CN109516999A - Compound and its application as protein kinase regulator - Google Patents
Compound and its application as protein kinase regulator Download PDFInfo
- Publication number
- CN109516999A CN109516999A CN201811283367.3A CN201811283367A CN109516999A CN 109516999 A CN109516999 A CN 109516999A CN 201811283367 A CN201811283367 A CN 201811283367A CN 109516999 A CN109516999 A CN 109516999A
- Authority
- CN
- China
- Prior art keywords
- enantiomter
- mixture
- mesomer
- diastereoisomer
- compound
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/18—Bridged systems
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Diabetes (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of I compounds represented of formula, and each symbol therein is as defined in the claims.Compound shown in formula I of the invention has good inhibitory activity to ALK, ROS1 and/or TRK kinases, can be used for preparing the drug for inhibiting ALK, ROS1 and/or TRK kinases, is used for treating cancer, pain, neurological disease, autoimmune disease or inflammation.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to the compound as protein kinase regulator, and contain
The pharmaceutical composition of the compound also relates to it and swashs in preparation for regulatory protein matter kinase activity or treatment albumen matter
Application in terms of the drug of enzyme related disease.
Background technique
Malignant tumour is one of primary killers of human health, and global cancer is predicted in " report of world's cancer " of latest edition
Swift and violent growing trend will be presented in case, by 14,000,000 people in 2012,19,000,000 people of cumulative year after year to 2025, to 2035
Year is up to 24,000,000 people.Report also shows that developing country's pathogenesis of cancer situation in Africa, Asia and Central and South America is the most
It is severe.The whole world in 2012 increases 14,000,000 cases of cancer newly altogether and has 8,200,000 people dead.Wherein, newly-increased 3,070,000 cancers of China
Patient simultaneously causes about 2,200,000 people dead, accounts for 21.9% and 26.8% (global cancer report 2014) of global total amount respectively.Mesh
Prehuman has the progress attracted attention to the level of understanding and treatment means of tumour, can accomplish to Partial tumors effectively
Ground control.But since the Forming Mechanism of tumour is extremely complex, the growth of most of malignant cell all there are many access,
Cause cancer cell to have extremely strong vitality, inhibits wherein that one or Part way can not eliminate cancer cell completely.Otherwise it removes
Common lesion transfer is outer, and chemotherapy frequently results in the mutation of cancer cell gene, it is caused to develop drug resistance.
Non-small cell lung cancer (NSCLC) is the most common Lung Cancer Types, the 80% to 85% of Zhan Suoyou patients with lung cancer,
Middle some patientss are accompanied by gene mutation.The case for having 2-5% in NSCLC is anaplastic lymphoma kinase (ALK) rearrangement type,
Anaplastic lymphoma kinase is a receptor type protein tyrosine phosphokinase of insulin receptor superfamily.Initial people
It is to have found ALK in the form of a kind of fusion oncogene of activation in primary cutaneous type, then continuous research
The fusion form that ALK is had found in kinds cancer, including systemic tissue abnormalities hyperplasia, inflammatory myofibroblasts cancer,
Non-small cell lung cancer etc..Mutation and abnormal activity of the ALK in kinds cancer, it is positive to have become a treatment ALK
The drug target of cancer.
The Crizotinib (Crizotinib) researched and developed by Pfizer pharmaceutical Co. Ltd can effectively contract according to clinical verification
The malignant tumour size of small late gene saltant type non-small cell lung cancer (NSCLC) patient.But Crizotinib will appear
Following side effect: dysopia, gastrointestinal side effect, 16% patient occur 3-4 grades of liver transaminase levels and increase, in addition,
ALK positive patient patient after the Crizotinib of incipient stage treats sensitive periods generally generates after the treatment through 1-2
Drug resistance.Inhibit currently, FDA has approved three second generation ALK such as ceritinib, alectinib and brigatinib in succession
Agent, the treatment for Crizotinib drug resistance patient.Although acquired resistance patient obtains in the drug that these are listed
Many benefits, but due to some side effects or tumour acquired drug resistance problems again, it often will limit these therapies
Effect, therefore, be badly in need of exploitation it is new, efficiently, the kinase inhibitor of wide spectrum.
A series of compound of high activities is disclosed in patent document WO2017004342A1, and Crizotinib is produced
Raw resistance mutation has very high inhibitor activity, and also has to the resistance mutation for using two generation ALK inhibitor to generate
Good inhibitor effect.Compound TPX-0005 disclosed in it is effective oral type for ALK, ROS1 and TRK family
Bioavailable small molecule kinase inhibitors.This molecule can effectively combine the ATP bound site of ALK, ROS1, TRK kinases
Point plays the role of inhibition to these albumen.More it is essential that it can be in conjunction with the saltant type of these albumen, such as ALK
G1202R, ALK L1196M, ROS1 G2032R, TRKA G595R, meanwhile, potential comprehensive solution is targeting ALK, ROS1,
After NTRK family, it is mutated related drug resistance problem with acquired resistance, and can solve bypass and EMT mechanism.Due to
In targeted therapies, bypass and EMT are common drug resistance mechanism, so TPX-0005 is very potential in the future to pass through combination
Therapy removes to capture the drug resistance problems that such as EGFR other treatment target spot generates.Currently, it has carried out Clinical experiment
And it is authorized by FDA for treating the orphan for carrying the non-small cell patients with lung adenocarcinoma that ALK, ROS1 or NTRK oncogene are reset
Medicine qualification.
Although TPX-0005 achieves relatively good effect in Clinical experiment, it is badly in need of to meet
Anti-drug resistance clinical demand, benefit many patients, develop new high activity and/or have more preferable pharmacodynamics/medicine for power
The compound for learning performance has become the critical issue of exploitation new type antineoplastic medicine urgently to be solved.
Summary of the invention
The present invention provides such as I compound represented of formula or its tautomer or its mesomer, racemic modification and
The mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric different
The mixture of structure body or its pharmaceutical salt:
In formula I:
M1Selected from CR9Or N；
M2Selected from CR10Or N；
X1、X2And X3It is independently selected from O, S, NR11, S (O) or S (O)2；
W is selected from C (O), S (O), C (S) or S (O)2；
C (O) isS (O) isC (S) isS(O)2For
Z1、Z2、Z3、Z4、Z5、Z6And Z7It is independently selected from N, NH or CR11, and Z1、Z2、Z3、 Z4、Z5、Z6And Z7In extremely
Few one is N or NH；
R1、R2、R9、R10And R11It is independently selected from H, deuterium, halogen, alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkanes
Base, alkoxy, halogenated alkoxy, hydroxyl, cyano, amino, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl,
Sulfonyl, phosphono,The wherein alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkane
Oxygroup, halogenated alkoxy, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, the H in phosphono can
To be mono-substituted or polysubstituted, substituent group be selected from fluorine, chlorine, bromine, amino, acetyl group, cyano, carboxyl, sulfonyl, phosphono,
C1-6Alkoxy, C1-4Alkyl, C3-6Naphthenic base, fluoro-alkyl, single fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy,
Trifluoro ethoxy, deuterated single fluorine methoxyl group or deuterated difluoro-methoxy；
R3、R4、R5、R6、R7And R8It is independently selected from H, deuterium, halogen, alkyl, halogenated alkyl, naphthenic base, halogenated ring
Alkyl, alkoxy, halogenated alkoxy, hydroxyl, cyano, amino, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl
Base, sulfonyl, phosphono,The wherein alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkanes
Base, alkoxy, halogenated alkoxy, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, in phosphono
H can be mono-substituted or polysubstituted, substituent group is selected from fluorine, chlorine, bromine, amino, acetyl group, cyano, carboxyl, sulfonyl, phosphono
Base, C1-6Alkoxy, C1-4Alkyl, C3-6Naphthenic base, fluoro-alkyl, single fluorine methoxyl group, difluoro-methoxy, trifluoro methoxy
Base, trifluoro ethoxy, deuterated single fluorine methoxyl group or deuterated difluoro-methoxy；
R12And R13It is independently selected from alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, aryl or heteroaryl；
M is 1 or 2；
N is 1 or 2.
