CN109942544A - A kind of novel indazole analog derivative kinase inhibitor - Google Patents

A kind of novel indazole analog derivative kinase inhibitor Download PDF

Info

Publication number
CN109942544A
CN109942544A CN201711394182.5A CN201711394182A CN109942544A CN 109942544 A CN109942544 A CN 109942544A CN 201711394182 A CN201711394182 A CN 201711394182A CN 109942544 A CN109942544 A CN 109942544A
Authority
CN
China
Prior art keywords
base
compound
indazole
alkyl
synthesis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201711394182.5A
Other languages
Chinese (zh)
Other versions
CN109942544B (en
Inventor
刘静
刘青松
刘学松
王蓓蕾
蒋宗儒
余凯琳
陈程
邹凤鸣
刘青旺
刘晓川
王伟
汪文亮
胡晨
王文超
王俊杰
王黎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hefei Institutes of Physical Science of CAS
Original Assignee
Hefei Institutes of Physical Science of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hefei Institutes of Physical Science of CAS filed Critical Hefei Institutes of Physical Science of CAS
Priority to CN201711394182.5A priority Critical patent/CN109942544B/en
Priority to PCT/CN2017/118602 priority patent/WO2019119481A1/en
Publication of CN109942544A publication Critical patent/CN109942544A/en
Application granted granted Critical
Publication of CN109942544B publication Critical patent/CN109942544B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The present invention relates to a kind of kinase inhibitors comprising the compound of formula (I) or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug.The invention further relates to the pharmaceutical compositions including the kinase inhibitor, and inhibit using these compounds and composition cell or subject selected from one of cKIT, BCR/ABL, PDGFR α, PDGFR β and VEGFR2 or a variety of tyrosine kinase activities and the purposes and method of preventing or treat kinase related disorder in subject.

