administering the compounds and/or compositions
  • written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflects approval by the agency of manufacture, use or sale for human administration.
  • the invention also provides a diagnostic agent comprising a compound of the invention and, optionally, pharmaceutically acceptable adjuvants and excipients.
  • the present invention provides processes for making compounds, and pharmaceutical compositions thereof, for modulating kinase activity and treating diseases mediated by kinase activity.
  • processes for making quinolines used for modulation of kinase activity are methods for making quinolines used for modulation of kinase activity, even more particularly inhibition of kinase activity, and yet even more particularly inhibition of c-Met, KDR, c- Kit, flt-3, and flt-4.
  • compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities.
  • Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, cancer (further discussed below), immunological disorders such as rheumatoid arthritis, graft-host diseases, multiple sclerosis, psoriasis; cardiovascular diseases such as artheroscrosis, myocardioinfarction, ischemia, stroke and restenosis; other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritus, macular degeneration, diabetic retinopathy.
  • cancer cancer
  • immunological disorders such as rheumatoid arthritis, graft-host diseases, multiple sclerosis, psoriasis
  • cardiovascular diseases such as artheroscrosis, myocardioinfarction, ischemia, stroke and restenosis
  • other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritus, macular degeneration, diabetic retinopathy.
  • the cells may not be in a hyper- or hypo- proliferative and/or migratory state (abnormal state) and still require treatment.
  • the cells may be proliferating "normally", but proliferation and migration enhancement may be desired.
  • reduction in "normal” cell proliferation and/or migration rate may be desired.
  • the present invention comprises a compound for modulating kinase activity according to Formula I,
  • R 1 is selected from -H, halogen, -OR 3 , -NO 2 , -NH 2 , -NR 3 R 4 , and optionally substituted lower alkyl;
  • Z is selected from -S(O) 0-2 -, -O-, and -NR 5 -;
  • Ar is either a group of formula II, or of formula III,
  • R 2 is selected from -H, halogen, trihalomethyl, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 4 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , and optionally substituted lower alkyl; q is O to 4;
  • G is a group -B-L-T, wherein
  • J is selected from -S(O) 0-2 -, -O, and -NR 15 -;
  • R 3 is -H or R 4 ;
  • R 4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or
  • R 3 and R 4 when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
  • R 5 is -H or optionally substituted lower alkyl;
  • D is selected from -0-, -S(O) 0-2 -, and -NR 15 -;
  • R 50 is either R 3 , or according to formula IV;
  • X 1 , X 2 , and optionally X 3 represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X , X , and X ; wherein, each X 1 is independently selected from -C(R 6 )R 7 -, -0-, -S(O) 0-2 -, and -NR 8 -; each X 2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X 3 is independently selected from -C(R 6 )R 7 -, -0-, -S(O) 0-2 -, and -NR 8 -; Y is either: an optionally substituted lower alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X when X is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R 6 or R 7 ; provided there are
  • R 6 and R 7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH 2 , -NO 2 , -OR 3 , -NR 3 R 4 , -S(O) 0-2 R 4 , -SO 2 NR 3 R 4 , -CO 2 R 3 , -C(O)NR 3 R 4 , -N(R 3 )SO 2 R 4 , -N(R 3 )C(O)R 3 , -NCO 2 R 3 , -C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, optionally substituted lower heterocyclylalkyl, and a bond to either Y or D; or
  • R 6 and R 7 when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
  • R 8 is selected from -R 3 , Y, -SO 2 NR 3 R 4 , -CO 2 R 4 , -C(O)NR 3 R 3 , -SO 2 R 4 , and -C(O)R 3 ;
  • R 14 is selected from -H, -NO 2 , -NH 2 , -N(R 3 )R 4 , -CN, -OR 3 , optionally substituted lower alkyl, optionally substituted heteroalicyclylalkyl, optional
  • Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R 20 ;
  • R 20 is selected from -H, halogen, trihalomethyl, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 4 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , and optionally substituted lower alkyl;
  • R 60 is selected from -H, halogen, trihalomethyl, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 4 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; two of R °, when attached to a non-aromatic carbon, can be oxo; with the proviso, only when Ar is according to formula II, if Y is a C 1-6 alkylene; Z is -NH- or -N(CH 3
  • R ,50 must be of formula IV; and with the proviso that when Ar is phenylene or substituted phenylene, Z is -S(O) 0-2 - or
  • the compound is according to paragraph [0033], wherein Z is either -O- or -NR 5 -.
  • the compound is according to paragraph [0035], wherein Ar is according to one of formula Ha, lib, and IHa.
  • the compound is according to paragraph [0036], wherein D is -O- and R 1 is -OR 3 .
  • the compound is according to paragraph [0037], wherein -O-R 50 and R 1 are interchangeably located at the 6-position and 7-position of the quinoline according to formula I.
  • the compound is according to paragraph [0038], wherein R 1 is -OH or -OC 1-6 alkyl.
  • G is selected from: wherein Q, R 20 , R 13 , E, and R 60 are as defined above; each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R 25 ; and R 25 is selected from halogen, trihalomethyl, oxo, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 4 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl
  • R is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.
  • P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.
  • R 25 is selected from halogen, trihalomethyl, oxo, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 4 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R 25 , together with the carbon or carbons
  • R 25 is selected from halogen, trihalomethyl, oxo, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 4 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R 25 , together with the carbon or carbon
  • the compound is according to paragraph [0043], wherein the methylene between the two carbonyls of the depicted formulae is di-substituted with either optionally substituted lower alkyl, or an optionally substituted spirocycle.
  • the compound is according to either [0042] or paragraph [0044], wherein R 50 is a heteroalicylic or a C 1-6 alkyl-heteroalicylic.
  • the compound is according to paragraph [0045], wherein at least one of R is halogen.
  • the compound is according to paragraph [0047], wherein the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1].
  • the compound is according to paragraph [0048], wherein Y is selected from -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 -, -CH 2 -, and absent.
  • the compound is according to paragraph [0049], wherein n is 0 and the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0].
  • the compound is according to paragraph [0050], wherein said saturated bridged ring system contains at least one annular nitrogen or at least one annular oxygen.
  • said saturated bridged ring system contains -NR -, wherein R is selected from -H, optionally substituted lower alkyl, -CO 2 R 3 , -C(O)NR 3 R 3 , -SO 2 R 3 , and -C(O)R 3 .
  • U 1 is selected from -O-, -S(O) 0-2 -, -NR 8 -, -CR 6 R 7 -, and absent; and e is 0 or 1.
  • the compound is according to paragraph [0053], wherein Y is -CH 2 -.
  • the compound is according to paragraph [0054], wherein U 1 is -NR 8 -, wherein R 8 is selected from -H, optionally substituted lower alkyl, -CO 2 R 3 , -C(O)NR 3 R 3 , -SO 2 R 3 , and -C(O)R 3 .
  • the compound is according to paragraph [0054], wherein U 1 is -O-.
  • the compound is according to paragraph [0054], wherein U 1 is absent.
  • the compound is according to paragraph [0051], wherein Y is selected from -CH 2 CH 2 -, -CH 2 -, and absent.
  • R 9 , R 10 , and R 11 are each independently selected from -H, and -OR 12 ; or R 9 is selected from -H, and -OR 12 , and R 10 and R 11 , when taken together, are either an optionally substituted alkylidene or an oxo;
  • R 12 is selected from -H, -C(O)R 3 , optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl; or two R 12 ' s, when taken together, form 1) a corresponding spirocyclic ketal when said two R 12 ' s stem from R 10 and R 11 , or 2) a corresponding cyclic ketal when said two R 12 's stem from R 9 and one of R 10 and R 11 .
  • the compound is according to paragraph [0059], wherein one of R 10 and R 11 is -OR 12 , wherein R 12 is selected from -H, -C(O)R 3 , and optionally substituted lower alkyl; and R 9 and the other of R 10 and R 11 are both -H.
  • the compound is according to paragraph [0060], wherein Y is either -CH 2 - or absent.
  • the compound is according to paragraph [0061], wherein R 9 is an alkyl group containing at least one fluorine substitution thereon.
  • the compound is according to paragraph [0063], wherein Y is either -CH 2 - or absent.
  • the compound is according to paragraph [0064], wherein R 8 is methyl or ethyl.
  • the compound is according to paragraph [0066], wherein Y is -CH 2 -.
  • the compound is according to paragraph [0067], wherein R is methyl or ethyl.
  • the compound is according to paragraph [0070], wherein U 2 is either -CR 6 R 7 - or absent.
  • the compound is according to paragraph [0071], wherein U 2 is either -CH 2 - or absent.
  • the compound is according to paragraph [0072], wherein Y is -CH 2 -.
  • the compound is according to paragraph [0033], selected from Table 1.
  • the invention comprises a compound for modulating kinase activity of formula A-B-C, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, A is selected from:
  • B is selected from:
  • C is selected from:
  • R 2 is selected from -H, halogen, trihalomethyl, -CN, -NH 2 , -NO 2 , -OR 3 , -NR 3 R 3 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , and optionally substituted lower alkyl; q is 0 to 2; each R 3 is independently selected from — H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; two R 3 , together with the nitrogen to which they are attached, form a four- to seven- membered heteroalicyclic, said four- to seven-membere
  • R 5 is -H or optionally substituted lower alkyl
  • R 8 is selected from R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -SO 2 R 3 , and -C(O)R 3 ;
  • R 9 , R 10 , and R 11 are each independently selected from -H, and -OR 12 ; or
  • R 9 is selected from -H, and -OR 12 , and R 10 and R 11 , when taken together, are either an optionally substituted alkylidene or an oxo;
  • R 12 is selected from -H, -C(O)R 3 , optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl; or two R 's, when taken together, form 1) a corresponding spirocyclic ketal when said two R 12 ' s stem from R 10 and R 11 , or 2) a corresponding cyclic ketal when said two R 12 's stem from R 9 and one of R 10 and R 11 ;
  • E 1 is selected from -0-, -CH 2 -, -N(R 5 )-, and -S(O) 0-2 -;
  • Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R 20 ;
  • R 20 is selected from -H, halogen, trihalomethyl, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 3 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , and optionally substituted lower alkyl;
  • R 60 is selected from -H, halogen, trihalomethyl, -CN 3 -NO 2 , -NH 2 , -OR 3 , -NR 3 R 3 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; two of R 60 , when attached to a non-aromatic carbon, can be oxo; each methylene in any of the above formulae is independently optionally substituted with R 25 ; each R 25 is independently selected from halogen, trihalomethyl, -CN,
  • A must be one of:
  • R 70 is selected from -H, C 1-4 alkyl, and C 1-4 alkoxyl.
  • Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, is
  • R 2 is selected from halogen, trihalomethyl, -CN, -NO 2 , -OR', -NR 3 J ⁇ R>3 ⁇ -CO 2 R", -C(O)NR 3 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , and optionally substituted lower alkyl
  • the compound is according to paragraph [0077], selected from Table 2.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to any one of paragraphs [0033]-[0085] and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a metabolite of the compound or the pharmaceutical composition according to any one of paragraphs [0022]-[0086].
  • Another aspect of the invention is a method of modulating the in vivo activity of a kinase, the method comprising administering to a subject an effective amount of the compound or the pharmaceutical composition according to any of paragraphs [0033]- [0086].
  • Another aspect of the invention is the method according to paragraph [0088], wherein modulating the in vivo activity of the kinase comprises inhibition of said kinase.
  • kinase is at least one of c-Met, KDR, c-Kit, flt-3, and flt-4.
  • Another aspect of the invention is the method according to paragraph [0091], wherein the kinase is c-Met.
  • Another aspect of the invention is a method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of the compound or the pharmaceutical composition as described in any one of paragraphs [0033]-[0086].
  • Another aspect of the invention is a method of screening for a modulator of a kinase, said kinase selected from c-Met, KDR, c-Kit, flt-3, and flt-4, the method comprising combining a compound according to any one of paragraphs [0033]-[0085], and at least one candidate agent and determining the effect of the candidate agent on the activity of said kinase.
  • Another aspect of the invention is a method of inhibiting proliferative activity in a cell, the method comprising administering an effective amount of a composition comprising a compound according any one of paragraphs [0033]-[0085] to a cell or a plurality of cells.
  • the present invention also comprises a process for preparing a compound of Formula XXI,
  • each R 1 is independently selected from halogen, -OR 3 , -NO 2 , -NH 2 , -NR 3 R 3 , -D-R 50 and optionally substituted C 1-6 alkyl;
  • R 70 is selected from -H, halogen, -OR 3 , -S(O) 0-2 R 3 , -NO 2 , -NH 2 , -NR 3 R 3 , and optionally substituted C 1-6 alkyl;
  • Z is selected from -S(O) 0-2 -, -0-, and -NR 5 -; each R 5 is independently selected from -H, optionally substituted C 1-6 alkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 alkyl;
  • Ar is either a five- to ten-membered arylene or a five- to ten-membered heteroarylene containing between one and three heteroatoms;
  • R 2 is selected from -H, halogen, trihalomethyl, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 3 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , and optionally substituted C 1-6 alkyl; each R 3 is independently selected from -H, -Si(R 5 )(R 5 )R 5 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; two R , together with the nitrogen to which they are attached, form a four- to seven- membered heteroali
  • Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R 20 ; each R is independently selected from -H, halogen, trihalomethyl, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 3 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted aryl C 1-6 alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C 1-6 alkyl; two of R 20 , together with the atom or atoms to which they
  • D is selected from -0-, -S(O) 0-2 -, and -NR 15 -;
  • R 50 is either R 3 , or according to formula XXIV;
  • X , X , and optionally X represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X 1 , X 2 , and X 3 ; wherein, each X 1 is independently selected from -C(R 6 )R 7 -, -O-, -S(O) 0-2 -, and -NR 8 -; each X is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X 3 is independently selected from -C(R 6 )R 7 -, -O, -S(O) 0-2 -, and -NR 8 -; Y is either: an optionally substituted C 1-6 alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X when X is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R 6 or R 7
  • R 6 and R 7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH 2 , -NO 2 , -OR 3 , -NR 3 R 3 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -NCO 2 R 3 , -C(O)R 3 , optionally substituted C ⁇ alkyl, optionally substituted aryl, optionally substituted aryl C 1-6 alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl a C 1-6 lkyl, and a bond to either Y or D; or R 6 and R 7 , when taken together are oxo; or
  • R 6 and R 7 when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
  • R 8 is selected from -R 3 , Y, -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -SO 2 R 3 , and -C(O)R 3 ;
  • two R 13 together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R 60 , said heteroalicyclic comprising up to four annular heteroatoms, and said heteroalicyclic optionally comprising an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R 60 ;
  • R 14 is selected from -H, -NO 2 , -NH 2 , -N(R 3 )R 3 , -CN, -OR 3 , optionally substituted C 1-6 alkyl, optionally substituted heteroalicyclyl C 1-6 alkyl, optionally substituted aryl, optionally substituted aryl C 1-6 alkyl and optionally substituted heteroalicyclic;
  • R 60 is selected from -H, halogen, trihalomethyl, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 3 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl C 1-6 alkyl, and optionally substituted aryl C 1-6 alkyl; two of R 60 , when attached to a non-aromatic carbon, can be oxo; P 1 is a suitable leaving group; and
  • P 2 is selected from -H, a metal, and a group removed in-situ when combining XXII and XXIII to make XXI.
  • Ar is para- phenylene as defined by the substitution pattern of -Z- and -B-L-T about said phenylene.
  • R 25 is selected from halogen, trihalomethyl, oxo, -CN, -NO 2 , -NH 2 , -OR 3 , -NR 3 R 3 , -S(O) 0-2 R 3 , -SO 2 NR 3 R 3 , -CO 2 R 3 , -C(O)NR 3 R 3 , -N(R 3 )SO 2 R 3 , -N(R 3 )C(O)R 3 , -N(R 3 )CO 2 R 3 , -C(O)R 3 , optionally substituted aryl, optionally substituted aryl C 1-6 alkyl, heteroaryl C 1-6 alkyl, and optionally substituted C 1-6 alkyl; two of R 25 ,
  • R 2 is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.
  • R 70 is selected from -H, -NO 2 , -NH 2 , and -NR 3 R 3 ; provided when Z is -N(R 5 )- that R 5 is selected from -H, C 1-3 alkyl, and aryl C 1-3 alkyl;
  • P 1 is selected from halogen, optionally substituted alkyl-S(0)o- 2 -, optionally substituted arylsulfonate, optionally substituted alkylsulfonate, a group containing boron, an azide, a group containing phosphorus, and a metal; and P 2 is selected from -H and a metal.
  • the process is according to paragraph [Oil 1], wherein the base is selected from an organic base, an inorganic base, and a combination of an organic base and an inorganic base.
  • the process is according to paragraph [0112], wherein the base is selected from 2,6-lutidine, 4-N,N-dimethylammopyridine, and a metal carbonate.
  • the process is according to paragraph [0114], wherein the solvent is an organic solvent.
  • the process is according to paragraph [0115], wherein one molar equivalent of XXIIa is combined with between about one quarter and four molar equivalents of XXIIIa.
  • the process is according to paragraph [0124], wherein the non- aromatic solvent comprises a functional group selected from an amide, and ether, a nitrile, a halide, an ester, an amine, and a ketone.
  • the non- aromatic solvent comprises a functional group selected from an amide, and ether, a nitrile, a halide, an ester, an amine, and a ketone.
  • the process is according to paragraph [0125], wherein the non- aromatic solvent is N,N-dimethylacetamide.
  • the process is according to paragraph [0126], wherein the base is potassium carbonate.
  • the process is according to paragraph [0138], wherein said mixture is heated to between about 150°C and 200°C for between about fifteen and twenty hours.
  • the process is according to any of paragraphs [0111] - [0139], wherein a compound of formula XXIIb is substituted for the compound of formula XXIIa, and a compound of formula XXIIIc is substituted for the compound of formula XXIIIa, in order to make a compound of formula XXIc 3 respectively,
  • R 50 , R 20 and R 2 are as defined above.
  • the process is according to paragraph [0141], wherein R 2 , if present, is fluorine.
  • R 2 if present, is up to two fluorines ortho to the oxygen of the phenylene to which R 2 is attached.
  • a substituent "R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • the "R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • the two "R's" may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively.
  • C 8 alkyl may refer to an r ⁇ -octyl, KO-octyl, cyclohexylethyl, and the like.
  • Lower alkyl refers to alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like.
  • Higher alkyl refers to alkyl groups containing more that eight carbon atoms.
  • alkyl groups are those of C 20 or below.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include c- propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
  • alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like.
  • alkyl residue having a specific number of carbons all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either “butyl” or “C 4 alkyl” is meant to include 77-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2- yne radicals; and for example, "propyl” or “C 3 alkyl” each include r ⁇ -propyl, propenyl, and isopropyl.
  • Alkylene refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to ten carbon atoms, for example, methylene, ethylene, propylene, r ⁇ butylene and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, fully saturated. Examples of alkylene include ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), dimethylpropylene (-CH 2 C(CHs) 2 CH 2 -), and cyclohexylpropylene (-CH 2 CH 2 CH(C 6 H 13 )).
  • Alkylidene refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to ten carbon atoms, for example, ethylidene, propylidene, ⁇ -butylidene, and the like. Alkylidene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, double bond unsaturation. The unsaturation present includes at least one double bond.
  • Alkylidyne refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms having from two to ten carbon atoms, for example, propylid-2-ynyl, n-butylid-1-ynyl, and the like. Alkylidyne is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, triple bond unsaturation. The unsaturation present includes at least one triple bond.
  • alkylene when optionally substituted, may contain alkyl substitution which itself contains unsaturation.
  • 2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains an ⁇ -butylid-3-ynyl radical with a vinyl substituent at the 2-position of said radical.
  • Alkoxy or “alkoxyl” refers to the group -O-alkyl, for example including from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons.
  • Substituted alkoxy refers to the group -O-(substituted alkyl), the substitution on the alkyl group generally containing more than only carbon (as defined by alkoxy).
  • One exemplary substituted alkoxy group is "polyalkoxy” or -O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as -OCH 2 CH 2 OCH 3 , and glycol ethers such as polyethyleneglycol and -0(CH 2 CH 2 O) x CHs, where x is an integer of between about two and about twenty, in another example, between about two and about ten, and in a further example between about two and about five.
  • Another exemplary substituted alkoxy group is hydroxyalkoxy or -OCH 2 (CH 2 ) y OH, where y is for example an integer of between about one and about ten, in another example y is an integer of between about one and about four.
  • Acyl refers to groups of from one to ten carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons.
  • ⁇ -Amino Acids refer to naturally occurring and commercially available amino acids and optical isomers thereof. Typical natural and commercially available ⁇ -amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline.
  • a “side chain of an ⁇ -amino acid” refers to the radical found on the ⁇ -carbon of an ⁇ -amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like. [0163J "Amino" refers to the group -NH 2 .
  • Substituted amino refers to the group -N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example, diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino.
  • Aryl refers to aromatic six- to fourteen-membered carbocyclic ring, for example, benzene, naphthalene, indane, tetralin, fluorene and the like, univalent radicals.
  • univalent radicals the aforementioned ring examples are named, phenyl, naphthyl, indanyl, tetralinyl, and fluorenyl.
  • Arylene generically refers to any aryl that has at least two groups attached thereto.
  • phenylene refers to a divalent phenyl ring radical.
  • a phenylene thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto.
  • Arylalkyl refers to a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. Both the aryl, and the corresponding alkylene, alkylidene, or alkylidyne radical portion of an arylalkyl group may be optionally substituted.
  • “Lower arylalkyl” refers to an arylalkyl where the "alkyl" portion of the group has one to six carbons; this can also be refered to as C 1-6 arylalkyl.
  • Exo-alkenyl refers to a double bond that emanates from an annular carbon, and is not within the ring system, for example the double bond depicted in the formula below.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups.
  • saturated carbons of such fused groups i.e. saturated ring structures
  • fused-polycyclic or "fused ring system” refers to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures.
  • fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems.
  • fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene.
  • a spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Haloalkyl and haloaryl refer genetically to alkyl and aryl radicals that are substituted with one or more halogens, respectively.
  • dihaloaryl refers to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3 -fluorophenyl is within the scope of dihaloaryl.
  • Heteroarylene generically refers to any heteroaryl that has at least two groups attached thereto.
  • pyridylene refers to a divalent pyridyl ring radical.
  • a pyridylene thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto.
  • Heteroatom refers to O, S, N, or P.
  • Heterocyclyl refers to a stable three- to fifteen-membered ring radical that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems; and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states.
  • the group -S(O) 0-2 - refers to -S- (sulf ⁇ de), -S(O)- (sulfoxide), and -SO 2 - (sulfone).
  • nitrogens particularly but not exclusively, those defined as annular aromatic nitrogens, are meant to include their corresponding JV-oxide form, although not explicitly defined as such in a particular example.
  • annular nitrogen atoms may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic.
  • heterocyclyl radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepiny
  • Heteroalicyclic refers specifically to a non-aromatic heterocyclyl radical.
  • a heteroalicyclic may contain unsaturation, but is not aromatic.
  • Heteroaryl refers specifically to an aromatic heterocyclyl radical.
  • Heterocyclylalkyl refers to a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include (4-methylpiperazin-l-yl) methyl, (morpholin-4-yl) methyl, (pyridine-4-yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methylpiperazin-l-yl)-2-butenyl, and the like. Both the heterocyclyl, and the corresponding alkylene, alkylidene, or alkylidyne radical portion of a heterocyclylalkyl group may be optionally substituted.
  • “Lower heterocyclylalkyl” refers to a heterocyclylalkyl where the “alkyl” portion of the group has one to six carbons.
  • “Heteroalicyclylalkyl” refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic; and “heteroarylalkyl” refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is aromatic
  • Such terms may be described in more than one way, for example, “lower heterocyclylalkyl” and “heterocyclyl C 1-6 alkyl” are equivalent terms.
  • Optionally substituted refers to all subsequent modifiers in a term, for example in the term “optionally substituted 3TyIC 1-8 alkyl,” optional substitution may occur on both the “C 1-8 alkyl” portion and the “aryl” portion of the molecule; and for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum. A list of exemplary optional substitution are listed below in the definition of "substituted.”
  • saturated bridged ring system refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-lH-indene, 7-aza-bicyclo[2.2.1]heptane, and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system.”
  • Spirocyclyl or "spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of a saturated bridged ring system (rings B and B'), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.
  • a spirocyclyl can be carbocyclic or heteroalicyclic.
  • Substituted alkyl, aryl, and heterocyclyl refer respectively to alkyl, aryl, and heterocyclyl, wherein one or more (for example up to about five, in another example, up to about three) hydrogen atoms are replaced by a substituent independently selected from: optionally substituted alkyl (for example, fluoromethyl), optionally substituted aryl (for example, 4-hydroxyphenyl), optionally substituted arylalkyl (for example, 1-phenyl-ethyl), optionally substituted heterocyclylalkyl (for example, l-pyridin-3-yl-ethyl), optionally substituted heterocyclyl (for example, 5-chloro-pyridin-3-yl or l-methyl-piperidin-4-yl), optionally substituted alkoxy, alkylenedioxy (for example methylenedioxy), optionally substituted amino (for example, alkylamino and dialkylamino), optionally substituted amidin
  • Suitable leaving group is defined as the term would be understood by one of ordinary skill in the art; that is, a carbon with such a group attached, upon reaction wherein a new bond is to be formed, loses such a group upon formation of the new bond.
  • the invention pertains particularly with respect convergent synthesis, to reactions where such a leaving group is bonded to a reaction partner that is aromatic, undergoes a bond- forming reaction and remains aromatic.
  • a typical example of such a reaction is a nucleophilic aromatic substitution reaction, as would be understood by one of ordinary skill in the art.
  • the invention is not limited to such mechanistic restrictions; for example, reactions where there is, for example, an insertion reaction (for example by a transition metal) into the bond between the aromatic reaction partner and its leaving group followed by reductive coupling can also be used within the scope of the invention.
  • suitable leaving groups include halogens, optionally substituted aryl or alkyl sulfonates, phosphonates, azides, RS(0)o -2 - where R is, for example optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • Sulfanyl refers to the groups: -S-(optionally substituted alkyl), -S-(optionally substituted aryl), and -S-(optionally substituted heterocyclyl).
  • Sulfinyl refers to the groups: -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-optionally substituted aryl), and -S(O)-(optionally substituted heterocyclyl).
  • Sulfonyl refers to the groups: -S(O 2 )-H, -S(O 2 )-(optionally substituted alkyl), -S( ⁇ 2 )-optionally substituted aryl), -S(O 2 )-(optionally substituted heterocyclyl), -S(O 2 )-(optionally substituted alkoxy), -S(O 2 )-optionally substituted aryloxy), and -S(O 2 )-(optionally substituted heterocyclyloxy).
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • Some of the compounds of the invention may have imino, amino, oxo or hydroxy substiruents off aromatic heterocyclyl systems.
  • imino, amino, oxo or hydroxy substituents may exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.
  • the compounds of the invention may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure.
  • the compounds of the invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
  • a particular group with its bonding structure is denoted as being bonded to two partners; that is, a divalent radical, for example, -OCH 2 -, then it is understood that either of the two partners may be bound to the particular group at one end, and the other partner is necessarily bound to the other end of the particular group, unless stated explicitly otherwise.
  • divalent radicals are not to be construed as limited to the depicted orientation, for example "-OCH 2 -" is meant to mean not only "-OCH 2 -" as drawn, but also "-CH 2 O-.”
  • optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Enantiomers may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomers enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
  • Patient for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human.
  • Kinase-dependent diseases or conditions refer to pathologic conditions that depend on the activity of one or more protein kinases.
  • Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion.
  • Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).
  • phosphatases can also play a role in "kinase-dependent diseases or conditions" as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example protein substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family. In any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (i.e.
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Carrier refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancrea
  • “Pharmaceutically acceptable acid addition salt” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like
  • organic acids such as acetic acid, trifluoro
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylarnme, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.
  • salts of primary, secondary, and tertiary amines substituted amines including naturally occurring substituted amines, cyclic
  • organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
  • Prodrug refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety.
  • Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) wherein the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
  • Methodabolite refers to . the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation).
  • the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken.
  • An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.
  • Treating covers the treatment of a disease-state in a human, which disease-state is characterized by abnormal cellular proliferation, and invasion and includes at least one of: (i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it; (ii) inhibiting the disease-state, i.e., arresting its development; and (iii) relieving the disease-state, i.e., causing regression of the disease-state.
  • Such suitable x-ray quality crystals can be used as part of a method of identifying a candidate agent capable of binding to and modulating the activity of kinases.
  • Such methods may be characterized by the following aspects: a) introducing into a suitable computer program, information defining a ligand binding domain of a kinase in a conformation (e.g.
  • aspects a-d are not necessarily carried out in the aforementioned order. Such methods may further entail: performing rational drug design with the model of the three-dimensional structure, and selecting a potential candidate agent in conjunction with computer modeling.
  • Such methods may further entail: employing a candidate agent, so-determined to fit spatially into the ligand binding domain, in a biological activity assay for kinase modulation, and determining whether said candidate agent modulates kinase activity in the assay. Such methods may also include administering the candidate agent, determined to modulate kinase activity, to a mammal suffering from a condition treatable by kinase modulation, such as those described above.
  • compounds of the invention can be used in a method of evaluating the ability of a test agent to associate with a molecule or molecular complex comprising a ligand binding domain of a kinase.
  • a method may be characterized by the following aspects: a) creating a computer model of a kinase binding pocket using structure coordinates obtained from suitable x-ray quality crystals of the kinase, b) employing computational algorithms to perform a fitting operation between the test agent and the computer model of the binding pocket, and c) analyzing the results of the fitting operation to quantify the association between the test agent and the computer model of the binding pocket.
  • Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
  • Compositions of the invention may be used in combination with anticancer or other agents that are generally administered to a patient being treated for cancer.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example,
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
  • the compounds of the invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • the protein is bound to a support, and a compound of the invention is added to the assay.
  • the compound of the invention is bound to the support and the protein is added.
  • Classes of candidate agents among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells.
  • assays may be used for this purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.) and the like.
  • the determination of the binding of the candidate agent to, for example, c-Met, KDR, c-Kit, flt-3, or flt-4 protein may be done in a number of ways.
  • the candidate agent (the compound of the invention) is labeled, for example, with a fluorescent or radioactive moiety and binding determined directly.
  • a labeled agent for example a compound of the invention in which at least one atom has been replaced by a detectable isotope
  • washing off excess reagent for example a compound of the invention in which at least one atom has been replaced by a detectable isotope
  • Various blocking and washing steps may be utilized as is known in the art.
  • labeled herein is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, etc.
  • Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc.
  • the complementary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above.
  • the label can directly or indirectly provide a detectable signal.
  • c-Met, KDR, c-Kit, flt-3, or flt-4 protein may be labeled at tyrosine positions using 125 I, or with fluorophores.
  • more than one component may be labeled with different labels; using 125 I for the proteins, for example, and a fluorophor for the candidate agents.
  • the compounds of the invention may also be used as competitors to screen for additional drug candidates.
  • "Candidate bioactive agent” or “drug candidate” or grammatical equivalents as used herein describe any molecule, e.g., protein, oligopeptide, small organic molecule, polysaccharide, polynucleotide, etc., to be tested for bioactivity. They may be capable of directly or indirectly altering the cellular proliferation phenotype or the expression of a cellular proliferation sequence, including both nucleic acid sequences and protein sequences. In other cases, alteration of cellular proliferation protein binding and/or activity is screened. In the case where protein binding or activity is screened, some embodiments exclude molecules already known to bind to that particular protein.
  • exogenous agents include candidate agents, which do not bind the target protein in its endogenous native state, termed herein as "exogenous" agents.
  • exogenous agents further exclude antibodies to c- Met, KDR, c-Kit, flt-3, or flt-4.
  • Candidate agents can encompass numerous chemical classes, though typically they are organic molecules having a molecular weight of more than about 100 daltons and less than about 2,500 daltons.
  • Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding and lipophilic binding, and typically include at least an amine, carbonyl, hydroxyl, ether, or carboxyl group, for example at least two of the functional chemical groups.
  • the candidate agents often comprise cyclical carbon or heterocyclyl structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups.
  • Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof.
  • Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification to produce structural analogs.
  • the binding of the candidate agent is determined through the use of competitive binding assays.
  • the competitor is a binding moiety known to bind to c-Met, KDR, c-Kit, flt-3, or flt-4, such as an antibody, peptide, binding partner, ligand, etc.
  • the candidate agent is labeled. Either the candidate agent, or the competitor, or both, is added first to for example c-Met, KDR, c-Kit, flt-3, or flt-4 for a time sufficient to allow binding, if present. Incubations may be performed at any temperature that facilitates optimal activity, typically between 4°C and 4O°C
  • Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high throughput screening. Typically between 0.1 and 1 hour will be sufficient. Excess reagent is generally removed or washed away. The second component is then added, and the presence or absence of the labeled component is followed, to indicate binding.
  • the competitor is added first, followed by the candidate agent.
  • Displacement of the competitor is an indication the candidate agent is binding to c-Met, KDR, c-Kit, flt-3, or flt-4 and thus is capable of binding to, and potentially modulating, the activity of the c-Met, KDR, c-Kit, flt-3, or flt-4.
  • either component can be labeled.
  • the presence of label in the wash solution indicates displacement by the agent.
  • the candidate agent is labeled, the presence of the label on the support indicates displacement.
  • the candidate agent is added first, with incubation and washing, followed by the competitor.
  • the absence of binding by the competitor may indicate the candidate agent is bound to c-Met, KDR, c-Kit, flt-3, or flt-4 with a higher affinity.
  • the candidate agent is labeled, the presence of the label on the support, coupled with a lack of competitor binding, may indicate the candidate agent is capable of binding to c-Met, KDR, c-Kit, flt-3, or flt-4.
  • c-Met, KDR, c-Kit, flt-3, or flt-4 it may be of value to identify the binding site of c-Met, KDR, c-Kit, flt-3, or flt-4. This can be done in a variety of ways. In one embodiment, once c-Met, KDR, c-Kit, flt-3, or flt-4 has been identified as binding to the candidate agent, the c-Met, KDR, c-Kit, flt-3, or flt-4 is fragmented or modified and the assays repeated to identify the necessary components for binding.
  • Modulation is tested by screening for candidate agents capable of modulating the activity of c-Met, KDR, c-Kit, flt-3, or flt-4 comprising the steps of combining a candidate agent with c-Met, KDR, c-Kit, flt-3, or flt-4, as above, and determining an alteration in the biological activity of the c-Met, KDR, c-Kit, flt-3, or flt-4.
  • the candidate agent should both bind to (although this may not be necessary), and alter its biological or biochemical activity as defined herein.
  • the methods include both in vifro screening methods and in vivo screening of cells for alterations in cell viability, morphology, and the like.
  • differential screening may be used to identify drug candidates that bind to native c-Met, KDR, c-Kit, flt-3, or flt-4, but cannot bind to modified c-Met, KDR, c-Kit, flt-3, or flt-4.
  • Positive controls and negative controls may be used in the assays. For example, all control and test samples are performed in at least triplicate to obtain statistically significant results. Incubation of samples is for a time sufficient for the binding of the agent to the protein. Following incubation, samples are washed free of non-specifically bound material and the amount of bound, generally labeled agent determined. For example, where a radiolabel is employed, the samples may be counted in a scintillation counter to determine the amount of bound compound.
  • reagents may be included in the screening assays. These include reagents like salts, neutral proteins, e.g., albumin, detergents, etc which may be used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Also reagents that otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc., may be used. The mixture of components may be added in any order that provides for the requisite binding.
  • Scheme 1 depicts a general synthetic route for compounds of the invention and is not intended to be limiting. More specifically, Scheme 1 depicts synthesis of quinoline compounds. Specific examples are described subsequently to these general synthetic descriptions so as to allow one skilled in the art to make and use quinolines of the invention.
  • Scheme 1 shows a general route used to make exemplary quinolines of the invention.
  • compound 9 contains an alkyl group, R 1 , a protecting group, P.
  • the arrangement of the protected and alkylated phenolic oxygens may vary from the pattern depicted in compound 9.
  • Compound 9 is nitrated to provide compound 10.
  • the nitro group of compound 10 is reduced to give aniline 11.
  • Compound 11 is treated, for example, with ethyl formate under basic conditions followed by acidification and isolation to form 4-hydroxy quinoline 12.
  • Quinoline 12 may be converted to compounds of the invention in a number of ways.
  • the 4-oxygen is used as a nucleophile in a nucleophilic aromatic substitution reaction to form quinoline-aryl-ether 13.
  • compound 13 is further derivatized, via removal of protecting group P, to afford compound 14.
  • the 7-hydroxy of compound 14 is alkylated, for example with electrophile E, to provide a compound of the invention.
  • compounds 12, 13, and 14 may also be compounds of the invention according to formula I.
  • the 4-hydroxy quinoline compound 12 are converted to a corresponding 4-nitrogen or 4-sulfur quinoline using chemistry known in the art to make compounds of the invention, or alternatively the corresponding 4-nitrogen or 4-sulfur quinolines are made via routes analogous to that depicted in Scheme 1.
  • Scheme 1 is illustrative of quinolines having oxygen substitution at their respective 6- and 7-positions; the invention is not so limited, but rather is intended to encompass quinolines not necessarily having substitution, oxygen or otherwise, at their respective 6- or 7-positions.
  • Schemes 2 and 3 depict generalized synthetic routes to show the process of the invention to make compounds of formua XXI and is not intended to be limiting. More specifically, Schemes 2 and 3 depict convergent syntheses of quinoline compounds as described herein. Specific examples are described subsequently to this general synthetic description so as to allow one of ordinary skill in the art to practice the invention.
  • a benzoic ester 16 for example, where R is typically but not necessarily a methyl radical and R 1 is typically but not necessarily one or more alkoxy or hydroxy groups.
  • R 1 within Scheme 2 is a hydroxyl which is converted (or protected )via one or more steps to a group important to the activity of the compounds as described as kinase modulators (in the case that -OH itself is desired in the final compound, then deprotection affords the -OH, vide supra).
  • this group is complete once the synthesis of XXII is complete.
  • Radical R 70 is in accord with formula XXI.
  • Introduction of 4-position functionality is carried out by methods known in the art.
  • 4-one 18 is converted to XXII, where "P 1 " represents a suitable leaving group (in accord with formula XXI), e.g. chlorine (via dehydration/chlorination of 18 to give XXII).
  • a 4-hydroxy analog is converted to a sulfonyl ester, e.g. the trifluoromethane sulfonate.
  • Sc eme 3 shows a general route used to make compounds of formula XXIII.
  • aromatic compound 19, where "X" is a leaving group, such as fluorine and "E” is an electron withdrawing group such as nitro is converted to 20 by reaction with a range of nucleophiles, e.g. amines, alcohols, and thiols (where "Z” is oxygen, nitrogen (substituted or not), or sulfur).
  • "R” represents a removable group, for example benzyl.
  • group "E” is either left “as is” or converted at some subsequent stage to a derivative thereof.
  • E is converted to B', a precursor to B in accord with formula XXI, to make 21.
  • B' could might be an amino group, made via reduction of the nitro group.
  • Structure 21 may be further derivitized by synthesis of -B-L-T in accord with formula XXI.
  • scheme 3 this is depicted as a serial process whereby L', a precursor to L, is introduced to give 22, followed by introduction of T' (a precursor to T) to give 23.
  • T' a precursor to T
  • -L-T is preformed and appended to B.
  • Compound 23 is converted to XXIII via conversion of T' to T and introduction of P 2 (for example, when R is benzyl, removal of the benzyl after completion of -B-L-T).
  • one aspect of the invention encompasses combination of XXII and XXIII to make compounds of formula XXI. Because of the diversity and complexity of compounds described for kinase modulation (vide supra), methods of the invention provide advantages to serial synthesis.
  • reaction mixture was then cooled to 0° C and 37% solution of formaldehyde in water was added (0.2 g, 7.8 mmol, 2.0 eq). While keeping the temperature at O 0 C Na(OAc) 3 BH was added (4.4g, 20.7 mmol, 3.0 eq). After 1 hour the pH was adjusted to 10 and the aqueous was extracted 2 x DCM (100 ml). Removal of the DCM resulted in a white solid.
  • the Pd/C (10% by weight) (0.090 g, 20% by weight) was then added.
  • a balloon filled with H 2 was connected to the flask after the nitrogen was vacuumed out.
  • the reaction mixture was stirred at room temperature for 4 hours.
  • the palladium was filtered out through Celite, and the filtrated was collected and concentrated via rotary evaporation.
  • the resulting oil-like product was taken up into 5 mL of water and 1 mL of acetonitrile and lyophilized to yield 6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine as a light brown solid (0.411 g, 98.1%).
  • Trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolm-4-yl ester.
  • DCM dimethylaminopyridme
  • 2,6-lutidine 62 mL, 534 mmol.
  • the mixture was cooled to -2O°C by controlled addition of dry ice to an acetone bath.
  • Trifluoromethanesulfonyl chloride 37 mL, 350 mmol was added drop wise to the cooled solution with magnetic stirring over 25 minutes.
  • Trifluoromethanesulfonyl chloride 14 mL, 132 mmol was added dropwise to the solution. After addition was complete, the mixture was stirred ice bath for 2 to 3 hrs. On LC/MS indicating the reaction completion, the reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (250 mL). The resulting slurry was stirred for 30 min before adding water (1 L). The solids were isolated by filtration, followed by a water wash.
  • Ethyl [Y4-benzyloxy-3 -fluorophenvl)amino] (oxo)acetate Ethyl oxalyl chloride (44 mL, 390 mmol) was added to a solution of 4-benzyloxy-3-fluoroaniline (44 g, 180 mmol) in diisopropylethylamine (69 mL, 400 mmol) and stirred at room temperature for 15 min. The mixture was extracted with dichloromethane and washed with water and brine.
  • bridged bicyclics with appended leaving groups for use as, for example, alkylating agents.
  • these alkylating agents are used, for example, to alkylate the quinolines on the 6- or 7-oxygens to make compounds of the invention.
  • the invention is not limited to alkylation chemistry to append such bridged bicyclics, but rather the aforementioned description is meant only to be illustrative of an aspect of the invention.
  • reaction mixture was diluted with ethyl acetate (10OmL), washed with saturated aqueous sodium bicarbonate (2 x 5OmL) then brine (5OmL), and dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography on silica (1:1 hexane/ethyl acetate) provided 1.44g (61% yield) of l,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D- fructose ethylene glycol acetal as a colorless solid.
  • l,4:3,6-dianhydro-2-deoxy-2-methylidene-D- ⁇ ra5zno-hexitol To a solution of l,4:3,6-dianhydro-2-deoxy-2-methylidene-5-C>-(phenylcarbonyl)-D- ⁇ r ⁇ mo-hexitol (329mg, 1.34 mmol) in methanol (1OmL) was added 50% aqueous sodium hydroxide (95mg, 1.19 mmol) and the mixture was stirred at room temperature for 30 minutes.
  • Methyl 3,6-anhvdro-2-O-methyl-5-(9-(phenylcarbonyl)- ⁇ -L-glucofuranoside A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)- ⁇ -L-glucofuranoside (1.03g, 3.7 mmol), silver (T) oxide (0.85g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 6O°C for 1 hour.
  • reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (1Og) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)- ⁇ -L-glucofuranoside as a colorless oil, 0.82g, 76% yield.
  • Methyl 3 ,6-anhydro-2-O-methyl- ⁇ -D-idofuranoside A solution of methyl 3,6- anhydro-2-C>-methyl-5-O-(phenylcarbonyl)- ⁇ -L-glucofuranoside (820mg, 3.1mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (1OmL) was stirred at room temperature for 30 minutes.
  • Methyl 3,6-arihydro-2-O-methyl- ⁇ -D-idofuranoside (420 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at O°C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and the resulting mixture was stirred at O°C for 1 hour then at room temperature for 2 hours.
  • Methyl 3,6-anhydro-2-O-methyl-5-(9-(methylsulfonyl)- ⁇ -L-glucof ⁇ ranoside A solution of methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)- ⁇ -L-glucofuranoside (230mg, 0.92 mmol) and 50% sodium hydroxide (74 mg, 0.92 mmol) in methanol (5 mL) was stirred at room temperature for 30 minutes.
  • the mixture was adsorbed on silica gel (2g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to afford a colorless oil which was employed directly in the next step, 140 mg, 0.72 mmol, 95% yield.
  • the alcohol was dissolved in dichloromethane (5 mL) and pyridine (121 ⁇ L, 1.03 mmol) was added at O°C. Methanesulfonyl chloride (27 ⁇ L, 0.88 mmol) was added and the resulting mixture was stirred at O°C for 1 hour then at room temperature for 2 hours.
  • the mixture was then adsorbed on silica gel (5g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) and the alcohol intermediate, 390 mg, 70% yield, was used immediately in the next step.
  • the alcohol was dissolved in dichloromethane (10 mL) and pyridine (0.32 mL) at O°C. Methanesulfonyl chloride (0.12 mL) was added and the resulting mixture was stirred at O°C for 1 hour then at room temperature for 2 hours.
  • Hexahydro-1 H-pyrrolo[2,l-c][l,4]oxazin-3-yhnethyl acetate (2.36 g, 11.9 mmol) was treated with sodium methoxide (25 wt% solution in methanol; 2.7 mL) for 0.5 h. The mixture was cooled in an ice bath and a solution of 4M HCl in 1,4-dioxane (3 mL, 12.0 mmol) was added slowly.
  • Octahvdro-2H-quinolizin-3-ylmethyl methanesulfonate Octahydro-2H-quinolizin- 3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) was added at 0°C followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution.
  • the resulting mixture was heated to 200°C for 0.5 h then poured carefully onto wet ice, which was allowed to melt.
  • the aqueous solution was carefully made basic using solid sodium bicarbonate and the resulting mixture was filtered using water and 10% methanol in ethyl acetate as eluent. The layers were separated and the aqueous layer was extracted with 10% methanol in ethyl acetate.
  • Methanesulfonyl chloride (0.11 mL, 1.42 mmol) was added slowly and mixture was allowed to warm to room temperature and stirred for Ih. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 35.1 mg (89%) of 1,1- dimethylethyl (3 -endo)-3 - ⁇ 2- [(methylsulfonyl)oxy] ethyl ⁇ - 8-azabicyclo [3.2.1] octane-8 - carboxylate, which was carried forward for alkylation without purification.
  • kinase assays were performed by measurement of incorporation of ⁇ - 33 P ATP into immobilized myelin basic protein (MBP).
  • MBP myelin basic protein
  • High binding white 384 well plates (Greiner) were coated with MBP (Sigma #M-1891) by incubation of 60ul/well of 20 ⁇ g/ml MBP in Tris-buffered saline (TBS; 5OmM Tris pH 8.0, 138mM NaCl, 2.7mM KCl) for 24 hours at 4° C. Plates were washed 3X with lOO ⁇ l TBS.
  • kinase reactions were carried out in a total volume of 34 ⁇ l in kinase buffer (5mM Hepes pH 7.6, 15mM NaCl, 0.01% bovine gamma globulin (Sigma #1-5506), 1OmM MgCl 2 , ImM DTT, 0.02% TritonX-100).
  • Compound dilutions were performed in DMSO and added to assay wells to a final DMSO concentration of 1%. Each data point was measured in duplicate, and at least two duplicate assays were performed for each individual compound determination. Enzyme was added to final concentrations of 1OnM or 2OnM, for example.
  • the above assay procedure can be used to determine the IC 50 for inhibition and/or the inhibition constant, K;.
  • the IC 50 is defined as the concentration of compound required to reduce the enzyme activity by 50% under the conditions of the assay.
  • Exemplary compositions have IC 50 5 S of, for example, less than about 100 ⁇ M, less than about 10 ⁇ M, less than about 1 ⁇ M, and further for example having IC 5 o's of less than about 100 nJVl, and still further, for example, less than about 10 nM.
  • the Kj for a compound may be determined from the IC 50 based on three assumptions. First, only one compound molecule binds to the enzyme and there is no cooperativity.
  • the concentrations of active enzyme and the compound tested are known (i.e., there are no significant amounts of impurities or inactive forms in the preparations).
  • the enzymatic rate of the enzyme-inhibitor complex is zero.
  • the rate (i.e., compound concentration) data are fitted to the equation:
  • V is the observed rate
  • V max is the rate of the free enzyme
  • Io is the inhibitor concentration
  • E 0 is the enzyme concentration
  • Ka is the dissociation constant of the enzyme-inhibitor complex.
  • ATP concentrations for each assay are selected to be close to the Michaelis-Menten constant (K M ) for each individual kinase.
  • K M Michaelis-Menten constant
  • Dose- response experiments are performed at 10 different inhibitor concentrations in a 384-well plate format. The data are fitted to the following four-parameter equation:
  • Y Min + (Max - Min) / (1 + (X/IC 50 ) ⁇ H)
  • Y is the observed signal
  • X is the inhibitor concentration
  • Min is the background signal in the absence of enzyme (0% enzyme activity)
  • Max is the signal in the absence of inhibitor (100% enzyme activity)
  • IC 50 is the inhibitor concentration at 50% enzyme inhibition
  • H represents the empirical Hill's slope to measure the cooperativity. Typically H is close to unity.
  • c-Met biochemical activity was assessed using a Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format as described above. Again, kinase activity was measured as the percent ATP remaining following the kinase reaction. Remaining ATP was detected by luciferase-luciferm-coupled chemiluminescence.
  • LCCA Luciferase-Coupled Chemiluminescent Kinase assay
  • reaction was initiated by mixing test compounds, l ⁇ M ATP, l ⁇ M poly- EY and 1OnM c-Met (baculovirus expressed human c-Met kinase domain P948-S1343) in a 2OuL assay buffer (2OmM Tris-HCL pH7.5, 1OmM MgCl 2 , 0.02% Triton X-100, 10OmM DTT, 2mM MnCl 2 ). The mixture is incubated at ambient temperature for 2hours after which 2OuL luciferase-luciferin mix is added and the chemiluminescent signal read using a Wallac Victor 2 reader.
  • test compounds l ⁇ M ATP, l ⁇ M poly- EY and 1OnM c-Met (baculovirus expressed human c-Met kinase domain P948-S1343) in a 2OuL assay buffer (2OmM Tris-HCL pH7.5, 1OmM MgCl 2 , 0.0
  • the luciferase-luciferin mix consists of 50 rnM HEPES, pH 7.8, 8.5ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-IOO 3 0.25 mg/mL coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase.
  • KDR biochemical activity was assessed using a Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format. Kinase activity was measured as the percent ATP remaining following the kinase reaction. Remaining ATP was detected by luciferase-luciferin-coupled chemiluminescence.
  • LCCA Luciferase-Coupled Chemiluminescent Kinase assay
  • reaction was initiated by mixing test compounds, 3 ⁇ M ATP, 1.6 ⁇ M poly-EY and 5 nM KDR (baculovirus expressed human KDR kinase domain D807-V1356) in a 2OuL assay buffer (2OmM Tris- HCL pH7.5, 1OmM MgCl 2 , 0.01% Triton X-100, ImM DTT, 3mM MnCl 2 ).
  • 2OuL luciferase-luciferin mix is added and the chemiluminescent signal read using a Wallac Victor 2 reader.
  • the luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0.25 mg/mL coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase.
  • Biochemical activity for flt-4 was assessed using an Alphascreen Tyrosine Kinase protocol.
  • AlphaScreenTM (Perkin Elmer) technology is a proximity assay employing microparticles. Singlet oxygen derived from a donor bead following laser excitation results in chemiluminescence when in proximity (100 A) to an acceptor bead due to biomolecular interactions.
  • donor beads coated with streptavidin and acceptor beads coated with PYlOO anti-phosphotyrosine antibody were used (Perkin Elmer).
  • Biotinylated poly(Glu,Tyr) 4:1 was used as the substrate.
  • Substrate phosphorylation was measured by addition of donor/acceptor beads by chemiluminescence following donor-acceptor bead complex formation.
  • Test compounds 5 ⁇ M ATP, 3 nM biotinylated poly(Glu, Tyr) and 1 nM Flt-4 (baculovirus expressed human Flt-4 kinase domain D725-R1298) were combined in a volume of 20 ⁇ L in a 384- well white, medium binding microtiter plate (Greiner). Reaction mixtures were incubated for 1 hr at ambient temperature.
  • Biochemical activity for flt-3 was assessed using a Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format. Kinase activity was measured as the percent ATP remaining following the kinase reaction. Remaining ATP was detected by luciferase-luciferin-coupled chemiluminescence.
  • LCCA Luciferase-Coupled Chemiluminescent Kinase assay
  • the reaction was initiated by mixing test compounds, 5 ⁇ M ATP, 3 ⁇ M poly-EY and 5 nM Flt-3 (baculovirus expressed human Flt-3 kinase domain R571-S993) in a 2OuL assay buffer (2OmM Tris- HCL pH7.5, 1OmM MgCl 2 , 0.01% Triton X-100, ImM DTT, 2mM MnCl 2 ).
  • the mixture is incubated at ambient temperature for 3 hours after which 2OuL luciferase-luciferin mix is added and the chemiluminescent signal read using a Wallac Victor 2 reader.
  • the luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0.25 mg/mL coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase.
  • c-Kit biochemical activity was assessed using AlphaScreen TM (Perkin Elmer) technology, described above.
  • Test compounds, ATP, biotinylated poly(Glu, Tyr) and c- Kit kinase were combined in a volume of 20 ⁇ L in a 384-well white, medium binding microtiter plate (Greiner). Reaction mixtures were incubated for 1 hr at ambient temperature. Reactions were quenched by addition of 10 uL of 15-30 mg/mL AlphaScreen bead suspension containing 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20. After 16 hr incubation at ambient temperature plates were read using an AlphaQuest reader (Perkin Elmer).
  • exemplary compounds of the invention exhibit selectivity for any of c-Met, KDR, c-Kit, flt-3, and flt-4.
  • c-Met refers to hepatocyte growth factor receptor kinase
  • KDR refers to kinase insert domain receptor tyrosine kinase
  • flt-4 fins-like tyrosine kinase-4, representative of the FLK family of receptor tyrosine kinases
  • c-Kit also called stem cell factor receptor or steel factor receptor
  • flt-3 fins-like tyrosine kinase-3. Empty cells in the tables indicate lack of data only.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention provides compounds, which have activity for modulating protein kinase enzymatic activity and are potentially useful for modulating cellular activities such as, e.g., proliferation, differentiation, programmed cell death, migration and chemoinvasion. The present invention also provides compositions containing such compounds, and methods for producing and using such compounds and compositions.