The present invention also provides II compound represented of formula or its tautomers or its mesomer, racemic modification
And the mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric
The mixture of isomers or its pharmaceutical salt:
In formula II:
A is 3~8 member rings, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8, m, n such as institute in formula I
Definition.
The present invention also provides III compound represented of formula or its tautomers or its mesomer, racemic modification
And the mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric
The mixture of isomers or its pharmaceutical salt:
In formula III:
B is 3~8 member rings, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8, m, n such as institute in formula I
Definition.
The present invention also provides IV compound represented of formula or its tautomers or its mesomer, racemic modification
And the mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric
The mixture of isomers or its pharmaceutical salt:
In formula IV:
C is 3~8 member rings, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8, m, n such as institute in formula I
Definition.
The present invention also provides V compound represented of formula or its tautomers or its mesomer, racemic modification
And the mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric
The mixture of isomers or its pharmaceutical salt:
In formula V:
A, it is 3~8 member rings that B is independent, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8, m, n such as institute in formula I
Definition.
The present invention also provides VI compound represented of formula or its tautomers or its mesomer, racemic modification
And the mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric
The mixture of isomers or its pharmaceutical salt:
In formula VI:
B, it is 3~8 member rings that C is independent, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8, m, n such as institute in formula I
Definition.
The present invention also provides VII compound represented of formula or its tautomers or its mesomer, racemic modification
And the mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric
The mixture of isomers or its pharmaceutical salt:
In formula VII:
A, it is 3~8 member rings that C is independent, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8, m, n such as institute in formula I
Definition.
The present invention also provides VIII compound represented of formula or its tautomers or its mesomer, racemic modification
And the mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric
The mixture of isomers or its pharmaceutical salt:
In formula VIII:
A, it is 3~8 member rings that B, C are independent, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8, m, n such as institute in formula I
Definition.
It further limits, in I-formula of formula VIII, R1Selected from deuterium, halogen, alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl,
Alkoxy, halogenated alkoxy, hydroxyl, cyano, amino, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl, sulphonyl
Base, phosphono,The wherein alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alcoxyl
Base, halogenated alkoxy, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, phosphono,In H can be mono-substituted or polysubstituted, substituent group is selected from fluorine, chlorine, bromine, amino, acetyl group, cyanogen
Base, carboxyl, sulfonyl, phosphono, C1-6Alkoxy, C1-4Alkyl, C3-6Naphthenic base, fluoro-alkyl, single fluorine methoxy
Base, difluoro-methoxy, trifluoromethoxy, trifluoro ethoxy, deuterated single fluorine methoxyl group or deuterated difluoro-methoxy.
Further limit, formula I, formula III, formula IV, in formula VI, R3For deuterium.
Further limit, formula I, formula II, formula IV, in formula VII, R5For deuterium.
It further limits, in formula I, formula IV, R3、R5It is deuterium.
Invention further provides appoint particular compound selected from the following or its tautomer or its meso
The mixture or its enantiomter, diastereoisomer and mapping of body, racemic modification and mesomer and racemic modification are different
The mixture or its pharmaceutical salt of structure body and diastereoisomer:
The specific compound of the above can effectively inhibit the activity of ALK, ROS1 and/or TRK kinases.It can be used as
ALK/ROS1/TRK kinase inhibitor treats ALK/ROS1/TRK related disease.The especially medicine of non-small cell lung cancer
Object.
Wherein, pharmaceutical salt can be inorganic acid salt or acylate, such as inorganic acid salt can be selected from hydrochloride, hydrogen
Bromate, hydriodate, sulfate, disulfate, nitrate, phosphate, acid phosphate；Acylate can be selected from formic acid
Salt, acetate, trifluoroacetate, propionate, acetonate, oxyacetate, oxalate, malonate, fumarate, horse
Come hydrochlorate, lactate, malate, citrate, tartrate, mesylate, esilate, benzene sulfonate, salicylic acid
Salt, picrate, glutamate, ascorbate, camphor hydrochlorate, camsilate.
A kind of pharmaceutical composition, it includes:
Pharmaceutically acceptable carrier；
And
Above-described compound or its tautomer or its mesomer, racemic modification and mesomer and outer
The mixing of the mixture of raceme or its enantiomter, diastereoisomer and enantiomter and diastereoisomer
Object or its pharmaceutical salt or its crystal form, hydrate or solvate, prodrug or isotopic variations.
Above-described compound or its tautomer or its mesomer, racemic modification and mesomer and outer
The mixing of the mixture of raceme or its enantiomter, diastereoisomer and enantiomter and diastereoisomer
The purposes of object or its pharmaceutical salt is used to prepare treating cancer, pain, neurological disease, autoimmune disease or inflammation
Purposes in terms of drug.The cancer includes but is not limited to: lung cancer, head and neck cancer, breast cancer, prostate cancer, cancer of the esophagus,
The carcinoma of the rectum, colon cancer, nasopharyngeal carcinoma, uterine cancer, cancer of pancreas, lymthoma, leukemia, osteosarcoma, melanoma, kidney, gastric cancer, liver
Cancer, bladder cancer, thyroid cancer or colorectal cancer.
Above-described compound or its tautomer or its mesomer, racemic modification and mesomer and outer
The mixing of the mixture of raceme or its enantiomter, diastereoisomer and enantiomter and diastereoisomer
The purposes of object or its pharmaceutical salt is used to prepare the purposes in terms of the drug for inhibiting cell Proliferation.
Above-described compound or its tautomer or its mesomer, racemic modification and mesomer and outer
The mixing of the mixture of raceme or its enantiomter, diastereoisomer and enantiomter and diastereoisomer
The purposes of object or its pharmaceutical salt is used to prepare the purposes in terms of the drug for the treatment of cancer.
Above-described compound or its tautomer or its mesomer, racemic modification and mesomer and outer
The mixing of the mixture of raceme or its enantiomter, diastereoisomer and enantiomter and diastereoisomer
The purposes of object or its pharmaceutical salt is used to prepare the purposes in terms of the drug for inhibiting ALK, ROS1 and/or TRK kinases.
Above-described compound or its tautomer or its mesomer, racemic modification and mesomer and outer
The mixing of the mixture of raceme or its enantiomter, diastereoisomer and enantiomter and diastereoisomer
The purposes of object or its pharmaceutical salt is used to prepare the purposes in terms of the drug for the treatment of non-small cell lung cancer.
Unless stated otherwise, otherwise the following term used in the application (including specification and claims) has
Definition given below.
" alkyl " refers to that the monovalent straight chain containing 1 to 12 carbon atom or branch that are only made of carbon and hydrogen atom are satisfied
And hydrocarbyl group." alkyl " is preferably the alkyl group of 1 to 6 carbon atom, i.e. C1-C6Alkyl, more preferably C1-C4Alkyl.Alkane
The example of base group include but is not limited to methyl, ethyl, propyl, isopropyl, isobutyl group, sec-butyl, tert-butyl, amyl, just oneself
Base, octyl, dodecyl etc..