Description

A kind of novel indazole analog derivative kinase inhibitor
Technical field
The present invention relates to a kind of novel kinase inhibitor compounds, the pharmaceutical composition including the compound, and make Reduced or inhibited with these compound or compositions cell or subject cKIT (especially saltant type cKIT/T670I), BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 activity, and in subject The purposes and method of middle prevention or treatment kinase related disorder.
Background technique
Tyrosine kinase is that γ-phosphoric acid is transferred to the kinases on protein-tyrosine residue on a kind of catalysis ATP, can be catalyzed more Kind substrate protein white matter tyrosine residue phosphorylation plays a significant role in cell growth, proliferation, differentiation.Kinase function is abnormal It is of great significance in cancer, immune, nerve, metabolism and infectious diseases.About nearly 30 kinds different kinases conducts at present The drug of target spot, the overwhelming majority are used to treating cancer.Majority is to belong to carcinogenic RNA disease in the protein tyrosine kinase found so far The oncoprotein of poison, can also be generated by the proto-oncogene of vertebrate.
Tyrosine kinase inhibitor can be used as competitive inhibitor of the atriphos (ATP) in conjunction with tyrosine kinase, Also the analog that can be used as tyrosine blocks the activity of tyrosine kinase, inhibits cell Proliferation, has developed several antitumor Drug.
The kinases encoded in human genome has 518 kinds, and almost each signal transduction process is required to pass through phposphate Cascade reaction (cascade) is got in touch with: prompt inhibition kinase activity can really eliminate the physiological reaction of cell.For example, cancer Gene BCR (Breakpoint cluster region)-ABL fusion protein is the key that lead to chronic myelogenous leukemia Factor, tyrosine activity have apparent therapeutic potential.Although ATP-binding site has the conservative of height, can open Send out the small molecule on pharmacological characteristic with obvious selectivity.Normal cell can usually be resistant to the inhibition of kinases, therefore be Selectivity kills tumour cell and provides the window of a treatment.Such as Dasatinib treats the drug resistant chronic marrow of Imatinib Property leukaemia CML, can almost inhibit 9 kinases (and other multiple tyrosine kinase) of SRC family, but with it is traditional thin Born of the same parents' chemotherapy is compared, and side effect is still easy tolerance.Therefore, the exploitation of new kinase inhibitor has important clinical meaning.
Summary of the invention
The present invention provides a kind of Azaindole kinase inhibitors, compound or its pharmaceutically acceptable salt, solvent including formula (I) Compound, ester, acid, metabolin or prodrug:
Wherein, X is selected from
Y be selected from phenyl, thiophene -2- base, isoxazole -3- base, pyridin-3-yl, pyridin-4-yl, 2-Pyrrolidone -5- base, N- methyl -2 (1H)-pyridone -5- base and furans -2- base；
R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3Group replace pyridin-3-yl, optionally By R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces；
(R2)nIt indicates optionally by n independent R2Replaced substituent group, wherein n is the integer of 0-5, R2Independently selected from hydroxyl Base, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4- Methyl-imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl；
R5Selected from hydrogen and C1-6Alkyl amino.
In a preferred embodiment, kinase inhibitor of the invention includes the compound of formula (Ia) or its is pharmaceutically acceptable Salt, solvate, ester, acid, metabolin or pro-drug:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl of group substitution, Optionally by R3The phenyl that group replaces；
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group, wherein n is The integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Alkyl amino, 4- methyl- Imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl；
R5Selected from C1-6Alkyl amino.
In other preferred embodiment, kinase inhibitor of the invention includes the compound of formula (Ib) or its pharmacy can Salt, solvate, ester, acid, metabolin or the pro-drug of receiving:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl of group substitution, Optionally by R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces；
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group, Middle n is the integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Alkyl halide Oxygroup, C2-6Acylamino-, C1-6Alkyl amino, 4- methyl-imidazoles -1- base,
R3Selected from C1-6Alkyl and
R4Selected from C1-6Alkyl；
R5Selected from hydrogen and C1-6Alkyl amino.
The invention further relates to the pharmaceutical compositions for including the above compound and the compound or pharmaceutical composition to prevent Or treat disease that is being adjusted by tyrosine kinase activity or being affected by it or being directed to tyrosine kinase activity, barrier Hinder or the method and purposes of illness.
Detailed description of the invention
Fig. 1 a to 1c shows tumour of the compound 4 in TEL-cKIT/T670I-BaF3 cell tumour transplanting mouse model Inhibitory effect.
Fig. 2 a to 2c shows tumour suppression of the compound 142 in P210/T315I-BaF3 cell tumour transplanting mouse model Effect processed.
Specific embodiment
Term
Unless otherwise defined, all scientific and technical terminologies used herein all have the skill with claimed theme fields Art personnel are commonly understood by identical meaning.
Unless otherwise indicated, the present invention is using mass spectrum, the NMR, HPLC, protein chemistry, life within the scope of art technology The conventional methods such as object chemistry, recombinant DNA technology and pharmacology.Unless provide specific definition, otherwise with analysis described herein The chemically relevant name of chemistry, synthetic organic chemistry and medicine and pharmaceutical chemistry etc. and laboratory operation and technology, are these Known to the technical staff of field.In general, aforementioned techniques and step can be by well-known in the art and various one As conventional method described in document and more specific document implement, these documents are cited in the present specification and discuss.
Term " alkyl " refers to aliphatic hydrocarbon groups, can be the alkyl of branch or straight chain.According to structure, alkyl be can be Monoradical or bivalent radical (i.e. alkylidene).In the present invention, alkyl is preferably the alkyl with 1-8 carbon atom, more excellent " low alkyl group " with 1-6 carbon atom is selected, even more preferably with the alkyl of 1-4 carbon atom.Typically alkyl includes But be not limited to methyl, ethyl, propyl, butyl, amyl, hexyl etc..It should be understood that " alkyl " that is mentioned herein includes that may be present The alkyl of all configurations and conformation, such as " propyl " that is mentioned herein includes n-propyl and isopropyl, " butyl " includes positive fourth Base, isobutyl group and tert-butyl, " amyl " include n-pentyl, isopropyl, neopentyl, tertiary pentyl and amyl- 3- base etc..
Term " alkoxy " refers to-O- alkyl, and wherein alkyl is as defined herein.Typically alkoxy includes but is not limited to Methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy etc..
Term " alkoxyalkyl " refers to that alkyl defined herein is replaced by alkoxy defined herein.
Term " aromatic radical " refers to that planar rings have the pi-electron system of delocalization and contain 4n+2 pi-electron, and wherein n is Integer.Fragrant basic ring can be by five, six, seven, eight, nine or more than nine atomic buildings.Aromatic radical, which can be, optionally to be replaced.Art Language " aromatic radical " includes isocyclic aryl (such as phenyl) and heterocyclic aryl (or " heteroaryl " or " heteroaryl perfume base ") group (such as pyrrole Pyridine).The term includes monocycle or polycyclic (sharing the ring of the adjacent carbon atom pair) group of condensed ring.
The atom that terms used herein " aryl " refer to that each in fragrant basic ring constitutes ring is carbon atom.Aryl rings By five, six, seven, eight, nine or nine atomic buildings can be more than.Aryl, which can be, optionally to be replaced.The example of aryl include but It is not limited to phenyl, naphthalene, phenanthryl, anthryl, fluorenyl and indenyl.According to structure, aryl can be monoradical or bivalent radical (i.e. Arlydene).
Term " aryloxy group " refers to-O- aryl, and wherein aryl is as defined herein.
Term " heteroaryl " refers to include one or more ring hetero atoms selected from nitrogen, oxygen and sulphur in aryl.Containing N " heteroaryl Base " partially refers to that at least one skeletal atom is nitrogen-atoms in aromatic radical middle ring.According to structure, heteroaryl can be monovalent radical Group or bivalent radical (i.e. inferior heteroaryl).The example of heteroaryl include but is not limited to pyridyl group, imidazole radicals, pyrimidine radicals, pyrazolyl, Triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrole radicals, quinoline Quinoline base, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, indazolyl, indolizine base, phthalazinyl, pyridazinyl, iso-indoles Base, pteridyl, purine radicals, oxadiazoles base, thiadiazolyl group, furazanyl, benzofuraxan base, benzothienyl, benzothiazolyl, benzene And oxazolyl, quinazolyl, naphthyridines base and furopyridyl etc..
Term " alkyl (aryl) " or " aralkyl " refer to that alkyl defined herein is replaced by aryl defined herein.Non- limit The alkyl (aryl) of property processed includes benzyl, phenethyl etc..
Term " alkyl (heteroaryl) " or " heteroaryl alkyl " refer to alkyl defined herein by heteroaryl defined herein Replace.
Terms used herein " miscellaneous alkyl " refer to that one or more skeletal chain atoms in alkyl defined herein are miscellaneous Atom, such as oxygen, nitrogen, sulphur, silicon, phosphorus or their combination.The hetero atom (one or more) can be located inside miscellaneous alkyl Any position or in the position that miscellaneous alkyl is connected with the rest part of molecule.
Terms used herein " Heterocyclylalkyl " or " heterocycle " refer to one or more composition rings in non-aromatic basic ring Atom is the hetero atom selected from nitrogen, oxygen and sulphur.Heterocycloalkyl ring can be by three, four, five, six, seven, eight, nine or more than nine originals Son is constituted.Heterocycloalkyl ring, which can be, optionally to be replaced.The example of Heterocyclylalkyl includes but is not limited to lactams, lactone, ring Asia Amine, ring thioimines, cyclic carbramates, tetrahydric thiapyran, 4H- pyrans, oxinane, piperidines, 1,3- dioxin, 1,3- bis- are disliked Alkane, 1,4- dioxin, 1,4- dioxanes, piperazine, 1,3- thioxane, 1,4- oxathiin, 1,4- oxygen thia Hexamethylene, tetrahydro -1,4- thiazine, 2H-1,2- oxazines, maleimide, succinimide, barbiturates, thiobarbituricacidα-, Dioxopiperazine, hydantoins, dihydrouracil, morpholine, trioxane, hexahydro -1,3,5- triazine, thiophane, tetrahydrofuran, Pyrrolin, pyrrolidines, imidazolidine, pyrrolidones, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3- dioxole, 1, 3- dioxolane, 1,3- dithiole, 1,3- dithiolane, isoxazoline, isoxazole alkane, oxazoline, evil Oxazolidine, oxazolidone, thiazoline, thiazolidine and 1,3- oxathiolane.According to structure, Heterocyclylalkyl can be monoradical Or bivalent radical (i.e. sub- Heterocyclylalkyl).
Term " alkyl (Heterocyclylalkyl) " or " hetercycloalkylalkyl " refer to alkyl defined herein by defined herein miscellaneous Naphthenic base replaces.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Term " halogenated alkyl ", " halogenated alkoxy " and " halogenated miscellaneous alkyl " include the knot of alkyl, alkoxy or miscellaneous alkyl Structure, wherein at least one hydrogen are replaced by halogen atom.In some embodiments, if two or more hydrogen atoms are set by halogen atom It changes, the halogen atom is same or different to each other.
Term " hydroxyl " refers to formula-OH group.
Term " cyano " refers to formula-CN group.
Term " ester group " refers to the chemical part with formula-COOR, and wherein R is selected from alkyl, naphthenic base, aryl, heteroaryl (being connected by ring carbon) (is connected) with heterocycle by ring carbon.
Term " amino " refers to group-NH2。
Term " aminoacyl " refers to-CO-NH2。
Term " amide groups " or " acylamino- " refer to-NR-CO-R ', and wherein R and R ' are each independently hydrogen or alkyl.
Term " alkyl amino " refers to further by one or two alkyl-substituted amino-substituent, in particular to base Group-NRR ', wherein R and R ' is each independently selected from hydrogen or low alkyl group, and condition is that-NRR ' is not-NH2." alkyl amino " packet Include wherein-NH2Nitrogen connect at least one alkyl group compound group.The example of alkylamino group includes but unlimited In methylamino, ethylamino etc.." dialkyl amido " includes wherein-NH2Nitrogen connect at least two other alkyl groups Group.The example of dialkyl amino group includes but is not limited to dimethylamino, diethylamino etc..
Term " acyl group " refers to remaining monovalent radical after organic or inorganic oxyacid removes hydroxyl, general formula R-M (O)-, wherein M is usually C.
Term " carbonyl " is the organo-functional group (C=O) being formed by connecting by two kinds of atoms of carbon and oxygen by double bond.
Term " alkanoyl " or " alkyl-carbonyl " refer to further by an alkyl-substituted carbonyl.Typical alkanoyl packet Include but be not limited to acetyl group, propiono, bytyry, valeryl, caproyl etc..
Term " aryl carbonyl " refers to that carbonyl defined herein is replaced by aryl defined herein.
Term " optional " refers to that the one or more events described below may or may not occur, and the thing including generation Both part and the event not occurred.Term " optionally replacing " or " substituted " refer to that mentioned group can be by one or more A additional group replaces, and the additional group is respectively and independently selected from alkyl, naphthenic base, aryl, heteroaryl, heterocycle Base, hydroxyl, alkoxy, cyano, halogen, amide groups, nitro, halogenated alkyl, amino, mesyl, alkyl-carbonyl, alkoxy carbonyl Base, heteroaryl alkyl, hetercycloalkylalkyl, aminoacyl, amino protecting group etc..Wherein, amino protecting group is preferably selected from pivaloyl Base, tertbutyloxycarbonyl, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, benzyl, to methoxybenzyl, allyloxycarbonyl and trifluoroacetyl group Deng.
Terms used herein " tyrosine protein kinase (tyrosine protein kinase, TPK) " are a kind of catalysis Upper γ-the phosphoric acid of ATP is transferred to the kinases on protein-tyrosine residue, can be catalyzed a variety of substrate protein white matter tyrosine residue phosphoric acid Change, plays a significant role in cell growth, proliferation, differentiation.
" inhibition ", " inhibition " or " inhibitor " of terms used herein kinases, refers to that phosphate transferase activity is pressed down System.
" metabolin " of compound disclosed herein is the derivative of the compound formed when the compound is metabolized.Art Language " active metabolite " refers to the biologically active derivatives of the compound formed when the compound is metabolized.Art used herein Language " is metabolized ", refers to the process of predetermined substance by organism transform summation (including but not limited to hydrolysis and by enzymatic Reaction, such as oxidation reaction).Therefore, enzyme can produce specific structure and be changed into compound.For example, Cytochrome P450 It is catalyzed various oxidations and reduction reaction, while the glucuronic acid molecule of diphosphate glucose sweet acid based transferase catalytic activation is extremely The conversion of aromatic alcohol, aliphatic alcohol, carboxylic acid, amine and free sulfydryl.The further information of metabolism can be from " The Pharmacological Basis of Therapeutics ", the 9th edition, McGraw-Hill (1996) is obtained.It is disclosed herein The metabolin of compound can be by giving compound to host and analyzing tissue sample from the host or by that will change Object is closed to be incubated in vitro with liver cell and analyze gained compound to identify.Both methods is all known in the art.? In some embodiments, the metabolin of compound be by oxidation process formed and it is corresponding with corresponding hydroxy-containing compounds.? In some embodiments, compound is metabolized as pharmaceutical active metabolite.Terms used herein " adjusting ", refer to directly or It connects and interacts with target, to change the activity of target, for example only, activity, suppression target including enhancing target Activity, limit target target activity or the activity for extending target.
Terms used herein " target protein " refer to the protein molecule that can be combined by selective binding compounds or portion Divide protein.In some embodiments, target protein is tyrosine kinase KIT (wild type or various mutation or combinations thereof), ABL (wild type or various mutation or combinations thereof), EGFR (wild type or various mutation or combinations thereof), (wild type is various prominent by FLT3 Become or combinations thereof), VEGFR2 (wild type or various mutation or combinations thereof), RET (wild type or various mutation or combinations thereof), PDGFR α (wild type or various mutation or combinations thereof), PDGFR β (wild type or various mutation or combinations thereof), BCR/ABL are (wild Raw type or various mutation or combinations thereof), FGFR1 (wild type or various mutation or combinations thereof), (wild type is various prominent by FGFR2 Become or combinations thereof), FGFR3 (wild type or various mutation or combinations thereof), FGFR4 (wild type or various mutation or combinations thereof).
IC used herein50Refer to that the 50% of ceiling effect is obtained in the analysis for measuring such effect inhibits specific Test amount, concentration or the dosage of compound.
EC used herein50Dosage, concentration or the amount for referring to measurement compound, particular assay compound is caused to induce, The dose-dependant reaction of 50% maximum expression of stimulation or the specific reaction reinforced.
GI used herein50It is that the growth of 50% cell is instigated to be suppressed required drug concentration, i.e. drug makes 50% cell The drug concentration when growth of (such as cancer cell) is inhibited or controls.
The novel kinase inhibitor of the present invention
The present invention provides a kind of Azaindole kinase inhibitors, compound or its pharmaceutically acceptable salt, solvent including formula (I) Compound, ester, acid, metabolin or pro-drug:
Wherein, X is selected from
Y be selected from phenyl, thiophene -2- base, isoxazole -3- base, pyridin-3-yl, pyridin-4-yl, 2-Pyrrolidone -5- base, N- methyl -2 (1H)-pyridone -5- base and furans -2- base；
R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3Group replace pyridin-3-yl, optionally By R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces；
(R2)nIt indicates optionally by n independent R2Replaced substituent group, wherein n is the integer of 0-5, R2Independently selected from hydroxyl Base, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4- Methyl-imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl；
R5Selected from hydrogen and C1-6Alkyl amino.
In a preferred embodiment, kinase inhibitor of the invention includes the compound of formula (Ia) or its is pharmaceutically acceptable Salt, solvate, ester, acid, metabolin or pro-drug:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl of group substitution, Optionally by R3The phenyl that group replaces；
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group, wherein n is The integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Alkyl amino, 4- methyl- Imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl；
R5Selected from C1-6Alkyl amino.
In other preferred embodiment, kinase inhibitor of the invention includes the compound of formula (Ib) or its pharmacy can Salt, solvate, ester, acid, metabolin or the pro-drug of receiving:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl of group substitution, Optionally by R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces；