Description

C-MET MODULATORS AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional Patent Application No. 60/669,207, filed April 6, 2005.
FIELD OF THE INVENTION
[0002] This invention relates to compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Even more specifically, the invention relates to quinolines which inhibit, regulate and/or modulate kinase receptor signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, methods of using them to treat kinase-dependent diseases and conditions, synthesis of the compounds as well as processes for formulating the compounds for pharmaceutical purposes.
BACKGROUND OF THE INVENTION
[0003] Improvements in the specificity of agents used to treat cancer is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms.
[0004] Protein kinases are enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell differentiation and proliferation; i.e., virtually all aspects of cell life in one-way or another depend on protein kinase activity. Furthermore, abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
[0005] Protein kinases can be categorized as receptor type or non-receptor type. Receptor- type tyrosine kinases have an extracellular, a transmembrane, and an intracellular portion, while non-receptor type tyrosine kinases are wholly intracellular.
[0006] Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily, designated the HER subfamily, is comprised of EGFR (HERl), HER2, HER3, and HER4. Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF- IR, and IR-R. The PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-Kit and FLK-II. Then there is the FLK family, which is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-I), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1). The PDGF and FLK families are usually considered together due to the similarities of the two groups. For a detailed discussion of the receptor- type tyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994, which is hereby incorporated by reference.
[0007] The non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of the non-receptor type of tyrosine kinases, see Bolen, Oncogene, 8:2025-2031 (1993), which is hereby incorporated by reference.
[0008] Since protein kinases and their ligands play critical roles in various cellular activities, deregulation of protein kinase enzymatic activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer. In addition to oncological indications, altered kinase signaling is implicated in numerous other pathological diseases. These include, but are not limited to: immunological disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases. Therefore, both receptor and non-receptor protein kinases are attractive targets for small molecule drug discovery.
[0009] One particularly attractive goal for therapeutic use of kinase modulation relates to oncological indications. For example, modulation of protein kinase activity for the treatment of cancer has been demonstrated successfully with the FDA approval of Gleevec® (imatmib mesylate, produced by Novartis Pharmaceutical Corporation of East Hanover, NJ) for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers (GIST). Gleevec is a c-Kit and AbI kinase inhibitor.
[0010] Modulation (particularly inhibition) of cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. Drug Disc Technol 2001 6, 1005-1024), is an attractive goal for development of small-molecule drugs. Anti- angiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularization, including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. As well, cell antiproliferative agents are desirable to slow or stop the growth of tumors.
[0011] One particularly attractive target for small-molecule modulation, with respect to antiangiogenic and antiproliferative activity is c-Met. The kinase, c-Met, is the prototypic member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) which include Met, Ron and Sea. Expression of c-Met occurs in a wide variety of cell types including epithelial, endothelial and mesenchymal cells where activation of the receptor induces cell migration, invasion, proliferation and other biological activities associated with "invasive cell growth." As such, signal transduction through c-Met receptor activation is responsible for many of the characteristics of tumor cells.
[0012] The endogenous ligand for c-Met is the hepatocyte growth factor (HGF), a potent inducer of angiogenisis, also known as "scatter factor" (SF). Binding of HGF to c-Met induces activation of the receptor via autophosphorylation resulting in an increase of receptor dependent signaling, which promotes cell growth and invasion. Anti-HGF antibodies or HGF antagonists have been shown to inhibit tumor metastasis in vivo (See: Maulik et al Cytokine & Growth Factor Reviews 2002 13, 41-59).
[0013] Tumor growth progression requires the recruitment of new blood vessels into the tumor from preexisting vessels as well as invasion, adhesion and proliferation of malignant cells. Accordingly, c-Met overexpression has been demonstrated on a wide variety of tumor types including breast, colon, renal, lung, squamous cell myeloid leukemia, hemangiomas, melanomas, astrocytomas, and glioblastomas. Additionally activating mutations in the kinase domain of c-Met have been identified in hereditary and sporadic renal papilloma and squamous cell carcinoma. (See: Maulik et al Cytokine & growth Factor reviews 2002 13, 41-59; Longati et al Curr Drug Targets 2001, 2, 41-55; Funakoshi et al Clinica Chimica Acta 2003 1-23). Thus modulation of c-Met is desirable as a means to treat cancer and cancer-related disease.
[0014] The Eph receptors comprise the largest family of receptor tyrosine kinases and are divided into two groups, EphA and EphB, based on their sequence homology. The ligands for the Eph receptors are ephrin, which are membrane anchored. Ephrin A ligands bind preferentially to EphA receptors whilst ephrin B ligands bind to EphB receptors. Binding of ephrin to Eph receptors causes receptor autophosphorylation and typically requires a cell-cell interaction since both receptor and ligand are membrane bound.
[0015] Overexpression of Eph receptors has been linked to increased cell proliferation in a variety of tumors (Zhou R 1998 Pharmacol Ther. 77, 151-181; Kiyokawa E, Takai S, Tanaka M et al 1994 Cancer Res 54, 3645-3650; Takai N Miyazaki T, Fujisawa K, Nasu K and Miyakawa. 2001 Oncology reports 8, 567-573). The family of Eph receptor tyrosine kinases and their ephrin ligands play important roles in a variety of processes during embryonic development and also in pathological angiogenesis and potentially metastasis. Therefore modulation of Eph receptor kinase activity should provide means to treat or prevent disease states associated with abnormal cell proliferation such as those described above.
[0016] Inhibition of EGF, VEGF and ephrin signal transduction will prevent cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. Drug Disc. Technol. 2001 6, 1005-1024). EGF and VEGF receptors are previously described targets for small molecule inhibition. KDR and flt-4 are both VEGF receptors
[0017] One particularly attractive target for small-molecule modulation is c-Kit. The proto-oncogene c-Kit was first identified as the oncogenic component of the acutely transforming Hardy-Zuckerman 4-feline sarcoma virus (Besmer et al Nature 1986 320:415-421). c-Kit (also called stem cell factor receptor or steel factor receptor) is a type 3 receptor tyrosine kinase (RTK) belonging to the platelet-derived growth factor receptor subfamily. c-Kit binds the ligand stem cell factor (SCF), and triggers its multiple signal transduction pathways including Src family kinases, phosphatidyl-inositol 3 kinase, the Ras-Raf-Map kinase cascade, and phospholipase C (Broudy et al Blood 1999 94: 1979- 1986; Lennartsson et al Oncogene 1999 18: 5546-5553 ; Timokhina et al EMBO J 1998 17;6250-6262; Chian et al Blood 2001 98(5)1365-1373; Blume-Jensen et al Curr Biol
1998 8:779-782; Kissel et al EMBO J 2000 19:1312-1326; Lennartsson et al. Oncogene
1999 18: 5546-5553; Sue et al Blood, 199892:1242-1149; Lev etal EMBO J 1991 10:647- 654). c-Kit is required for normal hematopoiesis, melanonogenesis, and gametogenesis. c-Kit is expressed in mast cells, immature myeloid cells, melanocytes, epithelial breast cells and the interstitial cells of Cajal (ICC). In mast cells, it is required not only for the differentiation, maturation, chemotaxis, and haptotaxis but also for the promotion of survival and proliferation.
[0018] Mutations in c-Kit have been implicated in human disease. Mutations in the juxtamembrane domain are found in many human gastrointestinal stromal tumors, and mutations in the kinase domain are found in mastocytosis, germ cell tumors, acute myeloid leukemia (AML), NK lymphoma, and other hematologic disorders (Hirota et al Science 1998 279:577-580; Singer et al J Clin Oncol 2002 203898-3905; Longley et al Proc Natl Aca Sci USA 1999: 1609-1614; Tian et al Am J Pathol 1999 154: 1643-1647; Beghini et al Blood 2000 95:726-727; Hongyo et al Cancer Res 2000 60:2345-2347). These mutations result in ligand-independent tyrosine kinase activity, autophosphorylation of c- Kit, uncontrolled cell proliferation, and stimulation of downstream signaling pathways. Overexpression of c-Kit and c-Kit ligand have also been described in other tumors including small-cell lung cancer, neuroblastomas, gynecological tumors, and colon carcinoma, which might result in autocrine or paracrine c-Kit activation.
[0019] The overexpression of c-Kit has also been implicated in the development of neoplasia associated with neurofibromatosis type 1 (NFl). Mutations in the tumor suppressor gene NFl lead to a deficiency in neurofibromin, a GTPase-activating protein for Ras. This deficiency results in abnormal proliferation of Schwann cells in the peripheral nervous system, and predisposes affected individuals to peripheral nerve sheath tumors (neurofibromas), astrocytomas (optic pathway gliomas), learning disabilities, seizures, strokes, macrocephaly, vascular abnormalities, and juvenile myelomonocytic leukemia (Lynch & Gutmann Neurol Clin 2002 20:841-865). Genetic experiments in mice demonstrate that haploinsufficiency at NFl partially rescues some of the phenotypes associated with mutations in the gene for c-Kit, indicating that these genes function along a common developmental pathway (Ingram, et al. J. Exp Med 2000 191:181-187). Also, c- Kit is expressed in schwannoma cells from NFl patients, but not in normal Schwann cells (Ryan et al. J Neurosci Res 1994 37:415-432). These data indicate that elevated c-Kit expression and sensitivity to stem cell factor may play important roles in the development of proliferative disorders associated with NF-I. Therefore, c-Kit inhibitors may be effective chemotherapeutic agents for treating patients with NF-I.
[0020] GISTs are the most common mesenchymal tumors of the gastrointestinal tract, and they are generally resistant to chemotherapy and radiation therapy. However, recent results with the c-Kit/BCR-Abl inhibitor STI571 indicate that targeting c-Kit may be an effective therapeutic strategy for this disease (Eisenberg & Mehren Expert Opin Pharmacother 2003 4:869-874). Malignant mast cell disease often suggests an extremely poor prognosis, and no reliable effective chemotherapeutic agents have been identified (Marone et al Leuk Res 2001 25:583-594). Systemic mast cell disorders have been treated with interferon-alpha, although the effectiveness of this therapy has been variable (Lehmann & Lammle Ann Hematol 1999 78:483-484; Butterfield Br J Dermatol 1998 138: 489-495). Therefore, activated c-Kit might serve as a therapeutic target in GISTs and mast cell disease, as well as other disorders associated with activated c-Kit.
[0021] Flt-3 is normally expressed on hematopoietic progenitor cells and a subset of mature myeloid and lymphoid cells, where it modulates cell survival and proliferation. Flt-3 is constitutively activated via mutation, either in the juxtamembrane region or in the activation loop of the kinase domain, in a large proportion of patients with AML (Reilly Leuk Lymphoma 2003 44: 1-7). Also, mutations in flt-3 are significantly correlated with poor prognosis in AML patients (Sawyers Cancer Cell 2002 1: 413-415).
[0022] Accordingly, the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of kinases, particularly including c-Met, KDR, c-Kit, flt-3, and flt-4, is desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis, and is an object of this invention.
[0023] Quinolines bearing substitution, for example at the two, four, six and seven positions of their fused ring system have been shown to be particularly attractive targets for kinase inhibition by a number of groups. Conventional quinoline kinase inhibitors typically have fairly simple substitution about the quinoline fused ten-membered ring system, but recently more complex molecules are being disclosed. For example, we have previously disclosed, in U.S. provisional patent applications 60/506,181 and 60/535,377 which are both incorporated by reference herein in their entirety for all purposes, that certain quinolines are particularly well suited as kinase modulators, more particularly inhibitors of for example c-Met, KDR, c-Kit, flt-3, and flt-4. These molecules in some cases are particularly complex and although they can be made via conventional methods, more efficient routes are desirable, especially in a pharmaceutical setting.
[0024] Conventional methods of making quinolines with the aforementioned substitution patterns usually involve linear construction of a quinoline template upon which relatively simple substitutions are appended. With the advent of more complex substitution about such quinolines (vide supra), for example side chains containing cyclic and bicyclic systems with multiple functional groups, conventional methods of synthesis become problematic due to the linear or serial reactions used. Indeed, as such molecules become more complex and the utility of such complex groups is realized, the quinoline ring system becomes more of a sub-structure than a main structure of such inhibitors. Thus it is desirable to find more efficient methods of synthesis, particularly convergent syntheses which are an object of this invention.
SUMMARY OF THE INVENTION
[0025] In one aspect, the present invention provides compounds for modulating kinase activity and methods of treating diseases mediated by kinase activity utilizing the compounds and pharmaceutical compositions thereof. Diseases mediated by kinase activity include, but are not limited to, diseases characterized in part by migration, invasion, proliferation and other biological activities associated with invasive cell growth. In particular to this invention is modulation, even more particularly inhibition, of c-Met, KDR, c-Kit, flt-3 , and flt-4.
[0026] In another aspect, the invention provides methods of screening for modulators of c- Met, KDR, c-Kit, flt-3, and flt-4 activity. The methods comprise combining a composition of the invention, a kinase, e.g. c-Met, KDR, c-Kit, flt-3, or flt-4, and at least one candidate agent and determining the effect of the candidate agent on the c-Met, KDR, c-Kit, flt-3, or flt-4, activity.
[0027] In yet another aspect, the invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the ingredients of pharmaceutical compounds and/or compositions of the present invention, including, one or more kinase, e.g. c-Met, KDR, c-Kit, flt-3, or flt-4, enzyme activity modulators as described herein. Such kits can also include, for example, other compounds and/or compositions (e.g., diluents, permeation enhancers, lubricants, and the like), a device(s) for administering the compounds and/or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflects approval by the agency of manufacture, use or sale for human administration.
[0028] In another aspect, the invention also provides a diagnostic agent comprising a compound of the invention and, optionally, pharmaceutically acceptable adjuvants and excipients.
[0029] In still yet another aspect, the present invention provides processes for making compounds, and pharmaceutical compositions thereof, for modulating kinase activity and treating diseases mediated by kinase activity. In particular to this invention are methods for making quinolines used for modulation of kinase activity, even more particularly inhibition of kinase activity, and yet even more particularly inhibition of c-Met, KDR, c- Kit, flt-3, and flt-4.
[0030] These and other features and advantages of the present invention will be described in more detail below with reference to the associated drawings.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities. Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, cancer (further discussed below), immunological disorders such as rheumatoid arthritis, graft-host diseases, multiple sclerosis, psoriasis; cardiovascular diseases such as artheroscrosis, myocardioinfarction, ischemia, stroke and restenosis; other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritus, macular degeneration, diabetic retinopathy.
[0032] It is appreciated that in some cases the cells may not be in a hyper- or hypo- proliferative and/or migratory state (abnormal state) and still require treatment. For example, during wound healing, the cells may be proliferating "normally", but proliferation and migration enhancement may be desired. Alternatively, reduction in "normal" cell proliferation and/or migration rate may be desired.
[0033] Thus, in one aspect the present invention comprises a compound for modulating kinase activity according to Formula I,
Figure imgf000010_0001
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein,
R1 is selected from -H, halogen, -OR3, -NO2, -NH2, -NR3R4, and optionally substituted lower alkyl;
Z is selected from -S(O)0-2-, -O-, and -NR5-;
Ar is either a group of formula II, or of formula III,
Figure imgf000010_0002
II III wherein,
R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is O to 4;
G is a group -B-L-T, wherein
B is selected from absent, -N(R13)-, -N(SO2R13)-, -0-, -S(O)0-2-, and -C(=0)-;
L is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SO2N(R13)-, -SO2-, -C(=0)N(R13)-, -N(R13)-, -C(=O)C1-2alkylN(R13)-, -N(R13)C1-2alkylC(=O)-, -C(=0)Co-ialkylC(=0)N(R13)-, -C0-4alkylene-, -C(=O)C0-1alkylC(=O)OR3-, -C(=NR14)C0-1alkylC(=O)-, -C(=0)-, -C(=O)C0-1alkylC(=O)-, and an optionally substituted four to six-membered heterocyclyl containing between one and three annular heteroatoms including at least one nitrogen; and T is selected from -H, -R13, -C04alkyl, -C0-4alkylQ, -OC0-4alkylQ, -C0-4alkylOQ, -N(R13)C0-4alkylQ, -SO2C0-4alkylQ, -C(=O)C0-4alkylQ, -Co-4alkylN(R13)Q, and -C(=0)N(R13)Co-4alkylQ, wherein each of the aforementioned C0-4alkyl is optionally substituted;
J is selected from -S(O)0-2-, -O, and -NR15-; R3 is -H or R4;
R4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or
R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
A2 and A3 are each independently selected from =N-, =C(R )-; R5 is -H or optionally substituted lower alkyl; D is selected from -0-, -S(O)0-2-, and -NR15-; R50 is either R3, or according to formula IV;
Figure imgf000011_0001
IV wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X , X , and X ; wherein, each X1 is independently selected from -C(R6)R7-, -0-, -S(O)0-2-, and -NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -0-, -S(O)0-2-, and -NR8-; Y is either: an optionally substituted lower alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X when X is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R or R ; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -SO2-, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system; m and p are each independently 1-4; n is 0-2, when n = 0, then there is a single bond between the two bridgehead X2 's;
R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R4, -S(O)0-2R4, -SO2NR3R4, -CO2R3, -C(O)NR3R4, -N(R3)SO2R4, -N(R3)C(O)R3, -NCO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, optionally substituted lower heterocyclylalkyl, and a bond to either Y or D; or
R and R , when taken together are oxo; or
R6 and R7, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
R8 is selected from -R3, Y, -SO2NR3R4, -CO2R4, -C(O)NR3R3, -SO2R4, and -C(O)R3;
R13 is selected from -H, -C(=O)R3, -C(=0)0R3, -C(=O)SR3, -SO2R4, -C(=O)N(R3)R3, and optionally substituted lower alkyl, two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic can have up to four annular heteroatoms, and said heteroalicyclic can have an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R60; R14 is selected from -H, -NO2, -NH2, -N(R3)R4, -CN, -OR3, optionally substituted lower alkyl, optionally substituted heteroalicyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroalicyclic;
R15 is a group -M^M2, wherein M1 is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SO2N(R13)-, -SO2-, -C(=0)N(R13)-, -C(=O)C(=O)N(R13)-, -C0- 4alkylene-, -C(=O)-, and an optionally substituted four to six-membered hetercyclyl annular containing between one and three heteratoms including at least one nitrogen; and M2 is selected from -H, -C0-6alkyl, alkoxy, -C(-O)C0-4alkylQ, -C0-4alkylQ, -OCo^alkylQ-, -N(R13)C0-4alkylQ-, and -C(=O)N(R13)C0-4alkylQ; and
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl;
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; two of R °, when attached to a non-aromatic carbon, can be oxo; with the proviso, only when Ar is according to formula II, if Y is a C1-6 alkylene; Z is -NH- or -N(CH3)-; R1 is a C1-6alkyl optionally substituted in the 2-position by -OH or a C1- 4alkoxy group; R2 is -H or halogen; n = O; and the atoms, X1, of one bridge of the saturated bridged ring system, when combined with both bridgehead atoms, X2, of the saturated bridged ring system, represent:
1) either a pyrrolidine or a piperidine, and any atom, X1 or X2, of either of said pyrrolidine or said piperidine is attached to Y, then the other bridge of said saturated bridged ring system cannot be any one of -OC(O)CH2-, -CH2OC(O)-, -OC(O)CH2CH2-, -CH2OC(O)CH2-, -CH2CH2OC(O)-, -OC(O)CH2NH-, -OC(O)CH2N(C1-4alkyl)-, and -OC(O)CH2O-; or
2) either a piperazine or a 4-(C1-4alkyl)-piperazine, and any atom, X1 or X2, of either of said piperazine or said 4-(C1-4alkyl)-piperazine is attached to Y, then the other bridge of said saturated bridged ring system, only when attached via the 2- and the 3-position of either of said piperazine or said 4-(C1-4alkyl)-piperazine, cannot be one of -CH2OC(O)CH2-, -CH2CH2OC(O)-, and either of the two aforementioned bridges optionally substituted by one or two C1-2alkyl groups; or
3) a piperazine, and any atom, X1 or X2, of said piperazine is attached to Y, then the other bridge of said saturated bridged ring system, only when attached via the 3- and the 4-position of said piperazine, cannot be one of -C(O)OCH2CH2-, -CH2OC(O)CH2-, and either of the two aforementioned bridges optionally substituted by one or two C1-2alkyl groups, and only when either of the two aforementioned bridges are attached to the 3-position of said piperazine via their left-hand end as depicted above; or
4) a 2-oxomorpholine, said 2-oxomorpholine attached to Y via its 4-position, then the other bridge of said saturated bridged ring system, only when attached via the 5- and the 6-position of said 2-oxomorpholine, cannot be one of -(CH2V, -CH2WCH2-, -CH2WCH2CH2-, and -CH2CH2WCH2-, wherein W is -0-, -S(O)0-2-, -NH-, or -N(CMalkyl)- wherein g is 2, 3, or 4; and with the proviso that when Z is-O-, Ar is according to formula II, and the portion of G directly attached to Ar is selected from:
Figure imgf000014_0001
then R ,50 must be of formula IV; and with the proviso that when Ar is phenylene or substituted phenylene, Z is -S(O)0-2- or
-O-, then the portion of G directly attached to Ar cannot contain
Figure imgf000015_0001
when R »70 is selected from -H, C1-4alkyl, and Ci^alkoxyl.
[0034] In one example, the compound is according to paragraph [0033], wherein Z is either -O- or -NR5-.
[0035] In another example, the compound is according to paragraph [0034], wherein G is selected from the following:
Figure imgf000015_0002
Figure imgf000016_0001
Figure imgf000017_0001
wherein wherein Q, R20, and R13 are as defined above; each E is selected from -O-, -N(R13)-, -CH2-, and -S(O)0-2-; M is selected from -O-, -N(R13)-, -CH2-, and -C(^O)N(R13)-; each V is independently either =N- or =C(H)-; each methylene in any of the above formulae is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic, two of R25 on a single carbon can be oxo.
[0036] In another example, the compound is according to paragraph [0035], wherein Ar is according to one of formula Ha, lib, and IHa.
Figure imgf000017_0002
Ha lib Ilia
[0037] In another example, the compound is according to paragraph [0036], wherein D is -O- and R1 is -OR3.
[0038] In another example, the compound is according to paragraph [0037], wherein -O-R50 and R1 are interchangeably located at the 6-position and 7-position of the quinoline according to formula I.
[0039] In another example, the compound is according to paragraph [0038], wherein R1 is -OH or -OC1-6alkyl.
[0040] In another example, the compound is according to paragraph [0039], wherein G is selected from:
Figure imgf000018_0001
wherein Q, R20, R13, E, and R60 are as defined above; each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic.
[0041] In another example, the compound is according to paragraph [0040], wherein Q is selected from:
Figure imgf000018_0002
wherein R is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms. [0042] In another example, the compound is according to paragraph [0041], wherein Ar is according to formula Ha, and G is selected from:
Figure imgf000019_0001
wherein Q, R20, R13, E, and R60 are as defined above, and each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic.
[0043] In another example, the compound is according to paragraph [0041], wherein Ar is according to formula Hb, and G is selected from:
Figure imgf000019_0002
wherein Q, R20, R13, E, and R60 are as defined above, and each, methylene in any of the above formulae, other than those depicted in a ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic.
[0044] In another example, the compound is according to paragraph [0043], wherein the methylene between the two carbonyls of the depicted formulae is di-substituted with either optionally substituted lower alkyl, or an optionally substituted spirocycle.
[0045] In another example, the compound is according to either [0042] or paragraph [0044], wherein R50 is a heteroalicylic or a C1-6alkyl-heteroalicylic.
[0046] In another example, the compound is according to paragraph [0045], wherein at least one of R is halogen.
[0047] In another example, the compound is according to paragraph [0045], wherein R50 is according to formula IV.
[0048] In another example, the compound is according to paragraph [0047], wherein the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1].
[0049] In another example, the compound is according to paragraph [0048], wherein Y is selected from -CH2CH2CH2CH2-, -CH2CH2CH2-, -CH2CH2-, -CH2-, and absent.
[0050] In another example, the compound is according to paragraph [0049], wherein n is 0 and the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0].
[0051] In another example, the compound is according to paragraph [0050], wherein said saturated bridged ring system contains at least one annular nitrogen or at least one annular oxygen. [0052] In another example, the compound is according to paragraph [0051], wherein said saturated bridged ring system contains -NR -, wherein R is selected from -H, optionally substituted lower alkyl, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3.
[0053] In another example, the compound is according to paragraph [0051], wherein said saturated bridged ring system is of formula V,
Figure imgf000021_0001
V wherein U1 is selected from -O-, -S(O)0-2-, -NR8-, -CR6R7-, and absent; and e is 0 or 1.
[0054] In another example, the compound is according to paragraph [0053], wherein Y is -CH2-.
[0055] In another example, the compound is according to paragraph [0054], wherein U1 is -NR8-, wherein R8 is selected from -H, optionally substituted lower alkyl, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3.
[0056] In another example, the compound is according to paragraph [0054], wherein U1 is -O-.
[0057] In another example, the compound is according to paragraph [0054], wherein U1 is absent.
[0058] In another example, the compound is according to paragraph [0051], wherein Y is selected from -CH2CH2-, -CH2-, and absent.
[0059] In another example, the compound is according to paragraph [0058], wherein said saturated bridged ring system is of formula VI,
Figure imgf000021_0002
VI wherein R9, R10, and R11 are each independently selected from -H, and -OR12; or R9 is selected from -H, and -OR12, and R10 and R11, when taken together, are either an optionally substituted alkylidene or an oxo;
R12 is selected from -H, -C(O)R3, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl; or two R12' s, when taken together, form 1) a corresponding spirocyclic ketal when said two R12' s stem from R10 and R11, or 2) a corresponding cyclic ketal when said two R12's stem from R9 and one of R10 and R11.
[0060] In another example, the compound is according to paragraph [0059], wherein one of R10 and R11 is -OR12, wherein R12 is selected from -H, -C(O)R3, and optionally substituted lower alkyl; and R9 and the other of R10 and R11 are both -H.
[0061] In another example, the compound is according to paragraph [0060], wherein Y is either -CH2- or absent.
[0062] In another example, the compound is according to paragraph [0061], wherein R9 is an alkyl group containing at least one fluorine substitution thereon.
[0063] In another example, the compound is according to paragraph [0052], wherein said saturated bridged ring system is of formula VII.
Figure imgf000022_0001
VII
[0064] In another example, the compound is according to paragraph [0063], wherein Y is either -CH2- or absent.
[0065] In another example, the compound is according to paragraph [0064], wherein R8 is methyl or ethyl.
[0066] In another example, the compound is according to paragraph [0052], wherein said saturated bridged ring system is of formula VIII.
Figure imgf000023_0001
VIII
[0067] In another example, the compound is according to paragraph [0066], wherein Y is -CH2-.
[0068] In another example, the compound is according to paragraph [0067], wherein R is methyl or ethyl.
[0069] In another example, the compound is according to paragraph [0052], wherein said saturated bridged ring system is of formula IX
Figure imgf000023_0002
IX wherein U2 is selected from -O-, -S(O)0-2-, -NR8-, -CR6R7-, and absent.
[0070] In another example, the compound is according to paragraph [0069], wherein R3 of formula IX is selected from -H and optionally substituted alkyl.
[0071] In another example, the compound is according to paragraph [0070], wherein U2 is either -CR6R7- or absent.
[0072] In another example, the compound is according to paragraph [0071], wherein U2 is either -CH2- or absent.
[0073] In another example, the compound is according to paragraph [0072], wherein Y is -CH2-.
[0074] In another example, the compound is according to paragraph [0052], wherein said saturated bridged ring system is according to formula X.
Figure imgf000023_0003
X [0075] In another example, the compound is according to paragraph [0074], wherein R is methyl or ethyl.
[0076] In another example, the compound is according to paragraph [0033], selected from Table 1.
Table 1
Figure imgf000024_0002
[0077] In another aspect, the invention comprises a compound for modulating kinase activity of formula A-B-C, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, A is selected from:
Figure imgf000024_0001
Figure imgf000025_0001
B is selected from:
Figure imgf000025_0003
and, C is selected from:
Figure imgf000025_0002
Figure imgf000026_0001
wherein R2 is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is 0 to 2; each R3 is independently selected from — H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; two R3, together with the nitrogen to which they are attached, form a four- to seven- membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SO2NR5R5, -CO2R5, -C(O)NR5R5, -C(O)R5, and optionally substituted lower alkyl; each R35 is independently selected from -H, -C(=0)R3, -C(=O)OR3, -C(=O)SR3, -SO2R3, -C(=O)N(R3)R3, and optionally substituted lower alkyl; two R35, together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aryl fused thereto, said aryl optionally substituted with an additional one to four of
