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WO2016015604A1 - Compounds as cdk small-molecule inhibitors and uses thereof - Google Patents

Compounds as cdk small-molecule inhibitors and uses thereof Download PDF

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Publication number
WO2016015604A1
WO2016015604A1 PCT/CN2015/085034 CN2015085034W WO2016015604A1 WO 2016015604 A1 WO2016015604 A1 WO 2016015604A1 CN 2015085034 W CN2015085034 W CN 2015085034W WO 2016015604 A1 WO2016015604 A1 WO 2016015604A1
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WIPO (PCT)
Prior art keywords
independently
compound
alkyl
haloalkyl
inhibitor
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Ceased
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PCT/CN2015/085034
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French (fr)
Inventor
Bing Liu
Yingjun Zhang
Linlin NIE
Shun BAI
Mingyu GUAN
Xuke Li
Changchung CHENG
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • 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
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Definitions

  • the present invention relates to novel compounds as CDK small-molecule inhibitors and pharmaceutical compositions thereof, and also to uses of the compounds and the pharmaceutical compositions in the treatment of exceedingly proliferative disorders.
  • CDK cyclin-dependent kinase
  • CDKs The activity of CDKs is regulated post-translationally, by transitory associations with other proteins, and by alterations of their intracellular localization. Tumor development is closely associated with genetic alteration and dysregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful for anti-cancer therapeutics.
  • CDKs and their associated proteins, in co-ordinating and driving the cell cycle in proliferating cells play key roles in some biochemical pathways.
  • Using therapeutics targeted generically at CDKs, or at specific CDKs can be for the treatment of proliferative disorders, such as cancers.
  • CDK inhibitors could conceivably also be used to treat other conditions such as viral infections, autoimmune diseases and neuro-degenerative diseases, amongst others.
  • CDK targeted therapeutics may also provide clinical benefits in the treatment of the previously described diseases when used in combination therapy with existing therapeutic agents.
  • CDK targeted anticancer therapies could potentially have advantages over many current antitumour agents as they would not directly interact with DNA and should therefore reduce the risk of secondary tumour development.
  • CDKs compounds have been disclosed in the art, in view of the number of pathological responses that are mediated by CDK, there remains a continuing need for drugs which can be used in the treatment of a variety of conditions mediated by CDK, especially CDK4/6.
  • the compounds provided herein can be used in regulating the activities of protein kinases such as CDKs, regulating or inhibiting the activities of CDK1, CDK2, CDK4, CDK6 or CDK9, especially regulating or inhibiting the activities of CDK4 or CDK6, which have good clinical prospects.
  • the compounds provided herein have better characteristics of pharmacodynamics in vivo, pharmacokinetics and/or toxicology than the existing similar compound.
  • the parent structure of the compounds disclosed herein is completely different from those disclosed in prior art, and the prior arts do not indicate the inventor any relative technical enlightenment; the compounds disclosed herein have an advantage in inhibiton on CDK4/6, and have prominent substantive features.
  • a compound having Formula (I) or a stereoisomer a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • each Y 3 , Y 4 , Y 5 , Y 6 , Y 8 and Y 7 is independently CR 4 or N;
  • each of R 1 and R 2 is independently H, F, Cl, Br, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy;
  • R 3 is H, C 5-12 spiro heterobicyclyl, C 5-12 bridged heterobicyclyl, C 5-12 fused heterobicyclyl, C 3-9 cycloalkyl, C 3-9 heterocyclyl or C 1-9 heteroaryl;
  • each n and n1 is independently 0, 1, 2, 3, or 4;
  • each t is independently 0, 1, or 2;
  • a compound having Formula (II) or Formula (III) or a stereoisomer a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • R 1 , R 2 , R 3 , L 1 , Y, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are as defined herein.
  • n is as defined herein.
  • n is as defined herein.
  • each e and f is independently 0, 1, 2 or 3;
  • n, R 4 , R 6 and R 7 are as defined herein.
  • R 3 is H
  • each X 3 , X 4 and X 5 is independently CR 4b or N;
  • each e, g and f is independently 0, 1, 2 or 3;
  • R 3 is optionallysubstituted with one or more R 8 ;
  • each R 8 is optionally and independently substituted with one or more R 9 ;
  • R 4 , R 6 , R 7 and n is as defined herein.
  • R 3 is H
  • n 0, 1, 2 or 3;
  • each moiety represented by R 3 is independently and optionally substituted with one or more R 8 ;
  • R 8 is as defined herein.
  • R 5 , R 4 , R 7 , R 6 and n are as defined herein.
  • provided herein is a pharmaceutical composition comprising the compound disclosed herein.
  • the pharmaceutical composition disclosed herein further comprises at least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles.
  • the pharmaceutical composition further comprises an additional therapeutic agent, wherein the additional therapeutic agent is a chemotherapeutic drug, an antiproliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, a CDK4/6 kinase inhibitor, an ABL inhibitor, an ABL/Scr inhibitor, an aurora kinase inhibitor, a non-ATP competitive inhibitor of BCR-ABL, a c-KIT mutation inhibitor, a RET inhibitor, a PDGFR inhibitor, a VEGFRinhibitor, a CSF1R inhibitor, an FLT3 inhibitor, an FLT3-ITD inhibitor or a combination thereof.
  • the additional therapeutic agent is a chemotherapeutic drug, an antiproliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, a CDK4/6
  • the additional therapeutic agent of the pharmaceutical composition disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cis-platinum, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbozine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, pharmorubicin, daunomycin, mitoxantrone, bleomycin, mitomycinC, ixabepilone, tamoxifen, flutamide, gonadorel
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture a medicament for preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection.
  • the abnormal cell proliferation disorder or disease is ovarian cancer, cervical cancer, testiculoma, esophagus cancer, gastric cancer, skin cancer, lung cancer, osteocarcinoma, acute myeloid leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myelocytic leukemia (AML) , chronic myeloid leukemia (CML) with mutation, acute lymphoblastic leukemia (ALL) , colorectal cancer, gastric cancer, breast cancer, lung cancer, cancer of the liver, prostate cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, cancer of the central nervous system, spongioblastoma, myelodysplastic syndrome, atherosclerosis, pulmonary fibrosis, leukemia, lymph cancer, rheumatic disease, cryoglobulinemia, non-lymphoreticular system tumor, papular mucinosis, familial splenic anemia, multiple myelom
  • the autoimmune disease is rheumatic arthritis, lupus, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
  • the inflammatory disease is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
  • the infection disease is virus infection or fungal infection.
  • the disease is a disease caused by changes in cyclin-dependent kinase.
  • the cyclin-dependent kinase is CDK1, CDK2, CDK4, CDK6 or CDK9.
  • the disease is a disease caused by changes in CDK4 or CDK6 protein kinase.
  • a drug combination comprising the compound or the pharmaceutical composition disclosed herein and one or more other activity agents used for treating proliferative diseases, autoimmune diseases or inflammatory diseases.
  • the other activity agent of the drug combination comprises a chemotherapeutic drug, an antiproliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, a CDK 4/6 kinase inhibitor, an ABL inhibitor, an ABL/Scr inhibitor, an aurora kinase inhibitor, a non-ATP competitive inhibitor of BCR-ABL, a c-KIT mutation inhibitor, a RET inhibitor, a PDGFR inhibitor, a VEGFRinhibitor, a CSF1R inhibitor, an FLT3 inhibitor, an FLT3-ITD inhibitor or a combination thereof
  • the invention provides a method of preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection in a patient, comprising administrating to the patient a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein.
  • the compound or the pharmaceutical composition for use in preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection
  • the compound of the invention is suitable as an active agent in a pharmaceutical composition
  • the pharmaceutical composition can be used in effectively treating especially diseases related to protein kinases, such as cancer, graft rejection and autoimmune disease.
  • the pharmaceutical composition of each embodiment has a pharmaceutically effective active agent of the invention and other pharmaceutically acceptable excipients, carriers, fillers, diluents, and the like.
  • pharmaceutically effective amount indicates an amount necessary to administer to a host, or to a cell, issue, or organ of a host, to achieve a therapeutic result, especially the regulating, modulating, or inhibiting protein kinase activity, e.g., inhibition of the activity of a protein kinase, or treatment of cancer, graft rejection and autoimmune disease.
  • the present invention provides a method for inhibiting the activity of a protein kinase.
  • the method includes contacting a cell with any one of the compounds of the present invention.
  • the method further provides that the compound is present in an amount effective to selectively inhibit the activity of a protein kinase.
  • grammatical articles “a” , “an” and “the” are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context.
  • the articles are used herein to refer to one or more than one (i.e. at least one) of the grammatical objects of the article.
  • a component means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
  • the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
  • Stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc.
  • Chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • Enantiomers refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boling points, spectral properties or biological activities. Mixture of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
  • optically active compounds i.e., they have the ability to rotate the plane of plane-polarized light.
  • 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 1 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.
  • a specific stereoisomer is 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.
  • any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -or (R, S) -configuration.
  • each asymmetric atom has at least 50%enantiomeric excess, at least 60%enantiomeric excess, at least 70%enantiomeric excess, at least 80%enantiomeric excess, at least 90%enantiomeric excess, at least 95%enantiomeric excess, or at least 99%enantiomeric excess in the (R) -or (S) -configuration.
  • the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • Optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis-or trans-configuration.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization.
  • racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
  • Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto-enol tautomerisms is hexane-2, 4-dione and 4-hydroxyhex-3-en-2-one tautomerism.
  • tautomerisms is phenol-keto tautomerism.
  • the specific example of phenol-keto tautomerisms is pyridin-4-ol and pyridin-4 (1H) -one tautomerism. Unless otherwise stated, all tautomers of the present compounds within the scope disclosed herein.
  • compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” .
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a give an structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
  • substituents of compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1 -C 6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” .
  • substituted whether behind of the term “optionally” or not refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group.
  • the substituent may be either the same or different at each position.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms, wherein the alkyl radical may be optionally and independently substituted with one or more substituents described herein.
  • the alkyl group contains 1-10 carbon atoms.
  • the alkyl group contains 1-8 carbon atoms.
  • the alkyl group contains 1-6 carbon atoms.
  • the alkyl group contains 1-4 carbon atoms.
  • the alkyl group contains 1-3 carbon atoms and in still yet other embodiments, the alkyl group contains 2-6 carbon atoms.
  • alkyl group examples include, 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 ) , 2-methyl-propyl or isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ) , 1-methyl-propyl or 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 ) ,
  • haloalkyl refers to an alkyl group substituted with one or more identical or different halogen atoms. Wherein the alkyl group is as defined herein. Some non-limiting examples of the haloalkyl group include trifluoromethyl, 1-chloroethyl, difluoromethyl, 2-fluoroethyl, 3, 3, 3-trifluoropropyl, and the like.
  • amino refers to -NH 2 .
  • cycle or “ring” embraces carbolic cycle, heterocycle, aromatic cycle, heteroaromatic cycle, spiro cycle and fused cycle, and the like, wherein the carbolic cycle, heterocycle, aromatic cycle, heteroaromatic cycle, spiro cycle and fused cycle are as defined herein.
  • alkamino 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 radical is “lower alkylamino” radical having one or two C 1-6 alkyl groups attached to a nitrogen atom.
  • the alkylamino radical is “lower alkylamino” radical having one or two C 1-3 alkyl groups attached to a nitrogen atom.
  • suitable alkylamino radical include mono or dialkylamino. Some examples include, but not limited to, methylamino, ethylamino, dimethylamino and diethylamino, and the like.
  • aminoalkyl refers to an alkyl substituted with one or more amino groups. Wherein the alkyl group is as defined herein. In some embodiments, the aminoalkyl is an amino-C 1-6 -alkyl group. In other embodiments, the aminoalkyl is an amino-C 1-3 -alkyl group. Some non-limiting examples of the aminoalkyl group include aminomethyl, aminoethyl and aminopropyl, 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.
  • cycloalkyl refers to a monovalent or multitivalent, non-aromatic, 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 ring 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.
  • cycloalkyl 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.
  • the cycloalkyl group can be a monoradical or a diradical, i.e.
  • aryl 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 diradical such as an arylene group.
  • heteroaryl refers to a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the bicyclic heteroaryl, tricyclic heteroaryl or tetracyclic heteroaryl ring system is fused to form a ring.
  • the heteroaryl ring system is aromatic, in which one or more ring members are an independently selected heteroatom (heteroatoms selected from N, O, P and S, wherein the N, S or P is optionally substituted with one or more oxo to provide the group NO, SO, SO 2 , PO or PO 2 ) .
  • the heteroaryl 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 system group 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
  • 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 monoradical or a diradical such as a heteroarylene group.
  • heteroaryl system 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., 3-pyridazinyl) , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl) , triazolyl (e.
  • 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 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 group can be a monoradical or a diradical, i.e., heterocyclylene.
  • N atoms of a heterocyclyl containing N can be oxidized to form an N-oxide.
  • 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 1, 2, 3, 4-tetrahydropyridyl, piperidyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, homopiperazin
  • spirocyclyl refers to a ring originating from a particular annular carbon of another ring.
  • a saturated bridged ring system (ring D and B’ ) is termed as “fused bicyclic”
  • ring A and ring D 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 such group include, 4-azaspiro [2.4] heptan-5-yl, 4-oxaspiro [2.4] heptan-5-yl, 5-azaspiro [2.4] heptan-5-yl, spiro [2.4] heptyl, spiro [4.4] nonyl, 7-hydroxy-5-azaspiro [2.4] heptan-5-yl, and thelike.
  • spiro heterobicyclyl refers to a ring originating from a particular annular carbon of another ring.
  • a saturated bridged ring system (ring D and B’ ) is termed as “fused bicyclic” , whereas ring A and ring D share an atom between the two saturated ring system, which terms as a “spirocyclyl” .
  • 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
  • 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. 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.
  • fused heterobicyclic 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. 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 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, 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, 3-aza-7-oxabicyclo [3.3.0] octyl, 3, 7-diazabicyclo [3.3.0] octyl, 2,
  • 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 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 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) .
  • Some non-limiting examples of the such group include 2-oxa-5-azabicyclo [2.2.1] heptyl, 2-thia-5-azabicyclo [2.2.1] heptyl, 2-oxo-5-azabicyclo [2.2.1] heptyl, 2, 5-diazabicyclo [2.2.1] heptyl, (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptyl, 3, 8-diazabicyclo [3.2.1] octyl, (1S, 5S) -3, 8-diazabicyclo [3.2.1] octyl, 1, 4-diazabicyclo [3.2.2] nonan-3-one-yl, 8-oxa-3-azabicyclo [3.2.1] octyl, and the like.
  • Anti-proliferation agents refers to anti-metabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine) , antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel, docetaxel) , alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea) , platinum agents (e.g.
  • cisplatin carboplatin, oxaliplatin, JM-216, CI-973) , anthracyclines (e.g., doxorubicin, daunorubicin) , antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin, daunomycin) , topoisomerase inhibitors (e.g., etoposide, camptothecins) , anti-angiogenesis agents (e.g. Bevacizumab) or any other cytotoxic agents (e.g. estramustine phosphate, prednimustine) , hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment.
  • anthracyclines e.g., doxorubicin, daunorubicin
  • antitumor antibiotics e.g., mitomycin, idarubicin,
  • 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.
  • the attachment point can attach to the rest of the molecule at any attachable position on the rings.
  • Formula i represents attaching at any attachable position on ring A' or ring B'.
  • two attachment points within a ring system 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; the two attachment points can be interchanged.
  • Formula x represents attaching at any attachable position on the rings, and the two attachment points can be used interchangeably with each other.
  • each...is independently is used interchangeably with the phrase “each (of) ...and...is independently” .
  • the specific options expressed by the same symbol are independently of each other in different radicals; or the specific options expressed by the same symbol are independently of each other in same radicals.
  • the sign refers to a single bond or a double bond disclosed herein.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E.W. Martin.
  • 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.
  • isomers refers to different compounds having same molecular formula. “Stereisomer” refers to isormers differ in just spatial arrangement of atoms. The term isomers as used herein embrace any and all geometric isomers and stereoisomers. For example, “isomers” include cis-and trans-isomer, E-and Z-isomer, R-and S-enantiomer, diastereoisomer, (d) -isomer, (l) -isomer, racemic mixture thereof, as well as other mixtures fall in the scope of the invention.
  • 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) - (III) containing hydroxy group.
  • 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.
  • 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-chloro
  • prodrug refers to a compound that is transformed in vivo into a compound of Formula (I) - (III) . Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound disclosed herein that contains a hydroxy 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 a hydroxy group on the parent compound.
  • phosphates such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound.
  • a thorough discussion of prodrugs is provided in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, et al. ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entireties.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • the present invention includes isotopically-labeled compounds, which are identical to those recited in Formula (I) - (III) , but that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • isotopically labeled compounds of Formula (I)- (III) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • metabolite refers to a product produced through metabolism in the body of a specified compound or salt thereof.
  • the metabolites 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 oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme 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.
  • pharmaceutically acceptable salt refers to organic or inorganic salts of a compound disclosed herein.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19, which is incorporated herein by reference.
  • Examples of pharmaceutically acceptable, nontoxic salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid and nitric acid or with organic acids such as acetic acid, propionic acid, glycollic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid or salts obtained by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid and nitric acid
  • organic acids such as acetic acid, propionic acid, glycollic acid, oxalic acid,
  • salts include adipate, malate, 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, pectate, persulfate
  • alkali or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, ferric salt, zinc salt, copper salt, manganese salt, aluminium salt, 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-butoxy-carbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxy-carbonyl (Fmoc) .
  • a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable 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. Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methy-l, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) -ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like.
  • the compound is characterized by the corresponding structure.
  • the compounds provided herein can be used in regulating the activities of protein kinases such as CDKs, especially regulating or inhibiting the activities of CDK4 or CDK6.
  • a compound having Formula (I) or a stereoisomer a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • R 1 , R 2 , R 3 , L 1 and ring B are as defined herein.
  • ring B is
  • each Y 3 , Y 4 , Y 5 , Y 6 , Y 8 and Y 7 is independently CR 4 or N;
  • R 4 , t, R 6 , R 7 , R 5 and n are as defined herein.
  • R 1 is H, F, Cl, Br, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy, which is substituted optionally with one or more independent R 8 ;
  • R 8 is as defined herein.
  • R 2 is H, F, Cl, Br, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy, which is substituted optionally with one or more independent R 8 ;
  • R 8 is as defined herein.
  • R 4c , R 5c and n1 are as defined herein.
  • R 3 is H, C 5-12 spiro heterobicyclyl, C 5-12 bridged heterobicyclyl, C 5-12 fused heterobicyclyl, C 3-9 cycloalkyl, C 3-9 heterocyclyl or C 1-9 heteroaryl, which is substituted optionally with one or more independent R 8 ; and
  • R 8 are as defined herein.
  • R 6 , R 7 and n are as defined herein.
  • R 6 , R 7 and n are as defined herein.
  • R 4 , R 6 , R 7 , R 8 and n are as defined herein.
  • R 4 , R 6 , R 7 , R 8 and n are as defined herein.
  • each n1 is independently 0, 1, 2, 3 or 4.
  • each n is independently 0, 1, 2, 3 or 4.
  • each t is independently 0, 1 or 2.
  • n is as defined herein.
  • n is as defined herein.
  • R 4 , R 6 , R 7 and n are as defined herein.
  • a compound having Formula (II) or a stereoisomer a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of Y 3 , Y 4 , Y 5 and Y 6 is independently CR 4 or N;
  • R 1 , R 2 , R 3 , L 1 , t, R 4 and R 5 are as defined herein.
  • a compound having Formula (III) or a stereoisomer a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of Y 3 , Y 4 , Y 5 and Y 6 is independently CR 4 or N;
  • R 1 , R 2 , R 3 , L 1 , t, R 4 and R 5 are as defined herein.
  • R 4 , R 7 , R 6 and n are as defined herein.
  • R 4 , R 7 , R 6 and n are as defined herein.
  • R 7 , R 6 and n are as defined herein.
  • R 7 , R 6 and n are as defined herein.
  • n is as defined herein.
  • n is as defined herein.
  • R 4 , R 7 , R 6 and n are as defined herein.
  • R 4 , R 7 , R 6 and n are as defined herein.