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Substituent group is taken In generation, wherein n is the integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6 Halogenated alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4- methyl-imidazoles -1- base,
R3Selected from C1-6Alkyl and
R4Selected from C1-6Alkyl；
R5Selected from hydrogen and C1-6Alkyl amino.
In the present invention, substituent group C1-6Alkyl is more preferably methyl, ethyl, isopropyl or tert-butyl, and halogen is more preferably Fluorine or chlorine, C1-6Alkoxy is more preferably methoxyl group, C1-6Halogenated alkoxy is more preferably trifluoromethoxy, C1-6Halogenated alkyl is more Preferably trifluoromethyl, C1-6Alkyl amino is more preferably dimethylamino, C2-6Acylamino- is more preferably acetyl group.
For each variable, any combination of above-mentioned group also among considering herein.It is to be understood that being mentioned herein Substituent group and substitute mode on the compound of confession can be selected by those skilled in the art, in order to provide chemically stable And can be used techniques known in the art and technology set forth herein synthesis compound.
Described herein is novel kinase inhibitor.The pharmaceutically acceptable salt, molten of this compound has been also described herein Agent compound, ester, acid, pharmaceutical active metabolite and prodrug.
In other or further embodiment, by compound described herein give after organism in need Its metabolism in vivo generates metabolin, and generated metabolin is subsequently used for generating desired effect, including desired therapeutic effect.
Compound described herein can be made into and/or be used as pharmaceutically acceptable salt.Pharmaceutically acceptable salt Type includes but is not limited to: (1) acid-addition salts, by by the free alkali form of compound and pharmaceutically acceptable inorganic acid reaction It is formed, described inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc.；Or formed with organic acid reaction, it is described Organic acid for example acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, Succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3- (4- hydroxy benzoyl) benzoic acid, cortex cinnamomi Acid, mandelic acid, Loprazolam, ethane sulfonic acid, 1,2- ethionic acid, 2- ethylenehydrinsulfonic acid, benzene sulfonic acid, toluenesulfonic acid, 4- methyl Bicyclic-[2.2.2] oct-2-ene -1- formic acid, 2- naphthalene sulfonic acids, butylacetic acid, glucoheptonic acid, 4,4' methylene bis-(3- hydroxyl Base -2- alkene -1- formic acid), 3- phenylpropionic acid, trimethylace tonitric, dodecyl sulphate, gluconic acid, glutamic acid, salicylic acid, hydroxyl Naphthoic acid, stearic acid, muconic acid etc.；(2) base addition salts, the shape when acid proton in parent compound is replaced by metal ion At, such as alkali metal ion (such as lithium, sodium, potassium), alkaline-earth metal ions (such as magnesium or calcium) or aluminium ion；Or match with organic base Position.Acceptable organic base includes ethanol amine, diethanol amine, triethanolamine, trimethylamine, N- methyl glucose osamine, etc..It can connect The inorganic base received includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc..
Various method analyses and identification can be used in the corresponding ion balance of pharmaceutically acceptable salt, the method includes But be not limited to ion-exchange chromatography, ion chromatography, Capillary Electrophoresis, inductively coupled plasma body, atomic absorption spectrum, mass spectrum or Any combination of them.
Recycle the salt using at least one of following technology: filtering is then filtered, solvent evaporation with non-solvent precipitation, Or desivac is used in the case where aqueous solution.
Screening and characterize pharmaceutically acceptable salt, polymorphic and/or solvate can be used multiple technologies completion, described Technology includes but is not limited to heat analysis, X-ray diffraction, spectrum, microscopy, elemental analysis.The various spectral techniques used Including but not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).Various microscopies include but is not limited to IR Microscopy and Raman (Raman) microscopy.
Pharmaceutical composition of the invention
The application also provides pharmaceutical composition, and it includes the compounds of at least one formula (I), (Ia) or (Ib) or described Pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutical active metabolite or the prodrug of compound and pharmaceutically acceptable load The other therapeutic agents of body or excipient and person optionally.
Over the course for the treatment of, it according to circumstances can individually or with one or more other therapeutic agents be applied in combination.It can be with By injecting, taking orally, suck, at least one of rectum and transdermal administration by the medicament administration comprising the compounds of this invention to suffering from Person.Other therapeutic agents can be selected from following drug: immunosuppressor (such as tacrolimus, encircle rhzomorph, rapamycin, first The ridge An Die, cyclophosphamide, imuran, mercaptopurine, mycophenolate or FTY720), glucocorticoids medicine (such as prednisone, Cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydrogen hydroxyl prednisolone, times chlorine rice Pine, fludrocortisone acetate, percorten, aldosterone), non-steroidal anti-inflammatory drugs (such as salicylate, aryl alkanoic acid, 2- arylpropionic acid, former times health class, examines former times class or sulphonanilid at N- aryl-anthranilic acid), allergic reaction bacterin, antihistamine Medicine, anti-leukotriene medicine, beta-2-agonists, theophylline, anticholinergic agent or other selective kinase inhibitors (such as mTOR inhibitors, c- Met inhibitor) or her2 antibody-drug.In addition, mentioned other therapeutic agents can also be rapamycin (Rapamycin), Gram azoles replaces Buddhist nun (Crizotinib), tamoxifen, Raloxifene, Anastrozole, Exemestane, Letrozole, TrastuzumabTMIt is (bent appropriate Pearl monoclonal antibody), GleevecTM(Imatinib), taxolTM(taxol), cyclophosphamide, Lovastatin, U.S. promise tetracycline (Minosine), cytarabine, 5 FU 5 fluorouracil (5-FU), methotrexate (MTX) (MTX), taxotereTM(docetaxel), promise thunder MoralTM(Goserelin), vincristine, vincaleukoblastinum, nocodazole, Teniposide, Etoposide, gemzarTM(gemcitabine), angstrom Rich mycin (Epothilone), promise only sheet, camptothecine, daunorubicin (Daunonibicin), dactinomycin D, mitoxantrone, peace Acridine, Doxorubicin (adriamycin), epirubicin or idarubicin.Alternatively, other therapeutic agents be also possible to cell because Son such as G-CSF (granulocyte colony stimulating factor).Alternatively, other therapeutic agents are also possible to be such as, but not limited to, CMF (ring phosphorus Amide, methotrexate (MTX) and 5 FU 5 fluorouracil), CAF (cyclophosphamide, adriamycin and 5 FU 5 fluorouracil), AC (sub- Baudrillard Mycin and cyclophosphamide), FEC (5 FU 5 fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, ring phosphorus Amide and taxol) or CMFP (cyclophosphamide, methotrexate (MTX), 5 FU 5 fluorouracil and prednisone).
In embodiments of the present invention, when treating according to the present invention to patient, the amount of given drug is depended on Factors, such as specific dosage regimen, disease or implant treatment and its seriousness, subject in need for the treatment of or host Unique (such as weight), still, according to specific ambient conditions, including for example used specific drug, administration route, control The illness for the treatment of and the subject or host for the treatment of, administration dosage can routinely be determined by methods known in the art.In general, For the dosage that adult treatment uses, administration dosage is typically at 0.02-5000mg/ days, for example, about 1-1500mg/ days models It encloses.The required dosage is expressed as (or in a short time) one or be administered simultaneously or at interval appropriate in which can be convenient Divided dose, such as daily two, three, four doses or more divided agent.It will be appreciated by persons skilled in the art that although giving Dosage range is stated, but specific effective quantity can suitably be adjusted according to the case where patient and in conjunction with doctor diagnosed.
The purposes of drug of the invention
The compound or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or preceding of formula (I), (Ia) and (Ib) The pharmaceutical composition of medicine or the compound including formula (I), (Ia) and (Ib) can be used for inhibiting tyrosine kinase KIT (wild type or Various mutation or combinations thereof), ABL (wild type or various mutation or combinations thereof), EGFR (wild type or various mutation or its group Close), FLT3 (wild type or various mutation or combinations thereof), VEGFR2 (wild type or various mutation or combinations thereof), RET it is (wild Type or various mutation or combinations thereof), PDGFR α (wild type or various mutation or combinations thereof), (wild type is various prominent by PDGFR β Become or combinations thereof), BCR/ABL (wild type or various mutation or combinations thereof), FGFR1 (wild type or various mutation or its group Close), FGFR2 (wild type or various mutation or combinations thereof), FGFR3 (wild type or various mutation or combinations thereof), and/or FGFR4 (wild type or various mutation or combinations thereof).
Preferably, the compound of the present invention and pharmaceutical composition are able to suppress tyrosine kinase KIT (especially saltant type CKIT/T670I), BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 activity. Therefore, the compound of the present invention and pharmaceutical composition can be used in treat or prevent KIT (especially saltant type cKIT/T670I), BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 related disease.
Specifically, the compound of the present invention or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, And pharmaceutical composition can be used for treating or preventing one or more diseases selected from the following: solid tumor (including it is benign and dislike Property type), especially sarcoma, gastrointestinal stromal tumor (Gastrointestinal Stromal Tumors, GIST), acute grain it is thin Born of the same parents' leukaemia (Acute Myeloblastic Leukemia, AML), chronic myelogenous leukemia (Chronic Myelogenous Leukemia, CML), celiothelioma, thyroid cancer (thyroid carcinoma), systemic mast cell disease, acidophic cell Increase syndrome (HES), fibre modification, rheumatoid arthritis, panarthritis, chorionitis, lupus erythematosus, graft-versus-host Sick (graft-versus-host disease, GVHD), neurofibroma, pulmonary hypertension, Alzheimer disease, seminoma, Psoriasis, dysgerminoma, mast cell tumor, lung cancer, bronchiolar carcinoma, dysgerminoma, the formation of testis intraepithelial neoplasia, black Plain tumor, breast cancer, neuroblastoma, mamillary/follicular thyroid cancer, malignant lymphoma, non-Hodgkin lymphoma, 2 types are more The formation of hair property endocrine tumor, pheochromocytoma, thyroid cancer, parathyroid hyperplasia/adenoma, colon cancer, colorectal adenomas, ovum Nest cancer, prostate cancer, spongioblastoma, brain tumor, glioblastoma, cancer of pancreas, malignant pleural mesothelioma, at blood vessel Cytoma, hemangioma, kidney, liver cancer, adrenal, bladder cancer, gastric cancer, the carcinoma of the rectum, carcinoma of vagina, cervical carcinoma, carcinoma of endometrium, Huppert's disease, neck and head tumor, arthritis, rheumatic arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammation Property enteropathy, psoriasis arthropathica, osteoarthritis, Still disease (Still's disease), adolescent arthritis, diabetes, Myasthenia gravis, Hashimoto thyroiditis (Hashimoto's thyroiditis), Order thyroiditis (Ord's Hyroiditis), Graves disease (Graves'disease), rheumatoid arthritis syndrome ( Syndrome), multiple sclerosis, Guillain-Barre syndrome (Guillain-Barr é syndrome), acute disseminated brain ridge Marrow inflammation, Addision's disease (Addison's disease), view property eye battle array it is twin-the twin syndrome of flesh battle array, ankylosing spondylitis, anti-phosphatide Antibody Syndrome, alpastic anemia, oneself immunity hepatitis, chylous diarrhea (coeliac disease), Gourde(G) Paasche are thorough comprehensive Simulator sickness (Goodpasture's syndrome), Idiopathic Thrombocytopenic Purpura, optic neuritis, chorionitis, primary gallbladder Juice cirrhosis, Reiter syndrome (Reiter's syndrome), takayasu's arteritis (Takayasu's arteritis), It is temporal arteritis, warm type autoimmune hemolytic anemia, Wegner's granulomatosis (Wegener's granulomatosis), complete Body depilation, behcet disease (Behcet's disease), confirmed fatigue, familial dysautonomia, endometrium Dystopy, interstitial cystitis, neuromyotonia, chorionitis, Vulvodynia, or combinations thereof.Particularly preferred treatment gastrointestinal stromal tumor, Acute myeloblastic leukemia, chronic myelogenous leukemia, thyroid cancer, or combinations thereof.
The preparation of compound
Using Standard synthetic techniques well known by persons skilled in the art or using methods known in the art be described herein Method combination, the compound of formula (I), (Ia) and (Ib) can be synthesized.In addition, solvent given herein, temperature and other anti- Answer condition that can be changed according to art technology.As further guidance, synthetic method below also can use.
The reaction can use in order, to provide compound described herein；Or they can be used for synthesizing segment, The segment is then added by method described herein and/or methods known in the art.
In some embodiments, it provided herein is the preparation sides of tyrosine kinase inhibitor compound described herein Method and its application method.In some embodiments, the scheme synthesis of following synthesis can be used in compound described herein.It can Compound is synthesized by using selectable starting material appropriate with following similar methods to use.
Starting material for synthesizing compound described herein can be synthesized or can obtain from commercial source.Herein Technology well known by persons skilled in the art can be used to other related compounds with different substituents in the compound of description And Material synthesis.The conventional method for preparing compound disclosed herein can come from reaction known in the art, and the reaction It can be modified by the reagent and condition being deemed appropriate by those skilled in the art, it is each in the molecule of offer to be incorporated herein Kind part.
If desired, routine techniques separation and purifying can be used in reaction product, including but not limited to filters, distills, knot The methods of brilliant, chromatography.Conventional method characterization, including physical constant and spectrum data can be used in these products.
Using synthetic method described herein, compound disclosed herein is obtained with good yield and purity.According to herein The compound of disclosed method preparation is purified by conventional method known in the art, such as filtering, recrystallization, chromatography, distillation And combinations thereof.
Site on the aromatic moiety of the compound of formula (I), (Ia) and (Ib) may be easy to that various metabolism occur instead It answers, therefore substituent group appropriate is introduced on aromatic ring structure, for example, only for example, halogen can restore, reduces or disappear Except this metabolic pathway.
Embodiment
Non-limiting embodiment in detail below is to be interpreted as being merely illustrative, not limit in any way originally It is open.Although without being described in further detail, it is believed that those skilled in the art can be based on description herein, completely benefit Use the disclosure.
Embodiment 1:(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (3- tolyl) third The synthesis of diamides
(E) -3- oxo -3- (3- (2- (2- pyridyl group) vinyl) -1- (and tetrahydro -2H- pyrans -2- base] -1H- indazole -6- Base) amino)-methyl propionate (1b): (E) -3- (2- (pyridine -2- base) vinyl) -1- (tetrahydro -2H- is added in round-bottomed flask Pyrans -2- base) anhydrous methylene chloride (100 milliliters), triethylamine (6.8 milliliters) is added in -1H- indazole -6- amine (10.0 grams) afterwards, so System is set to be cooled to 0 degree with ice-water bath afterwards.Then methylmalonate list acyl chlorides (3.9 milliliters) are slowly added to.Reaction system is in room Under temperature, argon gas protection reaction 14 hours.After reaction, system solvent evaporated under reduced pressure, gains be diluted with water after with two Chloromethanes extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, decompression Crude Compound 1b is obtained after being evaporated.LC/MS:M+H 421.18.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.62 (s, 1H), 8.22 (s, 1H), 8.15 (d, J=8.5Hz, 1H), 7.86 (dd, J=24.7,13.4Hz, 2H), 7.69 (d, J= 7.3Hz, 1H), 7.58 (d, J=16.4Hz, 1H), 7.31 (d, J=8.5Hz, 2H), 5.76 (s, 1H), 3.92 (d, J= 10.0Hz, 1H), 3.69 (s, 4H), 3.56 (s, 2H), 2.43 (d, J=11.1Hz, 1H), 2.03 (s, 2H), 1.80 (s, 1H), 1.61(s,2H)。
(E) -3- oxo -3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- Base) amino) propionic acid (1c): (E) -3- oxo -3- (3- (2- (2- pyridyl group) vinyl) -1- (four is added in round-bottomed flask Hydrogen -2H- pyrans -2- base] -1H- indazole -6- base) amino) tetrahydrofuran (40 milliliters), water (40 is added in-methyl propionate (8 grams) afterwards Milliliter), lithium hydroxide (2.5 grams).Reaction system at room temperature, argon gas protection reaction 4 hours.After reaction, system is subtracting Solvent evaporated is depressed, it is 3-5 that gains, which are neutralized to pH with the dilute hydrochloric acid of 1 mol/L, there is solid precipitation.Water phase is filtered to obtain analysis Solid out obtains crude Compound 1c after solid is dry.LC/MS:M+H407.17.1H NMR(400MHz,DMSO-d6)δ10.46 (s, 1H), 8.62 (s, 1H), 8.24 (s, 1H), 8.14 (d, J=8.5Hz, 1H), 8.00-7.79 (m, 2H), 7.71 (d, J= 7.2Hz, 1H), 7.59 (d, J=16.3Hz, 1H), 7.33 (d, J=9.3Hz, 2H), 5.77 (d, J=8.6Hz, 1H), 3.92 (d, J=9.7Hz, 1H), 3.73 (s, 1H), 3.63 (s, 2H), 2.44 (d, J=10.5Hz, 1H), 2.03 (s, 2H), 1.79 (s, 1H),1.60(s,2H)。
(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (3- tolyl) malonamide (1): (E) -3- oxo -3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- being added in round-bottomed flask Base) -1H- indazole -6- base) amino) N,N-dimethylformamide (5 milliliters), meta-aminotoluene (27 is added in propionic acid (100 milligrams) afterwards Milligram), 2- (7- aoxidize benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (120 milligrams) and triethylamine (0.05 Milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, gained Object is extracted with ethyl acetate after being diluted with water.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Have Machine obtains crude product mutually through filtering, after evaporated under reduced pressure and is dissolved in anhydrous methylene chloride (5 milliliters), is added trifluoroacetic acid (1 milliliter).Reactant System is stirred at room temperature 14 hours under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, after gains are diluted with water PH > 10 are neutralized to saturated sodium bicarbonate solution.Water phase is extracted with ethyl acetate, and organic phase uses water, saturated common salt washing respectively It is dry with anhydrous sodium sulfate after washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.After the pressurized silica gel column chromatography purification of crude product Obtain embodiment compound 1.LC/MS:M+H 412.16.1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),10.43(s, 1H), 10.16 (s, 1H), 8.62 (s, 1H), 8.18 (d, J=24.7Hz, 2H), 7.86 (d, J=33.3Hz, 2H), 7.68 (s, 1H),7.48(s,3H),7.23(s,3H),6.92(s,1H),3.54(s,2H),2.30(s,3H)。
Embodiment 2:(E)-N1- (4- fluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third Diamides
The synthesis of 2 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M +1)+:416.14。
Embodiment 3:(E)-N1- phenyl-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) malonamide
The synthesis of 3 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M +1)+:398.15。
Embodiment 4:(E)-N1- (3- fluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third Diamides
The synthesis of 4 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M +1)+:416.14。