R60;
A2 is either =N- or =C(H)-;
R5 is -H or optionally substituted lower alkyl;
R8 is selected from R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3;
R9, R10, and R11 are each independently selected from -H, and -OR12; or
R9 is selected from -H, and -OR12, and R10 and R11, when taken together, are either an optionally substituted alkylidene or an oxo; and
R12 is selected from -H, -C(O)R3, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl; or two R 's, when taken together, form 1) a corresponding spirocyclic ketal when said two R12' s stem from R10 and R11, or 2) a corresponding cyclic ketal when said two R12's stem from R9 and one of R10 and R11;
E1 is selected from -0-, -CH2-, -N(R5)-, and -S(O)0-2-;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl;
R60 is selected from -H, halogen, trihalomethyl, -CN3 -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; two of R60, when attached to a non-aromatic carbon, can be oxo; each methylene in any of the above formulae is independently optionally substituted with R25; each R25 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryL optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic, two of R25 on a single carbon can be oxo; with the proviso that when B is selected from:
Figure imgf000028_0001
and C contains
Figure imgf000028_0002
and the remaining portion of C contains one of:
Figure imgf000028_0003
directly attached to
Figure imgf000028_0004
then A must be one of:
Figure imgf000029_0001
and with the proviso that when C contains
Figure imgf000029_0002
and B is selected from:
then the
Figure imgf000029_0003
ot contain
Figure imgf000029_0004
when R70 is selected from -H, C1-4alkyl, and C1-4alkoxyl. [0078] In another example the compound is according to paragraph [0077], wherein Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; each optionally substituted with between one and four of R20; wherein each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl.
[0079] In another example the compound is according to paragraph [0078], wherein B is either of the following:
Figure imgf000030_0001
[0080] In another example the compound is according to paragraph [0079], wherein B is
Figure imgf000030_0002
[0081] In another example the compound is according to paragraph [0080], wherein C is selected from:
Figure imgf000030_0003
Figure imgf000031_0001
Figure imgf000032_0001
wherein R2 , R3, R5, R20, R25 and R60 are as defined above. [0082] In another example the compound is according to paragraph [0082], R2 is selected from halogen, trihalomethyl, -CN, -NO2, -OR', -NR 3JτR>3\ -CO2R", -C(O)NR3R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl
[0083] In another example the compound is according to paragraph [0083], wherein R2 is halogen.
[0084] In another example the compound is according to paragraph [0084], wherein R2 is either fluorine or chlorine.
[0085] In another example, the compound is according to paragraph [0077], selected from Table 2.
Table 2
Figure imgf000032_0002
[0086] Another aspect of the invention is a pharmaceutical composition comprising a compound according to any one of paragraphs [0033]-[0085] and a pharmaceutically acceptable carrier.
[0087] Another aspect of the invention is a metabolite of the compound or the pharmaceutical composition according to any one of paragraphs [0022]-[0086].
[0088] Another aspect of the invention is a method of modulating the in vivo activity of a kinase, the method comprising administering to a subject an effective amount of the compound or the pharmaceutical composition according to any of paragraphs [0033]- [0086].
[0089] Another aspect of the invention is the method according to paragraph [0088], wherein modulating the in vivo activity of the kinase comprises inhibition of said kinase.
[0090] Another aspect of the invention is the method according to paragraph [0089], wherein the kinase is at least one of c-Met, KDR, c-Kit, flt-3, and flt-4.
[0091] Another aspect of the invention is the method according to paragraph [0091], wherein the kinase is c-Met.
[0092] Another aspect of the invention is a method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of the compound or the pharmaceutical composition as described in any one of paragraphs [0033]-[0086].
[0093] Another aspect of the invention is a method of screening for a modulator of a kinase, said kinase selected from c-Met, KDR, c-Kit, flt-3, and flt-4, the method comprising combining a compound according to any one of paragraphs [0033]-[0085], and at least one candidate agent and determining the effect of the candidate agent on the activity of said kinase.
[0094] Another aspect of the invention is a method of inhibiting proliferative activity in a cell, the method comprising administering an effective amount of a composition comprising a compound according any one of paragraphs [0033]-[0085] to a cell or a plurality of cells.
[0095] As mentioned, although improved quinolines of the invention can be made via conventional serial methods, due to their complex structure, more efficient routes are desirable, particularly convergent syntheses. Thus, the present invention also comprises a process for preparing a compound of Formula XXI,
Figure imgf000034_0001
XXI comprising reaction of a compound of Formula XXII, with a compound of Formula XXIII
Figure imgf000034_0002
XXII XXIII wherein, each R1 is independently selected from halogen, -OR3, -NO2, -NH2, -NR3R3, -D-R50 and optionally substituted C1-6alkyl;
R70 is selected from -H, halogen, -OR3, -S(O)0-2R3, -NO2, -NH2, -NR3R3, and optionally substituted C1-6alkyl;
Z is selected from -S(O)0-2-, -0-, and -NR5-; each R5 is independently selected from -H, optionally substituted C1-6alkyl, optionally substituted aryl, and optionally substituted aryl C1-6alkyl;
Ar is either a five- to ten-membered arylene or a five- to ten-membered heteroarylene containing between one and three heteroatoms;
R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted C1-6alkyl; each R3 is independently selected from -H, -Si(R5)(R5)R5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; two R , together with the nitrogen to which they are attached, form a four- to seven- membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SO2NR5R5, -CO2R5, -C(O)NR5R5, -C(O)R5, and optionally substituted lower alkyl;
B is selected from absent, -N(R13)-, -N(SO2R13)-, -0-, -S(O)0-2-, and -C(=0>;
L is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SO2N(R13)-, -SO2-, -C(=0)N(R13)-, -N(R13)-, -C(-O)C1.2alkylN(R13)-, -N(R13)C1-2alkylC(=O)-, -C(=O)C0-1alkylC(=O)N(R13)-, -C(=0)-s -C0-4alkylene-, -C(=O)C0-1alkylC(=O)OR3-, -C(=NR14)C0-1alkylC(=O)-, -C(=O)C0-1alkylC(=O)-, and an optionally substituted four- to six-membered heterocyclyl containing between one and three annular heteroatoms and comprising at least one nitrogen;
T is selected from -H, -R13, -C0-4alkyl, -C0-4alkylQ, -OC0-4alkylQ, -C0-4alkylOQ, -N(R13)C0-4alkylQ, -SO2C0-4alkylQ, -C(=O)C0-4alkylQ, -C0-4alkylN(R13)Q, and -C(=0)N(R13)Co-4alkylQ, wherein each of the aforementioned C0-4alkyl is optionally substituted;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20; each R is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl; two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to Q or fused to Q;
D is selected from -0-, -S(O)0-2-, and -NR15-; R50 is either R3, or according to formula XXIV;
Figure imgf000036_0001
XXIV wherein X , X , and optionally X , represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -C(R6)R7-, -O-, -S(O)0-2-, and -NR8-; each X is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -O, -S(O)0-2-, and -NR8-; Y is either: an optionally substituted C1-6alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X when X is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R or R ; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -SO2-, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system; m and p are each independently one to four; n is zero to two, when n is zero, then there is a single bond between the two bridgehead
X2's;
R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -NCO2R3, -C(O)R3, optionally substituted C^alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl a C1-6lkyl, and a bond to either Y or D; or R6 and R7, when taken together are oxo; or
R6 and R7, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
R8 is selected from -R3, Y, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3;
R13 is selected from -H, -C(=O)R3, -C(=O)OR3, -C(=O)SR3, -SO2R3, -C(=O)N(R3)R3, and optionally substituted C1-6alkyl; two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic comprising up to four annular heteroatoms, and said heteroalicyclic optionally comprising an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R60;
R14 is selected from -H, -NO2, -NH2, -N(R3)R3, -CN, -OR3, optionally substituted C1-6alkyl, optionally substituted heteroalicyclyl C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl and optionally substituted heteroalicyclic;
R15 is a group -M^M2, wherein M1 is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SO2N(R13)-, -SO2-, -C(=0)N(R13)-, -C(=0)C(=0)N(R13)-, -Co-4alkylene-, -C(=0)-, and an optionally substituted four to six-membered heterocyclyl containing between one and three heteroatoms but comprising at least one nitrogen; and M2 is selected from -H, -C0-6alkyl, alkoxy, -C(=O)C0-4alkylQ, -C0-4alkylQ, -OC0-4alkylQ-, -N(R13)C0-4alkylQ-, and -C(=O)N(R13)C0-4alkylQ;
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted heteroaryl C1-6alkyl, and optionally substituted aryl C1-6alkyl; two of R60, when attached to a non-aromatic carbon, can be oxo; P1 is a suitable leaving group; and
P2 is selected from -H, a metal, and a group removed in-situ when combining XXII and XXIII to make XXI. [0096] In one example, the process is according to paragraph [0095], wherein Ar is para- phenylene as defined by the substitution pattern of -Z- and -B-L-T about said phenylene.
[0097] In another example, the process is according to paragraph [0096], wherein Z is either -O- or -NR5-.
[0098] In another example, the process is according to paragraph [0097], wherein -B-L-T is selected from the following:
Figure imgf000038_0001
Figure imgf000039_0001
wherein Q3 R20, and R13 are as defined above; each E is selected from -O-, -N(R13)-, -CH2, and -S(O)0-2-; M is selected from -O-, -N(R13)-, -CH2-, and -C(=O)N(R13)-; each V is independently either =N- or =C(H)-; each methylene in any of the above formulae is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted aryl C1-6alkyl, heteroaryl C1-6alkyl, and optionally substituted C1-6alkyl; two of R25, togetlier with the carbon or carbons to which they are attached, can combine to form an optionally substituted three- to seven-membered alicyclic or heteroalicyclic; two of R25 on a single carbon can be oxo.
[0099] In another example, the process is according to paragraph [0098], wherein there is one of R1 that is -D-R50 and another of R1 that is -OR3a.
[0100] In another example, the process is according to paragraph [0099], wherein D is -O-.
[0101] In another example, the process is according to paragraph [0100], wherein -O-R50 and -OR3a are interchangeably located at the 6-position and 7-position of the quinoline according to Formula XXI.
[0102] In another example, the process is according to paragraph [0101], wherein -OR3a is selected from -OH, -OSi(R5)(R5)R5, and optionally substituted -OC1-6alkyl.
[0103] In another example, the process is according to paragraph [0102], wherein -B-L-T is selected from:
Figure imgf000040_0001
Figure imgf000041_0001
wherein Q, R2 , R13, E, and R60 are as defined above; each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted aryl C1-6alkyl, heteroaryl C1-6alkyl, and optionally substituted C1-6alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered optionally substituted alicyclic or heteroalicyclic.
[0104] In another example, the process is according to paragraph [0103], wherein Q is selected from the following three formula:
Figure imgf000041_0002
wherein R2 is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.
[0105] In another example, the process is according to paragraph [0104], wherein a compound of formula XXIIa is combined with a compound of formula XXIIIa to make a compound of formula XXIa,
Figure imgf000041_0003
Figure imgf000041_0004
XXIIIa
Figure imgf000041_0005
XXIa wherein -B-L-T, Z, R50, and R2 are as defined above; R70 is selected from -H, -NO2, -NH2, and -NR3R3; provided when Z is -N(R5)- that R5 is selected from -H, C1-3alkyl, and aryl C1-3alkyl; P1 is selected from halogen, optionally substituted alkyl-S(0)o-2-, optionally substituted arylsulfonate, optionally substituted alkylsulfonate, a group containing boron, an azide, a group containing phosphorus, and a metal; and P2 is selected from -H and a metal.
[0106] In another example, the process is according to paragraph [0105], wherein P2 is selected from -H, lithium, sodium, potassium, cesium, copper, palladium, and titanium.
[0107] In another example, the process is according to paragraph [0106], wherein Z is -O-.
[0108] In another example, the process is according to paragraph [0107], wherein P1 is selected from chlorine, bromine, a toluene sulfonate, and trifluoromethansulfonate.
[0109] In another example, the process is according to paragraph [0108], wherein R70 is -H.
[0110] In another example, the process is according to paragraph [0109], wherein R2 is selected from C1-6 alkyl, perfluoro C1-6 alkyl, and halogen.
[0111] In another example, the process is according to paragraph [0110], wherein XXIIa and XXIIIa are heated together, optionally with a base, optionally with microwave radiation, to form XXIa.
[0112] In another example, the process is according to paragraph [Oil 1], wherein the base is selected from an organic base, an inorganic base, and a combination of an organic base and an inorganic base.
[0113] In another example, the process is according to paragraph [0112], wherein the base is selected from 2,6-lutidine, 4-N,N-dimethylammopyridine, and a metal carbonate.
[0114] In another example, the process is according to paragraph [0113], wherein XXIIa and XXIIIa are heated together in a solvent with said base, at between about 40°C and 200°C for between about one hour and twenty-four hours to form XXIa.
[0115] In another example, the process is according to paragraph [0114], wherein the solvent is an organic solvent. [0116] In another example, the process is according to paragraph [0115], wherein one molar equivalent of XXIIa is combined with between about one quarter and four molar equivalents of XXIIIa.
[0117] In another example, the process is according to paragraph [0116], wherein one molar equivalent of XXIIa is combined with more than one but less than two molar equivalents of XXIIIa.
[0118] In another example, the process is according to paragraph [0117], wherein XXIIa is combined with XXIIIa and said base in an aromatic solvent to form a mixture, and said mixture is heated to between about 100°C and 200°C for between about one and ten hours to form Ia.
[0119] In another example, the process is according to paragraph [0118], wherein the aromatic solvent is an optionally substituted benzene.
[0120] In another example, the process is according to paragraph [0119], wherein the aromatic solvent is bromobenzene.
[0121] In another example, the process is according to paragraph [0120], wherein the base is 4-N,N-dimethylaminopyridine.
[0122] In another example, the process is according to paragraph [0121], wherein said mixture is heated to reflux for between about three and seven hours.
[0123] In another example, the process is according to paragraph [0122], wherein said mixture is heated to reflux for between about four and six hours.
[0124] In another example, the process is according to paragraph [0117], wherein XXIIa is combined with XXIIIa and said base in a non-aromatic solvent to form a mixture, and said mixture is heated to between about 4O°C and 100°C for between about one and twenty hours to form XXIa.
[0125] In another example, the process is according to paragraph [0124], wherein the non- aromatic solvent comprises a functional group selected from an amide, and ether, a nitrile, a halide, an ester, an amine, and a ketone.
[0126] In another example, the process is according to paragraph [0125], wherein the non- aromatic solvent is N,N-dimethylacetamide. [0127] In another example, the process is according to paragraph [0126], wherein the base is potassium carbonate.
[0128] In another example, the process is according to paragraph [0127], wherein said mixture is heated to about 50°C between about ten and twenty hours.
[0129] In another example, the process is according to paragraph [0128], wherein the aromatic solvent is an optionally substituted pyridine.
[0130] In another example, the process is according to paragraph [0129], wherein the aromatic solvent is 2,6-lutidine.
[0131] In another example, the process is according to paragraph [0130], wherein the base is 2,6-lutidine.
[0132] In another example, the process is according to paragraph [0131], wherein said mixture is heated to reflux for between about three and seven hours.
[0133] In another example, the process is according to paragraph [0132], wherein said mixture is heated to reflux for between about four and six hours.
[0134] In another example, the process is according to paragraph [0116], wherein one molar equivalent of XXIIIa is combined with more than one but less than two molar equivalents of XXIIa.
[0135] In another example, the process is according to paragraph [0134], wherein XXIIa is combined with XXIIIa and said base in an aromatic solvent to form a mixture, and said mixture is heated to between about 100°C and 200°C for between about ten and twenty hours to form XXIa.
[0136] In another example, the process is according to paragraph [0135], wherein the aromatic solvent is an optionally substituted pyridine.
[0137] In another example, the process is according to paragraph [0136], wherein the aromatic solvent is 2,6-lutidine.
[0138] In another example, the process is according to paragraph [0137], wherein the base is 2,6-lutidine.
[0139] hi another example, the process is according to paragraph [0138], wherein said mixture is heated to between about 150°C and 200°C for between about fifteen and twenty hours. [0140] In another example, the process is according to any of paragraphs [0111] - [0139], wherein a compound of formula XXIIb is substituted for the compound of formula XXIIa, and a compound of formula XXIIIc is substituted for the compound of formula XXIIIa, in order to make a compound of formula XXIc3 respectively,
Figure imgf000045_0001
XXIIIb XXIIIc
Figure imgf000045_0002
Figure imgf000045_0003
wherein R50, R20 and R2 are as defined above.
[0141] In another example, the process is according to paragraph [0140], wherein R2, if present, is halogen.
[0142] In another example, the process is according to paragraph [0141], wherein R2, if present, is fluorine. [0143] In another example, the process is according to paragraph [0142], wherein R2, if present, is up to two fluorines ortho to the oxygen of the phenylene to which R2 is attached.
[0144] In another example, the process is according to paragraph [0095], used to make a compound listed in either Table 1 or Table 2.
[0145] In another example the process is according to any of paragraphs [0095] - [0144], further comprising converting said compound to a pharmaceutically acceptable salt, hydrate, or prodrug thereof.
Definitions
[0146] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise or they are expressly defined to mean something different.
[0147] The symbol "-" means a single bond, "=" means a double bond, "≡" means a triple bond. The symbol "*/vwr" refers to a group on a double-bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is, the geometry, E- or Z-, of the double bond is ambiguous. When a group is depicted removed from its parent formula, the " --^ " symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural formula.
[0148] When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left-hand side of the schematic below there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, -CH2CH2-. It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.
Figure imgf000047_0001
[0149] In this application, some ring structures are depicted generically and will be described textually. For example, in the schematic below, if in the structure on the left, ring A is used to describe a "spirocyclyl," then if ring A is cyclopropyl, there are at most four hydrogens on ring A (when "R" can also be -H). In another example, as depicted on the right side of the schematic below, if ring B is used to describe a "phenylene" then there can be at most four hydrogens on ring B (assuming depicted cleaved bonds are not C-H bonds).
Figure imgf000047_0002
[0150] If a group "R" is depicted as "floating" on a ring system, as for example in the formula:
Figure imgf000047_0003
then, unless otherwise defined, a substituent "R" may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
[0151] If a group "R" is depicted as floating on a fused ring system, as for example in the formulae:
Figure imgf000047_0004
then, unless otherwise defined, a substituent "R" may reside on any atom of the fused ring system, assuming replacement of a depicted (for example the -NH- in the formula above), implied (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, "X" equals =CH-) from one of the ring atoms, so long as a stable structure is formed. In the example depicted, the "R" group may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula depicted above, when y is 2 for example, then the two "R's" may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
[0152] When there are more than one such depicted "floating" groups, as for example in the formulae:
Figure imgf000048_0001
where there are two groups, namely, the "R" and the bond indicating attachment to a parent structure; then, unless otherwise defined, the "floating" groups may reside on any atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
[0153] When a group "R" is depicted as existing on a ring system containing saturated carbons, as for example in the formula:
Figure imgf000048_0002
where, in this example, "y" can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "R's" may reside on the same carbon. A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an "annular" carbon). In another example, two R's on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring (a "spirocyclyl" group) structure with the depicted ring as for example in the formula:
Figure imgf000048_0003
[0154] "Alkyl" is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively. For example, "C8 alkyl" may refer to an rø-octyl, KO-octyl, cyclohexylethyl, and the like. Lower alkyl refers to alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like. Higher alkyl refers to alkyl groups containing more that eight carbon atoms. Exemplary alkyl groups are those of C20 or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include c- propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. In this application, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus when an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either "butyl" or "C4 alkyl" is meant to include 77-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2- yne radicals; and for example, "propyl" or "C3 alkyl" each include rø-propyl, propenyl, and isopropyl.
[0155] "Alkylene" refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to ten carbon atoms, for example, methylene, ethylene, propylene, rø~butylene and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, fully saturated. Examples of alkylene include ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C(CHs)2CH2-), and cyclohexylpropylene (-CH2CH2CH(C6H13)).
[0156] "Alkylidene" refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to ten carbon atoms, for example, ethylidene, propylidene, π-butylidene, and the like. Alkylidene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, double bond unsaturation. The unsaturation present includes at least one double bond.
[0157] "Alkylidyne" refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms having from two to ten carbon atoms, for example, propylid-2-ynyl, n-butylid-1-ynyl, and the like. Alkylidyne is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, triple bond unsaturation. The unsaturation present includes at least one triple bond.
[0158] Any of the above radicals, "alkylene," "alkylidene" and "alkylidyne," when optionally substituted, may contain alkyl substitution which itself contains unsaturation. For example, 2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains an π-butylid-3-ynyl radical with a vinyl substituent at the 2-position of said radical. [0159] "Alkoxy" or "alkoxyl" refers to the group -O-alkyl, for example including from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons.
[0160] "Substituted alkoxy" refers to the group -O-(substituted alkyl), the substitution on the alkyl group generally containing more than only carbon (as defined by alkoxy). One exemplary substituted alkoxy group is "polyalkoxy" or -O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as -OCH2CH2OCH3, and glycol ethers such as polyethyleneglycol and -0(CH2CH2O)xCHs, where x is an integer of between about two and about twenty, in another example, between about two and about ten, and in a further example between about two and about five. Another exemplary substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is for example an integer of between about one and about ten, in another example y is an integer of between about one and about four.
[0161] "Acyl" refers to groups of from one to ten carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons.
[0162] "α-Amino Acids" refer to naturally occurring and commercially available amino acids and optical isomers thereof. Typical natural and commercially available α-amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. A "side chain of an α-amino acid" refers to the radical found on the α-carbon of an α-amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like. [0163J "Amino" refers to the group -NH2. "Substituted amino," refers to the group -N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example, diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino.
[0164] "Aryl" refers to aromatic six- to fourteen-membered carbocyclic ring, for example, benzene, naphthalene, indane, tetralin, fluorene and the like, univalent radicals. As univalent radicals, the aforementioned ring examples are named, phenyl, naphthyl, indanyl, tetralinyl, and fluorenyl.
[0165] "Arylene" generically refers to any aryl that has at least two groups attached thereto. For a more specific example, "phenylene" refers to a divalent phenyl ring radical. A phenylene, thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto.
[0166] "Arylalkyl" refers to a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. Both the aryl, and the corresponding alkylene, alkylidene, or alkylidyne radical portion of an arylalkyl group may be optionally substituted. "Lower arylalkyl" refers to an arylalkyl where the "alkyl" portion of the group has one to six carbons; this can also be refered to as C1-6 arylalkyl.
[0167] "Exo-alkenyl" refers to a double bond that emanates from an annular carbon, and is not within the ring system, for example the double bond depicted in the formula below.
Figure imgf000051_0001
[0168] In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups.
[0169] "Fused-polycyclic" or "fused ring system" refers to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
[0170] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. "Haloalkyl" and "haloaryl" refer genetically to alkyl and aryl radicals that are substituted with one or more halogens, respectively. Thus, "dihaloaryl," "dihaloalkyl," "trihaloaryl" etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3 -fluorophenyl is within the scope of dihaloaryl.
[0171] "Heteroarylene" generically refers to any heteroaryl that has at least two groups attached thereto. For a more specific example, "pyridylene" refers to a divalent pyridyl ring radical. A pyridylene, thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto.
[0172] "Heteroatom" refers to O, S, N, or P.
[0173] "Heterocyclyl" refers to a stable three- to fifteen-membered ring radical that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems; and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states. In a specific example, the group -S(O)0-2-, refers to -S- (sulfϊde), -S(O)- (sulfoxide), and -SO2- (sulfone). For convenience, nitrogens, particularly but not exclusively, those defined as annular aromatic nitrogens, are meant to include their corresponding JV-oxide form, although not explicitly defined as such in a particular example. Thus, for a compound of the invention having, for example, a pyridyl ring; the corresponding pyridyl-JV-oxide is meant to be included as another compound of the invention. In addition, annular nitrogen atoms may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic. Examples of heterocyclyl radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.
[0174] "Heteroalicyclic" refers specifically to a non-aromatic heterocyclyl radical. A heteroalicyclic may contain unsaturation, but is not aromatic.
[0175] "Heteroaryl" refers specifically to an aromatic heterocyclyl radical.
[0176] "Heterocyclylalkyl" refers to a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include (4-methylpiperazin-l-yl) methyl, (morpholin-4-yl) methyl, (pyridine-4-yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methylpiperazin-l-yl)-2-butenyl, and the like. Both the heterocyclyl, and the corresponding alkylene, alkylidene, or alkylidyne radical portion of a heterocyclylalkyl group may be optionally substituted. "Lower heterocyclylalkyl" refers to a heterocyclylalkyl where the "alkyl" portion of the group has one to six carbons. "Heteroalicyclylalkyl" refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic; and "heteroarylalkyl" refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is aromatic Such terms may be described in more than one way, for example, "lower heterocyclylalkyl" and "heterocyclyl C1-6alkyl" are equivalent terms.
[0177] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. One of ordinary skill in the art would understand that, with respect to any molecule described as containing one or more optional substituents, that only sterically practical and/or synthetically feasible compounds are meant to be included. "Optionally substituted" refers to all subsequent modifiers in a term, for example in the term "optionally substituted 3TyIC1-8 alkyl," optional substitution may occur on both the "C1-8 alkyl" portion and the "aryl" portion of the molecule; and for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum. A list of exemplary optional substitution are listed below in the definition of "substituted."
[0178] "Saturated bridged ring system" refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-lH-indene, 7-aza-bicyclo[2.2.1]heptane, and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system."
[0179] "Spirocyclyl" or "spirocyclic ring" refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, a ring atom of a saturated bridged ring system (rings B and B'), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto. A spirocyclyl can be carbocyclic or heteroalicyclic.
Figure imgf000054_0001
[0180] "Substituted" alkyl, aryl, and heterocyclyl, refer respectively to alkyl, aryl, and heterocyclyl, wherein one or more (for example up to about five, in another example, up to about three) hydrogen atoms are replaced by a substituent independently selected from: optionally substituted alkyl (for example, fluoromethyl), optionally substituted aryl (for example, 4-hydroxyphenyl), optionally substituted arylalkyl (for example, 1-phenyl-ethyl), optionally substituted heterocyclylalkyl (for example, l-pyridin-3-yl-ethyl), optionally substituted heterocyclyl (for example, 5-chloro-pyridin-3-yl or l-methyl-piperidin-4-yl), optionally substituted alkoxy, alkylenedioxy (for example methylenedioxy), optionally substituted amino (for example, alkylamino and dialkylamino), optionally substituted amidino, optionally substituted aryloxy (for example, phenoxy), optionally substituted arylalkyloxy (for example, benzyloxy), carboxy (-CO2H), carboalkoxy (that is, acyloxy or -OC(=O)R), carboxyalkyl (that is, esters or -CO2R), carboxamido, benzyloxycarbonylamino (CBZ-amino), cyano, acyl, halogen, hydroxy, nitro, sulfanyl, sulfinyl, sulfonyl, thiol, halogen, hydroxy, oxo, carbamyl, acylamino, and sulfonamido.
