WO2015043492A1 - Substituted urea derivatives and uses thereof in medicine - Google Patents

Substituted urea derivatives and uses thereof in medicine Download PDF

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Publication number
WO2015043492A1
WO2015043492A1 PCT/CN2014/087469 CN2014087469W WO2015043492A1 WO 2015043492 A1 WO2015043492 A1 WO 2015043492A1 CN 2014087469 W CN2014087469 W CN 2014087469W WO 2015043492 A1 WO2015043492 A1 WO 2015043492A1
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Prior art keywords
alkyl
alkoxy
cancer
independently
hydroxy
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PCT/CN2014/087469
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French (fr)
Inventor
Changchung CHENG
Bing Liu
Yingjun Zhang
Bohua LONG
Weihong Zhang
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Sunshine Lake Pharma Co., Ltd.
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Publication of WO2015043492A1 publication Critical patent/WO2015043492A1/en

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61P35/00—Antineoplastic agents
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
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    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to pharmaceutical field, and more specifically relates to novel substituted urea derivatives, pharmaceutical compositions thereof and uses thereof for the treatment of FLT3 mediated or FLT3-ITD caused diseases.
  • novel substituted urea derivatives and pharmaceutical compositions are useful in treating, ameliorating or preventing a disease related to tyrosine kinase activity, or one or more symptoms thereof.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins.
  • Protein kinases and in particular the receptor protein tyrosine kinase (RTK) family of protein kinases, act primarily as growth factor receptors and play a central role in signal transduction pathways regulating a number of cellular functions, such as cell cycle, cell growth, cell differentiation and cell death.
  • RTK receptor protein tyrosine kinase
  • RPTK receptor protein tyrosine kinase
  • Dysregulated activity of the receptor tyrosine kinase of the platelet growth factor receptor (PDGFR) family has been implicated in various proliferative disorders.
  • Gene amplification or upregulation of PDGFR occurs in patients with gliomas or sarcomas (See, Kumabe et al. , Oncogene, 1992, 7: 627-633, and Ostman et al. , Cancer Res. , 2001, 80: 1-38) .
  • FLT3 also called Flk2
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • Kiyoi et al. Int J Hematol. , 2005, 82: 85-92
  • FLT3 inhibitors More than a dozen known FLT3 inhibitors are being developed and some have shown promising clinical effects against AML (See, Levis et al. , Int J Hematol. , 2005, 82: 100-107) .
  • the FLT3 receptor is also expressed in a large portion of dendritic cell progenitors and stimulation of the receptor causes the proliferation and differentiation of these progenitors into dendritic cells (DC) . Since dendritic cells are the main initiators of the T-cell mediated immune response, including the autoreactive immune response, FLT3 inhibition is a mechanism for downregulating DC-mediated inflammatory and autoimmune responses.
  • EAE experimental autoimmune encephalomyelitis
  • a high level of the FLT3 ligand is found in the serum of patients with Langerhans cell histiocytosis and systemic lupus erythematosus, which further implicates FLT3 signaling in the dysregulation of dendritic cell progenitors in those autoimmune diseases (See, Rolland et al. , J. Immunol. , 2005, 174: 3067-3071) .
  • FLT3-ITD Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20%of acute myeloid leukemia patients and are associated with a poor prognosis. Abundant scientific and clinical evidence including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion, which is dispensable for cancer initiation and maintenance. It is reported that some patients have the tendency of recurrence after treatment, which may be due to mutations of FLT3 kinase (See, Heidel et al. , Blood, 2006, 107: 293–300) .
  • FLT3-ITD can represent a driver lesion, which has causative role in malignancy pathogenesis, and valid therapeutic target in human AML (See, Catherine et al. , Nature, 2012, 485: 260-263) .
  • FLT3 gene is a frequent event in AML and usually involves internal tandem duplication (ITD) of the juxtamembrane domain coding region or point mutations of the tyrosine kinase domain (TKD) .
  • ITD internal tandem duplication
  • TKD tyrosine kinase domain
  • Both FLT3-ITD and FLT3-TKD mutations result in ligand-independent proliferation due to constitutive dimerisation and activation of the FLT3 receptor.
  • High mutant-to-wild type allelic ratios of FLT3-ITD are associated with a very poor prognosis in both adults and children (See, AS Moore et al. , Leukemia, 2012, 26: 1462-1470) .
  • kinase inhibitors for use in cancer therapy.
  • urea derivatives have been reported to be selective FLT3 inhibitors.
  • substituted urea derivatives and pharmaceutical compositions thereof used in drug therapy as well as the uses thereof for the treatment of FLT3 kinase mediated or FLT3-ITD caused diseases, of which the substituted urea compounds are useful in the modulation of FLT3 kinase activity and in the inhibition of FLT3-ITD.
  • a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of Q and W is independently CH or N;
  • ring K is a 5-to 6-membered heteroaryl group, of which at least two ring members are heteroatoms independently selected from O, S, NR 4 and N;
  • ring E is a bicyclic or tricyclic heteroarylene group
  • each X 8 , X 9 and X 10 is independently N or CH;
  • each of X, Y, Z 1 , Z 2 , Z 3 and Z is independently N or CH;
  • T is-O-, -S-, -NR 4 -or-CH 2 -;
  • each of R 2 and R 3 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl;
  • each R 4a and R 4 is independently hydrogen, C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl;
  • each q, m, p, r and s is independently 0, 1, 2, 3 or 4;
  • each of d and n is independently 1, 2, 3 or 4;
  • each t is independently 0, 1 or 2;
  • a 0, 1, 2, 3 or 4,
  • each aryl, bicyclic heteroarylene, tricyclic heteroarylene, alkoxy, alkyl-S ( O) t -, -G- (CH 2 ) n -R, arylalkyl, heteroarylalkyl, heteroaryl, heteroarylene, heterocycly, bridged heterobicyclyl, spiro heterobicyclyl, fused heterobicyclyl, alkyl, haloalkyl, alkylamino, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, alkoxyalkyl, hydroxyalkyl, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, cycloalkyloxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclo,
  • ring E is
  • each X, Y, Z, Z 1 , Z 2 , Z 3 and Z 4 is independently N or CH;
  • each T and T 1 is independently -O-, -S-, -NR 4 -or-CH 2 -;
  • each X 8 , X 9 and X 10 is independently N or CH;
  • each q, m, p, r and s is independently 0, 1, 2, 3 or 4;
  • each of R 2 and R 3 is independently C 1-6 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl;
  • each of R 4a and R 4 is independently hydrogen, C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl;
  • ring E is
  • each of R 2 and R 3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl; and provided that:
  • substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, tri
  • G is-O-or furylene.
  • ring K is a group selected from the following:
  • each U is independently -CH 2 -, -O-, -NR 4 -or-S-;
  • each V, V 1 and V 2 is independently CH or N;
  • R 4 is hydrogen, C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl;
  • ring K is a group selected from the following:
  • the compound disclosed herein has formula (II) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of Q and W is independently CH or N;
  • each of d and n is independently 1, 2, 3 or 4;
  • each t is independently 0, 1 or 2;
  • a 0, 1, 2, 3 or 4;
  • each of R 2 and R 3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl; and provided that:
  • substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, tri
  • the compound disclosed herein has formula (III) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of X, Y, Z, Z 1 , Z 2 , Z 3 and Z 4 is independently N or CH;
  • composition comprising the compound disclosed herein.
  • the pharmaceutical composition disclosed herein further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
  • the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent, wherein the additional therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-inflammatory agent, an immunosuppressant, an immunostimulant, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis or a combination thereof.
  • the additional therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-inflammatory agent, an immunosuppressant, an immunostimulant, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis or a combination thereof.
  • the additional therapeutic agent disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
  • provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient comprising administrating a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein to the patient.
  • provided herein is the compound or the pharmaceutical composition disclosed herein for use in preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
  • the proliferative disease disclosed herein is acute myelogenous leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute lymphocytic leukemia (ALL) , colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, CNS (central nervous system) cancer, malignant glioma or bone marrow hyperplasia, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic diseases, cryoglobulinemia, non-lymphoreticular system tumor, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia
  • the autoimmune disease disclosed herein is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, I-type diabetes, sarcoidosis, inflammatory bowel disease, Crohn’s disease or systemic lupus.
  • the inflammatory disease disclosed herein is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
  • the disease is mediated by FLT3 kinase or caused by FLT3-ITD.
  • provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, wherein the method comprise administering to the patient a therapeutically effective amount of the compound disclosed herein.
  • provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, wherein the method comprise administering to the patient a therapeutically effective amount of the pharmaceutical composition containing the compound disclosed herein.
  • provided herein is use of the compound disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
  • compounds may optionally be substituted with one or more substituents, such as those illustrated above, or as exemplified by particular classes, subclasses, and species disclosed herein.
  • substituents such as those illustrated above, or as exemplified by particular classes, subclasses, and species disclosed herein.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” .
  • substituted whether preceded by the term “optionally” or not, refers to the replacement of one or more hydrogen groups in a given structure with the group of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon group of 1 to 20 carbon atoms, wherein the alkyl group is optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In other embodiments, the alkyl group contains 1 to 8 carbon atoms. In still other embodiments, the alkyl group contains 1 to 6 carbon atoms. In yet other embodiments, the alkyl group contains 1 to 4 carbon atoms and in yet other embodiments, the alkyl group contains 1 to 3 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl (Me, -CH 3 ) , ethyl (Et, -CH 2 CH 3 ) , n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) , isopropyl (i-Pr, -CH (CH 3 ) 2 ) , n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ) , isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ) , sec-butyl (s-Bu, -CH (CH 3 ) CH 2 CH 3 ) , tert-butyl (t-Bu, -C(CH 3 ) 3 ) , n-pentyl (-CH 2 CH 2 CH 2 CH 3 ) , 2-pentyl (-CH (CH 3 ) CH 2 CH 2 CH 3 ) , 3-pentyl (-CH (CH (CH (CH 3
  • alkynyl refers to a linear or branched-chain monovalent hydrocarbon group of 2 to 12 carbon atoms, with at least one site of unsaturation, i. e. , a carbon-carbon sp triple bond, wherein the alkynyl group is optionally substituted with one or more substituents described herein.
  • Some non-limiting examples of the alkynyl group include ethynyl (-C ⁇ CH) , propargyl (-CH 2 C ⁇ CH) , and the like.
  • alkenyl refers to a linear or branched-chain monovalent hydrocarbon group of 2 to 12 carbon atoms, with at least one site of unsaturation, i. e. , a carbon-carbon sp 2 double bond, wherein the alkenyl group is optionally substituted with one or more substituents described herein, and includes groups having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkylene and alkylene chain refer to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having 1 to 8 carbon atoms.
  • alkylene group include methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through any two carbons within the chain.
  • alkenylene and alkenylene chain refer to a straight or branched divalent unsaturated hydrocarbon chain consisting solely of carbon and hydrogen and having 1 to 8 carbon atoms, wherein the unsaturated bond exists only as a double bond and the double bond may be located between any two carbon atoms of the chain.
  • alkenylene group include ethenylene, 1, 3-propenylene, 2-butenylene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through any two carbons within the chain.
  • alkynylene and alkynylene chain refer to a straight or branched divalent unsaturated hydrocarbon chain consisting solely of carbon and hydrogen and having 1 to 8 carbon atoms, wherein the unsaturated bond exists only as a triple bond and the triple bond may be located between any two carbon atoms of the chain.
  • alkynylene group include ethynylene, 1-propynylene 2-butynylene, 1-pentynylene 3-pentynylene, and the like.
  • the alkynylene chain is attached to the rest of the molecule through any two carbons within the chain.
  • halogen or “halogen atom” refers to fluoro, chloro, bromo or iodo.
  • amino refers to -NH 2 .
  • alkamino or “alkylamino” refers to “N-alkylamino” and “N, N-dialkylamino” , wherein the amino groups are independently substituted with one or two alkyl groups, respectively, and wherein the alkyl group is as defined herein.
  • the alkylamino group is lower alkylamino group having one or two alkyl groups of 1 to 6 carbon atoms attached to nitrogen atom.
  • the alkylamino group is lower alkylamino group having 1 to 3 carbon atoms.
  • alkylamino group examples include monoalkylamino or dialkylamino such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, and the like.
  • alkoxy refers to an alkyl group, as defined herein, attached to the principal carbon chain through an oxygen atom.
  • alkoxy group include methoxy, ethoxy, propoxy, and the like.
  • alkoxyalkyl or “alkoxyalkoxy” refers to an alkyl group or alkoxy group substituted with one or more identical or different alkoxy groups, wherein the alkyl group and alkoxy group are as defined herein.
  • alkoxyalkyl group and alkoxyalkoxy group include methoxymethyl, ethoxymethyl, methoxypropoxy, methoxymethoxy, and the like.
  • haloalkyl or “haloalkoxy” refers to an alkyl group or alkoxy group substituted with one or more identical or different halogen atoms, wherein the alkyl group and alkoxy group are as defined herein.
  • Some non-limiting examples of the haloalkyl group and haloalkoxy group include trifluoromethyl, trifluoromethoxy, and the like.
  • alkylaminohaloalkoxy refers to a haloalkoxy group substituted with one or more identical or different alkylamino groups, wherein the alkylamino group and haloalkoxy group are as defined herein.
  • alkylaminohaloalkoxy group include methylaminodifluoromethyloxy, and the like.
  • hydroxyalkyl or “hydroxyalkoxy” refers to an alkyl group or alkoxy group substituted with one or more hydroxy groups, wherein the alkyl group and alkoxy group are as defined herein.
  • Some non-limiting examples of the hydroxyalkyl group and hydroxyalkoxy group include hydroxymethyl, 1-hydroxyethyl, hydroxypropyl, 1, 2-dihydroxypropyl, hydroxymethoxy, 1-hydroxyethoxy, and the like.
  • aminoalkoxy or “alkylaminoalkoxy” refers to an alkoxy group substituted with one or more amino groups or alkylamino groups, wherein the alkylamino group and alkoxy group are as defined herein.
  • aminoalkoxy group and alkylaminoalkoxy group include aminomethoxy, 1-aminoethoxy, methylaminomethoxy, ethylaminoethoxy, and the like.
  • aryl used alone or as part of a larger moiety as in “arylalkyl” , “arylalkoxy” or “aryloxyalkyl” refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring” or “aromatic ring” .
  • Some non-limiting examples of the aryl group include phenyl, naphthyl and anthracene.
  • the aryl group can be a monoradical or a
  • heteroaryl or “heteroaryl ring” as used interchangeably herein, used alone or as part of a larger moiety as in “heteroarylalkyl” or “heteroarylalkoxy” , refers to a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the bicyclic heteroaryl, tricyclic heteroaryl or tetracyclic heteroaryl ring system is a fused ring.
  • the heteroaryl ring system is aromatic, in which one or more ring members are an independently selected heteroatom selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , and PO or PO 2 .
  • the heteroaryl ring system may be attached to the main structure at any heteroatom or carbon atom, which results in the creation of a stable compound.
  • the heteroaryl ring system may be 3-7 membered monocyclic ring, 7-10 membered bicyclic ring or 10-15 membered tricyclic ring.
  • Bicyclic heteroaryl ring having 7-10 ring atoms can be arranged as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system, and tricyclic heteroaryl ring having 10-15 ring atoms can be arranged as a tricyclo [5, 5, 6] , [5, 7, 6] or [6, 5, 6] system.
  • the heteroaryl group may be a mono
  • heteroaryl group examples include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e. g.
  • 2-pyrazolyl) isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazol-2-yl, pyrazinyl, 2-pyrazinyl, 1,3, 5-triazinyl, benzo [d] thiazol-2-yl, imidazo [1, 5-a] pyridin-6-yl, benzimidazolyl, benzoxazolyl, 1,8-naphthyridinyl, benzothienyl, indolyl (e.
  • bicyclic heteroaryl or “bicyclic heteroaryl ring” as used interchangeably herein, refers to a fused heteroaryl ring system, which is a bicyclic ring system.
  • the fused heteroaryl ring system is aromatic, in which one or more ring members are an independently selected heteroatom selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , and PO or PO 2 .
  • the fused heteroaryl ring system may be attached to the main structure at any heteroatom or carbon atom, which results in the creation of a stable compound.
  • the fused heteroaryl ring system is a 7-10 membered bicyclic ring, which can be arranged as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system.
  • the bicyclic heteroaryl group may be a monoradical or a diradical such as a bicyclic heteroarylene group, wherein the term “bicyclic heteroarylene” refers to the divalent form of bicyclic heteroaryl defined above.
  • bicyclic heteroaryl group examples include benzo [d] thiazol-2-yl, imidazo [1, 5-a] pyridin-6-yl, benzimidazolyl, benzoxazolyl, 1, 8-naphthyridinyl, benzothienyl, indolyl (e. g., 2-indolyl) , purinyl, quinolinyl (e. g.
  • tricyclic heteroaryl or “tricyclic heteroaryl ring” as used interchangeably herein, refers to a fused heteroaryl ring system, which is a tricyclic ring system.
  • the fused heteroaryl ring system is aromatic, in which one or more ring members are an independently selected heteroatom selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , and PO or PO 2 .
  • the fused heteroaryl ring system may be attached to the main structure at any heteroatom or carbon atom, which results in the creation of a stable compound.
  • the fused heteroaryl ring system is a 10-15 membered tricyclic ring, which can be arranged as a tricyclo [5, 5, 6] , [5, 7, 6] or [6, 5, 6] system.
  • the tricyclic heteroaryl group may be a monoradical or a diradical such as a tricyclic heteroarylene group, wherein the term “tricyclic heteroarylene” refers to the divalent form of tricyclic heteroaryl defined above.
  • tricyclic heteroaryl group examples include benzo [4, 6] imidazo [1, 2-a] pyridinyl, benzo [d] imidazo [2, 1-b] thiazolyl, pyrazolo [2’, 1’: 2, 3] oxazolo [4, 5-c] pyridinyl, imidazo [2’, 1’: 2, 3] thiazolo [4, 5-c] pyridinyl, imidazo [2’, 1’: 2, 3] thiazolo [4, 5-b] pyridinyl, imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridinyl, pyrazolo [2’, 1’: 2, 3] thiazolo [4, 5-b] pyrazinyl, 1H-benzo [4, 5] thieno [2, 3-d] imidazolyl, 1-methyl-1H-benzo [4, 5] thieno [2, 3-d] imidazolyl,
  • Carbocyclyl refers to a monovalent or multitivalent, non-aromatic, and saturated or partially unsaturated ring consisting solely of carbon and hydrogen atoms and including 3-12 carbon atoms as a monocyclic ring or 7-12 carbon atoms as a bicyclic or tricyclic ring.
  • Bicyclic carbocycles having 7-12 ring atoms can be arranged, for example, as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5, 6] or [6, 6] system.
  • the carbocyclyl, cycloaliphatic or carbocycle group can be a monoradical or a diradical, i. e. , in some embodiments, the carbocyclyl, cycloaliphatic or carbocycle group can be replaced by or used as carbocyclylene.
  • cycloaliphatic group examples include cycloalkyl, cycloalkenyl and cycloalkynyl. Further examples of the cycloaliphatic group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantly, and the like.
  • cycloalkyl refers to a monovalent or multitivalent, non-aromatic, and saturated or partially unsaturated ring consisting solely of carbon and hydrogen atoms and including 3-12 carbon atoms as a monocyclic ring or 7-12 carbon atoms as a bicyclic or tricyclic ring.
  • Bicyclic carbocycles having 7-12 ring atoms can be arranged, for example, as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5, 6] or [6, 6] system.
  • the cycloalkyl group can be a monoradical or a diradical, i. e. , in some embodiments, the cycloalkyl group can be replaced by or used as cycloalkylene.
  • Some non-limiting examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantly, and the like.
  • heterocyclyl refers to a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic.
  • the heterocyclyl, heterocycloalkyl, heterocycle, heterocycloaliphatic or heterocyclic group can be a monoradical or a diradical, i. e.
  • the heterocyclyl, heterocycloalkyl, heterocycle, heterocycloaliphatic or heterocyclic group can be replaced by or used as heterocyclylene.
  • the heterocyclyl system may be attached to the main structure at any heteroatom or carbon atom, which results in the creation of a stable compound.
  • One or more hydrogen atoms on the heterocyclic ring are optionally substituted with one or more substituents described herein.
  • the heterocyclyl, heterocycloalkyl, heterocycle, heterocycloaliphatic or heterocyclic group is a monocyclic ring having 3-7 ring members (e. g.
  • 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , and PO or PO 2 , and the carbon atom can also be optionally substituted with one or more oxo to provide the group -C O-, with the proviso that when the ring is a 3-membered ring, there is only one heteroatom) or a bicyclic ring having 7-10 ring members (e. g.
  • the heterocyclyl may be a carbon radical or heteroatom radical.
  • the heterocyclyl group also includes a group in which the heterocyclyl group is fused with a saturated or partially unsaturated ring or a heterocyclic ring.
  • Some non-limiting examples of the heterocyclyl group include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl,
  • the substituted heterocyclyl include cyclohex-2,
  • fused bicyclic refers to a saturated or unsaturated fused ring system, which refers to a bicyclic ring system that is not aromatic and includes at least one non-aromatic ring.
  • the fused bicyclic, fused cyclic, fused bicyclyl or fused cyclyl group can be a monoradical or a diradical, i. e. , in some embodiments, the fused bicyclic, fused cyclic, fused bicyclyl or fused cyclyl group can be replaced by or used as fused bicyclylene.
  • 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) .
  • Each cyclic ring in the fused bicyclyl can be either a carbocyclic ring or a heteroalicyclic ring.
  • fused bicyclic ring system examples include hexahydro-furo [3, 2-b] furanyl, 2, 3, 3a, 4, 7, 7a-hexahydro-1H-indenyl, 7-azabicyclo [2.2.1] heptyl, fused bicyclo [3.3.0] octyl, fused bicyclo [3.1.0] hexyl, 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl, and the like.
  • substituents include, but are not limited to, hydrogen, aminoalkyl
  • fused heterobicyclyl refers to saturated or unsaturated fused ring system, which refers to a bicyclic ring system that is not aromatic and includes at least one non-aromatic ring. 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) .
  • the fused heterobicyclyl group can be a monoradical or a diradical, i. e. , in some embodiments, the fused heterobicyclyl group can be replaced by or used as fused heterobicyclylene. And at least one ring in the fused ring system contains one or more heteroatoms.
  • fused heterobicyclyl group examples include hexahydro-2H- [1, 4] dioxin [2, 3-c] pyrrolyl, 3-azabicyclo [3.3.0] octyl, 3-methyl-3, 7-diazabicyclo [3.3.0] octyl, 8-azabicyclo [4.3.0] nonyl, 8-azabicyclo [4.3.0] non-3-yl, 3-azabicyclo [4.3.0] non-3-yl, 1, 5-dioxa-8-azabicyclo [4.3.0] nonyl, (1R, 6S) -2, 5-dioxa-8-azabicyclo [4.3.0] nonyl, (1R, 6R) -2, 5-dioxa-8-azabicyclo [4.3.0] nonyl, isoindolinyl, 1, 2, 3, 4-tetrahydroquinolyl, (1S, 5S) -1-hydroxy-3-azabicyclo [3.1.0
  • bridged bicyclyl refers to a saturated or unsaturated bridged ring system, which refers to a bicyclic 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) , in which each ring contains 3 to 7 ring members.
  • Some non-limiting examples of the bridged bicyclyl group include bicyclo [2.2.1] heptyl, 2-methyl-heterobicyclo [2.2.1] heptyl, and the like.
  • bridged heterobicyclyl refers to saturated or unsaturated bridged ring system, which refers to a bicyclic ring system that is not aromatic.
  • the bridged heterobicyclyl group can be a monoradical or a diradical, i. e. , in some embodiments, the bridged heterobicyclyl group can be replaced by or used as fused heterobicyclylene.
  • 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) .
  • at least one ring in the bridged ring system contains one or more heteroatoms.
  • Each ring in the bridged ring system contains 3 to 7 ring members (i.
  • bridged heterobicyclyl group examples include 2-oxa-5-azabicyclo [2.2.1] heptyl, 2-thio-5-azabicyclo [2.2.1] heptyl, 2-oxo-5-azabicyclo [2.2.1] heptyl, 2, 5-diazabicyclo [2.2.1] heptyl, 2-methyl-2, 5-diazabicyclo [2.2.1] heptyl, and the like.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein the alkyl group and cycloalkyl group are as defined herein.
  • Some non-limiting examples of the cycloalkylalkyl group include cyclopropylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein the alkyl and heterocyclyl group are as defined herein.
  • Some non-limiting examples of the heterocyclylalkyl group include oxiranylmethyl, morpholinylmethyl, piperidylethyl, and the like.
  • cycloalkyloxy refers to an optionally substituted cycloalkyl or carbocyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • cycloalkyloxy group include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like.
  • cycloalkylamino refers to an amino group substituted with one or two cycloalkyl groups, wherein the cycloalkyl group is as defined herein.
  • Some non-limiting examples of the cycloalkylamino group include cyclopropylamino, cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino, and the like.
  • arylalkoxy refers to an alkoxy group substituted with one or more aryl groups, wherein the aryl group and alkoxy group are as defined herein.
  • arylalkoxy group include phenylmethoxy, phenylethoxy, (p-tolyl) methoxy, phenylpropoxy, and the like.
  • arylalkylamino refers to an alkylamino group substituted with one or more aryl groups, wherein the aryl group and alkylamino group are as defined herein.
  • arylalkylamino group include phenylmethylamino, phenylethylamino, phenylpropylamino, (p-tolyl) methylamino, and the like.
  • heteroarylalkoxy refers to an alkoxy group substituted with one or more heteroaryl groups, wherein the heteroaryl group and alkoxy group are as defined herein.
  • Some non-limiting examples of the heteroarylalkoxy group include pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, and the like.
  • heteroarylalkylamino refers to a heteroarylalkyl group attached via a nitrogen atom to other groups, wherein the heteroarylalkyl group is as defined herein.
  • the heteroarylalkylamino group include pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino, and the like.
  • heterocyclylalkoxy refers to a heterocyclyl-substituted alkoxy group wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • heterocyclylalkylamino refers to a heterocyclyl-substituted alkylamino group wherein the nitrogen atom serves as the attaching point to the rest of the molecule. Wherein the heterocyclyl, alkoxy and alkylamino group are as defined herein.
  • heterocyclylalkoxy group and heterocyclylalkylamino group include morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino, and the like.
  • cycloalkylalkoxy refers to an alkoxy group substituted with one or more cycloalkyl or carbocyclyl groups, wherein the cycloalkyl or carbocyclyl group and alkoxy group are as defined herein.
  • Some non-limiting examples of the cycloalkylalkoxy group include cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy, cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy, and the like.
  • cycloalkylalkylamino or “carbocyclylalkylamino” refers to an alkylamino group substituted with one or more cycloalkyl or carbocyclyl groups, wherein the cycloalkyl or carbocyclyl group and alkylamino group are as defined herein.
  • Some non-limiting examples of the cycloalkylalkylamino group include cyclopropylmethylamino, cyclopropylethylamino, cyclopentylethylamino, cyclohexylethylamino, cyclohexylmethylamino, cyclopropylpropylamino, and the like.
  • aryloxyalkoxy refers to an alkoxy group substituted with one or more aryloxy groups, wherein the alkoxy group and aryloxy group are as defined herein.
  • aryloxyalkoxy group include phenyloxymethoxy, phenyloxyethoxy, phenyloxypropoxy, and the like.
  • heteroaryloxyalkoxy refers to an alkoxy group substituted with one or more heteroaryloxy groups, wherein the alkoxy group and heteroaryloxy group are as defined herein.
  • Some non-limiting examples of the heteroaryloxyalkoxy group include pyridinyloxymethoxy, pyrimidinyloxyethoxy, thiazolyloxypropoxy, and the like.
  • aromaticity refers to an optionally substituted aryl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • aryloxy group include phenyloxy, methylphenyloxy, ethylphenyloxy, and the like.
  • heteroaryloxy refers to an optionally substituted heteroaryl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • the heteroaryloxy group include pyrid-2-yloxy, thiazol-2-yloxy, imidazol-2-yloxy, pyrimidin-2-yloxy, and the like.
  • heterocyclyloxyalkoxy refers to an alkoxy group substituted with one or more heterocyclyloxy groups, wherein the alkoxy group and heterocyclyloxy group are as defined herein.
  • Some non-limiting examples of the heterocyclyloxyalkoxy group include pyrrol-2-yloxymethoxy, pyrrol-3-yloxyethoxy, piperidin-2-yloxyethoxy, piperidin-3-yloxyethoxy, piperazin-2-yloxymethoxy, piperidin-4-yloxyethoxy, and the like.
  • carbocyclyloxyalkoxy refers to an alkoxy group substituted with one or more carbocyclyloxy groups, wherein the alkoxy group and carbocyclyloxy group are as defined herein.
  • carbocyclyloxyalkoxy group include cyclopropyloxymethoxy, cyclopropyloxyethoxy, cyclopentyloxyethoxy, cyclohexyloxyethoxy, cyclohexen-3-yloxyethoxy, and the like.
  • heterocyclyloxy refers to an optionally substituted heterocyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • the heterocyclyloxy group include pyrrol-2-yloxy, pyrrol-3-yloxy, piperidin-2-yloxy, piperidin-3-yloxy, piperazin-2-yloxy, piperidin-4-yloxy, and the like.
  • fused bicyclyloxy refers to an optionally substituted fused bicyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • fused bicyclyloxy group include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyloxy, fused bicyclo [3.3.0] oct-2yloxy, fused bicyclo [3.1.0] hex-2yloxy, and the like.
  • fused heterobicyclyloxy refers to an optionally substituted fused heterobicyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • fused heterobicyclyloxy group include hexahydro-furo [3, 2-b] furan-2-yloxy, 7-azabicyclo [2.3.0] hept-2-yloxy, 7-azabicyclo [2.3.0] hept-4-yloxy, and the like.
  • fused bicyclylamino refers to an amino group substituted with one or two fused bicyclyl groups, wherein the fused bicyclyl group is as defined herein.
  • fused bicyclylamino group include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylamino, di(1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl) amino, fused bicyclo [3.3.0] octylamino, fused bicyclo [3.1.0] hexylamino, and the like.
  • fused heterobicyclylamino refers to an amino group substituted with one or two fused heterobicyclyl groups, wherein the fused heterobicyclyl group is as defined herein.
  • fused heterobicyclylamino group include hexahydro-furo [3, 2-b] furan-2-ylamino, 7-azabicyclo [2.3.0] hept-2-ylamino, 7-azabicyclo [2.3.0] hept-4-ylamino, and the like.
  • fused bicyclylalkylamino refers to an alkylamino group substituted with one or two fused bicyclyl groups, wherein the fused bicyclyl group is as defined herein.
  • fused bicyclylalkylamino group include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylmethylamino, di(1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl) methylamino, fused bicyclo [3.3.0] octylmethylamino, fused bicyclo [3.1.0] hexylmethylamino, and the like.
  • fused heterobicyclylalkylamino refers to an alkylamino group substituted with one or two fused heterobicyclyl groups, wherein the fused heterobicyclyl group is as defined herein.
  • fused heterobicyclylalkylamino group include hexahydro-furo [3, 2-b] furan-2-ylmethylamino, 7-azabicyclo [2.3.0] hept-2-ylmethylamino, 7-azabicyclo [2.3.0] hept-4-ylmethylamino, and the like.
  • fused bicyclylalkoxy refers to an alkoxy group substituted with one or more fused bicyclyl groups, wherein the alkoxy group and fused bicyclyl group are as defined herein.
  • fused bicyclylalkoxy include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylmethoxy, 1,2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylethoxy, fused bicyclo [3.3.0] octylethoxy, fused bicyclo [3.1.0] hexylpropoxy, and the like.
  • fused heterobicyclylalkoxy refers to an alkoxy group substituted with one or more fused heterobicyclyl groups, wherein the alkoxy group and fused heterobicyclyl group are as defined herein.
  • fused heterobicyclylalkoxy group include hexahydro-furo [3, 2-b] furan-2-ylpropoxy, 7-azabicyclo [2.2.1] hept-2-ylethoxy, 7-azabicyclo [2.3.0] hept-4-ylpropoxy, hexahydro-furo [3, 2-b] furan-2-ylethoxy, 7-azabicyclo [2.3.0] hept-2-ylpropoxy, 7-azabicyclo [2.3.0] hept-4-ylethoxy, and the like.
  • fused bicyclylalkyl refers to an alkyl group substituted with one or more fused bicyclyl groups, wherein the alkyl group and fused bicyclyl group are as defined herein.
  • fused bicyclylalkyl group include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylmethyl, 1,2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylethyl, fused bicyclo [3.3.0] octylethyl, fused bicyclo [3.1.0] hexylpropyl, and the like.
  • fused heterobicyclylalkyl refers to an alkyl group substituted with one or more fused heterobicyclyl groups, wherein the alkyl group and fused heterobicyclyl group are as defined herein.
  • fused heterobicyclylalkyl group include hexahydro-furo [3, 2-b] furan-2-ylpropyl, 7-azabicyclo [2.2.1] hept-2-ylethyl, 7-azabicyclo [2.3.0] hept-4-ylpropyl, hexahydro-furo [3, 2-b] furan-2-ylethyl, 7-azabicyclo [2.3.0] hept-2-ylpropyl, 7-azabicyclo [2.3.0] hept-4-ylethyl, and the like.
  • fused heterobicyclyloxyalkoxy refers to an alkoxy group substituted with one or more fused heterobicyclyloxy groups, wherein the alkoxy group and fused heterobicyclyloxy group are as defined herein.
  • fused heterobicyclyloxyalkoxy group examples include hexahydro-furo [3, 2-b] furan-2-yloxypropoxy, 7-azabicyclo [2.2.1] hept-2-yloxyethoxy, 7-azabicyclo [2.3.0] hept-4-yloxypropoxy, hexahydro-furo [3, 2-b] furan-2-yloxyethoxy, 7-azabicyclo [2.3.0] hept-2-yloxypropoxy, 7-azabicyclo [2.3.0] hept-4-yloxyethoxy, and the like.
  • fused heterobicyclyloxyalkylamino refers to an alkylamino group substituted with one or more fused heterobicyclyloxy groups, wherein the alkylamino group and fused heterobicyclyloxy group are as defined herein.
  • fused heterobicyclyloxyalkylamino group examples include hexahydro-furo [3, 2-b] furan-2-yloxypropylamino, 7-azabicyclo [2.2.1] hept-2-yloxyethylamino, 7-azabicyclo [2.3.0] hept-4-yloxypropylamino, hexahydro-furo [3, 2-b] furan-2-yloxyethylamino, 7-azabicyclo [2.3.0] hept-2-yloxypropylamino, 7-azabicyclo [2.3.0] hept-4-yloxyethylamino, and the like.
  • bridged heterobicyclylalkoxy refers to an alkoxy group substituted with one or more bridged heterobicyclyl groups, wherein the bridged heterobicyclyl group and alkoxy group are as defined herein.
  • Some non-limiting examples of the bridged heterobicyclylalkoxy group include 2-oxa-5-azabicyclo [2.2.1] heptylmethoxy, 2, 5-diazabicyclo [2.2.1] heptylethoxy, 2-methyl-2, 5-diazabicyclo [2.2.1] heptylpropoxy, and the like.
  • bridged heterobicyclylalkyl refers to an alkyl group substituted with one or more bridged heterobicyclyl groups, wherein the bridged heterobicyclyl group and alkyl group are as defined herein.
  • Some non-limiting examples of the bridged heterobicyclylalkyl group include 2-oxa-5-azabicyclo [2.2.1] heptylmethyl, 2,5-diazabicyclo [2.2.1] heptylethyl, 2-methyl-2, 5-diazabicyclo [2.2.1] heptylpropyl, and the like.
  • bridged heterobicyclylalkylamino refers to an alkylamino group substituted with one or more bridged heterobicyclyl groups, wherein the bridged heterobicyclyl group and alkylamino group are as defined herein.
  • Some non-limiting examples of the bridged heterobicyclylalkylamino group include 2-oxa-5-azabicyclo [2.2.1] heptylmethylamino, 2, 5-diazabicyclo [2.2.1] heptylethylamino, 2-methyl-2, 5-diazabicyclo [2.2.1] heptylpropylamino, and the like.
  • bridged heterobicyclyloxy refers to an optionally substituted bridged heterobicyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • Some non-limiting examples of the bridged heterobicyclyloxy group include 2-methyl-2, 5-diazabicyclo [2.2.1] heptyloxy, 2, 5-diazabicyclo [2.2.1] heptyloxy, and the like.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, wherein the alkyl group and aryl group are as defined herein.
  • arylalkyl group include phenylethyl, phenylmethyl, (p-tolyl) ethyl, and the like.
  • heteroarylalkyl refers to an alkyl group substituted with one or more heteroaryl groups, wherein the alkyl group and heteroaryl group are as defined herein.
  • heteroarylalkyl group include pyrid-2-ylethyl, thiazol-2-ylmethyl, imidazol-2-ylethyl, pyrimidin-2-ylpropyl, and the like.
  • alkylthio refers to a group in which a linear or branched alkyl group having 1 to 10 carbon atoms is attached to a divalent sulfur atom, wherein the alkyl group is as defined herein. In some embodiments, the alkylthio group is lower alkylthio group having 1 to 3 carbon atoms. Some non-limiting examples of the alkylthio group include methylthio (CH 3 S-) , ethylthio, and the like.
  • spirocyclyl refers to a ring originating from a particular annular carbon of another ring.
  • a saturated bridged ring system (ring B and B’ ) is termed as “fused bicyclic”
  • ring A and ring B share an atom between the two saturated ring system, which terms as a “spirocyclyl” or “spiro bicyclyl” .
  • Each cyclic ring in a spirocyclyl can be either a carbocyclic or a heteroalicyclic.
  • spiro bicyclyl group examples include 4-azaspiro [2.4] hept-5-yl, 4-oxaspiro [2.4] hept-5-yl, 5-azaspiro [2.4] hept-5-yl, spiro [2.4] heptyl, spiro [4.4] nonyl, 7-hydroxy-5-azaspiro [2.4] hept-5-yl, and the like.
  • spiro heterobicyclyl refers to a ring originating from a particular annular carbon of another ring.
  • a saturated bridged ring system (ring B and B’ ) is termed as “fused bicyclic”
  • ring A and ring B share an atom between the two saturated ring system, which terms as a “spirocyclyl” or “spiro bicyclyl”
  • at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members (i. e.
  • spiro heterobicyclyl group examples include 4-azaspiro [2, 4] heptyl, 4-oxaspiro [2, 4] heptyl, 5-azaspiro [2, 4] heptyl, 7-hydroxy-5-azaspiro [2, 4] heptyl, 2-azaspiro [4, 5] decyl, 2-azaspiro [3, 3] heptyl, 2-azaspiro [4.4] nonyl, 2-methyl-2, 6-diazaspiro [4.5] decyl, 3-azaspiro [5.4] decyl, 2-methyl-2-azaspiro [3.3] heptyl, 2-oxa-6-azaspiro [3.3] heptyl, 2, 6-diazaspiro [3.3] heptyl, 2-thia-6-azaspiro [3.3] heptyl 2-oxide, 2-thia-6-azaspiro [3.3] heptyl 2, 2-dioxide
  • spiro heterobicyclylalkoxy refers to an alkoxy group substituted with one or more spiro heterobicyclyl groups, wherein the spiro heterobicyclyl group and alkoxy group are as defined herein.
  • Some non-limiting examples of the spiro heterobicyclylalkoxy group include 4-azaspiro [2, 4] hept-5-ylmethoxy, 4-azaspiro [2, 4] hept-2-ylethoxy, 4-oxaspiro [2, 4] hept-5-ylethoxy, 5-azaspiro [2, 4] hept-5-ylpropoxy, and the like.
  • spiro heterobicyclylalkyl refers to an alkyl group substituted with one or more spiro heterobicyclyl groups, wherein the spiro heterobicyclyl group and alkyl group are as defined herein.
  • Some non-limiting examples of the spiro heterobicyclylalkyl group include 4-azaspiro [2, 4] hept-5-ylmethyl, 4-azaspiro [2, 4] hept-2-ylethyl, 4-oxaspiro [2, 4] hept-5-ylethyl, 5-azaspiro [2, 4] hept-5-ylpropyl, and the like.
  • Anti-proliferative agent refers to anti-metabolites (e. g. , 5-fluoro-uracil, methotrexate and fludarabine) , antimicrotubule agents (e. g. , vinca alkaloids such as vincristine and vinblastine, taxanes such as paclitaxel and docetaxel) , alkylating agents (e. g. , cyclophosphamide, melphalan, carmustine and nitrosoureas such as bischloroethylnitrosourea and hydroxyurea) , platinum agents (e. g.
  • cisplatin carboplatin, oxaliplatin, JM-216 and Cl-973
  • anthracyclines e. g. , doxorubicin and daunorubicin
  • antitumor antibiotics e. g. , mitomycin, idarubicin, doxorubicin and daunorubicin
  • topoisomerase inhibitors e. g. , etoposide and camptothecin
  • anti-angiogenesis agents e. g.
  • any other cytotoxic agents estramustine phosphate and prednimustine
  • hormones or hormone agonists, antagonists, partial agonist or partial antagonists kinase inhibitors and radiation treatment.
  • a bond drawn from a substituent R to the center of one ring within a ring system represents substitution of the substituent R at any substitutable position on the ring.
  • Formula a represents possible substitution of the substituent R in any of the position on ring A or ring B, as shown in Formula b, Formula c, Formula d, Formula e, Formula f, Formula g and Formula h.
  • a bond drawn from a substituent (R) n to the center of one ring within a ring system represents substitution of n substituents R at any substitutable position on the rings.
  • Formula i represents possible substitution of n substituents R in any of the position on ring A or ring B.
  • two attachment points within a ring system for example, either E or E’ on ring C as shown in Formula j, can attach to the rest of the molecule and can be used interchangeably with each other.
  • the attachment point can attach to the rest of the molecule at any attachable position on the rings.
  • Formula k represents attaching at any attachable position on ring A or ring B.
  • the attachment points can attach to the rest of the molecule at any attachable position on the rings, meanwhile, the attachment points can be used interchangeably with each other.
  • Formula m represents attaching at any attachable position on the rings, and the two attachment points can be used interchangeably with each other.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center (s) .
  • the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the term “racemic mixture” or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • a “hydrate” refers to a compound disclosed herein or a salt thereof, which further includes a stoichiometric or non-stoichiometeric amount of water bound by non-covalent intermolecular forces, and also refers to the complex where the solvent molecule is water.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
  • Some non-limiting examples of the solvent that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.
  • esters refers to an in vivo hydrolysable ester of a compound of the Formula (I) , Formula (II) or Formula (III) containing hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent alcohol.
  • in vivo hydrolysable ester forming groups for hydroxy include phosphate, acetoxymethoxy, 2, 2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, N- (dialkylaminoethyl) -N-alkylcarbamoyl, and the like.
  • N-oxide refers to one or more than one nitrogen atoms oxidised to form an N-oxide, where a compound contains several amine functions.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e. g. a peroxycarboxylic acid) (See, Advanced Organic Chemistiy, by Jerry March, 4 th Edition, Wiley Interscience, pages) . More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) , for example, in an inert solvent such as dichloromethane.
  • MCPBA m-ch
  • prodrug refers to a compound that is transformed in vivo into a compound of Formula (I) , Formula (II) or Formula (III) . Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation of the prodrug form in blood or tissue to the parent form.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains an OH group may be acylated at this position in its prodrug form.
  • prodrug forms include phosphates such as those phosphate compounds derived from the phosphonation of an OH group on the parent compound.
  • phosphates such as those phosphate compounds derived from the phosphonation of an OH group on the parent compound.
  • a thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, Edward B. Roche, ed. , Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al. , Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al. , Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entireties.
  • a “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof.
  • the metabolite of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
  • the invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient time period.
  • compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
  • a “pharmaceutically acceptable salts” refers to organic or inorganic salts of a compound disclosed herein.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. , describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1977, 66: 1-19, which is incorporated herein by reference.
  • Some non-limiting examples of pharmaceutically acceptable and nontoxic salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, 2-hydroxy propionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oilsoluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate or aryl sulfonate.
  • Amine salts include, but are not limited to, N, N’ -dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamine, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1’-ylmethylbenzimidazole, diethylamine and other alkylamine, piperazine and tris (hydroxymethyl) aminomethane.
  • Alkali earth metal salts include, but are not limited to, barium, calcium and magnesium. Transition metal salts include, but are not limited to, zinc.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc) , benzyloxycarbonyl (Cbz) and 9-fluorenylmethylenoxycarbonyl (Fmoc) .
  • a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • suitable hydroxy-protecting groups include acetyl and silyl.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Some non-limiting examples of the carboxy-protecting group include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2-(p-nitrophenylsulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like.
  • the structure preferably controls.
  • substituted urea derivatives and pharmaceutical compositions thereof used in drug therapy as well as the uses thereof for the treatment of FLT3 kinase mediated or FLT3-ITD caused diseases, of which the substituted urea compounds are useful in the modulation of FLT3 kinase activity and in the inhibition of FLT3-ITD.
  • a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of Q and W is independently CH or N;
  • ring K is a 5-to 6-membered heteroaryl group, of which at least two ring members are heteroatoms independently selected from O, S, NR 4 and N;
  • ring E is a bicyclic or tricyclic heteroarylene group
  • each X 8 , X 9 and X 10 is independently N or CH;
  • each of X, Y, Z 1 , Z 2 , Z 3 and Z is independently N or CH;
  • T is-O-, -S-, -NR 4 -or -CH 2 -;
  • each of R 2 and R 3 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl;
  • each R 4a and R 4 is independently hydrogen, C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl;
  • each q, m, p, r and s is independently 0, 1, 2, 3 or 4;
  • each of d and n is independently 1, 2, 3 or 4;
  • each t is independently 0, 1 or 2;
  • a 0, 1, 2, 3 or 4,
  • each aryl, bicyclic heteroarylene, tricyclic heteroarylene, alkoxy, alkyl-S ( O) t -, -G- (CH 2 ) n -R, arylalkyl, heteroarylalkyl, heteroaryl, heteroarylene, heterocycly, bridged heterobicyclyl, spiro heterobicyclyl, fused heterobicyclyl, alkyl, haloalkyl, alkylamino, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, alkoxyalkyl, hydroxyalkyl, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, cycloalkyloxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclo,
  • ring E is
  • each X, Y, Z, Z 1 , Z 2 , Z 3 and Z 4 is independently N or CH;
  • each T and T 1 is independently -O-, -S-, -NR 4 -or-CH 2 -;
  • each X 8 , X 9 and X 10 is independently N or CH;
  • each q, m, p, r and s is independently 0, 1, 2, 3 or 4;
  • each of R 2 and R 3 is independently C 1-6 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl;
  • each of R 4a and R 4 is independently hydrogen, C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl; and provided that:
  • ring E is
  • each of R 2 and R 3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl; andprovided that:
  • substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, tri
  • G is-O-or furylene.
  • ring K is a group selected from the following:
  • each U is independently -CH 2 -, -O-, -NR 4 -or-S-;
  • each V, V 1 and V 2 is independently CH or N;
  • R 4 is hydrogen, C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl;
  • ring K is a group selected from the following:
  • the compound disclosed herein has formula (II) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of Q and W is independently CH or N;
  • each of d and n is independently 1, 2, 3 or 4;
  • each t is independently 0, 1 or 2;
  • a 0, 1, 2, 3 or 4;
  • each of R 2 and R 3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or hydroxy-C 1-4 -alkyl; and provided that:
  • substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, tri
  • the compound disclosed herein has formula (III) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of X, Y, Z, Z 1 , Z 2 , Z 3 and Z 4 is independently N or CH;
  • a substituted urea derivative having one of the following structures,
  • composition comprising the compound disclosed herein.
  • the pharmaceutical composition disclosed herein further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or the combination thereof.
  • the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent, wherein the additional therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-inflammatory agent, an immunosuppressant, an immunostimulant, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis or a combination thereof.
  • the additional therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-inflammatory agent, an immunosuppressant, an immunostimulant, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis or a combination thereof.
  • the additional therapeutic agent disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
  • provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient comprising administrating a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein to the patient.
  • provided herein is the compound or the pharmaceutical composition disclosed herein for use in preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
  • the proliferative disease disclosed herein is acute myelogenous leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute lymphocytic leukemia (ALL) , colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, CNS (central nervous system) cancer, malignant glioma or bone marrow hyperplasia, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic diseases, cryoglobulinemia, non-lymphoreticular system tumor, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia
  • the autoimmune disease disclosed herein is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, I-type diabetes, sarcoidosis, inflammatory bowel disease, Crohn’s disease or systemic lupus.
  • the inflammatory disease disclosed herein is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
  • the disease is mediated by FLT3 kinase or caused by FLT3-ITD.
  • provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, wherein the method comprise administering to the patient a therapeutically effective amount of the compound disclosed herein.
  • provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, wherein the method comprise administering to the patient a therapeutically effective amount of the pharmaceutical composition containing the compound disclosed herein.
  • provided herein is use of the compound disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
  • provided herein is use of the compound of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of FLT3 mediated diseases, wherein the use comprise administering a therapeutically effective amount of the compound of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutically acceptable salts, isomers, solvates, hydrates or prodrugs thereof.
  • the compounds and the compositions provided herein are effective to modulate the activity of the AbI protein tyrosine family.
  • the compounds and the compositions provided herein are effective to modulate the activity of the fms-like tyrosine kinase 3 receptor kinase (FLT-3 kinase) .
  • FLT-3 kinase fms-like tyrosine kinase 3 receptor kinase
  • the compounds and the compositions provided herein are effective to inhibit the mutation of the fms-like tyrosine kinase 3 receptor kinase (FLT-3-ITD) .
  • FLT-3-ITD fms-like tyrosine kinase 3 receptor kinase
  • the compounds and the compositions provided herein are effective to modulate the activity of the Src subfamily, which includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk.
  • the compounds and the compositions provided herein are effective to modulate the activity of one or more kinases selected from the group consisting of sterile 20, sterile 11, sterile, the camk subfamily (calmodulin regulated kinases and related kinases) , the AGC subfamily (protein kinase A, protein kinase G and protein kinase C) , the CMGC subfamily (cdk, map kinase, glycogen synthetase kinase and clk) , the sterile 20 subfamily, Frk, Btk, Csk, AbI, Zap70, Fes, Fps, Fak, Jak and Ack (and their respective subfamilies) .
  • the camk subfamily calmodulin regulated kinases and related kinases
  • AGC subfamily protein kinase A, protein kinase G and protein kinase C
  • CMGC subfamily cdk,
  • provided herein are methods of using the disclosed compounds and compositions, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, for the local or systemic treatment or prophylaxis of human and veterinary diseases, disorders and conditions modulated or otherwise affected mediated via kinase activity.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable refers to that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the compounds disclosed herein also include salts of the compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I), Formula (II) or Formula (III) , and/or for separating enantiomers of compounds of Formula (I) , Formula (II) or Formula (III) .
  • the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid; a pyranosidyl acid, such as glucuronic acid and galacturonic acid; an alpha-hydroxy acid, such as citric acid and tartaric acid; an amino acid, such as aspartic acid and glutamic acid; an aromatic acid, such as benzoic acid and cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid, benzenes
  • an inorganic acid such as hydro
  • the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide, ammonium, N + (R 14 ) 4 salt or alkaline earth metal hydroxide, and the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide, ammonium, N + (R 14 ) 4 salt or alkaline earth metal hydroxide, and the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine; ammonia, such as primary, secondary and tertiary amine, N + (R 14 ) 4 salt, wherein R 14 is H, C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 -alkyl, and the like; and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like, and further include, when appropriate, nontoxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate or aryl sulfonate.
  • the invention features pharmaceutical compositions that include a compound of Formula (I) , Formula (II) or Formula (III) , a hydrate, a solvate, an isomer, a physiologically/pharmaceutically acceptable salt or a prodrug thereof, a compound listed herein, or a compound named in Examples 1-45, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the compositions disclosed herein can be used in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a disease mediated by protein kinase.
  • the compositions disclosed herein, acting as FLT3 kinase or FLT3-ITD kinase inhibitor are used for preparation of a medicament.
  • the pharmaceutical compositions disclosed herein may include a compound of Formula (I) , Formula (II) or Formula (III) , and a pharmaceutically acceptable carrier.
  • the compounds of Formula (I) , Formula (II) or Formula (III) can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.
  • liquid carriers are sugar syrup, peanut oil, olive oil, water, and the like.
  • gaseous carriers include carbon dioxide, nitrogen, and the like.
  • the carrier or diluent may include any time delay material well known to the art, such as glyceryl monostearate or glyceryl stearate, alone or mixed with a wax.
  • Some non-limiting examples of materials which can serve as pharmaceutically acceptable carriers include ion exchanger; aluminum; alumina; aluminum stearate; lecithin; serum protein such as human serum albumin; buffer substance such as phosphate; glycine; sorbic acid; potassium sorbate; partial glyceride mixture of saturated vegetable fatty acid; water; electrolyte such as protamine sulfate, disodium hydrogen phosphate and potassium hydrogen phosphate; salt such as sodium chloride and zinc salt; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylate; waxe; polyethylene-polyoxypropylene-block polymer; wool fat; sugar such as lactose, glucose and sucrose; starch such as corn starch and potato starch; cellulose and its derivative such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as
  • FLT3 activity increase includes, but is not limited to, enhanced FLT3 activity resulting from increased or denovo expression of FLT3 in cells, increased FLT3 expression or activity, and FLT3 mutations resulting in constitutive activation.
  • the existence of inappropriate or abnormal FLT3 ligand and FLT3 levels or activity can be determined using well-known methods in the art. For example, abnormally high FLT3 levels can be determined using commercially available ELISA kits. FLT3 levels can also be determined using flow cytometric analysis, immunohistochemical analysis and in situ hybridization techniques.
  • An inappropriate activation of FLT3 can be determined by an increase in one or more of the activities occurring subsequent to FLT3 binding: (1) phosphorylation or autophosphorylation of FLT3; (2) phosphorylation of FLT3 substrates such as Stat5 and Ras; (3) activation of related complexes such as PI3K; (4) activation of adaptor molecules; and (5) cell proliferation. These activities can be readily measured by well-known methods in the art.
  • the compounds of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutical compositions thereof disclosed herein are useful in, but not limited to, preventing or treating of proliferative diseases, conditions, or disorders in a patient by administering to the patient the compound of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutical composition thereof disclosed herein in an effective amount.
  • diseases, conditions, or disorders include cancer, particularly hematopoietic cancer, metastatic cancer, atherosclerosis, and lung fibrosis.
  • neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer of bladder, breast, colon, kidney, liver, lung (including small cell lung cancer) , esophageal, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma) ; hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell leukemia and Burkett’s lymphoma; hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumor
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma , thyroid follicular cancer and Kaposi’s sarcoma.
  • the compounds or the pharmaceutical compositions thereof disclosed herein are also useful for the treatment of FLT3 mediated, FLT3-ITD mediated and/or CSF-1R mediated diseases like autoimmune diseases, kidney diseases, tissue transplant rejection, lupus erythematosis, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, arthritis, asthma, and the like.
  • the compounds or the pharmaceutical compositions thereof disclosed herein are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy.
  • the compounds or the pharmaceutical compositions thereof disclosed herein are also useful in the reduction of blood flow in a tumor.
  • the compounds or the pharmaceutical compositions thereof disclosed herein are also useful in the reduction of metastasis of a tumor.
  • these compounds or the pharmaceutical compositions are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • animals include horses, dogs and cats.
  • the compounds of Formula (I) , Formula (II) or Formula (III) disclosed herein include the pharmaceutically acceptable derivatives thereof.
  • the compounds or the pharmaceutical compositions thereof disclosed herein are also useful for inhibiting the growth of a cell that expresses VEGFR or c-Met, which includes contacting the cell with a compound or composition disclosed herein.
  • a cell whose growth can be inhibited include: a breast cancer cell, a colorectal cancer cell, a lung cancer cell, a papillary carcinoma cell, a prostate cancer cell, a lymphoma cell, a colon cancer cell, a pancreatic cancer cell, an ovarian cancer cell, a cervical cancer cell, a central nervous system cancer cell, an osteogenic sarcoma cell, a renal carcinoma cell, a hepatocellular carcinoma cell, a bladder cancer cell, a gastric carcinoma cell, a head and neck squamous carcinoma cell, a melanoma cell or a leukemia cell.
  • the compounds or the pharmaceutical compositions thereof disclosed herein are also useful for inhibiting VEGFR and/or c-Met kinase activity in a biological sample, which includes contacting the biological sample with a compound or composition disclosed herein.
  • biological sample means a sample outside a living organism and includes, without limitation, cell cultures or extracts thereof; biopsied materials obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body liquids or extracts thereof.
  • Inhibition of kinase activity, particularly VEGFR or c-Met kinase activity, in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage and biological assays.
  • the treatment method that includes administering a compound or composition disclosed herein can further include administering to the patient an additional therapeutic agent (combination therapy) selected from: a chemotherapeutic or anti-proliferative agent, or an anti-inflammatory agent, wherein the additional therapeutic agent is appropriate for the disease being treated and the additional therapeutic agent is administered together with a compound or composition disclosed herein as a single dosage form or separately from the compound or composition as part of a multiple dosage form.
  • the additional therapeutic agent may be administered at the same time as the compound disclosed herein or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
  • a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-100 ⁇ g/ml.
  • the pharmaceutical compositions disclosed herein should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
  • Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg, and in some embodiments, from about 10 mg to about 500 mg, from about 20 mg to about 250 mg or from about 25 mg to about 100 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form. In some embodiments, pharmaceutical dosage unit forms are prepared to provide about 1 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the essential active ingredient. In some embodiments, pharmaceutical dosage unit forms are prepared to provide about 50 mg of the essential active ingredient.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is also to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
  • an “effective amount” or “effective dose” is that amount effective for treating or lessening the severity of one or more of the aforementioned disorders.
  • the compounds and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and the general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • a compound or composition can also be administered with one or more other therapeutic agents, as discussed above.
  • the compounds or the pharmaceutical compositions thereof disclosed herein may also be used for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury) .
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound disclosed herein.
  • the dosage used can be varied depending upon the type of cancer, the age and general condition of the patient, the particular compound administered, the presence or level of toxicity or adverse effects experienced with the drug, and other factors.
  • a representative example of a suitable dosage range is from as low as about 0.01 mg/kg to as high as about 100 mg/kg. However, the dosage administered is generally left to the discretion of the physician.
  • the methods of treatment are preferably carried out by delivering the compounds of Formula (I) , Formula (II) or Formula (III) disclosed herein orally or parenterally.
  • parenteral as used herein includes intravenous, intramuscular or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • the invention can also be carried out by delivering the compounds of Formula Formula (I) , Formula (II) or Formula (III) disclosed herein subcutaneously, intranasally, intrarectally, transdermally or intravaginally.
  • the compounds of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutical compositions disclosed herein may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by convention techniques.
  • the compounds of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutical compositions disclosed herein can be employed to prepare a wide variety of pharmaceutical dosage forms.
  • a solid dosage is used for oral administration, the preparation can be in the form of a tablet, hard gelatin capsule, lozenge, troche, drop, lotion, and the like.
  • the amount of solid carrier will vary widely, but generally will be from about 0.025 mg to about 1 g.
  • the preparation is typically in the form of a syrup, emulsion, soft gelatin capsule, suspension or solution.
  • the drug may be in solid or liquid form, and may be formulated for administration directly or may be suitable for reconstitution.
  • Topical dosage forms are also included.
  • Examples of topical dosage forms are solids, liquids and semi-solids. Solids would include dusting powders, poultices, and the like. Liquids include solutions, suspensions and emulsions. Semi-solids include creams, ointments, gels, and the like.
  • a representative, topical dose of a compound of Formula (I) , Formula (II) or Formula (III) is from as low as about 0.01 mg to as high as about 2.0 g, administered one to four, preferably one to two times daily.
  • the active ingredient may comprise, for topical administration, from about 0.001 %to about 10%w/w.
  • Drops according to the invention may comprise sterile or non-sterile aqueous or oil solutions or suspensions, and may be prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent.
  • a suitable aqueous solution optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container aseptically.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%) , benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%) .
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Lotions according to the invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis.
  • Creams, ointments or pastes according to the invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous liquid, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, com, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicas, and other ingredients such as lanolin may also be included.
  • the compounds or the pharmaceutical compositions disclosed herein can also be administered in the form of coating, and suitable coated implantable devices are known in the art.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • the compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a “drug depot” thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I) , Formula (II) or Formula (III) above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium.
  • Anhydrous CH 2 Cl 2 and CHCl 3 were obtained by refluxing the solvent with CaH 2 .
  • EtOAc, PE, hexane, DMAC and DMF were treated with anhydrous Na 2 SO 4 prior to use.
  • reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • MS data were determined by an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column was operated at 30 °C) .
  • G1329A autosampler and G1315B DAD detector were applied in the analysis, and an ESI source was used in the LC-MS spectrometer.
  • MS data were determined by an Agilent 6120 Series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column was operated at 30 °C) .
  • G1329A autosampler and G1315D DAD detector were applied in the analysis, and an ESI source was used on the LC-MS spectrometer.
  • Compound 2 can be prepared by the following two methods, wherein each R and n is as defined herein. Method one: compound 1A can react with compound 2A to form compound 3A in the presence of a base, and then compound 3A can be converted to compound 2 by chlorination. Method two: compound 1A can react with compound 4A to afford compound 2 in the presence of a base.
  • Compound 8A can be prepared by the following method.
  • Compound 5A can react with compound 6A to form compound 7A in the presence of a base, and compound 7A can be then converted to compound 8A by deprotection.
  • Compound 6 can be prepared by the process illustrated in Scheme 1, wherein each R 1 , a, R, E, G and n is as defined herein.
  • Compound 1 can react with compound 2 to form compound 3 in the presence of a base.
  • Compound 3 can be then converted to compound 4 by reduction reaction. Reaction of compound 4 with compound 5 can afford the objective compound 6.
  • Compound 6 can be prepared by the process illustrated in Scheme 3, wherein each R 1 , a, R, E, G and n is as defined herein.
  • Compound 1 can react with compound 2a to form compound 3a in the presence of a base.
  • the hydroxy group of compound 3a can be protected to give compound 8, and
  • Compound 8 can be then converted to compound 4 by reduction reaction. Reaction of compound 4 with compound 5 can afford the objective compound 6.
  • Step 2) (4aS, 7aS) -6- (2-chloroethyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
  • Step 4) 4- (7- (2- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethoxy) benzo [d] imidazo [2, 1-b] -thiazol-2-yl) aniline
  • Step 5 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (2- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) -ethoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
  • Step 2) (4aR, 7aS) -6- (2-chloroethyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
  • the title compound was prepared by the procedure described in step 2 of example 1, using 2- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethanol (3.15 g, 18.19 mmol) and thionyl chloride (1.98 mL) to give the title compound as deep yellow liquid, which was used directly in the next step.
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 192.1 [M+1] + .
  • the title compound was prepared by the procedure described in step 3 of example 1, using 2-(4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-ol (1.71 g, 5.49 mmol) , (4aR, 7aS) -6- (2-chloroethyl) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (2.1 g, 10.96 mmol) , potassium carbonate (2.27 g, 16.43 mmol) and tetrabutylammonium iodide (0.41 g, 1.1 mmol) to give the title compound as a yellow solid (4.0 g, >100%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 467.3 [M+1] + .
  • Step 4) 4- (7- (2- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethoxy) benzo [d] imidazo [2, 1-b] -thiazol-2-yl) aniline
  • the title compound was prepared by the procedure described in step 4 of example 1, using (4aR, 7aS) -6- (2- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) ethyl) hexahydro-2H- [1, 4] dioxino [2, 3 -c]pyrrole (2.56 g, 5.49 mmol) , zinc powder (3.58 g, 55.08 mmol) and ammonium chloride (1.17 g, 22.03 mmol) to give the title compound as a brown solid (2.09 g, 87%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 437.2 [M+1] + .
  • Step 5 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (2- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) -ethoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
  • Step 1) (4aR, 7aS) -6- (3-chloropropyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
  • the organic phase was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give the title compound as claybank liquid (5.6 g, >100%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 206.2 [M+1] + .
  • Step 2) (4aR, 7aS) -6- (3- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) propyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
  • the title compound was prepared by the procedure described in step 3 of example 1, using 2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-ol (0.73 g, 2.34 mmol) , (4aR, 7aS) -6- (3-chloropropyl) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (0.96 g, 4.67 mmol) , potassium carbonate (0.97 g, 7.03 mmol) and tetrabutylammonium iodide (0.17 g, 0.46 mmol) to give the title compound as a yellow solid (1.1 g, 100%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 481.1 [M+1] + .
  • Step 3) 4- (7- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] -thiazol-2-yl) aniline
  • the title compound was prepared by the procedure described in step 4 of example 1, using (4aR, 7aS) -6- (3- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) propyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (1.1 g, 2.29 mmol) , iron powder (1.29 g, 23.04 mmol) and ammonium chloride (0.5 g, 9.34 mmol) to give the title compound as a khaki solid (0.84 g, 80%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 451.3 [M+1] + .
  • Step 4) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
  • the title compound was prepared by the procedure described in step 5 of example 1, using 4- (7- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) aniline (0.84 g, 1.86 mmol) , 5-tert-butyl-3-isoxazolyl isocyanate (0.37 g, 2.24 mmol) to give the title compound as a white solid (155 mg, 14%) .
  • Step 1) (4aR, 7aR) -6- (3-chloropropyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
  • the title compound was prepared by the procedure described in step 1 of example 3, using (4aR, 7aR) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (3.5 g, 27.10 mmol) and 1-bromo-3-chloropropane (4.69 g, 25.98 mmol) to give the title compound as deep yellow liquid (5.7 g, >100%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 206.2 [M+1] + .
  • Step 2) (4aR, 7aR) -6- (3- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) propyl) hexahydro-2H-[1,4] dioxino [2, 3-c] pyrrole
  • the title compound was prepared by the procedure described in step 3 of example 1, using 2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-ol (1.48 g, 4.75 mmol) , (4aR, 7aR) -6- (3-chloropropyl) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (1.95 g, 9.48 mmol) , potassium carbonate (1.97 g, 14.72 mmol) and tetrabutylammonium iodide (0.35 g, 0.94 mmol) to give the title compound as a yellow solid (2.28 g, 100%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 481.1 [M+1] + .
  • Step 3) 4- (7- (3- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] -thiazol-2-yl) aniline
  • the title compound was prepared by the procedure described in step 4 of example 1, using (4aR, 7aR) -6- (3- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) propyl) hexahydro-2H- [1, 4] dioxino [2 ,3-c] pyrrole (2.28 g, 4.75 mmol) , iron powder (2.62 g, 46.78 mmol) and ammonium chloride (1.01 g, 18.89 mmol) to give the title compound as a khaki solid (2.1 g, 100%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 451.3 [M+1] + .
  • Step 4) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (3- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
  • Step 3) 4- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-b] pyridazin-6-yl) oxy) propyl) morpholine
  • Step 4) 4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-2-yl) aniline
  • Step 5 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-2-yl) phenyl) urea
  • Step 3) 4- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-7-yl) oxy) propyl) morpholine
  • the resulting mixture was stirred at rt for 1.0 hour, filtered and the filter cake was dried under vacuum to give the title compound as a brown solid (1.69 g, 76%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 383.1 [M+1] + .
  • Step 4) 4- (7- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) aniline
  • Step 5 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) urea
  • Step 3) 4- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) propyl) morpholine
  • the resulting mixture was stirred at rt for 1.0 hour, filtered and the filter cake was dried under vacuum to give the title compound as a brown solid (0.61 g, 80%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 383.2 [M+1] + .
  • Step 4) 4- (6- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) aniline
  • Step 5 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) urea
  • the title compound was prepared by the procedure described in step 1 of example 6, using 2-amino-5-methoxypyridine (6.21 g, 50.02 mmol) , 2-bromo-4’ -nitroacetophenone (6.3 g, 75 mmol) and sodium bicarbonate (6.3 g, 75 mmol) to give the title compound as a yellow solid (1.84 g, 14%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 270.2 [M+1] + .
  • the title compound was prepared by the procedure described in step 2 of example 6, using 6-methoxy-2- (4-nitrophenyl) imidazo [1, 2-a] pyridine (1.84 g, 6.83 mmol) and boron tribromide (1.0 mL) to give the title compound as a brown solid (1.48 g, 85%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 256.0 [M+1] + .
  • the title compound was prepared by the procedure described in step 3 of example 6, using 2-(4-nitrophenyl) imidazo [1, 2-a] pyridin-6-ol (0.51 g, 1.99 mmol) , potassium carbonate (0.83 g, 6.01 mmol) , tetrabutylammonium iodide (0.15 g, 0.41 mmol) and (4aR, 7aS) -6- (3-chloropropyl) hexahydro-2H-[1,4] dioxino [2, 3-c] pyrrole (0.82 g, 3.99 mmol) in DMF (10 mL) to give the title compound as a brown solid (0.7 g, 83%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 425.1 [M+1] + .
  • Step 4) 4- (6- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) imidazo [1, 2-a] pyridin-2-yl) aniline
  • the title compound was prepared by the procedure described in step 4 of example 6, using (4aR, 7aS) -6- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) propyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrr ole (0.7 g, 1.65 mmol) , zinc powder (1.31 g, 20.15 mmol) and ammonium chloride (0.43 g, 8.04 mmol) to give the title compound as a brown solid (0.32 g, 41%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 395.2 [M+1] + .
  • Step 5 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) urea
  • the title compound was prepared by the procedure described in step 5 of example 6, using 4- (6- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) imidazo [1, 2-a] pyridin-2-yl) anilin e (0.32 g, 0.81 mmol) , phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (0.23 g, 0.88 mmol) , DMAP (6 mg, 0.05 mmol) and triethylamine (0.1 mL) to give the title compound as a white solid (52 mg, 11%) .
  • Step 1) 4- (2- ( (3-bromoimidazo [1, 2-b] pyridazin-6-yl) oxy) ethyl) morpholine
  • Step 2) tert-butyl (4- (6- (2-morpholinoethoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) carbamate
  • Step 3) 4- (6- (2-morpholinoethoxy) imidazo [1, 2-b] pyridazin-3-yl) aniline
  • Step 4) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (2-morpholinoethoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) urea
  • Step 1) 4- (3- ( (3-bromoimidazo [1, 2-b] pyridazin-6-yl) oxy) propyl) morpholine
  • Step 2 tert-butyl (4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) carbamate
  • Step 3 4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-3-yl) aniline
  • Step 4) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) urea
  • Step 2) 4- (2- ( (3-iodopyrazolo [1, 5-a] pyrimidin-7-yl) oxy) ethyl) morpholine
  • Step 5 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (2-morpholinoethoxy) pyrazolo [1, 5-a] pyrimidin-3-yl) phenyl) urea
  • Step 2) 6-methoxy-2- (4-nitrophenyl) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridine
  • Step 4) 4- (2- ( (2- (4-nitrophenyl) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridin-6-yl) oxy) ethyl) morpholine
  • the filter cake was dried under vacuum to give the title compound as a yellow solid (1.8 g, 95%) .
  • the compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 426.1 [M+1] + .
  • Step 6) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (2-morpholinoethoxy) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridin-2-yl) phenyl) urea
  • Step 2) 2- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) ethyl methanesulfonate
  • Step 3) 6- (2- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) ethyl) -2-oxa-6-azaspiro [3.3] heptane
  • Step 4) 4- (6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) imidazo [1, 2-a] pyridin-2-yl) aniline
  • Step 5) 1- (4- (6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) -3- (5- (tert-butyl) isoxazol-3-yl) urea
  • HEPES (2-hydroxyethyl) -1-piperazineethanesulfonic acid
  • Brij-35 diodecyl polyglycol ether
  • DTT dithiothreitol
  • EDTA ethylenediamine tetraacetic acid
  • EGFR human epidermal growth factor receptor
  • HER2 human epidermal growth factor receptor 2
  • EGFR T790M human epidermal growth factor receptor T790M mutation
  • Peptide FAM-P22 fluorescein-labeled peptide 22
  • ATP adenosine triphosphate
  • DMSO dimethyl sulfoxide
  • staurosporine Coating Reagent #3 and so on, all of which are commercially available.
  • 1x Kinase buffer without MnCl 2 was prepared from 50 mM HEPES, pH 7.5, 0.0015%Brij-35, 10 mM MgCl 2 and 2 mM DTT. Stop buffer was prepared from 100 mM HEPES, pH 7.5, 0.015%Brij-35, 0.2%Coating Reagent #3 and 50 mM EDTA.
  • the compound to be tested was diluted to a concentration with 100%DMSO which is 50x of the highest final concentration, and 100 ⁇ L of the diluted compound solution was transferred to a well in a 96-well plate; (2) the compound was gradiently diluted by transferring 20 ⁇ L original solution to 60 ⁇ L of 100%DMSO in the next well and so forth for a total of 10 concentrations; (3) DMSO (100 ⁇ L, 100%) was added to two empty wells as a no-compound control and a no-enzyme control in the same 96-well plate, and the plate was marked as source plate; (4) intermediate plate was prepared by transferring 10 ⁇ L of each compound from source plate to a new 96-well plate as the intermediate plate, and to each well of the intermediate plate was added 90 ⁇ L of 1x Kinase base buffer, then the intermediate plate was mixed for 10 min on shaker; and (5) assay plate was prepared by transferring 5 ⁇ L of each well from the 96
  • kinase reaction was performed according to the following procedures: (1) 2.5x kinase solution was prepared by adding kinase into 1x kinase base buffer; (2) 2.5x peptide solution was prepared by adding FAM-labeled peptide and ATP into 1x kinase base buffer; (3) 2.5x kinase solution (10 ⁇ L) was added to each well of the 384-well assay plate containing 5 ⁇ L of compound in 10%DMSO and then the assay plate was incubated at room temperature for 10 minutes; (4) 2.5x peptide solution (10 ⁇ L) was added to each well of the 384-well assay plate; and (5) stop buffer (25 ⁇ L) was added to stop the kinase reaction after incubation at 28 °Cfor a specified period of time.
  • the data were fitted in XLfit to obtain IC 50 values.
  • Cell suspension density was adjusted to 1.5 x 10 5 cells/ml, which was counted by Vi-Cell XR cell counter, with an appropriate culture medium, and then 100 ⁇ l of the cell suspension was plated in a white 96-well plate having transparent bottom at a final concentration of 15,000 cells per well.
  • the 96-well plate was incubated in a 5%CO 2 and 95%humidity incubator at 37 °C overnight.
  • test compound stock solution was prepared by dissolving a weighed compound in DMSO to a concentration of 10 mM, and then diluted to the concentration of 4 mM, which was then diluted to the concentration of 0.4 mM used as the highest concentration for testing with DMSO. The highest concentration was sequentially followed by 3-fold dilution for a total of 10 concentrations. Staurosporine was the positive control drug.
  • test compound prepared above in compound plate 0.5 ⁇ L was added into the cell culture plate that was incubated overnight, and then the culture plate was incubated in a incubator at 37 °C for 72 hours.
  • the cell culture plate was placed at room temperature for 30 minutes, and then the inhibitory activity of the compounds disclosed herein on MV4-11 cell proliferation was determined by using CellTiter-Glo assay. The obtained results were recorded and analyzed.
  • Example No. MV4-11 (IC 50 , nM) Example No. MV4-11 (IC 50 , nM) 6 0.7 9 63.1 7 0.46 10 54.6 8 1.0

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Abstract

Provided herein are substituted urea derivatives or stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutical compositions thereof, which are useful in modulating the FLT3 kinase activity, inhibiting FLT3-ITD, and treating the diseases mediated by FLT3 kinase or caused by FLT3-ITD.

Description

SUBSTITUTED UREA DERIVATIVES AND USES THEREOF IN MEDICINE
RELATED APPLICATIONS
This application claims the priorities and benefits of Chinese Patent Application Nos. 201310445605.7 and 201410107854. X, filed with the State Intellectual Property Office of China respectively on September 26, 2013 and March 22, 2014, which are incorporated hereby by reference in their entireties.
FIELD OF THE INVENTION
The present invention belongs to pharmaceutical field, and more specifically relates to novel substituted urea derivatives, pharmaceutical compositions thereof and uses thereof for the treatment of FLT3 mediated or FLT3-ITD caused diseases. The novel substituted urea derivatives and pharmaceutical compositions are useful in treating, ameliorating or preventing a disease related to tyrosine kinase activity, or one or more symptoms thereof.
BACKGROUND OF THE INVENTION
Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. Protein kinases, and in particular the receptor protein tyrosine kinase (RTK) family of protein kinases, act primarily as growth factor receptors and play a central role in signal transduction pathways regulating a number of cellular functions, such as cell cycle, cell growth, cell differentiation and cell death. Aberrant or excessive activity or dysregulation of activity of receptor protein tyrosine kinase (RPTK) has been observed in many disease states including benign and malignant proliferative disorders as well as inflammatory disorders and immune system disorders that result from inappropriate activation of the immune system to cause, for example, autoimmune diseases.
Dysregulated activity of the receptor tyrosine kinase of the platelet growth factor receptor (PDGFR) family, as one example, has been implicated in various proliferative disorders. Gene amplification or upregulation of PDGFR occurs in patients with gliomas or sarcomas (See, Kumabe et al. , Oncogene, 1992, 7: 627-633, and Ostman et al. , Cancer Res. , 2001, 80: 1-38) . A member of the PDGFR family, FLT3 (also called Flk2) , plays an important role in the proliferation and differentiation of hematopoietic stem cells, and activating mutation or overexpression of this receptor is found in AML (acute myeloid leukemia) (See, Heinrich, Mini-Reviews in Medicinal Chemistry, 2004, 4 (3) : 255-271, and Kiyoi et al. , Int J Hematol. , 2005, 82: 85-92) . More than a dozen known FLT3 inhibitors are being developed and some have shown promising clinical effects against AML (See, Levis et al. , Int J Hematol. , 2005, 82: 100-107) . The FLT3 receptor is also expressed in a large portion of dendritic cell progenitors and stimulation of the receptor causes the proliferation and differentiation of these progenitors into dendritic cells (DC) . Since dendritic cells are the main initiators of the T-cell mediated immune response, including the autoreactive immune response, FLT3 inhibition is a mechanism  for downregulating DC-mediated inflammatory and autoimmune responses. One study shows the FLT3 inhibtor CEP-701 to be effective in reducing myelin loss in experimental autoimmune encephalomyelitis (EAE) , a mouse model for multiple sclerosis (See, Whartenby et al. , PNAS, 2005, 102: 16741-16746) . A high level of the FLT3 ligand is found in the serum of patients with Langerhans cell histiocytosis and systemic lupus erythematosus, which further implicates FLT3 signaling in the dysregulation of dendritic cell progenitors in those autoimmune diseases (See, Rolland et al. , J. Immunol. , 2005, 174: 3067-3071) .
It has been reported that some of small-molecule FLT3 inhibitors are effective in inducing apoptosis in cell lines with FLT3-activating mutations and prolonging survival of mice that express mutated FLT3 in their bone marrow cells (See, Levis et al. , Blood, 2002, 99: 3885-3891, Kelly et al. , Cancer Cell, 2002, 1: 421-432, Weisberg et al. , Cancer Cell, 2002, 1: 433-443, and Yee et al. , Blood, 2002, 100: 2941-2949) .
Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20％of acute myeloid leukemia patients and are associated with a poor prognosis. Abundant scientific and clinical evidence including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion, which is dispensable for cancer initiation and maintenance. It is reported that some patients have the tendency of recurrence after treatment, which may be due to mutations of FLT3 kinase (See, Heidel et al. , Blood, 2006, 107: 293–300) . Research has shown that FLT3-ITD can represent a driver lesion, which has causative role in malignancy pathogenesis, and valid therapeutic target in human AML (See, Catherine et al. , Nature, 2012, 485: 260-263) .
Mutation of FLT3 gene is a frequent event in AML and usually involves internal tandem duplication (ITD) of the juxtamembrane domain coding region or point mutations of the tyrosine kinase domain (TKD) . Both FLT3-ITD and FLT3-TKD mutations result in ligand-independent proliferation due to constitutive dimerisation and activation of the FLT3 receptor. High mutant-to-wild type allelic ratios of FLT3-ITD are associated with a very poor prognosis in both adults and children (See, AS Moore et al. , Leukemia, 2012, 26: 1462-1470) .
There is considerable interest in the development of kinase inhibitors for use in cancer therapy. Among them, urea derivatives have been reported to be selective FLT3 inhibitors.
SUMMARY OF THE INVENTION
Provided herein are substituted urea derivatives and pharmaceutical compositions thereof used in drug therapy, as well as the uses thereof for the treatment of FLT3 kinase mediated or FLT3-ITD caused diseases, of which the substituted urea compounds are useful in the modulation of FLT3 kinase activity and in the inhibition of FLT3-ITD.
In one aspect, provided herein is a compound having Formula (I) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2014087469-appb-000001
wherein
each of Q and W is independently CH or N；
G is-O-, -S (＝O) t-, -S-, -C (＝O) -or a 5-membered heteroarylene group；
R is-NR3R2, alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkyl-S (＝O) t-, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy, heterocyclyloxy, carbocyclyloxyalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryl, arylalkyl, aryloxyalkoxy, aryloxy, arylalkoxy, arylalkylamino, heteroarylalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkylamino, heteroaryloxy, heteroaryloxyalkoxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, bridged heterobicyclyl, spiro heterobicyclyl or fused heterobicyclyl；
ring K is a 5-to 6-membered heteroaryl group, of which at least two ring members are heteroatoms independently selected from O, S, NR4 and N；
each L is independently amino, nitro, C1-4 alkylthio, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-4 haloalkyl, C1-4 alkylamino, hydroxy, fluoro, chloro, bromo, iodo, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or cyano；
ring E is a bicyclic or tricyclic heteroarylene group；
provided that:
when ring E is
Figure PCTCN2014087469-appb-000002
Figure PCTCN2014087469-appb-000003
Figure PCTCN2014087469-appb-000004
wherein each X8, X9 and X10 is independently N or CH；
each X1, X3, X4, X5, X6 and X7 is independently -CH2-, -O-, -NR4a-, -S (＝O) t-or-S-；
each of X, Y, Z1, Z2, Z3 and Z is independently N or CH；
T is-O-, -S-, -NR4-or-CH2-；
with the proviso that at least two of X, Y, T, Z1, Z2, Z3 and Z are independently heteroatoms；
each R1 is independently hydrogen, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-6 alkyl-S (＝O) t-, C1-6 alkoxy-C1-6-alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio；
each of R2 and R3 is independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl；
each R4a and R4 is independently hydrogen, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl；
each q, m, p, r and s is independently 0, 1, 2, 3 or 4；
each of d and n is independently 1, 2, 3 or 4；
each t is independently 0, 1 or 2； and
a is 0, 1, 2, 3 or 4,
wherein each aryl, bicyclic heteroarylene, tricyclic heteroarylene, alkoxy, alkyl-S (＝O) t-, -G- (CH2) n-R, arylalkyl, heteroarylalkyl, heteroaryl, heteroarylene, heterocycly, bridged heterobicyclyl, spiro heterobicyclyl, fused heterobicyclyl, alkyl, haloalkyl, alkylamino, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, alkoxyalkyl, hydroxyalkyl, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, cycloalkyloxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkylamino, cycloalkylamino, heterocyclylalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, alkyl-C (＝O) -NH-, alkylthio, cycloalkyl and ring E is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, amino, methyl-C (＝O) -NH-, oxo (＝O) , C1-4 alkyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
In some embodiments, ring E is
Figure PCTCN2014087469-appb-000005
wherein each X, Y, Z, Z1, Z2, Z3 and Z4 is independently N or CH；
each T and T1 is independently -O-, -S-, -NR4-or-CH2-；
with the proviso that at least two ring members of ring E are independently heteroatoms；
R is-NR3R2, C2-4 alkenyl, C2-4 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C2-10 heterocyclyl-C1-4-alkyl, C1-6 alkyl-S (＝O) t-, C1-6 alkoxy-C1-6-alkyl, hydroxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, amino-C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylamino-C1-4-haloalkoxy, C1-4 alkylamino-C1-4-alkoxy, C1-4 alkoxy-C1-4-alkoxy, C3-10 cycloalkyloxy, C6-10 aryl-C1-4-alkoxy, C6-10 aryl-C1-4-alkylamino, C1-9 heteroaryl-C1-4-alkoxy, C1-9 heteroaryl-C1-4-alkylamino, C2-10 heterocyclyl-C1-4-alkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylamino, C2-10 heterocyclyl-C1-4-alkoxy, C3-10 carbocyclyl-C1-4-alkoxy, C3-10 carbocyclyl-C1-4-alkylamino, C6-10 aryloxy-C1-4-alkoxy, C6-10 aryloxy, C1-9 heteroaryloxy, C1-9 heteroaryloxy-C1-4-alkoxy, C2-10 heterocyclyloxy-C1-4-alkoxy, C3-10 carbocyclyloxy-C1-4-alkoxy, C2-10 heterocyclyloxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl, C6-10 aryl, C6-10 aryl-C1-6-alkyl, C1-9 heteroaryl-C1-6-alkyl or C1-9 heteroaryl, or R is
Figure PCTCN2014087469-appb-000006
Figure PCTCN2014087469-appb-000007
wherein each X8, X9 and X10 is independently N or CH；
each X1, X2, X3, X4, X5, X6 and X7 is independently-CH2-, -O-, -NR4a-, -S (＝O) t-or-S-；
each q, m, p, r and s is independently 0, 1, 2, 3 or 4；
each of R2 and R3 is independently C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl；
each of R4a and R4 is independently hydrogen, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and
provided that:
Figure PCTCN2014087469-appb-000008
wherein each of ring E and R is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, amino, methyl-C (＝O) -NH-, oxo (＝O) , C1-4 alkyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
In some embodiments, ring E is
Figure PCTCN2014087469-appb-000009
Figure PCTCN2014087469-appb-000010
R is-NR3R2, C2-4 alkenyl, C2-4 alkynyl, C2-10 heterocyclyl-C1-4-alkyl, C1-6 alkyl-S (＝O) t-, C1-4 alkoxy-C1-4 alkyl, hydroxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, amino-C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylamino-C1-4-haloalkoxy, C1-4 alkylamino-C1-4-alkoxy, C1-4 alkoxy-C1-4-alkoxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl or C1-9 heteroaryl-C1-6-alkyl, or R is
Figure PCTCN2014087469-appb-000011
Figure PCTCN2014087469-appb-000012
Figure PCTCN2014087469-appb-000013
each of R2 and R3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and provided that:
when ring E is
Figure PCTCN2014087469-appb-000014
Figure PCTCN2014087469-appb-000015
Figure PCTCN2014087469-appb-000016
wherein each of ring E and R is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxy, cyano, nitro, oxo (＝O) , methyl-C (＝O) -, ethyl-C (＝O) -, (n-propyl) -C (＝O) -, isopropyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
In some embodiments, G is-O-or furylene.
In some embodiments, ring K is a group selected from the following:
Figure PCTCN2014087469-appb-000017
wherein each U is independently -CH2-, -O-, -NR4-or-S-；
each V, V1 and V2 is independently CH or N；
with the proviso that at least two ring members of ring K are independently heteroatoms；
R4 is hydrogen, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and
each L is independently amino, nitro, C1-4 alkylthio, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-4 haloalkyl, C1-4 alkylamino, hydroxy, fluoro, chloro, bromo, iodo, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or cyano.
In some embodiments, ring K is a group selected from the following:
Figure PCTCN2014087469-appb-000018
each L is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3-6 heterocycloalkyl, amino, cyano, nitro, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, methyl, ethyl, butyl, n-propyl, isopropyl, tert-butyl, C1-4 alkylamino, hydroxy, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio.
In some embodiments, the compound disclosed herein has formula (II) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2014087469-appb-000019
wherein
each of Q and W is independently CH or N；
each R1 is independently hydrogen, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-6 alkyl-S (＝O) t-, C1-6 alkoxy-C1-6-alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio；
each L is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3-6 heterocycloalkyl, amino, cyano, nitro, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, methyl, ethyl, butyl, n-propyl, isopropyl, tert-butyl, C1-4 alkylamino, hydroxy, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio；
each of d and n is independently 1, 2, 3 or 4；
each t is independently 0, 1 or 2；
a is 0, 1, 2, 3 or 4；
ring E is
Figure PCTCN2014087469-appb-000020
R is-NR3R2, C2-4 alkenyl, C2-4 alkynyl, C2-10 heterocyclyl-C1-4-alkyl, C1-6 alkyl-S (＝O) t-, C1-4 alkoxy-C1-4-alkyl, hydroxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, amino-C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylamino-C1-4-haloalkoxy, C1-4 alkylamino-C1-4-alkoxy, C1-4 alkoxy-C1-4-alkoxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl or C1-9 heteroaryl-C1-6-alkyl, or R is
Figure PCTCN2014087469-appb-000021
Figure PCTCN2014087469-appb-000022
Figure PCTCN2014087469-appb-000023
each of R2 and R3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and provided that:
when ring E is
Figure PCTCN2014087469-appb-000024
Figure PCTCN2014087469-appb-000025
Figure PCTCN2014087469-appb-000026
wherein each of ring E and R is optionally and independently substituted with one or more substituents  independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxy, cyano, nitro, oxo (＝O) , methyl-C (＝O) -, ethyl-C (＝O) -, (n-propyl) -C (＝O) -, isopropyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
In some embodiments, the compound disclosed herein has formula (III) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2014087469-appb-000027
wherein each of X, Y, Z, Z1, Z2, Z3 and Z4 is independently N or CH；
with the proviso that at least two of X, Y, Z, Z1, Z2, Z3 and Z4 are independently heteroatoms； andeach R1, a, n and R is independently as defined herein.
In another aspect, provided herein is a pharmaceutical composition comprising the compound disclosed herein.
In some embodiments, the pharmaceutical composition disclosed herein further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
In other embodiments, the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent, wherein the additional therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-inflammatory agent, an immunosuppressant, an immunostimulant, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis or a combination thereof.
In other embodiments, the additional therapeutic agent disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab,  bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab or a combination thereof.
In another aspect, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
In another aspect, provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient comprising administrating a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein to the patient.
In another aspect, provided herein is the compound or the pharmaceutical composition disclosed herein for use in preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
In some embodiments, the proliferative disease disclosed herein is acute myelogenous leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute lymphocytic leukemia (ALL) , colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, CNS (central nervous system) cancer, malignant glioma or bone marrow hyperplasia, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic diseases, cryoglobulinemia, non-lymphoreticular system tumor, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia, semi-molecular disease, monocytic leukemia, primary macroglobulinemia purpura, secondary benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin’s lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis, Hodgkin’s lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyp, small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterine cancer, ovarian cancer, head and neck squamous cell carcinoma, alimentary canal malignancy, non-small cell lung cancer, cervical cancer, testiculoma, bladder cancer or myeloma.
In other embodiments, the autoimmune disease disclosed herein is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, I-type diabetes, sarcoidosis, inflammatory bowel disease, Crohn’s disease or systemic lupus.
In other embodiments, the inflammatory disease disclosed herein is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
In other embodiments, the disease is mediated by FLT3 kinase or caused by FLT3-ITD.
In another aspect, provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, wherein the  method comprise administering to the patient a therapeutically effective amount of the compound disclosed herein.
In another aspect, provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, wherein the method comprise administering to the patient a therapeutically effective amount of the pharmaceutical composition containing the compound disclosed herein.
In another aspect, provided herein is use of the compound disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS AND GENERAL TERMINOLOGY
Reference will now be made in detail to certain embodiments disclosed herein, examples of which are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice disclosed herein. Described herein is in no way limited to the methods and materials. In the event that one or more of the incorporated literature, patents, and similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
As used herein, the following definitions shall be applied unless otherwise indicated. For purposes disclosed herein, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry are described in Sorrell et al. , “Organic Chemistry” , University Science Books, Sausalito: 1999, and Smith et al. , “March’s Advanced Organic Chemistry” , John Wiley &Sons, New York: 2007, all of which are incorporated herein by reference in their entireties.
As described herein, compounds may optionally be substituted with one or more substituents, such as those illustrated above, or as exemplified by particular classes, subclasses, and species disclosed herein. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” . In general, the term “substituted” whether preceded by the term “optionally” or not, refers to the replacement of one or more hydrogen groups in a given structure with the group of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.  Wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like.
The term “alkyl” refers to a saturated linear or branched-chain monovalent hydrocarbon group of 1 to 20 carbon atoms, wherein the alkyl group is optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In other embodiments, the alkyl group contains 1 to 8 carbon atoms. In still other embodiments, the alkyl group contains 1 to 6 carbon atoms. In yet other embodiments, the alkyl group contains 1 to 4 carbon atoms and in yet other embodiments, the alkyl group contains 1 to 3 carbon atoms. Further embodiments of the alkyl group include, but are not limited to, methyl (Me, -CH3) , ethyl (Et, -CH2CH3) , n-propyl (n-Pr, -CH2CH2CH3) , isopropyl (i-Pr, -CH (CH3) 2) , n-butyl (n-Bu, -CH2CH2CH2CH3) , isobutyl (i-Bu, -CH2CH (CH3) 2) , sec-butyl (s-Bu, -CH (CH3) CH2CH3) , tert-butyl (t-Bu, -C(CH3) 3) , n-pentyl (-CH2CH2CH2CH2CH3) , 2-pentyl (-CH (CH3) CH2CH2CH3) , 3-pentyl (-CH (CH2CH3) 2) , 2-methyl-2-butyl (-C (CH3) 2CH2CH3) , 3-methyl-2-butyl (-CH (CH3) CH (CH3) 2) , 3-methyl-1-butyl (-CH2CH2CH (CH3) 2) , 2-methyl-1-butyl (-CH2CH (CH3) CH2CH3) , n-hexyl (-CH2CH2CH2CH2CH2CH3) , 2-hexyl (-CH (CH3) CH2CH2CH2CH3) , 3-hexyl (-CH (CH2CH3) (CH2CH2CH3) ) , 2-methyl-2-pentyl (-C (CH3) 2CH2CH2CH3) , 3-methyl-2-pentyl (-CH (CH3) CH (CH3) CH2CH3) , 4-methyl-2-pentyl (-CH (CH3) CH2CH (CH3) 2) , 3-methyl-3-pentyl (-C (CH3) (CH2CH3) 2) , 2-methyl-3-pentyl (-CH (CH2CH3) CH (CH3) 2) , 2, 3-dimethyl-2-butyl (-C (CH3) 2CH (CH3) 2) , 3, 3-dimethyl-2-butyl (-CH (CH3) C (CH3) 3) , n-heptyl, n-octyl, and the like. The term “alkyl” or the prefix “alk-” is inclusive of both straight chain and branched saturated carbon chain.
The term “alkynyl” refers to a linear or branched-chain monovalent hydrocarbon group of 2 to 12 carbon atoms, with at least one site of unsaturation, i. e. , a carbon-carbon sp triple bond, wherein the alkynyl group is optionally substituted with one or more substituents described herein. Some non-limiting examples of the alkynyl group include ethynyl (-C≡CH) , propargyl (-CH2C≡CH) , and the like.
The term “alkenyl” refers to a linear or branched-chain monovalent hydrocarbon group of 2 to 12 carbon atoms, with at least one site of unsaturation, i. e. , a carbon-carbon sp2 double bond, wherein the alkenyl group is optionally substituted with one or more substituents described herein, and includes groups having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Some non-limiting examples of the alkenyl group include ethenyl or vinyl (-CH＝CH2) , allyl (-CH2CH＝CH2) , and the like.
The term “alkylene” and “alkylene chain” refer to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having 1 to 8 carbon atoms. Some non-limiting examples of the alkylene group include methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through any two carbons within the chain.
The term “alkenylene” and “alkenylene chain” refer to a straight or branched divalent unsaturated  hydrocarbon chain consisting solely of carbon and hydrogen and having 1 to 8 carbon atoms, wherein the unsaturated bond exists only as a double bond and the double bond may be located between any two carbon atoms of the chain. Some non-limiting examples of the alkenylene group include ethenylene, 1, 3-propenylene, 2-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through any two carbons within the chain.
The term “alkynylene” and “alkynylene chain” refer to a straight or branched divalent unsaturated hydrocarbon chain consisting solely of carbon and hydrogen and having 1 to 8 carbon atoms, wherein the unsaturated bond exists only as a triple bond and the triple bond may be located between any two carbon atoms of the chain. Some non-limiting examples of the alkynylene group include ethynylene, 1-propynylene 2-butynylene, 1-pentynylene 3-pentynylene, and the like. The alkynylene chain is attached to the rest of the molecule through any two carbons within the chain.
The term “halogen” or “halogen atom” refers to fluoro, chloro, bromo or iodo.
The term “amino” refers to -NH2.
The term “alkamino” or “alkylamino” refers to “N-alkylamino” and “N, N-dialkylamino” , wherein the amino groups are independently substituted with one or two alkyl groups, respectively, and wherein the alkyl group is as defined herein. In some embodiments, the alkylamino group is lower alkylamino group having one or two alkyl groups of 1 to 6 carbon atoms attached to nitrogen atom. In other embodiments, the alkylamino group is lower alkylamino group having 1 to 3 carbon atoms. Some non-limiting examples of the alkylamino group include monoalkylamino or dialkylamino such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, and the like.
The term “alkoxy” refers to an alkyl group, as defined herein, attached to the principal carbon chain through an oxygen atom. Some non-limiting examples of the alkoxy group include methoxy, ethoxy, propoxy, and the like.
The term “alkoxyalkyl” or “alkoxyalkoxy” refers to an alkyl group or alkoxy group substituted with one or more identical or different alkoxy groups, wherein the alkyl group and alkoxy group are as defined herein. Some non-limiting examples of the alkoxyalkyl group and alkoxyalkoxy group include methoxymethyl, ethoxymethyl, methoxypropoxy, methoxymethoxy, and the like.
The term “alkyl-S (＝O) t-” refers to a group in which-S (＝O) t-is attached to an alkyl group, wherein the alkyl group is as defined herein, and t is 0, 1 or 2. Some non-limiting examples include methyl-S (＝O) 2-, ethyl-S (＝O) 2-, propyl-S (＝O) 2-, methyl-S (＝O) -, ethyl-S (＝O) -, propyl-S (＝O) -, methyl-S-, ethyl-S-, propyl-S-, and the like.
The term “alkyl-C (＝O) -” refers to a group in which acyl (-C (＝O) -) is attached to an alkyl group, wherein the alkyl group is as defined herein. Some non-limiting examples include acetyl (CH3-C (＝O) -) , propionyl (C2H5-C (＝O) -) , and the like.
The term “haloalkyl” or “haloalkoxy” refers to an alkyl group or alkoxy group substituted with one or  more identical or different halogen atoms, wherein the alkyl group and alkoxy group are as defined herein. Some non-limiting examples of the haloalkyl group and haloalkoxy group include trifluoromethyl, trifluoromethoxy, and the like.
The term “alkylaminohaloalkoxy” refers to a haloalkoxy group substituted with one or more identical or different alkylamino groups, wherein the alkylamino group and haloalkoxy group are as defined herein. Some non-limiting examples of the alkylaminohaloalkoxy group include methylaminodifluoromethyloxy, and the like.
The term “hydroxyalkyl” or “hydroxyalkoxy” refers to an alkyl group or alkoxy group substituted with one or more hydroxy groups, wherein the alkyl group and alkoxy group are as defined herein. Some non-limiting examples of the hydroxyalkyl group and hydroxyalkoxy group include hydroxymethyl, 1-hydroxyethyl, hydroxypropyl, 1, 2-dihydroxypropyl, hydroxymethoxy, 1-hydroxyethoxy, and the like.
The term “aminoalkoxy” or “alkylaminoalkoxy” refers to an alkoxy group substituted with one or more amino groups or alkylamino groups, wherein the alkylamino group and alkoxy group are as defined herein. Some non-limiting examples of the aminoalkoxy group and alkylaminoalkoxy group include aminomethoxy, 1-aminoethoxy, methylaminomethoxy, ethylaminoethoxy, and the like.
The term “aryl” used alone or as part of a larger moiety as in “arylalkyl” , “arylalkoxy” or “aryloxyalkyl” refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring” or “aromatic ring” . Some non-limiting examples of the aryl group include phenyl, naphthyl and anthracene. And the aryl group defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like. Depending on the structure, the aryl group can be a monoradical or a diradical such as an arylene group, wherein the term “arylene” refers to the divalent form of aryl defined above.
The term “heteroaryl” or “heteroaryl ring” as used interchangeably herein, used alone or as part of a larger moiety as in “heteroarylalkyl” or “heteroarylalkoxy” , refers to a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the bicyclic heteroaryl, tricyclic heteroaryl or tetracyclic heteroaryl ring system is a fused ring. The heteroaryl ring system is aromatic, in which one or more ring members are an independently selected heteroatom selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, and PO or PO2. The heteroaryl ring system may be attached to the main structure at any heteroatom or carbon atom, which results in the creation of a stable compound. The heteroaryl ring system may be 3-7 membered monocyclic ring, 7-10 membered bicyclic ring or 10-15 membered tricyclic ring. Bicyclic heteroaryl ring having 7-10 ring atoms can be arranged as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system, and tricyclic heteroaryl ring having 10-15 ring atoms can be arranged as a tricyclo [5, 5, 6] , [5, 7, 6] or  [6, 5, 6] system. And the heteroaryl or heteroaryl ring defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like. Depending on the structure, the heteroaryl group may be a monoradical or a diradical such as a heteroarylene group, wherein the term “heteroarylene” refers to the divalent form of heteroaryl defined above.
Some non-limiting examples of the heteroaryl group include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e. g. , 3-pyridazinyl) , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e. g. , 5-tetrazolyl) , triazolyl (e. g. , 2-triazolyl and 5-triazolyl) , 2-thienyl, 3-thienyl, pyrazolyl (e. g. , 2-pyrazolyl) , isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazol-2-yl, pyrazinyl, 2-pyrazinyl, 1,3, 5-triazinyl, benzo [d] thiazol-2-yl, imidazo [1, 5-a] pyridin-6-yl, benzimidazolyl, benzoxazolyl, 1,8-naphthyridinyl, benzothienyl, indolyl (e. g. , 2-indolyl) , purinyl, quinolinyl (e. g. , 2-quinolinyl, 3-quinolinyl and 4-quinolinyl) , tetrahydronaphthyl, benzopyrazolyl, acridinyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, benzo [d] imidazo [2, 1-b] thiazolyl, benzofuryl, naphthofuryl, benzothiadiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, cinnolinyl, dibenzofuryl, imidazopyridyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isobenzothianthrenyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, naphthyridinyl, oxazolidinedionyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridyl, quinazolinyl, quinoxalinyl, thiophenyl, triazinyl, 2H-pyrrolo [3, 4-c] pyridinyl, pyrazolo [2’, 1’: 2, 3] oxazolo [4, 5-c] pyridinyl, imidazo [2’, 1’: 2, 3] thiazolo [4, 5-c] pyridinyl, imidazo [2’ , 1’: 2, 3] thiazolo [4, 5-b] pyridinyl, imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridinyl, pyrazolo [2’, 1’: 2, 3] thiazolo [4, 5-b] pyrazinyl, 1H-benzo [4, 5] thieno [2, 3-d] imidazolyl, 1-methyl-1H-benzo [4, 5] thieno [2, 3-d] imidazolyl, imidazo [2’, 1’: 2, 3] thiazolo [4, 5-b] pyrazinyl, 1H-benzo [f] imidazo [4, 5-b] [1, 4] thiazepinyl, and the like.
The term “bicyclic heteroaryl” or “bicyclic heteroaryl ring” as used interchangeably herein, refers to a fused heteroaryl ring system, which is a bicyclic ring system. The fused heteroaryl ring system is aromatic, in which one or more ring members are an independently selected heteroatom selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, and PO or PO2. In addition, the fused heteroaryl ring system may be attached to the main structure at any heteroatom or carbon atom, which results in the creation of a stable compound. The fused heteroaryl ring system is a 7-10 membered  bicyclic ring, which can be arranged as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system. The bicyclic heteroaryl or bicyclic heteroaryl ring defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like. Depending on the structure, the bicyclic heteroaryl group may be a monoradical or a diradical such as a bicyclic heteroarylene group, wherein the term “bicyclic heteroarylene” refers to the divalent form of bicyclic heteroaryl defined above.
Some non-limiting examples of the bicyclic heteroaryl group include benzo [d] thiazol-2-yl, imidazo [1, 5-a] pyridin-6-yl, benzimidazolyl, benzoxazolyl, 1, 8-naphthyridinyl, benzothienyl, indolyl (e. g., 2-indolyl) , purinyl, quinolinyl (e. g. , 2-quinolinyl, 3-quinolinyl and 4-quinolinyl) , tetrahydronaphthyl, benzopyrazolyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzofuryl, naphthofuryl, benzothiadiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, cinnolinyl, dibenzofuryl, imidazopyridyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isobenzothianthrenyl, isoindolinyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridyl, quinazolinyl, quinoxalinyl, and the like.
The term “tricyclic heteroaryl” or “tricyclic heteroaryl ring” as used interchangeably herein, refers to a fused heteroaryl ring system, which is a tricyclic ring system. The fused heteroaryl ring system is aromatic, in which one or more ring members are an independently selected heteroatom selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, and PO or PO2. In addition, the fused heteroaryl ring system may be attached to the main structure at any heteroatom or carbon atom, which results in the creation of a stable compound. The fused heteroaryl ring system is a 10-15 membered tricyclic ring, which can be arranged as a tricyclo [5, 5, 6] , [5, 7, 6] or [6, 5, 6] system. The tricyclic heteroaryl or tricyclic heteroaryl ring defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like. Depending on the structure, the tricyclic heteroaryl group may be a monoradical or a diradical such as a tricyclic heteroarylene group, wherein the term “tricyclic heteroarylene” refers to the divalent form of tricyclic heteroaryl defined above.
Some non-limiting examples of the tricyclic heteroaryl group include benzo [4, 6] imidazo [1, 2-a] pyridinyl, benzo [d] imidazo [2, 1-b] thiazolyl, pyrazolo [2’, 1’: 2, 3] oxazolo [4, 5-c] pyridinyl, imidazo [2’, 1’: 2, 3] thiazolo [4, 5-c] pyridinyl, imidazo [2’, 1’: 2, 3] thiazolo [4, 5-b] pyridinyl, imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridinyl, pyrazolo [2’, 1’: 2, 3] thiazolo [4, 5-b] pyrazinyl,  1H-benzo [4, 5] thieno [2, 3-d] imidazolyl, 1-methyl-1H-benzo [4, 5] thieno [2, 3-d] imidazolyl, imidazo [2’, 1’: 2, 3] thiazolo [4, 5-b] pyrazinyl, 1H-benzo [f] imidazo [4, 5-b] [1, 4] thiazepinyl, and the like.
The term “carbocyclyl” , “cycloaliphatic” or “carbocycle” as used interchangeably herein refers to a monovalent or multitivalent, non-aromatic, and saturated or partially unsaturated ring consisting solely of carbon and hydrogen atoms and including 3-12 carbon atoms as a monocyclic ring or 7-12 carbon atoms as a bicyclic or tricyclic ring. Bicyclic carbocycles having 7-12 ring atoms can be arranged, for example, as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5, 6] or [6, 6] system. Depending on the structure, the carbocyclyl, cycloaliphatic or carbocycle group can be a monoradical or a diradical, i. e. , in some embodiments, the carbocyclyl, cycloaliphatic or carbocycle group can be replaced by or used as carbocyclylene. Some non-limiting examples of the cycloaliphatic group include cycloalkyl, cycloalkenyl and cycloalkynyl. Further examples of the cycloaliphatic group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantly, and the like. The carbocyclyl, cycloaliphatic or carbocycle group described herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like.
The term “cycloalkyl” refers to a monovalent or multitivalent, non-aromatic, and saturated or partially unsaturated ring consisting solely of carbon and hydrogen atoms and including 3-12 carbon atoms as a monocyclic ring or 7-12 carbon atoms as a bicyclic or tricyclic ring. Bicyclic carbocycles having 7-12 ring atoms can be arranged, for example, as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5, 6] or [6, 6] system. Depending on the structure, the cycloalkyl group can be a monoradical or a diradical, i. e. , in some embodiments, the cycloalkyl group can be replaced by or used as cycloalkylene. Some non-limiting examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantly, and the like.
The term “heterocyclyl” , “heterocycloalkyl” , “heterocycle” , “heterocycloaliphatic” or “heterocyclic” as used interchangeably herein refers to a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic. Depending on the structure, the heterocyclyl, heterocycloalkyl, heterocycle, heterocycloaliphatic or heterocyclic group can be a monoradical or a diradical, i. e. , in some embodiments, the heterocyclyl, heterocycloalkyl, heterocycle, heterocycloaliphatic or heterocyclic  group can be replaced by or used as heterocyclylene. The heterocyclyl system may be attached to the main structure at any heteroatom or carbon atom, which results in the creation of a stable compound. One or more hydrogen atoms on the heterocyclic ring are optionally substituted with one or more substituents described herein. In some embodiments, the heterocyclyl, heterocycloalkyl, heterocycle, heterocycloaliphatic or heterocyclic group is a monocyclic ring having 3-7 ring members (e. g. , 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, and PO or PO2, and the carbon atom can also be optionally substituted with one or more oxo to provide the group -C＝O-, with the proviso that when the ring is a 3-membered ring, there is only one heteroatom) or a bicyclic ring having 7-10 ring members (e. g. , 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, and PO or PO2) .
The heterocyclyl may be a carbon radical or heteroatom radical. The heterocyclyl group also includes a group in which the heterocyclyl group is fused with a saturated or partially unsaturated ring or a heterocyclic ring. Some non-limiting examples of the heterocyclyl group include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, 4-methoxy-piperidin-1-yl, thiazepinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, dithianyl, dithiolanyl, dihydrothienyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 1, 2, 6-thidiazine-1, 1-dioxo-2-yl, hexahydro-2H- [1, 4] dioxin [2, 3-c] pyrrolyl, 1, 1-dioxothiomorpholinyl, 2, 3, 3a, 7a-tetrahydro-1H-isoindolyl, 1, 2, 3, 4-tetrahydroquinolyl, N-pyridyl urea, dioxolanyl, dihydropyrazinyl, dihydropyridyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1, 4-dithianyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothianthrenyl, morpholinyl, decahydroindolyl, decahydroisoindolyl, piperazinyl, piperidinyl, 4-piperidonyl, thiomorpholinyl, and the like. The heterocyclyl group described herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like. Some non-limiting examples of the substituted heterocyclyl include cyclohex-2, 4-dienone, 2, 6-dimethylmorpholinyl, and the like.
The term “fused bicyclic” , “fused cyclic” , “fused bicyclyl” or “fused cyclyl” refers to a saturated or unsaturated fused ring system, which refers to a bicyclic ring system that is not aromatic and includes at least one non-aromatic ring. Depending on the structure, the fused bicyclic, fused cyclic, fused bicyclyl or fused cyclyl group can be a monoradical or a diradical, i. e. , in some embodiments, the fused bicyclic, fused cyclic, fused bicyclyl or fused cyclyl group can be replaced by or used as fused bicyclylene. 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) . Each cyclic ring in the fused bicyclyl can be either a carbocyclic ring or a heteroalicyclic ring. Some non-limiting examples of the fused bicyclic ring system include hexahydro-furo [3, 2-b] furanyl, 2, 3, 3a, 4, 7, 7a-hexahydro-1H-indenyl, 7-azabicyclo [2.2.1] heptyl, fused bicyclo [3.3.0] octyl, fused bicyclo [3.1.0] hexyl, 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl, and the like. And the fused bicyclyl group defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like.
The term “fused heterobicyclyl” refers to saturated or unsaturated fused ring system, which refers to a bicyclic ring system that is not aromatic and includes at least one non-aromatic ring. 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) . Depending on the structure, the fused heterobicyclyl group can be a monoradical or a diradical, i. e. , in some embodiments, the fused heterobicyclyl group can be replaced by or used as fused heterobicyclylene. And at least one ring in the fused ring system contains one or more heteroatoms. Each ring in the fused ring system contains 3 to 7 ring members (i. e. , 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, and PO or PO2, and the carbon atom can also be optionally substituted with one or more oxo to provide the group-C＝O-) . Some non-limiting examples of the fused heterobicyclyl group include hexahydro-2H- [1, 4] dioxin [2, 3-c] pyrrolyl, 3-azabicyclo [3.3.0] octyl, 3-methyl-3, 7-diazabicyclo [3.3.0] octyl, 8-azabicyclo [4.3.0] nonyl, 8-azabicyclo [4.3.0] non-3-yl, 3-azabicyclo [4.3.0] non-3-yl, 1, 5-dioxa-8-azabicyclo [4.3.0] nonyl, (1R, 6S) -2, 5-dioxa-8-azabicyclo [4.3.0] nonyl, (1R, 6R) -2, 5-dioxa-8-azabicyclo [4.3.0] nonyl, isoindolinyl, 1, 2, 3, 4-tetrahydroquinolyl, (1S, 5S) -1-hydroxy-3-azabicyclo [3.1.0] hexyl, (1R, 5S) -1-hydroxy-3-azabicyclo [3.1.0] hexyl, (1R, 5S) -1-N, N-dimethylamino-3-azabicyclo [3.1.0] hexyl, (1S, 5R, 6R) -1-methyl-6-ol-3-azabicyclo [3.2.0] heptyl, 3-aza-7-oxabicyclo [3.3.0] octyl, 3, 7-diazabicyclo [3.3.0] octyl, 2, 6-diazabicyclo [3.3.0] octyl, 3-ethyl-3, 7-diazabicyclo [3.3.0] octyl, 2, 7-diazabicyclo [3.3.0] octyl, 7-acetyl-2, 7-diazabicyclo [3.3.0] octyl, 2, 8-diazabicyclo [4.3.0] nonyl, 2-methyl-2, 8-diazabicyclo [4.3.0] nonyl, 3-oxa-8-azabicyclo [4.3.0] nonyl, 2-oxa-8-azabicyclo [4.3.0] nonyl, 2, 8-diaza-5-oxabicyclo [4.3.0] nonyl, (1S, 6R) -2-methyl-2, 8-diaza-5-oxabicyclo [4.3.0] nonyl, 3-ethyl-3, 9-diazabicyclo [4.3.0] nonyl, 4, 9-diazabicyclo [4.3.0] nonyl, 2, 9-diazabicyclo [4.3.0] nonyl, 3-methyl-3, 9-diazabicyclo [4.3.0] nonyl, 3-ethyl-3, 7-diazabicyclo [4.3.0] nonyl, 3-methyl-3, 7-diazabicyclo [4.3.0] nonyl, 2-ethyl-2, 8-diazabicyclo [4.3.0] nonyl, 3-oxo-2, 4, 8-triazabicyclo [4.3.0] nonyl, 3-oxo-4-oxa-2, 8-diazabicyclo [4.3.0] nonyl, 3-oxo-2, 8-diazabicyclo [4.3.0] nonyl, 3, 8-diazabicyclo [4.3.0] nonyl,  8-methyl-2, 8-diazabicyclo [4.3.0] nonyl, 3, 7-diazabicyclo [4.3.0] nonyl, 3, 9-diazabicyclo [4.3.0] nonyl, 3-oxa-8-azabicyclo [4.3.0] nonyl, 3-thia-8-azabicyclo [4.3.0] nonyl, 9-methyl-3, 9-diazabicyclo [4.3.0] nonyl, 7-methyl-3, 7-diazabicyclo [4.3.0] nonyl, 9-ethyl-3, 9-diazabicyclo [4.3.0] nonyl, 7-ethyl-3, 7-diazabicyclo [4.3.0] nonyl, 8-ethyl-2, 8-diazabicyclo [4.3.0] nonyl, 5, 6-dihydro-4H-pyrrolo [3, 4-c] isoxazolyl, 3-ethyl- [1, 2, 4] triazolo [4, 3-a] piperidyl, [1, 2, 4] triazolo [4, 3-a] piperidyl, 3-methyl-isoxazolo [4, 3-c] piperidinyl, 3-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-c] isoxazolyl, 2-methyl-4, 5, 6, 7-tetrahydro-1H-imidazo [4, 5-c] pyridinyl, 2-methyl-4, 5, 6, 7-tetrahydrooxazolo [4, 5-c] pyridinyl, 2-methyl-4, 5, 6, 7-tetrahydro-1H-thiazolo [4, 5-c] pyridinyl, isoxazolo [4, 3-c] piperidinyl, 4, 5, 6, 7-tetrahydroisoxazolo [3, 4-c] pyridinyl, [1, 2, 4] triazolo [4, 3-a] piperazinyl, 3-trifluoromethyl- [1, 2, 4] triazolo [4, 3-a] piperazinyl, 3-methyl- [1, 2, 4] triazolo [4, 3-a] piperazinyl, 2-oxo-3-oxa-8-azabicyclo [4.3.0] nonyl, 1, 3-dimethyl-4, 5, 6, 7-tetrahydro-1H-pyrazolo [4, 3-c] pyridinyl, 2-oxa-7-azabicyclo [4.4.0] decyl, 1, 5-dioxa-9-azabicyclo [4.4.0] decyl, 2, 3-dimethyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridinyl, 3-azabicyclo [4.4.0] decyl, 5-benzyl-2-oxa-5, 8-diazabicyclo [4.3.0] nonyl, 2, 7-diaza-decahydronaphthyl, 2-oxa-8-azabicyclo [4.4.0] decyl, and the like. The fused heterobicyclyl group defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like.
The term “bridged bicyclyl” refers to a saturated or unsaturated bridged ring system, which refers to a bicyclic 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) , in which each ring contains 3 to 7 ring members. Some non-limiting examples of the bridged bicyclyl group include bicyclo [2.2.1] heptyl, 2-methyl-heterobicyclo [2.2.1] heptyl, and the like. The bridged bicyclyl group defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like.
The term “bridged heterobicyclyl” refers to saturated or unsaturated bridged ring system, which refers to a bicyclic ring system that is not aromatic. Depending on the structure, the bridged heterobicyclyl group can be a monoradical or a diradical, i. e. , in some embodiments, the bridged heterobicyclyl group can be replaced by or used as fused heterobicyclylene. 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) . And at least one ring in the bridged ring system contains one or more heteroatoms. Each ring in the bridged ring system  contains 3 to 7 ring members (i. e. , 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, and PO or PO2, and the carbon atom can also be optionally substituted with one or more oxo to provide the group -C＝O-) . Some non-limiting examples of the bridged heterobicyclyl group include 2-oxa-5-azabicyclo [2.2.1] heptyl, 2-thio-5-azabicyclo [2.2.1] heptyl, 2-oxo-5-azabicyclo [2.2.1] heptyl, 2, 5-diazabicyclo [2.2.1] heptyl, 2-methyl-2, 5-diazabicyclo [2.2.1] heptyl, and the like. The bridged heterobicyclyl group defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like.
The term “cycloalkylalkyl” refers to an alkyl group substituted with one or more cycloalkyl groups, wherein the alkyl group and cycloalkyl group are as defined herein. Some non-limiting examples of the cycloalkylalkyl group include cyclopropylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.
The term “heterocyclylalkyl” refers to an alkyl group substituted with one or more heterocyclyl groups, wherein the alkyl and heterocyclyl group are as defined herein. Some non-limiting examples of the heterocyclylalkyl group include oxiranylmethyl, morpholinylmethyl, piperidylethyl, and the like.
The term “cycloalkyloxy” or “carbocyclyloxy” refers to an optionally substituted cycloalkyl or carbocyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the cycloalkyloxy group include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like.
The term “cycloalkylamino” refers to an amino group substituted with one or two cycloalkyl groups, wherein the cycloalkyl group is as defined herein. Some non-limiting examples of the cycloalkylamino group include cyclopropylamino, cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino, and the like.
The term “arylalkoxy” refers to an alkoxy group substituted with one or more aryl groups, wherein the aryl group and alkoxy group are as defined herein. Some non-limiting examples of the arylalkoxy group include phenylmethoxy, phenylethoxy, (p-tolyl) methoxy, phenylpropoxy, and the like.
The term “arylalkylamino” refers to an alkylamino group substituted with one or more aryl groups, wherein the aryl group and alkylamino group are as defined herein. Some non-limiting examples of the arylalkylamino group include phenylmethylamino, phenylethylamino, phenylpropylamino, (p-tolyl) methylamino, and the like.
The term “heteroarylalkoxy” refers to an alkoxy group substituted with one or more heteroaryl groups, wherein the heteroaryl group and alkoxy group are as defined herein. Some non-limiting examples of the heteroarylalkoxy group include pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy,  pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, and the like.
The term “heteroarylalkylamino” refers to a heteroarylalkyl group attached via a nitrogen atom to other groups, wherein the heteroarylalkyl group is as defined herein. Some non-limiting examples of the heteroarylalkylamino group include pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino, and the like.
The term “heterocyclylalkoxy” refers to a heterocyclyl-substituted alkoxy group wherein the oxygen atom serves as the attaching point to the rest of the molecule. The term “heterocyclylalkylamino” refers to a heterocyclyl-substituted alkylamino group wherein the nitrogen atom serves as the attaching point to the rest of the molecule. Wherein the heterocyclyl, alkoxy and alkylamino group are as defined herein. Some non-limiting examples of the heterocyclylalkoxy group and heterocyclylalkylamino group include morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino, and the like.
The term “cycloalkylalkoxy” or “carbocyclylalkoxy” refers to an alkoxy group substituted with one or more cycloalkyl or carbocyclyl groups, wherein the cycloalkyl or carbocyclyl group and alkoxy group are as defined herein. Some non-limiting examples of the cycloalkylalkoxy group include cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy, cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy, and the like.
The term “cycloalkylalkylamino” or “carbocyclylalkylamino” refers to an alkylamino group substituted with one or more cycloalkyl or carbocyclyl groups, wherein the cycloalkyl or carbocyclyl group and alkylamino group are as defined herein. Some non-limiting examples of the cycloalkylalkylamino group include cyclopropylmethylamino, cyclopropylethylamino, cyclopentylethylamino, cyclohexylethylamino, cyclohexylmethylamino, cyclopropylpropylamino, and the like.
The term “aryloxyalkoxy” refers to an alkoxy group substituted with one or more aryloxy groups, wherein the alkoxy group and aryloxy group are as defined herein. Some non-limiting examples of the aryloxyalkoxy group include phenyloxymethoxy, phenyloxyethoxy, phenyloxypropoxy, and the like.
The term “heteroaryloxyalkoxy” refers to an alkoxy group substituted with one or more heteroaryloxy groups, wherein the alkoxy group and heteroaryloxy group are as defined herein. Some non-limiting examples of the heteroaryloxyalkoxy group include pyridinyloxymethoxy, pyrimidinyloxyethoxy, thiazolyloxypropoxy, and the like.
The term “aroxy” or “aryloxy” refers to an optionally substituted aryl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the aryloxy group include phenyloxy, methylphenyloxy, ethylphenyloxy, and the like.
The term “heteroaryloxy” refers to an optionally substituted heteroaryl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the heteroaryloxy group include pyrid-2-yloxy, thiazol-2-yloxy, imidazol-2-yloxy, pyrimidin-2-yloxy, and the like. 
The term “heterocyclyloxyalkoxy” refers to an alkoxy group substituted with one or more heterocyclyloxy groups, wherein the alkoxy group and heterocyclyloxy group are as defined herein. Some non-limiting examples of the heterocyclyloxyalkoxy group include pyrrol-2-yloxymethoxy, pyrrol-3-yloxyethoxy, piperidin-2-yloxyethoxy, piperidin-3-yloxyethoxy, piperazin-2-yloxymethoxy, piperidin-4-yloxyethoxy, and the like.
The term “carbocyclyloxyalkoxy” refers to an alkoxy group substituted with one or more carbocyclyloxy groups, wherein the alkoxy group and carbocyclyloxy group are as defined herein. Some non-limiting examples of the carbocyclyloxyalkoxy group include cyclopropyloxymethoxy, cyclopropyloxyethoxy, cyclopentyloxyethoxy, cyclohexyloxyethoxy, cyclohexen-3-yloxyethoxy, and the like.
The term “heterocyclyloxy” refers to an optionally substituted heterocyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the heterocyclyloxy group include pyrrol-2-yloxy, pyrrol-3-yloxy, piperidin-2-yloxy, piperidin-3-yloxy, piperazin-2-yloxy, piperidin-4-yloxy, and the like.
The term “fused bicyclyloxy” refers to an optionally substituted fused bicyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the fused bicyclyloxy group include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyloxy, fused bicyclo [3.3.0] oct-2yloxy, fused bicyclo [3.1.0] hex-2yloxy, and the like.
The term “fused heterobicyclyloxy” refers to an optionally substituted fused heterobicyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the fused heterobicyclyloxy group include hexahydro-furo [3, 2-b] furan-2-yloxy, 7-azabicyclo [2.3.0] hept-2-yloxy, 7-azabicyclo [2.3.0] hept-4-yloxy, and the like.
The term “fused bicyclylamino” refers to an amino group substituted with one or two fused bicyclyl groups, wherein the fused bicyclyl group is as defined herein. Some non-limiting examples of the fused bicyclylamino group include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylamino, di(1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl) amino, fused bicyclo [3.3.0] octylamino, fused bicyclo [3.1.0] hexylamino, and the like.
The term “fused heterobicyclylamino” refers to an amino group substituted with one or two fused heterobicyclyl groups, wherein the fused heterobicyclyl group is as defined herein. Some non-limiting examples of the fused heterobicyclylamino group include hexahydro-furo [3, 2-b] furan-2-ylamino, 7-azabicyclo [2.3.0] hept-2-ylamino, 7-azabicyclo [2.3.0] hept-4-ylamino, and the like.
The term “fused bicyclylalkylamino” refers to an alkylamino group substituted with one or two fused bicyclyl groups, wherein the fused bicyclyl group is as defined herein. Some non-limiting examples of the fused bicyclylalkylamino group include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylmethylamino, di(1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl) methylamino, fused bicyclo [3.3.0] octylmethylamino, fused  bicyclo [3.1.0] hexylmethylamino, and the like.
The term “fused heterobicyclylalkylamino” refers to an alkylamino group substituted with one or two fused heterobicyclyl groups, wherein the fused heterobicyclyl group is as defined herein. Some non-limiting examples of the fused heterobicyclylalkylamino group include hexahydro-furo [3, 2-b] furan-2-ylmethylamino, 7-azabicyclo [2.3.0] hept-2-ylmethylamino, 7-azabicyclo [2.3.0] hept-4-ylmethylamino, and the like.
The term “fused bicyclylalkoxy” refers to an alkoxy group substituted with one or more fused bicyclyl groups, wherein the alkoxy group and fused bicyclyl group are as defined herein. Some non-limiting examples of the fused bicyclylalkoxy include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylmethoxy, 1,2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylethoxy, fused bicyclo [3.3.0] octylethoxy, fused bicyclo [3.1.0] hexylpropoxy, and the like.
The term “fused heterobicyclylalkoxy” refers to an alkoxy group substituted with one or more fused heterobicyclyl groups, wherein the alkoxy group and fused heterobicyclyl group are as defined herein. Some non-limiting examples of the fused heterobicyclylalkoxy group include hexahydro-furo [3, 2-b] furan-2-ylpropoxy, 7-azabicyclo [2.2.1] hept-2-ylethoxy, 7-azabicyclo [2.3.0] hept-4-ylpropoxy, hexahydro-furo [3, 2-b] furan-2-ylethoxy, 7-azabicyclo [2.3.0] hept-2-ylpropoxy, 7-azabicyclo [2.3.0] hept-4-ylethoxy, and the like.
The term “fused bicyclylalkyl” refers to an alkyl group substituted with one or more fused bicyclyl groups, wherein the alkyl group and fused bicyclyl group are as defined herein. Some non-limiting examples of the fused bicyclylalkyl group include 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylmethyl, 1,2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylethyl, fused bicyclo [3.3.0] octylethyl, fused bicyclo [3.1.0] hexylpropyl, and the like.
The term “fused heterobicyclylalkyl” refers to an alkyl group substituted with one or more fused heterobicyclyl groups, wherein the alkyl group and fused heterobicyclyl group are as defined herein. Some non-limiting examples of the fused heterobicyclylalkyl group include hexahydro-furo [3, 2-b] furan-2-ylpropyl, 7-azabicyclo [2.2.1] hept-2-ylethyl, 7-azabicyclo [2.3.0] hept-4-ylpropyl, hexahydro-furo [3, 2-b] furan-2-ylethyl, 7-azabicyclo [2.3.0] hept-2-ylpropyl, 7-azabicyclo [2.3.0] hept-4-ylethyl, and the like.
The term “fused heterobicyclyloxyalkoxy” refers to an alkoxy group substituted with one or more fused heterobicyclyloxy groups, wherein the alkoxy group and fused heterobicyclyloxy group are as defined herein. Some non-limiting examples of the fused heterobicyclyloxyalkoxy group include hexahydro-furo [3, 2-b] furan-2-yloxypropoxy, 7-azabicyclo [2.2.1] hept-2-yloxyethoxy, 7-azabicyclo [2.3.0] hept-4-yloxypropoxy, hexahydro-furo [3, 2-b] furan-2-yloxyethoxy, 7-azabicyclo [2.3.0] hept-2-yloxypropoxy, 7-azabicyclo [2.3.0] hept-4-yloxyethoxy, and the like.
The term “fused heterobicyclyloxyalkylamino” refers to an alkylamino group substituted with one or more fused heterobicyclyloxy groups, wherein the alkylamino group and fused heterobicyclyloxy group are as defined herein. Some non-limiting examples of the fused heterobicyclyloxyalkylamino group include  hexahydro-furo [3, 2-b] furan-2-yloxypropylamino, 7-azabicyclo [2.2.1] hept-2-yloxyethylamino, 7-azabicyclo [2.3.0] hept-4-yloxypropylamino, hexahydro-furo [3, 2-b] furan-2-yloxyethylamino, 7-azabicyclo [2.3.0] hept-2-yloxypropylamino, 7-azabicyclo [2.3.0] hept-4-yloxyethylamino, and the like.
The term “bridged heterobicyclylalkoxy” refers to an alkoxy group substituted with one or more bridged heterobicyclyl groups, wherein the bridged heterobicyclyl group and alkoxy group are as defined herein. Some non-limiting examples of the bridged heterobicyclylalkoxy group include 2-oxa-5-azabicyclo [2.2.1] heptylmethoxy, 2, 5-diazabicyclo [2.2.1] heptylethoxy, 2-methyl-2, 5-diazabicyclo [2.2.1] heptylpropoxy, and the like.
The term “bridged heterobicyclylalkyl” refers to an alkyl group substituted with one or more bridged heterobicyclyl groups, wherein the bridged heterobicyclyl group and alkyl group are as defined herein. Some non-limiting examples of the bridged heterobicyclylalkyl group include 2-oxa-5-azabicyclo [2.2.1] heptylmethyl, 2,5-diazabicyclo [2.2.1] heptylethyl, 2-methyl-2, 5-diazabicyclo [2.2.1] heptylpropyl, and the like.
The term “bridged heterobicyclylalkylamino” refers to an alkylamino group substituted with one or more bridged heterobicyclyl groups, wherein the bridged heterobicyclyl group and alkylamino group are as defined herein. Some non-limiting examples of the bridged heterobicyclylalkylamino group include 2-oxa-5-azabicyclo [2.2.1] heptylmethylamino, 2, 5-diazabicyclo [2.2.1] heptylethylamino, 2-methyl-2, 5-diazabicyclo [2.2.1] heptylpropylamino, and the like.
The term “bridged heterobicyclyloxy” refers to an optionally substituted bridged heterobicyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule. Some non-limiting examples of the bridged heterobicyclyloxy group include 2-methyl-2, 5-diazabicyclo [2.2.1] heptyloxy, 2, 5-diazabicyclo [2.2.1] heptyloxy, and the like.
The term “arylalkyl” refers to an alkyl group substituted with one or more aryl groups, wherein the alkyl group and aryl group are as defined herein. Some non-limiting examples of the arylalkyl group include phenylethyl, phenylmethyl, (p-tolyl) ethyl, and the like.
The term “heteroarylalkyl” refers to an alkyl group substituted with one or more heteroaryl groups, wherein the alkyl group and heteroaryl group are as defined herein. Some non-limiting examples of the heteroarylalkyl group include pyrid-2-ylethyl, thiazol-2-ylmethyl, imidazol-2-ylethyl, pyrimidin-2-ylpropyl, and the like.
The term “alkylthio” refers to a group in which a linear or branched alkyl group having 1 to 10 carbon atoms is attached to a divalent sulfur atom, wherein the alkyl group is as defined herein. In some embodiments, the alkylthio group is lower alkylthio group having 1 to 3 carbon atoms. Some non-limiting examples of the alkylthio group include methylthio (CH3S-) , ethylthio, and the like.
The term “aminoacyl” refers to -C (＝O) NH2.
The term “alkyl-C (＝O) NH-” refers to a group in wnich a linear or branched alkyl group having 1 to 10 carbon atoms is attached to -C (＝O) NH-, wherein the alkyl group is as defined herein. Some non-limiting  examples of the alkyl-C (＝O) NH-group include acetamido (CH3C (＝O) NH-) , propionamido (C2H5C (＝O) NH-) , and the like.
The term “spirocyclyl” , “spirocyclic” , “spiro bicyclyl” or “spiro bicyclic” refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, a saturated bridged ring system (ring B and B’ ) is termed as “fused bicyclic” , whereas ring A and ring B share an atom between the two saturated ring system, which terms as a “spirocyclyl” or “spiro bicyclyl” . Each cyclic ring in a spirocyclyl can be either a carbocyclic or a heteroalicyclic. Some non-limiting examples of the spiro bicyclyl group include 4-azaspiro [2.4] hept-5-yl, 4-oxaspiro [2.4] hept-5-yl, 5-azaspiro [2.4] hept-5-yl, spiro [2.4] heptyl, spiro [4.4] nonyl, 7-hydroxy-5-azaspiro [2.4] hept-5-yl, and the like. The spirocyclyl or spiro bicyclyl may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like.
Figure PCTCN2014087469-appb-000028
The term “spiro heterobicyclyl” refers to a ring originating from a particular annular carbon of another ring. For example, as depicted above, a saturated bridged ring system (ring B and B’ ) is termed as “fused bicyclic” , whereas ring A and ring B share an atom between the two saturated ring system, which terms as a “spirocyclyl” or “spiro bicyclyl” . And at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members (i. e. , 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, and PO or PO2) . Some non-limiting examples of the spiro heterobicyclyl group include 4-azaspiro [2, 4] heptyl, 4-oxaspiro [2, 4] heptyl, 5-azaspiro [2, 4] heptyl, 7-hydroxy-5-azaspiro [2, 4] heptyl, 2-azaspiro [4, 5] decyl, 2-azaspiro [3, 3] heptyl, 2-azaspiro [4.4] nonyl, 2-methyl-2, 6-diazaspiro [4.5] decyl, 3-azaspiro [5.4] decyl, 2-methyl-2-azaspiro [3.3] heptyl, 2-oxa-6-azaspiro [3.3] heptyl, 2, 6-diazaspiro [3.3] heptyl, 2-thia-6-azaspiro [3.3] heptyl 2-oxide, 2-thia-6-azaspiro [3.3] heptyl 2, 2-dioxide, and the like. The spiro heterobicyclyl group defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (＝O) , fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, alkyl-S (＝O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C＝O) -, benzyl, cyclopropyl, phenyl, methyl- (C＝O) NH-, alkoxyalkyl, and the like.
The term “spiro heterobicyclylalkoxy” refers to an alkoxy group substituted with one or more spiro  heterobicyclyl groups, wherein the spiro heterobicyclyl group and alkoxy group are as defined herein. Some non-limiting examples of the spiro heterobicyclylalkoxy group include 4-azaspiro [2, 4] hept-5-ylmethoxy, 4-azaspiro [2, 4] hept-2-ylethoxy, 4-oxaspiro [2, 4] hept-5-ylethoxy, 5-azaspiro [2, 4] hept-5-ylpropoxy, and the like.
The term “spiro heterobicyclylalkyl” refers to an alkyl group substituted with one or more spiro heterobicyclyl groups, wherein the spiro heterobicyclyl group and alkyl group are as defined herein. Some non-limiting examples of the spiro heterobicyclylalkyl group include 4-azaspiro [2, 4] hept-5-ylmethyl, 4-azaspiro [2, 4] hept-2-ylethyl, 4-oxaspiro [2, 4] hept-5-ylethyl, 5-azaspiro [2, 4] hept-5-ylpropyl, and the like.
“Anti-proliferative agent” refers to anti-metabolites (e. g. , 5-fluoro-uracil, methotrexate and fludarabine) , antimicrotubule agents (e. g. , vinca alkaloids such as vincristine and vinblastine, taxanes such as paclitaxel and docetaxel) , alkylating agents (e. g. , cyclophosphamide, melphalan, carmustine and nitrosoureas such as bischloroethylnitrosourea and hydroxyurea) , platinum agents (e. g. , cisplatin, carboplatin, oxaliplatin, JM-216 and Cl-973) , anthracyclines (e. g. , doxorubicin and daunorubicin) , antitumor antibiotics (e. g. , mitomycin, idarubicin, doxorubicin and daunorubicin) , topoisomerase inhibitors (e. g. , etoposide and camptothecin) , anti-angiogenesis agents (e. g. , bevacizumab) , any other cytotoxic agents (estramustine phosphate and prednimustine) , hormones or hormone agonists, antagonists, partial agonist or partial antagonists, kinase inhibitors and radiation treatment.
As described herein, a bond drawn from a substituent R to the center of one ring within a ring system represents substitution of the substituent R at any substitutable position on the ring. For example, Formula a represents possible substitution of the substituent R in any of the position on ring A or ring B, as shown in Formula b, Formula c, Formula d, Formula e, Formula f, Formula g and Formula h.
Figure PCTCN2014087469-appb-000029
As described herein, a bond drawn from a substituent (R) n to the center of one ring within a ring system represents substitution of n substituents R at any substitutable position on the rings. For example, Formula i represents possible substitution of n substituents R in any of the position on ring A or ring B.
Figure PCTCN2014087469-appb-000030
As described herein, two attachment points within a ring system, for example, either E or E’ on ring C as shown in Formula j, can attach to the rest of the molecule and can be used interchangeably with each other.
Figure PCTCN2014087469-appb-000031
As described herein, the attachment point can attach to the rest of the molecule at any attachable position on the rings. For example, Formula k represents attaching at any attachable position on ring A or ring B.
Figure PCTCN2014087469-appb-000032
As described herein, the attachment points can attach to the rest of the molecule at any attachable position on the rings, meanwhile, the attachment points can be used interchangeably with each other. For example, Formula m represents attaching at any attachable position on the rings, and the two attachment points can be used interchangeably with each other.
Figure PCTCN2014087469-appb-000033
Furthermore, what need to be explained is that the phrase “each…is independently” and “each of…and…is independently” , unless otherwise stated, should be broadly understood, i. e. , the specific options expressed by the same symbol are independent of each other in different groups； or the specific options expressed by the same symbol are independent of each other in same groups. For example, the specific options of Z1 in Formula q and in Formula s are independent of each other； meanwhile, the specific options of multiple G in Formula q are independent of each other, and the specific options of multiple R9 in Formula s are independent of each other.
Figure PCTCN2014087469-appb-000034
Stereochemical definitions and conventions used herein generally follow Parker et al. , McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York and Eliel et al. , “Stereochemistry of Organic Compounds” , John Wiley &Sons, Inc. , New York, 1994. The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present  invention. Many organic compounds exist in optically active forms, i. e. , they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center (s) . The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The term “racemic mixture” or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.
The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Some non-limiting examples of proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
A “hydrate” refers to a compound disclosed herein or a salt thereof, which further includes a stoichiometric or non-stoichiometeric amount of water bound by non-covalent intermolecular forces, and also refers to the complex where the solvent molecule is water.
A “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of the solvent that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.
An “ester” refers to an in vivo hydrolysable ester of a compound of the Formula (I) , Formula (II) or Formula (III) containing hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent alcohol. Some non-limiting examples of in vivo hydrolysable ester forming groups for hydroxy include phosphate, acetoxymethoxy, 2, 2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, N- (dialkylaminoethyl) -N-alkylcarbamoyl, and the like.
A “N-oxide” refers to one or more than one nitrogen atoms oxidised to form an N-oxide, where a compound contains several amine functions. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e. g. a peroxycarboxylic acid) (See, Advanced Organic Chemistiy, by Jerry March, 4th Edition, Wiley Interscience, pages) . More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) , for example, in an inert solvent such as dichloromethane.
Compounds may exist in a number of different geometric isomeric and tautomeric forms and references to compounds of the Formula (I) , Formula (II) or Formula (III) include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by Formula (I) , Formula (II) or Formula (III) .
The term “prodrug” refers to a compound that is transformed in vivo into a compound of Formula (I) , Formula (II) or Formula (III) . Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation of the prodrug form in blood or tissue to the parent form. Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains an OH group may be acylated at this position in its prodrug form. Other prodrug forms include phosphates such as those phosphate compounds derived from the phosphonation of an OH group on the parent compound. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, Edward B. Roche, ed. , Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al. , Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al. , Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51， 2328-2345, all of which are incorporated herein by reference in their entireties.
Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
A “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof. The metabolite of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient time period.
The compounds disclosed herein are useful in various pharmaceutically acceptable salt forms. The term “pharmaceutically acceptable salt” refers to those salt forms which would be apparent to the pharmaceutical chemist, i. e. , those which are substantially nontoxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
A “pharmaceutically acceptable salts” refers to organic or inorganic salts of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. , describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1977, 66: 1-19, which is incorporated herein by reference. Some non-limiting examples of pharmaceutically acceptable and nontoxic salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, 2-hydroxy propionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C1-4 alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oilsoluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C1-8 sulfonate or aryl sulfonate. Amine salts include, but are not limited to, N, N’ -dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamine, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1’-ylmethylbenzimidazole, diethylamine and other alkylamine, piperazine and tris (hydroxymethyl) aminomethane. Alkali earth metal salts include, but are not limited to, barium, calcium and magnesium. Transition metal salts include, but are not limited to, zinc.
The term “protecting group” or “Pg” refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Some non-limiting examples of suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc) , benzyloxycarbonyl (Cbz) and 9-fluorenylmethylenoxycarbonyl (Fmoc) . Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Some non-limiting examples of suitable hydroxy-protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Some non-limiting examples of the carboxy-protecting group include -CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl,  2-(p-nitrophenylsulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. For a general description of protecting groups and their use, see Greene et al. , Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991 and Kocienski et al. , Protecting Groups, Thieme, Stuttgart, 2005.
In the description herein, if there is any discrepancy between a chemical name and chemical structure, the structure preferably controls.
As used herein, the abbreviations for any protective groups, amino acids and other compounds are, unless otherwise indicated, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 1972, 11: 942-944) .
DESCRIPTION OF COMPOUNDS OF THE INVENTION
Provided herein are substituted urea derivatives and pharmaceutical compositions thereof used in drug therapy, as well as the uses thereof for the treatment of FLT3 kinase mediated or FLT3-ITD caused diseases, of which the substituted urea compounds are useful in the modulation of FLT3 kinase activity and in the inhibition of FLT3-ITD.
In one aspect, provided herein is a compound having Formula (I) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2014087469-appb-000035
wherein
each of Q and W is independently CH or N；
G is-O-, -S (＝O) t-, -S-, -C (＝O) -or a 5-membered heteroarylene group；
R is-NR3R2, alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkyl-S (＝O) t-, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy, heterocyclyloxy, carbocyclyloxyalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryl, arylalkyl, aryloxyalkoxy, aryloxy, arylalkoxy, arylalkylamino, heteroarylalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkylamino, heteroaryloxy, heteroaryloxyalkoxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, bridged heterobicyclyl, spiro heterobicyclyl or fused heterobicyclyl；
ring K is a 5-to 6-membered heteroaryl group, of which at least two ring members are heteroatoms  independently selected from O, S, NR4 and N；
each L is independently amino, nitro, C1-4 alkylthio, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-4 haloalkyl, C1-4 alkylamino, hydroxy, fluoro, chloro, bromo, iodo, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or cyano；
ring E is a bicyclic or tricyclic heteroarylene group；
provided that:
when ring E is
Figure PCTCN2014087469-appb-000036
Figure PCTCN2014087469-appb-000037
wherein each X8, X9 and X10 is independently N or CH；
each X1, X3, X4, X5, X6 and X7 is independently -CH2-, -O-, -NR4a-, -S (＝O) t-or-S-；
each of X, Y, Z1, Z2, Z3 and Z is independently N or CH；
T is-O-, -S-, -NR4-or -CH2-；
with the proviso that at least two of X, Y, T, Z1, Z2, Z3 and Z are independently heteroatoms；
each R1 is independently hydrogen, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-6 alkyl-S (＝O) t-, C1-6 alkoxy-C1-6-alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio；
each of R2 and R3 is independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl；
each R4a and R4 is independently hydrogen, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl；
each q, m, p, r and s is independently 0, 1, 2, 3 or 4；
each of d and n is independently 1, 2, 3 or 4；
each t is independently 0, 1 or 2； and
a is 0, 1, 2, 3 or 4,
wherein each aryl, bicyclic heteroarylene, tricyclic heteroarylene, alkoxy, alkyl-S (＝O) t-, -G- (CH2) n-R, arylalkyl, heteroarylalkyl, heteroaryl, heteroarylene, heterocycly, bridged heterobicyclyl, spiro heterobicyclyl, fused heterobicyclyl, alkyl, haloalkyl, alkylamino, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, alkoxyalkyl, hydroxyalkyl, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, cycloalkyloxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkylamino, cycloalkylamino, heterocyclylalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, alkyl-C (＝O) -NH-, alkylthio, cycloalkyl and ring E is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, amino, methyl-C (＝O) -NH-, oxo (＝O) , C1-4 alkyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
In some embodiments, ring E is
Figure PCTCN2014087469-appb-000038
wherein each X, Y, Z, Z1, Z2, Z3 and Z4 is independently N or CH；
each T and T1 is independently -O-, -S-, -NR4-or-CH2-；
with the proviso that at least two ring members of ring E are independently heteroatoms；
R is-NR3R2, C2-4 alkenyl, C2-4 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C2-10 heterocyclyl-C1-4-alkyl, C1-6 alkyl-S (＝O) t-, C1-6 alkoxy-C1-6-alkyl, hydroxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, amino-C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylamino-C1-4-haloalkoxy, C1-4 alkylamino-C1-4-alkoxy, C1-4 alkoxy-C1-4-alkoxy, C3-10 cycloalkyloxy, C6-10 aryl-C1-4-alkoxy, C6-10 aryl-C1-4-alkylamino, C1-9 heteroaryl-C1-4-alkoxy, C1-9 heteroaryl-C1-4-alkylamino, C2-10 heterocyclyl-C1-4-alkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylamino, C2-10 heterocyclyl-C1-4-alkoxy, C3-10 carbocyclyl-C1-4-alkoxy, C3-10  carbocyclyl-C1-4-alkylamino, C6-10 aryloxy-C1-4-alkoxy, C6-10 aryloxy, C1-9 heteroaryloxy, C1-9 heteroaryloxy-C1-4-alkoxy, C2-10 heterocyclyloxy-C1-4-alkoxy, C3-10 carbocyclyloxy-C1-4-alkoxy, C2-10 heterocyclyloxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl, C6-10 aryl, C6-10 aryl-C1-6-alkyl, C1-9 heteroaryl-C1-6-alkyl or C1-9 heteroaryl, or R is
Figure PCTCN2014087469-appb-000039
wherein each X8, X9 and X10 is independently N or CH；
each X1, X2, X3, X4, X5, X6 and X7 is independently -CH2-, -O-, -NR4a-, -S (＝O) t-or-S-；
each q, m, p, r and s is independently 0, 1, 2, 3 or 4；
each of R2 and R3 is independently C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl；
each of R4a and R4 is independently hydrogen, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and provided that:
when ring E is
Figure PCTCN2014087469-appb-000040
Figure PCTCN2014087469-appb-000041
Figure PCTCN2014087469-appb-000042
wherein each of ring E and R is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, amino, methyl-C (＝O) -NH-, oxo (＝O) , C1-4 alkyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
In some embodiments, ring E is
Figure PCTCN2014087469-appb-000043
R is-NR3R2, C2-4 alkenyl, C2-4 alkynyl, C2-10 heterocyclyl-C1-4-alkyl, C1-6 alkyl-S (＝O) t-, C1-4 alkoxy-C1-4 alkyl, hydroxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, amino-C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylamino-C1-4-haloalkoxy, C1-4 alkylamino-C1-4-alkoxy, C1-4 alkoxy-C1-4-alkoxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl or C1-9 heteroaryl-C1-6-alkyl, or R is
Figure PCTCN2014087469-appb-000045
Figure PCTCN2014087469-appb-000046
each of R2 and R3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； andprovided that:
when ring E is
Figure PCTCN2014087469-appb-000047
Figure PCTCN2014087469-appb-000048
Figure PCTCN2014087469-appb-000049
Figure PCTCN2014087469-appb-000050
wherein each of ring E and R is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxy, cyano, nitro, oxo (＝O) , methyl-C (＝O) -, ethyl-C (＝O) -, (n-propyl) -C (＝O) -, isopropyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
In some embodiments, G is-O-or furylene.
In some embodiments, ring K is a group selected from the following:
Figure PCTCN2014087469-appb-000051
wherein each U is independently -CH2-, -O-, -NR4-or-S-；
each V, V1 and V2 is independently CH or N；
with the proviso that at least two ring members of ring K are independently heteroatoms；
R4 is hydrogen, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and
each L is independently amino, nitro, C1-4 alkylthio, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-4 haloalkyl, C1-4 alkylamino, hydroxy, fluoro, chloro, bromo, iodo, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or cyano.
In some embodiments, ring K is a group selected from the following:
Figure PCTCN2014087469-appb-000052
each L is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3-6 heterocycloalkyl, amino, cyano, nitro, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, methyl, ethyl, butyl, n-propyl, isopropyl, tert-butyl, C1-4 alkylamino, hydroxy, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio.
In some embodiments, the compound disclosed herein has formula (II) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2014087469-appb-000053
wherein
each of Q and W is independently CH or N；
each R1 is independently hydrogen, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-6 alkyl-S (＝O) t-, C1-6 alkoxy-C1-6-alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio；
each L is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3-6 heterocycloalkyl, amino, cyano, nitro, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, methyl, ethyl, butyl, n-propyl, isopropyl, tert-butyl, C1-4 alkylamino, hydroxy, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio；
each of d and n is independently 1, 2, 3 or 4；
each t is independently 0, 1 or 2；
a is 0, 1, 2, 3 or 4；
ring E is
Figure PCTCN2014087469-appb-000054
R is-NR3R2, C2-4 alkenyl, C2-4 alkynyl, C2-10 heterocyclyl-C1-4-alkyl, C1-6 alkyl-S (＝O) t-, C1-4 alkoxy-C1-4-alkyl, hydroxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, amino-C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylamino-C1-4-haloalkoxy, C1-4 alkylamino-C1-4-alkoxy, C1-4 alkoxy-C1-4-alkoxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl or C1-9 heteroaryl-C1-6-alkyl, or R is
Figure PCTCN2014087469-appb-000055
Figure PCTCN2014087469-appb-000056
Figure PCTCN2014087469-appb-000057
each of R2 and R3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and provided that: 
when ring E is
Figure PCTCN2014087469-appb-000058
Figure PCTCN2014087469-appb-000059
Figure PCTCN2014087469-appb-000060
wherein each of ring E and R is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxy, cyano, nitro, oxo (＝O) , methyl-C (＝O) -, ethyl-C (＝O) -, (n-propyl) -C (＝O) -, isopropyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
In some embodiments, the compound disclosed herein has formula (III) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2014087469-appb-000061
wherein each of X, Y, Z, Z1, Z2, Z3 and Z4 is independently N or CH；
with the proviso that at least two of X, Y, Z, Z1, Z2, Z3 and Z4 are independently heteroatoms； and each R1, a, n and R is independently as defined herein.
In some embodiments, provided herein is a substituted urea derivative having one of the following structures,
Figure PCTCN2014087469-appb-000062
Figure PCTCN2014087469-appb-000063
Figure PCTCN2014087469-appb-000064
Figure PCTCN2014087469-appb-000065
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof.
In another aspect, provided herein is a pharmaceutical composition comprising the compound disclosed herein.
In some embodiments, the pharmaceutical composition disclosed herein further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or the combination thereof.
In other embodiments, the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent, wherein the additional therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-inflammatory agent, an immunosuppressant, an immunostimulant, an agent for  treating atherosclerosis, an agent for treating pulmonary fibrosis or a combination thereof.
In other embodiments, the additional therapeutic agent disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab or a combination thereof.
In another aspect, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
In another aspect, provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient comprising administrating a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein to the patient.
In another aspect, provided herein is the compound or the pharmaceutical composition disclosed herein for use in preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
In other embodiments, the proliferative disease disclosed herein is acute myelogenous leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute lymphocytic leukemia (ALL) , colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, CNS (central nervous system) cancer, malignant glioma or bone marrow hyperplasia, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic diseases, cryoglobulinemia, non-lymphoreticular system tumor, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia, semi-molecular disease, monocytic leukemia, primary macroglobulinemia purpura, secondary benign  monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin’s lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis, Hodgkin’s lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyp, small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterine cancer, ovarian cancer, head and neck squamous cell carcinoma, alimentary canal malignancy, non-small cell lung cancer, cervical cancer, testiculoma, bladder cancer or myeloma.
In other embodiments, the autoimmune disease disclosed herein is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, I-type diabetes, sarcoidosis, inflammatory bowel disease, Crohn’s disease or systemic lupus.
In other embodiments, the inflammatory disease disclosed herein is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
In other embodiments, the disease is mediated by FLT3 kinase or caused by FLT3-ITD.
In another aspect, provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, wherein the method comprise administering to the patient a therapeutically effective amount of the compound disclosed herein.
In another aspect, provided herein is a method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient, wherein the method comprise administering to the patient a therapeutically effective amount of the pharmaceutical composition containing the compound disclosed herein.
In another aspect, provided herein is use of the compound disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
In another aspect, provided herein is use of the compound of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of FLT3 mediated diseases, wherein the use comprise administering a therapeutically effective amount of the compound of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutically acceptable salts, isomers, solvates, hydrates or prodrugs thereof.
In another aspect, the compounds and the compositions provided herein are effective to modulate the activity of the AbI protein tyrosine family.
In some embodiments, the compounds and the compositions provided herein are effective to modulate the activity of the fms-like tyrosine kinase 3 receptor kinase (FLT-3 kinase) .
In some embodiments, the compounds and the compositions provided herein are effective to inhibit the mutation of the fms-like tyrosine kinase 3 receptor kinase (FLT-3-ITD) .
In some embodiments, the compounds and the compositions provided herein are effective to modulate  the activity of the Src subfamily, which includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk.
In some embodiments, the compounds and the compositions provided herein are effective to modulate the activity of one or more kinases selected from the group consisting of sterile 20, sterile 11, sterile, the camk subfamily (calmodulin regulated kinases and related kinases) , the AGC subfamily (protein kinase A, protein kinase G and protein kinase C) , the CMGC subfamily (cdk, map kinase, glycogen synthetase kinase and clk) , the sterile 20 subfamily, Frk, Btk, Csk, AbI, Zap70, Fes, Fps, Fak, Jak and Ack (and their respective subfamilies) .
In other embodiments, provided herein are methods of using the disclosed compounds and compositions, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, for the local or systemic treatment or prophylaxis of human and veterinary diseases, disorders and conditions modulated or otherwise affected mediated via kinase activity.
Unless otherwise stated, all stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds disclosed herein are within the scope of the invention. In certain embodiments, the salt is a pharmaceutically acceptable salt. The phrase “pharmaceutically acceptable” refers to that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith. The compounds disclosed herein also include salts of the compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I), Formula (II) or Formula (III) , and/or for separating enantiomers of compounds of Formula (I) , Formula (II) or Formula (III) .
If the compound disclosed herein is a base, the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid； a pyranosidyl acid, such as glucuronic acid and galacturonic acid； an alpha-hydroxy acid, such as citric acid and tartaric acid； an amino acid, such as aspartic acid and glutamic acid； an aromatic acid, such as benzoic acid and cinnamic acid； a sulfonic acid, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and the like； or the combination thereof.
If the compound disclosed here in is an acid, the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide, ammonium, N+ (R14) 4 salt or alkaline earth metal hydroxide, and the like. Some non-limiting examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine； ammonia, such as primary, secondary and tertiary amine, N+ (R14) 4 salt, wherein R14 is H, C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4-alkyl, and the like； and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,  aluminum, lithium, and the like, and further include, when appropriate, nontoxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C1-8 sulfonate or aryl sulfonate.
COMPOSITIONS OF COMPOUNDS OF THE INVENTION
According to another aspect, the invention features pharmaceutical compositions that include a compound of Formula (I) , Formula (II) or Formula (III) , a hydrate, a solvate, an isomer, a physiologically/pharmaceutically acceptable salt or a prodrug thereof, a compound listed herein, or a compound named in Examples 1-45, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The compositions disclosed herein can be used in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a disease mediated by protein kinase. The compositions disclosed herein, acting as FLT3 kinase or FLT3-ITD kinase inhibitor, are used for preparation of a medicament.
The pharmaceutical compositions disclosed herein may include a compound of Formula (I) , Formula (II) or Formula (III) , and a pharmaceutically acceptable carrier. The compounds of Formula (I) , Formula (II) or Formula (III) can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds. The pharmaceutical carrier employed can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, water, and the like. Examples of gaseous carriers include carbon dioxide, nitrogen, and the like. Similarly, the carrier or diluent may include any time delay material well known to the art, such as glyceryl monostearate or glyceryl stearate, alone or mixed with a wax.
In another aspect, Some non-limiting examples of materials which can serve as pharmaceutically acceptable carriers include ion exchanger； aluminum； alumina； aluminum stearate； lecithin； serum protein such as human serum albumin； buffer substance such as phosphate； glycine； sorbic acid； potassium sorbate； partial glyceride mixture of saturated vegetable fatty acid； water； electrolyte such as protamine sulfate, disodium hydrogen phosphate and potassium hydrogen phosphate； salt such as sodium chloride and zinc salt； colloidal silica； magnesium trisilicate； polyvinyl pyrrolidone； polyacrylate； waxe； polyethylene-polyoxypropylene-block polymer； wool fat； sugar such as lactose, glucose and sucrose； starch such as corn starch and potato starch； cellulose and its derivative such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate； powdered tragacanth； malt； gelatin； talc； excipients such as cocoa butter and suppository waxes； oil such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil； glycol such as propylene glycol and polyethylene glycol； ester such as ethyl oleate and ethyl laurate； agar； buffering agent such as magnesium hydroxide and aluminum hydroxide； alginic acid； pyrogen-free water； isotonic saline； Ringer’s solution； ethyl alcohol and phosphate buffer solution, as well as other non-toxic compatible lubricant such as sodium lauryl sulfate and magnesium stearate, coloring agent, releasing agent, coating agent, sweetening, flavoring and perfuming agent, preservative and antioxidant. For convenience, topical anesthetic, preservative  and buffer, etc. , can be directly dissolved in the carriers.
USES OF THE COMPOUNDS AND COMPOSITIONS OF THE INVENTION
The compounds of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutical compositions thereof disclosed herein are useful in treating conditions characterized by inappropriate FLT3 activity such as proliferative disorders. FLT3 activity increase includes, but is not limited to, enhanced FLT3 activity resulting from increased or denovo expression of FLT3 in cells, increased FLT3 expression or activity, and FLT3 mutations resulting in constitutive activation. The existence of inappropriate or abnormal FLT3 ligand and FLT3 levels or activity can be determined using well-known methods in the art. For example, abnormally high FLT3 levels can be determined using commercially available ELISA kits. FLT3 levels can also be determined using flow cytometric analysis, immunohistochemical analysis and in situ hybridization techniques.
An inappropriate activation of FLT3 can be determined by an increase in one or more of the activities occurring subsequent to FLT3 binding: (1) phosphorylation or autophosphorylation of FLT3； (2) phosphorylation of FLT3 substrates such as Stat5 and Ras； (3) activation of related complexes such as PI3K； (4) activation of adaptor molecules； and (5) cell proliferation. These activities can be readily measured by well-known methods in the art.
The compounds of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutical compositions thereof disclosed herein are useful in, but not limited to, preventing or treating of proliferative diseases, conditions, or disorders in a patient by administering to the patient the compound of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutical composition thereof disclosed herein in an effective amount. Such diseases, conditions, or disorders include cancer, particularly hematopoietic cancer, metastatic cancer, atherosclerosis, and lung fibrosis.
The compounds or the pharmaceutical compositions thereof disclosed herein are useful for the treatment of neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer of bladder, breast, colon, kidney, liver, lung (including small cell lung cancer) , esophageal, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma) ； hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell leukemia and Burkett’s lymphoma； hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia； tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e. g. , soft tissue and bone； tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannomas； and other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma , thyroid follicular cancer and Kaposi’s sarcoma.
The compounds or the pharmaceutical compositions thereof disclosed herein are also useful for the treatment of FLT3 mediated, FLT3-ITD mediated and/or CSF-1R mediated diseases like autoimmune diseases,  kidney diseases, tissue transplant rejection, lupus erythematosis, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, arthritis, asthma, and the like.
The compounds or the pharmaceutical compositions thereof disclosed herein are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy.
The compounds or the pharmaceutical compositions thereof disclosed herein are also useful in the reduction of blood flow in a tumor.
The compounds or the pharmaceutical compositions thereof disclosed herein are also useful in the reduction of metastasis of a tumor.
Besides being useful for human treatment, these compounds or the pharmaceutical compositions are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. In other embodiments, animals include horses, dogs and cats. As used herein, the compounds of Formula (I) , Formula (II) or Formula (III) disclosed herein include the pharmaceutically acceptable derivatives thereof.
The compounds or the pharmaceutical compositions thereof disclosed herein are also useful for inhibiting the growth of a cell that expresses VEGFR or c-Met, which includes contacting the cell with a compound or composition disclosed herein. Examples of a cell whose growth can be inhibited include: a breast cancer cell, a colorectal cancer cell, a lung cancer cell, a papillary carcinoma cell, a prostate cancer cell, a lymphoma cell, a colon cancer cell, a pancreatic cancer cell, an ovarian cancer cell, a cervical cancer cell, a central nervous system cancer cell, an osteogenic sarcoma cell, a renal carcinoma cell, a hepatocellular carcinoma cell, a bladder cancer cell, a gastric carcinoma cell, a head and neck squamous carcinoma cell, a melanoma cell or a leukemia cell.
The compounds or the pharmaceutical compositions thereof disclosed herein are also useful for inhibiting VEGFR and/or c-Met kinase activity in a biological sample, which includes contacting the biological sample with a compound or composition disclosed herein. The term “biological sample” as used herein, means a sample outside a living organism and includes, without limitation, cell cultures or extracts thereof； biopsied materials obtained from a mammal or extracts thereof； and blood, saliva, urine, feces, semen, tears, or other body liquids or extracts thereof. Inhibition of kinase activity, particularly VEGFR or c-Met kinase activity, in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage and biological assays.
ADMINISTRATION OF THE COMPOUNDS AND COMPOSITIONS OF THE INVENTION
Where the plural form is used for compounds, salts, pharmaceutical compositions thereof, and the like, this is taken to refer to also a single compound, salt, pharmaceutical composition thereof, and the like.
The treatment method that includes administering a compound or composition disclosed herein can further include administering to the patient an additional therapeutic agent (combination therapy) selected from:  a chemotherapeutic or anti-proliferative agent, or an anti-inflammatory agent, wherein the additional therapeutic agent is appropriate for the disease being treated and the additional therapeutic agent is administered together with a compound or composition disclosed herein as a single dosage form or separately from the compound or composition as part of a multiple dosage form. The additional therapeutic agent may be administered at the same time as the compound disclosed herein or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
Typically a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-100 μg/ml. The pharmaceutical compositions disclosed herein should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg, and in some embodiments, from about 10 mg to about 500 mg, from about 20 mg to about 250 mg or from about 25 mg to about 100 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form. In some embodiments, pharmaceutical dosage unit forms are prepared to provide about 1 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the essential active ingredient. In some embodiments, pharmaceutical dosage unit forms are prepared to provide about 50 mg of the essential active ingredient.
The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is also to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
An “effective amount” or “effective dose” is that amount effective for treating or lessening the severity of one or more of the aforementioned disorders. The compounds and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and the general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. A compound or composition can also be administered with one or more other therapeutic agents, as discussed above.
The compounds or the pharmaceutical compositions thereof disclosed herein may also be used for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury) . However, patients using stents or other implantable devices risk clot formation or platelet activation.  These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound disclosed herein.
When administered to a patient for the treatment of cancer, the dosage used can be varied depending upon the type of cancer, the age and general condition of the patient, the particular compound administered, the presence or level of toxicity or adverse effects experienced with the drug, and other factors. A representative example of a suitable dosage range is from as low as about 0.01 mg/kg to as high as about 100 mg/kg. However, the dosage administered is generally left to the discretion of the physician.
The methods of treatment are preferably carried out by delivering the compounds of Formula (I) , Formula (II) or Formula (III) disclosed herein orally or parenterally. The term “parenteral” as used herein includes intravenous, intramuscular or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The invention can also be carried out by delivering the compounds of Formula Formula (I) , Formula (II) or Formula (III) disclosed herein subcutaneously, intranasally, intrarectally, transdermally or intravaginally.
The compounds of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutical compositions disclosed herein may also be administered by inhalation. By “inhalation” is meant intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by convention techniques.
FORMULATIONS AND ADMINISTRATION OF THE COMPOUNDS AND COMPOSITIONS OF THE INVENTION
The compounds of Formula (I) , Formula (II) or Formula (III) , or the pharmaceutical compositions disclosed herein can be employed to prepare a wide variety of pharmaceutical dosage forms. If a solid dosage is used for oral administration, the preparation can be in the form of a tablet, hard gelatin capsule, lozenge, troche, drop, lotion, and the like. The amount of solid carrier will vary widely, but generally will be from about 0.025 mg to about 1 g. When a liquid dosage form is desired for oral administration, the preparation is typically in the form of a syrup, emulsion, soft gelatin capsule, suspension or solution. When a parenteral dosage form is to be employed, the drug may be in solid or liquid form, and may be formulated for administration directly or may be suitable for reconstitution. Topical dosage forms are also included. Examples of topical dosage forms are solids, liquids and semi-solids. Solids would include dusting powders, poultices, and the like. Liquids include solutions, suspensions and emulsions. Semi-solids include creams, ointments, gels, and the like.
The amount of a compound of Formula (I) , Formula (II) or Formula (III) , or a pharmaceutical composition disclosed herein used topically will, of course, vary with the compound chosen, the nature and severity of the condition, and can be varied in accordance with the discretion of the physician. A representative, topical dose of a compound of Formula (I) , Formula (II) or Formula (III) is from as low as about 0.01 mg to as high as about 2.0 g, administered one to four, preferably one to two times daily. The active ingredient may comprise, for topical administration, from about 0.001 ％to about 10％w/w. 
Drops according to the invention may comprise sterile or non-sterile aqueous or oil solutions or suspensions, and may be prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100℃ for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container aseptically. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002％) , benzalkonium chloride (0.01％) and chlorhexidine acetate (0.01％) . Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
Lotions according to the invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis.
Creams, ointments or pastes according to the invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous liquid, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap； a mucilage； an oil of natural origin such as almond, com, arachis, castor or olive oil； wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicas, and other ingredients such as lanolin may also be included.
The compounds or the pharmaceutical compositions disclosed herein can also be administered in the form of coating, and suitable coated implantable devices are known in the art. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. The compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a “drug depot” thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.
GENERAL SYNTHETIC PROCEDURES
Generally, the compounds disclosed herein may be prepared by methods described herein, wherein the  substituents are as defined for Formula (I) , Formula (II) or Formula (III) above, except where further noted. The following non-limiting schemes and examples are presented to further exemplify the invention.
Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are deemed to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e. g. , by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds disclosed herein.
In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd. , Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd. , Qingdao Tenglong Reagent Chemical Ltd. , and Qingdao Ocean Chemical Factory.
Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium. Anhydrous CH2Cl2 and CHCl3 were obtained by refluxing the solvent with CaH2. EtOAc, PE, hexane, DMAC and DMF were treated with anhydrous Na2SO4 prior to use.
The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
Column chromatography was conducted using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. 1H NMR spectra were obtained by using CDCl3, d6-DMSO, CD3OD or d6-acetone solutions (reported in ppm) , with TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities were reported, the following abbreviations were used: s (singlet) , d (doublet) , t (triplet) , m (multiplet) , br (broadened) , dd (doublet of doublets) , and dt (doublet of triplets) . Coupling constants, when given, were reported in Hertz (Hz) .
Low-resolution mass spectral (MS) data were determined by an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column was operated at 30 ℃) . G1329A autosampler and G1315B DAD detector were applied in the analysis, and an ESI source was used in the LC-MS spectrometer.
Low-resolution mass spectral (MS) data were determined by an Agilent 6120 Series LC-MS  spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column was operated at 30 ℃) . G1329A autosampler and G1315D DAD detector were applied in the analysis, and an ESI source was used on the LC-MS spectrometer.
Both LC-MS spectrometers described above were equipped with Agilent Zorbax SB-C18 (2.1 x 30 mm, 5 μm column) . Injection volume was decided by the sample concentration. The flow rate was 0.6 mL/min. The HPLC peaks were recorded by UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was 0.1％formic acid in acetonitrile (phase A) and 0.1％formic acid in ultrapure water (phase B) . The gradient elution conditions were showed in Table 1:
Table 1
Time (min) A (CH3CN, 0.1％HCOOH) B (H2O, 0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Purities of compounds were assessed by Agilent 1100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C18, 2.1 x 30 mm, 4 micron) . The run time was 10 min, and the flow rate was 0.6 mL/min. The elution was performed with a gradient of 5 to 95％phase A (0.1％formic acid in CH3CN) in phase B (0.1％formic acid in H2O) . Column was operated at 40 ℃.
The following abbreviations are used throughout the specification:
BOC, Boc   tert-butoxycarbonyl
CHCl3    chloroform
CDC13   deuterated chloroform
DMF   N, N-dimethylformamide
DMAP   4-dimethylaminopyridine
DMSO   dimethyl sulfoxide
EDC, EDCI   1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
EtOAc   ethyl acetate
HCl   hydrochloric acid
H2   hydrogen
H2O2   hydrogen peroxide
Fe   iron
MeOH, CH3OH   methanol
CH2Cl2, DCM   dichloromethane
mL, ml   milliliter 
N2   nitrogen
Pd/C   palladium on carbon
PE   petroleum ether (60 -90 ℃)
RT, rt   room temperature
Rt   retention time
NaHCO3   sodium bicarbonate
Na2SO4   sodium sulfate
THF   tetrahydrofuran
Et3N, TEA   triethylamine
TFA   trifluoroacetic acid
NBS   N-bromo butanediimide
H2O   water
General Procedures for the Synthesis of Intermediates
Synthesis of intermediate 2
Figure PCTCN2014087469-appb-000066
Compound 2 can be prepared by the following two methods, wherein each R and n is as defined herein. Method one: compound 1A can react with compound 2A to form compound 3A in the presence of a base, and then compound 3A can be converted to compound 2 by chlorination. Method two: compound 1A can react with compound 4A to afford compound 2 in the presence of a base.
Synthesis of intermediate 8A
Figure PCTCN2014087469-appb-000067
Compound 8A can be prepared by the following method. Compound 5A can react with compound 6A to form compound 7A in the presence of a base, and compound 7A can be then converted to compound 8A by deprotection.
General Procedures for the Synthesis of Compounds
Scheme 1
Figure PCTCN2014087469-appb-000068
Compound 6 can be prepared by the process illustrated in Scheme 1, wherein each R1, a, R, E, G and n is as defined herein. Compound 1 can react with compound 2 to form compound 3 in the presence of a base. Compound 3 can be then converted to compound 4 by reduction reaction. Reaction of compound 4 with compound 5 can afford the objective compound 6.
Scheme 2
Figure PCTCN2014087469-appb-000069
Compound 6 can be prepared by the process illustrated in Scheme 2, wherein each R1, a, R, E, G and n is as defined herein. Reaction of compound 4 with compound 7 can afford the objective compound 6.
Scheme 3
Figure PCTCN2014087469-appb-000070
Compound 6 can be prepared by the process illustrated in Scheme 3, wherein each R1, a, R, E, G and n is as defined herein. Compound 1 can react with compound 2a to form compound 3a in the presence of a base. The hydroxy group of compound 3a can be protected to give compound 8, and Compound 8 can be then converted to compound 4 by reduction reaction. Reaction of compound 4 with compound 5 can afford the  objective compound 6.
The following examples disclosed herein are presented to further describe the invention. However, these examples should not be used to limit the scope of the invention.
EXAMPLES
Example 1
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (7- (2- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
Figure PCTCN2014087469-appb-000071
Step 1) 2- ( (4aS, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethanol
To a solution of (4aS, 7aS) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (2.15 g, 16.64 mmol) in ethanol (30 mL) were added 2-chloroethanol (1.22 g, 15.15 mmol) and potassium carbonate (2.75 g, 19.93 mmol) in turn. Then the reaction mixture was refluxed overnight. The resulting mixture was filtered to remove solid and the filtrate was concentrated in vacuo. The residue was confirmed correctly and then used directly in the next step. The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 174.1 [M+1] +.
Step 2) (4aS, 7aS) -6- (2-chloroethyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
To a solution of 2- ( (4aS, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethanol (2.87 g, 16.57 mmol) in toluene (40 mL) was added thionyl chloride (1.8 mL) dropwise at 0 ℃, then the reaction mixture was heated to 80 ℃ and stirred for 2.0 hours. The resulting mixture was cooled to rt, adjusted the pH to neutral with saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane (200 mL x 3) . The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was confirmed by LC-MS and then used directly in the next step. The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 192.1 [M+1] +.
Step 3) (4aR, 7aR) -6- (2- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) ethyl) hexahydro-2H- [1, 4] -dioxino [2, 3-c] pyrrole
A mixture of 2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-ol (1.79 g, 5.75 mmol) (process for the specific synthesis of 2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-ol linked WO 2007109120) , (4aS, 7aS) -6- (2-chloroethyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (2.2 g, 11.48 mmol) , potassium carbonate (2.38 g, 17.25 mmol) and tetrabutylammonium iodide (0.42 g, 1.14 mmol) in DMF (40 mL) was refluxed for 6.0 hours, and then poured into water (350 mL) . The resulting mixture was stirred at rt for 1.0 hour and then filtered. The filter cake was dried under vacuum to give the title compound as a yellow solid (2.74 g, >100％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 467.1  [M+1] +.
Step 4) 4- (7- (2- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethoxy) benzo [d] imidazo [2, 1-b] -thiazol-2-yl) aniline
A mixture of (4aR, 7aR) -6- (2- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) ethyl) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (2.67 g, 5.72 mmol) , zinc powder (3.75 g, 57.69 mmol) and ammonium chloride (1.23 g, 22.96 mmol) in a mixture of ethanol and water (v/v ＝ 9/2, 55 mL) was refluxed for 4.0 hours, and then filtered to remove solid. The filtrate was concentrated in vacuo. The residue was diluted with dichloromethane (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL) . The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (1.34 g, 54％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 437.3 [M+1] +.
Step 5) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (2- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) -ethoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
To a solution of 4- (7- (2- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethoxy) -benzo [d] imidazo [2, 1-b] thiazol-2-yl) aniline (1.34 g, 3.07 mmol) in anhydrous dichloromethane (12 mL) were added phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (0.89 g, 34.19 mmol) , DMAP (22 mg, 0.18 mmol) and triethylamine (0.2 mL) with stirring. The reaction mixture was refluxed overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝20/1) , triturated with dichloromethane (10 mL) and then filtered to give the title compound as a white solid (551 mg, 30％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 603.4 [M+1] + and 1H NMR (400 MHz, d-DMSO) δ (ppm) : 9.53 (s, 1H) , 8.89 (s, 1H) , 8.60 (s, 1H) , 7.87 (d, J＝9.2 Hz, 1H), 7.78 (d, J＝8.4 Hz, 2H) , 7.67 (d, J＝2.4 Hz, 1H) , 7.51 (d, J＝8.8 Hz, 2H) , 7.14-7.16 (dd, J＝2.4, 8.8 Hz, 1H), 6.52 (s, 1H) , 4.10-4.07 (t, J＝6.0 Hz, 2H) , 3.78-3.76 (d, J＝8.0 Hz, 2H) , 3.66-3.64 (d, J＝8.4 Hz, 2H) , 3.36-3.35 (m, 2H) , 2.99-2.96 (m, 4H) , 2.69-2.64 (t, J＝9.2 Hz, 2H) , 1.30 (s, 9H) .
Example 2
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (7- (2- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethoxy) b enzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
Figure PCTCN2014087469-appb-000072
Step 1) 2- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethanol
To a solution of (4aR, 7aS) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (2.35 g, 18.19 mmol) in ethanol (30 mL) were added 2-chloroethanol (1.35 mL, 20.14 mmol) and potassium carbonate (3.02 g, 21.88 mmol) , then the reaction mixture was refluxed overnight. The resulting mixture was filtered to remove solid and the  filtrate was concentrated in vacuo to give the title compound which was used directly in the next step. The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 174.1 [M+1] +.
Step 2) (4aR, 7aS) -6- (2-chloroethyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
The title compound was prepared by the procedure described in step 2 of example 1, using 2- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethanol (3.15 g, 18.19 mmol) and thionyl chloride (1.98 mL) to give the title compound as deep yellow liquid, which was used directly in the next step. The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 192.1 [M+1] +.
Step 3) (4aR, 7aS) -6- (2- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) ethyl) hexahydro-2H- [1, 4] -dioxino [2, 3-c] pyrrole
The title compound was prepared by the procedure described in step 3 of example 1, using 2-(4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-ol (1.71 g, 5.49 mmol) , (4aR, 7aS) -6- (2-chloroethyl) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (2.1 g, 10.96 mmol) , potassium carbonate (2.27 g, 16.43 mmol) and tetrabutylammonium iodide (0.41 g, 1.1 mmol) to give the title compound as a yellow solid (4.0 g, >100％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 467.3 [M+1] +.
Step 4) 4- (7- (2- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethoxy) benzo [d] imidazo [2, 1-b] -thiazol-2-yl) aniline
The title compound was prepared by the procedure described in step 4 of example 1, using (4aR, 7aS) -6- (2- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) ethyl) hexahydro-2H- [1, 4] dioxino [2, 3 -c]pyrrole (2.56 g, 5.49 mmol) , zinc powder (3.58 g, 55.08 mmol) and ammonium chloride (1.17 g, 22.03 mmol) to give the title compound as a brown solid (2.09 g, 87％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 437.2 [M+1] +.
Step 5) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (2- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) -ethoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
The title compound was prepared by the procedure described in step 5 of example 1, using 4- (7- (2- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) ethoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl ) aniline (0.6 g, 1.37 mmol) , phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (0.39 g, 15.12 mmol) (process for the specific synthesis of phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate linked WO 2007109120) , DMAP (0.01 g, 0.08 mmol) and a mixture of triethylamine (0.02 g, 0.21 mmol) in dichloromethane (0.1 mL) to give the title compound as a white solid (578 mg, 51％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 603.3 [M+1] + and 1H NMR (400 MHz, d-DMSO) δ (ppm) : 9.55 (s, 1H) , 8.89 (s, 1H) , 8.59 (s, 1H) , 7.85 (d, J＝8.8 Hz, 1H) , 7.78 (d, J＝8.0 Hz, 2H) , 7.66 (s, 1H) , 7.51 (d, J＝8.4 Hz, 2H) , 7.14 (d, J＝8.8 Hz, 1H) , 6.52 (s, 1H) , 4.10-4.07 (t, J＝5.6 Hz, 2H) , 3.99 (s, 2H) , 3.70-3.67 (t, J＝5.2 Hz, 2H) ,  2.92-2.88 (m, 4H) , 2.81-2.77 (m, 2H) , 1.30 (s, 9H) .
Example 3
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (7- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy ) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
Figure PCTCN2014087469-appb-000073
Step 1) (4aR, 7aS) -6- (3-chloropropyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
A mixture of (4aR, 7aS) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (3.5 g, 27.10 mmol) , 1-bromo-3-chloropropane (4.69 g, 25.98 mmol) and potassium carbonate (9.36 g, 67.83 mmol) in acetone (30 mL) was heated to 60 ℃ and stirred for 6.0 hours. The reaction mixture was cooled to rt, poured into water (100 mL) and then extracted with dichloromethane (200 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as claybank liquid (5.6 g, >100％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 206.2 [M+1] +.
Step 2) (4aR, 7aS) -6- (3- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) propyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
The title compound was prepared by the procedure described in step 3 of example 1, using 2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-ol (0.73 g, 2.34 mmol) , (4aR, 7aS) -6- (3-chloropropyl) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (0.96 g, 4.67 mmol) , potassium carbonate (0.97 g, 7.03 mmol) and tetrabutylammonium iodide (0.17 g, 0.46 mmol) to give the title compound as a yellow solid (1.1 g, 100％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 481.1 [M+1] +.
Step 3) 4- (7- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] -thiazol-2-yl) aniline
The title compound was prepared by the procedure described in step 4 of example 1, using (4aR, 7aS) -6- (3- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) propyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (1.1 g, 2.29 mmol) , iron powder (1.29 g, 23.04 mmol) and ammonium chloride (0.5 g, 9.34 mmol) to give the title compound as a khaki solid (0.84 g, 80％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 451.3 [M+1] +.
Step 4) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
The title compound was prepared by the procedure described in step 5 of example 1, using  4- (7- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) aniline (0.84 g, 1.86 mmol) , 5-tert-butyl-3-isoxazolyl isocyanate (0.37 g, 2.24 mmol) to give the title compound as a white solid (155 mg, 14％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 617.4 [M+1] + and 1H NMR (400 MHz, d-DMSO) δ (ppm) : 9.54 (s, 1H) , 8.91 (s, 1H) , 8.58 (s, 1H) , 7.85 (d, J＝8.4 Hz, 1H) , 7.78 (d, J＝8.8 Hz, 2H) , 7.64 (d, J＝2.0 Hz, 1H) , 7.50 (d, J＝8.8 Hz, 2H) , 4.08-4.05 (t, J＝6.0 Hz, 2H) , 3.98 (s, 2H) , 3.70-3.60 (m, 4H) , 2.68-2.66 (t, J＝4.0 Hz, 2H) , 2.62-2.59 (m, 4H) , 1.89-1.85 (t, J＝6.8 Hz, 2H) , 1.29 (s, 9H) .
Example 4
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (7- (3- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy )benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
Figure PCTCN2014087469-appb-000074
Step 1) (4aR, 7aR) -6- (3-chloropropyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole
The title compound was prepared by the procedure described in step 1 of example 3, using (4aR, 7aR) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (3.5 g, 27.10 mmol) and 1-bromo-3-chloropropane (4.69 g, 25.98 mmol) to give the title compound as deep yellow liquid (5.7 g, >100％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 206.2 [M+1] +.
Step 2) (4aR, 7aR) -6- (3- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) propyl) hexahydro-2H-[1,4] dioxino [2, 3-c] pyrrole
The title compound was prepared by the procedure described in step 3 of example 1, using 2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-ol (1.48 g, 4.75 mmol) , (4aR, 7aR) -6- (3-chloropropyl) -hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrrole (1.95 g, 9.48 mmol) , potassium carbonate (1.97 g, 14.72 mmol) and tetrabutylammonium iodide (0.35 g, 0.94 mmol) to give the title compound as a yellow solid (2.28 g, 100％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 481.1 [M+1] +.
Step 3) 4- (7- (3- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] -thiazol-2-yl) aniline
The title compound was prepared by the procedure described in step 4 of example 1, using (4aR, 7aR) -6- (3- ( (2- (4-nitrophenyl) benzo [d] imidazo [2, 1-b] thiazol-7-yl) oxy) propyl) hexahydro-2H- [1, 4] dioxino [2 ,3-c] pyrrole (2.28 g, 4.75 mmol) , iron powder (2.62 g, 46.78 mmol) and ammonium chloride (1.01 g, 18.89 mmol) to give the title compound as a khaki solid (2.1 g, 100％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 451.3 [M+1] +.
Step 4)  1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (3- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) benzo [d] imidazo [2, 1-b] thiazol-2-yl) phenyl) urea
A mixture of 4- (7- (3- ( (4aR, 7aR) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) -benzo [d] imidazo [2, 1-b] thiazol-2-yl) aniline (1.2 g, 2.66 mmol) and 5-tert-butyl-3-isoxazolyl isocyanate (0.53 g, 3.19 mmol) in toluene (18 mL) and DMF (10 mL) was refluxed at 90 ℃ overnight, and then the reaction mixture was cooled. The resulting mixture was diluted with dichloromethane (100 mL) , methanol (1 mL) and saturated aqueous sodium bicarbonate solution (50 mL) . The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝20/1) , refluxed with methanol (5 mL) and then filtered at high temperature to give the title compound as a white solid (346 mg, 21％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 617.4 [M+1] + and 1H NMR (400 MHz, d-DMSO) δ (ppm) : 9.68 (s, 1H) , 9.27 (s, 1H) , 8.60 (s, 1H), 7.87 (d, J＝8.8 Hz, 1H) , 7.78 (d, J＝8.4 Hz, 2H) , 7.65 (d, J＝2.4 Hz, 1H) , 7.52 (d, J＝8.8 Hz, 2H) , 7.13 (d, J＝2.4, 8.8 Hz, 1H) , 6.53 (s, 1H) , 4.12-4.09 (t, J＝6.0 Hz, 2H) , 3.84 (d, J＝8.8 Hz, 2H) , 3.69-3.67 (m, 5H) , 3.18 (s, 3H) , 3.02 (s, 2H) , 2.07 (s, 2H) , 1.30 (s, 9H) .
Example 5
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-2-yl) phenyl) urea
Figure PCTCN2014087469-appb-000075
Step 1) 6-methoxy-2- (4-nitrophenyl) imidazo [1, 2-b] pyridazine
To a solution of 3-amino-6-methoxypyridazine (250 mg, 2.0 mmol) in acetonitrile (50 mL) was added 2-bromo-4’-nitroacetophenone (970 mg, 3.99 mmol) , and then the reaction mixture was refluxed for 5.0 hours. The resulting mixture was filtered and the filter cake was dried under vacuum to give the title product (408 mg, 75.7％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 271.2 [M+1] +.
Step 2) 2- (4-nitrophenyl) imidazo [1, 2-b] pyridazin-6-ol
A mixture of 6-methoxy-2- (4-nitrophenyl) imidazo [1, 2-b] pyridazine (540 mg, 2.0 mmol) and pyridine hydrochloride (1.15g, 10.0 mmol) was heated to 150 ℃, while the mixture was molten, and stirred for 5.0 hours. The resulting mixture was diluted with water (100 mL) , extracted with dichloromethane (400 mL) and then washed with saturated aqueous sodium chloride solution (100 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ＝5/1) to give the title compound as a white solid (260 mg, 50.7％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 257.1 [M+1] +.
Step 3) 4- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-b] pyridazin-6-yl) oxy) propyl) morpholine 
To a solution of 2- (4-nitrophenyl) imidazo [1, 2-b] pyridazin-6-ol (256 mg, 1.0 mmol) in acetonitrile (30 mL) were added N- (3-chloropropyl) morpholine (187 mg, 1.14 mmol) and potassium carbonate (430 mg, 3.12 mmol) . The reaction mixture was refluxed for 10.0 hours and then concentrated in vacuo. The residue was diluted with water (50 mL) , extracted with dichloromethane (300 mL) and then washed with saturated aqueous sodium chloride solution (50 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as a white solid (276 mg, 72％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 384.2 [M+1] +.
Step 4) 4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-2-yl) aniline
To a solution of 4- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-b] pyridazin-6-yl) oxy) propyl) morpholine (766 mg, 2.0 mmol) in a mixture of methanol and water (v/v＝3/1, 160 mL) were added ammonium chloride (830 mg, 15.65 mmol) and iron powder (438 mg, 7.83 mmol) . The reaction mixture was heated to 80 ℃ and refluxed for 3.0 hours while the reaction was monitored by TLC. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate solution (100 mL) . The resulting mixture was extracted with ethyl acetate (300 mL) , and washed with water (100 mL) and saturated aqueous sodium chloride solution (50 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as oil (550 mg, 78.3％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 354.3 [M+1] +.
Step 5) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-2-yl) phenyl) urea 
To a solution of 4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-2-yl) aniline (172 mg, 0.5 mmol) in acetonitrile (30 mL) were added triethylamine (0.3 mL, 2.2 mmol) and phenyl (5-(tert-butyl) isoxazol-3-yl) carbamate (0.29 g, 1.1 mmol) in turn. The reaction mixture was refluxed overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as a white solid (50 mg, 19.2％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 520.5 [M+1] + and 1H NMR (400 MHz, d6-DMSO) δ (ppm) : 9.89 (s, 2H) , 8.53 (s, 1H) , 7.98 (d, J＝9.6 Hz, 1H) , 7.90 (d, J＝8.4 Hz, 2H) , 7.53 (d, J＝8.5 Hz, 2H) , 6.85 (d, J＝9.6 Hz, 1H) , 6.54 (s, 1H) , 4.34 (t, J＝6.5 Hz, 2H) , 3.58-3.56 (m, 4H) , 3.43 (t, J＝6.3 Hz, 2H), 2.48-2.39 (m, 4H) , 1.57 (dd, J＝13.1, 6.6 Hz, 2H) , 1.30 (s, 9H) .
Example 6
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (7- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) urea
Figure PCTCN2014087469-appb-000076
Step 1) 7-methoxy-2- (4-nitrophenyl) imidazo [1, 2-a] pyridine
A mixture of 2-amino-4-methoxypyridine (6.21 g, 50.02 mmol) , 2-bromo-4’-nitroacetophenone (6.3 g, 75 mmol) and sodium bicarbonate (6.3 g, 75 mmol) in ethanol (125 mL) was refluxed for 1.0 hour. The reaction mixture was cooled to 0 ℃ and then filtered. The filter cake was washed with a small amount of ethanol and purified by silica gel column chromatography (PE/EtOAc (v/v) ＝3/2) to give a yellow solid (1.84 g, 14％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 270.2 [M+1] +.
Step 2) 2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-7-ol
To a mixture of 7-methoxy-2- (4-nitrophenyl) imidazo [1, 2-a] pyridine (1.84 g, 6.83 mmol) in DCM (300 mL) was added boron tribromide (1.0 mL) dropwise under ice bath cooling. After the reaction mixture was stirred for 0.5 hour under ice-cooling, it was heated to rt and stirred overnight. The reaction was monitored by MS.After the starting material was completely consumed, saturated aqueous sodium bicarbonate solution was added to the reaction mixture until no gas produced. The resulting mixture was stirred for a further 0.5 hour, and then filtered. The filter cake was dried under vacuum to give the title compound as a brown solid (1.48 g, 85％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 256.0 [M+1] +.
Step 3) 4- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-7-yl) oxy) propyl) morpholine
A mixture of 2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-7-ol (1.48 g, 5.80 mmol) , potassium carbonate (2.4 g, 17.39 mmol) , tetrabutylammonium iodide (0.43 g, 1.16 mmol) and 4- (3-chloropropyl) morpholine (2.37 g, 14.48 mmol) in DMF (30 mL) was refluxed for 6.0 hours. After the reaction was finished, the reaction mixture was cooled to rt, and then poured into water (200 mL) . The resulting mixture was stirred at rt for 1.0 hour, filtered and the filter cake was dried under vacuum to give the title compound as a brown solid (1.69 g, 76％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 383.1 [M+1] +.
Step 4) 4- (7- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) aniline
A mixture of 4- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-7-yl) oxy) propyl) morpholine (1.69 g, 4.42 mmol) , zinc powder (2.89 g, 44.46 mmol) and ammonium chloride (0.95 g, 17.68 mmol) in a mixture of ethanol and water (v/v＝15/4, 38 mL) was refluxed for 4.0 hours. The resulting mixture was filtered to remove solid and the filtrate was concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL) . The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (1.48 g, 95％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 353.1 [M+1] +.
Step 5) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) urea
To a solution of 4- (7- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) aniline (0.6 g, 1.70 mmol) in anhydrous dichloromethane (8 mL) were added phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (0.49 g, 1.88 mmol) , DMAP (12 mg, 0.1 mmol) and a mixture of triethylamine (0.035 mL) in dichloromethane (0.1 mL)  dropwise with stirring at rt. The reaction mixture was refluxed overnight, and then filtered. The filter cake was washed with dichloromethane (10 mL) to give the title compound as a white solid (208 mg, 24％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 519.4 [M+1] + and 1H NMR (400 MHz, d6-DMSO) δ (ppm) : 9.55 (s, 1H) , 8.90 (s, 1H) , 8.33 (d, J＝7.2 Hz, 1H) , 8.10 (s, 1H), 7.85 (d, J＝8.8 Hz, 2H) , 7.52 (d, J＝8.8 Hz, 2H) , 6.92 (d, J＝2.0 Hz, 1H) , 6.56-6.58 (dd, J＝2.4, 7.2 Hz, 1H), 6.53 (s, 1H) , 4.08-4.05 (t, J＝6.0 Hz, 2H) , 3.58-3.56 (t, J＝4.4 Hz, 4H) , 2.44-2.40 (t, J＝6.8 Hz, 2H) , 2.36 (s, 4H) , 1.91-1.88 (t, J＝6.8 Hz, 2H) , 1.30 (s, 9H) .
Example 7
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (6- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) urea
Figure PCTCN2014087469-appb-000077
Step 1) 6-methoxy-2- (4-nitrophenyl) imidazo [1, 2-a] pyridine
A mixture of 2-amino-5-methoxypyridine (6.21 g, 50.02 mmol) , 2-bromo-4’-nitroacetophenone (6.3 g, 75 mmol) and sodium bicarbonate (6.3 g, 75 mmol) in ethanol (125 mL) was refluxed for 1.0 hour. The reaction mixture was cooled to 0 ℃ and then filtered. The filter cake was washed with a small amount of ethanol and purified by silica gel column chromatography (PE/EtOAc (v/v) ＝3/2) to give a yellow solid (1.84 g, 14％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 270.2 [M+1] +.
Step 2) 2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-ol
To a mixture of 6-methoxy-2- (4-nitrophenyl) imidazo [1, 2-a] pyridine (1.84 g, 6.83 mmol) in DCM (300 mL) was added boron tribromide (1.0 mL) dropwise under ice bath cooling. After the reaction mixture was stirred for 0.5 hour under ice-cooling, it was heated to rt and stirred overnight. The reaction was monitored by LC-MS. After the starting material was completely consumed, saturated aqueous sodium bicarbonate solution was added to the reaction mixture until no gas produced. The resulting mixture was stirred for a further 0.5 hour, and then filtered. The filter cake was dried under vacuum to give the title compound as a brown solid (1.48 g, 85％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 256.0 [M+1] +.
Step 3) 4- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) propyl) morpholine
A mixture of 2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-ol (0.51 g, 1.99 mmol) , potassium carbonate (0.83 g, 6.01 mmol) , tetrabutylammonium iodide (0.15 g, 0.41 mmol) and 4- (3-chloropropyl) morpholinium chloride (0.8 g, 4 mmol) in DMF (20 mL) was refluxed for 6.0 hours. After the reaction was finished, the reaction mixture was cooled to rt, and then poured into water (200 mL) . The resulting mixture was stirred at rt for 1.0 hour, filtered and the filter cake was dried under vacuum to give the title compound as a brown solid  (0.61 g, 80％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 383.2 [M+1] +.
Step 4) 4- (6- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) aniline
A mixture of 4- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) propyl) morpholine (0.61 g, 1.60 mmol) , zinc powder (1.31 g, 20 mmol) and ammonium chloride (0.5 g, 9.35 mmol) in a mixture of ethanol and water (v/v＝15/4, 40 mL) was refluxed for 4.0 hours. The resulting mixture was filtered to remove solid and the filtrate was concentrated in vacuo. The residue was diluted with dichloromethane (300 mL) and saturated aqueous sodium bicarbonate solution (100 mL) . The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (0.4 g, 70％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 353.2 [M+1] +.
Step 5) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) urea
To a solution of 4- (6- (3-morpholinopropoxy) imidazo [1, 2-a] pyridin-2-yl) aniline (0.4 g, 1.13 mmol) in anhydrous dichloromethane (20 mL) were added phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (1.04 g, 4.0 mmol) , DMAP (20 mg, 0.16 mmol) and triethylamine (0.3 mL) dropwise at rt. The reaction mixture was refluxed overnight, and then filtered. The filter cake was washed with dichloromethane (10 mL) to give the title compound as a white solid (176 mg, 30％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 519.3 [M+1] + and 1H NMR (400 MHz, d-DMSO) δ (ppm) : 9.57 (s, 1H) , 8.93 (s, 1H) , 8.21-8.04 (m, 2H) , 7.88 (d, J＝8.6 Hz, 2H) , 7.55 (d, J＝8.7 Hz, 2H) , 7.45 (d, J＝9.7 Hz, 1H) , 6.98 (dd, J＝9.7, 2.2 Hz, 1H) , 6.55 (s, 1H) , 3.91 (t, J＝6.2 Hz, 2H) , 3.54 (m, 8H) , 2.36 (m, 6H) , 1.94-1.70 (m, 2H) , 1.28 (s, 9H) .
Example 8
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (6- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) urea
Figure PCTCN2014087469-appb-000078
Step 1) 6-methoxy-2- (4-nitrophenyl) imidazo [1, 2-a] pyridine
The title compound was prepared by the procedure described in step 1 of example 6, using 2-amino-5-methoxypyridine (6.21 g, 50.02 mmol) , 2-bromo-4’ -nitroacetophenone (6.3 g, 75 mmol) and sodium bicarbonate (6.3 g, 75 mmol) to give the title compound as a yellow solid (1.84 g, 14％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 270.2 [M+1] +.
Step 2) 2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-ol
The title compound was prepared by the procedure described in step 2 of example 6, using 6-methoxy-2- (4-nitrophenyl) imidazo [1, 2-a] pyridine (1.84 g, 6.83 mmol) and boron tribromide (1.0 mL) to give  the title compound as a brown solid (1.48 g, 85％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 256.0 [M+1] +.
Step 3) (4aR, 7aS) -6- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) propyl) hexahydro-2H-[1,4] dioxino [2, 3-c] pyrrole
The title compound was prepared by the procedure described in step 3 of example 6, using 2-(4-nitrophenyl) imidazo [1, 2-a] pyridin-6-ol (0.51 g, 1.99 mmol) , potassium carbonate (0.83 g, 6.01 mmol) , tetrabutylammonium iodide (0.15 g, 0.41 mmol) and (4aR, 7aS) -6- (3-chloropropyl) hexahydro-2H-[1,4] dioxino [2, 3-c] pyrrole (0.82 g, 3.99 mmol) in DMF (10 mL) to give the title compound as a brown solid (0.7 g, 83％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 425.1 [M+1] +.
Step 4) 4- (6- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) imidazo [1, 2-a] pyridin-2-yl) aniline
The title compound was prepared by the procedure described in step 4 of example 6, using (4aR, 7aS) -6- (3- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) propyl) hexahydro-2H- [1, 4] dioxino [2, 3-c] pyrr ole (0.7 g, 1.65 mmol) , zinc powder (1.31 g, 20.15 mmol) and ammonium chloride (0.43 g, 8.04 mmol) to give the title compound as a brown solid (0.32 g, 41％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 395.2 [M+1] +.
Step 5) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) urea
The title compound was prepared by the procedure described in step 5 of example 6, using 4- (6- (3- ( (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl) propoxy) imidazo [1, 2-a] pyridin-2-yl) anilin e (0.32 g, 0.81 mmol) , phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (0.23 g, 0.88 mmol) , DMAP (6 mg, 0.05 mmol) and triethylamine (0.1 mL) to give the title compound as a white solid (52 mg, 11％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 561.3 [M+1] + and 1H NMR (400 MHz, d6-DMSO) δ (ppm) : 9.53 (s, 1H) , 8.90 (s, 1H) , 8.21-8.22 (d, J＝2.0 Hz, 1H) , 8.19 (s, 1H) , 7.85 (d, J＝8.4 Hz, 2H) , 7.52 (d, J＝8.8 Hz, 2H) , 7.46 (d, J＝9.6 Hz, 1H) , 7.01 (dd, J＝2.4, 10.0 Hz, 1H) , 6.52 (s, 1H) , 4.02-3.99 (t, J＝6.4 Hz, 4H) , 3.72-3.68 (m, 2H) , 3.47-3.44 (m, 2H) , 2.87-2.83 (m, 2H) 2.70-2.67 (m, 2H) , 2.65-2.61 (t, J＝7.2 Hz, 2H) , 1.90-1.85 (m, 2H) , 1.31 (s, 9H) .
Example 9
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (6- (2-morpholinoethoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) urea
Figure PCTCN2014087469-appb-000079
Step 1) 4- (2- ( (3-bromoimidazo [1, 2-b] pyridazin-6-yl) oxy) ethyl) morpholine
To a solution of 2-morpholinoethanol (1.15 g, 8.4 mmol) in THF (50 mL) was added potassium tert-butoxide (1.45 g, 12.6 mmol) at -10 ℃. The mixture was heated to rt and stirred for 30 minutes. Then the mixture was cooled to -10 ℃ again, and to it was added a mixture of 3-bromo-6-chloroimidazo [1, 2-b] pyridazine (1.5 g, 6.5 mmol) in THF (30 mL) dropwise. The reaction mixture was stirred at rt overnight, quenched with water (10 mL) , and then concentrated in vacuo. The residue was dissolved in dichloromethane (200 mL) and washed with saturated aqueous sodium chloride solution (50 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝15/1) to give the title compound as a yellow solid (1.86 g, 88％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 327.1 [M+1] +.
Step 2) tert-butyl (4- (6- (2-morpholinoethoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) carbamate
To a mixture of 4- (2- ( (3-bromoimidazo [1, 2-b] pyridazin-6-yl) oxy) ethyl) morpholine (700 mg, 2.14 mmol) and potassium acetate (460 mg, 4.64 mmol) in a mixture of DMF (100 mL) and water (25 mL) were added PdCl2 (dppf) (180 mg, 0.24 mmol) and tert-butyl (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -carbamate (770 mg, 2.41mmol) with stirring. The reaction mixture was purged with nitrogen three times, and then stirred at 80 ℃ overnight under a nitrogen atmosphere. The resulting mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in dichloromethane (300 mL) and washed with saturated aqueous sodium chloride solution (50 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝15/1) to give the title compound as yellow oil (350 mg, 37.22％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 440.3 [M+1] +.
Step 3) 4- (6- (2-morpholinoethoxy) imidazo [1, 2-b] pyridazin-3-yl) aniline
To a solution of tert-butyl (4- (6- (2-morpholinoethoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) carbamate (350 mg, 0.80 mmol) in DCM (20 mL) was added trifluoroacetic acid (5 mL) dropwise at 0 ℃. The reaction mixture was stirred at rt for 3.0 hours and then concentrated in vacuo. The residue was quenched with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (400 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as yellow oil (232 mg, 85.5％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 340.2 [M+1] +.
Step 4) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (2-morpholinoethoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) urea
To a solution of 4- (6- (2-morpholinoethoxy) imidazo [1, 2-b] pyridazin-3-yl) aniline (232 mg, 0.68 mmol) in dichloromethane (30 mL) were added phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (0.78 g, 3.0 mmol) , DMAP (45 mg, 0.37 mmol) and triethylamine (0.3 mL) dropwise. The reaction mixture was refluxed overnight, which was monitored by TLC, and then cooled to rt. The organic phase was washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL) , dried over anhydrous Na2SO4 and concentrated in vacuo.  The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as a pale yellow solid (180 mg, 54％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 506.3 [M+1] + and 1H-NMR (400 MHz, CDCl3 ) δ (ppm) : 8.04 (d, J＝8.7 Hz, 2H) , 7.90 (s, 1H) , 7.87 (d, J＝9.6 Hz, 1H) , 7.68 (d, J＝8.7 Hz, 2H) , 6.76 (d, J＝9.6 Hz, 1H) , 5.95 (s, 1H) , 4.52 (t, J＝5.5 Hz, 2H) , 3.77 (m, 4H) , 2.88 (t, J＝5.5 Hz, 2H) , 2.61 (s, 4H) , 1.38 (s, 9H) .
Example 10
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) urea
Figure PCTCN2014087469-appb-000080
Step 1) 4- (3- ( (3-bromoimidazo [1, 2-b] pyridazin-6-yl) oxy) propyl) morpholine
To a solution of 3-morpholinopropan-1-ol (1.39 g, 9.50 mmol) in THF (35 mL) was added potassium tert-butoxide (1.65 g, 14.4 mmol) at 0 ℃. The mixture was heated to rt and stirred for 30 minutes. Then the mixture was cooled to 0 ℃ again, and to it was added a mixture of 3-bromo-6-chloroimidazo [1, 2-b] pyridazine (1.5 g, 6.5 mmol) in THF (25 mL) with stirring. The reaction mixture was stirred at rt overnight, quenched with water (10 mL) , and then concentrated in vacuo. The residue was dissolved in dichloromethane (200 mL) and washed with saturated aqueous sodium chloride solution (50 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝20/1) to give the title compound as a yellow solid (1.65 g, 75％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 341.1 [M+1] +.
Step 2) tert-butyl (4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) carbamate
To a mixture of 4- (3- ( (3-bromoimidazo [1, 2-b] pyridazin-6-yl) oxy) propyl) morpholine (900 mg, 2.64 mmol) and potassium acetate (520 mg, 5.31mmol) in a mixture of DMF (80 mL) and water (20 mL) were added PdCl2 (dppf) (200 mg, 0.27 mmol) and tert-butyl (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -carbamate (960 mg, 3.00 mmol) with stirring. The reaction mixture was purged with nitrogen three times, and then stirred at 80 ℃ overnight under a nitrogen atmosphere, which was monitored by TLC. The resulting mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in dichloromethane (300 mL) and washed with saturated aqueous sodium chloride solution (50 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as yellow oil (357 mg, 29.8％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 454.3 [M+1] +.
Step 3) 4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-3-yl) aniline
To a solution of tert-butyl (4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) - carbamate (320 mg, 0.70 mmol) in DCM (20 mL) was added trifluoroacetic acid (5 mL) dropwise at 0 ℃. The reaction mixture was stirred at rt for 4.0 hours and then concentrated in vacuo. The residue was quenched with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (400 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as yellow oil (205 mg, 82.2％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 354.2 [M+1] +.
Step 4) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-3-yl) phenyl) urea
To a solution of 4- (6- (3-morpholinopropoxy) imidazo [1, 2-b] pyridazin-3-yl) aniline (205 mg, 0.58 mmol) in dichloromethane (30 mL) were added phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (0.34 g, 1.16 mmol) , DMAP (40 mg, 0.33 mmol) and triethylamine (0.3 mL) dropwise. The reaction mixture was refluxed overnight, which was monitored by TLC, and then cooled to rt. The organic phase was washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL) , dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as a pale yellow solid (120 mg, 39.8％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 520.4 [M+1] + and 1H NMR (600 MHz, CDCl3) δ (ppm) : 8.06 (d, J＝8.7 Hz, 2H) , 7.89 (dd, J＝36.9, 19.9 Hz, 2H) , 7.68 (d, J＝8.7 Hz, 2H) , 6.72 (d, J＝9.6 Hz, 1H) , 5.93 (s, 1H) , 4.43 (t, J＝6.2 Hz, 2H) , 3.75 (t, J＝4.5 Hz, 4H) , 2.58-2.51 (m, 6H) , 2.18-1.90 (m, 2H) , 1.39 (s, 9H) .
Example 11
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (7- (2-morpholinoethoxy) pyrazolo [1, 5-a] pyrimidin-3-yl) phenyl) urea
Figure PCTCN2014087469-appb-000081
Step 1) 7-chloro-3-iodopyrazolo [1, 5-a] pyrimidine
To a solution of 7-chloropyrazolo [1, 5-a] pyrimidine (3.0 g, 19.5mmol) in DMF (30 mL) was added N-iodobutanimide (5.3 g, 23 mmol) , and then the reaction mixture was stirred at rt for 12.0 hours. To the reaction mixture was added water (25 mL) , and a lot of solid precipitated out. The resulting mixture was stirred for 15 minutes, and then filtered. The filter cake was dried under vacuum to give the title compound as a white solid (4.8 g, 88％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 280.0 [M+1] +.
Step 2) 4- (2- ( (3-iodopyrazolo [1, 5-a] pyrimidin-7-yl) oxy) ethyl) morpholine
To a solution of potassium tert-butoxide (0.60 g, 5.0 mmol) in THF (50 mL) was added 2-morpholinoethanol (0.71 g, 5.4 mmol) at 0 ℃. After the mixture was stirred at 0 ℃ for 30 minutes, to it was added 7-chloro-3-iodopyrazolo [1, 5-a] pyrimidine (1.0 g, 3.6 mmol) slowly while the temperature was maintained at no more than 10 ℃, and then the reaction mixture was stirred at 0 ℃ for 2.0 hours. The resulting mixture was  quenched with water (30 mL) and concentrated in vacuo. The residue was diluted with dichloromethane (300 mL) , and then washed with water (50 mL) and saturated brine (50 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a pale yellow solid (0.98 g, 73％) , which was used in the next step without further purification. The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 375.1 [M+1] +.
Step 3) tert-butyl (4- (7- (2-morpholinoethoxy) pyrazolo [1, 5-a] pyrimidin-3-yl) phenyl) carbamate
To a mixture of 4- (2- ( (3-iodopyrazolo [1, 5-a] pyrimidin-7-yl) oxy) ethyl) morpholine (800 mg, 2.14 mmol) and potassium acetate (460 mg, 4.64 mmol) in a mixture of DMF (100 mL) and water (25 mL) were added PdCl2 (dppf) (180 mg, 0.24 mmol) and tert-butyl (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -carbamate (770 mg, 2.41mmol) . The reaction mixture was purged with nitrogen three times, and then stirred at 80 ℃ overnight under a nitrogen atmosphere, which was monitored by TLC. The resulting mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in dichloromethane (200 mL) , and then washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝15/1) to give the title compound as yellow oil (250 mg, 27.12％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 440.3 [M+1] +.
Step 4) 4- (7- (2-morpholinoethoxy) pyrazolo [1, 5-a] pyrimidin-3-yl) aniline
To a solution of tert-butyl (4- (7- (2-morpholinoethoxy) pyrazolo [1, 5-a] pyrimidin-3-yl) phenyl) -carbamate (250 mg, 0.57 mmol) in DCM (20 mL) was added trifluoroacetic acid (5 mL) dropwise at 0 ℃. The reaction mixture was stirred at rt for 4.0 hours and then concentrated in vacuo. The residue was quenched with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (400 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as yellow oil (150 mg, 78.1％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 340.2 [M+1] +.
Step 5) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (2-morpholinoethoxy) pyrazolo [1, 5-a] pyrimidin-3-yl) phenyl) urea
To a solution of 4- (7- (2-morpholinoethoxy) pyrazolo [1, 5-a] pyrimidin-3-yl) aniline (75 mg, 0.23 mmol) in dichloromethane (40 mL) were added phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (117 mg, 0.45 mmol) , DMAP (45 mg, 0.37 mmol) and triethylamine (0.3 mL) dropwise. The reaction mixture was refluxed overnight, which was monitored by TLC, and then cooled to rt. The organic phase was washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL) , dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as a pale yellow solid (18 mg, 16％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 506.2 [M+1] + and 1H NMR (400 MHz, CDCl3) δ (ppm) : 9.25 (s, 1H) , 8.44 (d, J＝12.0 Hz, 1H) , 8.29 (s, 1H) , 7.97 (d, J＝8.5 Hz, 2H) , 7.59 (d, J＝8.5 Hz, 2H) , 6.40 (d, J＝7.5 Hz,  1H), 5.95 (s, 1H) , 5.37 (s, 1H) , 4.63 (t, J＝5.7 Hz, 2H) , 3.79-3.72 (m, 4H) , 2.88 (t, J＝5.7 Hz, 2H) , 2.65-2.57 (m, 4H), 1.38 (s, 9H) .
Examples 12-17
The compounds of examples 12-17 were prepared by the procedure described in examples 1-4 by using appropriate starting materials.
Figure PCTCN2014087469-appb-000082
Examples 18-32
The compounds of examples 18-32 were prepared by the procedure described in examples 8-11 by using appropriate starting materials.
Figure PCTCN2014087469-appb-000083
Figure PCTCN2014087469-appb-000084
Figure PCTCN2014087469-appb-000085
Example 33 
1- (5- (Tert-butyl) isoxazol-3-yl) -3- (4- (6- (2-morpholinoethoxy) imidazo [2’ , 1’ : 2, 3] thiazolo [5, 4-b] pyridin-2-yl) phen yl)urea
Figure PCTCN2014087469-appb-000086
Step 1) 6-methoxythiazolo [5, 4-b] pyridin-2-amine
To a solution of potassium thiocyanate (9.85 g, 101 mmmol) in glacial acetic acid (100 mL) was added a mixture of 5-amino-2-methoxypyridine (3.0 g, 24.2 mmol) in glacial acetic acid (200 mL) . After the mixture was stirred at rt for 0.5 hour, to it was added a mixture of bromine (1.63 mL, 31.8 mmol) in acetic acid (100 mL) , and then the reaction mixture was stirred at rt for 5.0 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL) , and then adjusted to pH 8 with aqueous sodium hydroxide solution (1 mol/L, 20 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (4.0 g, 75％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 182.1 [M+1] +.
Step 2) 6-methoxy-2- (4-nitrophenyl) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridine
A solution of 6-methoxythiazolo [5, 4-b] pyridin-2-amine (1.5g, 8.28 mmol) and 2-bromo-4’ -nitroacetophenone (2.1 g, 8.6 mmol) in ethanol (100 mL) was refluxed for 5.0 hours, cooled to rt and then filtered. The filter cake was washed with ethanol (15 mL) and dried under vacuum to give the title compound as a yellow solid (1.5 g, 48％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 327.1 [M+1] +.
Step 3) 2- (4-nitrophenyl) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridin-6-ol
A mixture of 6-methoxy-2- (4-nitrophenyl) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridine (0.65 g, 2.0 mmol) and pyridine hydrochloride (3.5 g, 30 mmol) was heated to 180 ℃ and stirred for 3.0 hours. The resulting mixture was poured into water (50 mL) and then filtered. The filter cake was dried under vacuum to give the title compound as a yellow solid (0.59 g, 95％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 313.1 [M+1] + and 1H NMR (400 MHz, d-DMSO) δ (ppm) : 11.59 (s, 1H) , 8.96 (s, 1H) , 8.25-8.31 (m, 3H) , 8.06-8.09 (d, J＝8.8 Hz, 2H) , 6.86-6.88 (d, J＝8.8 Hz, 1H) .
Step 4) 4- (2- ( (2- (4-nitrophenyl) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridin-6-yl) oxy) ethyl) morpholine
A mixture of 2- (4-nitrophenyl) imidazo [2’ , 1’ : 2, 3] thiazolo [5, 4-b] pyridin-6-ol (1.39 g, 4.45 mmol) , 4-(2-chloroethyl) morpholine hydrochloride (1.5 g, 10 mmol) , potassium carbonate (1.38 g, 10 mmol) and tetrabutylammonium iodide (0.2 g, 0.54 mmol) in DMF (25 mL) was stirred at 90 ℃ for 6.0 hours, and then poured into water (400 mL) . The resulting mixture was stirred at rt for 1.0 hour and then filtered. The filter cake was dried under vacuum to give the title compound as a yellow solid (1.8 g, 95％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 426.1 [M+1] +.
Step 5) 4- (6- (2-morpholinoethoxy) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridin-2-yl) aniline 
To a solution of 4- (2- ( (2- (4-nitrophenyl) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridin-6-yl) oxy) ethyl) -morpholine (1.8 g, 4.23 mmol) in a mixture of ethanol (35 mL) and water (8 mL) were added zinc powder (2.77 g, 42.3 mmol) and ammonium chloride (2.26 g, 42.3 mmol) . The reaction mixture was refluxed for 3.0 hours, and then filtered to remove solid. The filtrate was concentrated in vacuo, and the residue was diluted with dichloromethane (200 mL) and saturated aqueous sodium bicarbonate solution (50 mL) . The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (1.38 g, 83％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 396.2 [M+1] +.
Step 6) 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (6- (2-morpholinoethoxy) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridin-2-yl) phenyl) urea
To a solution of 4- (6- (2-morpholinoethoxy) imidazo [2’, 1’: 2, 3] thiazolo [5, 4-b] pyridin-2-yl) aniline (0.6 g， 1.52 mmol) in anhydrous dichloromethane (10 mL) were added phenyl (5- (tert-butyl) isoxazol-3-yl) carbamate (0.78 g, 3.0 mmol) , DMAP (20 mg, 0.16 mmol) and triethylamine (0.3 mL) dropwise. The reaction mixture was refluxed overnight, cooled in an ice bath and then filtered. The filter cake was washed with dichloromethane (3 mL) and dried under vacuum to give the title compound as a white solid (0.27 g, 32％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 562.2 [M+1] + and 1H NMR (400 MHz, d-DMSO) δ (ppm) : 9.56 (s, 1H) , 8.92 (s, 1H) , 8.60 (s, 1H) , 8.27-8.29 (d, J＝8.8 Hz, 1H) , 7.76-7.78 (d, 2H), 7.51-7.53 (d, J＝8.8 Hz, 2H) , 7.02-7.05 (d, J＝8.8 Hz, 1H) , 6.52 (s, 1H) , 4.40-4.43 (t, J＝5.6 Hz, 2H) , 3.55-3.58 (t, J＝4.4 Hz, 4H) , 2.69-2.72 (t, J＝5.6 Hz, 2H) , 2.47 (s, 4H) , 1.30 (s, 9H) .
Example 34
1- (4- (6- (2- (2-Oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) -3- (5- (tert-butyl) isoxaz ol-3-yl) urea
Figure PCTCN2014087469-appb-000087
Step 1) 2- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) ethanol
To a solution of 2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-ol (2.0 g, 7.84 mmol) in DMF (30 mL) were added potassium carbonate (14 g, 101.30 mmol) and 2-bromoethanol (3.0 mL, 42.33 mmol) . The reaction mixture was heated to 80 ℃ and stirred for 6.0 hours. Then the reaction mixture was concentrated in vacuo. The resulting mixture was extracted with ethyl acetate (100 mL x 3) and washed with water (100 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as a brown solid (1.5 g, 64％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 300.1 [M+1] +. 
Step 2) 2- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) ethyl methanesulfonate
To a solution of 2- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) ethanol (1.0 g, 3.34 mmol) in THF (50 mL) were added triethylamine (2.5 mL, 18 mmol) and methanesulfonyl chloride (0.52 mL, 6.7 mmol) dropwise at 0 ℃. The reaction mixture was stirred at rt for 2.0 hours, and then quenched with saturated aqueous sodium bicarbonate solution (50 mL) . The resulting mixture was extracted with ethyl acetate (300 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound which was used in the next step without further purification.
Step 3) 6- (2- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) ethyl) -2-oxa-6-azaspiro [3.3] heptane
To a solution of 2- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) ethyl methanesulfonate (100 mg, 0.265 mmol) in acetonitrile (20 mL) were added 2-oxa-6-azaspiro [3.3] heptane (80 mg, 0.423 mmol) , potassium carbonate (0.21 g, 1.5 mmol) and potassium iodide (25 mg, 0.15 mmol) . The reaction mixture was refluxed for 7.0 hours, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as a brown solid (70 mg, 70％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 381.2 [M+1] +.
Step 4) 4- (6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) imidazo [1, 2-a] pyridin-2-yl) aniline
To a solution of 6- (2- ( (2- (4-nitrophenyl) imidazo [1, 2-a] pyridin-6-yl) oxy) ethyl) -2-oxa-6-azaspiro [3.3] heptane (80 mg, 0.21 mmol) in a mixture of methanol and water (v/v ＝3/1, 40 mL) were added ammonium chloride (170 mg, 3.21 mmol) and iron powder (100 mg, 1.79 mmol) . The reaction mixture was refluxed for 4.0 hours, and then concentrated in vacuo. The residue was extracted with ethyl acetate (200 mL) . The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as a brown solid (40 mg, 55％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 351.2 [M+1] +.
Step 5) 1- (4- (6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) imidazo [1, 2-a] pyridin-2-yl) phenyl) -3- (5- (tert-butyl) isoxazol-3-yl) urea
To a solution of 4- (6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) imidazo [1, 2-a] pyridin-2-yl) aniline (140 mg, 0.40 mmol) in dichloromethane (20 mL) were added triethylamine (0.6 mL, 4 mmol) and phenyl (5-(tert-butyl) isoxazol-3-yl) carbamate (0.21 g, 0.81 mmol) . The reaction mixture was refluxed for 4.0 hours, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ＝10/1) to give the title compound as a brown solid (80 mg, 39％) . The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 517.3 [M+1] + and 1H NMR (600 MHz, CD3OD) δ (ppm) : 8.12 (d, J＝2.0 Hz, 1H) , 8.09 (s, 1H) , 7.90-7.83 (m, 2H) , 7.57 (d, J＝8.7 Hz, 2H) , 7.47 (d, J＝9.7 Hz, 2H), 7.38 (t, J＝8.4 Hz, 1H) , 7.14 (dd, J＝9.7, 2.3 Hz, 1H) , 6.43 (s, 1H) , 4.57 (s, 4H) , 4.06 (t, J＝5.1 Hz, 2H) ,  3.69 (s, 4H) , 3.00 (dd, J＝11.0, 6.0 Hz, 2H) , 1.38 (s, 9H) .
Examples 35-45
The compounds of examples 35-45 were prepared by the procedure described in example 34 by using appropriate starting materials.
Figure PCTCN2014087469-appb-000088
Figure PCTCN2014087469-appb-000089
In vitro anti-tumor activity assay
Example 46 FLT3 kinase inhibition assay
Test Method
Materials used include HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) , Brij-35 (dodecyl polyglycol ether) , DTT (dithiothreitol) , EDTA (ethylenediamine tetraacetic acid) , EGFR (human epidermal growth factor receptor) , HER2 (human epidermal growth factor receptor 2) , EGFR T790M (human epidermal growth factor receptor T790M mutation) , Peptide FAM-P22 (fluorescein-labeled peptide 22) , ATP (adenosine triphosphate) , DMSO (dimethyl sulfoxide) , staurosporine, Coating Reagent #3 and so on, all of which are commercially available.
1.Preparation of 1x kinase base buffer and stop buffer
1x Kinase buffer without MnCl2 was prepared from 50 mM HEPES, pH 7.5, 0.0015％Brij-35, 10 mM MgCl2 and 2 mM DTT. Stop buffer was prepared from 100 mM HEPES, pH 7.5, 0.015％Brij-35, 0.2％Coating Reagent #3 and 50 mM EDTA.
2.Preparation of the compounds for testing kinases
Preparation of the compounds was performed according to the following procedures: (1) the compound to be tested was diluted to a concentration with 100％DMSO which is 50x of the highest final concentration, and 100 μL of the diluted compound solution was transferred to a well in a 96-well plate； (2) the compound was gradiently diluted by transferring 20 μL original solution to 60 μL of 100％DMSO in the next well and so forth for a total of 10 concentrations； (3) DMSO (100 μL, 100％) was added to two empty wells as a no-compound  control and a no-enzyme control in the same 96-well plate, and the plate was marked as source plate； (4) intermediate plate was prepared by transferring 10 μL of each compound from source plate to a new 96-well plate as the intermediate plate, and to each well of the intermediate plate was added 90 μL of 1x Kinase base buffer, then the intermediate plate was mixed for 10 min on shaker； and (5) assay plate was prepared by transferring 5 μL of each well from the 96-well intermediate plate to a 384-well plate in duplicates.
3.Kinase reaction
Kinase reaction was performed according to the following procedures: (1) 2.5x kinase solution was prepared by adding kinase into 1x kinase base buffer； (2) 2.5x peptide solution was prepared by adding FAM-labeled peptide and ATP into 1x kinase base buffer； (3) 2.5x kinase solution (10 μL) was added to each well of the 384-well assay plate containing 5 μL of compound in 10％DMSO and then the assay plate was incubated at room temperature for 10 minutes； (4) 2.5x peptide solution (10 μL) was added to each well of the 384-well assay plate； and (5) stop buffer (25 μL) was added to stop the kinase reaction after incubation at 28 ℃for a specified period of time.
4.Data measurement
The data were read and collected.
5.Curve fitting
Conversion data were copied, and then converted to inhibition values with the following formula: percent inhibition＝ (max-conversion) / (max-min) *100 where “max” stands for the DMSO control value, “conversion” stands for the sample value and “min” stands for the no-kinase control value. The data were fitted in XLfit to obtain IC50 values.
The IC50 values of the compounds disclosed herein in inhibiting FLT3 kinase were showed in Table 2.
Table 2
Example No. FLT3 (IC50, nM)
1 88
2 39
3 18
4 90
6 107
7 50
8 <3
The results, shown in Table 2, demonstrated that the compounds disclosed herein exhibited good FLT3 kinase inhibitory activity. 
Example 47 MV4-11 cell proliferation assay
Test Method
Cell assay condition was showed below:
Cell name Cells/per well Incubation time (h) Complete medium
MV4-11 15000 72 IMDM+10％FBS
1.Plating cells
Cell suspension density was adjusted to 1.5 x 105 cells/ml, which was counted by Vi-Cell XR cell counter, with an appropriate culture medium, and then 100μl of the cell suspension was plated in a white 96-well plate having transparent bottom at a final concentration of 15,000 cells per well. The 96-well plate was incubated in a 5％CO2 and 95％humidity incubator at 37 ℃ overnight.
2.Preparation and addition of test compounds
The compound plate and serial dilutions of the test compound solution were prepared according to the following procedures. First, test compound stock solution was prepared by dissolving a weighed compound in DMSO to a concentration of 10 mM, and then diluted to the concentration of 4 mM, which was then diluted to the concentration of 0.4 mM used as the highest concentration for testing with DMSO. The highest concentration was sequentially followed by 3-fold dilution for a total of 10 concentrations. Staurosporine was the positive control drug. 
0.5 μL of test compound prepared above in compound plate was added into the cell culture plate that was incubated overnight, and then the culture plate was incubated in a incubator at 37 ℃ for 72 hours.
3.Detection and Analysis
After 72 hours, the cell morphology was observed under an inverted microscope. The cell culture plate was placed at room temperature for 30 minutes, and then the inhibitory activity of the compounds disclosed herein on MV4-11 cell proliferation was determined by using CellTiter-Glo assay. The obtained results were recorded and analyzed.
The IC50 values of the compounds disclosed herein in inhibiting MV4-11 cell proliferation were showed in Table 3.
Table 3
Example No. MV4-11 (IC50, nM) Example No. MV4-11 (IC50, nM)
6 0.7 9 63.1
7 0.46 10 54.6
8 1.0    
The results, shown in Table 3, demonstrated that the compounds disclosed herein exhibited good inhibitory activity on MV4-11 cell proliferation.
Reference throughout this specification to “one embodiment” , “an embodiment” , “some embodiments” , “explanatory embodiment” , “an example” , “aspecific example” or “some examples” , means that a particular feature, structure, material or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as “in  some embodiments” , “in one embodiment” , “in an embodiment” , “in another example” , “in an example” , “in a specific examples” , or “in some examples” in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.
Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments can not be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.

Claims (28)

  1. A compound having Formula (I) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
    Figure PCTCN2014087469-appb-100001
    wherein
    each of Q and W is independently CH or N；
    G is-O-, -S (＝O) t-, -S-, -C (＝O) -or a 5-membered heteroarylene group；
    R is-NR3R2, alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkyl-S (＝O) t-, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy, heterocyclyloxy, carbocyclyloxyalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryl, arylalkyl, aryloxyalkoxy, aryloxy, arylalkoxy, arylalkylamino, heteroarylalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkylamino, heteroaryloxy, heteroaryloxyalkoxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, bridged heterobicyclyl, spiro heterobicyclyl or fused heterobicyclyl；
    ring K is a 5-to 6-membered heteroaryl group, of which at least two ring members are heteroatoms independently selected from O, S, NR4 and N；
    each L is independently amino, nitro, C1-4 alkylthio, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-4 haloalkyl, C1-4 alkylamino, hydroxy, fluoro, chloro, bromo, iodo, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or cyano；
    ring E is a bicyclic or tricyclic heteroarylene group；
    provided that:
    when ring E is
    Figure PCTCN2014087469-appb-100002
    Figure PCTCN2014087469-appb-100003
    wherein each X8, X9 and X10 is independently N or CH；
    each X1, X3, X4, X5, X6 and X7 is independently -CH2-, -O-, -NR4a-, -S (＝O) t-or -S-；
    each of X, Y, Z1, Z2, Z3 and Z is independently N or CH；
    T is-O-, -S-, -NR4-or -CH2-；
    with the proviso that at least two of X, Y, T, Z1, Z2, Z3 and Z are independently heteroatoms；
    each R1 is independently hydrogen, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-6 alkyl-S (＝O) t-, C1-6 alkoxy-C1-6-alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio；
    each of R2 and R3 is independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl；
    each R4a and R4 is independently hydrogen, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl；
    each q, m, p, r and s is independently 0, 1, 2, 3 or 4；
    each of d and n is independently 1, 2, 3 or 4；
    each t is independently 0, 1 or 2； and
    a is 0, 1, 2, 3 or 4,
    wherein each aryl, bicyclic heteroarylene, tricyclic heteroarylene, alkoxy, alkyl-S (＝O) t-, -G- (CH2) n-R, arylalkyl, heteroarylalkyl, heteroaryl, heteroarylene, heterocycly, bridged heterobicyclyl, spiro heterobicyclyl, fused heterobicyclyl, alkyl, haloalkyl, alkylamino, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, alkoxyalkyl, hydroxyalkyl, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, cycloalkyloxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkylamino, cycloalkylamino, heterocyclylalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro  heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, alkyl-C (＝O) -NH-, alkylthio, cycloalkyl and ring E is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, amino, methyl-C (＝O) -NH-, oxo (＝O) , C1-4 alkyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
  2. The compound according to claim 1, wherein ring E is
    Figure PCTCN2014087469-appb-100004
    wherein each X, Y, Z, Z1, Z2, Z3 and Z4 is independently N or CH；
    each T and T1 is independently -O-, -S-, -NR4-or-CH2-；
    with the proviso that at least two ring members of ring E are independently heteroatoms；
    R is -NR3R2, C2-4 alkenyl, C2-4 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C2-10 heterocyclyl-C1-4-alkyl, C1-6 alkyl-S (＝O) t-, C1-6 alkoxy-C1-6-alkyl, hydroxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, amino-C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylamino-C1-4-haloalkoxy, C1-4 alkylamino-C1-4-alkoxy, C1-4 alkoxy-C1-4-alkoxy, C3-10 cycloalkyloxy, C6-10 aryl-C1-4-alkoxy, C6-10 aryl-C1-4-alkylamino, C1-9 heteroaryl-C1-4-alkoxy, C1-9 heteroaryl-C1-4-alkylamino, C2-10 heterocyclyl-C1-4-alkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylamino, C2-10 heterocyclyl-C1-4-alkoxy, C3-10 carbocyclyl-C1-4-alkoxy, C3-10 carbocyclyl-C1-4-alkylamino, C6-10 aryloxy-C1-4-alkoxy, C6-10 aryloxy, C1-9 heteroaryloxy, C1-9 heteroaryloxy-C1-4-alkoxy, C2-10 heterocyclyloxy-C1-4-alkoxy, C3-10 carbocyclyloxy-C1-4-alkoxy, C2-10 heterocyclyloxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl, C6-10 aryl, C6-10 aryl-C1-6-alkyl, C1-9 heteroaryl-C1-6-alkyl or C1-9 heteroaryl, or R is
    Figure PCTCN2014087469-appb-100005
    Figure PCTCN2014087469-appb-100006
    wherein each X8, X9 and X10 is independently N or CH；
    each X1, X2, X3, X4, X5, X6 and X7 is independently -CH2-, -O-, -NR4a-, -S (＝O) t-or-S-；
    each q, m, p, r and s is independently 0, 1, 2, 3 or 4；
    each of R2 and R3 is independently C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl；
    each of R4a and R4 is independently hydrogen, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and
    provided that:
    when ring E is
    Figure PCTCN2014087469-appb-100007
    Figure PCTCN2014087469-appb-100008
    wherein each of ring E and R is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, amino, methyl-C (＝O) -NH-, oxo (＝O) , C1-4 alkyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
  3. The compound according to claim 2, wherein ring E is
    Figure PCTCN2014087469-appb-100009
    R is-NR3R2, C2-4 alkenyl, C2-4 alkynyl, C2-10 heterocyclyl-C1-4-alkyl, C1-6 alkyl-S (＝O) t-, C1-4 alkoxy-C1-4 alkyl, hydroxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, amino-C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylamino-C1-4-haloalkoxy, C1-4 alkylamino-C1-4-alkoxy, C1-4 alkoxy-C1-4-alkoxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl or C1-9 heteroaryl-C1-6-alkyl, or R is
    Figure PCTCN2014087469-appb-100010
    Figure PCTCN2014087469-appb-100011
    Figure PCTCN2014087469-appb-100012
    each of R2 and R3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and provided that:
    when ring E is
    Figure PCTCN2014087469-appb-100013
    Figure PCTCN2014087469-appb-100014
    Figure PCTCN2014087469-appb-100015
    wherein each of ring E and R is optionally and independently substituted with one or more substituents  independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxy, cyano, nitro, oxo (＝O) , methyl-C (＝O) -, ethyl-C (＝O) -, (n-propyl) -C (＝O) -, isopropyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
  4. The compound according to claim 1, wherein G is-O-or furylene.
  5. The compound according to claim 1, wherein ring K is a group selected from the following:
    Figure PCTCN2014087469-appb-100016
    wherein each U is independently -CH2-, -O-, -NR4-or-S-；
    each V, V1 and V2 is independently CH or N；
    with the proviso that at least two ring members of ring K are independently heteroatoms；
    R4 is hydrogen, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and
    each L is independently amino, nitro, C1-4 alkylthio, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C1-4 haloalkyl, C1-4 alkylamino, hydroxy, fluoro, chloro, bromo, iodo, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or cyano.
  6. The compound according to claim 5, wherein ring K is a group selected from the following:
    Figure PCTCN2014087469-appb-100017
    each L is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3-6 heterocycloalkyl, amino, cyano, nitro, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, methyl, ethyl, butyl, n-propyl, isopropyl, tert-butyl, C1-4 alkylamino, hydroxy, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio.
  7. The compound according to claim 1 having formula (II) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
    Figure PCTCN2014087469-appb-100018
    wherein
    each of Q and W is independently CH or N；
    each R1 is independently hydrogen, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, C1-4 alkyl, C1-6 alkyl-S (＝O) t-, C1-6 alkoxy-C1-6-alkyl, C1-4 alkylamino, hydroxy, cyano, nitro, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy,  hydroxy-C1-4-alkyl or C1-4 alkylthio；
    each L is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3-6 heterocycloalkyl, amino, cyano, nitro, fluoro, chloro, bromo, iodo, C1-4 haloalkyl, methyl, ethyl, butyl, n-propyl, isopropyl, tert-butyl, C1-4 alkylamino, hydroxy, C1-4 alkyl-C (＝O) -NH-, C1-4 alkoxy, hydroxy-C1-4-alkyl or C1-4 alkylthio；
    each of d and n is independently 1, 2, 3 or 4；
    each t is independently 0, 1 or 2；
    a is 0, 1, 2, 3 or 4；
    ring E is
    Figure PCTCN2014087469-appb-100019
    R is-NR3R2, C2-4 alkenyl, C2-4 alkynyl, C2-10 heterocyclyl-C1-4-alkyl, C1-6 alkyl-S (＝O) t-, C1-4 alkoxy-C1-4-alkyl, hydroxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, amino-C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylamino-C1-4-haloalkoxy, C1-4 alkylamino-C1-4-alkoxy, C1-4 alkoxy-C1-4-alkoxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl or C1-9 heteroaryl-C1-6-alkyl, or R is
    Figure PCTCN2014087469-appb-100020
    Figure PCTCN2014087469-appb-100021
    Figure PCTCN2014087469-appb-100022
    each of R2 and R3 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, C2-10 heterocycloalkyl, C1-6 alkoxy-C1-6-alkyl or hydroxy-C1-4-alkyl； and provided that:
    when ring E is
    Figure PCTCN2014087469-appb-100023
    Figure PCTCN2014087469-appb-100024
    Figure PCTCN2014087469-appb-100025
    Figure PCTCN2014087469-appb-100026
    wherein each of ring E and R is optionally and independently substituted with one or more substituents independently selected from hydrogen, aminoalkyl, aminoacyl, fluoro, chloro, bromo, iodo, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxy, cyano, nitro, oxo (＝O) , methyl-C (＝O) -, ethyl-C (＝O) -, (n-propyl) -C (＝O) -, isopropyl-C (＝O) -, C2-10 heterocyclyl, benzyl and phenyl.
  8. The compound according to claim 1 having formula (III) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,
    Figure PCTCN2014087469-appb-100027
    wherein each of X, Y, Z, Z1, Z2, Z3 and Z4 is independently N or CH； and
    with the proviso that at least two of X, Y, Z, Z1, Z2, Z3 and Z4 are independently heteroatoms.
  9. The compound according to claim 1 having one of the following structures:
    Figure PCTCN2014087469-appb-100028
    Figure PCTCN2014087469-appb-100029
    Figure PCTCN2014087469-appb-100030
    Figure PCTCN2014087469-appb-100031
    or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof.
  10. A pharmaceutical composition comprising the compound according to any one of claims 1-9.
  11. The pharmaceutical composition according to claim 10 further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
  12. The pharmaceutical composition according to claim 10 further comprising an additional therapeutic agent, wherein the additional therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-inflammatory agent, an immunosuppressant, an immunostimulant, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis or a combination thereof.
  13. The pharmaceutical composition according to claim 12, wherein the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib,  quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab or a combination thereof.
  14. Use of the compound according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 10-13 in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
  15. The use according to claim 14, wherein the proliferative disease is acute myelogenous leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute lymphocytic leukemia (ALL) , colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, CNS (central nervous system) cancer, malignant glioma or bone marrow hyperplasia, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic diseases, cryoglobulinemia, non-lymphoreticular system tumor, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia, semi-molecular disease, monocytic leukemia, primary macroglobulinemia purpura, secondary benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin’s lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis, Hodgkin’s lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyp, small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterine cancer, ovarian cancer, head and neck squamous cell carcinoma, alimentary canal malignancy, non-small cell lung cancer, cervical cancer, testiculoma, bladder cancer or myeloma.
  16. The use according to claim 14, wherein the autoimmune disease is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, I-type diabetes, sarcoidosis, inflammatory bowel disease, Crohn’s disease or systemic lupus.
  17. The use according to claim 14, wherein the inflammatory disease is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
  18. The use according to any one of claims 14-17, wherein the disease is mediated by FLT3 kinase or caused by FLT3-ITD.
  19. A method of preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient comprising administrating a therapeutically effective amount of the compound according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 10-13 to the patient.
  20. The method according to claim 19, wherein the proliferative disease is acute myelogenous leukemia,  chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute lymphocytic leukemia (ALL) , colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, CNS (central nervous system) cancer, malignant glioma or bone marrow hyperplasia, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic diseases, cryoglobulinemia, non-lymphoreticular system tumor, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia, semi-molecular disease, monocytic leukemia, primary macroglobulinemia purpura, secondary benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin’s lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis, Hodgkin’s lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyp, small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterine cancer, ovarian cancer, head and neck squamous cell carcinoma, alimentary canal malignancy, non-small cell lung cancer, cervical cancer, testiculoma, bladder cancer or myeloma.
  21. The method according to claim 19, wherein the autoimmune disease is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, I-type diabetes, sarcoidosis, inflammatory bowel disease, Crohn’s disease or systemic lupus.
  22. The method according to claim 19, wherein the inflammatory disease is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
  23. The method according to any one of claims 19-22, wherein the disease is mediated by FLT3 kinase or caused by FLT3-ITD.
  24. The compound according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 10-13 for use in preventing, managing, treating or lessening the severity of a proliferative disease, an autoimmune disease or an inflammatory disease in a patient.
  25. The compound or the pharmaceutical composition according to claim 24, wherein the proliferative disease is acute myelogenous leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute lymphocytic leukemia (ALL) , colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, CNS (central nervous system) cancer, malignant glioma or bone marrow hyperplasia, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic diseases, cryoglobulinemia, non-lymphoreticular system tumor, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia, semi-molecular disease, monocytic leukemia, primary macroglobulinemia purpura, secondary benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin’s lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis,  Hodgkin’s lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyp, small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterine cancer, ovarian cancer, head and neck squamous cell carcinoma, alimentary canal malignancy, non-small cell lung cancer, cervical cancer, testiculoma, bladder cancer or myeloma.
  26. The compound or the pharmaceutical composition according to claim 24, wherein the autoimmune disease is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, I-type diabetes, sarcoidosis, inflammatory bowel disease, Crohn’s disease or systemic lupus.
  27. The compound or the pharmaceutical composition according to claim 24, wherein the inflammatory disease is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
  28. The compound or the pharmaceutical composition according to any one of claims 24-27, wherein the disease is mediated by FLT3 kinase or caused by FLT3-ITD. 
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