Embodiment 5:(E)-N1- (4- ((4- methyl piperazine base -1- base) methyl) phenyl)-N3- (3- (2- (2- pyridyl group) Vinyl) -1H- indazole -6- base) malonamide
The synthesis of 5 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M +1)+:510.25。
Embodiment 6:(E)-N1- (4- chlorphenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third Diamides
The synthesis of 6 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M +1)+:432.11。
Embodiment 7:(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (thiophene -2- Ji Jia Base) malonamide
The synthesis of 7 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M +1)+:418.12。
Embodiment 8:(E)-N1- (3- bromophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third Diamides
The synthesis of 8 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M +1)+:476.06。
Embodiment 9:(E)-N1- (3- chlorphenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third Diamides
The synthesis of 9 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M +1)+:432.11。
Embodiment 10:(E)-N1- (3 (4- methylpiperazine-1-yl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)- 1H- indazole -6- base) malonamide
The synthesis of 10 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:496.23。
Embodiment 11:(E)-N1- (the chloro- 4- fluorophenyl of 3-)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- Base) malonamide
The synthesis of 11 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:450.10。
Embodiment 12:(E)-N1- (3- (dimethylamino) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- Yin Azoles -6- base) malonamide
The synthesis of 12 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:441.19。
Embodiment 13:(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (3,4,5- front three Phenyl) malonamide
The synthesis of 13 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:488.18。
Embodiment 14:(E)-N1- (3- methoxyphenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- Base) malonamide
The synthesis of 14 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:428.16。
Embodiment 15:(E)-N1- (4- ((4- ethyl piperazidine -1- base) methyl) -3- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) malonamide
The synthesis of 15 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:592.25。
Embodiment 16:(E)-N1- (4- ((4- isopropyl piperazine -1- base) methyl) -3- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) malonamide
The synthesis of 16 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:606.27。
Embodiment 17:(R, E)-N1- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3- (trifluoromethyl) benzene Base)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) malonamide
The synthesis of 17 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:692.26。
Embodiment 18:(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (3- trifluoromethyl Phenyl) malonamide
The synthesis of 18 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:466.14。
Embodiment 19:(E)-N1- (2- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)- 1H- indazole -6- base) malonamide
The synthesis of 19 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:484.13。
Embodiment 20:(E)-N1- (2- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)- 1H- indazole -6- base) malonamide
The synthesis of 20 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:484.13。
Embodiment 21:(E)-N1- (2- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)- 1H- indazole -6- base) malonamide
The synthesis of 21 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:500.10。
Embodiment 22:(E)-N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)- 1H- indazole -6- base) malonamide
The synthesis of 22 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:484.13。
Embodiment 23:(E)-N1- (2,3- difluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- Base) malonamide
The synthesis of 23 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:434.13。
Embodiment 24:(E)-N1- (2- chlorphenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third Diamides
The synthesis of 24 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:432.11。
Embodiment 25:(E)-N1- (2,3,4- trifluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole - 6- yl) malonamide
The synthesis of 25 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:452.12。
Embodiment 26:(E)-N1- (3,5- difluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- Base) malonamide
The synthesis of 26 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:434.13。
Embodiment 27:(E)-N1- (3,4- difluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- Base) malonamide
The synthesis of 27 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:434.13。
Embodiment 28:(E)-N1- (2,3,4,5,6- pentafluorophenyl group)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- Yin Azoles -6- base) malonamide
The synthesis of 28 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:488.10。
Embodiment 29:(E)-N1- (2- fluoro- 4- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)- 1H- indazole -6- base) malonamide
The synthesis of 29 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:484.13。
Embodiment 30:(E)-N1- (2,4 difluorobenzene base)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- Base) malonamide
The synthesis of 30 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:434.13。
Embodiment 31:(E)-N1- (2- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)- 1H- indazole -6- base) malonamide
The synthesis of 31 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:500.10。
Embodiment 32:(E)-N1- (2,5- difluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- Base) malonamide
The synthesis of 32 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+:434.13。
The synthesis of embodiment 33:N1- (3- chlorphenyl)-N3- (1H- indazole -6- base) malonamide
6- nitro -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (2b): 6- nitro -1H- Yin is added in round-bottomed flask Tetrahydrofuran (40 milliliters), 3,4- dihydro -2H- pyrans (80 grams) and methanesulfonic acid (89 microlitres) is added in azoles (1.5 grams) afterwards.Reactant System is heated to back flow reaction 14 hours under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, gains water It is extracted with ethyl acetate after dilution.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase warp It filters, crude product 2b is obtained after evaporated under reduced pressure.LC/MS:M+H 248.09.
6- amino -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (2c): compound 6- nitro -1- is added in methyl alcohol (tetrahydro -2H- pyrans -2- base) -1H- indazole (1.5 grams), adds palladium/carbon (64 milligrams), is stirred at room temperature 4 hours under atmosphere of hydrogen.Silicon Diatomaceous earth filtering, filtrate decompression obtain crude product 2c after being evaporated.LC/MS:M+H 218.12.
3- oxo -3- ((1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) methyl propionate (2d): in circle 6- amino -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (1 gram) is added in the flask of bottom, anhydrous methylene chloride (30 millis are added afterwards Rise), triethylamine (1 milliliter), then so that system is cooled to 0 degree with ice-water bath.Then it is slowly added to methylmalonate list acyl chlorides (0.6 milliliter).Reaction system at room temperature, argon gas protection reaction 14 hours.After reaction, system is evaporated molten under reduced pressure Agent, gains are extracted with dichloromethane after being diluted with water.Organic phase is respectively with using anhydrous sodium sulfate after water, saturated common salt water washing It is dry.Organic phase obtains crude product 2d through filtering after evaporated under reduced pressure.LC/MS:M+H 318.13.
3- oxo -3- ((1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) propionic acid (2e): by 3- oxo - 3- ((1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) (1 gram) addition tetrahydrofuran (10 milliliters) of methyl propionate With water (10 milliliters), lithium hydroxide (0.7 gram) then is added.Reaction system at room temperature, argon gas protection reaction 4 hours.Reaction After, system solvent evaporated under reduced pressure, gains, which are neutralized to pH 3-5 with the dilute hydrochloric acid of 1 mol/L, solid precipitation.Water It is mutually filtered to be precipitated solid, obtains crude product 2e after solid is dry.LC/MS:M+H 304.12.
N1- (3- chlorphenyl)-N3- (1H- indazole -6- base) malonamide (33): 3- oxo -3- is added in round-bottomed flask N,N-dimethylformamide is added in ((1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) propionic acid (50 milligrams) afterwards (5 milliliters), m-chloroaniline (25 milligrams), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (94 Milligram) and triethylamine (0.05 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system exists Lower solvent evaporated is depressurized, gains are extracted with ethyl acetate after being diluted with water.After organic phase uses water, saturated common salt water washing respectively It is dry with anhydrous sodium sulfate.Organic phase obtains crude product through filtering, after evaporated under reduced pressure and is dissolved in anhydrous methylene chloride (5 milliliters), is added three Fluoroacetic acid (1 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system is evaporated under reduced pressure Solvent, gains with saturated sodium bicarbonate solution are neutralized to pH > 10 after being diluted with water.Water phase is extracted with ethyl acetate, organic phase Respectively with dry with anhydrous sodium sulfate after water, saturated common salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Crude product Sterling compound 33 is obtained after pressurized silica gel column chromatography purification.LC/MS:329.07.
Embodiment 34:N1- (4- ((4- ethyl piperazidine -1- base) methyl) -3- (trifluoromethyl) phenyl)-N3- (1H- indazole - 6- yl) malonamide
The synthesis of 34 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:489.21。
Embodiment 35:N1- (1H- indazole -6- base)-N3- malonamide
The synthesis of 35 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:294.11。
Embodiment 36:N1- (3- fluorophenyl)-N3- (1H- indazole -6- base) malonamide
The synthesis of 36 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:313.10。
Embodiment 37:N1- (1H- indazole -6- base)-N3- (3- (4- methylpiperazine-1-yl) phenyl) malonamide
The synthesis of 37 compound of embodiment is completed by using the step of being similar to described in embodiment 33.
MS(ESI)m/z(M+1)+:393.19。
Embodiment 38:N1- (1H- indazole -6- base)-N3- (3,4,5- trimethoxyphenyl) malonamide
The synthesis of 38 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:385.14。
Embodiment 39:N1- (the chloro- 4- fluorophenyl of 3-)-N3- (1H- indazole -6- base) malonamide
The synthesis of 39 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:347.06。
Embodiment 40:N1- (3- (dimethylamino) phenyl)-N3- (1H- indazole -6- base) malonamide
The synthesis of 40 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:338.15。
Embodiment 41:N1- (1H- indazole -6- base)-N3- (3- methoxyphenyl) malonamide
The synthesis of 41 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:325.12。
Embodiment 42:N1- (4- chlorphenyl)-N3- (3- methyl-1 H- indazole -6- base) malonamide
The synthesis of 42 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:343.08。
Embodiment 43:N1- (3- fluorophenyl)-N3- (3- methyl-1 H- indazole -6- base) malonamide
The synthesis of 43 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:327.11。
Embodiment 44:N1- (3- methyl-1 H- indazole -6- base)-N3- (3- (trifluoromethyl) phenyl) malonamide
The synthesis of 44 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:377.11。
Embodiment 45:N1- (4- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- methyl-1 H- indazole -6- base) malonamide
The synthesis of 45 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z (M+1)+:411.07。
The synthesis of embodiment 46:N1- phenyl-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
6- nitro -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (3b): add in round-bottomed flask Enter the iodo- 6- nitro -1- of 3- (tetrahydro -2H- pyrans -2- base) -1H- indazole (5 grams) be added afterwards 1,4- dioxane (100 milliliters), Water (20 milliliters), 3- pyridine boronic acid (2.7 grams), Pd (Ph3P)4(0.7 gram) and potassium carbonate (5.5 grams).Reaction system is protected in argon gas 80 DEG C are heated under shield to react 14 hours.After reaction, solvent evaporated, gains use second after being diluted with water to system under reduced pressure Acetoacetic ester extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, decompression Crude product is obtained after being evaporated.Sterling 3b is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 325.12.
6- amino -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (3c): additionization in methyl alcohol Close object 6- nitro -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (3 grams), palladium/carbon (97 milligrams), hydrogen Atmosphere is stirred at room temperature 4 hours under enclosing.Diatomite filtering, filtrate decompression obtain crude product 3c after being evaporated.LC/MS:M+H 295.15.
3- oxo -3- ((pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) propionic acid first Ester (3d): 6- amino -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (1 is added in round-bottomed flask Gram) anhydrous methylene chloride (30 milliliters), triethylamine (0.7 milliliter) are added afterwards, then so that system is cooled to 0 degree with ice-water bath.It connects Be slowly added to methylmalonate list acyl chlorides (0.4 milliliter).Reaction system at room temperature, argon gas protection reaction 14 hours.Reaction After, solvent evaporated, gains are extracted with dichloromethane system after being diluted with water under reduced pressure.Organic phase with respectively with water, It is dry with anhydrous sodium sulfate after saturated common salt water washing.Organic phase obtains crude product 3d through filtering after evaporated under reduced pressure.LC/MS:M+H 395.16。
3- oxo -3- ((pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) propionic acid (3e): by 3- oxo -3- ((pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) methyl propionate Then lithium hydroxide (0.6 gram) is added in (1 gram) addition tetrahydrofuran (10 milliliters) and water (10 milliliters).Reaction system is in room temperature Under, argon gas protection reaction 4 hours.After reaction, system solvent evaporated under reduced pressure, the dilute hydrochloric acid of 1 mol/L of gains Being neutralized to pH 3-5 has solid precipitation.Water phase is filtered to be precipitated solid, obtains crude product 3e after solid is dry.LC/MS:M+H 381.14。
N1- phenyl-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide (46): it is added in round-bottomed flask 3- oxo -3- ((pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) after propionic acid (50 milligrams) N,N-dimethylformamide (5 milliliters), aniline (16 milligrams), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethyl is added Base urea hexafluorophosphoric acid ester (75 milligrams) and triethylamine (0.05 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas. After reaction, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase is used respectively It is dry with anhydrous sodium sulfate after water, saturated common salt water washing.Organic phase obtains crude product through filtering, after evaporated under reduced pressure and is dissolved in anhydrous dichloro Methane (5 milliliters) is added trifluoroacetic acid (1 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.Reaction terminates Afterwards, system solvent evaporated under reduced pressure, gains with saturated sodium bicarbonate solution are neutralized to pH > 10 after being diluted with water.Water phase is used Ethyl acetate extraction, organic phase are dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, and is subtracted Pressure obtains crude product after being evaporated.Sterling compound 46 is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:372.13.
Embodiment 47:N1- (3- fluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 47 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:390.39。
Embodiment 48:N1- (4- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third Diamides
The synthesis of 48 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:474.84。
Embodiment 49:N1- (5- (tert-butyl) isoxazole -3- base)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third Diamides
The synthesis of 49 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:419.45。
Embodiment 50:N1- (3- (4- methyl-1 H-imidazole-1-group) -5- (trifluoromethyl) phenyl)-N3- (3- (pyridine -3- Base) -1H- indazole -6- base) malonamide
The synthesis of 50 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:520.48。
Embodiment 51:N1- (3- (pyridin-3-yl) -1H- indazole -6- base)-N3- (3- (trifluoromethyl) phenyl) malonyl Amine
The synthesis of 51 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:540.39。
Embodiment 52:N1- (2- fluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide.
The synthesis of 52 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:390.39。
Embodiment 53:N1- (the chloro- 4- fluorophenyl of 3-)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 53 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:424.83。
Embodiment 54:N1- (4- methoxyl group -3- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- Base) malonamide
The synthesis of 54 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:470.42。
Embodiment 55:N1- (2,6- difluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 55 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:408.38。
Embodiment 56:N1- (2- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third Diamides
The synthesis of 56 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:458.11。
Embodiment 57:N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third Diamides
The synthesis of 57 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:458.11。
Embodiment 58:N1- (2,3,4- trifluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 58 compound of compound is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:426.11。
Embodiment 59:N1- (2,3- difluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 59 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:408.12。
Embodiment 60:N1- (3,5- difluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 60 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:408.12。
Embodiment 61:N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third Diamides
The synthesis of 61 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:458.11。
Embodiment 62:N1- (2- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third Diamides
The synthesis of 62 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:474.09。
Embodiment 63:N1- (4- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third Diamides
The synthesis of 63 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:458.11。
Embodiment 64:N1- (4- chlorphenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 64 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:406.10。
Embodiment 65:N1- (2- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third Diamides
The synthesis of 65 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:458.12。
Embodiment 66:N1- (the chloro- 4- fluorophenyl of 3-)-N3- (3- (3- fluorophenyl) -1H- indazole -6- base) malonamide
The synthesis of 66 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:441.06。
Embodiment 67:N1- (4- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- (3- fluorophenyl) -1H- indazole -6- base) third Diamides
The synthesis of 67 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:491.08。
Embodiment 68:N1- (4- chlorphenyl)-N3- (3- (3- fluorophenyl) -1H- indazole -6- base) malonamide
The synthesis of 68 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:423.09。
Embodiment 69:N1- (3- fluorophenyl)-N3- (3- (3- fluorophenyl) -1H- indazole -6- base) malonamide
The synthesis of 69 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:407.12。
Embodiment 70:N1- (3- (3- fluorophenyl) -1H- indazole -6- base)-N3- (3- (4- methyl-1 H-imidazole-1-group) - 5- (trifluoromethyl) phenyl) malonamide
The synthesis of 70 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:537.15。
Embodiment 71:N1- (3- (3- fluorophenyl) -1H- indazole -6- base)-N3- (m- tolyl) malonamide
The synthesis of 71 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:403.14。
Embodiment 72:N1- (3- (4- methyl-1 H-imidazole-1-group) -5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- first Base piperazine -1- base) phenyl) -1H- indazole -6- base) malonamide