[0181] "Suitable leaving group" is defined as the term would be understood by one of ordinary skill in the art; that is, a carbon with such a group attached, upon reaction wherein a new bond is to be formed, loses such a group upon formation of the new bond. The invention pertains particularly with respect convergent synthesis, to reactions where such a leaving group is bonded to a reaction partner that is aromatic, undergoes a bond- forming reaction and remains aromatic. A typical example of such a reaction is a nucleophilic aromatic substitution reaction, as would be understood by one of ordinary skill in the art. However, the invention is not limited to such mechanistic restrictions; for example, reactions where there is, for example, an insertion reaction (for example by a transition metal) into the bond between the aromatic reaction partner and its leaving group followed by reductive coupling can also be used within the scope of the invention. Examples of suitable leaving groups include halogens, optionally substituted aryl or alkyl sulfonates, phosphonates, azides, RS(0)o-2- where R is, for example optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
[0182] "Sulfanyl" refers to the groups: -S-(optionally substituted alkyl), -S-(optionally substituted aryl), and -S-(optionally substituted heterocyclyl).
[0183] "Sulfinyl" refers to the groups: -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-optionally substituted aryl), and -S(O)-(optionally substituted heterocyclyl).
[0184] "Sulfonyl" refers to the groups: -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(θ2)-optionally substituted aryl), -S(O2)-(optionally substituted heterocyclyl), -S(O2)-(optionally substituted alkoxy), -S(O2)-optionally substituted aryloxy), and -S(O2)-(optionally substituted heterocyclyloxy).
[0185] "Yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield.
[0186] Some of the compounds of the invention may have imino, amino, oxo or hydroxy substiruents off aromatic heterocyclyl systems. For purposes of this disclosure, it is understood that such imino, amino, oxo or hydroxy substituents may exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.
[0187] Compounds of the invention are named according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), International Union of Biochemistry and Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS).
[0188] The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure.
[0189] The compounds of the invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
[0190] It is assumed that when considering generic descriptions of compounds of the invention for the purpose of constructing a compound, such construction results in the creation of a stable structure. That is, one of ordinary skill in the art would recognize that there can theoretically be some constructs which would not normally be considered as stable compounds (that is, sterically practical and/or synthetically feasible, supra).
[0191] When a particular group with its bonding structure is denoted as being bonded to two partners; that is, a divalent radical, for example, -OCH2-, then it is understood that either of the two partners may be bound to the particular group at one end, and the other partner is necessarily bound to the other end of the particular group, unless stated explicitly otherwise. Stated another way, divalent radicals are not to be construed as limited to the depicted orientation, for example "-OCH2-" is meant to mean not only "-OCH2-" as drawn, but also "-CH2O-."
[0192] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
[0193] "Patient" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human.
[0194] "Kinase-dependent diseases or conditions" refer to pathologic conditions that depend on the activity of one or more protein kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).
[0195] While not wishing to be bound to theory, phosphatases can also play a role in "kinase-dependent diseases or conditions" as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example protein substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family. In any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth. [0196] "Therapeutically effective amount" is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
[0197] "Cancer" refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal lands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions.
[0198] "Pharmaceutically acceptable acid addition salt" refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
[0199] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylarnme, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
[0200] "Prodrug" refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) wherein the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
[0201] "Metabolite" refers to. the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics" 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure. [0202] In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
[0203] In addition, it is intended that the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.
[0204] "Treating" or "treatment" as used herein covers the treatment of a disease-state in a human, which disease-state is characterized by abnormal cellular proliferation, and invasion and includes at least one of: (i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it; (ii) inhibiting the disease-state, i.e., arresting its development; and (iii) relieving the disease-state, i.e., causing regression of the disease-state. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.
[0205] One of ordinary skill in the art would understand that certain crystallized, protein- ligand complexes, in particular c-Met, c-Kit, KDR, flt-3, or flt-4-ligand complexes, and their corresponding x-ray structure coordinates can be used to reveal new structural information useful for understanding the biological activity of kinases as described herein. As well, the key structural features of the aforementioned proteins, particularly, the shape of the ligand binding site, are useful in methods for designing or identifying selective modulators of kinases and in solving the structures of other proteins with similar features. Such protein-ligand complexes, having compounds of the invention as their ligand component, are an aspect of the invention.
[0206] As well, one of ordinary skill in the art would appreciate that such suitable x-ray quality crystals can be used as part of a method of identifying a candidate agent capable of binding to and modulating the activity of kinases. Such methods may be characterized by the following aspects: a) introducing into a suitable computer program, information defining a ligand binding domain of a kinase in a conformation (e.g. as defined by x-ray structure coordinates obtained from suitable x-ray quality crystals as described above) wherein the computer program creates a model of the three dimensional structures of the ligand binding domain, b) introducing a model of the three dimensional structure of a candidate agent in the computer program, c) superimposing the model of the candidate agent on the model of the ligand binding domain, and d) assessing whether the candidate agent model fits spatially into the ligand binding domain. Aspects a-d are not necessarily carried out in the aforementioned order. Such methods may further entail: performing rational drug design with the model of the three-dimensional structure, and selecting a potential candidate agent in conjunction with computer modeling.
[0207] Additionally, one skilled in the art would appreciate that such methods may further entail: employing a candidate agent, so-determined to fit spatially into the ligand binding domain, in a biological activity assay for kinase modulation, and determining whether said candidate agent modulates kinase activity in the assay. Such methods may also include administering the candidate agent, determined to modulate kinase activity, to a mammal suffering from a condition treatable by kinase modulation, such as those described above.
[0208] Also, one skilled in the art would appreciate that compounds of the invention can be used in a method of evaluating the ability of a test agent to associate with a molecule or molecular complex comprising a ligand binding domain of a kinase. Such a method may be characterized by the following aspects: a) creating a computer model of a kinase binding pocket using structure coordinates obtained from suitable x-ray quality crystals of the kinase, b) employing computational algorithms to perform a fitting operation between the test agent and the computer model of the binding pocket, and c) analyzing the results of the fitting operation to quantify the association between the test agent and the computer model of the binding pocket.
General Administration
[0209] Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
[0210] The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Compositions of the invention may be used in combination with anticancer or other agents that are generally administered to a patient being treated for cancer. Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[0211] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
[0212] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
[0213] One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
[0214] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
[0215] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
[0216] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
[0217] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
[0218] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
[0219] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
[0220] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
[0221] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
[0222] The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
Utility of compounds of the invention as screening agents
[0223] To employ the compounds of the invention in a method of screening for candidate agents that bind to, for example c-Met, KDR, c-Kit, flt-3, or flt-4, the protein is bound to a support, and a compound of the invention is added to the assay. Alternatively, the compound of the invention is bound to the support and the protein is added. Classes of candidate agents among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells. A wide variety of assays may be used for this purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.) and the like.
[0224] The determination of the binding of the candidate agent to, for example, c-Met, KDR, c-Kit, flt-3, or flt-4 protein may be done in a number of ways. In one example, the candidate agent (the compound of the invention) is labeled, for example, with a fluorescent or radioactive moiety and binding determined directly. For example, thus may be done by attaching all or a portion of the c-Met, KDR, c-Kit, flt-3, or flt-4 protein to a solid support, adding a labeled agent (for example a compound of the invention in which at least one atom has been replaced by a detectable isotope), washing off excess reagent, and determining whether the amount of the label is that present on the solid support. Various blocking and washing steps may be utilized as is known in the art.
[0225] ■ By "labeled" herein is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, etc. Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc. For the specific binding members, the complementary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above. The label can directly or indirectly provide a detectable signal.
[0226] In some embodiments, only one of the components is labeled. For example, c-Met, KDR, c-Kit, flt-3, or flt-4 protein may be labeled at tyrosine positions using 125I, or with fluorophores. Alternatively, more than one component may be labeled with different labels; using 125I for the proteins, for example, and a fluorophor for the candidate agents.
[0227] The compounds of the invention may also be used as competitors to screen for additional drug candidates. "Candidate bioactive agent" or "drug candidate" or grammatical equivalents as used herein describe any molecule, e.g., protein, oligopeptide, small organic molecule, polysaccharide, polynucleotide, etc., to be tested for bioactivity. They may be capable of directly or indirectly altering the cellular proliferation phenotype or the expression of a cellular proliferation sequence, including both nucleic acid sequences and protein sequences. In other cases, alteration of cellular proliferation protein binding and/or activity is screened. In the case where protein binding or activity is screened, some embodiments exclude molecules already known to bind to that particular protein. Exemplary embodiments of assays described herein include candidate agents, which do not bind the target protein in its endogenous native state, termed herein as "exogenous" agents. In one example, exogenous agents further exclude antibodies to c- Met, KDR, c-Kit, flt-3, or flt-4.
[0228] Candidate agents can encompass numerous chemical classes, though typically they are organic molecules having a molecular weight of more than about 100 daltons and less than about 2,500 daltons. Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding and lipophilic binding, and typically include at least an amine, carbonyl, hydroxyl, ether, or carboxyl group, for example at least two of the functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclyl structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof. [0229] Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification to produce structural analogs.
[0230] In one example, the binding of the candidate agent is determined through the use of competitive binding assays. In this example, the competitor is a binding moiety known to bind to c-Met, KDR, c-Kit, flt-3, or flt-4, such as an antibody, peptide, binding partner, ligand, etc. Under certain circumstances, there may be competitive binding as between the candidate agent and the binding moiety, with the binding moiety displacing the candidate agent.
[0231] In some embodiments, the candidate agent is labeled. Either the candidate agent, or the competitor, or both, is added first to for example c-Met, KDR, c-Kit, flt-3, or flt-4 for a time sufficient to allow binding, if present. Incubations may be performed at any temperature that facilitates optimal activity, typically between 4°C and 4O°C
[0232] Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high throughput screening. Typically between 0.1 and 1 hour will be sufficient. Excess reagent is generally removed or washed away. The second component is then added, and the presence or absence of the labeled component is followed, to indicate binding.
[0233] In one example, the competitor is added first, followed by the candidate agent. Displacement of the competitor is an indication the candidate agent is binding to c-Met, KDR, c-Kit, flt-3, or flt-4 and thus is capable of binding to, and potentially modulating, the activity of the c-Met, KDR, c-Kit, flt-3, or flt-4. In this embodiment, either component can be labeled. Thus, for example, if the competitor is labeled, the presence of label in the wash solution indicates displacement by the agent. Alternatively, if the candidate agent is labeled, the presence of the label on the support indicates displacement. [0234] In an alternative embodiment, the candidate agent is added first, with incubation and washing, followed by the competitor. The absence of binding by the competitor may indicate the candidate agent is bound to c-Met, KDR, c-Kit, flt-3, or flt-4 with a higher affinity. Thus, if the candidate agent is labeled, the presence of the label on the support, coupled with a lack of competitor binding, may indicate the candidate agent is capable of binding to c-Met, KDR, c-Kit, flt-3, or flt-4.
[0235] It may be of value to identify the binding site of c-Met, KDR, c-Kit, flt-3, or flt-4. This can be done in a variety of ways. In one embodiment, once c-Met, KDR, c-Kit, flt-3, or flt-4 has been identified as binding to the candidate agent, the c-Met, KDR, c-Kit, flt-3, or flt-4 is fragmented or modified and the assays repeated to identify the necessary components for binding.
[0236] Modulation is tested by screening for candidate agents capable of modulating the activity of c-Met, KDR, c-Kit, flt-3, or flt-4 comprising the steps of combining a candidate agent with c-Met, KDR, c-Kit, flt-3, or flt-4, as above, and determining an alteration in the biological activity of the c-Met, KDR, c-Kit, flt-3, or flt-4. Thus, in this embodiment, the candidate agent should both bind to (although this may not be necessary), and alter its biological or biochemical activity as defined herein. The methods include both in vifro screening methods and in vivo screening of cells for alterations in cell viability, morphology, and the like.
[0237] Alternatively, differential screening may be used to identify drug candidates that bind to native c-Met, KDR, c-Kit, flt-3, or flt-4, but cannot bind to modified c-Met, KDR, c-Kit, flt-3, or flt-4.
[0238] Positive controls and negative controls may be used in the assays. For example, all control and test samples are performed in at least triplicate to obtain statistically significant results. Incubation of samples is for a time sufficient for the binding of the agent to the protein. Following incubation, samples are washed free of non-specifically bound material and the amount of bound, generally labeled agent determined. For example, where a radiolabel is employed, the samples may be counted in a scintillation counter to determine the amount of bound compound.
[0239] A variety of other reagents may be included in the screening assays. These include reagents like salts, neutral proteins, e.g., albumin, detergents, etc which may be used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Also reagents that otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc., may be used. The mixture of components may be added in any order that provides for the requisite binding.
Abbreviations and their Definitions 40] The following abbreviations and terms have the indicated meanings throughout. Abbreviation Meanin
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Synthesis of Compounds [0241] Scheme 1 depicts a general synthetic route for compounds of the invention and is not intended to be limiting. More specifically, Scheme 1 depicts synthesis of quinoline compounds. Specific examples are described subsequently to these general synthetic descriptions so as to allow one skilled in the art to make and use quinolines of the invention.
Scheme 1
Figure imgf000073_0001
[0242] Scheme 1 shows a general route used to make exemplary quinolines of the invention. For example, compound 9 contains an alkyl group, R1, a protecting group, P. The arrangement of the protected and alkylated phenolic oxygens may vary from the pattern depicted in compound 9. Compound 9 is nitrated to provide compound 10. The nitro group of compound 10 is reduced to give aniline 11. Compound 11 is treated, for example, with ethyl formate under basic conditions followed by acidification and isolation to form 4-hydroxy quinoline 12. Quinoline 12 may be converted to compounds of the invention in a number of ways. For example, the 4-oxygen is used as a nucleophile in a nucleophilic aromatic substitution reaction to form quinoline-aryl-ether 13. In another example, compound 13 is further derivatized, via removal of protecting group P, to afford compound 14. The 7-hydroxy of compound 14 is alkylated, for example with electrophile E, to provide a compound of the invention. As discussed in relation to Scheme 1, variations on any of the above steps are possible, and intermediates in these schemes, for example compounds 12, 13, and 14 may also be compounds of the invention according to formula I. Also, for example, the 4-hydroxy quinoline compound 12 are converted to a corresponding 4-nitrogen or 4-sulfur quinoline using chemistry known in the art to make compounds of the invention, or alternatively the corresponding 4-nitrogen or 4-sulfur quinolines are made via routes analogous to that depicted in Scheme 1.
[0243] Scheme 1 is illustrative of quinolines having oxygen substitution at their respective 6- and 7-positions; the invention is not so limited, but rather is intended to encompass quinolines not necessarily having substitution, oxygen or otherwise, at their respective 6- or 7-positions.
[0244] Schemes 2 and 3 depict generalized synthetic routes to show the process of the invention to make compounds of formua XXI and is not intended to be limiting. More specifically, Schemes 2 and 3 depict convergent syntheses of quinoline compounds as described herein. Specific examples are described subsequently to this general synthetic description so as to allow one of ordinary skill in the art to practice the invention.
[0245] Referring to Scheme 2, a benzoic ester 16 for example, where R is typically but not necessarily a methyl radical and R1 is typically but not necessarily one or more alkoxy or hydroxy groups. In a typical synthesis, at least one of R1 within Scheme 2 is a hydroxyl which is converted (or protected )via one or more steps to a group important to the activity of the compounds as described as kinase modulators (in the case that -OH itself is desired in the final compound, then deprotection affords the -OH, vide supra). Preferably, but not necessarily, this group is complete once the synthesis of XXII is complete. By building desired complexity into XXII prior to combination with XXIII, convergent syntheses' advantages over serial syntheses are realized more fully. Regioselective aromatic ring nitration, and reduction of the corresponding nitro group, are carried out in a regio- and chemoselective manner by methods well known in the art to give anthranilate derivative 17. Formation of quinoline 4-one 18 is carried out by methods well known in the art. For example by heating 17 in formamide solution in the presence of ammonium formate. In another example 17 is treated, for example, with ethyl formate under basic conditions followed by acidification and isolation to form the 4-hydroxy quinoline analog (a tautomer of the 4-one). Radical R70 is in accord with formula XXI. Introduction of 4-position functionality is carried out by methods known in the art. For example, 4-one 18 is converted to XXII, where "P1" represents a suitable leaving group (in accord with formula XXI), e.g. chlorine (via dehydration/chlorination of 18 to give XXII). In another example, a 4-hydroxy analog is converted to a sulfonyl ester, e.g. the trifluoromethane sulfonate.
Scheme 2
Figure imgf000075_0001
46] Sc eme 3 shows a general route used to make compounds of formula XXIII. For example, aromatic compound 19, where "X" is a leaving group, such as fluorine and "E" is an electron withdrawing group such as nitro, is converted to 20 by reaction with a range of nucleophiles, e.g. amines, alcohols, and thiols (where "Z" is oxygen, nitrogen (substituted or not), or sulfur). In this case, "R" represents a removable group, for example benzyl. In a typical synthesis, after formation of 20, group "E" is either left "as is" or converted at some subsequent stage to a derivative thereof. In the example depicted, E is converted to B', a precursor to B in accord with formula XXI, to make 21. For example if E is a nitro, then B' could might be an amino group, made via reduction of the nitro group. Structure 21 may be further derivitized by synthesis of -B-L-T in accord with formula XXI. In scheme 3, this is depicted as a serial process whereby L', a precursor to L, is introduced to give 22, followed by introduction of T' (a precursor to T) to give 23. In some cases, -L-T is preformed and appended to B. One of ordinary skill in the art would appreciate that variations on any of the above steps are possible. Compound 23 is converted to XXIII via conversion of T' to T and introduction of P2 (for example, when R is benzyl, removal of the benzyl after completion of -B-L-T). Scheme 3
Figure imgf000076_0001
[0247] As discussed above, one aspect of the invention encompasses combination of XXII and XXIII to make compounds of formula XXI. Because of the diversity and complexity of compounds described for kinase modulation (vide supra), methods of the invention provide advantages to serial synthesis.
Figure imgf000076_0002
Examples
[0248] The following examples serve to more fully describe the manner of using the above-described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes. All references cited herein are incorporated by reference in their entirety. Generally, but not necessarily, each example set out below describes a multi-step synthesis as outlined above.
Quinoline Syntheses Example 1
Figure imgf000077_0001
[0249] Synthesis of l-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone. l-(4-
Benzyloxy-3-methoxy-phenyl)-ethanone (200 mmol, 51.3 g) dissolved in DCM (750ml) and the mixture cooled to 0° C. Nitric acid (90%, 300 mmol, 14 ml) was added dropwise to the cooled solution over 20 minutes. Sulfuric acid (96.2%, 300 mmol, 8.75 ml) was then added dropwise over 40 minutes at 0° C.
[0250] Additional nitric acid (200 mmol, 9.4 ml) was added dropwise over 20 minutes. The reaction mixture was diluted with water (300 ml) and wash with water (3 X 200 ml), Sat. NaHC(B (4 X 200 ml, or until neutral). The organic layer was dried over Na2SO4 and concentrated.
[0251] The crude mixture was recrystallized with DMF to give 22.5 g of the nitro product. The DMF layer was concentrated and recrystallized with ethyl acetate to give additional 8.75g of the product. The ethyl acetate layer was concentrated and purified on silica column using 20% EtOAc/hexanes to gave another 4.75 g of the product. Total yield is 36 g, (-60%). IH NMR (CDC13): 7.647 (IH, s), 7.446-7.333 (5H, m), 6.745 (IH, s), 5.210 (2H, s), 3.968 (3H, s), 2.487 (3H, s).
Example 2
Figure imgf000077_0002
[0252] Synthesis of l-(2-Amino-4-benzyloxy-5-methoxy-phenyl)-ethanone. A Mixture of iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31.g), l-(4-Benzyloxy-5- methoxy-2-nitro-phenyl)-ethanone (120 mmol, 36 g), toluene (500 ml) and water (500 ml) was refluxed overnight, or until completion. The mixture was filtered through celite and washed with EtOAc. The organic layer was washed with water and Sat. NaCl, dried over Na2SO4, and concentrated to afford the product, 90%. IH NMR (CDC13): 7.408-7.298 (5H, m), 7.130 (IH, s), 6.155 (2H, br), 6.104 (IH, s), 5.134 (2H, s), 3.834 (3H, s), 2.507 (3H, s). LC/MS (M+l = 272).
Example 3
Figure imgf000078_0001
[0253] Synthesis of 7-Benzyloxy-6-methoxy-quinolin-4-ol. To a solution of l-(2-Amino- 4-benzyloxy-5-methoxy-phenyl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (Additional sodium methoxide may be needed if reaction is not complete as monitored by LC/MS.) After the reaction was completion, the mixture was diluted with water (40 ml) and acidified to neutral with IM HCl. The precipitate was filtered and washed with water, dried in vacuo to afford 22g (72%) of 7-benzyloxy-6-methoxy-quinolin-4-ol. IH NMR (CDC13): 10.7 (IH, br), 7.703 (IH, s), 7.493-7.461 (IH, t), 7.431-7.413 (2H, br d), 7.372- 7.333 (2H, 1), 7.296-7.283 (IH, d), 6.839 (IH, s), 6.212-6.193 (IH, d), 5.212 (2H, s), 3.965 (3H, s). LC/MS (M+l = 282).
Example 4
Figure imgf000078_0002
[0254] 7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline. To a round bottom flask equipped with a magnetic stir bar was added 7-Benzyloxy-6-methoxy-lH- quinolin-4-one (12.2 g, 43.3 mmol, 1.0 eq.), acetonitrile (150ml), DMF (150ml) and cesium carbonate (28.2 g, 86.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 30 minutes at which time l,2-difluoro-4-nitro-benzene (7.57 g, 47.6 mmol, 1.1 eq) was added over a 10 minute period. After 2 hours the reaction was complete at which time 75% of the MeCN and DMF was removed and the resulting solution was poured over into ice water. The solid was filtered and dried and further columned with a biotage system. The eluent was 1:3 ethyl acetate/hexane. Removal of the solvent afforded 7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline as a pale green solid (7.4 g, 41% yield). 1H NMR (400 MHz, CDCl3): 8.53 (d, IH), 8:42 (dd, IH), 8.16 (m, IH), 7.5 (m, 8H), 6.76 (d, IH), 5.31 (s, 2H), 3.92 (s, 3H); MS (EI) for C23H27FN2O5: 421 (MH+).
Figure imgf000079_0002
55] 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-oL To a round bottom flask equipped with a magnetic stir bar was added 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6- methoxy-quinoline (2.9 g, 6.9 mmol, l.Oeq) and 33% HBr in acetic acid (30 ml). The mixture was stirred at room temperature for 3 hours and diluted with ether to give a pale white solid. The solid was filtered, washed with ether and dried to yield 4-(2-Fluoro-4- nitro-phenoxy)-6-methoxy-quinolin-7-ol as a pale white solid (2.74 g, 97.5% yield). 1H NMR (400 MHz, CDCl3): 11.89 (bs, IH), 8.87 (d, IH), 8.57 (d, IH), 8.30 (d, IH), 7.89 (m, IH), 7.73 (s, IH), 7.55 (s, IH), 4.03 (s, 3H); MS (EI) for Ci6H11FN2O5: 421 (IVH-H+).
Example 6
Figure imgf000079_0001
[0256] 5-[4-(2-Fluoro-4-ni1jo-plienoxy)-6-methoxy-quinolm-7-yloxymethyl]-hexahvdro- cyclopentarc]pyrrole-2-carboxylic acid benzyl ester. To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (2.74 g, 6.7 mmol, 1.0 eq.), DMA (30ml) and cesium carbonate (6.6 g, 20.2 mmol, 3.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 5- methanesulfonyloxymethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (2.6 g, 7.3 mmol, 1.1 eq) was added. The reaction was heated to 75° C and allowed to stir overnight. After allowing the reaction to cool to room temperature the reaction was poured into water. The solid was filtered and was then dissolved in EtOAc and washed 2X water, IX brine and dried over NaSO4. The solvent was removed to yield 5-[4-(2- Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydro- cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester as a cream solid (3.7 g, 94% yield). 1H NMR (400 MHz, CDCl3): 8.55 (d, IH), 8.15 (d, IH), 8.09 (d, IH), 7.32 (m, 8H), 6.52 (d, IH), 5.11 (d, 2H), 4.13 (d, 2H), 3.95 (s, 3H), 3.57 (m, 2H), 3.43 (m, 2H), 2.93 (m, 3H), 2.16 (m, 2H), 1.39 (m, 2H); MS (EI) for C32H30FN3O7: 588 (M+H+).
Example 7
Figure imgf000080_0001
[0257] 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopentarc1pyrrol-5- ylmethoxy)-qumoline. To a round bottom flask equipped with a magnetic stir bar was added 5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]- hexahydrocyclopenta-[c]pyrrole-2-carboxylic acid benzyl ester (2.5 g, 4.1 mmol, l.Oeq), 33% HBr in acetic acid (5 ml) and acetic acid (5 ml). The mixture was stirred at room temperature for 1 hour and diluted with EtOAc to give a pale orange solid. The solid was filtered, washed with EtOAc and dried, giving 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7- (octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 95% yield). 1H NMR (400 MHz, CDCl3): 8.83 (d, IH), 8.32 (m, 2H), 8.02 (s, IH), 7.76 (t, IH), 7.65 (s, IH), 6.89 (d, IH), 5.3 (d, 2H), 4.11 (m, 3H)5 3.26 (m, 4H)5 2.95 (m, 2H), 2.68 (m, 3H), 2.36 (m5 2H), 1.68 (m, 2H); MS (EI) for C24H24FN3O5: 454 (MR-H+).
Example 8
Figure imgf000081_0001
[0258] 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydro- cvclopenta["c]pyrrol-5-ylmethoxy)-quinoline. To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro- cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 3.9 mmol, 1.0 eq.) and acetonitrile/water 1:1 (5ml, 5ml). The reaction mixture was then cooled to 0° C and 37% solution of formaldehyde in water was added (0.2 g, 7.8 mmol, 2.0 eq). While keeping the temperature at O0C Na(OAc)3BH was added (4.4g, 20.7 mmol, 3.0 eq). After 1 hour the pH was adjusted to 10 and the aqueous was extracted 2 x DCM (100 ml). Removal of the DCM resulted in a white solid. The compound was further purified with a biotage system using an eluent EtOAc and 5% MeOH, affording 4-(2-Fluoro-4-nitro-phenoxy)-6- methoxy-7-(2-methyl-octahydrocyclopenta-[c]pyrrol-5-ylmethoxy)-quinoline (0.9 g, 50% yield). ). 1H NMR (400 MHz, CDCl3): 8.57 (d, IH), 8.14 (dd, IH), 8.12 (dd, IH), 7.41 (s, 2H), 7.34 (t, IH), 6.54 (d, IH), 4.19 (d, 2H), 4.01 (s, 3H), 2.61 (m, 4H), 2.43 (m, IH), 2.33 (s, 3H), 2.11 (m, 4H), 1.32 (m, 2H); MS (EI) for C25H26FN3O5: 468 (M+H+).