  • R 7 , R 6 and n are as defined herein.
  • R 7 , R 6 and n are as defined herein.
  • n is as defined herein.
  • n is as defined herein.
  • X 1 , X, e, f, and n are as defined herein.
  • R 4 , R 7 , R 6 , X 1 , X, e, f and n are as defined herein.
  • R 4a , R 5a and t are as defined herein.
  • R 4 , R 7 , R 6 and n are as defined herein.
  • R 7 , R 6 and n are as defined herein.
  • each e is independently 0, 1, 2 or 3.
  • each f is independently 0, 1, 2 or 3.
  • n is as defined herein.
  • R 4 , R 6 , R 7 and n are as defined herein.
  • R 3 is H
  • each X 3 , X 4 and X 5 is independently CR 4b or N;
  • each e, g and f is independently 0, 1, 2 or 3;
  • R 3 is optionally and independently substituted with one or more R 8 ;
  • R 8 is optionally and independently substituted with one or more R 9 ;
  • R 4 , R 7 , R 6 and n are as defined herein.
  • R 7 , R 6 and n are as defined herein.
  • R 4 , R 7 , R 6 and n are as defined herein.
  • R 7 , R 6 and n are as defined herein.
  • R 3 is H
  • n 0, 1, 2 or 3;
  • each moiety represented by R 3 is independently and optionally substituted with one or more R 8 ;
  • R 8 is as defined herein.
  • R 4 and R 5 is as defined herein.
  • each Y 3 , Y 4 , Y 5 and Y 6 is independently CR 4 or N;
  • R 4 and R 5 is as defined herein.
  • provided herein is a pharmaceutical composition comprising the compound disclosed herein.
  • the pharmaceutical composition disclosed herein further comprises at least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles.
  • the pharmaceutical composition further comprises an additional therapeutic agent, the additional therapeutic agent is a chemotherapeutic drug, an antiproliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, a CDK4/6 kinase inhibitor, an ABL inhibitor, an ABL/Scr inhibitor, an aurora kinase inhibitor, a non-ATP competitive inhibitor of BCR-ABL, a c-KIT mutation inhibitor, a RET inhibitor, a PDGFR inhibitor, a VEGFRinhibitor, a CSF1R inhibitor, an FLT3 inhibitor, an FLT3-ITD inhibitoror a combination thereof.
  • the additional therapeutic agent is a chemotherapeutic drug, an antiproliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, a CDK4/6 kin
  • the additional therapeutic agent of the pharmaceutical composition disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cis-platinum, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbozine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, pharmorubicin, daunomycin, mitoxantrone, bleomycin, mitomycinC, ixabepilone, tamoxifen, flutamide, gonadorel
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture a medicament for preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection.
  • the abnormal cell proliferation disorder or disease is ovarian cancer, cervical cancer, testiculoma, esophagus cancer, gastric cancer, skin cancer, lung cancer, osteocarcinoma, acute myeloid leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myelocytic leukemia (AML) , chronic myeloid leukemia (CML) with mutation, acute lymphoblastic leukemia (ALL) , colorectal cancer, gastric cancer, breast cancer, lung cancer, cancer of the liver, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, neck cancer, cancer of the central nervous system, spongioblastoma or myelodysplastic syndrome, atherosclerosis, pulmonary fibrosis, leukemia, lymph cancer, rheumatic disease, cryoglobulinemia, non-lymphoreticular system tumor, papular mucinosis, familial splenic anemia, multiple mye
  • the autoimmune disease is rheumatic arthritis, lupus, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
  • the inflammatory disease is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
  • the infection disease is virus infection or fungal infection.
  • the disease is a disease caused by changes in cyclin-dependent kinase.
  • the cyclin-dependent kinase is CDK1, CDK2, CDK4, CDK6 or CDK9.
  • the disease is a disease caused by changes in CDK4 or CDK6 protein kinase.
  • a drug combination comprising the compound or the pharmaceutical composition disclosed herein and one or more other activity agents used for treating proliferative diseases, autoimmune diseases or inflammatory diseases.
  • the drug combination disclosed herein wherein the other activity agent comprises chemotherapeutic drug , antiproliferative agent, immunosuppressor, immunologic stimulant, anti-inflammatory agent, CDK4/6 kinase inhibitor, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitor, non-ATP competitive inhibitor of BCR-ABL, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFRinhibitor, CSF1R inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof.
  • the other activity agent comprises chemotherapeutic drug , antiproliferative agent, immunosuppressor, immunologic stimulant, anti-inflammatory agent, CDK4/6 kinase inhibitor, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitor, non-ATP competitive inhibitor of BCR-ABL, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFRinhibitor, CSF1R inhibitor, FLT3 inhibitor
  • the invention provides a method of the invention provides a method of preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection in a patient comprising administrating to the patient a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein.
  • the compound or the pharmaceutical composition for use in preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection
  • 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 salt of 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) to (III) and/or for separating enantiomers of compounds of Formula (I) to (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 the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like.
  • 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
  • cyclic amines such as piperidine,
  • 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.
  • the compounds of the present invention are specific inhibitors of CDK4 and CDK6 and are therefore useful in the treatment of a disease or disorder characterised by abnormal cell proliferation.
  • the compounds of the present invention are useful in the treatment of cancer.
  • CDK4 and CDK6 modulate their effects on the cell cycle through the phosphorylation of pRb.
  • the compounds of the present invention which are potent inhibitors of CDK4/6 activity and thus pRb phosphorylation, are expected to inhibit cell proliferation (and therefore tumour growth) in any cancer type where the cells are proliferating and contain a functional, intact Rb1 gene (which encodes pRb) .
  • the compounds of the invention are therefore useful in the treatment of pRb+ cancers such as colorectal cancer, breast cancer, lung cancer, prostate cancer, chronic granulocytic leukaemia, acute granulocytic leukaemia (Fry, D. W. et al. Mol. Cancer Ther.
  • the mammal to be treated is a human.
  • the compounds of the invention can be used in the treatment of cancers in mammal, especially in the methods of treating the aforementioned cancers, the methods comprise administrating to the mammal in need of the treatment a therapeutically effective amount of the compounds of the invention.
  • the compound of the invention can be used in the methods of treating cancers, the cancer is selected from colorectal cancer, mantle cell lymphoma, breast cancer, spongioblastoma, acute granulocytic leukemia and lung cancer, especially non-small cell lung cancer (NSCLC) .
  • NSCLC non-small cell lung cancer
  • the compound of the invention can be used in the methods of treating cancers, the cancer is selected from colorectal cancer, spongioblastoma, acute granulocytic leukemia and lung cancer.
  • the compound of the invention can be used in the methods of treating spongioblastoma or astrocytoma in mammal, the methods comprise administrating to the mammal in need of the treatment a therapeutically effective amount of a combination of the compounds of the invention and temozolomide.
  • the compound of the invention can be used in the methods of treating non-small cell lung cancer, pancreatic cancer, ovarian cancer or metastatic breast cancer in mammal, the methods comprise administrating to the mammal in need of the treatment a therapeutically effective amount of a combination of the compounds of the invention and gemcitabine hydrochloride.
  • the compounds of the invention can be used in the manufacture of a medicament for treating cancers, especially the aforementioned cancer.
  • the compounds of the invention can be used in the manufacture of a medicament for treating cancers, the cancer is selected from colorectal cancer, mantle cell lymphoma, breast cancer, spongioblastoma, acute granulocytic leukemia and lung cancer, especially non-small cell lung cancer (NSCLC) .
  • NSCLC non-small cell lung cancer
  • the compounds of the invention can be used in the manufacture of a medicine for treating cancers, the cancer is selected from colorectal cancer, spongioblastoma, acute granulocytic leukemia and lung cancer.
  • the present invention provides the use of the compounds of the invention in the manufacture of a medicament for treating spongioblastoma or astrocytoma, wherein the medicament also includes temozolomide or is to be administered simultaneously, separately or sequentially with temozolomide.
  • the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of NSCLC, pancreatic cancer, ovarian cancer or metastatic breast cancer, wherein the medicament also comprises gemcitabine hydrochloride or is to be administered simultaneously, separately or sequentially with gemcitabine hydrochloride.
  • a pharmaceutical formulation for treating cancers in particular the cancers described above comprising a compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
  • a pharmaceutical formulation for treating a cancer selected from the group consisting of colorectal cancer, mantel cell lymphoma, breast cancer, glioblastoma, acute myeloid leukaemia and lung cancer, especially NSCLC, comprising a compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
  • a pharmaceutical formulation for treating a cancer selected from the group consisting of colorectal cancer, glioblastoma, acute myeloid leukaemia and lung cancer, comprising a compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical formulation for treating glioblastoma or astrocytoma, comprising a compound of the invention and temozolomide, together with a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical formulation for treating NSCLC, pancreatic cancer, ovarian cancer or metastatic breast cancer, comprising a compound of the invention and gemcitabine hydrochloride, together with a pharmaceutically acceptable carrier.
  • the invention also provides a pharmaceutical formulation, comprising a compound of the invention or a pharmaceutically acceptable salt thereof and temozolomide, together with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention also provides a pharmaceutical formulation, comprising a compound of the invention or a pharmaceutically acceptable salt thereof and gemcitabine hydrochloride, together with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention further provides a pharmaceutical formulation comprising a compound of the invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • the compounds of the present invention have valuable pharmacological properties and are useful in the treatment of diseases.
  • compounds of the invention are useful in the treatment of a proliferative disease, or cancer.
  • a proliferative disease is mainly a tumor disease (or cancer) (and/or any metastases) .
  • the inventive compounds are particularly useful for treating a tumor which is a breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian cancer, pancreas cancer, neuroblastoma, head and/or neck cancer or bladder cancer, or in a broader sense renal, brain or gastric cancer; in particular (i) a breast tumor; an epidermoid tumor, such as an epidermoid head and/or neck tumor or a mouth tumor; a lung tumor, for example a small cell or non-small cell lung tumor; a gastrointestinal tumor, for example, a colorectal tumor; or a genitourinary tumor, for example, a prostate tumor (especially a hormone-refractory prostate tumor) ; or (ii) a proliferative disease that is refractory to the treatment with other chemotherapeutics; or (i
  • a proliferative disease may furthermore be a hyperproliferative condition such as leukemias, hyperplasias, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis) , angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • a hyperproliferative condition such as leukemias, hyperplasias, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis) , angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, whatever the location of the tumor and/or metastasis.
  • the inventive compound is selectively toxic or more toxic to rapidly proliferating cells than to normal cells, particularly in human cancer cells, e.g., cancerous tumors, the compound has significant antiproliferative effects and promotes differentiation, e.g., cell cycle arrest and apoptosis.
  • compounds of the invention are useful in the treatment of transplant rejections.
  • transplant rejections that may be treated by the compounds of the invention include, but are not limited to, graft versus host disease, rejection related to xeno transplantation, rejection related to organ transplant, rejection related to acute transplant, heterograft or homograft rejection and ischemic or reperfusion injury incurred during organ transplantation.
  • compounds of the invention are useful in the treatment of autoimmune diseases.
  • autoimmune diseases to be treated by the compounds of the invention include, but are not limited to, autoimmune hemolytic anemia, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenia purpura, autoimmunocytopenia, hemolytic anemia, antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, relapsing polychondritis, rheumatic heart disease, glomerulonephritis, multiple sclerosis, neuritis, uveitis ophthalmia, polyendocrinopathies, purpura, Reiter's Disease, Stiff-Man Syndrome, autoimmune pulmonary inflammation, autism, Guillain-Barre Syndrome, insulin dependent diabetes mellitis, autoimmune inflammatory eye, autoimmune thyroiditis, hypothyroidism, systemic lupus erhythematosus, Goodpasture's syndrome,
  • use includes any one or more of the following embodiments of the invention, respectively: the use in the treatment of protein kinase-associated disorders; the use for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, e.g., in the manufacture of a medicament; methods of use of compounds of the invention in the treatment of these diseases; pharmaceutical preparations having compounds of the invention for the treatment of these diseases; and compounds of the invention for use in the treatment of these diseases; as appropriate and expedient, if not stated otherwise.
  • diseases to be treated and are thus preferred for use of a compound of the present invention are selected from cancer, transplant rejections, or autoimmune diseases, as well as those diseases that depend on the activity of protein kinases.
  • compositions herein which bind to a protein kinase sufficiently to serve as tracers or labels, so that when coupled to a fluor or tag, or made radioactive, can be used as a research reagent or as a diagnostic or an imaging agent.
  • the invention provides pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) - (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier for administering.
  • the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • an effective amount of the compound is that amount necessary or sufficient to treat or prevent a protein kinase-associated disorder, e.g. prevent the various morphological and somatic symptoms of a protein kinase-associated disorder, and/or a disease or condition described herein.
  • an effective amount of the compound of the invention is the amount sufficient to treat a protein kinase-associated disorder in a subject.
  • the effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. For example, the choice of the compound of the invention can affect what constitutes an “effective amount. ”
  • One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount of the compounds of the invention without undue experimentation.
  • the regimen of administration can affect what constitutes an effective amount.
  • the compound of the invention can be administered to the subject either prior to or after the onset of a protein kinase-associated disorder. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the compound (s) of the invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • ком ⁇ онент there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the invention and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g. synergistic effect.
  • co-administration or “combined administration” or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination refers to a product obtained from mixing or combining active ingredients, and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound disclosed herein and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound of the invention and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • Compounds of the invention may be used in the treatment of states, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases. Methods of use of compounds of the present invention in the treatment of these diseases, or pharmaceutical preparations having compounds of the present invention for the treatment of these diseases.
  • composition includes preparations suitable for administration to mammals, e.g., humans.
  • compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • phrases “pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , lecithin, propyl gallate, ⁇ -tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA) , sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydroxytolu
  • Formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth) , powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose) , lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose) , surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient (s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluent commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils) , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluent commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides) . Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral and/or IV administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally (as by, a spray) , rectally, intravaginally, parenterally, intracistemally and topically (as by powders, ointments or drops, including buccally and sublingually) .
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • intravenous and subcutaneous doses of the compounds of this invention for a patient when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day.
  • An effective amount is that amount treats a protein kinase-associated disorder.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredients for a subject of about 50-70 kg, preferably about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg or about 1-50 mg of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 -3 molar and 10 -9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. In yet other embodiments, the subject is a human.
  • the compounds of the present invention can be given per se, preferentially administered to a subject in the form of a pharmaceutical composition.
  • combination therapies using one or more compounds or compositions provided herein, or pharmaceutically acceptable derivate, in combination with other pharmaceutically active agents for the treatment of the diseases and disorders described herein.
  • effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds which are formulated for oral, systemic, including parenteral or intravenous delivery, or for local or topical application are administered to an individual exhibiting the symptoms of the disease or disorder to be treated.
  • the amounts are effective to treat, manage or ameliorate the disease or ameliorate or eliminate one or more symptoms of the disease or disorder.
  • the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided herein can be used in a wide variety of combination therapies to treat the conditions and diseases described above.
  • combination therapies to treat the conditions and diseases described above.
  • compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided herein in combination with other active pharmaceutical agents for the treatment of the disease/conditions described herein.
  • the compound or composition provided herein, or pharmaceutically acceptable derivative thereof may be administered simultaneously with, prior to, or after administration of one or more of the above agents.
  • the other active pharmaceutical agents particularly therapeutic agents known to be useful for treating a proliferative disorder or cancer afflicting the subject.
  • the one or more other active pharmaceutical agents is selected from anticancer agents (such as a cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, anti-metabolites, intercalating anticancer agents, topoisomerase inhibitors, immunotherapeutic agents, or antihormonal agents) , steroid drugs, methotrexates, leflunomides, anti-TNF- ⁇ agents, calcineurin inhibitors, antihistaminic drugs, chemotherapeutic drugs, antiproliferative agents, immunosuppressors, immunologic stimulants, apronounced anti-inflammatory reagents, CDK4/6 kinases inhibitors, ABL inhibitors, ABL/Scr inhibitors, aurora kinase inhibitors, non-ATP competitive inhibitors of BCR-ABL, c-KIT mutation inhibitors, RET inhibitors, PDGFR inhibitors, VEGFRinhibitors, CSF1R inhibitors, FLT3 inhibitors, FLT3-ITD inhibitors or a combination
  • anticarcinogen is seclected from alkylating agents (such as cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ranimustine, dacarbazine, temozolomide, chlormethine hydrochloride, dibromannitol, and the like) , platinum complexing agents (such as cis-platinum, carboplatin, oxaliplatin, and the like) , metabolic antagonists (such as methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, and the like) , plant alkaloids (such as vincristine, vinblastine , vindesine, etoposide , docetaxel, paclitaxel, irinotecan, vinorelbine , mitoxantrone, vinflunine, topotecan, and the like) , antibody drugs (
  • the one or more other active pharmaceutical agents is selected from streptozotocin, oxaliplatin, temozolomide, methotrexate, fluorouracil, gemcitabine, purinethol, navelbine, docetaxel, topotecan, irinotecan, trabectedin, dactinomycin, mitomycin C, lxabepilone, gonadorelin analogues, megestrol acetate, prednisone, methylprednisolone, thalidomide, interferon ⁇ , calcium folinate, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib
  • the present invention also provided herein a pharmaceutical composition containing compounds disclosed herein or a pharmaceutically acceptable derivate, and one or more other active pharmaceutical agents as a single dosage form or separately from the compound or composition as part of a multiple dosage form.
  • the other active pharmaceutical agents may be administered at the same time as a 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.
  • the present invention also provided herein a combination therapy that treats or prevents the onset of the symptoms, or associated complications of cancer and related diseases and disorders comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more other active pharmaceutical agents.
  • two administrations in drug combinations 1) the compound or pharmaceutical composition disclosed herein and other active drugs which can be used in combination are in separate formulation, two formulations can be same or different, can be administered either in sequence or simultaneously; when administration in sequence, the second drug is administered during the effective period of the first drug in vivo; 2) the compound or pharmaceutical composition disclosed herein and other active drugs which can be used in combination are in single formulation and administered simultaneously.
  • specially provided herein is a drug combination of FLT3 inhibitor or FLT3-ITD inhibitor and CDK4/6 inhibitor.
  • the compound or composition provided herein or pharmaceutically acceptable derivative thereof as CDK4/6 inhibitor, may be administered simultaneously with, prior to, or after administration of one or more of the active agents.
  • the other active agents specially is FLT3 inhibiotr or FLT3-ITD inhibitor.
  • FLT3 inhibitor or FLT3-ITD inhibitor is cabozantinib, ponatinib, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, and so on.
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I) - (III) , above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • temperatures are set forth in degrees Celsius (°C) .
  • 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 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 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 on an Agilent 6120 Quadrupole HPLC-MS spectrometer equipped with an Agilent Zorbax SB-C18 (2.1 x 30 mm, 3.5 ⁇ m) . 6 min; the flow rate was 0.6 mL/min; the mobile phases consisted of a combination of A (0.1%formic acid in CH 3 CN) and B (0.1%formic acid in H 2 O) in gradient mode (5%to 95%) , and an ESI source was used, the peak of HPLC was recorded with UV-Vis detection at 210/254 nm.
  • the intermedia disclosed herein can be prepared by the process illustrated in scheme1intermedia.
  • Compound (1a) can react with compound (2a) in the present of a base under a heating condition to afford compound (3a) ; catalytic hydrogenation of compound (3) can give compound (1) ; wherein B, R 3 and L1 are as defined herein.
  • the intermedia disclosed herein can be prepared by the process illustrated in scheme 2 intermedia. Still reaction of compound (1ad) in the present of toluene-3.4-dithiol can afford compound (1ae) ; cyclization reaction of compound (1ae) in the present of a base (can be R 3 -L 1 -NH 2 with no limitation) under a heating condition can afford compound (1af) ; reduction of amide of conpound (1af) can afford compound (1ag) ; a methyl group of compound (1ag) can be removed in the present of HBr and AcOH to afford compound (1ah) ; compound (1ah) can form compound (1ai) in the present of POCl 3 ; compound (1ai) can convert to compound (4d) in the present of ammonium hydroxide; wherein L 1 and R 3 are as defined herein.