The synthesis of 72 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:617.61。
Embodiment 73:N1- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- base)-N3- (3- (fluoroform Base) phenyl) malonamide
The synthesis of 73 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:537.55。
Embodiment 74:N1- (2- fluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- base) Malonamide
The synthesis of 74 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:487.55。
Embodiment 75:N1- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- base)-N3- (m- tolyl) Malonamide
The synthesis of 75 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:483.58。
Embodiment 76:N1- (3- fluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- base) Malonamide
The synthesis of 76 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:487.55。
Embodiment 77:N1- (2- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)- 1H- indazole -6- base) malonamide
The synthesis of 77 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:555.54。
Embodiment 78:N1- (2- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)- 1H- indazole -6- base) malonamide
The synthesis of 78 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:572.00。
Embodiment 79:N1- (4- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)- 1H- indazole -6- base) malonamide
The synthesis of 79 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:555.55。
Embodiment 80:N1- (2,6- difluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- Base) malonamide
The synthesis of 80 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:505.54。
Embodiment 81:N1- (2- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)- 1H- indazole -6- base) malonamide
The synthesis of 81 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:555.55。
Embodiment 82:N1- (the chloro- 4- fluorophenyl of 3-)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole - 6- yl) malonamide
The synthesis of 82 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:521.99。
Embodiment 83:N1- (3- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)- 1H- indazole -6- base) malonamide
The synthesis of 83 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:571.17。
Embodiment 84:N1- (2,3,4- trifluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole - 6- yl) malonamide
The synthesis of 84 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:523.20。
Embodiment 85:N1- (2,3- difluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- Base) malonamide
The synthesis of 85 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:505.54。
Embodiment 86:N1- (3,5- difluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- Base) malonamide
The synthesis of 86 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:505.54。
Embodiment 87:N1- (3,4- difluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- Base) malonamide
The synthesis of 87 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:505.54。
Embodiment 88:N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)- 1H- indazole -6- base) malonamide
The synthesis of 88 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:555.55。
Embodiment 89:N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 89 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:567.22。
Embodiment 90:N1- (4- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 90 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:585.19。
Embodiment 91:N1- (2,3- difluorophenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H- Indazole -6- base) malonamide
The synthesis of 91 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:519.22。
Embodiment 92:N1- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H- indazole -6- base)-N3- is (m- Tolyl) malonamide
The synthesis of 92 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:497.25。
Embodiment 93:N1- (2- fluorophenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H- indazole - 6- yl) malonamide
The synthesis of 93 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:501.23。
Embodiment 94:N1- (3- fluorophenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H- indazole - 6- yl) malonamide
The synthesis of 94 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:501.23。
Embodiment 95:N1- (4- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 95 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:569.22。
Embodiment 96:N1- (2- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 96 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:569.22。
Embodiment 97:N1- (3- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 97 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:585.19。
Embodiment 98:N1- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H- indazole -6- base)-N3- phenyl Malonamide
The synthesis of 98 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:483.24。
Embodiment 99:N1- (3- (3- carbamoyl) phenyl -1H- indazole -6- base)-N3- (chloro- 5- of 3- (trifluoromethyl) Phenyl) malonamide
The synthesis of 99 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z (M+1)+:516.09。
Embodiment 100:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (4- chloro- 3- (trifluoromethyl) benzene Base) malonamide
The synthesis of 100 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:516.09。
Embodiment 101:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (m- tolyl) malonamide
The synthesis of 101 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:428.16。
Embodiment 102:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2- fluorophenyl) malonamide
The synthesis of 102 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:432.13。
Embodiment 103:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (4- fluoro- 3- (trifluoromethyl) benzene Base) malonamide
The synthesis of 103 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:500.12。
Embodiment 104:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3- fluoro- 5- (trifluoromethyl) benzene Base) malonamide
The synthesis of 104 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:500.12。
Embodiment 105:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2,3- difluorophenyl) malonyl Amine
The synthesis of 105 compound of compound is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:450.13。
Embodiment 106:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2- fluoro- 5- (trifluoromethyl) benzene Base) malonamide
The synthesis of 106 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:500.13。
Embodiment 107:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2,3,4- trifluorophenyl) the third two Amide
The synthesis of 107 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:468.12。
Embodiment 108:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3,5- difluorophenyl) malonyl Amine
The synthesis of 108 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:450.13。
Embodiment 109:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3- fluorophenyl) malonamide
The synthesis of 109 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:432.14。
Embodiment 110:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3- (trifluoromethyl) phenyl) third Diamides
The synthesis of 110 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:482.13。
Embodiment 111:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2- chloro- 5- (trifluoromethyl) benzene Base) malonamide
The synthesis of 111 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:516.10。
Embodiment 112:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (the chloro- 4- fluorophenyl of 3-) malonyl Amine
The synthesis of 112 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:466.10。
Embodiment 113:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (4- methoxyl group -3- (fluoroform Base) phenyl) malonamide
The synthesis of 113 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:512.14。
Embodiment 114:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3- (4- methyl-1 H- imidazoles -1- Base) -5- (trifluoromethyl) phenyl) malonamide
The synthesis of 114 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:562.17。
Embodiment 115:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2,6- difluorophenyl) malonyl Amine
The synthesis of 115 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:550.13。
Embodiment 116:N1- (5- (tert-butyl) isoxazole -3- base)-N3- (3- (3- aminoacyl) phenyl -1H- indazole -6- Base) malonamide
The synthesis of 116 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:461.18。
Embodiment 117:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (4- chlorphenyl) malonamide
The synthesis of 117 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:448.10。
Embodiment 118:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2- fluoro- 3- (trifluoromethyl) benzene Base) malonamide
The synthesis of 118 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:500.13。
Embodiment 119:N1- (3- fluorophenyl)-N3- (3- (6- picoline -3- base) -1H- indazole -6- base) malonamide
The synthesis of 119 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:404.14。
Embodiment 120:N1- (4- methoxyl group -3- (trifluoromethyl) phenyl)-N3- (3- (6- picoline -3- base) -1H- Indazole -6- base) malonamide
The synthesis of 120 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/ z(M+1)+:484.15。
Embodiment 121:(E)-N- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) ethyl) cigarette The synthesis of amide
(E) -2- ((3- (2- (pyridine -2- base) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) Sulphur) ethyl -1- amine (4c): the iodo- 3- of (E) -6- [2- (pyridine -2- base) vinyl] -1- (tetrahydro -2H- is added in round-bottomed flask Pyrans -2- base) DMAC N,N' dimethyl acetamide (20 milliliters), 2- aminoothyl mercaptan (1.1 grams), Pd is added in -1H- indazole (5 grams) afterwards (OAc)2(0.3 gram) and 9,9- dimethyl -4,5- double diphenylphosphine xanthenes (0.8 gram), N, N- diisopropylethylamine (6.5 millis It rises).Reaction system is heated to 150 DEG C under protection of argon gas and reacts 2 hours.After reaction, system solvent evaporated under reduced pressure, Gains are extracted with ethyl acetate after being diluted with water.Organic phase is done after using water, saturated common salt water washing respectively with anhydrous sodium sulfate It is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Sterling 4c is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 381.16。
(E)-N- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) ethyl) niacinamide (121): (E) -2- ((3- (2- (pyridine -2- base) vinyl) -1- (tetrahydro -2H pyrans -2- base) -1H- indazole-is added in round-bottomed flask 6- yl) sulphur) ethyl -1- amine (50 milligrams) be added afterwards N,N-dimethylformamide (5 milliliters), niacin (19 milligrams), 2- (7- oxidation Benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (75 milligrams) and triethylamine (0.04 milliliter).Reaction system exists It is stirred at room temperature 14 hours under argon gas protection.After reaction, solvent evaporated, gains use second after being diluted with water to system under reduced pressure Acetoacetic ester extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, decompression Crude product is obtained after being evaporated to be dissolved in anhydrous methylene chloride (5 milliliters), is added trifluoroacetic acid (1 milliliter).Reaction system is under protection of argon gas It is stirred at room temperature 14 hours.After reaction, solvent evaporated, gains use saturated sodium bicarbonate after being diluted with water to system under reduced pressure Solution is neutralized to pH > 10.Water phase is extracted with ethyl acetate, and organic phase is respectively with using anhydrous slufuric acid after water, saturated common salt water washing Sodium is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Sterling compound is obtained after the pressurized silica gel column chromatography purification of crude product 121.LC/MS:M+H 402.13.
Embodiment 122:(E) -5- oxo-N- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) Ethyl) pyrrolidines -2- formamide
The synthesis of 122 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI) m/z(M+1)+:408.14。
Embodiment 123:(E) -1- methyl -2- oxo-N- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- Base) sulphur) ethyl) -1,2- dihydropyridine -3- formamide
The synthesis of 123 compound of compound is completed by using the step of being similar to described in embodiment 121.MS(ESI) m/z(M+1)+:432.14。
Embodiment 124:(E) -1- (3,4- difluorophenyl) -3- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- Yin Azoles -6- base) sulphur) ethyl) and urea synthesis
(E) -2- ((3- (2- (pyridine -2- base) vinyl) -1- (tetrahydro -2H- pyrans -2- is added in round-bottomed flask Base) -1H- indazole -6- base) sulphur) methylene chloride (5 milliliters), 3,4- difluorophenyl isocyanic acid is added in ethyl -1- amine (50 milligrams) afterwards Ester (23 milligrams).Trifluoroacetic acid (1 milliliter) is added after being stirred at room temperature under protection of argon gas 14 hours in reaction system.Reaction system after It is continuous to be stirred at room temperature under protection of argon gas 14 hours.After reaction, system solvent evaporated under reduced pressure, after gains are diluted with water PH > 10 are neutralized to saturated sodium bicarbonate solution.Water phase is extracted with ethyl acetate, and organic phase uses water, saturated common salt washing respectively It is dry with anhydrous sodium sulfate after washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.After the pressurized silica gel column chromatography purification of crude product Obtain sterling compound 124.LC/MS:M+H 452.12.
Embodiment 125:(E) -1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- ((3- (2- (pyridine -2- base) ethylene Base) -1H- indazole -6- base) sulphur) ethyl) urea
The synthesis of 125 compound of embodiment is completed by using the step of being similar to described in embodiment 124.MS(ESI) m/z(M+1)+:518.09。
Embodiment 126:(E) -1- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) ethyl) -3- (3- (trifluoromethyl) phenyl) urea
The synthesis of 126 compound of embodiment is completed by using the step of being similar to described in embodiment 124.MS(ESI) m/z(M+1)+:484.13。
Embodiment 127:(E) -4- ((4- methylpiperazine-1-yl) methyl)-N- (3- ((3- (2- (pyridine -2- base) ethylene Base) -1H- indazole -6- base) sulphur) propyl) -3- (trifluoromethyl) benzamide
The synthesis of 127 compound of compound is completed by using the step of being similar to described in embodiment 121.MS(ESI) m/z(M+1)+:595.23。
Embodiment 128:(E)-N- (3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propyl) furan It mutters -2- formamide
The synthesis of 128 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI) m/z(M+1)+:405.48。
Embodiment 129:(E)-N- (3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propyl) benzene Amide
The synthesis of 129 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI) m/z(M+1)+:401.13。
Embodiment 130:(E) -2- hydroxy-n-(3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) Propyl) Pyrazinamide
The synthesis of 130 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI) m/z(M+1)+:432.51。
Embodiment 131:(E) the chloro- N- of -4- (3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) third Base) -3- (trifluoromethyl) benzamide
The synthesis of 131 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI) m/z(M+1)+:517.96。
Embodiment 132:(E) -4- ((4- methylpiperazine-1-yl) methyl)-N- (3- ((3- (2- (pyridine -2- base) ethylene Base) -1H- indazole -6- base) sulphur) propyl) benzamide
The synthesis of 132 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI) m/z(M+1)+:527.25。
Embodiment 133:(E)-N- (3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propyl) thiophene Pheno -2- formamide
The synthesis of 133 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI) m/z(M+1)+:421.11。
Embodiment 134:(E)-N (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -3- ((3- (2- (pyridine -2- base) second Alkenyl) -1H- indazole -6- base) sulphur) and propionamide synthesis
(E)-(3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) Methyl propionate (5b): the iodo- 3- of (E) -6- [2- (pyridine -2- base) vinyl] -1- (tetrahydro -2H- pyrrole is added in round-bottomed flask Mutter -2- base) DMAC N,N' dimethyl acetamide (20 milliliters), 3- mercapto-propionate (1.7 grams), Pd is added in -1H- indazole (5 grams) afterwards (OAc)2(0.3 gram) and 9,9- dimethyl -4,5- double diphenylphosphine xanthenes (0.8 gram), N, N- diisopropylethylamine (6.5 millis It rises).Reaction system is heated to 150 DEG C under protection of argon gas and reacts 2 hours.After reaction, system solvent evaporated under reduced pressure, Gains are extracted with ethyl acetate after being diluted with water.Organic phase is done after using water, saturated common salt water washing respectively with anhydrous sodium sulfate It is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Sterling 5b is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 424.16。
(E)-(3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) Propionic acid (5c): by (E)-(3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) Sulphur) (1 gram) addition tetrahydrofuran (20 milliliters) of methyl propionate and water (20 milliliters), lithium hydroxide (1.7 grams) then are added.Reaction System at room temperature, argon gas protection reaction 4 hours.After reaction, system solvent evaporated under reduced pressure, gains with 1 mole/ The dilute hydrochloric acid risen, which is neutralized to pH 3-5, solid precipitation.Water phase obtains crude product 5c after solid is dry through the solid was filtered.LC/MS:M+ H 410.14。
(E)-N (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- Indazole -6- base) sulphur) propionamide (134): (E)-(3- (3- (2- (2- pyridyl group) vinyl) -1- (four is added in round-bottomed flask Hydrogen -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) N,N-dimethylformamide (5 milliliters), 4- is added in propionic acid (50 milligrams) afterwards ((4- methylpiperazine-1-yl) methyl) aniline (28 milligrams), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea six Fluorophosphoric acid ester (70 milligrams) and triethylamine (0.05 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.Reaction knot Shu Hou, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase uses water, saturation respectively It is dry with anhydrous sodium sulfate after brine It.Organic phase obtains crude product through filtering, after evaporated under reduced pressure and is dissolved in anhydrous methylene chloride (5 Milliliter), it is added trifluoroacetic acid (1 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system Solvent evaporated under reduced pressure, gains with saturated sodium bicarbonate solution are neutralized to pH > 10 after being diluted with water.Water phase ethyl acetate Extraction, organic phase are dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is through filtering, after evaporated under reduced pressure Obtain crude product.Sterling compound 134 is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 513.23.
Embodiment 135:(E)-N- (3- fluorophenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) Sulphur) propionamide
The synthesis of 135 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:419.26。
Embodiment 136:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (3,4,5- Trimethoxyphenyl) propionamide
The synthesis of 136 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:491.16。
Embodiment 137:(E)-N- (3- chlorphenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) Sulphur) propionamide
The synthesis of 137 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:435.09。
Embodiment 138:(E)-N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) - 1H- indazole -6- base) sulphur) propionamide
The synthesis of 138 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:503.08。
Embodiment 139:(E)-N- (3- methoxyphenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- Base) sulphur) propionamide
The synthesis of 139 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:431.01。
Embodiment 140:(E)-N- (3- (dimethylamino) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- Indazole -6- base) sulphur) propionamide
The synthesis of 140 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:444.17。
Embodiment 141:(E)-N- (3- (4- methylpiperazine-1-yl) phenyl) -3- ((3- (2- (pyridine -2- base) ethylene Base) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 141 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:499.22。
Embodiment 142:(E)-N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl)-phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 142 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:581.22。