Example 9
Figure imgf000082_0001
[0259] 3-Fluoro-4-r6-methoxy-7-(2-methyl-octaliydro-cvclopenta['c]pyrrol-5-ylmethoxy)- quinolin-4- yloxyl -phenylamine. To a par hydrogenation reaction vessel was added 4-(2- fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5- ylmethoxy)-quinoline (0.800 g, 1.6 mmol, 1.0 eq.), DMF (50 ml), EtoAc (50ml), MeOH (50ml), TEA (5ml) and 10% Pd/C (200 mg). The vessel was placed on the par hydrogenator at 35 psi overnight. The Pd was filtered and the solvent removed to give 3- fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin- 4-yloxy] -phenylamine as an off yellow solid (0.78 g, 99% yield). 1H NMR (400 MHz, CDCl3): 8.45 (d, IH), 7.57 (s, IH), 7.36 (s, IH), 7.05 (t, IH), 6.54 (m, 2H), 6.39 (d, IH), 4.16 (d, 2H), 4.01 (s, 3H), 3.81 (m, 3H), 2.61 (m, 3H), 2.41 (m, IH), 2.29 (s, 3H), 2.23 (m, 2H), 1.32 (m, 2H); MS (EI) for C25H28FN3O3: 438 (M+H+).
Example 10
Figure imgf000082_0002
[0260] l-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[clpyriOl-5- ylmethoxy)-qumolin-4-yloxy] -phenyl 1-3 -phenylacetyl-thiourea. To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4-[6-methoxy-7-(2-methyl- octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenylamme (0.78 mg, 1.7 mmol, 1.0 eq.), toluene (10ml), ethanol (10ml) and phenyl-acetyl isothiocyanate (1.64 g, 9.2 mmol, 4.5 eq). The reaction mixture was stirred at room temperature overnight. After removal of the solvent the product was purified with a biotage system using an eluent EtOAc and 4% TEA (2L) then EtOAc, 4% TEA3 1% MeOH (IL). The solvent was removed to give l-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5- ylmethoxy)-quinolm-4-yloxy] -phenyl} -3 -phenylacetyl-thiourea (0.5 g, 50% yield). 1H NMR (400 MHz, DMSO): 8.48 (d, IH), 7.92 (dd, IH), 7.53 (s, IH), 7.40 (m, 4H), 7.33 (d, 2H), 7.23 (m, 2H), 6.54 (d, 2H), 6.39 (d, IH), 4.21 (d, 2H), 4.02 (s, 3H), 3.81 (m, 3H), 2.87 (d, 2H), 2.73 (m, 4H), 2.53 (m, IH), 2.27 (m, 2H), 2.01 (s, 3H), 1.36 (m, 2H); MS (EI) for C34H35FN4O4S: 615 (M+ϊt).
Example 11
Figure imgf000083_0001
[0261] 6-(6,7-Dimethoxy-quinolm-4-yloxy)-5-fluoro-benzothiazol-2-ylamme. 4-(6,7- dimethoxy-qumolin-4-yloxy)-3-fluoiO-phenylamine (1.0Og, 3.18mmol) was dissolved in AcOH (8.0ml), to which was added NH4SCN (486mg, 6.38mmol) and the mixture cooled in an ice bath. Br2 (0.33ml, 6.42mmol) in AcOH (0.33ml) was added dropwise with stirring. After addition was complete, the reaction mixture was stirred at room temperature. After one hour, more NH4SCN (1.Og, 13.1mmol) was added, followed by more Br2 (0.33ml, 6.42mmol) in AcOH (0.33ml), dropwise with stirring. The reaction mixture was then heated to reflux for several minutes. Upon cooling to room temperature, solids were filtered and washed with AcOH, followed by H2O. The volume of the filtrate was reduced in vacuo and the pH adjusted to pH 9-10 with 1.0N NaOH. The resulting solids were filtered, washed with H2O, and dried under high vacuum to give 6-(6,7- dimethoxy-quinolin-4-yloxy)-5-fluoro-benzotbiazol-2-ylamine (568mg, 48%). 1H-NMR (400MHz, DMSO): 8.45 (d, IH), 7.82 (d, IH), 7.73 (br s, 2H), 7.53 (s, IH), 7.38 (m, 2H), 6.44 (d, IH), 3.94 (s, 6H). LC/MS Calcd for [M+H]+ 372.1, found 372.2
Example 12
Figure imgf000084_0001
[0262] N-[6-f6,7-Dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-plienyl- acetamide. 6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (95mg, 0.25mmol), Et3N (0.10ml, 0.72mmol), phenylacetyl chloride (0.044ml, 0.33mmol), and THF (1.0ml) were combined and stirred at room temperature for 1 hr. Additional phenylacetyl chloride (0.044ml, 0.33mmol) was added and the mixture heated to reflux for 1-2 hrs. After cooling to room temperature, the reaction mixture was diluted with 1:1 AcC]ShH2O (1.0ml) and the resulting solids filtered, washed with 1:1 AcCN:H2O and dried under high vacuum to give N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol- 2-yl]-2-phenyl-acetamide (72mgs, 59%). 1H-NMR (400MHz, DMSO): 12.80 (s, IH), 8.54 (d, IH), 8.18 (d, IH), 7.91 (d, IH), 7.60 (s, IH), 7.45 (s, IH), 7.34 (m, 4H), 7.28 (m, IH), 6.60 (d, IH), 3.98 (s, 3H), 3.96 (s, 3H), 3.86 (s, 2H). LC/MS Calcd for [M+H]+ 490.1, found 490.0.
Example 13
Figure imgf000084_0002
[0263] 6,7-Dimethoxy-4-f5-mtro-pyridin-2-yloxy)-quinoline. To a round bottom flask equipped with a magnetic stir bar was added 6,7-dimethoxy-lff-quinolin-4-one (1.8 g, 8.77 mmol, 1.0 eq.), anhydrous acetonitrile (90 mL) and Cs2CO3 (3.13 g, 9.65 mmole, 1.1 eq.). The reaction mixture was stirred at room temperature for 5 minutes. Then, 2-C1-5- nitropyridine (1.53 g, 9.65 mmol, 1.1 eq.) was added. The reaction mixture was stirred at room temperature for 16 hours. The solids were then filtered off and the filtrate was concentrated via rotary evaporation. The resulting material was taken up in EtOAc, and again the solids were filtered off. The EtOAc filtrate was concentrated. Purification was done on Biotage with solvent system EtOAc 100%. The collected pure fractions were concentrated and dried on high vacuum overnight to give 6,7-dimethoxy-4-(5-nitro- pyridin-2-yloxy)-quinoline as a yellow foam solid (0.902 g, 31.4% yield). 1H NMR (400 MHz, CDC13): 9.08 (d, IH), 8.74 (d, IH), 8.60 (dd, IH), 7.49 (s, IH), 7.26 (d, IH), 7.16 (s, IH), 7.07 (d, IH), 4.06 (s, 3H), 3.95 (s, 3H); MS (EI) for C16H13N3O5: 328 QA+ϊf).
Example 14
Figure imgf000085_0001
[0264] 6-(6,7-Dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine. To a round bottom flask equipped with a magnetic stir bar was added 6,7-dimethoxy-4-(5-nitro-pyridin-2-yloxy)- quinoline (0.46 g, 1.41 mmol, 1.0 eq.), and THF (10 mL), MeOH (4 mL), DMF (2 mL), and TEA (2 mL). The 6,7-Dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline was dissolved completely in the above solution mixture, and was flushed with nitrogen for at least 5 minutes. The Pd/C (10% by weight) (0.090 g, 20% by weight) was then added. A balloon filled with H2 was connected to the flask after the nitrogen was vacuumed out. The reaction mixture was stirred at room temperature for 4 hours. The palladium was filtered out through Celite, and the filtrated was collected and concentrated via rotary evaporation. The resulting oil-like product was taken up into 5 mL of water and 1 mL of acetonitrile and lyophilized to yield 6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine as a light brown solid (0.411 g, 98.1%). 1H NMR (400 MHz, CDC13): 8.54 (d, IH), 7.85 (d, IH), 7.53 (s, IH), 7.41 (s, IH), 7.18 (dd, IH), 6.96 (d, IH), 6.61 (d, IH), 4.05 (s, 3H), 4.03 (s, 3H), 3.73 (s, 2H); MS (EI) for C16H15N3O3: 298 (M+H÷).
Example 15
Figure imgf000085_0002
[0265] l-r6-r6,7-Dimethoxy-quinolin-4-yloxy)-pyridin-3-yll-3-phenylacetyl-thiourea. To a round bottom flask equipped with a magnetic stir bar was added 6-(6,7-dimethoxy- quinolin-4-yloxy)-pyridin-3-ylamine (85 mg, 0.0285 mmol, 1.0 eq.), and Phenyl-acetyl isothiocyanate (256 mg, 1.44 mmol, 5.0 eq.) dissolved in EtOAc/MeOH 50:50 (2 mL). The reaction mixture was sittred at room temperature for 12 hours, and the solvent was evaporated via rotary evaporation. Purification was done on Biotage with solvent system 95% EtOAc, 4% TEA and 1% MeOH. The combined pure fractions were concentrated and dried under vacuum overnight to yield l-[6-(6,7-dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-3-phenylacetyl-thiourea as a light yellow solid (40.4 mg, 29.7%). 1H NMR (400 MHz, CDC13): 8.65 (d, IH), 8.33 (d, IH), 8.27 (dd, IH), 7.35 (m, 7H), 7.15 (d, IH), 6.92 (d, IH), 4.05 (s, 3H), 3.99 (s, 3H), 3.76 (s, 2H); MS (EI) for C25H22N4O4S: 475 (MH-H+).
Example 16
Figure imgf000086_0001
[0266] N- [4-(6,7-Dimethoxy-quinolin-4-yloxy)-3 -fluoro-phenyl] -N'-phenethyl-oxalamide. To a solution of 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (263 mg, 0.83 mmol) and Et3N (0.223 ml, 1.67 mmol) in CH2Cl2 (10 mL) was added dropwise a solution of ethyl oxalyl chloride in CH2Cl2 (1 mL). The stirring was continued for 0.5 h at rt. The reaction mixture was then washed with aqueous saturated NaHCO3 and dried over NaSO4. Removal of the solvent gave the crude oxamate, which was treated with neat phenethylamine (1.0 g, 8.3 mmol) at 80 °C for 3 h. Purification by flash column chromatography (hexanes:EtOAc = 1:3) gave N-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3- fluoro-phenyl]-N'-phenethyl-oxalamide (310 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 9.35 (br s, 1 H), 8.70 (d, J= 6.3 Hz, 1 H), 7.83 (dd, J= 11.9, 2.5 Hz, 1 H), 7.60-7.54 (m, 2 H), 7.43 (s, 1 H), 7.38-7.32 (m, 3 H), 7.30-7.20 (m, 4 H), 6.41 (d, J= 5.3 Hz, 1 H), 4.07 (s, 3 H), 4.05 (s, 3 H), 3.67 (dt, J= 7.0, 7.0 Hz, 2 H), 2.92 (t, J= 7.2 Hz, 2 H). LC-MS: 490 [M+H]+.
Example 17
Figure imgf000087_0001
[0267] N-{3-Fluoro-4-r6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy] -phenyll -N'-phenethyl-oxalamide. To a flask containing 7-benzyloxy-4-(2-fmoro-4- nitro-phenoxy)-6-methoxy-quinoline (850 mg, 2.0 mmol) was added 20 mL of 30% HBr in AcOH. The resulted solution was stirred for 4 h at rt; at this time, a large amount of precipitate formed. The crude product was filtered, washed with Et2O and dried in air, giving 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 92% yield).
[0268] To a solution of the 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 1.8 mmol) in DMF (9 mL) was added K2CO3 (1.24 g, 9.0 mmol) and N-Boc-4- piperidinemethanol mesylate (732 mg, 2.5 mmol). The mixture was then stirred at 80 °C for 2.5 h. After it was cooled to rt, the mixture was loaded directly to a Biotage column, and eluted with solvents (hexanes:EtOAc = 1 :3). The resulting product, 4-[4-(2-fluoro-4- nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-l -carboxylic acid tert- butyl ester, was obtained as a solid (556 mg, 56%).
[0269] To a solution of 4-[4-(2-fluoro-4-nitiO-phenoxy)-6-methoxy-quinolin-7- yloxymethyl]-piperidine-l -carboxylic acid tert-butyl ester (305 mg, 0.58 mmol) in CH2Cl2 (1 mL) was added 0.4 mL of TFA. The reaction mixture was stirred for 1.5 h and the solvents were removed under reduced pressure. The crude product was treated with NaBH(OAc)3 (381 mg, 1.80 mmol) and formaldehyde (0.5 mL, 37% in H2O). The stirring was continued for 12 h. The reaction was quenched with sat. aqueous NaHCO3. 15% NaOH was added until PH = 14. The product was extracted with EtOAc. Removal of the solvent in vacuo gave the crude product, 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(l- methyl-piperidin-4-ylmethoxy)-quinoline, (240 mg, 93%), which was used directly in the next reaction.
[0270] To a solution of 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(l-methyl-piperidin-4- ylmethoxy)-quinoline (240 mg, 0.54 mmol) in EtOH (20 mL) was added 10% Pd/C (50 mg). The mixture was then hydrogenated on a Parr hydrogenator (40 psi) for 1O h. AcOH was added to dissolve the intermediate (mostly the hydroxylamine) and the hydrogenation was continued for additional 12 h. LC-MS was used to monitor the reaction progress. The solvents were removed under reduced pressure and the resulting crude product of 3- fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenylamine (about 220 mg) was used directly in the next reaction.
[0271] To a 0 °C solution of 3-fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenylamine (66 mg, 0.13 mmol) and Et3N (0.34 mL) in CH2Cl2 (6 mL) was added slowly ethyl oxalyl chloride (98 mg). The reaction mixture was stirred at rt for 30 min, then diluted with CH2Cl2 and washed with sat. aqueous NaHCO3. After dried over MgSO4 and concentrated, the crude ethyl oxamate was reacted with phenethylamine (80 mg, 0.64 mmol) at 80 °C for 2 h. Purification by HPLC gave product, N-{3-fluoro-4- [6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'-phenethyl- oxalamide (52 mg, 68% yield). 1H NMR (400 MHz) δ 9.38 (br s, 1 H), 8.48 (d, J = 5.2 Hz, 1 H), 7.83 (dd, J = 11.7, 2.6 Hz, 1 H), 7.59 (t, J = 6.2 Hz, 1 H), 7.55 (s, 1 H), 7.40-7.20 (8 H), 6.39 (d, J - 5.3 Hz, 1 H), 4.06 (d, J = 6.6 Hz, 2 H), 4.04 (s, 3 H), 3.67 (q, J = 6.8 Hz, 2 H), 2.98 (br d, J = 11.5 Hz, 2 H), 2.92 (t, J = 7.0 Hz, 2 H), 2.34 (s, 3 H), 2.10-1.80 (m, 5 H), 1.60-1.54 (m, 2 H).
Figure imgf000088_0001
[0272] 1 -(4-Benzyloxy-3 -methoxyphenvl)ethanone. A solution of 4-hydroxy-3- methoxyacetophenone (40 g, 240 mmol), benzyl bromide (31.4 mL, 260 mmol) and potassium carbonate (99.6 g, 360 mmol) in DMF (800 mL) was heated to 40 °C overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give l-(4-benzyloxy-3- methoxyphenyl)ethanone (61 g, 99 %). [0273] l-r4-Benzyloxy-5-methoxy-2-nitrophenyl)ethanone. A stirred solution of l-(4- benzyloxy-3-methoxyphenyl)ethanone (51.3 g, 200 mmol) in dichloromethane (750 mL) was cooled to 0 °C. Nitric acid (90 %, 14 mL, 300 mmol) was added dropwise to the cooled solution over 20 min. Sulfuric acid (96.2 %, 16.3 mL, 300 mmol) was then added dropwise over 40 min at 0 °C Additional nitric acid (9.4 mL, 200 mmol) was added dropwise over 20 min. The reaction mixture was washed with water (3 x 200 mL), and saturated sodium bicarbonate (4 x 200 mL, or until neutral). The organic layer was dried over Na2SO4 and concentrated. The crude mixture was recrystallized from DMF to give l-(4-benzyloxy-5-methoxy-2-nitrophenyl)ethanone (36 g, 60 %). 1H NMR (400 MHz3. CDCl3): δ 7.65 (s, IH), 7.45-7.33 (m, 5H), 6.74 (s, IH), 5.21 (s, 2H), 3.97 (s, 3H), 2.49 (s, 3H).
[0274] l-(2-Ammo-4-benzyloxy-5-methoxyphenyl)ethanone. A mixture of iron powder (27 g, 0.48 g atoms), ammonium formate (31 g, 500 mmol), l-(4-benzyloxy-5-methoxy-2- nitrophenyl)ethanone (36 g, 120 mmol), toluene (500 mL) and water (500 mL) was heated to reflux overnight. The mixture was filtered through celite and washed with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to afford l-(2-amino-4-benzyloxy-5- methoxyphenyl)ethanone (29.3 g, 90 %). 1HNMR (CDCl3): δ 7.41-7.30 (m, 5H), 7.13 (s, IH), 6.16 (br s, 2H), 6.10 (s, IH), 5.13 (s, 2H), 3.83 (s, 3H), 2.51 (s, 3H). LC/MS (M+H = 272).
[0275] 7-Benzyloxy-6-methoxyquinolin-4-oL Sodium ethoxide (74.8 g, 1.1 mol) was added to a solution of l-(2-amino-4-benzyloxy-5-methoxyphenyl)ethanone (29.3 g, 108 mmol) in DME (700 mL) and stirred for 30 min. Ethyl formate (44 mL, 540 mmol) was added and the mixture was stirred overnight (in case of incomplete reaction, additional sodium ethoxide can be added and the reaction monitored by LC/MS). After the reaction was complete, the mixture was diluted with water (40 mL) and acidified to neutral pH with IM HCl. The solid was filtered, washed with water and dried to afford 7-benzyloxy- 6-methoxyquinolin-4-ol (22 g, 72%). 1H NMR (400 MHz, CDCl3): δ 10.7 (br s, IH), 7.70 (s, IH), 7.49-7.46 (t, IH), 7.43-7.41 (br d, 2H), 7.37-7.33 (t, 2H), 7.30-7.28 (d, IH), 6.84 (s, IH), 6.21-6.19 (d, IH), 5.21 (s, 2H), 3.96 (s, 3H). LC/MS (M+H = 282).
[0276] 7-Benzyloxy-4-chloro-6-methoxyquinoline. Phosphorus oxychloride (300 mL) was added to 7-benzyloxy-6-methoxyquinolin-4-ol (40 g, 140 mmol) and the mixture heated to reflux for 2 h. The mixture was carefully poured into a mixture of ice and sodium carbonate. The solution was adjusted to pH 8 with the addition of solid sodium bicarbonate and stirred at room temperature overnight. The solid was filtered and washed with water and dried to give 7-benzyloxy-4-chloro-6-methoxyquinoline as a pale brown solid (40.2 g, 95%). 1H NMR (400 MHz, J6-DMSO): δ 8.61 (s, IH), 7.57-7.37 (m, 8H), 5.32 (s, 2H), 3.98 (s, 3H); 13C NMR (100 MHz, J6-DMSO): δ 152.4, 151.5, 148.5, 146.2, 139.6, 137.0, 129.2, 128.8, 121.7, 120.4, 110.1, 101.9, 70.8, 56.5; IR (cm"1): 2359, 2341, 1506, 1456, 1435, 1252, 1227, 1146, 999, 845, 752, 698, 667; LC/MS (M+H = 300).
Example 19
Figure imgf000090_0001
[0277] Trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolm-4-yl ester. To a dry 2L RBF containing 7-benzyloxy-6-methoxyquinolin-4-ol (75.3 g, 267 mmol) was added DCM (1 L), 4-dimethylaminopyridme (3.28 g, 26.8 mmol) and 2,6-lutidine (62 mL, 534 mmol). The mixture was cooled to -2O°C by controlled addition of dry ice to an acetone bath. Trifluoromethanesulfonyl chloride (37 mL, 350 mmol) was added drop wise to the cooled solution with magnetic stirring over 25 minutes. After addition was complete, the mixture was stirred in bath for 20 minutes, then at room temperature for 3 hours. LCMS indicated reaction completion. The reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (3.5 L). The resulting slurry was stirred with mechanical stirrer for 30 min before adding water (1.5 L). The solids were isolated by filtration, followed by a water wash. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl ester as a light brown solid (92.2 g, 83.8%). 1H NMR (400MHz, DMSO, d6): δ 8.82 (d, IH), 7.67 (s, IH), 7.59 (d, IH), 7.54-7.52 (m, 2H), 7.46-7.42 (m, 2H), 7.39-7.36 (m, IH), 7.23 (s, IH), 5.35 (s, 2H), 3.97 (s, 3H). LC/MS: M+H = 414. Example 20
Figure imgf000091_0001
[0278] Trifluoromethanesulfonic acid 6,7-dimethoxyquinolin-4-yl ester from 6,7- Dimethoxy-quinolin-4-ol. To a dry IL RBF containing 6,7-dimethoxy-quinolin-4-ol (20.9 g, 102 mmol), which can be prepared according to the procedure of Riegel, B. (J. Amer. Chem. Soc. 1946, 68, 1264), was added DCM (500 niL), 4-dimethylaminopyridine (1.24 g, 10 mmol) and 2,6-lutidine (24 mL, 204 mmol). The mixture was vigorously stirred at RT. Trifluoromethanesulfonyl chloride (14 mL, 132 mmol) was added dropwise to the solution. After addition was complete, the mixture was stirred ice bath for 2 to 3 hrs. On LC/MS indicating the reaction completion, the reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (250 mL). The resulting slurry was stirred for 30 min before adding water (1 L). The solids were isolated by filtration, followed by a water wash. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 6, 7-dimethoxy-quinolin-4-yl ester as a light brown solid (27 g, 80%). 1H NMR (400MHz, DMSO, d6): δ 8.82 (d, IH), 7.59 (m, 2H), 7.20 (s, IH), 3.97 (d, 6H). LC/MS: M+H - 338.
Example 21
Figure imgf000091_0002
[0279] l-Benzyloxy-2-fluoro-4-nitrobenzene. A solution of 2-fluoro-4-nitrophenol (50.0 g, 318 mmol), benzyl bromide (42 mL, 350 mmol) and potassium carbonate (66.0 g, 478 mmol) in DMF (200 mL) was heated to 40 °C overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give l-benzyloxy-2-fluoro-4-nitrobenzene (75.0 g, 95 %). H NMR (400 MHz, J6-DMSO): δ 8.19-8.11 (m, 2H), 7.53-7.37 (m, 6H), 5.36 (s, 2H); 13C NMR (100 MHz, J6-DMSO): δ 152.8, 152.4, 149.9, 140.9, 136.1, 129.3, 129.1, 128.7, 122.0, 115.2, 112.8, 112.6, 71.6; IR (Cm-1): 1499, 1346, 1279, 1211, 1142, 1072, 986, 885, 812, 789, 754, 742, 700, 648, 577.
[0280] 4-Benzyloxy-3-fluoroaniline. A mixture of iron powder (45.2 g, 0.809 g atoms), ammonium formate (53.6 g, 0.850 mol), l-benzyloxy-2-fluoro-4-nitrobenzene (50.0 g, 0.200 mol), toluene (400 mL) and water (400 mL) was heated to reflux overnight. The mixture was filtered through Celite and washed with hot ethyl acetate. The combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated to afford 4-benzyloxy-3-fluoroaniline (44 g, 100 %). 1H NMR (400 MHz, J6-DMSO): δ 7.43-7.26 (m, 5H), 6.90 (dd, IH), 6.49 (dd, IH), 6.34 (m, IH), 4.99 (br s, 2H), 4.98 (s, 2H); 13C NMR (100 MHz, J6-DMSO): δ 171.1, 155.1, 152.7, 144.9, 138.0, 137.2, 129.6, 129.0, 128.5, 118.9, 110.0, 102.9, 72.5; IR (cm"1): 1510, 1454, 1277, 1215, 1126, 1007, 957, 843, 800, 789, 739, 694, 604; LC/MS (M+H = 218).
[0281] Ethyl [Y4-benzyloxy-3 -fluorophenvl)amino] (oxo)acetate. Ethyl oxalyl chloride (44 mL, 390 mmol) was added to a solution of 4-benzyloxy-3-fluoroaniline (44 g, 180 mmol) in diisopropylethylamine (69 mL, 400 mmol) and stirred at room temperature for 15 min. The mixture was extracted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to afford ethyl [(4- benzyloxy-3-fluorophenyl)amino](oxo)acetate (58.4 g, 100 %). 1H NMR (400 MHz, J6- DMSO): δ 10.87 (s, IH), 7.73 (d, IH), 7.69 (d, IH), 7.53 (d, IH), 7.46-7.40 (m, 4H), 5.17 (s, 2H), 4.31 (q, 2H), 1.31(t, 3H); IR (cm"1): 1732, 1705, 1558, 154I, 1508, 1456, 1273, 1186, 1167, HOl, 999, 858, 741, 694; LC/MS (M+H = 318).
[0282] N-r4-Benzyloxy-3-flourophenylVN'-('2-phenylethyl)ethanediamide. Phenethyl- amine (33 mL, 520 mmol) was added to ethyl [(4-benzyloxy-3- fluorophenyl)amino](oxo)acetate (81 g, 260 mmol) and the mixture was sonicated at room temperature for 30 min. The resulting solid was filtered, washed with water and dried to give iV-(4-benzyloxy-3-flourophenyl)-iV'-(2-phenylethyl)ethanediamide (100 g, 99 %). 1H NMR (400 MHz, J6-DMSO): δ 10.72 (br s, IH), 9.05 (m, IH), 8.78 (m, IH), 7.77 (m, IH), 7.59 (m, IH), 7.46-7.19 (m, 8H), 5.16 (m, 2H), 3.45 (m, 2H), 2.83 (m, 2H); IR (cm" l): 2980, 2883, 1653, 1522, 1506, 1441, 1385, 1221, 1122, 951, 808, 746, 696, 584; LC/MS (M+H = 393). [0283] JV-(3-Fluoro-4-hydroxyphenyl)-JV'-('2-phenyletlivl)ethanediamide. A mixture of N- (4-benzyloxy-3-flourophenyl)-iV'-(2-phenylethyl)ethanediamide (40 g, 100 mmol) and 38% hydrobromic acid in acetic acid (250 mL) was stirred at room temperature overnight. The resulting solid was filtered, washed with water and dried to give iV-(3-fluoro-4- hydroxyphenyl)-N'-(2-phenylethyl)ethanediamide as a slightly yellow solid (30.6 g, 99 %yield). 1H NMR (400 MHz, J6-DMSO): δ 10.60 (s, IH), 9.02 (t, IH), 7.70 (d, IH), 7.47 (d, IH), 7.32-7.20 (m, 3H), 6.91 (t, IH), 3.43 (m, 2H), 2.81 (m, 2H); 13C NMR (100 MHz, J6-DMSO): δ 160.5, 158.8, 152.0, 149.6, 142.2, 139.8, 130.3, 129.3, 129.0, 126.8, 118.1, 117.4, 109.6, 109.3 IR (cm"1): 3279, 1653, 1518, 1456, 1279, 1190, 742, 696, 584; LC/MS (M+H = 303).
Example 22
Figure imgf000093_0001
[0284] N-{4-r(7-Benzyloxy-6-methoxyqumolin-4-yl)oxy]-3-fluorophenvU-JV>-f2- phenylethvl)ethanediamide. A mixture of 7-benzyloxy-4-chloro-6-methoxyquinoline (30 g, 100 mmol), N-(3-fluoro-4-hydroxyphenyl)-N'-(2-phenylethyl)ethanediamide (32 g, 106 mmol), DMAP (125 g, 1.02 mol) and bromobenzene (500 mL) was heated to reflux for 6 h. The mixture was cooled to room temperature and the bromobenzene was removed under reduced pressure. Methanol (500 mL) was added to the residue and the mixture was stirred at room temperature for 2 h. The resulting solid was filtered, washed with methanol and dried to give iV-{4-[(7-benzyloxy-6-methoxyquinolm-4-yl)oxy]-3-fluorophenyl}-iV'- (2-phenylethyl) ethanediamide (34 g, 61 %). 1H NMR (400 MHz, J6-DMSO): δ 11.05 (s, IH), 9.15 (s, IH), 8.47 (d, IH), 8.05 (d, IH), 7.84 (d, IH), 7.56-6.36 (m, 13H), 6.46 (d, IH), 5.32 (s, 2H), 3.97 (s, 3H), 3.47 (q, 2H), 2.86 (t, 2H); 13C NMR (100 MHz, J6- DMSO): δ 160.5, 160.2, 159.9, 159.5, 155.2, 152.7, 152.2, 150.3, 149.6, 146.9, 139.7, 137.4, 137.3, 137.2, 137.1, 129.3, 129.2, 129.1, 129.0, 128.9, 128.7, 128.6, 126.9, 124.8, 117.9, 115.3, 109.9, 102.8, 99.8, 70.6, 56.5, 41.3, 35.2; IR (cm"1): 1657, 1510, 1481, 1433, 1416, 1352, 1310, 1252, 1215, 1609, 986, 891, 868, 850, 742, 696; LC/MS (M+H = 566).
Example 23
Figure imgf000094_0001
[0285] iV-(3-Fluoro-4-r(7-hvdroxy-6-methoxyquiiiolin-4-vnoxylphenvU-N'-(2- phenylethvl)ethanediamide. To a solution of Λr-{4-[(7-benzyloxy-6-methoxyquinolin-4- yl)oxy]-3-fluorophenyl}-N'-(2-phenylethyl)ethanediamide (32 g, 56 mmol) in methanol (200 mL), DMF (100 mL), dichloromethane (100 mL), ethyl acetate (100 mL) and acetic acid (5 mL) was added palladium hydroxide (4.2 g) and the mixture was shaken on a Parr hydrogenator under a hydrogen pressure of 45 psi for 4 h. The resulting suspension was filtered through celite and the solid residue was washed with boiling dichloromethane (2 L) and acetone (2 L). The combined filtrates were evaporated to yield N-{3-fluoro-4-[(7- hydroxy-6-methoxyquinolin-4-yl)oxy]phenyl}-N'-(2-phenylethyl)ethanediamide as an off- white solid (25.6 g, 95 %). 1H NMR (400 MHz, J6-DMSO): δ 11.06 (s, IH), 10.25 (br s, IH), 9.12 (t, IH), 8.40 (d, IH), 8.01 (dd, IH), 7.50-7.44 (m, 2H), 7.31-7.23 (m, 6H), 6.39 (d, IH), 3.95 (s, 3H), 2.85 (t, 2H), 2.50 (m, 2H); IR (cm-1): 1666, 1624, 1585, 1520, 1481, 1427, 1377, 1256, 1211, 1194, 1022, 880, 850, 839, 802, 750, 700; LC/MS (M+H = 476).
Example 24
Figure imgf000094_0002
[0286] 7V-(3-Fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolm-4- yl1oxylphenyl)-iV'-f2-phenγlethyl)ethanediarnide. A solution of N-{3-fluoro-4-[(7- hydroxy-6-methoxyquinolin-4-yl)oxy]phenyl}-N'-(2-phenylethyl)ethanediamide (25.6 g, 54 mmol), JV-(3-chloropropyl)morpholine hydrochloride (11.7 g, 592 mmol) and potassium carbonate (16.6 g, 120 mmol) in DMF (300 mL) was heated to 80 °C overnight. Upon cooling, a majority of the DMF (250 mL) was removed on a rotary evaporator, 5% aqueous LiCl (300 mL) was added and the mixture was sonicated at room temperature. The solid was filtered, suspended in IN HCl and washed with ethyl acetate (2 x 300 mL). The solution was adjusted to pH 14 using 2N sodium hydroxide and subsequently extracted with dichloromethane (3 x 200 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give N-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4- ylpropoxy)quinolin-4-yl]oxy}phenyl)-iV'-(2-phenylethyl)ethanediamide as a yellow solid (24 g, 74 %). 1H NMR (400 MHz, CDCl3): δ 9.37 (s, IH), 8.46 (d, IH), 7.81 (dd, IH), 7.57 (t, IH), 7.53 (s, IH), 7.42 (s, 2H), 7.34-7.20 (m, 6H), 6.39 (d, IH), 4.27 (t, 2H), 4.03 (s, 3H), 3.71 (m, 4H), 3.65 (q, 2H), 2.91 (t, 2H), 2.56 (br s, 4H), 2.13 (m, 2H); 13C NMR (100 MHz, ^-DMSO): δ 160.1, 160.0, 159.5, 155.2, 152.7, 152.6, 150.2, 149.5, 147.1, 139.7, 137.3, 137.1, 129.3, 129.1, 126.9, 124.8, 117.9, 115.1, 109.2, 102.7, 99.6, 67.4, 66.9, 56.5, 55.5, 54.1, 41.3, 35.2, 26.4; IR (cm"1): 1655, 1506, 1483, 1431, 1350, 1302, 1248, 1221, 1176, 1119, 864, 843, 804, 741, 700; LC/MS (M+H = 603).
Figure imgf000095_0001
[0287] 4,7-Dichloroquinolme. Phosphorus oxychloride (4mL, 429 mmol) was added to 7-chloro-4-hydroxyquinolme 2.86g, 15.9mmol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 2h, then allowed to cool to room temperature. The solution was concentrated in vacuo to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCO3 (aq). The slurry was filtered and washed with water. The solids were dried under vacuum, afforded 4,7-dichloroquinoline as a white solid (2.79g, 88.5% yield).
Synthesis of Bridged Bicyclics
[0288] The following describes synthesis of bridged bicyclics with appended leaving groups for use as, for example, alkylating agents. In the context of this invention, these alkylating agents are used, for example, to alkylate the quinolines on the 6- or 7-oxygens to make compounds of the invention. The invention is not limited to alkylation chemistry to append such bridged bicyclics, but rather the aforementioned description is meant only to be illustrative of an aspect of the invention.
Example 26
[0289] 1.4:3.6-dianhvdro-2-0-methyl-5-(9-rmethylsulfonyl)-D-glucitol: To a solution of l,4:3,6-dianhydro-2-0-methyl-D-glucitol (1.19g, 7.4 mmol) in dichloromethane was added pyridine (ImL, 12.36 mmol) followed by methanesulfonyl chloride (0.69mL, 8.92 mmol) and the mixture was allowed to stir at room temperature over 12 hours. The solvent was removed and the amorphous residue was partitioned with ethyl acetate and 0.1M aqueous hydrochloric acid. The aqueous phase was extracted once with additional ethyl acetate and the combined organic layers were washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration and concentration followed by drying in vacuo afforded l,4:3,6-dianhydro-2-O-methyl-5-O- (methylsulfonyl)-D-glucitol (1.67g, 94% yield) as a colorless oil. GC/MS calculated for C8H14SO6: 238 (M+).
Example 27
[0290] l,4:3,6-dianhvdro-5-6>-(phenylcarbonyl)-D-fructose ethylene glycol acetal: A solution of l,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D-fructose (2.0Og, 8.06 mmol), ethylene glycol (5.0Og, 80.6 mmol), and p-toluenesulfonic acid (1.53g, 8.06 mmol) in benzene (10OmL) was refluxed for 90 min using a Dean-Stark Trap apparatus. The reaction mixture was diluted with ethyl acetate (10OmL), washed with saturated aqueous sodium bicarbonate (2 x 5OmL) then brine (5OmL), and dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography on silica (1:1 hexane/ethyl acetate) provided 1.44g (61% yield) of l,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D- fructose ethylene glycol acetal as a colorless solid. 1H NMR (400 MHz; CDCl3): 8.08 (m, 2H), 7.58 (m, IH), 7.54 (m, 2H), 5.38 (dd, IH), 4.97 (t, IH), 4.21-4.02 (m, 7H), 3.86 (d, IH), 3.75 (d, IH). Example 28
[0291] l,4:3,6-dianhydro-D-fructose ethylene glycol acetal: To a solution of 1,4:3,6- dianhydro-5-O-(phenylcarbonyl)-D-fructose ethylene glycol acetal (1.44g, 4.93 mmol) in methanol (4OmL) was added 50% aqueous sodium hydroxide (0.38 g, 4.75 mmol) and the mixture was stirred at room temperature for 30 minutes. Neutralization with IM HCl, followed by concentration and column chromatography on silica (1:2 hexane/ethyl acetate) provided 0.74g (80% yield) of l,4:3,6-dianliydro-D-fructose ethylene glycol acetal as a colorless solid. 1H NMR (400 MHz; CDCl3): 4.60 (t, IH), 4.32 (m, IH), 4.14 (d, IH), 4.05-3.98 (m, 5H), 3.82 (s, 2H), 3.62 (dd, IH), 2.65 (d, IH).
[0292] l,4:3,6-dianhydro-5-O-(methylsulfonyl)-D-fructose ethylene glycol acetal: To a solution of l,4:3,6-dianhydro-D-fructose ethylene glycol acetal (0.74g, 3.93 mmol) and triethylamine (1.2Og, 11.86 mmol) in dichloromethane (4OmL) was added methanesulfonyl chloride (0.9Og, 7.88 mmol) at O°C under nitrogen. The solution was warmed to room temperature and stirred for 13 h. Dichloromethane (5OmL) was added, and the organic layer was washed with saturated aqueous sodium bicarbonate (3OmL), water (3OmL), and brine (3OmL) then dried over anhydrous sodium sulfate. Filtration and concentration provided 1.02g (97%) of l,4:3,6-dianhydro-5-(9-(methylsulfonyl)-D- fructose ethylene glycol acetal as a yellow oil. 1H NMR (400 MHz; CDCl3): 5.08 (m, IH), 4.82 (t, IH), 4.13 (dd, IH), 4.04 (m, 4H), 3.93 (dd, IH), 3.87 (d, IH), 3.81 (d, IH), 3.13 (s, 3H).
Example 29
[0293] l,4:3,6-dianhydro-2-deoxy-2-methylidene-D-αra5zno-hexitol: To a solution of l,4:3,6-dianhydro-2-deoxy-2-methylidene-5-C>-(phenylcarbonyl)-D-αrαόmo-hexitol (329mg, 1.34 mmol) in methanol (1OmL) was added 50% aqueous sodium hydroxide (95mg, 1.19 mmol) and the mixture was stirred at room temperature for 30 minutes. Neutralization with 4M hydrogen chloride in 1,4-dioxane followed by concentration and column chromatography on silica (1:1 hexane/ethyl acetate) provided 141mg (74%) of l,4:3,6-dianhydro-2-deoxy-2-methylidene-D-αrαδzπo-hexitol as a colorless solid. 1H NMR (400 MHz; CDCl3): 5.37 (m, IH), 5.20 (m, IH), 4.80 (m, IH), 4.54 (m, 2H), 4.43 (m, IH), 4.26 (m, IH), 3.95 (dd, IH), 3.54 (dd, IH), 2.70 (d, IH). [0294] lΛ:3,6-dianhvdro-2-deoxy-2-methylidene-5-O-(methylsulfonyl)-D-αrα6mo- hexitol: To a solution of l,4:3,6-diaiihydro-2-deoxy-2~methylidene-D-αrøδzτrø-hexitol (135mg, 0.95 mmol) and triethylamine (288mg, 2.85 mmol) in dichloromethane (1OmL) was added methanesulfonyl chloride (222mg, 1.94 mmol) at O°C under nitrogen. The solution was warmed to room temperature and stirred for 18 h. Dichloromethane (5OmL) was added and the organic layer was washed with saturated aqueous sodium bicarbonate (2 x 25mL), water (25mL) and brine (25mL) then dried over anhydrous sodium sulfate. Filtration and concentration provided 213mg (72%) of l,4:3,6-dianhydro-2-deoxy-2- methylidene-5-O-(methylsulfonyl)-D-αrøZnHθ-hexitol as a yellow oil. 1H NMR (400 MHz; CDCl3): 5.40 (m, IH), 5.23 (m, IH), 5.04 (m, IH), 4.85 (m, IH), 4.73 (t, IH), 4.58 (m, IH), 4.41 (m, IH), 4.08 (dd, IH), 3.86 (dd, IH), 3.14 (s, 3H).
Example 30
[0295] l,4:3,6-dianhydro-2-deoxy-5-O-(phenylcarbonyl)-L-flrαZ?^c>-hex-l-enitol: To a mixture of l,4:3,6-dianhydro-5-O-(phenylcarbonyl)-(D)-glycitol (4.32g, 17.3 mmol), triethylamine (4.91 mL, 35.3 mmol) and 4-dimethylaminopyridine (0.63g, 5.2 mmol) in dichloromethane (50 mL) at -10 ° to -15° was added trifluromethanesulfonic anhydride (3.48mL, 20.7 mmol) dropwise over ten minutes and the resulting mixture was stirred at this temperature for 3 hours. The mixture was poured into 100 mL of ice- water and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered then concentrated. The crude triflate was suspended in toluene (50 mL) followed by addition of 1,8- diazabicyclo[4,5,0]undec-7-ene (5.25 mL, 34.6 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice-water and partitioned then the aqueous portion was extracted with dichloromethane (3 x 50 mL). The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flashed chromatography (silica gel, 5-20% ethyl acetate-hexane) to give l,4:3,6-dianhydro-2-deoxy-5-O-(phenylcarbonyl)-L- arabino-hsxrl-emtol, as a white solid, 3.1Og, 77% yield. 1H NMR (400MHz; CDCl3): 8.08-8.06 (m, 2H), 7.61-7.57 (m, IH), 7.56-7.43 (m, 2H), 6.62-6.61 (d, IH), 5.48-5.46 (m,lH), 5.32-5.26 (m,lH), 5.13-5.10 (m, 2H), 4.18-4.14 (tr,lH), 3.61-3.56 (tr, IH). Example 31
[0296] Methyl 3,6-anhvdro-5-O-(phenylcarbonyl)-β-L-glucofuranoside: To a solution of l,4:3,6-dianhydro-2-deoxy-5-O-(plienylcarbonyl)-L-arabino-hex-l-enitol (1.0Og, 4.3 mmol) in methanol (17 mL) at -4°C was added 3-chloroperoxybenzoic acid (85%, 1.35g, 8.6 mmol), and the resulting mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated, diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 25-60% ethyl acetate-hexane) to give methyl 3,6-anhydro-5-O- (phenylcarbonyl)-β-L-glucofuranoside as a white solid, 1.03g, 83% yield. 1H NMR (400MHz; CDCl3): 8.11-8.08 (d, 2H), 7.61-7.56 (tr, IH), 7.48-7.44 (m, 2H), 5.24-5.17 (m, 2H), 4.96 (s, IH), 4.57-4.56 (d, IH), 4.27 (s, IH), 4.22-4.18 (dd, IH), 4.08-4.04 (dd, IH) 3.36 (s, 3H).
[0297] Methyl 3,6-anhvdro-2-O-methyl-5-(9-(phenylcarbonyl)-β-L-glucofuranoside: A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-L-glucofuranoside (1.03g, 3.7 mmol), silver (T) oxide (0.85g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 6O°C for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (1Og) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-L-glucofuranoside as a colorless oil, 0.82g, 76% yield. 1H NMR (400MHz; CDCl3): 8.11-8.09 (d, 2H), 7.60-7.56 (m, IH), 7.46-7.44 (m, 2H), 5.24-5.20 (m, IH), 5.18-5.09 (tr, IH), 4.99 (s, IH), 4.61-4.60 (d, IH), 4.21-4.17 (tr, IH), 4.08-4.03 (tr, IH), 3.81 (s, IH), 3.40 (s, 3H), 3.57 (s, 3H).
[0298] Methyl 3 ,6-anhydro-2-O-methyl-α-D-idofuranoside: A solution of methyl 3,6- anhydro-2-C>-methyl-5-O-(phenylcarbonyl)-β-L-glucofuranoside (820mg, 3.1mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (1OmL) was stirred at room temperature for 30 minutes. The material was adsorbed on silica gel (5g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to give methyl 3,6-anhydro-2-O-methyl-α-D-idofuranoside as a colorless oil, 420 mg, 85% yield. 1H NMR (400MHz; CDCl3): 5.04 (s, IH), 5.84-5.81 (tr, IH), 4.44-4.42 (tr, IH), 4.25-4.19 (m, IH), 3.85-3.75 (m, IH), 3.49 (s, 3H), 3.43 (s, 3H), 2.75-2.72 (d, IH). [0299] Methyl 3.6-anhvdro-2-0-methyl-5-C>-(methylsulfonyl)-β-L-glucofuranoside:
Methyl 3,6-arihydro-2-O-methyl-α-D-idofuranoside (420 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at O°C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and the resulting mixture was stirred at O°C for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β- L-glucofuranoside as a colorless oil, 669mg, 95% yield, which was used without further purification.
Example 32
[0300] 3,6-anhvdro-5-O-(phenylcarbonyl)-α-L-glucofuranose: A mixture of osmium tetroxide (4% in water, 0.25 mL, 0.03 mmol) and N-methylmorpholine (505 mg, 4.3 mmol) in 3 mL of 50% acetone in water was warmed to 6O°C. A solution of 1,4:3,6- dianhydro-2-deoxy-5-O-(phenylcarbonyl)-L-αraZ>mo-hex-l-enitol (2.00g, 8.6 mmol) in 6 mL of 50% acetone in water was added over 3 hours. During this time an additional amount of N-methylmorpholine (1.0 Ig, 8.6 mmol) was added in small portions periodically. Upon completion of the addition process the reaction was stirred for another hour and cooled to room temperature. The crude mixture was applied to a column of silica gel and flashed (0-6% methanol in 1:1 ethyl acetate :hexane) to give 3,6-anhydro-5-0 (phenylcarbonyl)-α-L-glucofuranose as a white solid, 1.5g, 65% yield. 1H NMR (400MHz; DMSO-d6): 8.01-7.95, (m, 2H), 7.68-7.66 (m, IH), 7.57-7.53 (m, 2H), 5.18- 5.11 (m, 2H), 4.85-4.81 (m, IH, m), 4.37-4.35 (m, IH), 4.05-3.96 (m, 2H), 3.85-3.83 (m, IH).
[0301] 3,6-anhydro-2-O-methyl-5-(9-(phenylcarbonyl)-α-L-glucofuranoside: 3,6-
Anhydro-5-O-(phenylcarbonyl)-α-L-glucofuranose (576 mg, 2.2 mmol) was added to a mixture of sodium hydride (60% oil dispersion, 346 mg, 8.7 mmol) and methyl iodide (0.54mL, 8.7 mmol) in 5 mL of DMF at O°C and the resulting mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and quenched with water (5 mL). The aqueous portion was extracted with ethyl acetate (3 x 5 mL). The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flashed chromatography (silica gel, 5-20% ethyl acetate in hexane) to give 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-α-L- glucofuranoside as a white solid, 270 mg, 42% yield. 1H NMR (400MHz; CDCl3): 8.09-
8.07 (m, 2H), 7.61-7.57 (m, IH), 7.48-7.27 (m, 2H), 5.25-5.22 (m, IH), 5.07-5.06 (d, IH), 4.94-4.91 (m, IH), 4.73-4.71 (m, IH), 4.20-4.16 (m, IH), 3.96-3.94 (m, IH)3 3.85-3.83 (tr, IH), 3.50 (s, 3H), 3.42 (s, 3H).
[0302] Methyl 3,6-anhydro-2-O-methyl-5-(9-(methylsulfonyl)-α-L-glucofαranoside: A solution of methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-α-L-glucofuranoside (230mg, 0.92 mmol) and 50% sodium hydroxide (74 mg, 0.92 mmol) in methanol (5 mL) was stirred at room temperature for 30 minutes. The mixture was adsorbed on silica gel (2g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to afford a colorless oil which was employed directly in the next step, 140 mg, 0.72 mmol, 95% yield. The alcohol was dissolved in dichloromethane (5 mL) and pyridine (121 μL, 1.03 mmol) was added at O°C. Methanesulfonyl chloride (27μL, 0.88 mmol) was added and the resulting mixture was stirred at O°C for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-(9-methyl-5-O-(methylsulfonyl)-α-L-glucofuranoside as a colorless oil, 190 mg, 96% yield.
Example 33
[0303] S.ό-Anhvdro-l^-O-fl-methylethylideneVS-O-fphenylcarbonvl)-α-L-gluco- furanose: A mixture of 3,6-anhydro-5-<9-(phenylcarbonyl)-α-L-glucofuranose (1.0Og), 2,2-dimethoxy propane (0.63 mL), p-toluenesulfonic acid (20 mg) and benzene (10 mL) was heated at reflux for 3 hours. The reaction mixture was cooled then adsorbed on silica gel (1Og) and purified by flash chromatography (silica gel, 5-35% ethyl acetate in hexanes) to give 3,6-anhydro-l,2-O-(l-methylethylidene)-5-O-(phenylcarbonyl)-α-L- glucofuranose as colorless oil, 0.85g, 74% yield. 1H NMR (400MHz; CDCl3): 8.08-8.06 (d, 2H), 7.59-7.56 (tr, IH), 7.46-7.42 (m, 2H), 5.99-5.98 (d, IH), 5.35-5.31 (tr, IH), 5.10-
5.08 (d, IH), 4.66-4.65 (d, IH), 4.61-4.60 (d, IH), 4.20-4.16 (dd, IH), 3.91-3.74 (tr, IH,), 1.50 (s, 3H), 1.34 (s, 3H).
[0304] S.ό-Anhvdro-l^-O-fl-methylethylideneVS-O-rmethylsulfonylVα-L-gluco- furanose: A solution of 3,6-anhydro-l,2-O-(l-methylethylidene)-5-O-(phenylcarbonyl)-α- L-glucofuranose (850mg) and 50% sodium hydroxide (111 mg) in methanol (1OmL) was stirred at room temperature for 30 minutes. The mixture was then adsorbed on silica gel (5g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) and the alcohol intermediate, 390 mg, 70% yield, was used immediately in the next step. The alcohol was dissolved in dichloromethane (10 mL) and pyridine (0.32 mL) at O°C. Methanesulfonyl chloride (0.12 mL) was added and the resulting mixture was stirred at O°C for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 3,6-anhydro-l,2-O-(l- methylethylidene)-5-O-(methylsulfonyl)-α-L-glucofuranose as a colorless oil, 485 mg, 90% yield, which was immediately employed in the next step.
Example 34
[0305] (3S,8aS)-3-(Chloromethyl)hexahydro-1 H-pyrrolo[2,1-c][1,4]oxazine: (S)-(+)- Prolinol (6.00 g, 59.3 mmol) was added to epichlorohydrin (47 mL, 600 mmol) at 0°C. The solution was stirred at 40°C for 0.5 h and then concentrated in vacuo. The residual oil was cooled in an ice bath and concentrated sulfuric acid (18 mL) was added dropwise with stirring. The mixture was heated at 170-180°C for 1.5 h, poured into ice (300 mL) and then basified with sodium carbonate to pH~8. The mixture was partitioned with ethyl acetate/hexanes and filtered. The filtrate was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford oil that was purified by column chromatography (ethyl acetate for less polar product and then 30% methanol in ethyl acetate). (3S,8aS)-3-(Chloromethyl)hexahydro-1 H-pyrrolo[2,1-c][1,4]oxazine (less polar product) (1.87 g, 10.7 mmol, 18% yield): 1H NMR (400 MHz, CDCl3): 4.06 (dd, IH), 3.79-3.71 (m, IH), 3.60-3.48 (m, 2H), 3.36 (dd, IH), 3.15 (dd, IH), 3.13-3.06 (m, IH), 2.21-2.01 (m, 3H), 1.90-1.68 (m, 3H), 1.39-1.24 (m, IH); MS (EI) for C8H14NOCl: 176 (MH+). (3R,8aS)-3-(Chloromethyl)hexahydro-1 H-pyrrolo[2,1-c][l,4]oxazine (1.54 g, 8.77 mmol, 15% yield): 1H NMR (400 MHz, CDCl3): 3.94-3.77 (m, 4H), 3.55 (dd, IH), 3.02- 2.93 (m, 2H), 2.45 (dd, IH), 2.29-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.38 (m, IH); MS (EI) for C8H14NOCl: 176 (MH+).
[0306] Using the same or analogous synthetic techniques and/or substituting with alternative starting materials, the following were prepared: [0307] (3R ,8a R)-3-(Chloromethvl)hexahvdro-1H-pyrrolor2.1-c][1,4]oxazine: 1H NMR (400 MHz, CDCl3): 4.05 (dd, IH), 3.79-3.70 (m, IH), 3.61-3.48 (m, 2H), 3.35 (dd, IH), 3.15 (dd, IH), 3.13-3.07 (m, IH), 2.21-2.01 (m, 3H), 1.89-1.67 (m, 3H), 1.39-1.25 (m, IH); MS (EI) for C8H14NOCl: 176 (MH+).
[0308] (3S ,8a R)-3-(Chloromethvl)hexahvdro-1H-pyrrolor2.1-c][1,4]oxazine: 1H NMR (400 MHz, CDCl3): 3.93-3.77 (m, 4H), 3.55 (dd, IH), 3.02-2.93 (m, 2H), 2.45 (dd, IH), 2.30-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.37 (m, IH); MS (EI) for C8H14NOCl: 176 (MH+).
Example 35
[0309] 3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate: (3S,8aS)-3- (Chloromethyl)hexahydro-1 H-pyrrolo[2,1-c][1,4]oxazine (2.30 g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred in dimethylformamide (25 mL) at 14O°C for 20 h. The mixture was partitioned between ethyl acetate and water. The organic portion was washed twice with water, then with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-hexahydro-1 H-pyrrolo[2,l- c][l,4]oxazin-3-ylmethyl acetate as a brown oil (2.53 g, 12.7 mmol, 97% yield). 1H NMR (400 MHz, CDCl3): 4.14-4.02 (m, 3H), 3.81-3.72 (m, IH), 3.37-3.31 (m, IH), 3.09 (dt, IH), 3.00 (dd, IH), 2.21-2.00 (m, 3H), 2.10 (s, 3H), 1.90-1.67 (m, 3H), 1.39-1.24 (m, IH); MS (EI) for C10H17NO3: 200 (MH+).
[0310] (3S,8aS)-Hexahvdro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethanol: (3S,8aS)-
Hexahydro-1 H-pyrrolo[2,l-c][l,4]oxazin-3-yhnethyl acetate (2.36 g, 11.9 mmol) was treated with sodium methoxide (25 wt% solution in methanol; 2.7 mL) for 0.5 h. The mixture was cooled in an ice bath and a solution of 4M HCl in 1,4-dioxane (3 mL, 12.0 mmol) was added slowly. The mixture was stirred at room temperature for 5 minutes and then was concentrated in vacuo to afford a suspension which was diluted with dichloromethane, filtered and the filtrate was concentrated in vacuo to afford (3S,8aS)- hexahydro-1 H-pyrrolo[2,l-c][l,4]oxazin-3-ylmethanol as a brown oil (1.93 g, >100% yield). 1H NMR (400 MHz, CDCl3): 4.05 (dd, IH), 3.73-3.65 (m, 2H), 3.62-3.56 (m, IH), 3.39-3.34 (m, IH), 3.10 (dt, IH), 3.00-2.95 (m, IH), 2.24-1.98 (m, 4H), 1.97-1.70 (m, 3H), 1.44-1.28 (m, IH); MS (EI) for C8H15NO2: 158 (MH+).
[0311] (35',8aiS^-hexahydro-lH'-pyrrolo[2,l-c]rL41oxazin-3-ylmethyl methanesulfonate: (35',8aS)-Hexahydro-lHr-pyrrolo[2,l-c][l,4]oxazm-3-ylmethanol (1.00 g, 6.37 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (2.4 mL, 17.3 mmol) was added at 0°C followed by dropwise addition of methanesulfonyl chloride (0.93 mL, 12.0 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with saturated sodium bicarbonate solution. The combined aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (SS^δa^-hexahydro-l/f-pyiToloPjl-c^l^oxazm-S- ylmethyl methanesulfonate as an orange-brown oil (1.20 g, 5.1 mmol, 80% yield). MS (EI) for C9Hj7NO4S: 236 (MH+).
Example 36
[0312] Octahvdro-2iJ"-quinolizin-3 - ylmethanol : Ethyl octahydro-2H-quinolizine-3- carboxylate (2.35 g, 11.1 mmol) was added dropwise to a stirred suspension of lithium aluminum hydride (I M solution in tetrahydrofuran, 33 mL, 33 mmol) in tetrahydrofuran (50 mL) at 0°C. The reaction was stirred at room temperature for 3 h. The mixture was cooled in an ice bath and ethyl acetate (6 mL) was added slowly, followed by water (1.25 mL), 15% aqueous sodium hydroxide solution (5 mL) and water (1.25 mL). The mixture was filtered through a pad of celite and washed with ether. The filtrate was concentrated in vacuo and dried rigorously to afford octahydro-2iJ-quinolizin-3-ylmethanol as a yellow oil (1.66 g, 9.82 mmol, 88% yield). MS (EI) for C10H19NO: 170 (MH+).
[0313] Octahvdro-2H-quinolizin-3-ylmethyl methanesulfonate: Octahydro-2H-quinolizin- 3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) was added at 0°C followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford octahydro- 2H"-quinolizin-3-ylmethyl methanesulfonate as an orange oil (796 mg, 3.22 mmol, 91% yield). MS (EI) for C11H21NO3S: 248 (MH+).
Example 37
[0314] f3£8aθV3-fHvdroxymethvnhexahvdropyrcolo[T .2-αipyrazm-l (2ff)-one: A solution of methyl l-[(2<S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L- prolinate (3.50 g, 10.4 mmol) in methanol was added to 5% palladium on carbon (50 wt.% in water) in methanol and treated with hydrogen at 40 psi for 1 h. The mixture was filtered and the filtrate was brought to reflux briefly and then cooled and concentrated in vacuo to afford (3iSr,8aS)-3-(hydroxymetliyl)hexahydropyrrolo[l,2-«]pyrazin-l(2H)-one as a colorless solid (1.50 g, 8.83 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): 7.28-7.22 (m, IH), 3.83-3.75 (m, IH), 3.69 (dd, IH), 3.56 (dd, IH), 3.31 (t, IH), 3.08 (dd, IH), 2.92 (dt, IH), 2.76-2.70 (m, IH), 2.66 (dd, IH), 2.28-2.16 (m, IH), 2.02-1.73 (m, 3H); MS (EI) for C8Hi4N2O2: 171 (MH+).
[0315] (3£8aSV3 -(([(1,1 -Dimethylethyl¥dimethyl)silyl1 oxy)methyl)hexahydro- pyrrolo [ 1 ,2-αlpyrazin- 1 (2/J)- one: To a solution of (35,8a5)-3-(hydroxymethyl) hexahydropyrrolo[1,2-a]pyrazin-l(2H)-one (1.49 g, 8.82 mmol) in dimethylformamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol) and 4-dimethylaminopyridine (90 mg, 0.882 mmol). The solution was cooled in an ice bath and tert-butyldimethylsilyl chloride (2.66 g, 17.6 mmol) was added. The mixture was warmed to room temperature and stirred for 14 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a pale brown solid which was triturated with ethyl acetate to afford (35',8aS)-3-({[(l,l-dimethylethyl)(dimethyl)silyl]oxy}methyl) hexahydropyrrolo[1,2-a]pyrazin-l(2H)-one as an off-white solid (1.74 g, 5.84 mmol, 66% yield). 1H NMR (400 MHz, CDCl3): 6.09-5.90 (m, IH), 3.86-3.76 (m, IH), 3.63 (dd, IH), 3.44 (dd, IH), 3.25 (t, IH), 3.10 (ddd, IH), 2.98-2.90 (m, IH), 2.68-2.60 (m, IH), 2.52 (dd, IH), 2.28-2.18 (m, IH), 2.06-1.95 (m, IH), 1.93-1.74 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H); MS (EI) for C14H28N2O2Si: 285 (MH+). [0316] (3S,8aS)-3-({[(1,1-Dimethylethvl)(dimethvl)silyl]oxy}methyl)-2-methvIhexahvdro pyrroolo[1 ,2-a]pγiazin-l (2H)-one: (3S,8aS)-3-({[(l,l-Dimethylethyl)(dimethyl)silyl]oxy} methyl)hexahydropyrrolo[1,2-a]pyrazin-l(2H)-one (1.5 Ig, 5.32mmol) in dimethylformamide (8 mL) was added to an ice-cooled suspension of sodium hydride (60 wt. % dispersion in oil; 213 mg, 5.32 mmol) in dimethylformamide (8 mL). The mixture was stirred at 0°C for 0.25 h and then iodomethane (0.332 mL, 5.32 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 h and then was stirred at 7O°C for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2- methylhexahydropyrrolo[l,2-a]pyrazin-l(2H)-one as a yellow oil (1.552 g, 5.21 mmol) which was dissolved in tetrahydrofuran (20 mL) and treated with tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran; 10.4 mL, 10.4 mmol) for 2 h at room temperature. The mixture was concentrated in vacuo and purified by column chromatography (10% methanol in dichloromethane) to afford (3S,8aS)-3- (hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-l(2H)-one as a yellow oil (496mg, 2.70mmoL 51% yield from (3S,8aS)-3-({[(l,l- dimethylethyl)(dimemyl)silyl]oxy } methyl)hexahydropyrrolo [ 1 ,2-α]pyrazin- 1 (2H)-one). 1H NMR (400 MHz, CDCl3): 3.98-3.93 (m, IH), 3.86 (dd, IH), 3.61-3.55 (m, IH), 3.29- 3.25 (m, IH), 3.09-3.03 (m, IH), 3.03-2.97 (m, IH), 3.02 (s, 3H), 2.93 (dd, IH), 2.87-2.79 (m, IH), 2.32-2.21 (m, IH), 2.00-1.86 (m, 2H), 1.83-1.64 (m, IH); MS (EI) for C9H16N2O2: 185 (MH+).
Example 38
[0317] 1,2-Dideoxy-1-[(2S)-2-(methoxycarbonvl)-l-pyrrolidinyll-2-[[(phenylmethoxy) carbonyl] amino] -D-glycero-hexitol : To a solution of 2-deoxy-2-{[(phenylmethyloxy) carbonyl]amino}-D-glycero-hexopyranose (5.0 g, 0.016 mol) in methanol (500 mL) was added L-proline methyl ester hydrochloride (2.8 g, 0.022 mol) and sodium cyanoborohydride (3.4 g, 0.054 mol). The solution was heated to 64 °C for 14 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo to afford 1,2- dideoxy- 1 - [(2<S)-2-(methoxycarbonyl)- 1 -pyrrolidinyl] -2- [ [(phenylmethoxy)carbonyl] aminoj-D-g/jcero-hexitol (6.81 g, 100%) as a clear and colorless oil. MS (EI) for C20H31N2O8: 427 (MH+).
Example 39
[0318] Methyl l-rf∑^-S-hvdroxy-l-drfphenylmethvπoxylcarbonyllamino^propyll-L- prolinate: l,2-dideoxy-l-[(25)-2-(methoxycarbonyl)-l-pyrrolidinyl]-2-[[(phenylmethoxy) carbonyl] amino] -D-g/yce/O-hexitol (6.81 g, 0.016 mol) was taken into water (100 mL) and the resulting solution was cooled to 0°C. Sodium periodiate (14.8 g, 0.069 mol) dissolved in water was added dropwise and the resulting mixture was stirred at 0°C for 2 h. The reaction mixture was partitioned with dichloromethane (3x100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in methanol (200 mL) and the resulting solution was cooled to 0°C. Sodium borohydride (1.98 g, 0.052 mol) was added and the reaction mixture was stirred for 1 h at 0°C. The reaction mixture was concentrated in vacuo and partitioned with dichloromethane and saturated aqueous ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (5% methanol in dichloromethane) to yield methyl 1- [(25)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (4.9 g, 92%) as a white solid. MS (EI) for C17H25N2O5: 337 (MH+).
[0319] Methyl l-[r25r)-3-r(methylsulfonvl)oxy1-2-r{r(phenylmethyl>)oxylcarbonyl|ammo) propyl] -L-prolinate : Methyl l-[(25)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino) propyl] -L-prolinate (200 mg, 0.594 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of 4-(dimethylamino)pyridine (3.6 mg, 0.039 mmol) and triethylamine (0.125 mL, 0.891 mmol) and the resulting mixture was cooled to 0 °C. Methanesulfonyl chloride (0.060 mL, 0.773 mmol) was added dropwise and the reaction mixture was stirred for 1 h at 0°C. The mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford methyl l-[(25)-3- [(methylsulfonyl)oxy]-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (246 mg, 100%) as a clear and colorless oil. MS (EI) for C18H27N2O7S: 415 (MH+). Example 40
[0320] 1 , 1 -Dimethylethyl Qaig^βaS^-S-fhydroxymethvl)hexahvdrocvclopental'clpyrrole- 2dijr)-carboxylate: Under a nitrogen atmosphere, borane tetrahydrofuran complex (IM in THF, 42 mL, 41.9 mmol) was diluted with tetrahydrofuran (42 mL) and cooled with an ice bath. Neat 2,3-dimethylbut-2-ene (5.0 mL, 41.9 mmol) was added in portions over 0.25 h and the solution was stirred at O°C for 3 h. A solution of 1,1 -dimethylethyl (3ai?,6aS)-5- methylidenehexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (1.98 g, 8.88 mmol) in tetrahydrofuran (10 mL) was added slowly, and the solution was warmed to room temperature and stirred 12 h. After cooling to O°C, 10% aqueous sodium hydroxide (17 mL, 41.7 mmol) was added slowly, followed by 30% aqueous hydrogen peroxide (13 mL, 128 mmol) and the solution was warmed to room temperature. The solvent was removed in vacuo and the solution was partitioned between water and diethyl ether. The layers were separated and the aqueous layer was further extracted (3 x 50 mL diethyl ether). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 2.04 (95%) of 1,1 -dimethylethyl (3ai?,6aS)-5- (hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate, which was used without purification. 1H NMR (400 MHz, CDCl3): 8.50 (broad s, IH), 3.66-3.46 (m, 3H), 3.20-3.00 (m, 2H), 2.70-2.59 (m, 2H), 2.37-2.18 (m, IH), 2.04 (m, IH), 1.84 (broad s, IH), 1.70-1.55 (m, IH), 1.46 (s, 9H), 1.17 (m, IH), 0.93 (m, IH).
[0321] 1,1-Dimethylethγl (3aR£aS)-5-{ [(methylsulfonyl)oxy]methyl}hexahvdrocyclo- penta [c]pyrrole-2(lH)-carboxylate: Methanesulfonyl chloride (0.2mL, 2.48mmol), was added dropwise to a solution of 1,1 -dimethylethyl (3ai?,6aS)-5-(hydroxymethyl)hexahydro cyclopenta[c] pyrrole-2(lH)-carboxylate (0.40 g, 1.65 mmol) and triethylamine (0.69 mL, 4.95 mmol) in 20 mL dichloromethane at O°C and the reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated, the resulting crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), IM aqueous sodium hydroxide, brine, IM aqueous hydrochloric acid and brine again. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting 1 , 1 -dimethylethyl (3ai?,6aS)-5- { [(methylsulfonyl)oxy]methyl}hexahydrocyclo- penta[c]pyrrole-2(l/i)-carboxylate was used without further purification. MS (EI) for C14H25NO5S: 320 (MH+), 264 (M-tBu). Example 41
[0322] U-Dimethylethyl Oa&όaSVS-fhydiOxyVhexahvdrocyclopentarcl pyrrole-2d/J)- carboxylate: Sodium borohydride (0.15 g, 4.00 mmol), was added to a solution of 1,1- dimethylethyl (3ai?,6aS)-5-oxo-hexahydrocyclopenta[c] pyrrole-2(lH)-carboxylate (0.45 g, 2.00 mmol) in 10 mL methanol at O°C and the reaction mixture was stirred for 1 h at this temperature. The solvent was evaporated, the crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), IM aqueous hydrochloric acid and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 1,1-dimethylethyl (3ai?,6aS)-5-(hydroxy)-hexahydrocyclopenta[c] pyrrole-2(lH)- carboxylate (0.44g, 98%). 1H NMR (400 MHz, d6-DMSO): 4.08 (m, IH), 3.40 (m, 2H)3 3.30 (m, 2H), 2.50 (m, 2H), 1.98 (m, 2H), 1.40 (s, 9H), 1.30 (m, 2H). MS (EI) for C12H21NO3: 228 (MH+).
[0323] 1.1-Dimethylethyl rSa^.όaS^-S-IITmethylsulfonvl)oxyilhexahvdrocvclo- pentarclpyrrole-2(lH)-carboxylate: Methanesulfonyl chloride (0.18 mL, 2.33 mmol), was added dropwise to a solution of 1,1-dimethylethyl (3ai?,6aS)-5-(hydroxy)- hexahydrocyclopenta[c] pyrrole-2(lH)-carboxylate (0.44 g, 1.94 mmol) and triethylamine (0.81 mL, 5.81 mmol) in 10 mL dichloromethane at O°C and the reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated, the resulting crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), brine, IM aqueous hydrochloric acid and brine again. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude 1,1-dimethylethyl (3ai?,6aS)-5-{[(methylsulfonyl)oxy]}hexaliydrocyclopenta[c]pyrrole-2(liϊ)-carboxylate was used without further purification. MS (EI) for C13H23NO5S: 306 (MH+).
Example 42
[0324] 3-(Chloromethyl)hexahydro-lH"-ri,41oxazinor3,4-ciri.41oxazine: A solution of (3i?)-moφholin-3-ylmethanol (4.21 g, 36.0 mmol) in 2-(chloromethyl)oxirane (28.2 mL, 0.360 mol) was heated to 4O°C for 3 h and then the solution was concentrated in vacuo. The intermediate was cooled in an ice bath and treated with 30.0 mL of concentrated sulfuric acid. The mixture was heated to 17O°C for 2 h and then allowed to cool to room temperature. The mixture was poured into ice-water and solid sodium bicarbonate was carefully added until the solution was basic. 10% methanol in ethyl acetate was added and the biphasic mixture was filtered. The layers were separated and the aqueous layer was extracted (3 x 100 mL 10% methanol in ethyl acetate). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 2:5 hexanesrethyl acetate) provided 3-(chloromethyl)hexahydro- 1 H-[l,4]oxazino[3,4-c][l,4]oxazine 2.44g (35%) as two separated diastereomers. (3i?,9aS)-3-(chloromethyl)hexahydro-1 H-[l,4]oxazino[3,4-c][l34]oxazine: (0.886 g, 13% yield): 1H NMR (400 MHz, CDCl3): 3.91 (m, 3H), 3.82 (m, IH), 3.68 (dt, IH), 3.61 (dd, IH), 3.47 (dd, IH), 3.35 (t, IH), 3.19 (t, IH), 2.80 (d, IH), 2.54 (m, 2H), 2.40 (m, 2H); MS (EI) for C8H14NO2Cl: 192 (MH+). (3S,9aS)-3-(chloromethyl)hexahydro-l/f- [l,4]oxazino[3,4-c][l,4]oxazme: (1.55 g, 22% yield): 1H NMR (400 MHz, CDCl3): 3.85 (m, 2H), 3.73 (m, 3H), 3.50 (m, 2H), 3.29 (t, IH), 3.18 (t, IH), 2.85 (dd, IH), 2.64 (dd, IH), 2.40 (m, 2H), 2.17 (t, IH); MS (EI) for C8H14NO2Cl: 192 (MH+).
[0325] Hexahvdro- 1 H-[1 ,41 oxazino [3 A-c] \ 1 ,4] oxazin-3 -yrmethyl acetate : A suspension of (3i?,9aS)-3-(chloromethyl)hexahydro-1 H-[l,4]oxazmo[3,4-c][l,4]oxazine (1.97 g, 10.3 mmol) and potassium acetate (10.1 g, 102 mmol) in DMF (20.0 mL) was stirred at 14O°C for 16 h, and then at 15O°C for another 12 h. The reaction mixture was partitioned between water (250 mL) and ethyl acetate (250 mL), the organic layer was washed with 5% lithium chloride (2 x 100 mL) and brine (100 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography (SiO2, 1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded 0.92 g (42%) of hexahydro-1 H- [ 1,4] oxazino [3 ,4-c][ 1,4] oxazin-3 -ylmethyl acetate as a yellow oil. Distinct diastereomers as described above were converted in this step to give: (3i?,9aS)-hexahydro-1 H- [l,4]oxazino[3,4-c][l,4]oxazin-3-ylmethyl acetate: 1H NMR (400 MHz, CDCl3): 4.18 (dd, IH), 4.00 (m, IH), 3.80 (dd, IH), 3.68 (dt, IH), 3.60 (dd, IH), 3.46 (m, 2H), 3.22 (t, IH), 2.64 (dd, IH), 2.53 (m, 2H), 2.43-2.35 (m, 2H), 2.10 (s, 3H), and (3S,9aS)- hexahydro-1 H-[l,4]oxazino[3,4-c][l,4]oxazin-3-ylmethyl acetate: 1H NMR (400 MHz, CDCl3): 4.09 (d, 2H), 3.90-3.82 (m, 2H), 3.75-3.64 (m, 3H), 3.27 (t, IH), 3.18 (t, IH), 2.69 (dd, IH), 2.63 (m, IH), 2.46-2.33 (m, 2H), 2.16 (t, IH), 2.10 (s, 3H).
[0326] r3i?.9a^-Hexahvdro-lH-rL41oxazinor3.4-ciri,41oxazin-3-ylmethyl methane- sulfonate: To a solution of (3i?,9aS)-hexahydro-1 H-[l,4]oxazino[3,4-c][l,4]oxazin-3- ylmethyl acetate (0.922 g, 4.28 mmol) in methanol (14.0 mL) was added 1.03 mL (4.50 mmol) of sodium methoxide (25% wt. in methanol) dropwise at room temperature. After 5 min., 1.6 mL (6.43 mmol) of 4.0M hydrogen chloride in dioxane was added and a pink precipitate formed. The solution was concentrated in vacuo and the pink solid was taken up in 30.0 mL dichloromethane. This sluny was cooled in an ice bath and triethylamine (3.0 mL, 21.5 mmol) was added, followed by methanesulfonyl chloride (0.37 mL, 4.71 mmol). The resultant yellow solution was stirred for 30 minutes at room temperature. The mixture was then partitioned between dichloromethane and saturated aqueous sodium bicarbonate then the aqueous layer was extracted (3 x 50 mL dichloromethane). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide crude (3i?,9aS)-hexahydro-1 H-[l,4]oxazino[3,4- c][l,4]oxazin-3-ylmethyl methanesulfonate which was taken on to the following reaction without purification.
Example 43
[0327] (8ai?V6-('Chloromethvntetrahvdro-l/f-ri.31thiazolor4,3-ciri,41oxazine: A solution of (4i?)-l,3-thiazolidin-4-ylmethanol (0.300 g, 2.52 mmol) in 2- (chloromethyl)oxirane (2.0 mL, 25.5 mmol) was heated under nitrogen to 4O°C for 12 h. The solution was then cooled to room temperature and 2-(chloromethyl)oxirane was removed in vacuo. The crude intermediate was cooled in ice, and was taken up in 2.0 mL of concentrated sulfuric acid. The resulting mixture was heated to 200°C for 0.5 h then poured carefully onto wet ice, which was allowed to melt. The aqueous solution was carefully made basic using solid sodium bicarbonate and the resulting mixture was filtered using water and 10% methanol in ethyl acetate as eluent. The layers were separated and the aqueous layer was extracted with 10% methanol in ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 11.6 mg (2.4% yield) of crude (8ai?)-6-(chloromethyl)tetrahydro-l/7- [l,3]thiazolo[4,3-c][l,4]oxazine as a mixture of diastereomers which was directly taken on to the next step.
Example 44
[0328] U-Dimethylethyl (3-e?7Jo)-3-f2-rrmethylsulfonvnoxylethyl>-8-azabicyclor3.2.11 octane-8-carboxylate: To a solution of 1,1-dimethylethyl (3-eπdø)-3-(2-hydroxyethyl)-8- azabicyclo[3.2.1]octane-8-carboxylate (30.3 mg, 1.19 mmol) in dichloromethane (4.0 mL), was added triethylamine (0.5 mL, 3.56 mmol) and the solution was cooled to O°C under nitrogen. Methanesulfonyl chloride (0.11 mL, 1.42 mmol) was added slowly and mixture was allowed to warm to room temperature and stirred for Ih. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 35.1 mg (89%) of 1,1- dimethylethyl (3 -endo)-3 - { 2- [(methylsulfonyl)oxy] ethyl } - 8-azabicyclo [3.2.1] octane-8 - carboxylate, which was carried forward for alkylation without purification.
Example 45
Figure imgf000112_0001
29] Preparation of 1 - r4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl] - cvclopropanecarboxylic acid. To the cyclopropyl di-carboxylic acid (449 mg, 3.45 mmol) in THF (3.5 mL) was added TEA (485 μL, 3.45 mmol). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 40 minutes before adding thionyl chloride (250 μL, 3.44 mmol). The reaction was monitored by LCMS for the formation of mono acid chloride (quenched the sample with MeOH and looked for corresponding mono methyl ester). After 3 hours stirring at room temperature, 4-(6,7-dimethoxy-quinolin-4- yloxy)-phenylamine (1.02 g, 3.44 mmol) was added as a solid, followed by more THF (1.5 mL). Continued to stir at room temperature for 16 hours. The resulting thick slurry was diluted with EtOAc (10 mL) and extracted with IN NaOH. The biphasic slurry was filtered and the aqueous phase was acidified with cone. HCl to pH = 6 and filtered. Both solids were combined and washed with EtOAc, then dried under vacuum. The desired product, l-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]- cyclopropanecarboxylic acid, was obtained (962 mg, 68.7% yield, 97% pure) as a white solid. 1H NMR (D2O/NaOH): 7.97 (d, IH), 7.18 (d, 2H), 6.76 (m, 4H), 6.08 (d, IH), 3.73 (s, 3H), 3.56 (s, 3H), 1.15 (d, 4H).
Il l Example 46
Figure imgf000113_0001
[0330] 'N-(4-{r6,7-Bis(metliyloxy)qumolin-4-vnoxy|phenylVN'-r(4-fluorophenyl)methvn cyclopropane- 1 , 1 -dicarboxamide. To a solution of l-[4-(6,7-dimethoxy-quinolin-4-yloxy)- phenylcarbamoyl]-cyclopropanecarboxylic acid (74.3 mg, 0.182 mmol), 4-Fluoro benzylamine (25 μL, 0.219 mmol), DIEA (90.0 μL, 0.544 mmol) in DMA (1.0 niL) was added HATU (203 mg, 0.534 mmol). The resulting solution was stirred at room temperature for 1 hour before adding dropwise to water (10 mL) with stirring. The slurry was sonicated, filtered and the solids were washed with 1 N NaOH followed by water. After air drying, the solids were further purified by prep HPLC, affording 'N-(4-{[6,7- bis(methyloxy)quinolin-4-yl] oxy } phenyl)-N'- [(4-fluorophenyl)methyl] cyclopropane- 1,1- dicarboxamide (33 mg, 35% yield, 98% pure) as a white solid. 1H NMR (DMSO, d6): 10.82 (s, IH), 8.80 (d, IH), 8.50 (t, IH), 7.83 (d, 2H), 7.74 (s, IH), 7.56 (s, IH), 7.30-7.38 (m, 4H), 7.15 (t, 2H), 6.80 (d, IH), 4.32 (d, 2H), 4.04 (s, 3H), 4.03 (s, 3H), 1.42 (s, 4H).
[0331] The following compounds were prepared, in a similar manner as above, from the coupling of 1 -[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropane carboxylic acid with a corresponding alkylamine or arylamine.
[0332] N-(4-{r6J-Bis(methyloxy)qumolin-4-ylloxy>phenyl)-N'-r2-fpiperidin-l- ylmethvl)phenyll cyclopropane- 1.1 -dicarboxamide. IH NMR (DMSO-d6): 10.62 (s, IH), 8.79 (d, IH), 8.24 (t, IH), 7.83 (d, 2H), 7.72 (s, IH), 7.58 (s, IH), 7.37 (d, 2H), 6.76 (d, IH), 4.04 (s, 3H), 4.03 (s, 3H), 3.98 (m, 2H), 3.66 (m, 2H), 3.49 (m, 4H)5 3.25 (t, 2H), 3.13 (br., 2H), 1.42 (d, 4H).
[0333] N-C4- { [6 J-Bis(methyloχy>)quinolin-4-ynoxy|phenyl')-N'-r2-('piperidin- 1 - ylmethyl)phenyncvclopropane-lJ-dicarboxamide. IH NMR (DMSO-d6): 10.78 (s, IH), 10.53 (s, IH), 8.43 (d, IH), 8.12 (d, IH), 7.82 (d, 2H), 7.49 (s, IH), 7.37 (s, IH), 7.20-7.28 (m5 3H)5 7.15 (dd, IH), 7.01 (td, IH), 6.35 (d, IH), 3.93 (s, 3H)5 3.92 (s, 3H), 3.47 (s, 2H), 2.17 (br., 4H), 1.49 (m, 4H)5 1.41 (m, 4H), 1.32 (br., 2H).
[0334] 'N-f4-(f6.7-Bis(methyloxyN)quinolin-4-ylloxylphenyl)-N'-r2-(pyrrolidin-l- ylmethvl)phenyll cyclopropane- 1.1 -dicarboxamide. IH NMR (DMSO-d6): 10.98 (s5 IH), 10.56 (s, IH), 8.42 (d, IH), 8.10 (dd, IH)3 7.81 (m, 2H), 7.49 (s, IH), 7.37 (s, IH), 7.17- 7.27 (m, 4H), 7.01 (td, IH), 6.35 (d, IH), 3.93 (s, 3H), 3.92 (s, 3H), 3.61 (s, 2H), 2.30 (br., 4H), 1.47 (br., 4H), 1.43 (m, 4H).
[0335] 'N-(4-{r6,7-Bis(methyloxyN)quinolin-4-vnoxy}phenylVN'-r3-rmorpholin-4- ylmethvl)phenyll cyclopropane- 1 , 1 -dicarboxamide. IH NMR (DMSO-d6): 10.12 (s, IH), 10.03 (s, IH), 8.44 (d, IH), 7.74 (d, 2H), 7.57 (s, IH), 7.53 (d, IH), 7.48 (s, IH), 7.37 (s, IH), 7.21 (m, 3H), 6.98 (d, IH), 6.40 (d, IH), 3.93 (s, 3H), 3.92 (s, 3H), 3.56 (t, 4H), 3.41 (s, 2H), 2.34 (br., 4H), 1.48 (s, 4H).
[0336] >N-r4-{r6.7-Bis(methyloxy)quinolin-4-vnoxy>phenyl)-N'-r2-('morpholm-4- ylmethvl)phenyll cyclopropane- 1 , 1 -dicarboxamide. IH NMR (DMSO-d6): 10.54 (s, IH), 10.47 (s, IH), 8.43 (d, IH), 8.08 (d, IH), 7.78 (d, 2H), 7.49 (s, IH), 7.37 (d, IH), 7.18- 7.30 (m, 4H), 7.03 (t, IH), 6.37 (d, IH), 3.94 (s, 3H), 3.93 (s, 3H), 3.50 (s, 2H), 3.44 (br., 4H), 2.20 (br., 4H), 1.48 (d, 4H).
[0337] 'N-(4-{r6J-Bis('methyloxy)qumolin-4-γlloxy>phenyl)-N'-r3-(piperidin-l- ylmethvl)phenylicvclopropane- 1 , 1 -dicarboxamide. IH NMR (DMSO-d6): 10.0-10.2 (br., 2H), 8.46 (d, IH), 7.76 (d, 2H), 7.53 (m, 3H), 7.39 (s, IH), 7.24 (m, 3H), 6.98 (d, IH), 6.43 (d, IH), 3.95 (s, 3H), 3.93 (s, 3H), 3.37 (s, 2H), 2.31 (br., 4H), 1.48 (m, 8H), 1.39 (br., 2H).
[0338] 'N-(4-{r6,7-Bis(methyloxy)quinolin-4-vnoxy|ρhenvl)-N'-r3-(pyrrolidin-l- ylmethvl)phenyll cyclopropane- 1 , 1 -dicarboxamide. IH NMR (DMSO-d6): 10.0-10.2 (br., 2H), 8.46 (d, IH), 7.77 (d, 2H), 7.59 (s, IH), 7.53 (d, IH), 7.51 (s, IH), 7.39 (s, IH), 7.23 (m, 3H), 6.99 (d, IH), 6.43 (d, IH), 3.95 (s, 3H), 3.93 (s, 3H), 3.52 (s, 2H), 2.42 (br., 4H), 1.69 (br, 4H), 1.48 (s, 4H).
Example 47
Figure imgf000114_0001
Figure imgf000115_0001
[0339] Synthesis of N-(4- ( r6.7-bisfmethyloxy)-2-(methylthio)quinolm-4-yll oxyl -3 - fluorophenyl)-N'-(4-fluorophenyl)cvclopropane- 1 , 1 -dicarboxamide Commercially available 5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[l,3]dioxane-4,6-dione (3.5 g, 14 mmol) and 3,4-dimethoxyoaniline (2.2 g, 14 mmol) were reflux in EtOH (20 mL) for 2 hours. The EtOH was removed under reduced pressure and EtOAc was added to the residue. The product was filtered and washed with cold EtOAc (3X). 5-[(3,4-dimethoxy- phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[l,3]dioxane-4,6-dione was obtained as a white solid (1.7 g, 47% yield) and used without further purification. LCMS: m/z 352 (M-H)'.
[0340] A mixture of 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2- dimethyl-[l,3]dioxane-4,6-dione (1.7 g, 6.6 mmol) and diphenylether (3.5 g, 21 mmol) were heated at 260 0C for 10 minutes. The mixture was cooled to room temperature and heptane ' was added. 6,7-Dimethoxy-2-methylsulfanyl-quinolin-4-ol was filtered and isolated as an orange solid and used without further purification (1.4 g, 83% yield). LCMS: m/z 352 (M+H)+.
[0341] A mixture of 6,7-dimethoxy-2-methylsulfanyl-quinolin-4-ol (1.0 g, 4.0 mmol), 3,4- difluoronitrobenzene (0.48 mL, 4.3 mmol), cesium carbonate (2.6 g, 8.0 mmol), and DMF (15 mL) was stirred at room temperature for 12 hours, after which time, the mixture was filtered. The filtrate was extracted with DCM, washed with 10% LiCl(aq.), water, (IX) and brine (IX), followed by drying over Na2SO4 and concentration in vacuo. The crude solids were purified by flash chromatography (silica gel, 5% MeOH in DCM), affording the nitroquinoline (1.3 g, 85.8% yield) as an orange solid. LCMS: m/z 391 (M+H)+. A mixture of nitroquinoline (0.33 g, 0.85 mmol), 5% Pt/S on carbon (0.050 g), ammonium formate (0.40 g, 6.3 mmol) in EtOH (5 mL) was heated at 80 0C for 1 hour The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was dissolved in DCM, the mixture filtered, and the precipitate discarded. Removal of the organic solvent afforded 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4- yloxy)-3-fluoro-phenylamine as an orange oil (220 mg, 73% yield). LCMS: m/z 361 (MH-H)+.
[0342] To a mixture of 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro- phenylamine (0.22 g, 0.61 mmol) and l-(4-Fluoro-phenylcarbamoyl)- cyclopropanecarboxylic acid (0.16 g, 0.73 mmol) in DMF (5 mL) was added TEA (0.25 mL, 1.8 mmol) followed by HATU (0.57 g, 1.5 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water and extracted with DCM (2X). The combined extracts were washed with 5% LiCl(aq.) (3X), water, (IX) and brine (IX), followed by drying over Na2SO4 and concentration in vacuo. The crude solids were purified by preparatory HPLC with ammonium acetate, affording N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide (0.39 g, 11% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.34 (s, IH), 9.94 (s, IH), 7.83 (d, IH), 7.59 (m, 2H), 7.56 (m, IH), 7.40 (m, 2H), 7.23 (s, IH), 7.09 (t, 2H), 6.12 (s, IH), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H), 1.40 (m, 4H).
Assays
[0343] Kinase assays were performed by measurement of incorporation of γ-33P ATP into immobilized myelin basic protein (MBP). High binding white 384 well plates (Greiner) were coated with MBP (Sigma #M-1891) by incubation of 60ul/well of 20μg/ml MBP in Tris-buffered saline (TBS; 5OmM Tris pH 8.0, 138mM NaCl, 2.7mM KCl) for 24 hours at 4° C. Plates were washed 3X with lOOμl TBS. Kinase reactions were carried out in a total volume of 34μl in kinase buffer (5mM Hepes pH 7.6, 15mM NaCl, 0.01% bovine gamma globulin (Sigma #1-5506), 1OmM MgCl2, ImM DTT, 0.02% TritonX-100). Compound dilutions were performed in DMSO and added to assay wells to a final DMSO concentration of 1%. Each data point was measured in duplicate, and at least two duplicate assays were performed for each individual compound determination. Enzyme was added to final concentrations of 1OnM or 2OnM, for example. A mixture of unlabeled ATP and γ- 33P ATP was added to start the reaction (2x106 cpm of γ-33P ATP per well (3000Ci/mmole) and either lOμM or 30μM unlabeled ATP, typically. The reactions were carried out for 1 hour at room temperature with shaking. Plates were washed 7x with TBS, followed by the addition of 50μl/well scintillation fluid (Wallac). Plates were read using a Wallac Trilux counter. This is only one format of such assays, various other formats are possible, as known to one skilled in the art.
[0344] The above assay procedure can be used to determine the IC50 for inhibition and/or the inhibition constant, K;. The IC50 is defined as the concentration of compound required to reduce the enzyme activity by 50% under the conditions of the assay. Exemplary compositions have IC50 5S of, for example, less than about 100 μM, less than about 10 μM, less than about 1 μM, and further for example having IC5o's of less than about 100 nJVl, and still further, for example, less than about 10 nM. The Kj for a compound may be determined from the IC50 based on three assumptions. First, only one compound molecule binds to the enzyme and there is no cooperativity. Second, the concentrations of active enzyme and the compound tested are known (i.e., there are no significant amounts of impurities or inactive forms in the preparations). Third, the enzymatic rate of the enzyme-inhibitor complex is zero. The rate (i.e., compound concentration) data are fitted to the equation:
Figure imgf000118_0001
where V is the observed rate, Vmax, is the rate of the free enzyme, Io is the inhibitor concentration, E0 is the enzyme concentration, and Ka is the dissociation constant of the enzyme-inhibitor complex.
Kinase specificity assays:
[0345] Kinase activity and compound inhibition are investigated using one or more of the three assay formats described below. The ATP concentrations for each assay are selected to be close to the Michaelis-Menten constant (KM) for each individual kinase. Dose- response experiments are performed at 10 different inhibitor concentrations in a 384-well plate format. The data are fitted to the following four-parameter equation:
Y = Min + (Max - Min) / (1 + (X/IC50)ΛH) where Y is the observed signal, X is the inhibitor concentration, Min is the background signal in the absence of enzyme (0% enzyme activity), Max is the signal in the absence of inhibitor (100% enzyme activity), IC50 is the inhibitor concentration at 50% enzyme inhibition and H represents the empirical Hill's slope to measure the cooperativity. Typically H is close to unity.
c-Met Assay
[0346] c-Met biochemical activity was assessed using a Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format as described above. Again, kinase activity was measured as the percent ATP remaining following the kinase reaction. Remaining ATP was detected by luciferase-luciferm-coupled chemiluminescence. Specifically, the reaction was initiated by mixing test compounds, lμM ATP, lμM poly- EY and 1OnM c-Met (baculovirus expressed human c-Met kinase domain P948-S1343) in a 2OuL assay buffer (2OmM Tris-HCL pH7.5, 1OmM MgCl2, 0.02% Triton X-100, 10OmM DTT, 2mM MnCl2). The mixture is incubated at ambient temperature for 2hours after which 2OuL luciferase-luciferin mix is added and the chemiluminescent signal read using a Wallac Victor2 reader. The luciferase-luciferin mix consists of 50 rnM HEPES, pH 7.8, 8.5ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-IOO3 0.25 mg/mL coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase.
KDR Assay
[0347] KDR biochemical activity was assessed using a Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format. Kinase activity was measured as the percent ATP remaining following the kinase reaction. Remaining ATP was detected by luciferase-luciferin-coupled chemiluminescence. Specifically, the reaction was initiated by mixing test compounds, 3 μM ATP, 1.6 μM poly-EY and 5 nM KDR (baculovirus expressed human KDR kinase domain D807-V1356) in a 2OuL assay buffer (2OmM Tris- HCL pH7.5, 1OmM MgCl2, 0.01% Triton X-100, ImM DTT, 3mM MnCl2). The mixture is incubated at ambient temperature for 4 hours after which 2OuL luciferase-luciferin mix is added and the chemiluminescent signal read using a Wallac Victor2 reader. The luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0.25 mg/mL coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase.
flt-4 Assay
[0348] Biochemical activity for flt-4 was assessed using an Alphascreen Tyrosine Kinase protocol. AlphaScreen™ (Perkin Elmer) technology is a proximity assay employing microparticles. Singlet oxygen derived from a donor bead following laser excitation results in chemiluminescence when in proximity (100 A) to an acceptor bead due to biomolecular interactions. For the Flt-4 assay, donor beads coated with streptavidin and acceptor beads coated with PYlOO anti-phosphotyrosine antibody were used (Perkin Elmer). Biotinylated poly(Glu,Tyr) 4:1 (Perkin Elmer) was used as the substrate. Substrate phosphorylation was measured by addition of donor/acceptor beads by chemiluminescence following donor-acceptor bead complex formation. Test compounds, 5 μM ATP, 3 nM biotinylated poly(Glu, Tyr) and 1 nM Flt-4 (baculovirus expressed human Flt-4 kinase domain D725-R1298) were combined in a volume of 20 μL in a 384- well white, medium binding microtiter plate (Greiner). Reaction mixtures were incubated for 1 hr at ambient temperature. Reactions were quenched by addition of 10 uL of 15-30 mg/mL AlphaScreen bead suspension containing 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20. After 2-16 hr incubation at ambient temperature plates were read using an AlphaQuest reader (Perkin Elmer). IC50 values correlate well with those determined by radiometric assays.
flt-3 Assay
[0349] Biochemical activity for flt-3 was assessed using a Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format. Kinase activity was measured as the percent ATP remaining following the kinase reaction. Remaining ATP was detected by luciferase-luciferin-coupled chemiluminescence. Specifically, the reaction was initiated by mixing test compounds, 5 μM ATP, 3 μM poly-EY and 5 nM Flt-3 (baculovirus expressed human Flt-3 kinase domain R571-S993) in a 2OuL assay buffer (2OmM Tris- HCL pH7.5, 1OmM MgCl2, 0.01% Triton X-100, ImM DTT, 2mM MnCl2). The mixture is incubated at ambient temperature for 3 hours after which 2OuL luciferase-luciferin mix is added and the chemiluminescent signal read using a Wallac Victor2 reader. The luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0.25 mg/mL coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase.
c-Kit Assay
[0350] c-Kit biochemical activity was assessed using AlphaScreen TM (Perkin Elmer) technology, described above. Test compounds, ATP, biotinylated poly(Glu, Tyr) and c- Kit kinase were combined in a volume of 20 μL in a 384-well white, medium binding microtiter plate (Greiner). Reaction mixtures were incubated for 1 hr at ambient temperature. Reactions were quenched by addition of 10 uL of 15-30 mg/mL AlphaScreen bead suspension containing 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20. After 16 hr incubation at ambient temperature plates were read using an AlphaQuest reader (Perkin Elmer).
Structure Activity Relationships 51] Table 3 shows structure activity relationship data for selected compounds of the invention. Inhibition is indicated as IC50 with the following key: A = IC50 less than 50 nM, B = IC50 greater than 50 nM, but less than 500 nM, C = IC50 greater than 500 nM, but less than 5000 nM, and D = IC5O greater than 5,000 nM. Depending upon the functionality about the quinoline, exemplary compounds of the invention exhibit selectivity for any of c-Met, KDR, c-Kit, flt-3, and flt-4. Abbreviations for enzymes listed in Tables 2-3 are defined as follows: c-Met refers to hepatocyte growth factor receptor kinase; KDR refers to kinase insert domain receptor tyrosine kinase; flt-4, fins-like tyrosine kinase-4, representative of the FLK family of receptor tyrosine kinases; c-Kit, also called stem cell factor receptor or steel factor receptor; and flt-3, fins-like tyrosine kinase-3. Empty cells in the tables indicate lack of data only.
Table 3
Figure imgf000121_0001
[0352] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
[0353] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
[0354] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:
1. A compound according to formula I,
Figure imgf000123_0001
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein,
R1 is selected from -H, halogen, -OR3, -NO2, -NH2, -NR3R4, and optionally substituted lower alkyl;
Z is selected from -S(O)0-2-, -O-, and -NR5-;
Ar is either a group of formula II, or of formula III,
Figure imgf000123_0002
II III wherein,
R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is O to 4;
G is a group -B-L-T, wherein
B is selected from absent, -N(R13)-, -N(SO2R13)-, -0-, -S(O)0-2-, and -C(O)-;
L is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SO2N(R13)-, -SO2-, -C(=0)N(R13)-, -N(R13)-, -C(=O)Ci-2alkylN(R13)-, -N(R13)C1-2alkylC(=O)-, -C(=O)C0-1alkylC(=O)N(R13)-, -C0-4alkylene-, -C(=O)C0-1alkylC(=O)OR3-, -C(=NR14)C0-1alkylC(=O>, -C(O)-, -C(=O)C0-1alkylC(=O)-, and an optionally substituted four to six-membered heterocyclyl containing between one and three annular heteroatoms including at least one nitrogen; and
T is selected from -H, -R13, -C0-4alkyl, -C0-4alkylQ, -OC0-4alkylQ, -C0-4alkylOQ, -N(R13)C0-4alkylQ, -SO2C0-4alkylQ, -C(=O)C0-4alkylQ, -C0-4alkylN(R13)Q, and -C(=0)N(R13)Co-4alkylQ, wherein each of the aforementioned Co^alkyl is optionally substituted;
J is selected from -S(O)0-2-, -O-, and -NR15-; R3 is -H or R4;
R4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or
R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
A2 and A3 are each independently selected from =N-, =C(R2)-; R5 is -H or optionally substituted lower alkyl; D is selected from -O-, -S(O)0-2-, and -NR15-; R50 is either R3, or according to formula IV;
Figure imgf000124_0001
IV wherein X1, X , and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -C(R6)R7-, -O-, -S(O)0-2-, and -NR8-; each X is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -0-, -S(O)0-2-, and -NR8-; Y is either: an optionally substituted lower alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X2 when X2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R6 or R7; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -SO2-, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system; m and p are each independently 1-4; n is 0-2, when n = 0, then there is a single bond between the two bridgehead X2 's;
R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R4, -S(O)0-2R4, -SO2NR3R4, -CO2R3, -C(O)NR3R4, -N(R3)SO2R4, -N(R3)C(O)R3, -NCO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, optionally substituted lower heterocyclylalkyl, and a bond to either Y or D; or
R and R , when taken together are oxo; or
R and R , when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
R8 is selected from -R3, Y, -SO2NR3R4, -CO2R4, -C(O)NR3R3, -SO2R4, and -C(O)R3;
R13 is selected from -H, -C(=O)R3, -C(O)OR3, -C(=O)SR3, -SO2R4, -C(=O)N(R3)R3, and optionally substituted lower alkyl, two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic can have up to four annular heteroatoms, and said heteroalicyclic can have an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R60;
R14 is selected from -H, -NO2, -NH2, -N(R3)R4, -CN, -OR3, optionally substituted lower alkyl, optionally substituted heteroalicyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroalicyclic;
R15 is a group -M^M2, wherein M1 is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SO2N(R13)-, -SO2-, -C(^O)N(R13)-, -C(=O)C(=O)N(R13)-, -C0- 4alkylene-, -C(=O)-, and an optionally substituted four to six-membered hetercyclyl annular containing between one and three heteratoms including at least one nitrogen; and M2 is selected from -H, -C0-6alkyl, alkoxy, -C(=O)C0-4alkylQ, -C0-4alkylQ, -OC0-4alkylQ-, -N(R13)C0-4alkylQ-, and -C(=O)N(R13)C0-4alkylQ; and
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl;
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; two of R60, when attached to a non-aromatic carbon, can be oxo; with the proviso, only when Ar is according to formula II, if Y is a C1-6 alkylene; Z is -NH- or -N(CH3)-; R1 is a C1-6alkyl optionally substituted in the 2-position by -OH or a C1- 4alkoxy group; R2 is -H or halogen; n = O; and the atoms, X1, of one bridge of the saturated bridged ring system, when combined with both bridgehead atoms, X , of the saturated bridged ring system, represent:
1) either a pyrrolidine or a piperidine, and any atom, X1 or X2, of either of said pyrrolidine or said piperidine is attached to Y, then the other bridge of said saturated bridged ring system cannot be any one of -OC(O)CH2-, -CH2OC(O)-, -OC(O)CH2CH2-, -CH2OC(O)CH2-, -CH2CH2OC(O)-, -OC(O)CH2NH-, -OC(O)CH2N(CMalkyl)-, and -OC(O)CH2O-; or 2) either a piperazine or a 4-(C1-4alkyl)-piperazine, and any atom, X1 or X2, of either of said piperazine or said 4-(C1-4alkyl)-piperazine is attached to Y, then the other bridge of said saturated bridged ring system, only when attached via the 2- and the 3 -position of either of said piperazine or said 4-(C1-4alkyl)-piperazine, cannot be one of -CH2OC(O)CH2-, -CH2CH2OC(O)-, and either of the two aforementioned bridges optionally substituted by one or two C1-2alkyl groups; or
3) a piperazine, and any atom, X or X2, of said piperazine is attached to Y, then the other bridge of said saturated bridged ring system, only when attached via the 3- and the 4-position of said piperazine, cannot be one of -C(O)OCH2CH2-, -CH2OC(O)CH2-, and either of the two aforementioned bridges optionally substituted by one or two Ci-2alkyl groups, and only when either of the two aforementioned bridges are attached to the 3 -position of said piperazine via their left-hand end as depicted above; or
4) a 2-oxomorpholine, said 2-oxomorpholine attached to Y via its 4-position, then the other bridge of said saturated bridged ring system, only when attached via the 5- and the 6-position of said 2-oxomorpholine, cannot be one of -(CH2)r, -CH2WCH2-, -CH2WCH2CH2-, and -CH2CH2WCH2-, wherein W is -0-, -S(O)0-2-, -NH-, or -N(C1-4alkyl)- wherein g is 2, 3, or 4; and with the proviso that when Z is-O-, Ar is according to formula II, and the portion of G directly attached to Ar is selected from:
Figure imgf000127_0001
then R , 50 must be of formula IV; and with the proviso that when Ar is phenylene or substituted phenylene, Z is -S(O)0-2- or
-O-, then the portion of G directly attached to Ar cannot contain
Figure imgf000128_0001
when R70 is selected from -H, C1-4alkyl, and C1-4alkoxyl.
2. The compound according to claim 1, wherein hi one example, the compound is according to paragraph [0033], wherein Z is either -O- or -NR5-.
3. The compound according to claim 2, wherein G is selected from the following:
Figure imgf000128_0002
Figure imgf000129_0001
Figure imgf000130_0001
wherein wherein Q, R20, and R13 are as defined above; each E is selected from -0-, -N(R13)-, -CH2-, and -S(O)0-2-; M is selected from -0-, -N(R13)-, -CH2-, and -C(=O)N(R13)-; each V is independently either =N- or =C(H)-; each methylene in any of the above formulae is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic, two of R on a single carbon can be oxo.
4. The compound according to claim 3, wherein Ar is according to one of formula Ila, Ub, and HIa.
Figure imgf000130_0002
Ha lib IHa
5. The compound according to claim 4, wherein D is -O- and R1 is -OR3.
6. The compound according to claim 5, wherein -O-R50 and R1 are interchangeably located at the 6-position and 7-position of the quinoline according to formula I.
7. The compound according to claim 6, wherein R1 is -OH or -OC1-6alkyl.
8. The compound according to claim 7, wherein G is selected from:
Figure imgf000130_0003
Figure imgf000131_0001
wherein Q, R2 , R , E, and R are as defined above; each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic.
9. The compound according to claim 8, wherein Q is selected from:
Figure imgf000131_0002
wherein R20 is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.
10. The compound according to claim 9, wherein Ar is according to formula Ila, and G is selected from:
Figure imgf000132_0001
wherein Q, R20, R13, E, and R60 are as defined above, and each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic.
11. The compound according to claim 9, wherein Ar is according to formula lib, and G is selected from:
Figure imgf000132_0002
wherein Q, R , R13, E, and R are as defined above, and each methylene in any of the above formulae, other than those depicted in a ring, is independently optionally substituted with R >2Z5D;. and R ,2Z5J is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic.
12. The compound according to claim 11, wherein the methylene between the two carbonyls of the depicted formulae is di-substituted with either optionally substituted lower alkyl, or an optionally substituted spirocycle.
13. The compound according to claim 10 or claim 11, wherein R50 is a heteroalicylic or a C1-6alkyl-heteroalicylic.
14. The compound according to claim 13, wherein at least one of R2 is halogen.
15. The compound according to claim 13, wherein R5 is according to formula IV.
16. The compound according to claim 15, wherein the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1].
17. The compound according to claim 16, wherein Y is selected from -CH2CH2CH2CH2-, -CH2CH2CH2-, -CH2CH2-, -CH2-, and absent.
18. The compound according to claim 17, wherein n is 0 and the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0].
19. The compound according to claim 18, wherein said saturated bridged ring system contains at least one annular nitrogen or at least one annular oxygen.
20. The compound according to claim 19, wherein said saturated bridged ring system contains -NR -, wherein R is selected from -H, optionally substituted lower alkyl, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3.
21. The compound according to claim 19, wherein said saturated bridged ring system is of formula V,
Figure imgf000134_0001
V wherein U1 is selected from -O-, -S(O)0-2-, -NR8-, -CR6R7-, and absent; and e is 0 or 1.
22. The compound according to claim 21 , wherein Y is -CH2-.
23. The compound according to claim 24, wherein U1 is -NR8-, wherein R8 is selected from -H, optionally substituted lower alkyl, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3.
24. The compound according to claim 22, wherein U1 is -O-.
25. The compound according to claim 22, wherein U1 is absent.
26. The compound according to claim 19, wherein Y is selected from -CH2CH2-, -CH2-, and absent.
27. The compound according to claim 26, wherein said saturated bridged ring system is of formula VI,
Figure imgf000134_0002
VI wherein R9, R10, and R11 are each independently selected from -H, and -OR12; or
R9 is selected from -H, and -OR12, and R10 and R11, when taken together, are either an optionally substituted alkylidene or an oxo;
R12 is selected from -H, -C(O)R3, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl; or two R12's, when taken together, form 1) a corresponding spirocyclic ketal when said two R12's stem from R10 and R11, or 2) a corresponding cyclic ketal when said two R12' s stem from R9 and one of R10 and R11.
28. The compound according to claim 27, wherein one of R10 and R11 is -OR12, wherein R12 is selected from -H, -C(O)R3, and optionally substituted lower alkyl; and R9 and the other of R10 and R11 are both -H.
29. The compound according to claim 28, wherein Y is either -CH2- or absent.
30. The compound according to claim 29, wherein R is an alkyl group containing at least one fluorine substitution thereon.
31. The compound according to claim 20, wherein said saturated bridged ring system is of formula VII.
Figure imgf000135_0002
VII
32. The compound according to claim 31, wherein Y is either -CH2- or absent.
33. The compound according to claim 32, wherein R8 is methyl or ethyl.
34. The compound according to claim 20, wherein said saturated bridged ring system is of formula VIII.
Figure imgf000135_0001
VIII
35. The compound according to claim 34, wherein Y is -CH2-.
36. The compound according to claim 35, wherein R8 is methyl or ethyl.
37. The compound according to claim 19, wherein said saturated bridged ring system is of formula IX
Figure imgf000136_0001
IX wherein U2 is selected from -O-, -S(O)0-2-, -NR8-, -CR6R7-, and absent.
38. The compound according to claim 37, wherein R3 of formula IX is selected from -H and optionally substituted alkyl.
39. The compound according to claim 38, wherein U is either -CR R - or absent.
40. The compound according to claim 39, wherein U2 is either -CH2- or absent.
41. The compound according to claim 40, wherein Y is -CH2-.
42. The compound according to claim 20, wherein said saturated bridged ring system is according to formula X.
Figure imgf000136_0002
X
43. The compound according to claim 42, wherein R8 is methyl or ethyl.
44. The compound according to claim 1, which is
Figure imgf000137_0001
45. A compound for modulating kinase activity of formula A-B-C, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, A is selected from:
Figure imgf000137_0002
Figure imgf000138_0001
B is selected from:
Figure imgf000138_0003
and, C is selected from:
Figure imgf000138_0002
Figure imgf000139_0001
wherein R2 is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl; q is 0 to 2; each R3 is independently selected from — H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; two R3, together with the nitrogen to which they are attached, form a four- to seven- membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SO2NR5R5, -CO2R5, -C(O)NR5R5, -C(O)R5, and optionally substituted lower alkyl; each R35 is independently selected from -H, -C(=0)R3, -C(=O)OR3, -C(=O)SR3, -SO2R3, -C(=O)N(R3)R3, and optionally substituted lower alkyl; two R35, together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aryl fused thereto, said aryl optionally substituted with an additional one to four of R60;
A2 is either =N- or =C(H)-;
R5 is -H or optionally substituted lower alkyl;
R8 is selected from R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -SO2R3, and -C(O)R3; R9, R10, and R11 are each independently selected from -H, and -OR12; or
R9 is selected from -H, and -OR12, and R10 and R11, when taken together, are either an optionally substituted alkylidene or an oxo; and
R12 is selected from -H, -C(O)R3, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl; or two R12' s, when taken together, form 1) a corresponding spirocyclic ketal when said two R12' s stem from R10 and R11, or 2) a corresponding cyclic ketal when said two R12's stem from R9 and one of R10 and R11;
E1 is selected from -O-, -CH2-, -N(R5)-, and -S(O)0-2-;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20;
R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl;
R60 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; two of R60, when attached to a non-aromatic carbon, can be oxo; each methylene in any of the above formulae is independently optionally substituted with R25; each R is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR , -NR3R3, -S(O)0-2R3, -SO2NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven- membered alicyclic or heteroalicyclic, two of R25 on a single carbon can be oxo; with the proviso that when B is selected from:
Figure imgf000141_0005
and C contains
Figure imgf000141_0004
, and the remaining portion of C contains one of:
Figure imgf000141_0001
directly attached to
Figure imgf000141_0002
then A must be one of:
Figure imgf000141_0003
Figure imgf000142_0002
and with the proviso that when C contains (R )q , and B is selected from:
Figure imgf000142_0003
then the portion of C directly attached to
Figure imgf000142_0004
cannot contain
Figure imgf000142_0001
when R70 is selected from -H, C1-4alkyl, and C1-4alkoxyl.
46. The compound according to claim 45, wherein Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; each optionally substituted with between one and four of R20; wherein each R20 is independently selected from -H3 halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)SO2R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl.
47. The compound according to claim 46, wherein B is either of the following:
Figure imgf000143_0001
wherein A1 is either =N- or =C(H)-.
48. The compound according to claim 47, wherein B is
Figure imgf000143_0002
49. The compound according to claim 48, wherein C is selected from:
Figure imgf000143_0003
Figure imgf000144_0001
wherein R2, R3, R5, R20, R25 and R60 are as defined above.
50. The compound according to claim 49, R2 is selected from halogen, trihalomethyl, -CN, -NO2, -OR3, -NR3R3, -CO2R3, -C(O)NR3R3, -N(R3)C(O)R3, -N(R3)CO2R3, -C(O)R3, and optionally substituted lower alkyl.
51. The compound according to claim 50, wherein R2 is halogen.
52. The compound according to claim 51, wherein R2 is either fluorine or chlorine.
53. A pharmaceutical composition comprising a compound according to any one of claims 1 - 52 and a pharmaceutically acceptable carrier.
54. A metabolite of the compound or the pharmaceutical composition according to any one of claims 1 - 53.
55. A method of modulating the in vivo activity of a kinase, the method comprising administering to a subject an effective amount of the compound or the pharmaceutical composition according to any of claims 1 - 52.
56. The method according to claim 55, wherein modulating the in vivo activity of the kinase comprises inhibition of said kinase.
57. The method according to claim 55, wherein the kinase is at least one of c- Met, KDR, c-Kit, flt-3, and flt-4.
58. The method according to claim 57, wherein the kinase is c-Met.
59. A method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of the compound or the pharmaceutical composition as described in any one of claims 1 - 53.
60. A method of screening for a modulator of a kinase, said kinase selected from c-Met, KDR, c-Kit, flt-3, and flt-4, the method comprising combining a compound according to any one of claims 1 - 52, and at least one candidate agent and determining the effect of the candidate agent on the activity of said kinase.
61. A method of inhibiting proliferative activity in a cell, the method comprising administering an effective amount of a composition comprising a compound according any one of claims 1 - 52 to a cell or a plurality of cells.
PCT/US2006/012709 2005-04-06 2006-04-06 C-met modulators and methods of use WO2006108059A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU2006231646A AU2006231646A1 (en) 2005-04-06 2006-04-06 C-Met modulators and methods of use
EP06749361A EP1874759A4 (en) 2005-04-06 2006-04-06 C-met modulators and methods of use
US11/910,720 US20080161305A1 (en) 2005-04-06 2006-04-06 C-Met Modulators and Methods of Use
JP2008505496A JP2008537748A (en) 2005-04-06 2006-04-06 c-Met Modulator and Method of Use
CA002603748A CA2603748A1 (en) 2005-04-06 2006-04-06 C-met modulators and methods of use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US66920705P 2005-04-06 2005-04-06
US60/669,207 2005-04-06

Publications (1)

Publication Number Publication Date
WO2006108059A1 true WO2006108059A1 (en) 2006-10-12

Family

ID=37073806

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/012709 WO2006108059A1 (en) 2005-04-06 2006-04-06 C-met modulators and methods of use

Country Status (6)

Country Link
US (1) US20080161305A1 (en)
EP (1) EP1874759A4 (en)
JP (1) JP2008537748A (en)
AU (1) AU2006231646A1 (en)
CA (1) CA2603748A1 (en)
WO (1) WO2006108059A1 (en)

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008112407A1 (en) 2007-03-14 2008-09-18 Advenchen Laboratories, Llc Spiro substituted compounds as angiogenesis inhibitors
WO2008101682A3 (en) * 2007-02-22 2008-10-09 Syngenta Participations Ag Iminipyridine derivatives and their uses as microbiocides
WO2008103277A3 (en) * 2007-02-16 2009-04-16 Amgen Inc Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
FR2922550A1 (en) * 2007-10-19 2009-04-24 Sanofi Aventis Sa NOVEL 6-ARYL / HETEROALKYLOXY BENZOTHIAZOLE AND BENZIMIDAZOLE DERIVATIVES, APPLICATION AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE, IN PARTICULAR AS CMET INHIBITORS
WO2009125597A1 (en) 2008-04-10 2009-10-15 大鵬薬品工業株式会社 Acylthiourea compound or salt thereof, and use of the compound or the salt
WO2010065838A1 (en) * 2008-12-04 2010-06-10 Exelixis, Inc. Methods of preparing quinoline derivatives
WO2010130944A1 (en) 2009-05-12 2010-11-18 Sanofi-Aventis Cyclopenta[c]pyrrole-2-carboxylate derivatives, preparation thereof, and therapeutic use thereof
WO2010130943A1 (en) 2009-05-12 2010-11-18 Sanofi-Aventis 5-membered heterocyclic compound cyclopenta[c]pyrrolylalkylcarbamate derivatives, preparation thereof, and therapeutic use thereof
US7872017B2 (en) 2006-05-19 2011-01-18 Abbott Laboratories Fused bicycloheterocycle substituted azabicyclic alkane derivatives
US7884114B2 (en) 2007-08-15 2011-02-08 Glaxo Group Limited Compounds
US8003662B2 (en) 2006-01-30 2011-08-23 Array Biopharma, Inc. Heterobicyclic thiophene compounds and methods of use
US8049014B2 (en) 2009-03-25 2011-11-01 Korea Institute Of Science And Technology Aminoquinoline derivatives, preparation method thereof and pharmaceutical composition comprising the same
WO2011145035A1 (en) 2010-05-17 2011-11-24 Indian Incozen Therapeutics Pvt. Ltd. Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
WO2012034055A2 (en) 2010-09-12 2012-03-15 Advenchen Laboratories, Llc Compounds as c-met kinase inhibitors
CN102617463A (en) * 2012-02-28 2012-08-01 苏州卡耐博生物技术有限公司 Quinoline derivative and quinazoline derivative and preparation method thereof
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
JP2012521348A (en) * 2009-03-21 2012-09-13 クイ ニング Amino ester derivatives, salts thereof, and methods of use
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
CN102030705B (en) * 2009-09-30 2012-12-19 上海睿智化学研究有限公司 Synthesis method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
EP2532657A3 (en) * 2008-10-14 2013-01-23 Sunshine Lake Pharma Co., Ltd Compounds and methods of use
WO2013100014A1 (en) * 2011-12-28 2013-07-04 大鵬薬品工業株式会社 Effect potentiator for antitumor agents
US20130197230A1 (en) * 2008-11-13 2013-08-01 Jo Ann Wilson Methods of preparing quinoline derivatives
WO2013144737A2 (en) 2012-03-30 2013-10-03 Rhizen Pharmaceuticals Sa Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of c-met protein kinases
US20140057908A1 (en) * 2010-09-27 2014-02-27 Exelixis, Inc. Method of Treating Cancer
US8729268B2 (en) 2008-03-05 2014-05-20 Methylgene Inc. Inhibitors of protein tyrosine kinase activity
US8759380B2 (en) 2011-04-22 2014-06-24 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
CN103965104A (en) * 2013-01-29 2014-08-06 正大天晴药业集团股份有限公司 Preparation methods of tyrosine kinase inhibitor and intermediates thereof
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
EP3299369A4 (en) * 2015-05-21 2018-05-02 Shanghai Institute of Materia Medica, Chinese Academy of Sciences Pyrido-azaheterecydic compound and preparation method and use thereof
CN108069919A (en) * 2016-11-08 2018-05-25 上海医药工业研究院 The preparation method of click azoles amine key intermediate
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US10166225B2 (en) 2011-09-22 2019-01-01 Exelixis, Inc. Method for treating osteoporosis
CN110423218A (en) * 2019-08-09 2019-11-08 新乡双鹭药业有限公司 A kind of rich preparation method for impurity in Buddhist nun's synthesis of malic acid card
US10487091B2 (en) 2015-10-05 2019-11-26 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
WO2020118753A1 (en) * 2018-12-12 2020-06-18 安徽中科拓苒药物科学研究有限公司 Pan-kit kinase inhibitor having quinoline structure and application thereof
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11110062B2 (en) 2017-02-15 2021-09-07 Taiho Pharmaceutical Co., Ltd. Pharmaceutical composition
RU2789405C2 (en) * 2018-12-12 2023-02-02 Тарапьютикс Сайенс Инк. Pan-kit kinase inhibitor having quinoline structure and its use

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI2213661T1 (en) * 2003-09-26 2011-11-30 Exelixis Inc c-Met Modulators and Methods of Use
US20110053931A1 (en) * 2006-06-08 2011-03-03 John Gaudino Quinoline compounds and methods of use
EP2387563B2 (en) 2009-01-16 2022-04-27 Exelixis, Inc. Malate salt of n- (4- { [ 6, 7-bis (methyloxy) quinolin-4-yl]oxy}phenyl-n' - (4 -fluorophenyl) cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
DE102009056886A1 (en) 2009-12-03 2011-06-09 Bayer Schering Pharma Aktiengesellschaft cMet inhibitors for the treatment of endometriosis
KR20190042768A (en) 2010-07-16 2019-04-24 엑셀리시스, 인코포레이티드 C-met modulator pharmaceutical compositions
SI2621481T2 (en) 2010-09-27 2023-02-28 Exelixis, Inc., Dual inhibitors of met and vegf for the treatment of castration-resistant prostate cancer and osteoblastic bone metastases
KR20210010671A (en) 2011-02-10 2021-01-27 엑셀리시스, 인코포레이티드 Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds
BR112013022307A2 (en) 2011-03-04 2020-09-24 Glaxosmithkline Intellectual Property (No. 2) Limited aminoquinolines as kinase inhibitors
US20120252840A1 (en) 2011-04-04 2012-10-04 Exelixis, Inc. Method of Treating Cancer
CN103717221A (en) 2011-05-02 2014-04-09 埃克塞里艾克西斯公司 Method of treating cancer and bone cancer pain
TWI547494B (en) 2011-08-18 2016-09-01 葛蘭素史克智慧財產發展有限公司 Amino quinazolines as kinase inhibitors
WO2013032797A2 (en) * 2011-08-26 2013-03-07 New Hope R & D Bioscience, Inc. Oxetane 3,3-dicarboxamide compounds and methods of making and using same
TWI642650B (en) 2011-10-20 2018-12-01 艾克塞里克斯公司 Process for preparing quinoline derivatives
WO2013166296A1 (en) 2012-05-02 2013-11-07 Exelixis, Inc. A dual met - vegf modulator for treating osteolytic bone metastases
AR092529A1 (en) 2012-09-13 2015-04-22 Glaxosmithkline Llc AMINOQUINAZOLINE COMPOUND, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND USE OF THIS COMPOSITE FOR THE PREPARATION OF A MEDICINAL PRODUCT
TW201425307A (en) 2012-09-13 2014-07-01 Glaxosmithkline Llc Amino-quinolines as kinase inhibitors
CN103664776B (en) * 2012-09-26 2016-05-04 正大天晴药业集团股份有限公司 The preparation method of a kind of tyrosine kinase inhibitor and intermediate thereof
ES2654100T3 (en) 2013-02-21 2018-02-12 Glaxosmithkline Intellectual Property Development Limited Quinazolines as kinase inhibitors
MX366003B (en) 2013-03-15 2019-06-24 Exelixis Inc Metabolites of n-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl) -n'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide.
WO2014165786A1 (en) 2013-04-04 2014-10-09 Exelixis, Inc. Cabozantinib dosage form and use in the treatment of cancer
WO2015123639A1 (en) 2014-02-14 2015-08-20 Exelixis, Inc. Crystalline solid forms of n-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-n'-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, processes for making, and methods of use
JP6666849B2 (en) 2014-03-17 2020-03-18 エグゼリクシス， インコーポレイテッド Administration of cabozantinib preparation
WO2016019285A1 (en) 2014-07-31 2016-02-04 Exelixis, Inc. Method of preparing fluorine-18 labeled cabozantinib and its analogs
BR112017002318A2 (en) 2014-08-05 2018-07-17 Exelixis, Inc. drug combinations to treat multiple myeloma.
CN109069499A (en) 2016-04-15 2018-12-21 埃克塞里艾克西斯公司 Use N- (4- (6,7- dimethoxy-quinoline -4- base oxygroup) phenyl)-N '-(4- fluorophenyl) cyclopropane -1,1- diformamide, the method for (2S)-hydroxysuccinic acid salts for treating clear-cell carcinoma
WO2018026877A1 (en) 2016-08-05 2018-02-08 Calitor Sciences, Llc Process for preparing substituted quinolin-4-ol compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3935229A (en) * 1972-07-28 1976-01-27 Synthelabo Esters of 2-[(4-quinolyl)amino]-benzoic acids
US6630489B1 (en) * 1999-02-24 2003-10-07 Astrazeneca Ab Quinoline derivatives as tyrosine kinase inhibitors
US6716847B2 (en) * 1998-10-01 2004-04-06 Astrazeneca Ab Substituted anilino-quinoline compounds and use thereof
US6809097B1 (en) * 1996-09-25 2004-10-26 Zeneca Limited Quinoline derivatives inhibiting the effect of growth factors such as VEGF
US6821987B2 (en) * 2001-04-27 2004-11-23 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives having azolyl group

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5278760A (en) * 1990-04-20 1994-01-11 Hitachi America, Ltd. Method and system for detecting the misfire of an internal combustion engine utilizing engine torque nonuniformity
US5041980A (en) * 1990-06-04 1991-08-20 Caterpillar Inc. Method and apparatus for producing fault signals responsive to malfunctions in individual engine cylinders
US5222392A (en) * 1990-09-21 1993-06-29 Nippondenso Co., Ltd. Control system with misfire detection function for internal combustion engine
JP3357091B2 (en) * 1992-07-21 2002-12-16 富士重工業株式会社 Engine misfire detection method
JP2856014B2 (en) * 1993-02-05 1999-02-10 三菱自動車工業株式会社 Misfire detection method due to crankshaft rotation fluctuation
US5574217A (en) * 1995-06-06 1996-11-12 Chrysler Corporation Engine misfire detection with compensation for normal acceleration of crankshaft
US5542291A (en) * 1995-08-04 1996-08-06 Ford Motor Company Misfire detection in an internal combustion engine using modified median averaging
US5728941A (en) * 1995-10-09 1998-03-17 Denso Corporation Misfire detecting apparatus using difference in engine rotation speed variance
JPH09137747A (en) * 1995-11-15 1997-05-27 Unisia Jecs Corp Flameout diagnostic device of internal combustion engine
JP3449170B2 (en) * 1996-08-09 2003-09-22 トヨタ自動車株式会社 Misfire detection device for internal combustion engine
JP3477016B2 (en) * 1997-02-19 2003-12-10 株式会社日立製作所 Device for detecting combustion state of internal combustion engine
US7425564B2 (en) * 2001-06-22 2008-09-16 Kirin Beer Kabushiki Kaisha Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus prolifertor receptor and medicinal composition containing the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3935229A (en) * 1972-07-28 1976-01-27 Synthelabo Esters of 2-[(4-quinolyl)amino]-benzoic acids
US6809097B1 (en) * 1996-09-25 2004-10-26 Zeneca Limited Quinoline derivatives inhibiting the effect of growth factors such as VEGF
US6716847B2 (en) * 1998-10-01 2004-04-06 Astrazeneca Ab Substituted anilino-quinoline compounds and use thereof
US6630489B1 (en) * 1999-02-24 2003-10-07 Astrazeneca Ab Quinoline derivatives as tyrosine kinase inhibitors
US6821987B2 (en) * 2001-04-27 2004-11-23 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives having azolyl group

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KUBO K.: "Synthesis and Structure - Activity Relationship for New Series of 4-Phenoxyquinoline Derivatives as Specific Inhibitors of Platelet-Derived growth Factor Receptor Tyrosine Kinase", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 11, August 2003 (2003-08-01), pages 5117 - 5133, XP003001996 *
See also references of EP1874759A4 *

Cited By (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8003662B2 (en) 2006-01-30 2011-08-23 Array Biopharma, Inc. Heterobicyclic thiophene compounds and methods of use
US7872017B2 (en) 2006-05-19 2011-01-18 Abbott Laboratories Fused bicycloheterocycle substituted azabicyclic alkane derivatives
US8314087B2 (en) 2007-02-16 2012-11-20 Amgen Inc. Nitrogen-containing heterocyclyl ketones and methods of use
WO2008103277A3 (en) * 2007-02-16 2009-04-16 Amgen Inc Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
RU2487119C2 (en) * 2007-02-22 2013-07-10 Зингента Партисипейшнс Аг Iminopyrimidine derivatives and use thereof as microbiocides
US8513286B2 (en) 2007-02-22 2013-08-20 Syngenta Crop Protection Llc Iminipyridine derivatives and their uses as microbiocides
CN103396359B (en) * 2007-02-22 2016-06-29 先正达参股股份有限公司 Iminipyridine derivatives and they purposes as microbicide
US9096525B2 (en) 2007-02-22 2015-08-04 Syngenta Crop Protection, Llc Iminipyridine derivatives and their uses as microbiocides
RU2532135C2 (en) * 2007-02-22 2014-10-27 Зингента Партисипейшнс Аг Iminopyridine derivatives and use thereof as microbiocides
CN101657423B (en) * 2007-02-22 2013-11-06 先正达参股股份有限公司 Iminipyridine derivatives and their uses as microbiocides
WO2008101682A3 (en) * 2007-02-22 2008-10-09 Syngenta Participations Ag Iminipyridine derivatives and their uses as microbiocides
WO2008112407A1 (en) 2007-03-14 2008-09-18 Advenchen Laboratories, Llc Spiro substituted compounds as angiogenesis inhibitors
US7884114B2 (en) 2007-08-15 2011-02-08 Glaxo Group Limited Compounds
US8188078B2 (en) 2007-10-19 2012-05-29 Sanofi-Aventis 6-aryl/heteroalkyloxy benzothiazole and benzimidazole derivatives, method for preparing same, application thereof as drugs, pharmaceutical compositions and novel use in particular as C-MET inhibitors
FR2922550A1 (en) * 2007-10-19 2009-04-24 Sanofi Aventis Sa NOVEL 6-ARYL / HETEROALKYLOXY BENZOTHIAZOLE AND BENZIMIDAZOLE DERIVATIVES, APPLICATION AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE, IN PARTICULAR AS CMET INHIBITORS
WO2009087305A1 (en) 2007-10-19 2009-07-16 Sanofi-Aventis 6-aryl/heteroalkyloxy benzothiazole and benzimidazole derivatives, method for preparing same, application thereof as drugs, pharmaceutical compositions and novel use in particular as c-met inhibitors
US8759522B2 (en) 2008-03-05 2014-06-24 Methylgene Inc. Inhibitors of protein tyrosine kinase activity
US8729268B2 (en) 2008-03-05 2014-05-20 Methylgene Inc. Inhibitors of protein tyrosine kinase activity
US8304427B2 (en) 2008-04-10 2012-11-06 Taiho Pharmaceutical Co., Ltd. Acylthiourea compound or salt thereof, and use thereof
AU2009234978B2 (en) * 2008-04-10 2014-03-06 Taiho Pharmaceutical Co., Ltd. Acylthiourea Compound or Salt Thereof, and use thereof
KR101414931B1 (en) 2008-04-10 2014-07-04 다이호야쿠힌고교 가부시키가이샤 Acylthiourea compound or salt thereof, and use of the compound or the salt
RU2503664C2 (en) * 2008-04-10 2014-01-10 Тайхо Фармасьютикал Ко., Лтд. Acyl thiourea derivative or salt thereof and use thereof
JP4667537B2 (en) * 2008-04-10 2011-04-13 大鵬薬品工業株式会社 Acylthiourea compounds or salts thereof, and uses thereof
WO2009125597A1 (en) 2008-04-10 2009-10-15 大鵬薬品工業株式会社 Acylthiourea compound or salt thereof, and use of the compound or the salt
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
EP2532657A3 (en) * 2008-10-14 2013-01-23 Sunshine Lake Pharma Co., Ltd Compounds and methods of use
US20130197230A1 (en) * 2008-11-13 2013-08-01 Jo Ann Wilson Methods of preparing quinoline derivatives
JP2012511017A (en) * 2008-12-04 2012-05-17 エグゼリクシス， インコーポレイテッド Method for preparing quinoline derivatives
CN102239148A (en) * 2008-12-04 2011-11-09 埃克塞里艾克西斯公司 Methods of preparing quinoline derivatives
WO2010065838A1 (en) * 2008-12-04 2010-06-10 Exelixis, Inc. Methods of preparing quinoline derivatives
US20130030172A1 (en) * 2008-12-04 2013-01-31 Exelixis, Inc. Methods of Preparing Quinoline Derivatives
JP2012521348A (en) * 2009-03-21 2012-09-13 クイ ニング Amino ester derivatives, salts thereof, and methods of use
US8049014B2 (en) 2009-03-25 2011-11-01 Korea Institute Of Science And Technology Aminoquinoline derivatives, preparation method thereof and pharmaceutical composition comprising the same
WO2010130943A1 (en) 2009-05-12 2010-11-18 Sanofi-Aventis 5-membered heterocyclic compound cyclopenta[c]pyrrolylalkylcarbamate derivatives, preparation thereof, and therapeutic use thereof
WO2010130944A1 (en) 2009-05-12 2010-11-18 Sanofi-Aventis Cyclopenta[c]pyrrole-2-carboxylate derivatives, preparation thereof, and therapeutic use thereof
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11433064B2 (en) 2009-08-07 2022-09-06 Exelixis, Inc. Methods of using c-Met modulators
CN102030705B (en) * 2009-09-30 2012-12-19 上海睿智化学研究有限公司 Synthesis method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline
US11369565B2 (en) 2010-04-23 2022-06-28 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10272030B2 (en) 2010-04-23 2019-04-30 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US10765624B2 (en) 2010-04-23 2020-09-08 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10076519B2 (en) 2010-04-23 2018-09-18 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US10590129B2 (en) 2010-05-17 2020-03-17 Rhizen Pharmaceuticals Sa 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases
US10087182B2 (en) 2010-05-17 2018-10-02 Incozen Therapeutics Pvt. Ltd. 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases
US8912331B2 (en) 2010-05-17 2014-12-16 Rhizen Pharmaceuticals Sa 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases
EP3450432A1 (en) 2010-05-17 2019-03-06 Incozen Therapeutics Pvt. Ltd. Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued - 3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases
WO2011145035A1 (en) 2010-05-17 2011-11-24 Indian Incozen Therapeutics Pvt. Ltd. Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases
US8481739B2 (en) 2010-05-17 2013-07-09 Incozen Therapeutics Pvt. Ltd. 3,5-Disubstituted-3H-imidazo[4,5-b]pyridine and 3,5-disubstituted-3H[1,2,3]triazolo [4,5-b] Pyridine Compounds as Modulators of protein kinases
WO2012034055A2 (en) 2010-09-12 2012-03-15 Advenchen Laboratories, Llc Compounds as c-met kinase inhibitors
US20140057908A1 (en) * 2010-09-27 2014-02-27 Exelixis, Inc. Method of Treating Cancer
US9278962B2 (en) 2011-04-22 2016-03-08 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US8759380B2 (en) 2011-04-22 2014-06-24 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US10166225B2 (en) 2011-09-22 2019-01-01 Exelixis, Inc. Method for treating osteoporosis
JPWO2013100014A1 (en) * 2011-12-28 2015-05-11 大鵬薬品工業株式会社 Antitumor agent effect enhancer
WO2013100014A1 (en) * 2011-12-28 2013-07-04 大鵬薬品工業株式会社 Effect potentiator for antitumor agents
CN102617463A (en) * 2012-02-28 2012-08-01 苏州卡耐博生物技术有限公司 Quinoline derivative and quinazoline derivative and preparation method thereof
US9815831B2 (en) 2012-03-30 2017-11-14 Rhizen Pharmaceuticals Sa 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of c-Met protein kinases
US11066402B2 (en) 2012-03-30 2021-07-20 Rhizen Pharmaceuticals Sa 3,5-disubstituted-3H-imidazo[4,5-b]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of c-Met protein kinases
WO2013144737A2 (en) 2012-03-30 2013-10-03 Rhizen Pharmaceuticals Sa Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of c-met protein kinases
CN103965104B (en) * 2013-01-29 2017-09-29 正大天晴药业集团股份有限公司 A kind of preparation method of tyrosine kinase inhibitor and its intermediate
CN103965104A (en) * 2013-01-29 2014-08-06 正大天晴药业集团股份有限公司 Preparation methods of tyrosine kinase inhibitor and intermediates thereof
EP3299369A4 (en) * 2015-05-21 2018-05-02 Shanghai Institute of Materia Medica, Chinese Academy of Sciences Pyrido-azaheterecydic compound and preparation method and use thereof
US10710996B2 (en) 2015-05-21 2020-07-14 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Pyrido-azaheterecydic compound and preparation method and use thereof
US11230558B2 (en) 2015-10-05 2022-01-25 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11261199B2 (en) 2015-10-05 2022-03-01 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies
US10865214B2 (en) 2015-10-05 2020-12-15 The Trustees of Columbia University in they City of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11008341B2 (en) 2015-10-05 2021-05-18 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US10487091B2 (en) 2015-10-05 2019-11-26 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
CN108069919A (en) * 2016-11-08 2018-05-25 上海医药工业研究院 The preparation method of click azoles amine key intermediate
US11110062B2 (en) 2017-02-15 2021-09-07 Taiho Pharmaceutical Co., Ltd. Pharmaceutical composition
WO2020118753A1 (en) * 2018-12-12 2020-06-18 安徽中科拓苒药物科学研究有限公司 Pan-kit kinase inhibitor having quinoline structure and application thereof
CN111303024A (en) * 2018-12-12 2020-06-19 安徽中科拓苒药物科学研究有限公司 Quinoline-structured pan-KIT kinase inhibitor and application thereof
RU2789405C2 (en) * 2018-12-12 2023-02-02 Тарапьютикс Сайенс Инк. Pan-kit kinase inhibitor having quinoline structure and its use
CN111303024B (en) * 2018-12-12 2023-03-28 安徽中科拓苒药物科学研究有限公司 Quinoline-structured pan-KIT kinase inhibitor and application thereof
CN110423218A (en) * 2019-08-09 2019-11-08 新乡双鹭药业有限公司 A kind of rich preparation method for impurity in Buddhist nun's synthesis of malic acid card

Also Published As

Publication number Publication date
EP1874759A1 (en) 2008-01-09
JP2008537748A (en) 2008-09-25
AU2006231646A2 (en) 2006-10-12
US20080161305A1 (en) 2008-07-03
CA2603748A1 (en) 2006-10-12
EP1874759A4 (en) 2009-07-15
AU2006231646A1 (en) 2006-10-12

Similar Documents

Publication Publication Date Title
EP1874759A1 (en) C-met modulators and methods of use
JP5694501B2 (en) c-Met modulators and uses thereof
EP1773826A2 (en) C-met modulators and method of use
JP2007506777A5 (en)
AU2017200555A1 (en) c-Met modulators and methods of use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006231646

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2603748

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2008505496

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2006231646

Country of ref document: AU

Date of ref document: 20060406

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: RU

WWE Wipo information: entry into national phase

Ref document number: 2006749361

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 11910720

Country of ref document: US