" alkoxy " refers to formula-OR group, and wherein R is alkyl group as defined herein.The example of alkoxy base
Including but not limited to methoxyl group, ethyoxyl, isopropoxy, tert-butoxy etc..
" halogen (halogenated) " refers to fluorine, chlorine, bromine or iodine substituent group.
It is as defined herein that " halogenated alkyl " refers to that wherein one or more hydrogen are replaced by identical or different halogen
Alkyl.The example of halogenated alkyl includes-CH2Cl、-CH2CF3、-CH2CCl3, perfluoroalkyl is (for example,-CF3) etc..
" halogenated alkoxy " refers to formula-OR group, and wherein R is halogenated alkyl group as defined herein.Haloalkoxy
The example of base group includes but is not limited to trifluoromethoxy, difluoro-methoxy, 2,2,2- trifluoro ethoxy etc..
" naphthenic base " refers to the monovalent saturated carbon ring group being made of mono- or two rings, with 3-12, preferably 3-
10, more preferable 3-6 annular atom.Naphthenic base can be optionally replaced one or more substituent groups, wherein each substituent group
It independently is hydroxyl, alkyl, alkoxy, halogen, halogenated alkyl, amino, alkyl monosubstituted amino or dialkyl amido.Naphthenic base base
The example of group includes but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc..
" cycloalkyloxy " refers to formula-OR group, and wherein R is naphthenic base as herein defined.Illustrative naphthenic base
Oxygroup includes cyclopropyl oxygroup, cyclobutyl oxygroup, cyclopentyloxy, cyclohexyl oxygroup etc..
" acyl group " refers to formula-C (O) R group, and wherein R is alkyl as herein defined.Illustratively acyl group includes
Acetyl group, positive propiono, iso-propionyl, positive bytyry, isobutyryl, tertiary bytyry etc..
Ester group refers to the group of formula-C (O) OR, and wherein R is alkyl as herein defined.Illustrative ester group includes-C
(O) OMe ,-C (O) OEt etc..
" alkylthio group " refers to formula-SRa group, and wherein Ra is H or alkyl as herein defined.
" alkylamino " refers to formula-NRaRb group, and wherein Ra is H or alkyl as herein defined, and Rb is as herein
Defined alkyl.
" naphthene amino " refers to formula-NRaRb group, wherein Ra be H, alkyl as herein defined or such as this paper institute
The naphthenic base of definition, Rb are naphthenic base as herein defined.
" heteroaryl " refers to the monocyclic, bicyclic or tricyclic group of 5 to 12 annular atoms, contain at least 1 comprising 1,
2 or 3 ring hetero atom, remaining annular atoms selected from N, O or S are the aromatic rings of C, it should be apparent that ground is the tie point of heteroaryl
It should be located on aromatic ring.The preferably specific 5-8 annular atom of heteroaryl more preferably has 5-6 annular atom.Heteroaryl groups
Example includes but is not limited to: imidazole radicals,It is oxazolyl, differentOxazolyl, thiazolyl, isothiazolyl,Di azoly, thiadiazolyl group, pyrrole
Piperazine base, thienyl, furyl, pyranose, pyridyl group, pyrrole radicals, pyrazolyl, pyrimidine radicals, quinolyl, isoquinolyl, benzo furan
It mutters base, benzofuranyl, benzothienyl, benzothiopyran derivative base, benzimidazolyl, benzoOxazolyl, benzoDi azoly, benzene
Benzothiazolyl, diazosulfide base, benzopyranyl, indyl, isoindolyl, triazolyl, triazine radical, quinoxalinyl, purine
Base, quinazolyl, quinazinyl, naphthyridines base, pteridyl, carbazyl, azepineBase, diazaBase, acridinyl etc..
Solvate mentioned in the present invention refers to the compound of the present invention and the complex that solvent is formed.They or
Person reacts in a solvent or Precipitation or crystallizes out from solvent.For example, being known as being hydrated with the complex that water is formed
Object；Other further include alcohol adduct, ketone conjunction object etc..Solvate of the present invention includes change shown in I-formula of formula VIII
Close the solvate of object and its salt, stereoisomer.
Stereoisomer mentioned by the present invention refers to that I-formula of Chinese style, VIII compound represented of the present invention can be containing one
Or multiple chiral centers, and exist with different optical active forms.When compound contains a chiral centre, compound
Include enantiomter.The present invention includes the mixture of both isomers and isomers, such as racemic mixture.Mapping is different
Structure body can be split by methods known in the art, such as the methods of crystallization and chiral chromatogram.When I-formula of formula, VIII institute
When the compound shown contains more than one chiral center, may exist non-corresponding isomers.Stereoisomer of the invention includes
The mixture of the optically pure specific isomers split and non-corresponding isomers.Diastereoisomer can be by this technology
Art-known methods are split, such as crystallization and preparation chromatography.
Prodrug mentioned by the present invention refers to including known amino protecting group and carboxyl-protecting group, in physiological conditions
Parent compound that is hydrolyzed or being discharged via enzyme reaction.Medicament preparation can refer to the prior art before specific
(Saulnier, M.G.；Frennesson, D.B.；Deshpande, M.S.；Hansel, S.B and Vysa,
D.M.Bioorg.Med.ChemLett.1994,4,1985-1990；And Greenwald, R.B.；Choe, Y.H.；Conover,
C.D.；Shum, K.；Wu, D.；Royzen, M.J.Med.Chem.2000,43,475.).
I-formula of formula, VIII compound represented of the invention, the compound can effectively inhibit ALK, ROS1 and/or TRK to swash
The activity of enzyme.It can be used as ALK/ROS1/TRK kinase inhibitor, treat ALK/ROS1/TRK related disease.It is especially non-small thin
The therapeutic agent of born of the same parents' lung cancer.
It can be by compound shown in I-formula of formula VIII of the invention or its pharmaceutically acceptable salt, stereoisomer, solvent
Compound or prodrug are made suitable dosage form with one or more pharmaceutical carriers and apply.These dosage forms include being suitable for taking orally, being straight
Enteral administration, local administration are administered in mouth and those of other parenteral routes application (for example, subcutaneous, muscle, vein etc.).
Pharmaceutical composition of the invention can be prepared in a manner of meeting medical practice specification, quantitative and administration.Giving
Close object " effective quantity " by specific illness to be treated, the individual for the treatment of, the cause of illness, drug target spot and give prescription
The factors such as formula determine.
The pharmaceutical composition also contains other therapeutic agent, and therapeutic agent in addition is cancer, cardiovascular disease
Disease, inflammation, infection, immunity disease, cell proliferation disorders, viral disease, metabolic disease or the medicine of organ transplant
Object.
Specific embodiment
Further description of the technical solution of the present invention combined with specific embodiments below, but protection model of the invention
It encloses without being limited thereto.
Embodiment 1
Target compound:
Synthetic route are as follows:
Specific synthesis process
The synthesis of compound 2
Nitrogen atmosphere, is stirred at room temperature down, by tetraethyl titanate (24g, 84mmol) be added drop-wise to compound 1 (5.0g,
32.4mmol) and in methylene chloride (150mL) solution of R- t-butyl sulfonamide (3.9g, 32.4mmol), after being added dropwise
It is stirred overnight at room temperature, adds water (100mL) quenching reaction, diatomite filtering, and wash filter cake with methylene chloride (300mL), point
Liquid, and water phase is extracted with dichloromethane, merge organic phase, anhydrous magnesium sulfate is dry, and silica gel column chromatography (PE:EA=1:1) obtains
To 2.8g yellow solid.
Characterize data:1H NMR (400MHz, CDCl3): δ 12.78 (s, 1H), 7.32 (dd, J=3.2,9.6Hz, 1H),
7.26 (m, 1H), 6.93 (dd, J=3.2,9.6Hz, 1H), 2.79 (s, 3H), 1.34 (s, 9H). MS m/z(ESI):258.1
[M+H]+。
The synthesis of compound 3
Compound 2 (9g, 35mmol) is dissolved in anhydrous tetrahydro furan (50mL), under nitrogen protection, is cooled to -50
DEG C, NaBD is added in batches4(4.5g, 105mmol) is warmed to room temperature after adding, and is stirred 2 hours, sample point TLC plate, raw material disappears
It loses, is added water (50mL), ethyl acetate (100mL*3) extraction merges organic phase, and anhydrous magnesium sulfate is dry, concentration, silicagel column
Chromatography (PE:EA=2:1) obtains 7.5g yellow solid, deuterated rate 97%.
Characterize data:1H NMR (400MHz, CDCl3): δ 9.05 (s, 1H), 6.77 (dd, J=3.2,8.8Hz, 1H),
6.56 (m, 1H), 6.42 (dd, J=3.2,8.8Hz, 1H), 5.01 (s, 1H), 1.50 (s, 3H), 1.26 (s, 9H).MS m/z
(ESI):261.1[M+H]+。
The synthesis of compound 4
At room temperature, by the hydrochloric acid Isosorbide-5-Nitrae of saturation-dioxane solution (20mL) be slowly added into compound 3 (7.5g,
In methylene chloride (100mL) solution 28.8mmol), be stirred at room temperature 2 hours, raw material disappears, remove solution, to residue plus
Enter ether, stirs 10 minutes, 5.2g gray solid is obtained by filtration.
Characterize data:1H NMR (400MHz, DMSO-d6): δ 10.19 (br s, 1H), 8.42 (br s, 3H), 7.29 (d,
J=3.2,9.6Hz, 1H), 7.01 (m, 1H), 6.92 (m, 1H), 1.45 (s, 3H).MS m/z(ESI):157.1[M+H]+。
The synthesis of compound 6
Under nitrogen protection, room temperature by cesium carbonate (65.7g, 202mmol) be added to compound 5 (15g, 108mmol) and
In the n,N-Dimethylformamide solution of 3- ethoxy ethyl acrylate (29.2g, 203mmol), 110 DEG C of stirring 8h are warming up to,
TLC (PE:EA=1:1) shows that compound 5 disappears.Reaction solution is cooled to room temperature, diatomite filtering, filter cake ethyl acetate
(200mL) is rinsed, and revolving removes most of ethyl acetate, water (200mL) is added in raffinate, and be adjusted to pH=4 with acetic acid,
There is solid precipitation, filter and is dried to obtain white solid 6 (17g, 85%).
Characterize data:1H NMR (400MHz, DMSO-d6): δ 8.54 (d, J=8.0Hz, 1H), 8.12 (s, 1H), 6.13
(d, J=8.0Hz, 1H), 4.27 (q, J=7.2Hz, 2H), 1.28 (t, J=7.2Hz, 3H).MS m/z(ESI):208.1 [M+
H]+。
The synthesis of compound 7
Under nitrogen protection, phosphorus oxychloride (58g, 380mmol) is added to compound 6 (16g, 76mmol) in room temperature
In acetonitrile solution, it is warming up to 100 DEG C of stirring 2h, TLC (PE:EA=1:1) and shows that compound 6 disappears.Reaction solution is cooled to room
Temperature imports in trash ice, stirs 20 minutes, and ethyl acetate extraction, anhydrous magnesium sulfate dries, filters, and is concentrated, and silica gel column chromatography obtains
To white solid 7 (10g, 62%).
Characterize data:1H NMR (400MHz, DMSO-d6): δ 9.33 (d, J=7.2Hz, 1H), 8.66 (s, 1H), 7.41
(d, J=7.2Hz, 1H), 4.31 (q, J=7.2Hz, 2H), 1.32 (t, J=7.2Hz, 3H).MS m/z(ESI):226.1 [M+
H]+。
The synthesis of compound 8
Compound 4 (2g, 10.5mmol) and compound 7 (2.4g, 10.5mmol) are first added sequentially to n-butanol
In (50mL), diisopropylethylamine (10.8g, 84mmol) then is added, is warming up to 120 DEG C and is stirred overnight, TLC shows raw material
It disappears, n-butanol is removed under reduced pressure, water (50mL) is added into residue, extracted with ethyl acetate (50mL*3), merged organic
Phase, anhydrous magnesium sulfate dry, filter, and concentration, silica gel column chromatography (PE:EA=1:1) obtains white solid 8 (3.1g), deuterated rate
97%.
Characterize data:1H NMR (400MHz, CDCl3): δ 9.10 (br s, 1H), 8.25 (s, 1H), 8.16 (d, J=
7.6Hz, 1H), 6.94 (m, 1H), 6.94 (m, 1H), 6.84 (m, 1H), 6.08 (d, J=7.6Hz, 1H), 5.52 (br s,
1H), 4.43 (m, 2H), 1.42 (t, J=7.2Hz, 3H).MS m/z(ESI):346.1[M+H]+。
The synthesis of compound 9
First by compound 8 (2.5g, 7.2mmol) and compound (R) -1- (BOC- amino) -2- propyl alcohol (1.9g,
10.8mmol) be added sequentially to anhydrous methylene chloride (10mL), then be added toluene (50mL), heating concentration water removal, then plus
Enter anhydrous methylene chloride (50mL).Under nitrogen protection, triphenylphosphine is added, DEAD, this process is added dropwise to being completely dissolved in stirring
There is heat release.It after being added dropwise, is stirred overnight at room temperature, the sodium hydrate aqueous solution (30mL) of 2N, methylene chloride extraction is added
(50mL*3) merges organic phase, and anhydrous magnesium sulfate dries, filters, and is concentrated, and silica gel column chromatography (PE:EA=5:1) obtains white
Solid 9 (1.8g).80% purity is directly used in next step.MS m/z(ESI):503.1[M+H]+。
The synthesis of compound 10
First crude product compound 9 (2.6g) obtained in the previous step is dissolved in methanol/tetrahydrofuran (60mL/20mL),
Then the lithium hydroxide aqueous solution (20mL) of 2N is added, is warming up to 70 DEG C and is stirred overnight, point TLC plate shows that raw material 9 disappears, will
Solution is spin-dried for, and modulates pH=5 with the aqueous hydrochloric acid solution of 2N, and methylene chloride extracts (50mL*3), merges organic phase, anhydrous slufuric acid
Magnesium dries, filters, and concentration, silica gel column chromatography (PE:EA=2:1) obtains white solid 10 (1.8g).90% purity is directly used
In in next step.MS m/z(ESI):475.2[M+H]+。
The synthesis of compound 11
First crude product compound 10 (1.8g) obtained in the previous step is dissolved into methylene chloride (100mL), at room temperature,
The hydrochloric acid Isosorbide-5-Nitrae of saturation-dioxane solution (20mL) is slowly added to, is stirred at room temperature 2 hours, raw material disappears, solution is removed,
Ether is added to residue, stirs 10 minutes, 1.2g gray solid is obtained by filtration.95% purity is directly used in next step.MS
m/z(ESI):375.1[M+H]+。
The synthesis of target compound TRN020201
Under nitrogen protection, the DMF solution (3mL) of compound 11 (200mg, 0.42mmol) is added to diisopropyl second
In the mixed solution of the DMF (6mL) and DCM (14mL) of amine (426mg, 3.3mmol), then be added FDPP (169mg,
0.44mmol), it is stirred at room temperature 2 hours, the aqueous sodium carbonate (10mL) of 2N, methylene chloride extraction, nothing is added into reaction solution
Water magnesium sulfate dries, filters, and concentration, silica gel column chromatography (DCM:MeOH=20:1) obtains white solid TRN020201
(108mg)。
Characterize data:1H NMR (400MHz, DMSO-d6): δ 9.81 (d, J=6.4Hz, 1H), 8.81 (s, 1H), 8.57
(d, J=7.6Hz, 1H), 8.04 (s, 1H), 7.14 (d, J=3.2,9.6Hz, 1H), 6.98 (m, 2H), 6.36 (d, J=
7.6Hz, 1H), 4.48 (m, 1H), 3.90 (m, 1H), 3.13 (m, 1H), 1.45 (m, 6H).LC-MS m/z(ESI):357.1
[M+H]+。
Embodiment 2
Target compound:
The synthesis of 2 target compound of embodiment, referring to embodiment 1, difference is, by the change in 9 synthesis step of compound
Close the replacement of object (R) -1- (BOC- amino) -2- propyl alcohol are as follows:
2 target compound of embodiment: MS m/z (ESI): 383.1 [M+H]+。
Embodiment 3
Target compound:
The synthesis of 3 target compound of embodiment, referring to embodiment 1, difference is, by the change in 9 synthesis step of compound
Close the replacement of object (R) -1- (BOC- amino) -2- propyl alcohol are as follows:
3 target compound of embodiment: MS m/z (ESI): 369.2 [M+H]+。
Embodiment 4
Target compound:
The synthesis of 4 target compound of embodiment, referring to embodiment 1, difference is, by the change in 9 synthesis step of compound
Close the replacement of object (R) -1- (BOC- amino) -2- propyl alcohol are as follows:
4 target compound of embodiment: MS m/z (ESI): 397.2 [M+H]+。
Embodiment 5
Target compound:
The synthesis of 5 target compound of embodiment, referring to embodiment 1, difference is, by the change in 9 synthesis step of compound
Close the replacement of object (R) -1- (BOC- amino) -2- propyl alcohol are as follows:
5 target compound of embodiment: MS m/z (ESI): 411.2 [M+H]+。
The particular compound of synthesis includes following compound:
The measurement of effect experimental examples bioactivity
Target compound is detected under ATP Km concentration using Caliper Mobility Shift Assay method
Activity of the TRN020201 to anaplastic lymphoma kinase (ALK).Caliper Mobility Shift Assay method is
The mobility detection technique (Mobility-Shift Assay) of Caliper company.
Leaching is denaturalized between detecting each compound pair under Km concentration using Caliper Mobility Shift Assay method
The external activity of bar tumor kinases (ALK), and reference substance is made using staurosporine (Staurosporine), the biology of compound is living
Property screening will under 10 concentration replication.
Experimental material:
Anaplastic lymphoma kinase (ALK) (Carna, Cat.No.08-105, Lot.No.08CBS-0112)；
Peptide FAM-P22 (GL Biochem, Cat.No.112393, Lot.No.P080401-XY112393)；
ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)；
DMSO(Sigma,Cat.No.D2650,Lot.No.474382)；
EDTA(Sigma,Cat.No.E5134,CAS No.60-00-4)；
The hole 96- test panel (Corning company, Cat.3365, Lot.No.22008026)；
The hole 384- test panel (Corning company, Cat.3573, Lot.No.12608008)；
Staurosporine (Staurosporine) (Sigma, Cat.No.S4400-1MG, Lot.No.046K4080).
Given the test agent
Each sample is made into the solution that concentration is 10mM respectively.
Experimental method
One, prepare the basic buffer solution of kinases of 1.25x for experiment kinases and buffer solution is quenched
1, manganous chloride (MnCl is free of2) the basic buffer solution of 1.25x kinases
HEPES solution of the concentration for 62.5mM, pH=7.5,
The Brij-35 that concentration is 0.001875%,
Concentration is the magnesium dichloride (MgCl of 12.5mM2) solution,
Concentration is the DTT solution of 2.5mM；
2, (the MnCl containing manganous chloride2) the basic buffer solution of 1.25x kinases
HEPES solution of the concentration for 62.5mM, pH=7.5,
The Brij-35 that concentration is 0.001875%,
Concentration is the magnesium dichloride (MgCl of 12.5mM2) solution,
Concentration is the manganous chloride (MnCl of 12.5mM2) solution,
Concentration is the DTT solution of 2.5mM；
3, buffer solution is quenched
HEPES solution of the concentration for 100mM, pH=7.5,
The Brij-35 that concentration is 0.015%,
No. 3 surface reagents that concentration is 0.2%,
Concentration is the EDTA solution of 50mM.
Two, prepare compound for experiment kinases
(continuous) dilution of series of compounds
1, it draws the compound solution that 5 microlitres of concentration are 10mM to be transferred in test tube, adds 95 microlitres of DMSO, being diluted to
Closing object concentration is 500 μM；
2, by the compound in test tube be transferred to the hole 96- storage disk in a wherein hole, will wherein 30 μ L be transferred to it is next
In a adjacent holes, and add the DMSO dilution of 60 μ L, serial dilution in this approach obtains 10 of concentration from 500 μM to 0.025 μM
A compound solution；
3, in the test board in the same hole 96-, the DMSO of 60 μ L is all added in each round, does DMSO control；
4, from taking 5 μ L solution to be transferred in the test panel in another 96 hole in each hole, and add the H of 45 μ L2O；
5, the EDTA for shifting 70 μ L 250mM makees low control；
6,5 μ L is taken to be transferred in the hole 384- analysis disk in each hole；A1 in 96- porose disc containing low control is shifted
To the A1 and A2 in 384- porose disc, the A2 of the compound concentration containing highest in 96- porose disc is transferred to the A3 and A4 of 384- porose disc, with
This analogizes.
In this way, just the 10%DMSO solution containing 5x compound, the initial concentration of compound are 50 μ in this analysis disk
M。
Three, kinase reaction
1, prepare 2.5x enzyme solutions
Kinases is added to the basic buffer solution of kinases of 1.25x；
2, prepare 2.5x peptide solution
The peptide of FAM- label and ATP are added to the basic buffer solution of kinases of 1.25x；
3,2.5x kinase solution is transferred in analysis disk
Has the 10%DMSO solution of the compound of 5 μ L in analysis disk now；
Add 10 μ L 2.5x enzyme solutions into each hole of the hole 384- analysis disk；
Hatch 10 minutes at room temperature；
4,2.5x peptide solution is transferred in analysis disk
Add 10 μ L 2.5x peptide solutions into each hole of the hole 384- analysis disk；
5, it enzyme reaction and is quenched
Hatch certain time at 28 DEG C, is 1 hour in this experiment；
Add 25 μ L that buffer solution is quenched to stop reacting；
6, Caliper reads data
Caliper collects data；
7, curve matching
Data are copied from Caliper；
Conversion values are changed into inhibiting value:
Inhibit percentage=(maximum value-conversion values)/(maximum value-minimum value) * 100,
Wherein, maximum value represents DMSO control (DMSO control)；Minimum value represents low control (low control)；
Fitting data is in Xlfit to obtain IC50Value
Use following equation:
Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X)*HillSlope))。
Inhibitory activity IC of the obtained given the test agent to anaplastic lymphoma kinase (ALK)50(nM) value is as shown in the table:
| Compound ID | Top Conc.(uM) | ALK IC50(nM) |
| Staurosporine | 1 | 14.42 |
| TPX-0005 | 10 | 14.64 |
| 1 target compound of embodiment | 10 | 7.90 |
| 2 target compound of embodiment | 10 | 1.01 |
| 3 target compound of embodiment | 10 | 7.80 |
| 4 target compound of embodiment | 10 | 8.92 |
| 5 target compound of embodiment | 10 | 25.63 |
As can be known from the above table, it is screened by Bioactivity, using Staurosporine and TPX-0005 as reference substance.With
Reference substance is compared, the compound synthesized by us, is become between showing pair such as embodiment 1, embodiment 2, embodiment 3 and embodiment 4
Property lymphom kinase (ALK) has better rejection ability.
Through detecting, the compound of the present invention can also effectively inhibit the activity of ROS1 and TRK kinases.
Pharmacokinetics in rats experiment
Experiment purpose: after research rat gives the compound of experiment, pharmacokinetics behavior.
Experimental animal: SD rat grade, SPF grades.
Animal Sex, that is, quantity: male, 18.
Weight range: 180-250 grams.
Source: Shanghai western Poole-Bi Kai experimental animal Co., Ltd.
Experimentation:
(1) animal dosage: each compound IV (intravenously administrable) dosage is 2mg, and PO (oral administration) dosage is
10mg。
(2) sample acquisition and processing:
It takes a blood sample through jugular puncture, each sample acquires about 0.25mL, and EDTA-K2 is anticoagulant, places on ice after acquisition.It adopts
Blood time point is as follows:
IV: before administration, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h after administration, for 24 hours.
PO: before administration, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h after administration, for 24 hours.
Blood specimen collection is placed on ice, and centrifugal separation plasma (centrifugal condition: 8000 revs/min, 6 minutes, 2-8
℃).- 80 DEG C of refrigerators are deposited in front of the plasma analysis of collection.
(3) pharmacokinetic analysis:
According to the plasma drug concentration data of drug, with Phoenix7.0 calculate pharmacokinetic parameter,
Parameters and its average and standard deviations such as AUC (0-t), AUC (0- ∞), MRT (0- ∞), Cmax, Tmax and t1/2 are provided.
It is lower than the sample of lower limit of quantitation for concentration, when carrying out pharmacokinetic parameter calculating, with no standard measure
(BLQ) it calculates.
Experiment shows and (see the table below) that the compound of the present invention has better pharmacokinetics than control sample TPX-0005
Matter.
The PK parameter comparison table of embodiment compound and TPX-0005 control sample
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Equivalent transformation made by bright description, is applied directly or indirectly in other relevant technical fields, and is included in this hair
In bright scope of patent protection.
Claims (20)
1. I compound represented of formula or its tautomer or its mesomer, racemic modification and mesomer and racemic
The mixture of the mixture of body or its enantiomter, diastereoisomer and enantiomter and diastereoisomer or its
Pharmaceutical salt:
In formula I:
M1Selected from CR9Or N；
M2Selected from CR10Or N；
X1、X2And X3It is independently selected from O, S, NR11, S (O) or S (O)2；
W is selected from C (O), S (O), C (S) or S (O)2；
Z1、Z2、Z3、Z4、Z5、Z6And Z7It is independently selected from N, NH or CR11, and Z1、Z2、Z3、Z4、Z5、Z6And Z7In at least one
For N or NH；
R1、R2、R9、R10And R11It is independently selected from H, deuterium, halogen, alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkane
Oxygroup, halogenated alkoxy, hydroxyl, cyano, amino, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl,
Phosphono,The wherein alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkoxy, halogen
It can be taken for the H in alkoxy, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, phosphono with coverlet
In generation, is polysubstituted, and substituent group is selected from fluorine, chlorine, bromine, amino, acetyl group, cyano, carboxyl, sulfonyl, phosphono, C1‐6Alcoxyl
Base, C1‐4Alkyl, C3‐6Naphthenic base, fluoro-alkyl, single fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, trifluoroethoxy
Base, deuterated single fluorine methoxyl group or deuterated difluoro-methoxy；
R3、R4、R5、R6、R7And R8Be independently selected from H, deuterium, halogen, alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl,
Alkoxy, halogenated alkoxy, hydroxyl, cyano, amino, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl, sulphonyl
Base, phosphono,Wherein the alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkoxy,
Halogenated alkoxy, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, the H in phosphono can be with coverlets
Replace or polysubstituted, substituent group is selected from fluorine, chlorine, bromine, amino, acetyl group, cyano, carboxyl, sulfonyl, phosphono, C1‐6Alcoxyl
Base, C1‐4Alkyl, C3‐6Naphthenic base, fluoro-alkyl, single fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, trifluoroethoxy
Base, deuterated single fluorine methoxyl group or deuterated difluoro-methoxy；
R12And R13It is independently selected from alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, aryl or heteroaryl；
M is 1 or 2；
N is 1 or 2.
2. II compound represented of formula or its tautomer or its mesomer, racemic modification and mesomer and racemic
The mixture of the mixture of body or its enantiomter, diastereoisomer and enantiomter and diastereoisomer or its
Pharmaceutical salt:
In formula II:
A is 3~8 member rings, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、R6、R7、R8, m, n such as institute in claim 1
Definition.
3. III compound represented of formula or its tautomer or its mesomer, racemic modification and mesomer and racemic
The mixture of the mixture of body or its enantiomter, diastereoisomer and enantiomter and diastereoisomer or its
Pharmaceutical salt:
In formula III:
B is 3~8 member rings, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、R6、R7、R8, m, n such as institute in claim 1
Definition.
4. IV compound represented of formula or its tautomer or its mesomer, racemic modification and mesomer and racemic
The mixture of the mixture of body or its enantiomter, diastereoisomer and enantiomter and diastereoisomer or its
Pharmaceutical salt:
In formula IV:
C is 3~8 member rings, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、R6、R7、R8, m, n such as institute in claim 1
Definition.
5. V compound represented of formula or its tautomer or its mesomer, racemic modification and mesomer and racemic
The mixture of the mixture of body or its enantiomter, diastereoisomer and enantiomter and diastereoisomer or its
Pharmaceutical salt:
In formula V:
A, it is 3~8 member rings that B is independent, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、R6、R7、R8, m, n such as institute in claim 1
Definition.
6. VI compound represented of formula or its tautomer or its mesomer, racemic modification and mesomer and racemic
The mixture of the mixture of body or its enantiomter, diastereoisomer and enantiomter and diastereoisomer or its
Pharmaceutical salt:
In formula VI:
B, it is 3~8 member rings that C is independent, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、R6、R7、R8, m, n such as institute in claim 1
Definition.
7. VII compound represented of formula or its tautomer or its mesomer, racemic modification and mesomer and racemic
The mixture of the mixture of body or its enantiomter, diastereoisomer and enantiomter and diastereoisomer or its
Pharmaceutical salt:
In formula VII:
A, it is 3~8 member rings that C is independent, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、R6、R7、R8, m, n such as institute in claim 1
Definition.
8. VIII compound represented of formula or its tautomer or its mesomer, racemic modification and mesomer and racemic
The mixture of the mixture of body or its enantiomter, diastereoisomer and enantiomter and diastereoisomer or its
Pharmaceutical salt:
In formula VIII:
A, it is 3~8 member rings that B, C are independent, wherein the ring is selected from carbocyclic ring or heterocycle；
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、R6、R7、R8, m, n such as institute in claim 1
Definition.
9. according to claim 1-the 8 any compounds or its tautomer or its mesomer, racemic modification and
The mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric different
The mixture of structure body or its pharmaceutical salt, which is characterized in that R1Selected from deuterium, halogen, alkyl, halogenated alkyl, naphthenic base, halogen
It is substituted naphthene base, alkoxy, halogenated alkoxy, hydroxyl, cyano, amino, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, miscellaneous
Aryl, sulfonyl, phosphono,The wherein alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkanes
Base, alkoxy, halogenated alkoxy, alkylamino, acyl group, ester group, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, phosphono,In H can be mono-substituted or polysubstituted, substituent group is selected from fluorine, chlorine, bromine, amino, acetyl group, cyanogen
Base, carboxyl, sulfonyl, phosphono, C1‐6Alkoxy, C1‐4Alkyl, C3‐6Naphthenic base, fluoro-alkyl, single fluorine methoxyl group,
Difluoro-methoxy, trifluoromethoxy, trifluoro ethoxy, deuterated single fluorine methoxyl group or deuterated difluoro-methoxy.
10. according to claim 1, any compound or its tautomer or its mesomer in 3,4,6, disappear outside
Revolve the mixture or its enantiomter, diastereoisomer and enantiomter of body and mesomer and racemic modification and non-
The mixture of enantiomter or its pharmaceutical salt, which is characterized in that R3For deuterium.
11. according to claim 1, any compound or its tautomer or its mesomer in 2,4,7, disappear outside
Revolve the mixture or its enantiomter, diastereoisomer and enantiomter of body and mesomer and racemic modification and non-
The mixture of enantiomter or its pharmaceutical salt, which is characterized in that R5For deuterium.
12. compound according to claim 1 or 4 or its tautomer or its mesomer, racemic modification and interior
The mixture or its enantiomter, diastereoisomer and enantiomter and diastereo-isomerism of raceme and racemic modification
The mixture of body or its pharmaceutical salt, which is characterized in that R3、R5It is deuterium.
13. a kind of compound as protein kinase regulator or its tautomer or its mesomer, racemic modification
And the mixture or its enantiomter, diastereoisomer and enantiomter of mesomer and racemic modification and diastereomeric
The mixture of isomers or its pharmaceutical salt, which is characterized in that the compound is selected from following any particular compound:
14. -8, the 13 any compound or its tautomer or its mesomer, racemic according to claim 1
The mixture or its enantiomter, diastereoisomer and enantiomter of body and mesomer and racemic modification and non-right
Reflect the mixture or its pharmaceutical salt of isomers, which is characterized in that the pharmaceutical salt is inorganic acid salt or organic acid
Salt, the inorganic acid salt are selected from hydrochloride, hydrobromate, hydriodate, sulfate, disulfate, nitrate, phosphate, acid
Acid phosphate；The acylate is selected from formates, acetate, trifluoroacetate, propionate, acetonate, oxyacetate, second
Diacid salt, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, mesylate,
Esilate, benzene sulfonate, salicylate, picrate, glutamate, ascorbate, camphor hydrochlorate, camsilate.
15. a kind of pharmaceutical composition, which is characterized in that it includes:
Pharmaceutically acceptable carrier；
And
Compound of any of claims 1-13 or its tautomer or its mesomer, racemic modification and interior
The mixture or its enantiomter, diastereoisomer and enantiomter and diastereo-isomerism of raceme and racemic modification
The mixture of body or its pharmaceutical salt or its crystal form, hydrate or solvate, prodrug or isotopic variations.
16. it is a kind of such as compound of any of claims 1-13 or its tautomer or its mesomer, it is outer
The mixture or its enantiomter, diastereoisomer and enantiomter of raceme and mesomer and racemic modification and
The purposes of the mixture of diastereoisomer or its pharmaceutical salt, be used to prepare treating cancer, pain, neurological disease, itself
Purposes in terms of immunological diseases or the drug of inflammation.
17. it is a kind of such as compound of any of claims 1-13 or its tautomer or its mesomer, it is outer
The mixture or its enantiomter, diastereoisomer and enantiomter of raceme and mesomer and racemic modification and
The purposes of the mixture of diastereoisomer or its pharmaceutical salt is used to prepare the use in terms of the drug for inhibiting cell Proliferation
On the way.
18. it is a kind of such as compound of any of claims 1-13 or its tautomer or its mesomer, it is outer
The mixture or its enantiomter, diastereoisomer and enantiomter of raceme and mesomer and racemic modification and
The purposes of the mixture of diastereoisomer or its pharmaceutical salt is used to prepare the purposes in terms of the drug for the treatment of cancer.
19. it is a kind of such as compound of any of claims 1-13 or its tautomer or its mesomer, it is outer
The mixture or its enantiomter, diastereoisomer and enantiomter of raceme and mesomer and racemic modification and
The purposes of the mixture of diastereoisomer or its pharmaceutical salt is used to prepare and inhibits ALK, ROS1 and/or TRK kinases
Purposes in terms of drug.
20. it is a kind of such as compound of any of claims 1-13 or its tautomer or its mesomer, it is outer
The mixture or its enantiomter, diastereoisomer and enantiomter of raceme and mesomer and racemic modification and
The purposes of the mixture of diastereoisomer or its pharmaceutical salt is used to prepare the drug aspect for the treatment of non-small cell lung cancer
Purposes.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711060594 | 2017-11-01 | ||
| CN2017110605945 | 2017-11-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109516999A true CN109516999A (en) | 2019-03-26 |
| CN109516999B CN109516999B (en) | 2021-08-17 |
Family
ID=65773018
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811283367.3A Active CN109516999B (en) | 2017-11-01 | 2018-10-31 | Compounds useful as protein kinase modulators and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109516999B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111971287A (en) * | 2018-03-28 | 2020-11-20 | 重庆复创医药研究有限公司 | Macrocyclic compounds as TRK kinase inhibitors |
| CN112110938A (en) * | 2019-06-21 | 2020-12-22 | 成都海博为药业有限公司 | Compound as protein kinase inhibitor and preparation method and application thereof |
| WO2021027503A1 (en) * | 2019-08-12 | 2021-02-18 | 罗欣药业(上海)有限公司 | Tricyclic compound, preparation method therefor, and intermediate and use thereof |
| WO2021042890A1 (en) * | 2019-09-04 | 2021-03-11 | 罗欣药业(上海)有限公司 | Heterocyclic compound and application thereof as trk kinase inhibitor |
| CN113527298A (en) * | 2020-04-17 | 2021-10-22 | 浙江海正药业股份有限公司 | Macrocyclic lactam derivative, preparation method and application thereof |
| CN113754682A (en) * | 2020-06-04 | 2021-12-07 | 成都倍特药业股份有限公司 | Compounds having macrocyclic structure and uses thereof |
| CN115368379A (en) * | 2021-05-18 | 2022-11-22 | 广州嘉越医药科技有限公司 | Crystal form of macrocyclic compound containing cyano substitution and preparation method thereof |
| CN115746023A (en) * | 2022-10-27 | 2023-03-07 | 复旦大学 | Indazole structure-containing heterocyclic macrocyclic compound as protein kinase inhibitor and preparation method thereof |
| WO2023078267A1 (en) * | 2021-11-02 | 2023-05-11 | 赛诺哈勃药业（成都）有限公司 | Amino-containing macrocyclic compound as protein kinase modulator |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102971322A (en) * | 2010-05-20 | 2013-03-13 | 阵列生物制药公司 | Macrocyclic compounds as TRK kinase inhibitors |
| CN106170289A (en) * | 2014-01-24 | 2016-11-30 | Tp生物医药公司 | The huge ring of diaryl as the regulator of protein kinase |
| WO2017004342A1 (en) * | 2015-07-02 | 2017-01-05 | Tp Therapeutics, Inc. | Chiral diaryl macrocycles as modulators of protein kinases |
| WO2017015367A1 (en) * | 2015-07-21 | 2017-01-26 | Tp Therapeutics, Inc. | Chiral diaryl macrocycles and uses thereof |
| CN109715165A (en) * | 2016-07-28 | 2019-05-03 | Tp生物医药公司 | Huge ring kinase inhibitor |
| CN111182903A (en) * | 2017-07-28 | 2020-05-19 | 特普医药公司 | Macrocyclic compounds and uses thereof |
-
2018
- 2018-10-31 CN CN201811283367.3A patent/CN109516999B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102971322A (en) * | 2010-05-20 | 2013-03-13 | 阵列生物制药公司 | Macrocyclic compounds as TRK kinase inhibitors |
| CN106170289A (en) * | 2014-01-24 | 2016-11-30 | Tp生物医药公司 | The huge ring of diaryl as the regulator of protein kinase |
| WO2017004342A1 (en) * | 2015-07-02 | 2017-01-05 | Tp Therapeutics, Inc. | Chiral diaryl macrocycles as modulators of protein kinases |
| WO2017015367A1 (en) * | 2015-07-21 | 2017-01-26 | Tp Therapeutics, Inc. | Chiral diaryl macrocycles and uses thereof |
| CN109715165A (en) * | 2016-07-28 | 2019-05-03 | Tp生物医药公司 | Huge ring kinase inhibitor |
| CN111182903A (en) * | 2017-07-28 | 2020-05-19 | 特普医药公司 | Macrocyclic compounds and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| SHUNPEI SATOH ET AL.: "Neuronalleucine-richrepeat1 negatively regulates anaplastic lymphoma kinase in neuroblastoma", 《SCIENTIFIC REPORTS》 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111971287A (en) * | 2018-03-28 | 2020-11-20 | 重庆复创医药研究有限公司 | Macrocyclic compounds as TRK kinase inhibitors |
| CN113773335A (en) * | 2019-06-21 | 2021-12-10 | 成都海博为药业有限公司 | Compound as protein kinase inhibitor and preparation method and application thereof |
| CN112110938A (en) * | 2019-06-21 | 2020-12-22 | 成都海博为药业有限公司 | Compound as protein kinase inhibitor and preparation method and application thereof |
| CN112110938B (en) * | 2019-06-21 | 2021-11-09 | 成都海博为药业有限公司 | Compound as protein kinase inhibitor and preparation method and application thereof |
| WO2021027503A1 (en) * | 2019-08-12 | 2021-02-18 | 罗欣药业(上海)有限公司 | Tricyclic compound, preparation method therefor, and intermediate and use thereof |
| WO2021042890A1 (en) * | 2019-09-04 | 2021-03-11 | 罗欣药业(上海)有限公司 | Heterocyclic compound and application thereof as trk kinase inhibitor |
| CN113527298A (en) * | 2020-04-17 | 2021-10-22 | 浙江海正药业股份有限公司 | Macrocyclic lactam derivative, preparation method and application thereof |
| CN113754682A (en) * | 2020-06-04 | 2021-12-07 | 成都倍特药业股份有限公司 | Compounds having macrocyclic structure and uses thereof |
| WO2021244609A1 (en) * | 2020-06-04 | 2021-12-09 | 成都倍特药业股份有限公司 | Compound having macrocyclic structure and use thereof |
| CN113754682B (en) * | 2020-06-04 | 2023-01-06 | 赛诺哈勃药业（成都）有限公司 | Compound having macrocyclic structure and use thereof |
| CN115368379A (en) * | 2021-05-18 | 2022-11-22 | 广州嘉越医药科技有限公司 | Crystal form of macrocyclic compound containing cyano substitution and preparation method thereof |
| WO2022242688A1 (en) * | 2021-05-18 | 2022-11-24 | 广州嘉越医药科技有限公司 | Crystal form of cyano-substituted macrocyclic compound and preparation method therefor |
| WO2023078267A1 (en) * | 2021-11-02 | 2023-05-11 | 赛诺哈勃药业（成都）有限公司 | Amino-containing macrocyclic compound as protein kinase modulator |
| CN115746023A (en) * | 2022-10-27 | 2023-03-07 | 复旦大学 | Indazole structure-containing heterocyclic macrocyclic compound as protein kinase inhibitor and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109516999B (en) | 2021-08-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109516999A (en) | Compound and its application as protein kinase regulator | |
| CN104640852B (en) | DNA-PK inhibitors | |
| CN105636958B (en) | DNA PK inhibitor | |
| CN105246883B (en) | DNA PK inhibitor | |
| EP3312180B1 (en) | Use of pteridinone derivative serving as egfr inhibitor | |
| CN108689994A (en) | Compound as ALK kinase inhibitors and its application | |
| CN105142641A (en) | Compounds for treatment of cancer | |
| JP7037483B2 (en) | Pyrimidone [1,2-a] pyrimidone analogs, their crystal forms, their intermediates, and methods of their manufacture. | |
| CN110483485A (en) | Pyrimidines, preparation method and medical usage | |
| CN105143208A (en) | Quinazolines as kinase inhibitors | |
| JP2019526605A (en) | Crystal form and salt form of substituted 2-H-pyrazole derivative and method for producing the same | |
| CN107531683A (en) | USP7 inhibitor compounds and application method | |
| CN106660970B (en) | Quinazoline derivatives | |
| EP3661935A1 (en) | Substituted pyrazolopyrimidines useful as kinases inhibitors | |
| CN112424202B (en) | Crystal forms of active compounds inhibiting CDK4/6 and uses thereof | |
| CN108463462A (en) | Benzene phenodiazine * classes are as bromine structural domain inhibitor | |
| CN103936762B (en) | Morpholine quinolines, Preparation Method And The Use | |
| CN110283162B (en) | Epidermal growth factor receptor inhibitor and application thereof | |
| TWI614251B (en) | Pyrazolo[4,3-c]quinoline derivatives inhibition β-glucuronidase | |
| CN104418867B (en) | As the compound of PI3K/mTOR inhibitor, Preparation Method And The Use | |
| CN103965175A (en) | 4-(substituted phenylamino)quinazoline compounds, and preparation method and application thereof | |
| CN114605391B (en) | Quinoxaline derivative, preparation method and application thereof | |
| CN109824690A (en) | Mcl-1 selective depressant and its preparation and use | |
| EP3632912B1 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
| US20210214351A1 (en) | Salt form |
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 |