Embodiment 143:(E)-N- (the fluoro- 4- aminomethyl phenyl of 3-) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- Yin Azoles -6- base) sulphur) propionamide
The synthesis of 143 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:433.14。
Embodiment 144:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (4- (trifluoro Methoxyl group) phenyl) propionamide
The synthesis of 144 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:485.11。
Embodiment 145:(E)-N- benzyl -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionyl Amine
The synthesis of 145 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:415.15。
Embodiment 146:(E)-N- (4- acetyl phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- Base) sulphur) propionamide
The synthesis of 146 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:443.14。
Embodiment 147:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (m- toluene Base) propionamide
The synthesis of 147 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:415.15。
Embodiment 148:(E)-N- (3,4- 3,5-dimethylphenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole - 6- yl) sulphur) propionamide
The synthesis of 148 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:429.16。
Embodiment 149:(E)-N- (4- methoxy-benzyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- Base) sulphur) propionamide
The synthesis of 149 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:445.16。
Embodiment 150:(E)-N- (4- (tert-butyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole - 6- yl) sulphur) propionamide
The synthesis of 150 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:457.18。
Embodiment 151:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (p- toluene Base) propionamide
The synthesis of 151 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:415.15。
Embodiment 152:(E)-N- (4- methoxyl group -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) ethylene Base) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 152 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:499.13。
Embodiment 153:(E)-N- (the fluoro- 4- aminomethyl phenyl of 3-) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- Yin Azoles -6- base) sulphur) propionamide
The synthesis of 153 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:433.14。
Embodiment 154:(E)-N- (4- methyl -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) ethylene Base) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 154 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:483.14。
Embodiment 155:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (3- (trifluoro Methyl) benzyl) propionamide
The synthesis of 155 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:483.14。
Embodiment 156:(E)-N- phenyl -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionyl Amine
The synthesis of 156 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:401.14。
Embodiment 157:(E)-N- (4- fluoro- 3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) - 1H- indazole -6- base) sulphur) propionamide
The synthesis of 157 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:487.11。
Embodiment 158:(E)-N- (4- ((4- ethyl piperazidine -1- base) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 158 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:595.24。
Embodiment 159:(E)-N- ((4- (((2- dimethylamino) ethyl) (methyl) amino) methyl) -3- (fluoroform Base) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 159 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:583.24。
Embodiment 160:(E)-N- (4- ((3- (dimethylamino) pyrroles -1- base) methyl) -3- (trifluoromethyl) phenyl) - 3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 160 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:595.24。
Embodiment 161:(E)-N- (3- (4- methyl-1 H-imidazole-1-group) -5- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 161 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:549.16。
Embodiment 162:(E)-N- (4- ((4- methyl piperidine -1- base) methyl) -3- (trifluoromethyl)-phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 162 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:580.23。
Embodiment 163:(E)-N- (4- (morpholine methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) Vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 163 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:568.19。
Embodiment 164:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (4- (pyrrole Cough up -1- ylmethyl) -3- (trifluoromethyl) phenyl) propionamide
The synthesis of 164 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:552.20。
Embodiment 165:3- ((1H- indazole -6- base) sulphur)-N- (4- methyl -3- (trifluoromethyl) phenyl) propionamide
The synthesis of 165 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:380.10。
Embodiment 166:3- ((1H- indazole -6- base) sulphur)-N- (4- ((4- ethyl piperazidine -1- base) methyl) -3- (fluoroform Base) phenyl) propionamide
The synthesis of 166 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:492.20。
Embodiment 167:3- ((1H- indazole -6- base) sulphur)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide
The synthesis of 167 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:400.04。
Embodiment 168:3- ((1H- indazole -6- base) sulphur)-N- (4- fluorophenyl) propionamide
The synthesis of 168 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:316.08。
Embodiment 169:3- ((1H- indazole -6- base) sulphur)-N- (thiophene -2- methyl) propionamide
The synthesis of 169 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:318.07。
Embodiment 170:3- ((1H- indazole -6- base) sulphur)-N- (3- (trifluoromethyl) phenyl) propionamide
The synthesis of 170 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:366.08。
Embodiment 171:3- ((1H- indazole -6- base) sulphur)-N- (3- fluorophenyl) propionamide
The synthesis of 171 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:316.08。
Embodiment 172:3- ((1H- indazole -6- base) sulphur)-N- (2,3- difluorophenyl) propionamide
The synthesis of 172 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI) m/z(M+1)+:334.07。
Embodiment 173:N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (pyridine - 3- yl) -1H- indazole -6- base) sulphur) and propionamide synthesis
6- iodo- 3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (6a): it is added in round-bottomed flask 6- amino -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (5 grams), after acetic acid (20ml) then is added System is set to be cooled to 0 degree with ice-water bath.The sulfuric acid (11 milliliters) of 3 mol/Ls is continuously added, is added sodium nitrite (1.8 grams), instead Answer system under protection of argon gas 0 degree stirring 4 hours after, be added 3 mol/Ls potassium iodide (17 milliliters).Reaction system is in argon gas Lower 0 degree of protection is stirred 3 hours.After reaction, filtering reacting solution obtained solid is dissolved with ethyl acetate, and organic phase is used respectively It is dry with anhydrous sodium sulfate after saturated sodium bicarbonate, saturated common salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure 6a.LC/MS:M+H 406.03.
3- ((3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) methyl propionate (6b): The iodo- 3- of 6- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (2 grams) is added in round-bottomed flask, N is added afterwards, N- dimethyl acetamide (10 milliliters), 3- mercapto-propionate (0.7 gram), palladium acetate (0.1 gram) and 9,9- dimethyl -4,5- are double Diphenylphosphine xanthene (0.3 gram), N, N- diisopropylethylamine (2.7 milliliters).Reaction system is heated to 150 under protection of argon gas DEG C reaction 2 hours.After reaction, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Have Machine is mutually respectively with dry with anhydrous sodium sulfate after water, saturated common salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure. Sterling 6b is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 398.14.
3- ((3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) propionic acid (6c): in circle 3- ((3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) methyl propionate is added in the flask of bottom Tetrahydrofuran (20 milliliters) and water (20 milliliters) is added in (1 gram) afterwards, and lithium hydroxide (0.6 gram) then is added.Reaction system is in room Under temperature, argon gas protection reaction 4 hours.After reaction, system solvent evaporated under reduced pressure, dilute salt of 1 mol/L of gains Acid, which is neutralized to pH 3-5, solid precipitation.Water phase obtains crude product 6c after solid is dry through the solid was filtered.LC/MS:M+H 384.13。
N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (pyridin-3-yl) -1H- Indazole -6- base) sulphur) propionamide (173): (3- ((3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans-is added in round-bottomed flask 2- yl) -1H- indazole -6- base) sulphur) N,N-dimethylformamide (5 milliliters), 4- ((4- methyl piperazine is added in propionic acid (50 milligrams) afterwards Piperazine -1- base) methyl) -3- (trifluoromethyl) aniline (42 milligrams), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethyl Urea hexafluorophosphoric acid ester (74 milligrams) and triethylamine (0.05 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.Instead After answering, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase use respectively water, It is dry with anhydrous sodium sulfate after saturated common salt water washing.Organic phase obtains crude product through filtering, after evaporated under reduced pressure and is dissolved in anhydrous dichloromethane Alkane (5 milliliters) is added trifluoroacetic acid (1 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, System solvent evaporated under reduced pressure, gains with saturated sodium bicarbonate solution are neutralized to pH > 10 after being diluted with water.Water phase acetic acid Ethyl ester extraction, organic phase are dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, and decompression is steamed Crude product is obtained after dry.Sterling compound 173 is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 555.20.
Embodiment 174:N- (3- fluorophenyl) -3- ((3- (pyridin-3-yl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 174 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI) m/z(M+1)+:393.11。
Embodiment 175:N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (6- first Yl pyridines -3- base) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 175 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI) m/z(M+1)+:568.22。
Embodiment 176:3- ((3- methyl-1 H- indazole -6- base) sulphur)-N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) phenyl) propionamide
The synthesis of 176 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI) m/z(M+1)+:492.20。
Embodiment 177:3- ((3- (1- methyl-1 H pyrazoles -4- base) -1H- indazole -6- base) sulphur)-N- (4- ((4- methyl piperazine Piperazine -1- base) methyl) -3- (trifluoromethyl) phenyl) propionamide
The synthesis of 177 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI) m/z(M+1)+:558.22。
Embodiment 178:N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (phenyl - 1H- indazole -6- base) sulphur) propionamide
The synthesis of 178 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI) m/z(M+1)+:554.21。
Embodiment 179: the influence to cancer cell multiplication
By testing influence (table 2) of the compound of the present invention to growth of cancer cells, compound pair in text is further assessed The inhibiting effect of cancer cell multiplication and its to inhibit cancer cell multiplication selectivity.It has been selected in the present embodiment, between human gastrointestinal tract Matter oncocyte system cell GIST-T1 (expression wild type C-KIT gene) (being purchased from Cosmo Bio Co., Ltd. (Japan)), mouse Pro B lymphocyte BaF3 (is purchased from ATCC).In addition, the present embodiment has also selected mouse P210/BaF3 (to stablize expression P210Bcr-Abl Mutated genes), mouse P210/T315I-BaF3 (stablize expression saltant type P210Bcr-Abl/T315I kinases), mouse Tel- CKit-BaF3 (stablizing expression C-KIT wild type kinase), mouse Tel-cKit/V559D-BaF3 (stablize expression C-KIT V559D be mutated type kinase), mouse Tel-cKit/V559D/T670I-BaF3 (stablize expression C-KIT V559D/T670I mutation Type kinase), mouse Tel-cKit/T670I-BaF3 (stablize expression C-KIT T670I be mutated type kinase), mouse Tel-PDGFR α-BaF3 (stablizing PDGF-B expression R alpha kinase), mouse Tel-PDGFR β-BaF3 (stablizing PDGF-B expression R beta kinase), mouse Tel- VEGFR2-BaF3 (stablizing VEGF expression R2 kinases), mouse Tel-RET-BaF3 (stablizing expression RET kinases), mouse Tel- FLT3-BaF3 (stablizing expression FLT3 kinases), mouse Tel-FGFR1-BaF3 (stablizing expression FGFR1 kinases), mouse Tel- FGFR2-BaF3 (stablizing expression FGFR2 kinases), mouse Tel-FGFR3-BaF3 (stablizing expression FGFR3 kinases), mouse Tel- FGFR4-BaF3 (stablizes expression FGFR4 kinases).Above-mentioned cell line is constructed by this laboratory, construction method are as follows: distinguish through PCR Expand mankind P210Bcr-Abl, P210Bcr-Abl/T315I, C-KIT, C-KIT V559D, C-KIT V559D/T670I, C- KIT T670I, PDGFR α, PDGFR β, VEGFR2, RET, FLT3, FGFR1, FGFR2, FGFR3, FGFR4 kinases region sequence, and The MSCV-Puro carrier with N-terminal TEL segment and/or NPM segment and/or TPR segment is inserted respectively into (to be purchased from Clontech), by retrovirus method, stabilization is transferred to mouse BaF3 cell, and removes IL-3 growth factor, final To dependence P210Bcr-Abl, P210Bcr-Abl/T315I, C-KIT, C-KIT/V559D, C-KIT/V559D/T670I, C- KIT/T670I, PDGFR α, PDGFR β, VEGFR2, RET, FLT3, FGFR1, FGFR2, FGFR3, FGFR4 are transferred to the cell of albumen System.
In embodiment by various concentration (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μ M, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM in DMSO) test compound be added separately to above-mentioned cell In, and it is incubated for 72 hours, with CCK8 (Bei Bo, China) cell viability detection kit, by the reduction dehydrogenation in living cells Enzyme is quantitative determined to detect number of viable cells.Determine that the compound of the present invention is directed to the GI of each test cell50It is worth (unit), Experimental result is shown in Table 2.
Table 2
2 (Continued) of table
2 (Continued) of table
By test discovery the compound of the present invention major target class be CKIT, CKIT/T670I, BCR-ABL/T315I, PDGFR α, PDGFR β and VEGFR2.The compound of the present invention is to TEL-CKIT/T670I-BaF3, gastrointestinal stromal tumor GIST- T1 has apparent inhibiting effect, this can prove that these compounds can be used in treating gastrointestinal stromal tumor, and for T670I It is especially effective that point mutation generates drug resistant gastrointestinal stromal tumor.In addition, some preferred compounds of the invention are also further right P210/T315I-BaF3 cell has effect.P210/T315I-BaF3 is a kind of cell line of BCR-ABL/T315I mutation, and BCR-ABL/T315I is medicament-resistant mutation common in chronic myelogenous leukemia clinic, currently without particularly preferred little molecules in inhibiting Agent can treat the chronic myelogenous leukemia of the mutation.
Based on the above discovery, present inventor further selects preferred compounds of the invention 142 to test, really It is thin to human chronic myeloblastic leukemia cell K562 (expression P210Bcr-Abl mutated genes), human chronic myeloblastic leukemia to determine it Born of the same parents MEG-01 (expression P210Bcr-Abl mutated genes), human chronic myeloblastic leukemia cell Ku812 (expression P210Bcr-Abl Mutated genes) (above-mentioned cell is purchased from ATCC (U.S.)) GI50It is worth (unit), experimental result is shown in Table 3.
Table 3
GI50/μM Compound 142
K562 0.0012
KU812 0.005
MEG01 0.0014
As shown above, some preferred compounds of the invention have very strong inhibition to make in P210/T315I-BaF3 cell With, and these compounds also express three kinds chronic myeloid leukemia cel l line K562, MEG- of BCR-ABL fusion 01, the proliferation of KU812 has significant inhibition, GI50Respectively less than 0.01 μM.This proves preferred compounds of the invention to chronic Myelogenous Leukaemia has preferable therapeutic effect, and also has to drug resistant chronic myelogenous leukemia caused by point mutation T315I certain Therapeutic effect.
Embodiment 180: zoopery
In the present embodiment, compound 4 and compound 142 are tested respectively in TEL-cKIT/T670I-BaF3 and P210/ Experimental result in the mouse model of T315I-BaF3.
Experimental procedure is as follows:
(1) small from the Bal b/c female of Beijing dimension experimental animal Co., Ltd, tonneau China purchase raising 4-6 week old Mouse is raised in SPF grades of laboratories, and through autoclave sterilization aseptic process, all operations in relation to mouse exist for drinking-water and padding It is carried out under aseptic condition；
Dorsal sc is injected separately into about 5 × 10 on the left of all mouse respectively within (2) the 0th days6A TEL-cKIT/T670I- BaF3 or 5 × 106A P210/T315I-BaF3 cell；
(3) for the mouse model of TEL-cKIT/T670I-BaF3 since the 6th day, every angel correspond to Mouse oral to Medicine methylcellulose (HKI) solvent (5 mouse)；Dosage is the compound 4 (5 mouse) of 25mg/kg mouse weight；Dosage is The Imatinib (being purchased from MedChem Express, China) (5 mouse) of 100mg/kg mouse weight.For P210/T315I-BaF3 Mouse model since the 6th day, every angel correspond to Mouse oral administration methylcellulose (HKI) solvent (5 mouse)；Dosage For the compound 142 (5 mouse) of 25mg/kg mouse weight；Dosage is the compound 142 (5 mouse) of 50mg/kg mouse weight；Dosage For the compound 142 (5 mouse) of 100mg/kg mouse weight；
(4) since the 6th day, the length/width of vernier caliper measurement subcutaneous tumor is used daily, and records mouse weight daily, The influence of compound 4 and compound 142 to mouse weight is determined respectively；
(5) the 18th days execution mouse take out subcutaneous tumor, and tumour weighing is compared；
(6) subendothelial tumour growth trend, gross tumor volume calculation method: length × wide × wide/2mm are counted3。
Experimental result is as shown in Fig. 1 a-c and 2a-c.Mouse tumor model of the compound 4 in TEL-cKIT/T670I-BaF3 In, dosage has shown the effect of certain inhibition mouse tumor when being 25mg/kg, and with the increasing of medication number of days Add, compound 4 is more significant to the inhibiting effect of mouse tumor, and tumour inhibiting rate is up to 49.6%.Compound 4 not only effectively inhibits The growth of mouse tumor, and the weight of mouse is not influenced substantially, show that compound 4 is applicable to animal administration.This Demonstrating CKIT/T670I inhibitor compound 4 of the invention can be used in treating the gastrointestinal stromal tumor of T670I mutation.For For compound 142 in P210/T315I-BaF3 mouse model, dosage has shown certain inhibition when being 25mg/kg The effect of mouse tumor, and with the increase of dosage and medication number of days, compound 142 is cured the inhibiting effect of mouse tumor Hair is significant, and tumour inhibiting rate is up to 69% when medication 100mg/kg.Compound 142 not only effectively inhibits the growth of mouse tumor, and And the weight of mouse is not influenced substantially, show that compound 142 is applicable to animal administration.This also demonstrates of the invention BCR-ABL/T315I inhibitor compound 142 can be used in treating the chronic myelogenous leukemia of T315I mutation.
Industrial applicability
The present invention provides a kind of Azaindole kinase inhibitors compound, can be used for reducing or inhibiting cell or subject CKIT (especially saltant type cKIT/T670I), BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 kinase activity, and/or prevent or treat cKIT (especially saltant type cKIT/ in subject T670I), BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 activity related diseases Disease.Thus, it can be made into corresponding drug, be suitable for industrial application.
Although being explained in detail herein to the present invention, however, the present invention is not limited thereto, those skilled in the art can It is modified with principle according to the present invention, therefore, the various modifications that all principles according to the invention carry out all should be understood as Fall into protection scope of the present invention.