  • the compound disclosed herein can be prepared by the process illustrated in scheme 1. Buchwald cross coupling reaction of compound (1) and compound (5) catalyzed by palladium can give target compound (2) , wherein B, L 1 , R 1 , R 2 and R 3 are as defined herein.
  • the compound disclosed herein can be prepared by the process illustrated in scheme 2. Buchwald cross coupling reaction of compound (13) and compound (5) catalyzed by palladium can give target compound (14) , wherein L 1 , R 1 , R 2 and R 3 are as defined herein.
  • the compound disclosed herein can be prepared by the process illustrated in scheme 3. Buchwald cross coupling reaction of compound (4d) and compound (5) catalyzed by palladium can give target compound (14a) , wherein L 1 , R 1 , R 2 and R 3 are as defined herein.
  • Step 1) tert-butyl 2- ( (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) amino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate
  • Step 2 N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8 -tetrahydro-1, 6-naphthyridin-2-amine
  • the reaction mixture was concentrated in vacuo, the residue was participated beween DCM (100 mL) and water (100 mL) .
  • the organic layer was washed with saturated aqueoussodium bicarbonate (80 mL ⁇ 3) and saturated aqueous NaCl (80 mL ⁇ 1) , dried over anhydrous Na 2 SO 4 and concentrated.
  • the reaction mixture was concentrated in vacuo, the residue was participated beween DCM (100 mL) and water (100 mL) .
  • the organic layer was washed with saturated aqueoussodium bicarbonate (80 mL ⁇ 3) and saturated aqueous NaCl (80 mL ⁇ 1) , dried over anhydrous Na 2 SO 4 and concentrated.
  • Step 2) 3- (2- ( (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) ami no) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) propan-1-ol
  • the reaction was monitored by TLC.
  • the reaction mixture was cooled and concentrated to remove tetrahydrofuran.
  • the residue was diluted with saturated aqueous sodium bicarbonate solution (100 mL) .
  • the resulting mixture was extracted with EtOAc (150 mL ⁇ 3) .
  • the combined organic layers were washed with saturated aqueous NaCl (50 mL) , dried over anhydrous Na 2 SO 4 and concentrated in vacuoto give a yellow solid product (88 mg, 78.19%) .
  • Step 1) tert-butyl 4- (7- ( (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) ami no) -3, 4-dihydro-2, 6-naphthyridin-2 (1H) -yl) piperidine-1-carboxylate
  • Step 2 N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -6- (pipe ridin-4-yl) -5, 6, 7, 8-tetrahydro-2, 6-naphthyridin-3-amine
  • Biologic example 1 Enzymatic inhibitory activity in vitro of the compound of the invention
  • HEPES 4- (2-Hydroxyethyl) piperazine-1-ethanesulfonic acid
  • DTT Dithiothreitol
  • EDTA Ethylene Diamine Tetraacetic Acid
  • CDK4/CycD3 Cyclin dependent kinase 4
  • CDK6/CycD3 Cyclin dependent kinase 6
  • Peptide FAM-P22 fluorescein-labeled peptide 22;
  • ATP adenosine triphosphate
  • DMSO dimethyl sulfoxide
  • 1 ⁇ Kinase buffer without MnCl 2 was prepared by using 50 mM HEPES, pH 7.5, 0.0015%Brij-35, 10 mM MgCl 2 , 2 mM DTT;
  • Stop buffer was prepared by using 100 mM HEPES, pH 7.5, 0.015%Brij-35, 0.2%Coating Reagent #3, 50 mM EDTA.
  • the compound was diluted to 50 ⁇ of the final desired highest inhibitor concentration in reaction by 100%DMSO. Transferring 100 ⁇ L of this compound dilution to a well in a 96-well plate. (2) The compound was diluted gradiently by transferring 20 ⁇ L of original solution to 60 ⁇ L of 100%DMSO in the next well and so forth to obtain 10 different concentrations. (3) Adding 100 ⁇ L of 100%DMSO to two empty wells for a control without compound and a control without enzyme. (4) Preparing intermediate plate, 10 ⁇ L of each compound solution was transfered from source plate to a new 96-well plate as the intermediate plate. Adding 90 ⁇ L of 1 ⁇ kinase buffer to each well of the intermediate plate. The compounds were mixed in intermediate plate for 10 min on shaker. (5) Preparing assay plate, 5 ⁇ L of each compound solution in well was transferred from the 96-well intermediate plate to a 384-well plate in duplicates.
  • the assay agents and samples are as shown below:
  • Propranolol Propranolol (internal standard) ;
  • Cremophor EL polyoxyethylated castor oil
  • KolliphorHS 15 polyethylene glycol 12-hydroxystearate
  • PEG400 polyethylene glycol 400
  • test compound prepared was completely dissolved in a mixture of 5%DMSO, 10%KolliphorHS 15, 35%Saline or 5%DMSO, 60%PEG400 and 35%Saline according solubility property thereof.
  • blood samples of intravenous injection group were collected at time points of 0.0833, 0.25, 0.5, 1, 2, 5, 7 and 24 h from caudal vein; blood samples of oral group were collected at time points of 0.25, 0.5, 1, 2, 5, 7 and 24 h from caudal vein.
  • Standard curve was plotted based on concentrations of the samples in a suitable range, the concentrations of test compounds in plasma samples were determined by using LC-MS/MS.
  • Pharmacokinetic parameters were calculated according to drug concentration -time curve using a noncompartmental method by WinNonLin 6.3 software.
  • Biologic example 3 In vivopharmacokinetic activity of the compound of the invention in mice
  • mice 18 ICR mice weighing 18-25 g randomly to three groups; each group has 6 mice. 3 mice of every group were administered by intravenous injection and the other 3 mice were administered by gavage with test compound. After administering, blood samples were collected at designed time points. The blood samples were centrifuged to collect plasma samples. After treating the plasma samples, the blood medicinal concentrations were determined by using LC-MS/MS. Pharmacokinetic parameters were calculated using a noncompartmental method by WinNonLin software. Results were shown as below:

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Abstract

The invention provides compounds as CDK small-molecule inhibitors and uses thereof, the compounds can be used for treating inflammation and cell proliferation diseases. The novel compound of the invention is a powerful cyclin-dependent kinase 4 (CDK 4) or cyclin-dependent kinase-6 (CDK 6) inhibitor.

Description

COMPOUNDS AS CDK SMALL-MOLECULE INHIBITORS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to Chinese Patent Application Serial No. 201410362374.8, filed with the State Intellectual Property Office of China on July 26, 2014 and Serial No. 201510015255.X, filed with the State Intellectual Property Office of China on January 13, 2015； both of which are hereby incorporated by reference in their entireties and for all purposes as if specifically and fully set forth herein.
FIELD OF THE INVENTION
The present invention relates to novel compounds as CDK small-molecule inhibitors and pharmaceutical compositions thereof, and also to uses of the compounds and the pharmaceutical compositions in the treatment of exceedingly proliferative disorders.
BACKGROUND OF THE INVENTION
In recent years, cancer has surpassed cardiovascular diseases to become the world’s leading death disease, antineoplastic research has an important academic and practical significance. The study found that almost all of the tumors are related to uncontrolled cell growth, blocked differentiation and apoptosis abnormalities caused by cell cycle control mechanisms disorder.
Initiation, progression, and completion of the mammalian cell cycle are regulated by various cyclin-dependent kinase (CDK) complexes, which are critical for cell growth. These complexes comprise at least a catalytic (the CDK itself) and a regulatory (cyclin) subunit. Some of the more important complexes for cell cycle regulation include cyclin A (CDK1—also known as CDC2, and CDK2) , cyclin B1-B3 (CDK1) and cyclin D1-D3 (CDK2, CDK4, CDK5, CDK6) , cyclin E (CDK2) . Each of these complexes is involved in a particular phase of the cell cycle. The activity of CDKs is regulated post-translationally, by transitory associations with other proteins, and by alterations of their intracellular localization. Tumor development is closely associated with genetic alteration and dysregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful for anti-cancer therapeutics.
CDKs, and their associated proteins, in co-ordinating and driving the cell cycle in proliferating cells play key roles in some biochemical pathways. Using therapeutics targeted generically at CDKs, or at specific CDKs can be for the treatment of proliferative disorders, such  as cancers. CDK inhibitors could conceivably also be used to treat other conditions such as viral infections, autoimmune diseases and neuro-degenerative diseases, amongst others. CDK targeted therapeutics may also provide clinical benefits in the treatment of the previously described diseases when used in combination therapy with existing therapeutic agents. CDK targeted anticancer therapies could potentially have advantages over many current antitumour agents as they would not directly interact with DNA and should therefore reduce the risk of secondary tumour development.
Although a number of CDKs compounds have been disclosed in the art, in view of the number of pathological responses that are mediated by CDK, there remains a continuing need for drugs which can be used in the treatment of a variety of conditions mediated by CDK, especially CDK4/6.
SUMMARY OF THE INVENTION
There remain needs for a large number of new therapies and drugs used for treating disorders related to protein kinases, as well as compounds used for treating, preventing, or improving one or more of cancer, autoimmune diseases and infection diseases. The compounds provided herein can be used in regulating the activities of protein kinases such as CDKs, regulating or inhibiting the activities of CDK1, CDK2, CDK4, CDK6 or CDK9, especially regulating or inhibiting the activities of CDK4 or CDK6, which have good clinical prospects. The compounds provided herein have better characteristics of pharmacodynamics in vivo, pharmacokinetics and/or toxicology than the existing similar compound. The parent structure of the compounds disclosed herein is completely different from those disclosed in prior art, and the prior arts do not indicate the inventor any relative technical enlightenment； the compounds disclosed herein have an advantage in inhibiton on CDK4/6, and have prominent substantive features.
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, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2015085034-appb-000001
wherein
ring B is
Figure PCTCN2015085034-appb-000002
Figure PCTCN2015085034-appb-000003
wherein each Y, Y1 and Y2 is independently -C (R4) 2-, -N (R5) -, -O-, -S (＝O) t-or -C (＝O) -；
each Y3, Y4, Y5, Y6, Y8 and Y7 is independently CR4 or N；
each of R1 and R2 is independently H, F, Cl, Br, hydroxy, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy；
L1 is a bond, - (C (R4c) 2) n1-, - (C (R4c) 2) n1-C (＝O) -N (R5c) - (C (R4c) 2) n1-, - (C(R4c) 2) n1-N (R5c) - (C (R4c) 2) n1-, - (C (R4c) 2) n1-O- (C (R4c) 2) n1-, - (C (R4c) 2) n1-S (＝O) t- (C (R4c) 2) n1-or - (C(R4c) 2) n1-C (＝O) - (C (R4c) 2) n1-；
R3 is H, C5-12 spiro heterobicyclyl, C5-12 bridged heterobicyclyl, C5-12 fused heterobicyclyl, C3-9 cycloalkyl, C3-9 heterocyclyl or C1-9 heteroaryl；
each R4c and R4 is independently H, C1-6 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-6 alkoxy, H2N- (CH2) n-, N (R6R7) -C (＝O) -, formyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H- (CH2) n-O- (CH2) n-, CN- (CH2) n-C (＝O) -, C3-9 heterocyclyl, C1-9 heteroaryl, C1-6 haloalkyl or C1-6 alkylamino；
each R5c and R5 is independently H, C1-6 alkyl, C1-6 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-9 heterocyclyl or C1-9 heteroaryl；
each n and n1 is independently 0, 1, 2, 3, or 4；
each t is independently 0, 1, or 2；
each R6 and R7 is independently H, C1-6 alkyl, hydroxy, carboxy, amino, C1-6 alkoxy, H2N- (CH2) n-, NH2-C (＝O) -, formyl, H- (CH2) n-O-C (＝O) - (CH2) n-, C3-9 heterocyclyl, C1-9 heteroaryl, C1-6 haloalkyl or C1-6 alkylamino；
each moiety represented by B is optionally and independently substituted with one or more substituents independently selected from H, C1-6 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-6 alkoxy, C1-6 haloalkyl, (R6R7) N- (C (R4) 2) n-, N (R6R7) -C (＝O) -, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, cyano or nitro；
each alkyl, alkoxy, haloalkyl, alkylamino, spiro heterobicyclyl, bridged heterobicyclyl, fused heterobicyclyl, heterocyclyl, heteroaryl, aryl, cycloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -and H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, described in R1, R2, R5c, R3 and/or R5 is optionally and independently substituted with one or more；
each R8 is independently H, oxo (＝O) , C1-6 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 haloalkyl, cyano, C3-9 heterocyclyl, C1-9 heteroaryl, H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-, HO- (CH2) n-C (＝O) -, NH2-C (＝O) -, CN- (CH2) n-C (＝O) -, C3-9 cycloalkyl or nitro； each alkyl, alkoxy, alkylamino, haloalkyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-C (＝O) -, HO- (CH2) n-, NH2-C (＝O) -, heterocyclyl, cycloalkyl and heteroaryl described in R8 is optionally and independently substituted with one or more R9； and
each R9 is independently H, oxo (＝O) , C1-6 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 haloalkyl, formyl, cyano, HO- (C (R4) 2) n-,  H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, CN-C (R4) 2-C (＝O) -, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, C3-9 heterocyclyl, C1-9 heteroaryl, C3-9 cycloalkyl or nitro.
In some embodiments, provided herein is a compound having Formula (II) or Formula (III) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2015085034-appb-000004
wherein when
Figure PCTCN2015085034-appb-000005
is
Figure PCTCN2015085034-appb-000006
T1 is Y6；
when
Figure PCTCN2015085034-appb-000007
is
Figure PCTCN2015085034-appb-000008
T1 is Y1； and
wherein R1, R2, R3, L1, Y, Y1, Y2, Y3, Y4, Y5 and Y6 are as defined herein.
In some embodiments, eachR5cand R5 is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or C1-9 heteroaryl；
each R4c and R4 is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino；
each R6 and R7 is independently H, C1-4 alkyl, hydroxy, carboxy, amino, C1-4 alkoxy, H2N- (CH2) n-, NH2-C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, C3-9 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
wherein n is as defined herein.
In some embodiments, each R5cand R5 is independently H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -,  HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, H, trifluoromethyl, 2-fluoroethyl, 3, 3, 3-trifluoropropyl, methyl, ethyl, n-propyl, i-propyl, t-butyl, 2-methylpropyl or n-butyl；
each R4c and R4 is independently H, methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, hydroxy, carboxy, amino, methoxy, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, trifluoromethyl or methylamino；
each R6 and R7is independently H, methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, hydroxy, carboxy, amino, methoxy, H2N- (CH2) n-, NH2-C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, trifluoromethyl or methylamino； and
wherein n is as defined herein.
In some embodiments, each R8 is independently H, oxo (＝O) , C1-4alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 haloalkyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-, HO- (CH2) n-C (＝O) -, NH2-C (＝O) -, cyano, CN- (CH2) n-C (＝O) -, C1-9heteroaryl, 
Figure PCTCN2015085034-appb-000009
or nitro；
each R9 is independently H, oxo (＝O) , C1-4 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 haloalkyl, cyano, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, CN-C (R4) 2-C (＝O) -, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, 
Figure PCTCN2015085034-appb-000010
C1-9 heteroaryl or nitro；
each X and X1 is independently -C (R4a) 2-, -N (R5a) -, -O-, -S (＝O) t-or -C (＝O) -；
each e and f is independently 0, 1, 2 or 3； and
wherein t, n, R4a, R5a, R6 and R7 are as defined herein.
In some embodiments, each R5a is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or C1-9 heteroaryl；
each R4a is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
wherein t, n, R4, R6 and R7 are as defined herein.
In some embodiments, each R8 is independently H, oxo (＝O) , methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, F, Cl, Br, amino, hydroxy, carboxy, methoxy, ethoxy, 1-chloroethyl, dimethylamino, diethylamino, methylamino, trifluoromethyl, cyano,
Figure PCTCN2015085034-appb-000011
H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-, HO- (CH2) n-C (＝O) -, NH2-C (＝O) -, CN- (CH2) n-C (＝O) -or nitro；
each R9 is independently H, oxo (＝O) , methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 haloalkyl, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, CN-C (R4) 2-C (＝O) -, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, cyano, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, 
Figure PCTCN2015085034-appb-000012
Figure PCTCN2015085034-appb-000013
C1-9 heteroaryl or nitro； and
wherein n, R4, R6 and R7 are as defined herein.
In some embodiments,
R3 is H , 
Figure PCTCN2015085034-appb-000014
Figure PCTCN2015085034-appb-000015
wherein each X2, X6 and X7 is independently -C (R4b) 2-, -N (R5b) -, -O-, -S (＝O) t-or -C (＝O) -；
each X3, X4 and X5 is independently CR4b or N；
each e, g and f is independently 0, 1, 2 or 3；
R3 is optionallysubstituted with one or more R8；
each R8 is optionally and independently substituted with one or more R9； and
wherein t, R4b, R5b, R8 and R9 are as defined herein.
In some embodiments, each R5b is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or C1-9 heteroaryl；
each R4b is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
wherein R4, R6, R7 and n is as defined herein.
In other embodiments,
R3 is H , 
Figure PCTCN2015085034-appb-000016
Figure PCTCN2015085034-appb-000017
Figure PCTCN2015085034-appb-000018
Figure PCTCN2015085034-appb-000019
n is0, 1, 2 or 3；
each moiety represented by R3 is independently and optionally substituted with one or more R8； and
wherein R8 is as defined herein.
In some embodiments,
ring B is
Figure PCTCN2015085034-appb-000020
Figure PCTCN2015085034-appb-000021
each moiety represented by B is optionally and independently substituted with one or more substituents independently selected from H, C1-4 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4 alkoxy, C1-6 haloalkyl, (R6R7) N- (C (R4) 2) n-, N (R6R7) -C (＝O) -, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, cyano or nitro； and
wherein R5, R4, R7, R6 and n are as defined herein.
In oneaspect, 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 pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles.
In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent, wherein the additional therapeutic agent is a chemotherapeutic drug, an antiproliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, a CDK4/6 kinase inhibitor, an ABL inhibitor, an ABL/Scr inhibitor, an aurora kinase inhibitor, a non-ATP competitive inhibitor of BCR-ABL, a c-KIT mutation inhibitor, a RET inhibitor, a PDGFR inhibitor, a VEGFRinhibitor, a CSF1R inhibitor, an FLT3 inhibitor, an FLT3-ITD inhibitor or a combination thereof.
In some embodiments, the additional therapeutic agent of the pharmaceutical composition disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cis-platinum, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbozine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, pharmorubicin, daunomycin, mitoxantrone, bleomycin, mitomycinC, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon α, calcium folinate, 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, zelboraf, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, cabozantinib, ponatinib, midostaurin, pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, crenolanib, ENMD-2076, famitinib, dovitinib, PLX-3397, palbociclib, abemaciclib, ribociclib, rigosertib sodium, selinexor, roniciclib, AT-7519, seliciclib, alvocidib or a combination thereof.
In other aspect, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture a medicament for preventing, managing,  treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection.
In some embodiments of the use of the invention, the abnormal cell proliferation disorder or disease is ovarian cancer, cervical cancer, testiculoma, esophagus cancer, gastric cancer, skin cancer, lung cancer, osteocarcinoma, acute myeloid leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myelocytic leukemia (AML) , chronic myeloid leukemia (CML) with mutation, acute lymphoblastic leukemia (ALL) , colorectal cancer, gastric cancer, breast cancer, lung cancer, cancer of the liver, prostate cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, cancer of the central nervous system, spongioblastoma, myelodysplastic syndrome, atherosclerosis, pulmonary fibrosis, leukemia, lymph cancer, rheumatic disease, 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, part of the 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, glioblastoma multiforme , mantle cell lymphoma, chronic granulocytic leukemia, acute granulocytic leukemia, bladder cancer or myeloma.
In some embodiments of the use of the invention, the autoimmune disease is rheumatic arthritis, lupus, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
In some embodiments of the use of the invention, the inflammatory disease is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
In some embodiments of the use of the invention, the infection disease is virus infection or fungal infection.
In some embodiments of the use of the invention, the disease is a disease caused by  changes in cyclin-dependent kinase.
In other embodiments of the use of the invention, the cyclin-dependent kinase is CDK1, CDK2, CDK4, CDK6 or CDK9.
In some embodiments of the use of the invention, the disease is a disease caused by changes in CDK4 or CDK6 protein kinase.
In one aspect, provided herein is a drug combination comprising the compound or the pharmaceutical composition disclosed herein and one or more other activity agents used for treating proliferative diseases, autoimmune diseases or inflammatory diseases.
In some embodiments, the other activity agent of the drug combination comprises a chemotherapeutic drug, an antiproliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, a CDK 4/6 kinase inhibitor, an ABL inhibitor, an ABL/Scr inhibitor, an aurora kinase inhibitor, a non-ATP competitive inhibitor of BCR-ABL, a c-KIT mutation inhibitor, a RET inhibitor, a PDGFR inhibitor, a VEGFRinhibitor, a CSF1R inhibitor, an FLT3 inhibitor, an FLT3-ITD inhibitor or a combination thereof
In one aspect, the invention provides a method of preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection in a patient, comprising administrating to the patient a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein.
In other aspect, provided herein is the compound or the pharmaceutical composition for use in preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection
The compound of the invention is suitable as an active agent in a pharmaceutical composition, the pharmaceutical composition can be used in effectively treating especially diseases related to protein kinases, such as cancer, graft rejection and autoimmune disease. The pharmaceutical composition of each embodiment has a pharmaceutically effective active agent of the invention and other pharmaceutically acceptable excipients, carriers, fillers, diluents, and the like. The term “pharmaceutically effective amount” as used herein indicates an amount necessary to administer to a host, or to a cell, issue, or organ of a host, to achieve a therapeutic result, especially the regulating, modulating, or inhibiting protein kinase activity, e.g., inhibition of the activity of a protein kinase, or treatment of cancer, graft rejection and autoimmune disease.
In addition, the present invention provides a method for inhibiting the activity of a protein kinase. The method includes contacting a cell with any one of the compounds of the present invention. In a related embodiment, the method further provides that the compound is present in an amount effective to selectively inhibit the activity of a protein kinase.
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 of the invention, examples of which are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present 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 of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entireties.
As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, 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 “Organic Chemistry” , Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic  Chemistry” by Michael B. Smith and Jerry March, John Wiley &Sons, New York: 2007, the entire contents of which are hereby incorporated by reference.
The grammatical articles “a” , “an” and “the” , as used herein, are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context. Thus, the articles are used herein to refer to one or more than one (i.e. at least one) of the grammatical objects of the article. By way of example, “a component” means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
As used herein, “patient” refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
The term “comprising” is meant to be open ended, including the indicated component but not excluding other elements.
“Stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc.
“Chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
“Enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
“Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boling points, spectral properties or biological activities. Mixture of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New  York； and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds” , John Wiley &Sons, Inc., New York, 1994.
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 1 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. A specific stereoisomer is 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.
Any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50％enantiomeric excess, at least 60％enantiomeric excess, at least 70％enantiomeric excess, at least 80％enantiomeric excess, at least 90％enantiomeric excess, at least 95％enantiomeric excess, or at least 99％enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis-or trans-configuration.
Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof. Racemic products can also be resolved by chiral chromatography,  e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ； Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012) ； Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) ； Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972) ； Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim, Germany, 2007) .
The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached. For example, 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. The specific example of keto-enol tautomerisms is hexane-2, 4-dione and 4-hydroxyhex-3-en-2-one tautomerism. Another example of tautomerisms is phenol-keto tautomerism. The specific example of phenol-keto tautomerisms is pyridin-4-ol and pyridin-4 (1H) -one tautomerism. Unless otherwise stated, all tautomers of the present compounds within the scope disclosed herein.
As described herein, compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” . In general, the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical 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 give an structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
Unless otherwise defined herein, for a variable that occurs more than one time in any substituent or in the compound of the invention or any other formulae herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of  substituents are permissible only if such combinations result in stable compound. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
At various places in the present specification, substituents of compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
At various places in the present specification, linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
As described herein, compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” . In general, the term “substituted” whether behind of the term “optionally” or not refers to the replacement of one or more hydrogen radicals in a given structure with the radical 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 give an structure can 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 substituent may be, but not limited to, H, oxo (＝O) , alkyl, F, Cl, Br, amino, hydroxy, carboxy, alkoxy, alkylamino, haloalkyl, formyl, cyano, heterocyclyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SOt- (C (R4) 2) n-, HO- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, CN- (C (R4) 2) n-C (＝O) -, heteroaryl, cycloalkyl or nitro, and the like, and wherein R4, R6, R7, n and t are defined herein.
The term “alkyl” or “alkyl group” refers to a saturated linear or branched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms, wherein the alkyl radical may be optionally and independently substituted with one or more substituents described herein. In some  embodiments, the alkyl group contains 1-10 carbon atoms. In other embodiments, the alkyl group contains 1-8 carbon atoms. In other embodiments, the alkyl group contains 1-6 carbon atoms. In still other embodiments, the alkyl group contains 1-4 carbon atoms. In yet other embodiments, the alkyl group contains 1-3 carbon atoms and in still yet other embodiments, the alkyl group contains 2-6 carbon atoms. Some non-limiting examples of the alkyl group include, methyl (Me, -CH3) , ethyl (Et, -CH2CH3) , n-propyl (n-Pr, -CH2CH2CH3) , isopropyl (i-Pr, -CH (CH3) 2) , n-butyl (n-Bu, -CH2CH2CH2CH3) , 2-methyl-propyl or isobutyl (i-Bu, -CH2CH (CH3) 2) , 1-methyl-propyl or 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-l-butyl (-CH2CH2CH (CH3) 2) , 2-methyl-l-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 and n-octyl, etc. The term “alkyl” or the prefix “alk-” is inclusive of both straight chain and branched saturated carbon chain.
The term “haloalkyl” refers to an alkyl group substituted with one or more identical or different halogen atoms. Wherein the alkyl group is as defined herein. Some non-limiting examples of the haloalkyl group include trifluoromethyl, 1-chloroethyl, difluoromethyl, 2-fluoroethyl, 3, 3, 3-trifluoropropyl, and the like.
The term “amino” refers to -NH2.
The term “cycle” or “ring” embraces carbolic cycle, heterocycle, aromatic cycle, heteroaromatic cycle, spiro cycle and fused cycle, and the like, wherein the carbolic cycle, heterocycle, aromatic cycle, heteroaromatic cycle, spiro cycle and fused cycle are as defined herein.
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 embidiments, the alkylamino radical is “lower alkylamino” radical having one or two C1-6 alkyl groups attached to  a nitrogen atom. In other embidiments, the alkylamino radical is “lower alkylamino” radical having one or two C1-3 alkyl groups attached to a nitrogen atom. Some non-limiting examples of suitable alkylamino radical include mono or dialkylamino. Some examples include, but not limited to, methylamino, ethylamino, dimethylamino and diethylamino, and the like.
The term “aminoalkyl” refers to an alkyl substituted with one or more amino groups. Wherein the alkyl group is as defined herein. In some embodiments, the aminoalkyl is an amino-C1-6-alkyl group. In other embodiments, the aminoalkyl is an amino-C1-3-alkyl group. Some non-limiting examples of the aminoalkyl group include aminomethyl, aminoethyl and aminopropyl, 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 “cycloalkyl” refers to a monovalent or multitivalent, non-aromatic, 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 ring 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. 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. Depending on the structure, the cycloalkyl group can be a monoradical or a diradical, i.e., cycloalkylene.
The term “aryl” 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. Depending on the structure, the aryl group can be a monoradical or a diradical such as an arylene group.
The term “heteroaryl” or “heteroaryl ring” as used interchangeably herein, refers to a  monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the bicyclic heteroaryl, tricyclic heteroaryl or tetracyclic heteroaryl ring system is fused to form a ring. The heteroaryl ring system is aromatic, in which one or more ring members are an independently selected heteroatom (heteroatoms selected from N, O, P and S, wherein the N, S or P is optionally substituted with one or more oxo to provide the group NO, SO, SO2, PO or PO2) . The heteroaryl 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 system group 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. Depending on the structure, the heteroaryl group may be a monoradical or a diradical such as a heteroarylene group.
Some non-limiting examples of the heteroaryl system (including heteroaryl and heteroaromatic ring) 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, quinoxalinyl, 1, 8-naphthyridinyl, benzothienyl, indolyl (e.g., 2-indolyl) , purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl and 4-quinolyl) , isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl) , 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, decahydroindolyl, decahydroisoindolyl, oxazolidinedionyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, oxiranyl,  perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridyl, quinazolinyl, 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 “heterocyclyl” , “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. 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, 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 N, S or P is optionally substituted with one or more oxo to provide the group NO, NO2, SO or SO2, PO or PO2, and the -CH2-can also be optionally replaced by 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 N, S or P is optionally substituted with one or more oxo to provide the group NO, NO2, SO or SO2, PO or PO2, and the -CH2-can also be optionally replaced by the group –C (＝O) -) . Depending on the structure, the heterocyclyl group can be a monoradical or a diradical, i.e., heterocyclylene. In some embodiments, N atoms of a heterocyclyl containing N can be oxidized to form an N-oxide.
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 1, 2, 3, 4-tetrahydropyridyl, piperidyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,  azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, homopiperazinyl, piperidinyl, oxazepinyl, diazepinyl, thiazepinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2-indolinyl, 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, isoindolinyl, 1, 2, 3, 4-tetrahydroquinolyl, N-pyridyl urea, dioxolanyl, dihydropyrazinyl, dihydropyridyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1, 4-dithianyl, morpholinyl, decahydroindolyl, decahydroisoindolyl, piperazinyl, piperidinyl, pteridinyl and purinyl, 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 D and B’ ) is termed as “fused bicyclic” , whereas ring A and ring D 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 such group include, 4-azaspiro [2.4] heptan-5-yl, 4-oxaspiro [2.4] heptan-5-yl, 5-azaspiro [2.4] heptan-5-yl, spiro [2.4] heptyl, spiro [4.4] nonyl, 7-hydroxy-5-azaspiro [2.4] heptan-5-yl, and thelike.
Figure PCTCN2015085034-appb-000022
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 D and B’ ) is termed as “fused bicyclic” , whereas ring A and ring D share an atom between the two saturated ring system, which terms as a “spirocyclyl” . 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 and that contains 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the N, S or P is optionally substituted with one or more oxo to provide the group NO, NO2, SO or SO2, PO or PO2, and the -CH2-can also be optionally replaced by the group –C (＝O) -. 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. Depending on the structure, the spiro heterobicyclyl group can be a monoradical or a diradical, i.e., spiro heterobicyclylene.
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. 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.
The term “fused heterobicyclic” 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. 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 fused ring system contains one or more heteroatoms. Each ring in the fused ring system contains 3 to 7 ring members and that contains 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the N, S or P is optionally substituted with one or more oxo to provide the group NO, NO2, SO or SO2, PO or PO2, and the -CH2-can also be optionally replaced by 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, 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, 3-aza-7-oxabicyclo [3.3.0] octyl, 3, 7-diazabicyclo [3.3.0] octyl, 2, 6-diazabicyclo [3.3.0] octyl, 2, 7-diazabicyclo [3.3.0] octyl, 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, 4, 9-diazabicyclo [4.3.0] nonyl, 2, 9-diazabicyclo [4.3.0] nonyl, 3- 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, 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, 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, isoxazolo [4, 3-c] piperidinyl, 4, 5, 6, 7-tetrahydroisoxazolo [3, 4-c] pyridinyl, [1, 2, 4] triazolo [4, 3-a] piperazinyl, 2-oxa-7-azabicyclo [4.4.0] decyl, 1, 5-dioxa-9-azabicyclo [4.4.0] decyl, 3-azabicyclo [4.4.0] decyl, 2, 7-diaza-decahydronaphthyl, 2-oxa-8-azabicyclo [4.4.0] decyl, 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 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 term “bridged heterobicyclyl” 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) . 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 and that contains 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the N, S or P is optionally substituted with one or more oxo to provide the group NO, NO2, SO or SO2, PO or PO2, the -CH2-group is optionally replaced by -C (＝O) -. Some non-limiting examples of the such group include 2-oxa-5-azabicyclo [2.2.1] heptyl, 2-thia-5-azabicyclo [2.2.1] heptyl, 2-oxo-5-azabicyclo [2.2.1] heptyl, 2, 5-diazabicyclo [2.2.1] heptyl, (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptyl, 3, 8-diazabicyclo [3.2.1] octyl, (1S, 5S) -3, 8-diazabicyclo [3.2.1] octyl, 1, 4-diazabicyclo [3.2.2] nonan-3-one-yl, 8-oxa-3-azabicyclo [3.2.1] octyl, and the like.
“Anti-proliferation agents” refers to anti-metabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine) , antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine； taxanes such as paclitaxel, docetaxel) , alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea) , platinum  agents (e.g. cisplatin, carboplatin, oxaliplatin, JM-216, CI-973) , anthracyclines (e.g., doxorubicin, daunorubicin) , antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin, daunomycin) , topoisomerase inhibitors (e.g., etoposide, camptothecins) , anti-angiogenesis agents (e.g. Bevacizumab) or any other cytotoxic agents (e.g. estramustine phosphate, prednimustine) , hormones or hormone agonists, antagonists, partial agonists 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 PCTCN2015085034-appb-000023
As described herein, the attachment point can attach to the rest of the molecule at any attachable position on the rings. For example, Formula i represents attaching at any attachable position on ring A' or ring B'.
Figure PCTCN2015085034-appb-000024
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. As described herein, for example, the two attachment points of“- (C (R4) 2) n1-C (＝O) -N (R5) - (C (R4) 2) n1-” or “- (C (R4) 2) m1-O- (C (R4) 2) n1-” can be used interchangeably with each other.
Figure PCTCN2015085034-appb-000025
As described herein, the attachment point can attach to the rest of the molecule at any  attachable position on the rings； the two attachment points can be interchanged. For example, Formula x represents attaching at any attachable position on the rings, and the two attachment points can be used interchangeably with each other.
Figure PCTCN2015085034-appb-000026
Furthermore, unless otherwise stated, the phrase “each…is independently” is used interchangeably with the phrase “each (of) …and…is independently” . It should be understood broadly that the specific options expressed by the same symbol are independently of each other in different radicals； or the specific options expressed by the same symbol are independently of each other in same radicals. For example, the specific options of R4 of “- (C (R4) 2) n1-C (＝O) -N (R5) - (C (R4) 2) n1-” are independent of each other； meanwhile, the specific options of multiple n1 are independent of each other, another example, and the specific options of multiple R4 of Formula y are independent of each other.
The sign
Figure PCTCN2015085034-appb-000027
refers to a single bond
Figure PCTCN2015085034-appb-000028
or a double bond
Figure PCTCN2015085034-appb-000029
disclosed herein.
The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E.W. Martin.
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 1 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.
“Isomers” refers to different compounds having same molecular formula. “Stereisomer” refers to isormers differ in just spatial arrangement of atoms. The term isomers as used herein embrace any and all geometric isomers and stereoisomers. For example, “isomers” include cis-and trans-isomer, E-and Z-isomer, R-and S-enantiomer, diastereoisomer, (d) -isomer, (l) -isomer, racemic mixture thereof, as well as other mixtures fall in the scope of the invention.
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) - (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.
An “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 of may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of the Formula (I) to (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) to (III) .
The term “prodrug” refers to a compound that is transformed in vivo into a compound of Formula (I) - (III) . Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue. Prodrugs of the compounds disclosed herein may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound disclosed herein that contains a hydroxy 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 a hydroxy group on the parent compound. A thorough discussion of prodrugs is provided in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, et al. ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987； Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345, all of  which are incorporated herein by reference in their entireties.
Unless otherwise stated, all tautomers of the present compounds within the scope disclosed herein.
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. The present invention includes isotopically-labeled compounds, which are identical to those recited in Formula (I) - (III) , but that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Isotopically labeled compounds of Formula (I)- (III) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The term “metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. The metabolites 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 oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme 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.
The term “pharmaceutically acceptable salt” disclosed herein refers to organic or inorganic salts of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19, which is incorporated herein by reference. Examples of pharmaceutically acceptable, nontoxic salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid and nitric acid or with organic acids such as acetic acid, propionic acid, glycollic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid or salts obtained by using other methods used in the art such as ion exchange.
Other pharmaceutically acceptable salts include adipate, malate, 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, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, 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 oil soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, ferric salt, zinc salt, copper salt, manganese salt, aluminium salt, 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. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxy-carbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxy-carbonyl (Fmoc) . Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable 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. Common carboxy-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methy-l, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) -ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991； and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
In the present invention, if the chemical name of the compound doesn’ t match the corresponding structure, the compound is characterized by the corresponding structure.
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
There remain needs for a large number of new therapies and drugs used for treating disorders related to protein kinases, as well as compounds used for treating, preventing, or improving one or more of cancer, autoimmune diseases and infection diseases. The compounds  provided herein can be used in regulating the activities of protein kinases such as CDKs, especially regulating or inhibiting the activities of CDK4 or CDK6.
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, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2015085034-appb-000030
wherein R1, R2, R3, L1 and ring B are as defined herein.
 In some embodiments, ring B is
Figure PCTCN2015085034-appb-000031
Figure PCTCN2015085034-appb-000032
wherein each Y, Y1 and Y2 is independently -C (R4) 2-, -N (R5) -, -O-, -S (＝O) t-or -C (＝O) -；
each Y3, Y4, Y5, Y6, Y8 and Y7 is independently CR4 or N；
each moiety represented by B is optionally and independently substituted with one or more substituents independently selected from H, C1-6 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-6 alkoxy, C1-6 haloalkyl, (R6R7) N- (C (R4) 2) n-, N (R6R7) -C (＝O) -, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-,  HO- (C (R4) 2) n-C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, cyano or nitro； and
wherein R4, t, R6, R7, R5 and n are as defined herein.
In some embodiments, R1 is H, F, Cl, Br, hydroxy, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy, which is substituted optionally with one or more independent R8； and
wherein R8 is as defined herein.
In some embodiments, R2 is H, F, Cl, Br, hydroxy, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy, which is substituted optionally with one or more independent R8； and
wherein R8 is as defined herein.
In some embodiments, L1 is a bond, - (C (R4c) 2) n1-, - (C (R4c) 2) n1-C (＝O) -N (R5c) - (C (R4c) 2) n1-, - (C (R4c) 2) n1-N (R5c) - (C (R4c) 2) n1-, - (C (R4c) 2) n1-O- (C (R4c) 2) n1-, - (C (R4c) 2) n1-S (＝O) t- (C (R4c) 2) n1-or - (C (R4c) 2) n1-C (＝O) - (C (R4c) 2) n1-；
wherein R4c, R5c and n1 are as defined herein.
In some embodiments, R3is H, C5-12 spiro heterobicyclyl, C5-12 bridged heterobicyclyl, C5-12 fused heterobicyclyl, C3-9 cycloalkyl, C3-9 heterocyclyl or C1-9 heteroaryl, which is substituted optionally with one or more independent R8； and
wherein R8 are as defined herein.
In some embodiments, each R4 is independently H, C1-6 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-6 alkoxy, H2N- (CH2) n-, N (R6R7) -C (＝O) -, formyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H- (CH2) n-O- (CH2) n-, CN- (CH2) n-C (＝O) -, C3-9 heterocyclyl, C1-9 heteroaryl, C1-6 haloalkyl or C1-6 alkylamino； and
wherein R6, R7 and n are as defined herein.
In some embodiments, each R4c is independently H, C1-6 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-6 alkoxy, H2N- (CH2) n-, N (R6R7) -C (＝O) -, formyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H- (CH2) n-O- (CH2) n-, CN- (CH2) n-C (＝O) -, C3-9 heterocyclyl, C1-9 heteroaryl, C1-6 haloalkyl or C1-6 alkylamino； and
wherein R6, R7 and n are as defined herein.
In some embodiments, each R5 is independently H, C1-6 alkyl, C1-6 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-,  H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-9 heterocyclyl or C1-9 heteroaryl, which is substituted optionally with one or more independent R8； and
wherein R4, R6, R7, R8 and n are as defined herein.
In some embodiments, each R5c is independently H, C1-6 alkyl, C1-6 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-9 heterocyclyl or C1-9 heteroaryl, which is substituted optionally with one or more independent R8； and
wherein R4, R6, R7, R8 and n are as defined herein.
In some embodiments, each n1 is independently 0, 1, 2, 3 or 4.
In some embodiments, each n is independently 0, 1, 2, 3 or 4.
In some embodiments, each t is independently 0, 1 or 2.
In some embodiments, each R6 is independently H, C1-6 alkyl, hydroxy, carboxy, amino, C1-6 alkoxy, H2N- (CH2) n-, NH2-C (＝O) -, formyl, H- (CH2) n-O-C (＝O) - (CH2) n-, C3-9 heterocyclyl, C1-9 heteroaryl, C1-6 haloalkyl or C1-6 alkylamino； and
wherein n is as defined herein.
In some embodiments, each R7 is independently H, C1-6 alkyl, hydroxy, carboxy, amino, C1-6 alkoxy, H2N- (CH2) n-, NH2-C (＝O) -, formyl, H- (CH2) n-O-C (＝O) - (CH2) n-, C3-9 heterocyclyl, C1-9 heteroaryl, C1-6 haloalkyl or C1-6 alkylamino； and
wherein n is as defined herein.
In some embodiments, each R8 is independently H, oxo (＝O) , C1-6 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 haloalkyl, cyano, C3-9 heterocyclyl, C1-9 heteroaryl, H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-, HO- (CH2) n-C (＝O) -, NH2-C (＝O) -, CN- (CH2) n-C (＝O) -, C3-9 cycloalkyl or nitro； each alkyl, alkoxy, alkylamino, haloalkyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-C (＝O) -, HO- (CH2) n-, NH2-C (＝O) -, heterocyclyl, cycloalkyl and heteroaryl described in R8 is optionally and independently substituted with one or more R9；
each R9 is independently H, oxo (＝O) , C1-6 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 haloalkyl, formyl, cyano, HO- (C (R4) 2) n-,  H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, CN-C (R4) 2-C (＝O) -, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, C3-9 heterocyclyl, C1-9 heteroaryl, C3-9 cycloalkyl or nitro； and
wherein R4, R6, R7 and n are as defined herein.
In some embodiments, provided herein is a compound having Formula (II) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2015085034-appb-000033
wherein when
Figure PCTCN2015085034-appb-000034
is
Figure PCTCN2015085034-appb-000035
T1 is Y6；
when
Figure PCTCN2015085034-appb-000036
is
Figure PCTCN2015085034-appb-000037
T1 is Y1；
wherein each of Y and Y1 is independently -C (R4) 2-, -N (R5) -, -O-, -S (＝O) t-or -C (＝O) -；
each of Y3, Y4, Y5 and Y6 is independently CR4 or N； and
wherein R1, R2, R3, L1, t, R4 and R5 are as defined herein.
In some embodiments, provided herein is a compound having Formula (III) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2015085034-appb-000038
wherein each of Y, Y2 and Y1 is independently -C (R4) 2-, -N (R5) -, -O-, -S (＝O) t-or -C (＝O) -；
each of Y3, Y4, Y5 and Y6 is independently CR4 or N； and
wherein R1, R2, R3, L1, t, R4 and R5 are as defined herein.
In some embodiments, each R5c is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or C1-9 heteroaryl； and
wherein R4, R7, R6 and n are as defined herein.
 In some embodiments, each R5 is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or C1-9 heteroaryl； and
wherein R4, R7, R6 and n are as defined herein.
In some embodiments, each R4c is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
wherein R7, R6 and n are as defined herein.
In some embodiments, each R4 is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
wherein R7, R6 and n are as defined herein.
In some embodiments, each R6 is independently H, C1-4 alkyl, hydroxy, carboxy, amino, C1-4 alkoxy, H2N- (CH2) n-, NH2-C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, C3-9 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
wherein n is as defined herein.
In some embodiments, each R7 is independently H, C1-4 alkyl, hydroxy, carboxy, amino, C1-4 alkoxy, H2N- (CH2) n-, NH2-C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, C3-9 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
wherein n is as defined herein.
In some embodiments, each R5 is independently H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, H, trifluoromethyl, 2-fluoroethyl, 3, 3, 3-trifluoropropyl, methyl, ethyl, n-propyl, i-propyl, t-butyl, 2-methylpropyl or n-butyl； and
wherein R4, R7, R6and n are as defined herein.
In some embodiments, each R5c is independently H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, H, trifluoromethyl, 2-fluoroethyl, 3, 3, 3-trifluoropropyl, methyl, ethyl, n-propyl, i-propyl, t-butyl, 2-methylpropyl or n-butyl； and
wherein R4, R7, R6and n are as defined herein.
In some embodiments, each R4c is independently H, methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, hydroxy, carboxy, amino, methoxy, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, trifluoromethyl or methylamino； and
wherein R7, R6 and n are as defined herein.
In some embodiments, each R4 is independently H, methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, hydroxy, carboxy, amino, methoxy, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, trifluoromethyl or methylamino； and
wherein R7, R6 and n are as defined herein.
In some embodiments, each R6 is independently H, methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, hydroxy, carboxy, amino, methoxy, H2N- (CH2) n-, NH2-C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, trifluoromethyl or methylamino； and
wherein n is as defined herein.
In some embodiments, each R7 is independently H, methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, hydroxy, carboxy, amino, methoxy, H2N- (CH2) n-, NH2-C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, trifluoromethyl or methylamino； and
wherein n is as defined herein.
In some embodiments, each R8 is independently H, oxo (＝O) , C1-4alkyl, F, Cl, Br, amino,  hydroxy, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 haloalkyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-, HO- (CH2) n-C (＝O) -, NH2-C (＝O) -, cyano, CN- (CH2) n-C (＝O) -, C1-9heteroaryl, 
Figure PCTCN2015085034-appb-000039
or nitro； and
wherein X1, X, e, f, and n are as defined herein.
In some embodiments, each R9 is independently H, oxo (＝O) , C1-4 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 haloalkyl, cyano, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, CN-C (R4) 2-C (＝O) -, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, 
Figure PCTCN2015085034-appb-000040
C1-9 heteroaryl or nitro； and
wherein R4, R7, R6, X1, X, e, f and n are as defined herein.
In some embodiments, each X and X1 is independently -C (R4a) 2-, -N (R5a) -, -O-, -S (＝O) t-or -C (＝O) -； and
wherein R4a, R5a and t are as defined herein.
In some embodiments, each R5a is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or C1-9 heteroaryl； and
wherein R4, R7, R6 and n are as defined herein.
In some embodiments, each R4a is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
wherein R7, R6 and n are as defined herein.
In some embodiments, each e is independently 0, 1, 2 or 3.
In some embodiments, each f is independently 0, 1, 2 or 3.
In some embodiments, each R8 is independently H, oxo (＝O) , methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, F, Cl, Br, amino, hydroxy, carboxy, methoxy, ethoxy,  1-chloroethyl, dimethylamino, diethylamino, methylamino, trifluoromethyl, cyano, 
Figure PCTCN2015085034-appb-000041
Figure PCTCN2015085034-appb-000042
H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-, HO- (CH2) n-C (＝O) -, NH2-C (＝O) -, CN- (CH2) n-C (＝O) -or nitro； and
wherein n is as defined herein.
In some embodiments, each R9 is independently H, oxo (＝O) , methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4alkoxy, C1-4 alkylamino, C1-4 haloalkyl, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, CN-C (R4) 2-C (＝O) -, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, cyano, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -,
Figure PCTCN2015085034-appb-000043
C1-9heteroaryl or nitro； and
wherein R4, R6, R7 and n are as defined herein.
In some embodiments,
R3 is H, 
Figure PCTCN2015085034-appb-000044
Figure PCTCN2015085034-appb-000045
Figure PCTCN2015085034-appb-000046
wherein each X2, X6 and X7 is independently -C (R4b) 2-, -N (R5b) -, -O-, -S (＝O) t-or -C (＝O) -；
each X3, X4 and X5 is independently CR4b or N；
each e, g and f is independently 0, 1, 2 or 3；
R3 is optionally and independently substituted with one or more R8；
R8 is optionally and independently substituted with one or more R9； and
wherein t, R4b, R5b, R8 and R9 are as defined herein.
In some embodiments, each R5b is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or C1-9 heteroaryl； and
wherein R4, R7, R6 and n are as defined herein.
In some embodiments, each R4b is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
wherein R7, R6 and n are as defined herein.
In some embodiments, each R5b is independently H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, H, trifluoromethyl, 2-fluoroethyl, 3, 3, 3-trifluoropropyl, methyl, ethyl, n-propyl, i-propyl, t-butyl, 
Figure PCTCN2015085034-appb-000047
Figure PCTCN2015085034-appb-000048
2-methylpropyl or n-butyl； and
wherein R4, R7, R6and n are as defined herein.
In some embodiments, each R4b is independently H, methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, hydroxy, carboxy, amino, methoxy, H2N- (CH2) n-,  N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, 
Figure PCTCN2015085034-appb-000049
trifluoromethyl or methylamino； and
wherein R7, R6 and n are as defined herein.
In some embodiments,
R3 is H, 
Figure PCTCN2015085034-appb-000050
Figure PCTCN2015085034-appb-000051
Figure PCTCN2015085034-appb-000052
Figure PCTCN2015085034-appb-000053
Figure PCTCN2015085034-appb-000054
n is 0, 1, 2 or 3；
each moiety represented by R3 is independently and optionally substituted with one or more R8； and
wherein R8 is as defined herein.
In some embodiments,
ring B is
Figure PCTCN2015085034-appb-000055
Figure PCTCN2015085034-appb-000056
Figure PCTCN2015085034-appb-000057
and
wherein R4 and R5 is as defined herein.
In some embodiments, 
Figure PCTCN2015085034-appb-000058
wherein each Y, Y1 and Y2 is independently -C (R4) 2-, -N (R5) -, -O-, -S (＝O) t-or -C (＝O) -；
each Y3, Y4, Y5 and Y6 is independently CR4 or N； and
wherein t, R4 and R5 are as defined herein.
In some embodiments, 
Figure PCTCN2015085034-appb-000059
is
Figure PCTCN2015085034-appb-000060
Figure PCTCN2015085034-appb-000061
and
wherein R4 and R5 is as defined herein.
In some embodiments, provided herein is a compound having one of the following structures, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2015085034-appb-000062
Figure PCTCN2015085034-appb-000063
Figure PCTCN2015085034-appb-000064
Figure PCTCN2015085034-appb-000065
Figure PCTCN2015085034-appb-000066
Figure PCTCN2015085034-appb-000067
Figure PCTCN2015085034-appb-000068
Figure PCTCN2015085034-appb-000069
Figure PCTCN2015085034-appb-000070
Figure PCTCN2015085034-appb-000071
Figure PCTCN2015085034-appb-000072
In one 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 pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles.
In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent, the additional therapeutic agent is a chemotherapeutic drug, an antiproliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, a CDK4/6 kinase inhibitor, an ABL inhibitor, an ABL/Scr inhibitor, an aurora kinase inhibitor, a non-ATP competitive inhibitor of BCR-ABL, a c-KIT mutation inhibitor, a RET inhibitor, a PDGFR inhibitor, a VEGFRinhibitor, a CSF1R inhibitor, an FLT3 inhibitor, an FLT3-ITD inhibitoror a combination thereof.
In some embodiments, the additional therapeutic agent of the pharmaceutical composition disclosed herein is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cis-platinum, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbozine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, pharmorubicin, daunomycin, mitoxantrone, bleomycin, mitomycinC, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon α, calcium folinate, 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, zelboraf, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, cabozantinib, ponatinib, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, palbociclib, abemaciclib, ribociclib, rigosertib sodium, Selinexor, Roniciclib, AT-7519, Seliciclib, Alvocidib or a combination thereof.
In other aspect, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture a medicament for preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection.
In some embodiments of the use of the invention, the abnormal cell proliferation disorder or disease is ovarian cancer, cervical cancer, testiculoma, esophagus cancer, gastric cancer, skin cancer, lung cancer, osteocarcinoma, acute myeloid leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myelocytic leukemia (AML) , chronic myeloid leukemia (CML) with mutation, acute lymphoblastic leukemia (ALL) , colorectal cancer, gastric cancer, breast cancer, lung cancer, cancer of the liver, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, neck cancer, cancer of the central nervous system, spongioblastoma or myelodysplastic syndrome, atherosclerosis, pulmonary fibrosis, leukemia, lymph cancer, rheumatic disease, 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, myeloma, lymphoblastoma, part of the 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, glioblastoma multiforme, mantle cell lymphoma, chronic granulocytic leukemia, acute  granulocytic leukemia, bladder cancer or myeloma.
In some embodiments of the use of the invention, the autoimmune disease is rheumatic arthritis, lupus, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
In some embodiments of the use of the invention, the inflammatory disease is diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.
In some embodiments of the use of the invention, the infection disease is virus infection or fungal infection.
In some embodiments of the use of the invention, the disease is a disease caused by changes in cyclin-dependent kinase.
In other embodiments of the use of the invention, the cyclin-dependent kinase is CDK1, CDK2, CDK4, CDK6 or CDK9.
In some embodiments of the use of the invention, the disease is a disease caused by changes in CDK4 or CDK6 protein kinase.
In one aspect, provided herein is a drug combination comprising the compound or the pharmaceutical composition disclosed herein and one or more other activity agents used for treating proliferative diseases, autoimmune diseases or inflammatory diseases.
In some embodiemtns, the drug combination disclosed herein, wherein the other activity agent comprises chemotherapeutic drug , antiproliferative agent, immunosuppressor, immunologic stimulant, anti-inflammatory agent, CDK4/6 kinase inhibitor, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitor, non-ATP competitive inhibitor of BCR-ABL, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFRinhibitor, CSF1R inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof.
In one aspect, the invention provides a method of the invention provides a method of preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection in a patient comprising administrating to the patient a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein.
In other aspect, provided herein is the compound or the pharmaceutical composition for use in preventing, managing, treating or lessening disorders or diseases caused by abnormal cell  proliferation, autoimmunity, inflammation or infection
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds disclosed herein are within the scope of the present invention. Specifically, 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 salt of 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) to (III) and/or for separating enantiomers of compounds of Formula (I) to (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 the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, 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.
The compounds of the present invention are specific inhibitors of CDK4 and CDK6 and are therefore useful in the treatment of a disease or disorder characterised by abnormal cell proliferation. In particular, the compounds of the present invention are useful in the treatment of cancer.
CDK4 and CDK6 modulate their effects on the cell cycle through the phosphorylation of pRb. The compounds of the present invention, which are potent inhibitors of CDK4/6 activity and thus pRb phosphorylation, are expected to inhibit cell proliferation (and therefore tumour growth) in any cancer type where the cells are proliferating and contain a functional, intact Rb1 gene (which encodes pRb) . The compounds of the invention are therefore useful in the treatment of pRb+ cancers such as colorectal cancer, breast cancer, lung cancer, prostate cancer, chronic granulocytic leukaemia, acute granulocytic leukaemia (Fry, D. W. et al. Mol. Cancer Ther. (2004) , 3 (11) , 1427) , mantel cell lymphoma (Marzec, M. et al., Blood (2006) , 108 (5) , 1744) ovarian cancer (Kim, T.M. et al., Cancer Research (1994) , 54, 605) , pancreatic cancer (Schutte, M. et al., Cancer Research (1997) , 57, 3126) malignant melanoma and metastatic malignant melanoma (Maelandsmo, G.M. et al., British Journal of Cancer (1996) , 73, 909) in mammals. The compounds of the invention are also expected to be useful in the treatment of rhabdomyosarcoma (Saab, R. et al., Mol. Cancer. Ther. (2006) , 5 (5) , 1299) and multiple myeloma (Baughn, L.B. et al., Cancer Res. (2006) , 66 (15) , 7661) in mammals. In some embodiments, the mammal to be treated is a human.
The compounds of the invention can be used in the treatment of cancers in mammal, especially in the methods of treating the aforementioned cancers, the methods comprise administrating to the mammal in need of the treatment a therapeutically effective amount of the compounds of the invention.
In some embodiments, the compound of the invention can be used in the methods of treating cancers, the cancer is selected from colorectal cancer, mantle cell lymphoma, breast cancer, spongioblastoma, acute granulocytic leukemia and lung cancer, especially non-small cell lung cancer (NSCLC) .
In other embodiments, the compound of the invention can be used in the methods of treating cancers, the cancer is selected from colorectal cancer, spongioblastoma, acute  granulocytic leukemia and lung cancer.
In other embodiments, the compound of the invention can be used in the methods of treating spongioblastoma or astrocytoma in mammal, the methods comprise administrating to the mammal in need of the treatment a therapeutically effective amount of a combination of the compounds of the invention and temozolomide.
In other embodiments, the compound of the invention can be used in the methods of treating non-small cell lung cancer, pancreatic cancer, ovarian cancer or metastatic breast cancer in mammal, the methods comprise administrating to the mammal in need of the treatment a therapeutically effective amount of a combination of the compounds of the invention and gemcitabine hydrochloride.
In addition, the compounds of the invention can be used in the manufacture of a medicament for treating cancers, especially the aforementioned cancer.
In some embodiments, the compounds of the invention can be used in the manufacture of a medicament for treating cancers, the cancer is selected from colorectal cancer, mantle cell lymphoma, breast cancer, spongioblastoma, acute granulocytic leukemia and lung cancer, especially non-small cell lung cancer (NSCLC) .
In other embodiments, the compounds of the invention can be used in the manufacture of a medicine for treating cancers, the cancer is selected from colorectal cancer, spongioblastoma, acute granulocytic leukemia and lung cancer.
In other embidments, the present invention provides the use of the compounds of the invention in the manufacture of a medicament for treating spongioblastoma or astrocytoma, wherein the medicament also includes temozolomide or is to be administered simultaneously, separately or sequentially with temozolomide.
In other embodiments, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of NSCLC, pancreatic cancer, ovarian cancer or metastatic breast cancer, wherein the medicament also comprises gemcitabine hydrochloride or is to be administered simultaneously, separately or sequentially with gemcitabine hydrochloride. There is also provided a pharmaceutical formulation for treating cancers, in particular the cancers described above comprising a compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
In some embodiments, there is also provided a pharmaceutical formulation for treating a  cancer selected from the group consisting of colorectal cancer, mantel cell lymphoma, breast cancer, glioblastoma, acute myeloid leukaemia and lung cancer, especially NSCLC, comprising a compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
In some embodiments, there is also provided a pharmaceutical formulation for treating a cancer selected from the group consisting of colorectal cancer, glioblastoma, acute myeloid leukaemia and lung cancer, comprising a compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
In other embodiments, the invention provides a pharmaceutical formulation for treating glioblastoma or astrocytoma, comprising a compound of the invention and temozolomide, together with a pharmaceutically acceptable carrier.
In other embodiments, the invention provides a pharmaceutical formulation for treating NSCLC, pancreatic cancer, ovarian cancer or metastatic breast cancer, comprising a compound of the invention and gemcitabine hydrochloride, together with a pharmaceutically acceptable carrier.
The invention also provides a pharmaceutical formulation, comprising a compound of the invention or a pharmaceutically acceptable salt thereof and temozolomide, together with a pharmaceutically acceptable carrier, diluent, or excipient.
The invention also provides a pharmaceutical formulation, comprising a compound of the invention or a pharmaceutically acceptable salt thereof and gemcitabine hydrochloride, together with a pharmaceutically acceptable carrier, diluent, or excipient.
The invention further provides a pharmaceutical formulation comprising a compound of the invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
USES IN CANCER, TRANSPLANT REJECTIONS, AND AUTOIMMUNE DISEASES
The compounds of the present invention have valuable pharmacological properties and are useful in the treatment of diseases. In certain embodiments, compounds of the invention are useful in the treatment of a proliferative disease, or cancer.
A proliferative disease is mainly a tumor disease (or cancer) (and/or any metastases) . The inventive compounds are particularly useful for treating a tumor which is a breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian  cancer, pancreas cancer, neuroblastoma, head and/or neck cancer or bladder cancer, or in a broader sense renal, brain or gastric cancer； in particular (i) a breast tumor； an epidermoid tumor, such as an epidermoid head and/or neck tumor or a mouth tumor； a lung tumor, for example a small cell or non-small cell lung tumor； a gastrointestinal tumor, for example, a colorectal tumor； or a genitourinary tumor, for example, a prostate tumor (especially a hormone-refractory prostate tumor) ； or (ii) a proliferative disease that is refractory to the treatment with other chemotherapeutics； or (iii) a tumor that is refractory to treatment with other chemotherapeutics due to multidrug resistance.
In a broader sense of the invention, a proliferative disease may furthermore be a hyperproliferative condition such as leukemias, hyperplasias, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis) , angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
Where a tumor, a tumor disease, a carcinoma or a cancer are mentioned, also metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, whatever the location of the tumor and/or metastasis.
The inventive compound is selectively toxic or more toxic to rapidly proliferating cells than to normal cells, particularly in human cancer cells, e.g., cancerous tumors, the compound has significant antiproliferative effects and promotes differentiation, e.g., cell cycle arrest and apoptosis.
In other certain embodiments, compounds of the invention are useful in the treatment of transplant rejections. Examples of transplant rejections that may be treated by the compounds of the invention include, but are not limited to, graft versus host disease, rejection related to xeno transplantation, rejection related to organ transplant, rejection related to acute transplant, heterograft or homograft rejection and ischemic or reperfusion injury incurred during organ transplantation.
In still other certain embodiments, compounds of the invention are useful in the treatment of autoimmune diseases. Examples of autoimmune diseases to be treated by the compounds of the invention include, but are not limited to, autoimmune hemolytic anemia, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenia purpura, autoimmunocytopenia, hemolytic anemia, antiphospholipid syndrome, dermatitis, allergic  encephalomyelitis, myocarditis, relapsing polychondritis, rheumatic heart disease, glomerulonephritis, multiple sclerosis, neuritis, uveitis ophthalmia, polyendocrinopathies, purpura, Reiter's Disease, Stiff-Man Syndrome, autoimmune pulmonary inflammation, autism, Guillain-Barre Syndrome, insulin dependent diabetes mellitis, autoimmune inflammatory eye, autoimmune thyroiditis, hypothyroidism, systemic lupus erhythematosus, Goodpasture's syndrome, Pemphigus, Receptor autoimmunities, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, rheumatoid arthritis, mixed connective tissue disease, polymyositis/dermatomyositis, pernicious anemia, idiopathic Addison's disease, infertility, glomerulonephritis, bullous pemphigoid, Sjogren's syndrome, diabetes millitus, adrenergic drug resistance, chronic active hepatitis, primary biliary cirrhosis, vitiligo, vasculitis, post-MI, cardiotomy syndrome, urticaria, atopic dermatitis, asthma, inflammatory myopathies, chronic active hepatitis, primary biliary cirrhosis and T-cell mediated hypersensitivity diseases.
The term “use” includes any one or more of the following embodiments of the invention, respectively: the use in the treatment of protein kinase-associated disorders； the use for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, e.g., in the manufacture of a medicament； methods of use of compounds of the invention in the treatment of these diseases； pharmaceutical preparations having compounds of the invention for the treatment of these diseases； and compounds of the invention for use in the treatment of these diseases； as appropriate and expedient, if not stated otherwise. In particular, diseases to be treated and are thus preferred for use of a compound of the present invention are selected from cancer, transplant rejections, or autoimmune diseases, as well as those diseases that depend on the activity of protein kinases. The term “use” further includes embodiments of compositions herein which bind to a protein kinase sufficiently to serve as tracers or labels, so that when coupled to a fluor or tag, or made radioactive, can be used as a research reagent or as a diagnostic or an imaging agent.
COMPOSITIONS OF THE COMPOUNDS OF THE INVENTION
The invention provides pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) - (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient. When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5％ (more  preferably, 0.5 to 90％) of active ingredient in combination with a pharmaceutically acceptable carrier.
“Effective amount” of the compound is that amount necessary or sufficient to treat or prevent a protein kinase-associated disorder, e.g. prevent the various morphological and somatic symptoms of a protein kinase-associated disorder, and/or a disease or condition described herein. In an example, an effective amount of the compound of the invention is the amount sufficient to treat a protein kinase-associated disorder in a subject. The effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. For example, the choice of the compound of the invention can affect what constitutes an “effective amount. ” One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount of the compounds of the invention without undue experimentation.
The regimen of administration can affect what constitutes an effective amount. The compound of the invention can be administered to the subject either prior to or after the onset of a protein kinase-associated disorder. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the compound (s) of the invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
By “combination” according to the invention, there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the invention and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g. synergistic effect. The terms “co-administration” or “combined administration” or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein refers to a product obtained from mixing or combining active ingredients, and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound disclosed herein and a co-agent, are both administered to a patient simultaneously in the form of  a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of the invention and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.
Compounds of the invention may be used in the treatment of states, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases. Methods of use of compounds of the present invention in the treatment of these diseases, or pharmaceutical preparations having compounds of the present invention for the treatment of these diseases.
The language “pharmaceutical composition” includes preparations suitable for administration to mammals, e.g., humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5％ (more preferably, 0.5 to 90％) of active ingredient in combination with a pharmaceutically acceptable carrier.
The phrase “pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose； starches, such as corn starch and potato starch； cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate； powdered tragacanth； malt； gelatin； talc； excipients, such as cocoa butter and suppository waxes； oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil； glycols, such as propylene glycol； polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol； esters, such as ethyl oleate and ethyl laurate； agar； buffering agents, such as magnesium hydroxide and aluminum hydroxide； alginic acid； pyrogen-free water； isotonic saline； Ringer's solution； ethyl  alcohol； phosphate buffer solutions； and other non-toxic compatible substances employed in pharmaceutical formulations.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like； oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , lecithin, propyl gallate, α-tocopherol, and the like； and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA) , sorbitol, tartaric acid, phosphoric acid, and the like.
Formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth) , powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as  an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like) , the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid； binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia； humectants, such as glycerol； disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate； solution retarding agents, such as paraffin； absorption accelerators, such as quaternary ammonium compounds； wetting agents, such as cetyl alcohol and glycerol monostearate； absorbents, such as kaolin and bentonite clay； lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof； and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose) , lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose) , surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid  compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient (s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluent commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils) , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) , and suitable mixtures thereof, vegetable oils,  such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides) . Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation； topical by lotion or ointment； and rectal by suppositories. Oral and/or IV administration is preferred.
The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal,  intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
The phrases “systemic administration, ” “administered systemically, ” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally (as by, a spray) , rectally, intravaginally, parenterally, intracistemally and topically (as by powders, ointments or drops, including buccally and sublingually) .
Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired  therapeutic effect and gradually increase the dosage until the desired effect is achieved.
In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day. An effective amount is that amount treats a protein kinase-associated disorder.
If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredients for a subject of about 50-70 kg, preferably about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg or about 1-50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10-3 molar and 10-9 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows,  sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. In yet other embodiments, the subject is a human.
Although the compounds of the present invention can be given per se, preferentially administered to a subject in the form of a pharmaceutical composition.
DRUG COMBINATIONS
Also contemplated herein are combination therapies using one or more compounds or compositions provided herein, or pharmaceutically acceptable derivate, in combination with other pharmaceutically active agents for the treatment of the diseases and disorders described herein.
In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds, which are formulated for oral, systemic, including parenteral or intravenous delivery, or for local or topical application are administered to an individual exhibiting the symptoms of the disease or disorder to be treated. The amounts are effective to treat, manage or ameliorate the disease or ameliorate or eliminate one or more symptoms of the disease or disorder.
Furthermore, it will be understood by those skilled in the art that the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided herein, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, also contemplated herein is the use of compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided herein in combination with other active pharmaceutical agents for the treatment of the disease/conditions described herein.
The compound or composition provided herein, or pharmaceutically acceptable derivative thereof, may be administered simultaneously with, prior to, or after administration of one or more of the above agents. The other active pharmaceutical agents particularly therapeutic agents known to be useful for treating a proliferative disorder or cancer afflicting the subject.
In some embodiments, the one or more other active pharmaceutical agents is selected from anticancer agents (such as a cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, anti-metabolites, intercalating anticancer agents, topoisomerase inhibitors, immunotherapeutic agents, or antihormonal agents) , steroid drugs, methotrexates, leflunomides,  anti-TNF-α agents, calcineurin inhibitors, antihistaminic drugs, chemotherapeutic drugs, antiproliferative agents, immunosuppressors, immunologic stimulants, apronounced anti-inflammatory reagents, CDK4/6 kinases inhibitors, ABL inhibitors, ABL/Scr inhibitors, aurora kinase inhibitors, non-ATP competitive inhibitors of BCR-ABL, c-KIT mutation inhibitors, RET inhibitors, PDGFR inhibitors, VEGFRinhibitors, CSF1R inhibitors, FLT3 inhibitors, FLT3-ITD inhibitors or a combination thereof.
In some embodiments, anticarcinogen is seclected from alkylating agents (such as cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ranimustine, dacarbazine, temozolomide, chlormethine hydrochloride, dibromannitol, and the like) , platinum complexing agents (such as cis-platinum, carboplatin, oxaliplatin, and the like) , metabolic antagonists (such as methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, and the like) , plant alkaloids (such as vincristine, vinblastine , vindesine, etoposide , docetaxel, paclitaxel, irinotecan, vinorelbine , mitoxantrone, vinflunine, topotecan, and the like) , antibody drugs (such as trastuzumab, pertuzumab, rituximab, cetuximab , panitumumab, bevacizumab, and the like) , hormone anticancer agents (such as leuprorelin, goserelin, dutasteride, dexamethasone, tamoxifon, and the like) , proteasome inhibitors (such as bortezomib, lenalidomide, and the like) , aromatase inhibitors (such as exemestane, letrozole, anastrozole, and the like) , VEGFR inhibitors (such as sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib, and the like) , mTOR inhibitors (such as everolimus, sirolimus, zotarolimus, and the like) .
In some embodiments, the one or more other active pharmaceutical agents is selected from streptozotocin, oxaliplatin, temozolomide, methotrexate, fluorouracil, gemcitabine, purinethol, navelbine, docetaxel, topotecan, irinotecan, trabectedin, dactinomycin, mitomycin C, lxabepilone, gonadorelin analogues, megestrol acetate, prednisone, methylprednisolone, thalidomide, interferon α, calcium folinate, 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, zelboraf, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, busulfan, sulfonated propyl amine ester, piposulfan, piposulfan, benzodepa, carboquone, meturedepa, uredepa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, aclacinomycins, actinomycin F (1) , anthramycin, azaserine, bleomycin, cactinomycin, carubicin, carzinophilin, chromomycin, dactinomycin, daunorubicin, daunomycin, 6-diazo-5-oxo-1-norleucine, doxorubicin, epirubicin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, fluorouracil, tegafur, L-asparaginase, pulmozyme, aceglatone, aldophosphamide glycoside, aminolevulinic acid, amsacrine, bestrabucil, bisantrene, carboplatin, cisplatin, defofamide, demecolcine, diaziquone, elformithine, elliptinium acetate, etoglucid, etoposide, flutamide, gallium nitrate, hydroxyurea, interferon-alpha, interferon-beta, interferon-gamma, interleukin-2, lentinan, lonidamine, prednisone, dexamethasone, leucovorin, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, sizofuran, spirogermanium, paclitaxel, tamoxifen, teniposide, tenuazonic acid, triaziquone, 2, 2′, 2″-trichlorotriethylamine, urethane, vinblastine, vincristine, vindesine, deferasirox, cabozantinib, ponatinib, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, palbociclib, abemaciclib, ribociclib, rigosertib sodium, Selinexor, Roniciclib, AT-7519, Seliciclib, Alvocidib or a combination thereof.
In some embodiments, the present invention also provided herein a pharmaceutical composition containing compounds disclosed herein or a pharmaceutically acceptable derivate, and one or more other active pharmaceutical agents as a single dosage form or separately from  the compound or composition as part of a multiple dosage form. The other active pharmaceutical agents may be administered at the same time as a 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.
In some embodiments, the present invention also provided herein a combination therapy that treats or prevents the onset of the symptoms, or associated complications of cancer and related diseases and disorders comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more other active pharmaceutical agents.
In some embodiments, two administrations in drug combinations: 1) the compound or pharmaceutical composition disclosed herein and other active drugs which can be used in combination are in separate formulation, two formulations can be same or different, can be administered either in sequence or simultaneously； when administration in sequence, the second drug is administered during the effective period of the first drug in vivo； 2) the compound or pharmaceutical composition disclosed herein and other active drugs which can be used in combination are in single formulation and administered simultaneously.
In some embodiments, specially provided herein is a drug combination of FLT3 inhibitor or FLT3-ITD inhibitor and CDK4/6 inhibitor. The compound or composition provided herein , or pharmaceutically acceptable derivative thereof as CDK4/6 inhibitor, may be administered simultaneously with, prior to, or after administration of one or more of the active agents. The other active agents specially is FLT3 inhibiotr or FLT3-ITD inhibitor.
In some embodiments, FLT3 inhibitor or FLT3-ITD inhibitor is cabozantinib, ponatinib, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, and so on.
GENERAL SYNTHETIC PROCEDURES
Generally, the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I) - (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 disclosed herein. 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 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 recorded by a Bruker Avance 400 MHz spectrometer or Bruker Avance III HD 600 spectrometer, using CDCl3, DMSO-d6, CD3OD or acetone-d6 (reported in ppm) as solvent, and using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet) , d (doublet) , t (triplet) , m (multiplet) , br (broadened) , dd (doublet of doublets) , dt (doublet of triplets) , ddd (doublet of doublet of doublets) , ddt (doublet of doublet of triplets) , dddd (doublet of doublet of doublet of doublets) . Coupling constants, when given, are reported in Hertz (Hz) .
Low-resolution mass spectral (MS) data were determined on an Agilent 6120 Quadrupole HPLC-MS spectrometer equipped with an Agilent Zorbax SB-C18 (2.1 x 30 mm, 3.5 μm) . 6 min； the flow rate was 0.6 mL/min； the mobile phases consisted of a combination of A (0.1％formic acid in CH3CN) and B (0.1％formic acid in H2O) in gradient mode (5％to 95％) , and an ESI source was used, the peak of HPLC was recorded with UV-Vis detection at 210/254 nm.
Purification of compound by preparative chromatography was implemented on Agilent 1260 Series high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 Series high performance liquid chromatography (Pre-HPLC) with UV detection at 210/254 nm (NOVASEP, 50/80 mm. DAC) .
The following abbreviations are used throughout the application:
BOC, Boc tert-butoxycarbonyl
CHCl3 chloroform
CDC13 chloroform-d
DMF N, N-dimethylformamide
DMSO-d6 dimethyl sulfoxide-d6
HATU 2- (7-aza-1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate
EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
CH3OH, MeOH methanol
DCM, CH2Cl2 dichloromethane
mL, ml millilitre
N2 nitrogen
Pd/C Palladium on activated carbon
RT rt room temperature
Rt retention time
Scheme
Scheme 1 of intermedia
Figure PCTCN2015085034-appb-000073
The intermedia disclosed herein can be prepared by the process illustrated in  scheme1intermedia. Compound (1a) can react with compound (2a) in the present of a base under a heating condition to afford compound (3a) ； catalytic hydrogenation of compound (3) can give compound (1) ； wherein B, R3 and L1 are as defined herein.
Scheme 2 of intermedia
Figure PCTCN2015085034-appb-000074
The intermedia disclosed herein can be prepared by the process illustrated in scheme 2 intermedia. Still reaction of compound (1ad) in the present of toluene-3.4-dithiol can afford compound (1ae) ； cyclization reaction of compound (1ae) in the present of a base (can be R3-L1-NH2 with no limitation) under a heating condition can afford compound (1af) ； reduction of amide of conpound (1af) can afford compound (1ag) ； a methyl group of compound (1ag) can be removed in the present of HBr and AcOH to afford compound (1ah) ； compound (1ah) can form compound (1ai) in the present of POCl3； compound (1ai) can convert to compound (4d) in the present of ammonium hydroxide； wherein L1 and R3 are as defined herein.
Scheme 1
Figure PCTCN2015085034-appb-000075
The compound disclosed herein can be prepared by the process illustrated in scheme 1. Buchwald cross coupling reaction of compound (1) and compound (5) catalyzed by palladium can give target compound (2) , wherein B, L1, R1, R2 and R3 are as defined herein.
Scheme 2
Figure PCTCN2015085034-appb-000076
The compound disclosed herein can be prepared by the process illustrated in scheme 2. Buchwald cross coupling reaction of compound (13) and compound (5) catalyzed by palladium can give target compound (14) , wherein L1, R1, R2 and R3 are as defined herein.
Scheme 3
Figure PCTCN2015085034-appb-000077
The compound disclosed herein can be prepared by the process illustrated in scheme 3. Buchwald cross coupling reaction of compound (4d) and compound (5) catalyzed by palladium can give target compound (14a) , wherein L1, R1, R2 and R3 are as defined herein.
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.
EXAMPLE
Example 1
N- (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -3- (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -1H-indol-5-amine
Figure PCTCN2015085034-appb-000078
A mixture of 6- (2-chloro-5-fluoropyrimidin-4-yl) -4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazole (100 mg, 0.31 mmol, prepared by the preparative method of example 43 of WO 2010075074) ,  3- (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -1H-indol-5-amine (72 mg, 0.31 mmol) , cesium carbonate (0.20 g, 0.62 mmol) , dimethylbisdiphenylphosphinoxanthene (18 mg, 0.025 mmol) and tris (dibenzylideneacetone) dipalladium (14 mg, 0.016 mmol) in 1, 4-dioxane (15 mL) under N2 was stirred at 110 ℃ for 4 h. The reaction mixture was cooled to rt and diluted with DCM (40 mL) and filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a yellow solid product (15 mg, 9.15 ％) .
MS-ESI: (ESI, pos. ion) m/z: 514.5 [M+1] +； and
1H NMR (400 MHz, CDCl3) δ 8.87 (d, J ＝ 9.0 Hz, 1H) , 8.61 (d, J ＝ 3.4 Hz, 1H) , 8.38 (d, J ＝3.8 Hz, 1H) , 8.26 (s, 1H) , 8.22 (d, J ＝ 1.8 Hz, 1H) , 8.16 (s, 1H) , 7.85 (dd, J ＝ 25.7, 11.7 Hz, 2H) , 7.60 (d, J ＝ 7.3 Hz, 1H) , 6.32 (s, 1H) , 4.77-4.65 (m, 1H) , 3.11 (s, 2H) , 2.74 (s, 2H) , 2.73 (s, 2H) , 2.69 (s, 3H) , 2.43 (s, 3H) , 1.75 (d, J ＝ 6.9 Hz, 6H) .
Example 2
N- (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine
Figure PCTCN2015085034-appb-000079
Step 1) tert-butyl 2- ( (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) amino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate
A mixture of 6- (2-chloro-5-fluoropyrimidin-4-yl) -4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazole (322 mg, 1.0 mmol, prepared by the preparative method of example 43 of WO 2010075074) , tert-butyl 2-amino-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate (250 mg, 1.0 mmol, intermedia 34 of WO 2009056556) , cesium carbonate (652 mg, 2.0 mmol) , dimethylbisdiphenylphosphinoxanthene (58 mg, 0.1 mmol) and tris (dibenzylideneacetone) dipalladium (92 mg, 0.1 mmol) in 1, 4-dioxane (25 mL) under N2 was stirred at 110 ℃ for 3 h. The reaction mixture was cooled to rt and diluted with DCM (30 mL) and filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a light  yellow solid product (246 mg, 46.0 ％) .
MS-ESI: (ESI, pos. ion) m/z: 536.4 [M+1] + .
Step 2) N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8 -tetrahydro-1, 6-naphthyridin-2-amine
To a solution of tert-butyl 2- ( (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) amino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate (200 mg, 0.37 mmol) in DCM (30 mL) was added trifluoroacetic acid (0.42 g, 3.7 mmol) . The mixture was stirred at rt for 3 h and concentrated. The residue was adjusted with saturated aqueous sodium carbonate to pH 7-8. The resulting mixture was extracted with DCM (100 mL x 3) . The combined organic layers were dried and concentrated to give a yellow oil product (115 mg, 71.3 ％) .
MS-ESI: (ESI, pos. ion) m/z: 436.5 [M+1] +； and
1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H) , 8.67 (s, 1H) , 8.30 (s, 1H) , 8.08 (d, J ＝ 8.4 Hz, 1H) , 7.69 (d, J ＝ 12.1 Hz, 1H) , 7.49 (d, J ＝ 8.4 Hz, 1H) , 4.91 –4.78 (m, 1H) , 3.97 (s, 2H) , 3.18 (d, J ＝ 5.9 Hz, 2H) , 3.17 (s, 1H) , 2.82 (s, 2H) , 2.64 (s, 3H) , 1.63 (d, J ＝ 6.5 Hz, 6H) .
Example 3
The compound of example 3 were prepared by a similar method to that described in example 2 by using suitable raw materials:
Figure PCTCN2015085034-appb-000080
Example 4
1- (2- ( (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl)  amino) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-hydroxyethanone
Figure PCTCN2015085034-appb-000081
To a solution of N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8 -tetrahydro-1, 6-naphthyridin-2-amine (101 mg, 0.232 mmol) in DCM (10 mL) were added HATU (93.3 mg, 0.24 mmol) and N, N-diisopropylethylamine (0.10 mL, 0.59 mmol) . After stirring the mixture for 10min, glycollic acid (30.8 mg, 0.41 mmol) was added. The mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo . The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a light yellow solid product (34 mg, 30％) .
MS-ESI: (ESI, pos. ion) m/z: 494.6 [M+1] +； and
1H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 1H) , 8.68 (d, J ＝ 3.2 Hz, 1H) , 8.31 (s, 1H) , 8.14 (d, J ＝ 7.8 Hz, 1H) , 7.70 (d, J ＝ 11.9 Hz, 1H) , 7.60 (dd, J ＝ 34.4, 8.2 Hz, 1H) , 4.90-4.80 (m, 1H) , 4.63 (s, 1H) , 4.56 (s, 1H) , 4.21 (d, J ＝ 17.6 Hz, 2H) , 3.90 (s, 1H) , 3.82 (s, 1H) , 3.70 (s, 1H) , 2.90 (s, 1H) , 2.82 (s, 1H) , 2.65 (s, 3H) , 1.64 (d, J ＝ 6.8 Hz, 6H) .
Example 5
N- (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -6- (3, 3, 3-trifluoropropyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine
Figure PCTCN2015085034-appb-000082
A solution of N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8 -tetrahydro-1, 6-naphthyridin-2-amine (72 mg, 0.17 mmol) and 3, 3, 3-trifluoropropanal (41.5 mg, 0.370 mmol) in DMF (10 mL) was stirred 10 min, sodium cyanoborohydride (35 mg, 0.55 mmol) was added. The mixture was stirred at rt. The reaction was monitored by LC-MS until the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by  silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a yellow solid product (11 mg, 13 ％) .
MS-ESI: (ESI, pos. ion) m/z: 532.4 [M+1] +； and
1H NMR (600 MHz, CDCl3) δ: 8.43 (d, J ＝ 3.6 Hz, 1H) , 8.25 (d, J ＝ 8.4 Hz, 1H) , 8.21 (s, 1H) , 8.00 (s, 1H) , 7.80 (d, J ＝ 11.6 Hz, 1H) , 7.39 (d, J ＝ 8.4 Hz, 1H) , 4.75 (td, J ＝ 13.8, 6.8 Hz, 1H) , 3.67 (s, 2H) , 3.00 (t, J ＝ 5.6 Hz, 2H) , 2.90 (t, J ＝ 5.8 Hz, 2H) , 2.84 (dd, J ＝ 16.3, 8.2 Hz, 2H) , 2.72 (s, 3H) , 2.46 (td, J ＝ 20.7, 10.5 Hz, 2H) , 1.73 (d, J ＝ 6.9 Hz, 6H) .
Example 6
2- (2- ( (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) amino) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) ethanol
Figure PCTCN2015085034-appb-000083
To a solution of 2-bromoethanol (55 mg, 0.44 mmol) in DMF (24 mL) in a 100 mL of one-neck flask were added N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8 -tetrahydro-1, 6-naphthyridin-2-amine (148 mg, 0.34 mmol) and potassium carbonate (155 mg, 1.12 mmol) in an ice-bath. The mixture was stirred in the ice-bath for 30 min, and then further stirred at rt for 6 h. The reaction mixture was concentrated in vacuo, the residue was participated beween DCM (100 mL) and water (100 mL) . The organic layer was washed with saturated aqueoussodium bicarbonate (80 mL × 3) and saturated aqueous NaCl (80 mL×1) , dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted withDCM/MeOH (V/V) ＝10/1 to give a light yellow solid (51 mg, 31.3％) .
MS-ESI: (ESI, pos. ion) m/z: 480.5 [M+1] +； and
1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H) , 8.67 (d, J ＝ 3.8 Hz, 1H) , 8.31 (s, 1H) , 8.05 (d, J ＝ 8.4 Hz, 1H) , 7.69 (d, J ＝ 11.9 Hz, 1H) , 7.45 (d, J ＝ 8.5 Hz, 1H) , 4.85 (dt, J ＝ 14.0, 7.0 Hz, 1H) , 4.48 (s, 1H) , 3.59 (s, 2H) , 2.90 –2.75 (m, 4H) , 2.65 (s, 3H) , 2.59 (t, J ＝ 6.1 Hz, 2H) , 1.64 (d, J ＝ 6.9 Hz, 6H) , 1.23 (s, 2H) .
Example 7
N- (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -6- (2-methoxyethyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine
Figure PCTCN2015085034-appb-000084
To a solution of 1-bromo-2-methoxyethane (89 mg, 0.64 mmol) in DMF (24 mL) in a 100 mL of one-neck flask were added N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine (235 mg, 0.54 mmol) and potassium carbonate (149 mg, 1.08mmol) in an ice-bath. The mixture was stirred in the ice-bath for 30 min, and then further stirred at rt for 6 h. The reaction mixture was concentrated in vacuo, the residue was participated beween DCM (100 mL) and water (100 mL) . The organic layer was washed with saturated aqueoussodium bicarbonate (80 mL × 3) and saturated aqueous NaCl (80 mL × 1) , dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted withDCM/MeOH (V/V) ＝10/1 to give a light yellow solid (21 mg, 12.5％) .
MS-ESI: (ESI, pos. ion) m/z: 494.5 [M+1] +；
1H NMR (600 MHz, DMSO-d6) δ 9.99 (s, 1H) , 8.67 (d, J ＝ 3.7 Hz, 1H) , 8.29 (s, 1H) , 8.11 (d, J ＝ 8.5 Hz, 1H) , 7.69 (d, J ＝ 12.0 Hz, 1H) , 7.59 (d, J ＝ 8.5 Hz, 1H) , 4.88 –4.81 (m, 1H) , 4.55 (s, 2H) , 3.71 (t, J ＝ 5.9 Hz, 2H) , 3.65 (s, 3H) , 3.52 (s, 2H) , 2.89 (s, 1H) , 2.83 (t, J ＝ 5.8 Hz, 2H) , 2.73 (s, 1H) , 2.64 (s, 3H) , 1.63 (d, J ＝ 6.9 Hz, 6H) .
Example 8
3- (2- ( (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) amino) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) propan-1-ol
Figure PCTCN2015085034-appb-000085
Step1)
6- (3- ( (tert-butyldimethylsilyl) oxy) propyl) -N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-ben zo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine
To a 100 mL of dry one-neck flask were added (3-bromopropoxy) (tert-butyl) dimethylsilane (0.15 mL) , N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8  -tetrahydro-1, 6-naphthyridin-2-amine (148 mg, 0.34 mmol) , potassium carbonate (200mg, 1.03 mmol) and DMF (24 mL) in turn. The mixture was stirred at rt. The reaction was monitored by TLC and LC-MS until the reaction was completed. The mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with DCM (100 mL × 2) . The combined organic layers were washed with saturated aqueous NaCl (100 mL × 1) and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝10/1 to give a yellow solid product (151 mg, 73.10％) .
MS-ESI: (ESI, pos. ion) m/z: 608.2 [M+1] +；
Step 2) 3- (2- ( (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) ami no) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) propan-1-ol
To a solution of 6- (3- ( (tert-butyldimethylsilyl) oxy) propyl) -N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-ben zo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine (139.7 mg, 0.23 mmol) in tetrahydrofuran (19 mL, 234 mmol) was added tetrabutylammonium fluoride (1.6 mL, 1.6 mmol, 1.0 mol/L) . The mixture was stirred at rt. The reaction was monitored by TLC. The reaction mixture was cooled and concentrated to remove tetrahydrofuran. The residue was diluted with saturated aqueous sodium bicarbonate solution (100 mL) . The resulting mixture was extracted with EtOAc (150 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl (50 mL) , dried over anhydrous Na2SO4 and concentrated in vacuoto give a yellow solid product (88 mg, 78.19％) .
MS-ESI: (ESI, pos. ion) m/z: 494.5 [M+1] +； and
1H NMR (600 MHz, DMSO-d6) δ: 9.97 (s, 1H) , 8.67 (d, J ＝ 3.0 Hz, 1H) , 8.30 (s, 1H) , 8.08 (d, J ＝ 8.2 Hz, 1H) , 7.69 (d, J ＝ 11.9 Hz, 1H) , 7.50 (d, J ＝ 8.1 Hz, 1H) , 4.89 –4.80 (m, 1H) , 4.16 (m, 2H) , 3.72 (s, 2H) , 2.90 (s, 2H) , 2.64 (s, 3H) , 1.75 –1.68 (m, 4H) , 1.62 (t, J ＝ 6.9 Hz, 6H) ., 1.24 (t, J ＝ 7.8 Hz, 2H) .
Examples 9-11
The compounds of examples 9-11 were prepared by a similar method to that described in example 4 or 5 by using suitable raw materials:
Figure PCTCN2015085034-appb-000086
Figure PCTCN2015085034-appb-000087
Examples 12-35
The compounds of examples 12-35 were prepared by a similar method to that described in example 1 by using suitable raw materials:
Figure PCTCN2015085034-appb-000088
Figure PCTCN2015085034-appb-000089
Figure PCTCN2015085034-appb-000090
Example 36
6-Ethyl-N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine
Figure PCTCN2015085034-appb-000091
To a solution ofiodoethane (41.8 mg, 0.27 mmol) and N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8 -tetrahydro-1, 6-naphthyridin-2-amine (example 2) (113 mg, 0.26 mmol) in DMF (15 mL) was added potassium carbonate (70 mg, 0.50mmol) . The mixture was stirred at rt, the reaction was  monitored by LC-MS until the reaction was completed. The reaction mixture was concentrated in vacuo. To the residue was silica gel, the resulting mixture was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a yellow solid product (59 mg, 49.4 ％) .
MS-ESI: (ESI, pos. ion) m/z: 564.4 [M+1] +； and
1H NMR (600 MHz, DMSO-d6) δ 10.18 (s, 1H) , 8.70 (d, J＝ 3.5 Hz, 1H) , 8.30 (s, 1H) , 8.18 (d, J＝ 8.4 Hz, 1H) , 7.70 (d, J＝ 12.0 Hz, 1H) , 7.62 (d, J＝ 8.4 Hz, 1H) , 4.85 (dd, J＝ 13.7, 6.8 Hz, 1H) , 4.28 (s, 2H) , 3.67 (s, 2H) , 3.19 (s, 2H) , 3.08 (s, 2H) , 2.65 (s, 3H) , 1.64 (d, J＝ 6.8 Hz, 6H) , 1.30 (d, J＝ 6.4 Hz, 3H) .
Example 37
Methyl
7- ( (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) ami no) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate
Figure PCTCN2015085034-appb-000092
To a solution of N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8 -tetrahydro-2, 6-naphthyridin-3-amine (example 2) (158 mg, 0.36 mmol) in DCM (40 mL) in a 100 mL of one-neck flask were added methylclhlorofonmate (0.4 mL, 5.0 mmol) and diisopropylethylamine (0.5 mL, 3.2 mmol) in an ice bath. The resulting mixture was stirred for 30 min and warmed to rt for 6 h. The reaction mixture was concentrated in vacuo. To the residue was added DCM (100 mL) and water (100 mL) . The organic layer was washed with saturated aqueous sodium bicarbonate (80 mL × 3) , saturated aqueous NaCl (80 mL × 1) and dried over anhydrous Na2SO4. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a light yellow solid product (51 mg, 28.48％) .
MS-ESI: (ESI, pos. ion) m/z: 494.5 [M+1] +； and
1H NMR (600 MHz, DMSO-d6) δ 9.99 (s, 1H) , 8.67 (d, J ＝ 3.7 Hz, 1H) , 8.29 (s, 1H) , 8.11 (d, J ＝ 8.5 Hz, 1H) , 7.69 (d, J ＝ 12.0 Hz, 1H) , 7.59 (d, J ＝ 8.5 Hz, 1H) , 4.84 (dt, J ＝ 13.9, 6.9 Hz, 1H) , 4.55 (s, 2H) , 3.71 (t, J ＝ 5.9 Hz, 2H) , 3.65 (s, 3H) , 2.83 (t, J ＝ 5.8 Hz, 2H) , 2.63 (d, J ＝ 10.0 Hz, 3H) , 1.63 (d, J ＝ 6.9 Hz, 6H) .
Example 38
3- (7- ( (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) amino) -3, 4-dihydro-2, 6-naphthyridin-2 (1H) -yl) -3-oxopropanenitrile
Figure PCTCN2015085034-appb-000093
To a solution of N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8 -tetrahydro-2, 6-naphthyridin-3-amine (example 2) (151 mg, 0.35 mmol) in DCM (40 mL) in a 100 mL of one-neck flask were added 2-cyanoacetic acid (50 mg, 0.59 mmol) , diisopropylethylamine (0.5 mL, 3 mmol) and HATU (170 mg, 0.43 mmol) in an ice bath. The resulting mixture was stirred for 30 min and warmed to rt for 6 h. The reaction mixture was concentrated in vacuo. To the residue was added DCM (100 mL) and water (100 mL) . The organic layer was washed with saturated aqueous sodium bicarbonate (80 mL × 3) , saturated aqueous NaCl (80 mL × 1) and dried over anhydrous Na2SO4. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a light yellow solid product (51 mg, 29.27％) .
MS-ESI: (ESI, pos. ion) m/z: 503.5 [M+1] +； and
1H NMR (600 MHz, DMSO-d6) δ 10.03 (d, J ＝ 13.8 Hz, 1H) , 8.65 (d, J ＝ 3.7 Hz, 1H) , 8.29 (s, 1H) , 8.12 (dd, J ＝ 11.8, 8.6 Hz, 1H) , 7.67 (d, J ＝ 12.0 Hz, 1H) , 7.62-7.50 (m, 1H) , 4.84 (dt, J ＝ 13.5, 6.7 Hz, 1H) , 4.60 (d, J ＝ 27.0 Hz, 2H) , 4.17 (d, J ＝ 20.6 Hz, 2H) , 3.83-3.68 (m, 2H) , 2.92 (dd, J ＝ 14.4, 8.7 Hz, 1H) , 2.82 (t, J ＝ 5.7 Hz, 1H) , 2.64 (s, 3H) , 1.63 (d, J ＝ 6.9 Hz, 6H) .
Example 39
N- (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -6- (oxetan-3-yl) -5, 6, 7, 8-tetrahydro-2, 6-naphthyridin-3-amine
Figure PCTCN2015085034-appb-000094
To a solution of N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8  -tetrahydro-2, 6-naphthyridin-3-amine (148 mg, 0.34 mmol) in DCM (19 mL) was added oxetan-3-one (41 mg, 0.57 mmol) in an ice bath. The resulting mixture was stirred for 30 min, and sodium cyanoborohydride (0.1 g, 2 mmol) was added. The mixture was stirred at rt. After the reaction was completed, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a light yellow solid product (38 mg, 22.75％) .
MS-ESI: (ESI, pos. ion) m/z: 492.4 [M+1] +； and
1H NMR (600 MHz, DMSO-d6) δ 10.10 (s, 1H) , 8.76 (d, J ＝ 3.3 Hz, 1H) , 8.49 (s, 1H) , 8.05 (d, J ＝ 8.4 Hz, 1H) , 7.96 (d, J ＝ 12.6 Hz, 1H) , 7.48 (d, J ＝ 8.5 Hz, 1H) , 5.10-5.08 (m, 1H) , 4.64 (t, J ＝ 6.5 Hz, 2H) , 4.55 (t, J ＝ 6.1 Hz, 2H) , 3.64 (dd, J ＝ 12.6, 6.3 Hz, 1H) , 3.46 (s, 2H) , 2.89 (s, 3H) , 2.86 (t, J ＝ 5.7 Hz, 2H) , 2.64 (t, J ＝ 5.8 Hz, 2H) , 1.71 (d, J ＝ 6.9 Hz, 6H) .
Example 40
N- (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -6- (piperidin-4-yl) -5, 6, 7, 8-tetrahydro-2, 6-naphthyridin-3-amine
Figure PCTCN2015085034-appb-000095
Step 1) tert-butyl 4- (7- ( (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) ami no) -3, 4-dihydro-2, 6-naphthyridin-2 (1H) -yl) piperidine-1-carboxylate
To a solution of N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -5, 6, 7, 8 -tetrahydro-2, 6-naphthyridin-3-amine (298 mg, 0.68 mmol) in DCM (19 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (181 mg, 0.91 mmol) in an ice bath. The resulting mixture was stirred for 30 min, and sodium cyanoborohydride (0.11 g, 1.7 mmol) was added. The mixture was stirred at rt. After the reaction was completed, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a light yellow solid product (38 mg, 8.98％) .
MS-ESI: (ESI, pos. ion) m/z: 619.5 [M+1] +；
Step 2) N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -6- (pipe  ridin-4-yl) -5, 6, 7, 8-tetrahydro-2, 6-naphthyridin-3-amine
To a solution of tert-butyl 4- (7- ( (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) ami no) -3, 4-dihydro-2, 6-naphthyridin-2 (1H) -yl) piperidine-1-carboxylate (105 mg, 0.17 mmol) in DCM (19 mL) was added trifluoroacetic acid (7 mL) . The mixture was stirred at rt overnight. Stopping stirring, the mixture was filtered, the filtrate was concentrated. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a light yellow solid product (67 mg, 76.13％) .
MS-ESI: (ESI, pos. ion) m/z: 519.5 [M+1] +； and
1H NMR (600 MHz, DMSO-d6) δ 10.08 (s, 1H) , 9.97 (s, 1H) , 8.68 (s, 1H) , 8.31 (s, 1H) , 8.08 (d, J ＝ 8.3 Hz, 1H) , 7.70 (d, J ＝ 11.9 Hz, 1H) , 7.47 (d, J ＝ 8.3 Hz, 1H) , 4.89 –4.81 (m, 1H) , 4.64 (t, J ＝ 6.1 Hz, 2H) , 4.58 –4.47 (m, 2H) , 3.68 –3.60 (m, 1H) , 3.51 (s, 1H) , 3.46 (s, 2H) , 3.18 (d, J ＝ 4.8 Hz, 1H) , 2.86 (s, 2H) , 2.65 (s, 3H) , 1.66 (d, J ＝ 21.3 Hz, 6H) , 1.26 –1.22 (m, 4H) .
Example 41
N- (5-Fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -6- (1-methylpiperidin-4-yl) -5, 6, 7, 8-tetrahydro-2, 6-naphthyridin-3-amine
Figure PCTCN2015085034-appb-000096
A solution of N- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) -6- (pipe ridin-4-yl) -5, 6, 7, 8-tetrahydro-2, 6-naphthyridin-3-amine (104 mg, 0.20 mmol) and formaldehyde (25 mg, 0.31 mmol) in DMF (20 mL) was stirred for 10 min, sodium triacetoxyborohydride (53 mg, 0.24 mmol) was added. The resulting mixture was stirred at rt. After the reaction was completed, the reaction mixture was concentrated in vacuo. To the residue was added silica gel, the resulting mixture was purified by silica gel chromatography eluted with DCM/MeOH (V/V) ＝ 10/1 to give a yellow solid product (56 mg, 52％) .
LC-MS: (pos. ion) m/z: 533.5 [M+1] +； and
1H NMR (600 MHz, DMSO-d6) δ 10.12 (s, 1H) , 8.72 (s, 1H) , 8.31 (s, 1H) , 8.05 (d, J ＝ 8.3 Hz, 1H) , 7.72 (d, J ＝ 11.9 Hz, 1H) , 7.45 (d, J ＝ 8.3 Hz, 1H) , 4.89 –4.81 (m, 1H) , 4.64 (t, J ＝ 6.1  Hz, 2H) , 4.58 –4.47 (m, 2H) , 3.65 –3.63 (m, 1H) , 3.56 (s, 1H) , 3.45 (s, 2H) , 3.15 (d, J ＝ 4.8 Hz, 1H) , 2.86 (s, 2H) , 2.65 (s, 3H) , 2.34 (s, 3H) , 1.66 (d, J ＝ 21.3 Hz, 6H) , 1.26 –1.22 (m, 4H) .
DETECTION OF ACTIVITY OF THE COMPOUNDS OF THE INVENTION
Biologic example 1 Enzymatic inhibitory activity in vitro of the compound of the invention 
Test method
The materials are used in the following assay:
HEPES: 4- (2-Hydroxyethyl) piperazine-1-ethanesulfonic acid；
Brij-35: Polyethylene Glycol Monoisotridecyl Ether；
DTT: Dithiothreitol； EDTA: Ethylene Diamine Tetraacetic Acid；
CDK4/CycD3: Cyclin dependent kinase 4；
CDK6/CycD3: Cyclin dependent kinase 6；
Peptide FAM-P22: fluorescein-labeled peptide 22；
ATP: adenosine triphosphate；
DMSO: dimethyl sulfoxide；
Staurosporine；
Coating Reagent #3；
1. Preparation of 1× kinase base buffer and stop buffer :
(1) 1× Kinase buffer without MnCl2 was prepared by using 50 mM HEPES, pH 7.5, 0.0015％Brij-35, 10 mM MgCl2, 2 mM DTT； (2) Stop buffer was prepared by using 100 mM HEPES, pH 7.5, 0.015％Brij-35, 0.2％Coating Reagent #3, 50 mM EDTA.
2. Preparetion of the compoundfor testing kinasesby serial dilution
(1) The compound was diluted to 50× of the final desired highest inhibitor concentration in reaction by 100％DMSO. Transferring 100 μL of this compound dilution to a well in a 96-well plate. (2) The compound was diluted gradiently by transferring 20 μL of original solution to 60 μL of 100％DMSO in the next well and so forth to obtain 10 different concentrations. (3) Adding 100 μL of 100％DMSO to two empty wells for a control without compound and a control without enzyme. (4) Preparing intermediate plate, 10 μL of each compound solution was transfered from source plate to a new 96-well plate as the intermediate plate. Adding 90μL of 1× kinase buffer to each well of the intermediate plate. The compounds were mixed in intermediate plate for 10 min on shaker. (5) Preparing assay plate, 5 μL of each compound solution in well was transferred from the 96-well intermediate plate to a 384-well  plate in duplicates.
3. Kinase reaction
(1) Preparing 2.5× enzyme solution, kinase was added in 1× kinase base buffer. (2) Preparing 2.5× peptide solution, FAM-labeled peptide and ATP were added in the 1× kinase base buffer. (3) Transferring10 μL of 2.5× enzyme solution to each well of the 384-well assay plate, and each well of 384-well assay plate already contains 5μLof compound in 10％DMSO, which was incubated at room temperature for 10 min. (4) Adding 10μL of 2.5× peptide solution to each well of the 384-well assay plate. (5) Kinase reaction and stop, the kinase was incubate at 28 ℃ for specified period of time and to which was added 25 μL of stop buffer to stop thereaction.
4. Caliper reading, collect data on Caliper.
5. Curve fitting
(1) Conversion data were collected and coverted to inhibition values；
Percent inhibition ＝ (max-conversion) / (max-min) *100；
“max” stands for the value of control without compound； “min” stands for the value of control without enzyme.
(2) Fitting the data in XLfit to obtain IC50 values.
6. Results
Table 2 Enzymatic inhibitory activity in vitro of the compound of the invention
Figure PCTCN2015085034-appb-000097
Conclusion: The results listed in Table 2 indicated that the compounds disclosed herein showed high inhibitory activity on CDK4 and CDK6, enzymatic inhibitory activity in vitro thereof are less than 0.1 μM.
Biologic example 2 Pharmacokinetic activity the compound of the invention
Test method
The assay agents and samples are as shown below:
Propranolol: Propranolol (internal standard) ；
MTBE: Methyl Tertiary Butyl Ether；
Cremophor EL: polyoxyethylated castor oil；
KolliphorHS 15: polyethylene glycol 12-hydroxystearate；
DMSO: dimethylsulfoxide；
PEG400: polyethylene glycol 400；
18 male SD rats.
1. Sample Preparation
Each test compound prepared was completely dissolved in a mixture of 5％DMSO, 10％KolliphorHS 15, 35％Saline or 5％DMSO, 60％PEG400 and 35％Saline according solubility property thereof.
2. Animal exeriment
Grouping male SD rats weighing 190-250 g randomly to two groups； one group was administered with test compound at a dose of 1.0 mg/kg by intravenous injection, the other group was administered with test compound at a dose of 5.0 mg/kg by oral. After administering, blood samples of intravenous injection group were collected at time points of 0.0833, 0.25, 0.5, 1, 2, 5, 7 and 24 h from caudal vein； blood samples of oral group were collected at time points of 0.25, 0.5, 1, 2, 5, 7 and 24 h from caudal vein. Standard curve was plotted based on concentrations of the samples in a suitable range, the concentrations of test compounds in plasma samples were determined by using LC-MS/MS. Pharmacokinetic parameters were calculated according to drug concentration -time curve using a noncompartmental method by WinNonLin 6.3 software.
3. Results were as shown below:
Table 3 Pharmacokinetic activity the compound of the invention
Figure PCTCN2015085034-appb-000098
Figure PCTCN2015085034-appb-000099
“/” means no detection.
Conclusion: The results indicated that the compounds disclosed herein had a good in vivo metabolism, better absorption and exposure, and high bioavailability， and which had an obvious advantage than abemaciclib in bioavailability.
Biologic example 3: In vivopharmacokinetic activity of the compound of the invention in mice
Test method:
Grouping 18 ICR mice weighing 18-25 g randomly to three groups； each group has 6 mice. 3 mice of every group were administered by intravenous injection and the other 3 mice were administered by gavage with test compound. After administering, blood samples were collected at designed time points. The blood samples were centrifuged to collect plasma samples. After treating the plasma samples, the blood medicinal concentrations were determined by using LC-MS/MS. Pharmacokinetic parameters were calculated using a noncompartmental method by WinNonLin software. Results were shown as below:
Table 4 In vivo pharmacokinetic activity of the compound of the invention in mice
Figure PCTCN2015085034-appb-000100
Conclusion: The results indicated that the compounds disclosed herein had a good in vivo metabolism, better absorption and exposure, and high bioavailability， and which had an obvious advantage than abemaciclib in exposure.

Claims (21)

  1. A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
    Figure PCTCN2015085034-appb-100001
    wherein
    ring B is
    Figure PCTCN2015085034-appb-100002
    Figure PCTCN2015085034-appb-100003
    each Y, Y1 and Y2 is independently -C (R4) 2-, -N (R5) -, -O-, -S (＝O) t- or -C (＝O) -；
    each Y3, Y4, Y5, Y6, Y8 and Y7 is independently CR4 or N；
    each of R1 and R2 is independently H, F, Cl, Br, hydroxy, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy；
    L1 is a bond, - (C (R4c) 2) n1-, - (C (R4c) 2) n1-C (＝O) -N (R5c) - (C (R4c) 2) n1-, - (C (R4c) 2) n1-N (R5c) - (C (R4c) 2) n1-, - (C (R4c) 2) n1-O- (C (R4c) 2) n1-, - (C (R4c) 2) n1-S (＝O) t- (C (R4c) 2) n1- or - (C (R4c) 2) n1-C (＝O) - (C (R4c) 2) n1-；
    R3 is H, C5-12 spiro heterobicyclyl, C5-12 bridged heterobicyclyl, C5-12 fused heterobicyclyl, C3-9 cycloalkyl, C3-9 heterocyclyl or C1-9 heteroaryl；
    each R4c andR4 is independently H, C1-6 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-6 alkoxy, H2N- (CH2) n-, N (R6R7) -C (＝O) -, formyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H- (CH2) n-O- (CH2) n-, CN- (CH2) n-C (＝O) -, C3-9 heterocyclyl, C1-9 heteroaryl, C1-6 haloalkyl or C1-6 alkylamino；
    each R5c andR5 is independently H, C1-6 alkyl, C1-6 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-9 heterocyclyl or C1-9 heteroaryl；
    each n and n1 is independently 0, 1, 2, 3, or 4；
    each t is independently 0, 1, or 2；
    each R6 and R7 is independently H, C1-6 alkyl, hydroxy, carboxy, amino, C1-6 alkoxy, H2N- (CH2) n-, NH2-C (＝O) -, formyl, H- (CH2) n-O-C (＝O) - (CH2) n-, C3-9 heterocyclyl, C1-9 heteroaryl, C1-6 haloalkyl or C1-6 alkylamino；
    each moiety represented by B is optionally and independently substituted with one or more substituents independently selected from H, C1-6 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-6 alkoxy, C1-6 haloalkyl, (R6R7) N- (C (R4) 2) n-, N (R6R7) -C (＝O) -, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, cyano or nitro；
    each alkyl, alkoxy, haloalkyl, alkylamino, spiro heterobicyclyl, bridged heterobicyclyl, fused heterobicyclyl, heterocyclyl, heteroaryl, aryl, cycloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) - and H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n- described in R1, R2, R5c, R3 and/or R5 is optionally and independently substituted with one or more R8；
    each R8 is independently H, oxo (＝O) , C1-6 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 haloalkyl, cyano, C3-9 heterocyclyl, C1-9 heteroaryl, H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-, HO- (CH2) n-C (＝O) -, NH2-C (＝O) -, CN- (CH2) n-C (＝O) -, C3-9 cycloalkyl or nitro； each alkyl, alkoxy, alkylamino, haloalkyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-,  HO- (CH2) n-C (＝O) -, HO- (CH2) n-, NH2-C (＝O) -, heterocyclyl, cycloalkyl and heteroaryl described in R8 is optionally and independently substituted with one or more R9； and
    each R9 is independently H, oxo (＝O) , C1-6 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 haloalkyl, formyl, cyano, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, CN-C (R4) 2-C (＝O) -, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, C3-9 heterocyclyl, C1-9 heteroaryl, C3-9 cycloalkyl or nitro.
  2. The compound according to claim 1 having Formula (II) or Formula (III) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
    Figure PCTCN2015085034-appb-100004
    wherein when
    Figure PCTCN2015085034-appb-100005
    is a double bond, T1 is Y6； and
    when
    Figure PCTCN2015085034-appb-100006
    is a single bond, T1 is Y1.
  3. The compound of claim 1 or 2, wherein
    each R5c andR5 is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or C1-9 heteroaryl；
    each R4c andR4 is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
    each R6 and R7 is independently H, C1-4 alkyl, hydroxy, carboxy, amino, C1-4 alkoxy, H2N- (CH2) n-, NH2-C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, C3-9 heterocyclyl, C1-9 heteroaryl,  C1-4haloalkyl or C1-4 alkylamino.
  4. The compound of claim 1 or 2, wherein
    each R5c andR5 is independently H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, H, trifluoromethyl, 2-fluoroethyl, 3, 3, 3-trifluoropropyl, methyl, ethyl, n-propyl, i-propyl, t-butyl, 2-methylpropyl or n-butyl；
    each R4c and R4 is independently H, methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, hydroxy, carboxy, amino, methoxy, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, trifluoromethyl or methylamino； and
    eachR6 and R7is independently H, methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, hydroxy, carboxy, amino, methoxy, H2N- (CH2) n-, NH2-C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, trifluoromethyl or methylamino.
  5. The compound of any one of claims 1 to 4, wherein
    each R8 is independently H, oxo (＝O) , C1-4alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 haloalkyl, H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-, HO- (CH2) n-C (＝O) -, NH2-C (＝O) -, cyano, CN- (CH2) n-C (＝O) -, C1-9heteroaryl, 
    Figure PCTCN2015085034-appb-100007
    or nitro；
    each R9 is independently H, oxo (＝O) , C1-4 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 haloalkyl, cyano, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, CN-C (R4) 2-C (＝O) -, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, 
    Figure PCTCN2015085034-appb-100008
    C1-9 heteroaryl or nitro；
    each Xand X1is independently -C (R4a) 2-, -N (R5a) -, -O-, -S (＝O) t- or -C (＝O) -； and
    each R5a is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or  C1-9heteroaryl；
    each R4a is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
    each e and f is independently 0, 1, 2 or 3.
  6. The compound of any one of claims 1 to 4, wherein
    each R8is independently H, oxo (＝O) , methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, F, Cl, Br, amino, hydroxy, carboxy, methoxy, ethoxy, 1-chloroethyl, dimethylamino, diethylamino, methylamino, trifluoromethyl, cyano, 
    Figure PCTCN2015085034-appb-100009
    Figure PCTCN2015085034-appb-100010
    H- (CH2) n-O-C (＝O) - (CH2) n-, H2N- (CH2) n-, H- (CH2) n-SO2- (CH2) n-, HO- (CH2) n-, HO- (CH2) n-C (＝O) -, NH2-C (＝O) -, CN- (CH2) n-C (＝O) - or nitro； and
    each R9 is independently H, oxo (＝O) , methyl, ethyl, n-propyl, i-propyl, t-butyl, n-butyl, 2-methylpropyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 haloalkyl, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, CN-C (R4) 2-C (＝O) -, H2N- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, cyano, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, 
    Figure PCTCN2015085034-appb-100011
    Figure PCTCN2015085034-appb-100012
    C1-9 heteroaryl or nitro.
  7. The compound of any one of claims 1 to 6, wherein
    R3 is H, 
    Figure PCTCN2015085034-appb-100013
    Figure PCTCN2015085034-appb-100014
    wherein each X2, X6and X7 is independently -C (R4b) 2-, -N (R5b) -, -O-, -S (＝O) t- or -C (＝O) -；
    each X3, X4and X5is independently CR4b or N；
    each R5b is independently H, C1-4 alkyl, C1-4 haloalkyl, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, (R6R7) N- (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, N (R6R7) -C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, C3-6 heterocyclyl or C1-9 heteroaryl；
    each R4b is independently H, H2N- (CH2) n-, N (R6R7) -C (＝O) -, H- (CH2) n-O-C (＝O) - (CH2) n-, CN- (CH2) n-C (＝O) -, H- (CH2) n-O- (CH2) n-, C1-4 alkyl, hydroxy, F, Cl, Br, carboxy, amino, C1-4 alkoxy, C3-6 heterocyclyl, C1-9 heteroaryl, C1-4 haloalkyl or C1-4 alkylamino； and
    each e, g and f is independently 0, 1, 2 or 3；
    R3 is optionally substituted with one or more R8； and
    each R8 is optionally and independently substituted with one or more R9.
  8. The compound of any one of claims 1 to 6, wherein
    R3 is H, 
    Figure PCTCN2015085034-appb-100015
    Figure PCTCN2015085034-appb-100016
    Figure PCTCN2015085034-appb-100017
    Figure PCTCN2015085034-appb-100018
    Figure PCTCN2015085034-appb-100019
    n is0, 1, 2 or 3； and
    each moiety represented by R3 is independently and optionally substituted with one or more R8.
  9. The compound of any one of claims 1 to 8, wherein
    ring B is
    Figure PCTCN2015085034-appb-100020
    Figure PCTCN2015085034-appb-100021
    Figure PCTCN2015085034-appb-100022
    each moiety represented by B is optionally and independently substituted with one or more substituents independently selected from H, C1-4 alkyl, F, Cl, Br, amino, hydroxy, carboxy, C1-4 alkoxy, C1-6 haloalkyl, (R6R7) N- (C (R4) 2) n-, N (R6R7) -C (＝O) -, H- (C (R4) 2) n-O-C (＝O) - (C (R4) 2) n-, HO- (C (R4) 2) n-C (＝O) -, HO- (C (R4) 2) n-, H- (C (R4) 2) n-O- (C (R4) 2) n-, H- (C (R4) 2) n-SO2- (C (R4) 2) n-, H- (C (R4) 2) n-C (＝O) - (C (R4) 2) n-, CN- (C (R4) 2) n-C (＝O) -, H- (C (R4) 2) n-O-C (＝O) -C (＝O) - (C (R4) 2) n-, cyano or nitro.
  10. The compound of claim 1 having one of the following structures or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:
    Figure PCTCN2015085034-appb-100023
    Figure PCTCN2015085034-appb-100024
    Figure PCTCN2015085034-appb-100025
    Figure PCTCN2015085034-appb-100026
    Figure PCTCN2015085034-appb-100027
    Figure PCTCN2015085034-appb-100028
    Figure PCTCN2015085034-appb-100029
    Figure PCTCN2015085034-appb-100030
    Figure PCTCN2015085034-appb-100031
    Figure PCTCN2015085034-appb-100032
  11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10.
  12. The pharmaceutical composition of claim 11 further comprisingat least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants or vehicles.
  13. Thepharmaceutical composition of claim 12 further comprising at least one activity agent used for treating proliferative diseases, autoimmune diseases or inflammatory diseases, wherein  theactivity agent comprises a chemotherapeutic drug, an antiproliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, a CDK4/6 kinase inhibitor, an ABL inhibitor, an ABL/Scr inhibitor, an aurora kinase inhibitor, a non-ATP competitive inhibitor of BCR-ABL, a c-KIT mutation inhibitor, a RET inhibitor, a PDGFR inhibitor, a VEGFRinhibitor, a CSF1R inhibitor, an FLT3 inhibitor, an FLT3-ITD inhibitor or a combination thereof.
  14. The pharmaceutical composition of claim 13, wherein the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cis-platinum, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbozine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, purinethol, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, pharmorubicin, daunomycin, mitoxantrone, bleomycin, mitomycinC, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon α, calcium folinate, 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, zelboraf, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, cabozantinib, ponatinib, midostaurin, pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, crenolanib, ENMD-2076, famitinib, dovitinib, PLX-3397, palbociclib, abemaciclib, ribociclib, rigosertib sodium, selinexor, roniciclib, AT-7519, seliciclib, alvocidib or a combination thereof.
  15. Use of the compound of any one of claims 1 to 10 or the pharmaceutical composition of any one of claims 11 to 14in the manufacture of a medicament for preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection.
  16. The use of claim15, wherein the disorder or disease is caused by changes in cyclin-dependent kinase； wherein the cyclin-dependent kinase is CDK1, CDK2, CDK4, CDK6 or CDK9.
  17. A method of preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infectionin a patient comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 10 or the pharmaceutical composition of any one of claims 11 to 14.
  18. The method of claim 17, wherein the disorder and disease is caused by changes in cyclin-dependent kinase； wherein the cyclin-dependent kinase is CDK1, CDK2, CDK4, CDK6 or CDK9.
  19. The compound of any one of claims 1 to 10 or the pharmaceutical composition of any one of claims 11 to 14for use in preventing, managing, treating or lessening disorders or diseases caused by abnormal cell proliferation, autoimmunity, inflammation or infection in a patient.
  20. The compound or pharmaceutical composition of claim19, wherein the disease is caused by changes in cyclin-dependent kinase； wherein the cyclin-dependent kinase is CDK1, CDK2, CDK4, CDK6 or CDK9.
  21. A drug combination comprising the compound of any one of claims 1 to 10 or the pharmaceutical composition of any one of claims 11 to 14and one or more other activity agents used for treating proliferative diseases, autoimmune diseases or inflammatory diseases； the other activity agent comprises a chemotherapeutic drug, an anti-proliferative agent, an immunosuppressor, an immunologic stimulant, an anti-inflammatory agent, a CDK4/6 kinase inhibitor, an ABL inhibitor, an ABL/Scr inhibitor, an aurora kinase inhibitor, a non-ATP competitive inhibitor of BCR-ABL, a c-KIT mutation inhibitor, a RET inhibitor, a PDGFR inhibitor, a VEGFRinhibitor, a CSF1R inhibitor, an FLT3 inhibitor, an FLT3-ITD inhibitor or a combination thereof.
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