Claims (11)

1. a kind of kinase inhibitor comprising the compound of formula (I) or its pharmaceutically acceptable salt, solvate, ester, acid, generation Thank object or pro-drug:
Wherein, X is selected from
Y is selected from phenyl, thiophene -2- base, isoxazole -3- base, pyridin-3-yl, pyridin-4-yl, 2-Pyrrolidone -5- base, N- first Base -2 (1H)-pyridone -5- base and furans -2- base；
R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3Group replace pyridin-3-yl, optionally by R3 Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces；
(R2)nIt indicates optionally by n independent R2Replaced substituent group, wherein n is the integer of 0-5, R2Independently selected from hydroxyl, halogen Element, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4- methyl- Imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl；
R5Selected from hydrogen and C1-6Alkyl amino.
2. kinase inhibitor according to claim 1 comprising the compound of (Ia) or its pharmaceutically acceptable salt, solvent Compound, ester, acid, metabolin or pro-drug:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl and appoint that group replaces Choosing is by R3The phenyl that group replaces；
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group, wherein n is 0-5's Integer, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Alkyl amino, 4- methyl-imidazoles- 1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl；
R5Selected from C1-6Alkyl amino.
3. kinase inhibitor according to claim 1 comprising the compound of (Ib) or its pharmaceutically acceptable salt, solvent Compound, ester, acid, metabolin or pro-drug:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3Group replace pyridin-3-yl, optionally By R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces；
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group, Middle n is the integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6It is halogenated Alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4- methyl-imidazoles -1- base,
R3Selected from C1-6Alkyl and
R4Selected from C1-6Alkyl；
R5Selected from hydrogen and C1-6Alkyl amino.
4. kinase inhibitor according to claim 1 comprising following compound or its pharmaceutically acceptable salt, solvation Object, ester, acid, metabolin or prodrug:
5. a kind of pharmaceutical composition comprising such as compound of any of claims 1-4 or its is pharmaceutically acceptable Salt, solvate, ester, acid, metabolin or pro-drug and pharmaceutically acceptable carrier or excipient, and optional Other therapeutic agents.
6. according to claim 1 kinase inhibitor described in any one of -4 preparation for inhibit selected from cKIT, BCR/ABL, Purposes in the drug of one of PDGFR α, PDGFR β and VEGFR2 or a variety of tyrosine kinase activities.
7. purposes according to claim 6, wherein the kinase inhibitor is selected from saltant type cKIT/T670I for inhibiting With one of saltant type BCR-ABL/T315I or a variety of tyrosine kinase activities.
8. according to claim 1 kinase inhibitor described in any one of -4 preparation for treat or prevent by selected from cKIT, It is that one of BCR/ABL, PDGFR α, PDGFR β and VEGFR2 or a variety of tyrosine kinase activities are adjusted or by its shadow Purposes in the drug of loud disease, obstruction and illness.
9. purposes according to claim 8, wherein the disease, obstruction and illness by selected from saltant type cKIT/T670I and One of saltant type BCR-ABL/T315I or a variety of tyrosine kinase activities are adjusted or are affected by it.
10. purposes according to claim 8 or claim 9, wherein the disease, obstruction and illness are selected from: solid tumor, especially meat Tumor, gastrointestinal stromal tumor, acute myeloblastic leukemia, chronic myelogenous leukemia, celiothelioma, thyroid cancer, systemic mast are thin Born of the same parents' disease, hypereosinophilic syndrome, fibre modification, rheumatoid arthritis, panarthritis, chorionitis, lupus erythematosus, shifting Graft versus host disease, neurofibroma, pulmonary hypertension, Alzheimer disease, seminoma, psoriasis, dysgerminoma, hypertrophy Cell tumour, lung cancer, bronchiolar carcinoma, dysgerminoma, the formation of testis intraepithelial neoplasia, melanoma, breast cancer, neuroblast Tumor, mamillary/follicular thyroid cancer, malignant lymphoma, non-Hodgkin lymphoma, the formation of 2 type Multiple Endocrine tumors, thermophilic chromium Cytoma, parathyroid hyperplasia/adenoma, colon cancer, colorectal adenomas, oophoroma, prostate cancer, spongioblastoma, brain Tumour, glioblastoma, cancer of pancreas, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney, liver cancer, on kidney Gland cancer, bladder cancer, gastric cancer, the carcinoma of the rectum, carcinoma of vagina, cervical carcinoma, carcinoma of endometrium, Huppert's disease, neck and head tumor, pass Save inflammation, rheumatic arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel disease, psoriasis arthropathica, Bones and joints Inflammation, Still disease, adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis, Order thyroiditis, Greif This disease, rheumatoid arthritis syndrome, multiple sclerosis, Guillain-Barre syndrome, acute diseminated encephalomyelitis, A Di It is gloomy disease, view property eye battle array it is twin-the twin syndrome of flesh battle array, ankylosing spondylitis, antiphospholipid antibody syndrome, alpastic anemia, from Body autoallergic, chylous diarrhea, goodpasture's syndrome, Idiopathic Thrombocytopenic Purpura, optic neuritis, chorionitis, Primary biliary cirrhosis, Reiter syndrome, takayasu's arteritis, temporal arteritis, warm type autoimmune hemolytic anemia, Wegner's granulomatosis, alopecia universalis, behcet disease, confirmed fatigue, familial dysautonomia, endometrium are different Position, interstitial cystitis, neuromyotonia, chorionitis, Vulvodynia, or combinations thereof.
11. purposes according to claim 8 or claim 9, wherein the disease, obstruction and illness are selected from: gastrointestinal stromal tumor, urgency Property granulocytic leukemia, chronic myelogenous leukemia, thyroid cancer, or combinations thereof.
CN201711394182.5A 2017-12-21 2017-12-21 Novel indazole derivative kinase inhibitor Active CN109942544B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201711394182.5A CN109942544B (en) 2017-12-21 2017-12-21 Novel indazole derivative kinase inhibitor
PCT/CN2017/118602 WO2019119481A1 (en) 2017-12-21 2017-12-26 Carbazole derivative kinase inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201711394182.5A CN109942544B (en) 2017-12-21 2017-12-21 Novel indazole derivative kinase inhibitor

Publications (2)

Publication Number Publication Date
CN109942544A true CN109942544A (en) 2019-06-28
CN109942544B CN109942544B (en) 2021-06-11

Family

ID=66993021

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201711394182.5A Active CN109942544B (en) 2017-12-21 2017-12-21 Novel indazole derivative kinase inhibitor

Country Status (2)

Country Link
CN (1) CN109942544B (en)
WO (1) WO2019119481A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111138426B (en) * 2018-11-02 2023-03-10 安徽中科拓苒药物科学研究有限公司 Indazole kinase inhibitor and application thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1747950A (en) * 2002-12-19 2006-03-15 美国辉瑞有限公司 2-(1h-indazole-6-ylamino)-benzamide compounds as protein kinases inhibitors useful for the treatment of ophthalmic diseases
CN101005843A (en) * 2004-06-28 2007-07-25 布里斯托尔-迈尔斯·斯奎布公司 Pyrrolotriazine kinase inhibitors
CN101052634A (en) * 2004-11-03 2007-10-10 拜耳先灵医药股份有限公司 Anthranilamide pyridinureas as vegf receptor kinase inhibitors
CN101056870A (en) * 2004-11-03 2007-10-17 拜耳先灵医药股份有限公司 Nicotinamide pyridinureas as vascular endothelial growth factor (vegf) receptor kinase inhibitors
CN102239150A (en) * 2008-12-05 2011-11-09 韩国科学技术研究院 Novel indazole derivatives or pharmaceutically acceptable salts thereof as protein kinase inhibitors for proliferative diseases treatment, and a pharmaceutical composition containing the same as an active ingredient
WO2012003418A2 (en) * 2010-07-02 2012-01-05 The University Of North Carolina At Chapel Hill Functionally selective ligands of dopamine d2 receptors
CN105906568A (en) * 2016-04-28 2016-08-31 西安交通大学 Cyclopropane diamide compound with antitumor activity and preparation method and application thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1747950A (en) * 2002-12-19 2006-03-15 美国辉瑞有限公司 2-(1h-indazole-6-ylamino)-benzamide compounds as protein kinases inhibitors useful for the treatment of ophthalmic diseases
CN101005843A (en) * 2004-06-28 2007-07-25 布里斯托尔-迈尔斯·斯奎布公司 Pyrrolotriazine kinase inhibitors
CN101052634A (en) * 2004-11-03 2007-10-10 拜耳先灵医药股份有限公司 Anthranilamide pyridinureas as vegf receptor kinase inhibitors
CN101056870A (en) * 2004-11-03 2007-10-17 拜耳先灵医药股份有限公司 Nicotinamide pyridinureas as vascular endothelial growth factor (vegf) receptor kinase inhibitors
CN102239150A (en) * 2008-12-05 2011-11-09 韩国科学技术研究院 Novel indazole derivatives or pharmaceutically acceptable salts thereof as protein kinase inhibitors for proliferative diseases treatment, and a pharmaceutical composition containing the same as an active ingredient
WO2012003418A2 (en) * 2010-07-02 2012-01-05 The University Of North Carolina At Chapel Hill Functionally selective ligands of dopamine d2 receptors
CN105906568A (en) * 2016-04-28 2016-08-31 西安交通大学 Cyclopropane diamide compound with antitumor activity and preparation method and application thereof

Also Published As

Publication number Publication date
WO2019119481A1 (en) 2019-06-27
CN109942544B (en) 2021-06-11

Similar Documents

Publication Publication Date Title
CN104844566B (en) A kind of kinase inhibitor of new structure
CN110582483B (en) Compound containing o-amino heteroaromatic alkynyl and preparation method and application thereof
CN104829610B (en) A kind of novel cloth Shandong tyrosine kinase inhibitor
CN106883213B (en) Dual inhibitor of EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase)
CN106008511B (en) Pteridine ketone derivatives and its application as EGFR, BLK, FLT3 inhibitor
CN107286077A (en) A kind of selective C-KIT kinase inhibitors
HUE031955T2 (en) Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
CN104341425B (en) Deuterated acetylene-derivative, its pharmaceutical composition and application
CN104854103B (en) There is the acyl amino compound cycloalkyl of the illness of reaction suitable for the regulation treated to dopamine D 3 receptor
BRPI0712816B1 (en) pyrrolpyrimidine compounds and their use
TW200829558A (en) Quinazolines for PDK1 inhibition
CN106928231A (en) The kinase inhibitor of the new EGFR wild types of one class and saltant type
BR112021018704B1 (en) HETEROARYL DERIVATIVE, METHOD FOR PRODUCING THE SAME, AND PHARMACEUTICAL COMPOSITION INCLUDING THE SAME AS AN EFFECTIVE COMPONENT
CN109867676A (en) Compound derived from a kind of pyrrolopyrimidine, pharmaceutical composition with and application thereof
CN108368060A (en) A kind of novel pyridine derivatives kinase inhibitor
CN107922350A (en) New benzimidazole compound and its medical usage
CN110256436B (en) Purines as Trk kinase inhibitors
CN107383019B (en) Pyrazolo [4,3-h] quinazoline compounds and application thereof
CN109942544A (en) A kind of novel indazole analog derivative kinase inhibitor
JP7311918B2 (en) Novel pan-RAF kinase inhibitor and use thereof
CN113350347B (en) Use of indazoles
CN111303024B (en) Quinoline-structured pan-KIT kinase inhibitor and application thereof
CN107033069A (en) A kind of novel cloth Shandong tyrosine kinase irreversible inhibitor
CN110283160A (en) A kind of PDGFR kinase inhibitor
JP2023508376A (en) Cyano-substituted pyridines and cyano-substituted pyrimidine-based compounds, methods of preparation and uses thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant