CN108864080A - Four cyclics alternatively adjusted under property estrogen receptor and its application - Google Patents
Four cyclics alternatively adjusted under property estrogen receptor and its application Download PDFInfo
- Publication number
- CN108864080A CN108864080A CN201810429737.3A CN201810429737A CN108864080A CN 108864080 A CN108864080 A CN 108864080A CN 201810429737 A CN201810429737 A CN 201810429737A CN 108864080 A CN108864080 A CN 108864080A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- alkoxy
- amino
- base
- halogenated
- 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
- GBWBHBGSOAJATD-GVJKXQQXSA-N CC(C)(CN(C(CCC1)C1C(c1ccccc1C)=C1C)[C@@H]1c(c(OC)cc(/C=C/C(O)=O)c1)c1F)F Chemical compound CC(C)(CN(C(CCC1)C1C(c1ccccc1C)=C1C)[C@@H]1c(c(OC)cc(/C=C/C(O)=O)c1)c1F)F GBWBHBGSOAJATD-GVJKXQQXSA-N 0.000 description 1
- FMLWXUAHKAGQGV-HSXXWRGVSA-N CC(C)(CN(C(CCC1)C1c1c2[nH]c(cc3)c1cc3F)[C@@H]2c(c(F)cc(/C=C/C(O)=O)c1)c1F)F Chemical compound CC(C)(CN(C(CCC1)C1c1c2[nH]c(cc3)c1cc3F)[C@@H]2c(c(F)cc(/C=C/C(O)=O)c1)c1F)F FMLWXUAHKAGQGV-HSXXWRGVSA-N 0.000 description 1
- 0 CC(C)(CN(C1C2CCC1)[C@](c(c(F)cc(C=C*)c1)c1F)C(N)=C2c1ccccc1C)F Chemical compound CC(C)(CN(C1C2CCC1)[C@](c(c(F)cc(C=C*)c1)c1F)C(N)=C2c1ccccc1C)F 0.000 description 1
- PRIWGNGWIBCZSQ-UHFFFAOYSA-N CC(C)(CNC(CCC1)C1c1c[nH]c2c1cccc2)F Chemical compound CC(C)(CNC(CCC1)C1c1c[nH]c2c1cccc2)F PRIWGNGWIBCZSQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
-
- 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
-
- 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
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- 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
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Addiction (AREA)
- Immunology (AREA)
- Psychology (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Communicable Diseases (AREA)
- Gastroenterology & Hepatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to medicinal chemistry arts, it is related to four cyclics of regulator and its application under a kind of alternatively property estrogen receptor, specifically, the present invention provides Formulas I compound represented or its isomers, pharmaceutically acceptable salt, solvate, crystallization or prodrug, their preparation method and pharmaceutical composition containing these compounds and these compound or compositions are for treating and/or preventing the purposes of the relevant disease of estrogen receptor.The compound of the present invention has more excellent anti-tumor activity, promises to be very much breast cancer treatment agent.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to adjust under a kind of alternatively property estrogen receptor (SERD)
Compound or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug, their preparation side
Method and pharmaceutical composition containing these compounds and these compound or compositions for treat and/or prevent estrogen by
The purposes of the relevant disease of body.
Background technique
Estrogen receptor (Estrogen Receptor, ER) is the transcript regutation protein of ligand activation, it by with it is endogenous
Property estrogen interaction mediate the inductions of a variety of biological effects.Endogenous estrogen includes 17 beta estradiols and oestrone.?
It was found that there are two types of isotypes for ER tool:ER- α and ER- β, respectively by being located at No. 6 of people and two different bases of No. 14 chromosome
Because of coding, for ER- α in various tissue wide expressions, the expression of ER- β is limited only to the tissue such as female reproductive system and brain, bone.
The two includes 6 structural domains and 4 functional areas, and the functional areas A/B of N-terminal have the transcriptional activation function domain of non-ligand-dependent
AF-1, has that constitutively activated is active (constitutive activity), by with basal transcription factor, association's activity factor
The transcription to activate target gene is acted on other transcription factors, in addition there are many places phosphorylation sites.The DNA being made of the domain C
Binding domain (DBD) can be specifically incorporated on target DNA, and include nuclear localization signal, while also have dimerization interface,
It plays an important role to the dimerization of receptor.The domain D is hinge area, is responsible for connection DBD and aglucon binding domain (LBD).The domain C-terminal E
LBD is formed, which determines the specific binding of the ligands such as ER and estrogen, the transcriptional activation function domain AF- with ligand-dependent
2, and LBD also has very strong dimerization interface, remains to play a role in the case where no ligand, is that dimerization occurs for receptor
The key position of change.LBD is made of 12 α spirals and a β-pleated sheet, forms three layers of antiparallel sandwich structure, wherein
H5, H6, H9 and H10 form middle layer, and H1, H2, H3, H4 and H7, H8, H11 separately constitute two outside layers, and wherein H12 contains AF-
2, hydrophobic surface is towards ligand binding pocket, and water-wetted surface is outwardly.The LBD of ER is wedge shaped, and H12 is in ligand binding pocket
Groove in, and seal ligand binding pocket.When ER is in conjunction with agonist, this conformation of H12 is become more stable, and is suitable for association
The combination of activity factor, the then transcription of activation target gene.And when ER is in conjunction with antagonist, the position of H12 changes simultaneously
The binding site of association's activity factor is occupied, and then generates estrogen antagonism effect.
Drug research for targeting estrogen receptor has been carried out for many years, clinically achieves some successes, especially
It has recently found that adjusting under selective estrogen receptor has the anti-female hormone effect more reinforced, such as interference estrogen receptor
Stability simultaneously leads to its degradation.But, it is still desirable to develop under more estrogen receptor and adjust, especially selective estrogen
Receptor down-regulated agent, so that the drug has more excellent characteristic, such as curative effect is better, and less side effects, dosing interval is more
It is long etc., to be preferably applied to prevent or treat the relevant disease of estrogen receptor.
Summary of the invention
It is an object of the present invention to provide one kind shown in general formula I, and there is selective estrogen receptor to lower activeization
Object or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug are closed,
Wherein,
X1、X2、X4, each X3Separately it is selected from C (R1R2)、N(R3), O, S, sulfone and sulfoxide;
R1、R2Separately it is selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, haloalkoxy
Base, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl,
Alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base, heterocycle, heteroaryl and aryl;Or R1、R2It is connected to it
Carbon atom is formed together carbonyl;R3Selected from hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxyl
Alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, heteroaryl and aryl, the group can by one or more halogens, hydroxyl,
Alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, single alkane
Base amino, double alkyl aminos, naphthenic base, heterocycle, aryl and heteroaryl replace;
R4Selected from hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxy alkyl, alkenyl,
Alkynyl, naphthenic base, heterocycle, heteroaryl and aryl, the group can be by one or more halogens, hydroxyl, alkyl, alkyl halides
Base, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkane
Base amino, naphthenic base, heterocycle, aryl and heteroaryl replace;
R5Selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy
Base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkyl amino acyl
Base, double alkyl aminos, alkenyl, alkynyl and naphthenic base;
Each R6, each R7Separately selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated
Alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl
Base, alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base and boric acid;
Y is selected from alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroarylalkoxy, alkyl ammonia
Base, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, naphthenic base, heterocycle, virtue
Base, heteroaryl, alkenyl and alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroaryl
Alkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, ring
Alkyl, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxyls
Base alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acyl ammonia
Base, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base, heterocycle and oxo base
Group replaces;With
M, n, o are each independently 1,2,3 or 4.
It is a further object to provide prepare compounds of formula I or its isomers of the invention, pharmaceutically may be used
The salt of receiving, solvate, crystallization, isostere or prodrug method.
It is also another object of the present invention to provide comprising compounds of formula I of the invention or its isomers, pharmaceutically may be used
Salt, solvate, crystallization, isostere or the prodrug of receiving and the composition of pharmaceutically acceptable carrier, and include this
The compounds of formula I of invention or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug
With the composition of one or more drugs.
Of the invention a further object is provides compounds of formula I or its isomers of the invention, pharmaceutically acceptable
Salt, solvate, crystallization, isostere or prodrug treatment and/or the relevant disease of prevention estrogen receptor method, with
And compounds of formula I or its isomers of the invention, pharmaceutically acceptable salt, solvate, crystallization, isostere or
Prodrug is preparing the application in the drug for treating and/or preventing the relevant disease of estrogen receptor.
For above-mentioned purpose, the present invention provides following technical scheme:
In a first aspect, the present invention provides general formula I compound represented or its isomers, pharmaceutically acceptable salt, solvent
Compound, crystallization, isostere or prodrug,
Wherein,
X1、X2、X4, each X3Separately it is selected from C (R1R2)、N(R3), O, S, sulfone and sulfoxide;
R1、R2Separately it is selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, haloalkoxy
Base, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl,
Alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base, heterocycle, heteroaryl and aryl;Or R1、R2It is connected to it
Carbon atom is formed together carbonyl;R3Selected from hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxyl
Alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, heteroaryl and aryl, the group can by one or more halogens, hydroxyl,
Alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, single alkane
Base amino, double alkyl aminos, naphthenic base, heterocycle, aryl and heteroaryl replace;
R4Selected from hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxy alkyl, alkenyl,
Alkynyl, naphthenic base, heterocycle, heteroaryl and aryl, the group can be by one or more halogens, hydroxyl, alkyl, alkyl halides
Base, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkane
Base amino, naphthenic base, heterocycle, aryl and heteroaryl replace;
R5Selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy
Base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkyl amino acyl
Base, double alkyl aminos, alkenyl, alkynyl and naphthenic base;
Each R6, each R7Separately selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated
Alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl
Base, alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base and boric acid;
Y is selected from alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroarylalkoxy, alkyl ammonia
Base, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, naphthenic base, heterocycle, virtue
Base, heteroaryl, alkenyl and alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroaryl
Alkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, ring
Alkyl, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxyls
Base alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acyl ammonia
Base, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base, heterocycle and oxo base
Group replaces;With
M, n, o are each independently 1,2,3 or 4.
In some specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization, isostere or prodrug, wherein when o is 1, X1、X2、X3、X4In have one for C
(R1R2), excess-three is N (R3), O, S, sulfone or sulfoxide.
In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy
Upper acceptable salt, solvate, crystallization, isostere or prodrug, wherein when o is 1, X1、X2、X3、X4In there are two being
C(R1R2), other two is N (R3), O, S, sulfone or sulfoxide.
In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy
Upper acceptable salt, solvate, crystallization, isostere or prodrug, wherein when o is 1, X1、X2、X3、X4In there are three being
C(R1R2), remaining one is N (R3), O, S, sulfone or sulfoxide.
In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy
Acceptable salt, solvate, crystallization, isostere or prodrug are gone up, wherein X1、X2, each X3It is C (R1R2), X4For N
(R3), O, S, sulfone or sulfoxide.
In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization, isostere or prodrug, wherein:
R1、R2Separately it is selected from hydrogen, halogen, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6Alkane
Oxygroup, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxyl, cyano, amino, list C1-6Alkyl amino, C1-6Alkyl acyl
Base amino, C1-6Alkyl acyl, aminoacyl, C1-6Alkylaminoacyl, double C1-6Alkyl amino, C2-10Alkenyl, C2-10Alkynyl,
C3-10Naphthenic base, C1-10Heterocycle, C6-18Aryl and C1-18Heteroaryl;
It is further preferred that R1、R2Separately it is selected from hydrogen, halogen, hydroxyl, C1-3Alkyl, halogenated C1-3Alkyl, hydroxyl
C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, hydroxyl C1-3Alkoxy, nitro, carboxyl, cyano, amino, list C1-3Alkyl ammonia
Base, C1-3Alkyl acylamino, C1-3Alkyl acyl, aminoacyl, C1-3Alkylaminoacyl, double C1-3Alkyl amino, C2-6Alkene
Base, C2-6Alkynyl, C3-8Naphthenic base, C1-8Heterocycle, C6-12Aryl and C1-12Heteroaryl;
It is further preferred that R1、R2Separately selected from hydrogen, halogen, hydroxyl, methyl, ethyl, propyl, isopropyl,
Trifluoromethyl, trifluoroethyl, pentafluoroethyl group, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyl, methoxyl group, ethyoxyl, the third oxygen
Base, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, dimethylamino,
Lignocaine, methylethylamine, dipropyl amino, methylpropylamino, ethylpropylamino, methylacyl amino, ethyl acyl
Base amino, vinyl acyl amino, methylacyl, ethyl acyl group, vinyl acyl group, aminoacyl, methylamino acyl group, ethyl
Aminoacyl, vinyl, acrylic, allyl, cyclobutenyl, alkene butyl, 3- methyl-2-butene base, acetenyl, propinyl, alkynes
Propyl, butynyl, alkynes butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, C1-6Heterocycle, C6-10Aryl and C1-10Heteroaryl.
In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization, isostere or prodrug, wherein:R1、R2Carbon atom connected to it is formed together carbonyl
Base.
In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization, isostere or prodrug, wherein R3Selected from hydrogen, C1-10Alkyl acyl, aminoacyl,
C1-10Alkylaminoacyl, C1-10Alkyl, halogenated C1-10Alkyl, hydroxyl C1-10Alkyl, C2-10Alkenyl, C2-10Alkynyl, C3-10Cycloalkanes
Base, C1-10Heterocycle, C6-18Aryl and C1-18Heteroaryl, the group can be by one or more halogens, hydroxyl, alkyl, halogenated
It is alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double
Alkyl amino, naphthenic base, heterocycle, aryl and heteroaryl replace;
It is further preferred that R3Selected from separately selected from hydrogen, C1-6Alkyl acyl, aminoacyl, C1-6Alkyl amino
Acyl group, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, C1-8Heterocycle, C6-12
Aryl and C1-12Heteroaryl, the group can be by one or more halogens, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl
C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxyl, cyano, amino, list C1-6Alkyl ammonia
Base, double C1-6Alkyl amino, C3-10Naphthenic base, C1-10Heterocycle, C6-18Aryl and C1-18Heteroaryl replaces;
It is further preferred that R3Selected from hydrogen, formoxyl, acetyl group, propiono, aminoacyl, methylamino acyl group, second
Base aminoacyl, propylcarbamic acyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, amyl, isopentyl, neopentyl,
Hexyl, trifluoromethyl, trifluoroethyl, bis- fluoropropyl of 2,2-, the fluoro- 2- methyl-propyl of 2-, the fluoro- 2- methyl-propyl of (S) -3-, hydroxyl first
Base, ethoxy, hydroxypropyl, 2- hydroxypropyl, vinyl, acrylic, cyclobutenyl, 3- methyl-2-butene base, C2-6Alkynyl, C3-6
Naphthenic base, C3-6Heterocycle, C6-10Aryl and C5-10Heteroaryl, the group can be by one or more halogens, hydroxyl, C1-3Alkane
Base, halogenated C1-3Alkyl, hydroxyl C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, hydroxyl C1-3Alkoxy, nitro, carboxyl, cyanogen
Base, amino, list C1-3Alkyl amino, double C1-3Alkyl amino, C3-6Naphthenic base, C1-6Heterocycle, C6-10Aryl and C1-10Heteroaryl takes
Generation.
In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization, isostere or prodrug, wherein:
R4Selected from hydrogen, C1-10Alkyl acyl, aminoacyl, C1-10Alkylaminoacyl, C1-10Alkyl, halogenated C1-10Alkyl,
Hydroxyl C1-10Alkyl, C2-10Alkenyl, C2-10Alkynyl, C3-10Naphthenic base, C1-10Heterocycle, C6-18Aryl and C1-18Heteroaryl, it is described
Group can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxyl alkane
Oxygroup, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkyl aminos, naphthenic base, heterocycle, aryl and heteroaryl take
Generation;
It is further preferred that R4Selected from separately selected from hydrogen, C1-6Alkyl acyl, aminoacyl, C1-6Alkyl amino
Acyl group, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, C1-8Heterocycle, C6-12
Aryl and C1-12Heteroaryl, the group can be by one or more halogens, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl
C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxyl, cyano, amino, list C1-6Alkyl ammonia
Base, double C1-6Alkyl amino, C3-10Naphthenic base, C1-10Heterocycle, C6-18Aryl and C1-18Heteroaryl replaces;
It is further preferred that R4Selected from hydrogen, formoxyl, acetyl group, propiono, aminoacyl, methylamino acyl group, second
Base aminoacyl, propylcarbamic acyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, amyl, isopentyl, neopentyl,
Hexyl, trifluoromethyl, trifluoroethyl, bis- fluoropropyl of 2,2-, the fluoro- 2- methyl-propyl of 2-, the fluoro- 2- methyl-propyl of (S) -3-, hydroxyl first
Base, ethoxy, hydroxypropyl, 2- hydroxypropyl, vinyl, acrylic, cyclobutenyl, 3- methyl-2-butene base, C2-6Alkynyl, C3-6
Naphthenic base, C3-6Heterocycle, C6-10Aryl and C5-10Heteroaryl, the group can be by one or more halogens, hydroxyl, C1-3Alkane
Base, halogenated C1-3Alkyl, hydroxyl C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, hydroxyl C1-3Alkoxy, nitro, carboxyl, cyanogen
Base, amino, list C1-3Alkyl amino, double C1-3Alkyl amino, C3-6Naphthenic base, C1-6Heterocycle, C6-10Aryl and C1-10Heteroaryl takes
Generation.
In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization, isostere or prodrug, wherein:
R5Selected from hydrogen, halogen, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6Alkoxy, halogenated C1-6
Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxyl, cyano, amino, list C1-6Alkyl amino, C1-6Alkyl acylamino, C1-6Alkane
Base acyl group, aminoacyl, C1-6Alkylaminoacyl, double C1-6Alkyl amino, C2-10Alkenyl, C2-10Alkynyl and C3-10Naphthenic base;
It is further preferred that R5Selected from hydrogen, halogen, hydroxyl, C1-3Alkyl, halogenated C1-3Alkyl, hydroxyl C1-3Alkyl, C1-3Alkane
Oxygroup, halogenated C1-3Alkoxy, hydroxyl C1-3Alkoxy, nitro, carboxyl, cyano, amino, list C1-3Alkyl amino, C1-3Alkyl acyl
Base amino, C1-3Alkyl acyl, aminoacyl, C1-3Alkylaminoacyl, double C1-3Alkyl amino, C2-6Alkenyl, C2-6Alkynyl and
C3-8Naphthenic base;
It is further preferred that R5Selected from hydrogen, halogen, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoro
Ethyl, pentafluoroethyl group, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy,
Nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, dimethylamino, lignocaine, first
Base ethylamino, dipropyl amino, methylpropylamino, ethylpropylamino, methylacyl amino, ethyl acyl amino, ethylene
Base acyl amino, methylacyl, ethyl acyl group, vinyl acyl group, aminoacyl, methylamino acyl group, ethylamino acyl group, second
Alkenyl, acrylic, allyl, cyclobutenyl, alkene butyl, 3- methyl-2-butene base, acetenyl, propinyl, propargyl, butynyl,
Alkynes butyl, cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization, isostere or prodrug, wherein:
Each R6, each R7Separately it is selected from hydrogen, halogen, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl,
C1-6Alkoxy, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxyl, cyano, amino, list C1-6Alkyl amino, C1-6Alkane
Base acyl amino, C1-6Alkyl acyl, aminoacyl, C1-6Alkylaminoacyl, double C1-6Alkyl amino, C2-10Alkenyl, C2-10Alkynes
Base, C3-10Naphthenic base and boric acid;
It is further preferred that each R6, each R7Separately it is selected from hydrogen, halogen, hydroxyl, C1-3Alkyl, halogenated C1-3Alkyl,
Hydroxyl C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, hydroxyl C1-3Alkoxy, nitro, carboxyl, cyano, amino, list C1-3Alkane
Base amino, C1-3Alkyl acylamino, C1-3Alkyl acyl, aminoacyl, C1-3Alkylaminoacyl, double C1-3Alkyl amino, C2-6
Alkenyl, C2-6Alkynyl, C3-8Naphthenic base and boric acid;
It is further preferred that each R6, each R7Separately it is selected from hydrogen, halogen, hydroxyl, methyl, ethyl, propyl, isopropyl
Base, trifluoromethyl, trifluoroethyl, pentafluoroethyl group, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyl, methoxyl group, ethyoxyl,
Propoxyl group, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, diformazan
Amino, lignocaine, methylethylamine, dipropyl amino, methylpropylamino, ethylpropylamino, methylacyl amino, second
Base acyl amino, vinyl acyl amino, methylacyl, ethyl acyl group, vinyl acyl group, aminoacyl, methylamino acyl group,
Ethylamino acyl group, vinyl, acrylic, allyl, cyclobutenyl, alkene butyl, 3- methyl-2-butene base, acetenyl, propine
Base, propargyl, butynyl, alkynes butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and boric acid.
In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization, isostere or prodrug, wherein:
Y is selected from C1-6Alkoxy, C3-10Naphthenic base C1-6Alkoxy, C1-10Heterocycle C1-6Alkoxy, C6-18Aryl C1-6Alcoxyl
Base, C1-18Heteroaryl C1-6Alkoxy, C1-6Alkyl amino, C3-10Naphthenic base C1-6Alkyl amino, C1-10Heterocycle C1-6Alkyl ammonia
Base, C6-18Aryl C1-6Alkyl amino, C1-18Heteroaryl C1-6Alkyl amino, C3-10Naphthenic base, C1-10Heterocycle, C6-18Aryl,
C1-18Heteroaryl, C2-10Alkenyl and C2-10Alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, arylalkoxy
Base, heteroarylalkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkane
Base amino, naphthenic base, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can be by one or more halogens, hydroxyl, C1-6Alkyl,
Halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxyl, cyano,
Amino, list C1-6Alkyl amino, C1-6Alkyl acylamino, C1-6Alkyl acyl, aminoacyl, C1-6Alkylaminoacyl, double C1-6
Alkyl amino, C2-10Alkenyl, C2-10Alkynyl, C1-10Heterocycle, C3-10Naphthenic base and oxo group replace;
It is further preferred that Y is selected from C1-3Alkoxy, C3-8Naphthenic base C1-3Alkoxy, C1-8Heterocycle C1-3Alkoxy,
C6-12Aryl C1-3Alkoxy, C1-12Heteroaryl C1-3Alkoxy, C1-3Alkyl amino, C3-8Naphthenic base C1-3Alkyl amino, C1-8Heterocycle
Base C1-3Alkyl amino, C6-12Aryl C1-3Alkyl amino, C1-8Heteroaryl C1-3Alkyl amino, C3-8Naphthenic base, C1-8Heterocycle,
C6-12Aryl, C1-12Heteroaryl, C2-6Alkenyl and C2-6Alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, virtue
It is base alkoxy, heteroarylalkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, miscellaneous
Aryl-alkyl amino, naphthenic base, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can by one or more halogens, hydroxyl,
C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxylic
Base, cyano, amino, list C1-6Alkyl amino, C1-6Alkyl acylamino, C1-6Alkyl acyl, aminoacyl, C1-6Alkyl amino acyl
Base, double C1-6Alkyl amino, C2-10Alkenyl, C2-10Alkynyl, C1-10Heterocycle, C3-10Naphthenic base and oxo group replace;
It is further preferred that Y is selected from C1-3Alkoxy, C3-8Naphthenic base C1-3Alkoxy, C1-8Heterocycle C1-3Alkoxy,
C6-12Aryl C1-3Alkoxy, C1-12Heteroaryl C1-3Alkoxy, C1-3Alkyl amino, C3-8Naphthenic base C1-3Alkyl amino, C1-8Heterocycle
Base C1-3Alkyl amino, C6-12Aryl C1-3Alkyl amino, C1-8Heteroaryl C1-3Alkyl amino, C3-8Naphthenic base, C1-8Heterocycle,
C6-12Aryl, C1-12Heteroaryl, C2-6Alkenyl and C2-6Alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, virtue
It is base alkoxy, heteroarylalkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, miscellaneous
Aryl-alkyl amino, naphthenic base, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can by one or more halogens, hydroxyl,
C1-3Alkyl, halogenated C1-3Alkyl, hydroxyl C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, hydroxyl C1-3Alkoxy, nitro, carboxylic
Base, cyano, amino, list C1-3Alkyl amino, C1-3Alkyl acylamino, C1-3Alkyl acyl, aminoacyl, C1-3Alkyl amino acyl
Base, double C1-3Alkyl amino, C2-6Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, C1-8Heterocycle and oxo group replace.
In some specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization, isostere or prodrug, wherein Y be
In some preferred embodiments, the compound of the present invention is the compound or its isomers, pharmacy of general formula Ia
Upper acceptable salt, solvate, crystallization, isostere or prodrug,
Wherein, each R6, each R7、R4, m, n be as defined in general formula I.
In some specific embodiments, the compound or its isomers of general formula Ia according to the present invention pharmaceutically may be used
Salt, solvate, crystallization, isostere or the prodrug of receiving, wherein each R6, each R7It is each independently selected from fluorine, chlorine, bromine, first
Base, ethyl, propyl, methoxyl group, ethyoxyl, propoxyl group, fluoro-methoxy, difluoromethoxy, trifluoromethoxy, fluoro ethoxy
Base, difluoroethoxy, R4It is selected from
The present invention provides compound or its isomers, pharmaceutically acceptable salt, solvate, crystallization, electricity in detail below
Sub- isostere or prodrug:
On the other hand, the present invention provides the preparation method of general formula compound of the invention, including:
Compounds of formula I can be known in the art as being suitable for by the compound of formula 1 and the compound of formula 2
In the presence of condition (such as in acid) of Pickett-Shi Penggele (Pictet-Spengler) reaction and a kind of suitable molten
It is made in agent with being reacted at suitable temperature,
Wherein the compound of formula 1 can pass through formula 3Compound and formula 4Change
It closes object reaction to be made, the compound of formula 4 can pass through formula 5Compound and trifluoromethanesulfonic acid anhydride reactant be made, formula 2
Compound, the compound of formula 3, formula 5 compound can be commercially available or customary preparation methods as known in the art
It is made,
X1、X2、X3、X4、R4、R5、R6、R7, m, n, o, Y be as defined in formula above I.
The third aspect, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its isomers, pharmaceutically may be used
Salt, solvate, crystallization, isostere or the prodrug of receiving.
In some embodiments, the present invention provides pharmaceutical composition, it includes the compound of the present invention or its isomers,
Pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug, also comprising one in the group selected from following composition
Kind or various medicaments:SERD, SERM, tyrosine protein enzyme inhibitor, EGFR inhibitor, VEGFR inhibitor, Bcr-Abl inhibit
Agent, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, inhibitors of histone deacetylase, VEGF antibody,
EGF antibody, HIV kinases inhibitor, HMG-CoA reductase inhibitor etc..
In some embodiments, the present invention provide the compound of the present invention or its isomers, pharmaceutically acceptable salt,
Solvate, crystallization, isostere or prodrug and include the compound of the present invention or its isomers, pharmaceutically acceptable
Salt, solvate, crystallization, isostere or prodrug pharmaceutical composition, the compound or pharmaceutical composition are for treating
And/or the relevant disease of prevention estrogen receptor.
It can be by the compound of the present invention or its isomers, pharmaceutically acceptable salt, solvate, crystallization, electronics etc.
Isostere or prodrug and pharmaceutically acceptable carrier, diluent or excipient are prepared by mixing into pharmaceutical preparation, oral to be suitable for
Or parenteral.Medication includes, but are not limited to that intradermal, intramuscular, peritonaeum is interior, intravenous, subcutaneous, intranasal and oral way
Diameter.The preparation can be applied by any approach, such as by being transfused or injecting, by transepithelial or it is mucocutaneous (such as
Oral mucosa or rectum etc.) absorb approach application.Administration can be whole body or local.The example packet of oral administration preparation
Solid or liquid dosage form are included, specifically, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..
The preparation can be prepared by methods known in the art, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or
Excipient.
Fourth aspect, the present invention provide general formula I compound represented of the present invention or its isomers, pharmaceutically acceptable
Salt, solvate, crystallization, isostere or prodrug, or comprising its pharmaceutical composition preparation treatment and/or prevent it is female swash
Purposes in the drug of the relevant disease of plain receptor, wherein the relevant disease of estrogen receptor or symptom includes but unlimited
In:Relevant to ER- α dysfunction cancer (such as osteocarcinoma, breast cancer, colorectal cancer, carcinoma of endometrium, prostate cancer, ovary
Cancer and uterine cancer etc.), liomyoma (such as leiomyoma of uterus etc.), central nervous system (CNS) defect is (such as in alcohol
Poison, migraine etc.), cardiovascular system defect (such as aortic aneurysm, myocardial infarction neurological susceptibility, aortic valve sclerosis, cardiovascular disease
Disease, coronary artery disease, hypertension etc.), hematological deficiencies (such as Deep vain thrombosis etc.), immune and inflammation disease
(such as Graves disease, arthritis, multiple sclerosis, cirrhosis etc.), susceptibility infection (such as hepatitis B, chronic liver disease
Deng), metabolic deficiency (such as bone density, cholestasis, hypospadia, obesity, osteoarthritis, sclerotin reduce, osteoporosis
Deng), neurologically handicapped (such as Alzheimer disease, Parkinson's disease, migraine, dizziness etc.), mental defect (such as detest by nerve
Food, Attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, mental disease etc.) and genetic defect (such as menstruation
Age of menarche exception, endometriosis, sterility etc.) etc..In some embodiments, the present invention relates to it is a kind of treat it is female
The method of the relevant disease of hormone receptor comprising give required bacterium general formula I compound represented or its
Isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug, or comprising its pharmaceutical composition,
Wherein the relevant disease of estrogen receptor includes but is not limited to:Relevant to ER dysfunction cancer (such as osteocarcinoma, cream
Gland cancer, colorectal cancer, carcinoma of endometrium, prostate cancer, oophoroma and uterine cancer etc.), liomyoma (such as leiomyoma of uterus
Deng), central nervous system (CNS) defect (such as alcoholism, migraine etc.), cardiovascular system defect (such as aortic aneurysm,
Myocardial infarction neurological susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension etc.), hematological deficiencies (example
Such as Deep vain thrombosis), immune and inflammation disease (such as Graves disease, arthritis, multiple sclerosis, cirrhosis
Deng), susceptibility infection (such as hepatitis B, chronic liver disease etc.), metabolic deficiency is (such as under bone density, cholestasis, urethra
Split, the reduction of obesity, osteoarthritis, sclerotin, osteoporosis etc.), neurologically handicapped (such as Alzheimer disease, Parkinson's disease,
Migraine, dizziness etc.), mental defect (such as anorexia nervosa, Attention deficit hyperactivity disorder (ADHD), dementia, serious suppression
Strongly fragrant obstacle, mental disease etc.) and genetic defect (such as Menarcheal Age exception, endometriosis, sterility etc.) etc..
The compound of the present invention has more excellent anti-tumor activity, and dosing interval is longer, less side effects.
Term explanation
Unless stated to the contrary, the term used in the specification and in the claims has following meanings.
" hydrogen ", " carbon " in the compounds of this invention include its all isotope.Isotope is understood to include with identical
Atomicity but there is those of different quality number atom.For example, the isotope of hydrogen includes tritium and deuterium, the isotope packet of carbon
It includes13C and14C。
" halogen " of the invention refers to fluorine, chlorine, bromine, iodine." halogenated " of the invention refers to be replaced by fluorine, chlorine, bromine or iodine.
" alkyl " of the invention refers to the saturated fat hydrocarbyl group of linear chain or branched chain, preferably the straight chain containing 1 to 6 carbon atom or
Branched group, the linear chain or branched chain group of further preferably 1 to 3 carbon atom, non-limiting example include methyl, second
Base, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl
Propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl etc..Alkyl can be substitution
Or it is unsubstituted, when substituted, substituent group can be on any workable tie point.
" alkylidene " of the invention refers to that alkyl formally removes group remained by a hydrogen atom, as methylene (-
CH2), ethylidene (- CH2-CH2), propylidene (- CH2-CH2-CH2) etc., herein, " the sub- C1-10Alkyl " refers to
C1-10Alkyl formally removes group remained by a hydrogen atom, " the sub- C1-6Alkyl " refers to C1-6Alkyl is from form
On remove group remained by a hydrogen atom.Alkylidene can be substituted or unsubstituted, and when substituted, substituent group can
On any workable tie point.
" halogenated alkyl " of the invention refers to the alkyl at least replaced by a halogen.
" hydroxy alkyl " of the invention refers to the alkyl at least replaced by a hydroxyl.
" alkoxy " of the invention refers to-O- alkyl.The non-limiting example of alkoxy includes:Methoxyl group, ethyoxyl, third
Oxygroup, positive propoxy, isopropoxy, isobutoxy, sec-butoxy etc..Alkoxy can be optionally it is substituted or unsubstituted,
When substituted, substituent group can be on any workable tie point.
" naphthenic base " of the invention refers to cricoid saturated hydrocarbyl.Suitable naphthenic base can be substituted or unsubstituted tool
There are the monocyclic, bicyclic or tricyclic saturated hydrocarbyl of 3-10 carbon atom, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.
" heterocycle " of the invention refers to ring carbon atom (preferably containing 1-10 carbon atom i.e. C1-10) and 1 to 4
3- to the 12- member non-aromatic ring system of ring hetero atom (wherein each hetero atom is independently selected from nitrogen, oxygen, sulphur, boron, phosphorus and silicon)
The group (" 3-12 circle heterocyclic ring base ") of system.In the heterocyclyl groups comprising one or more nitrogen-atoms, tie point can be carbon
Or nitrogen-atoms, as long as chemical valence is permitted.Heterocyclyl groups or (" heterocycle of monocycle ") that can be monocycle either merge
, bridging or spiral shell loop system (such as second cycle line system (" heterocycles of two rings ")) and can be saturation or can be portion
Divide unsaturated.The loop system of two ring of heterocycle can include one or more hetero atoms in one or two ring." heterocycle
Base " also includes loop system, and wherein heterocycle, as defined above, is to merge (wherein to connect with one or more carbocylic radical groups
Point in carbocylic radical or on heterocycle) or loop system in heterocycle, it is as defined above, be and one or more aryl or heteroaryl
(wherein tie point is on heterocycle) of base fusion, and in such cases, the number of ring members continues referred to as in heterocyclic ring system
In ring members number.Unless otherwise prescribed, each example of heterocycle is independently optionally to replace ground, that is, unsubstituted
(" unsubstituted heterocycle ") or (" the substituted heterocycle ") replaced with one or more substituent groups.In certain embodiments,
The heterocyclyl groups are unsubstituted 3-10 circle heterocyclic ring bases.In certain embodiments, which is the 3-10 member replaced
Heterocycle.It is fused to C6The exemplary 5- circle heterocyclic ring base group of aryl rings (herein be also referred to as 5,6- bicyclic heterocycles) includes but unlimited
In indoline base, isoindoline base, dihydro benzo furyl, dihydrobenzo thienyl, benzoxazolinone base etc..Fusion
Exemplary 6- circle heterocyclic ring base group (herein be also referred to as 6,6- bicyclic heterocycles) to aryl rings includes but is not limited to tetrahydroquinoline
Base, tetrahydro isoquinolyl etc..
" aryl " of the invention refers to the aroma system that may include monocycle or fused polycycle, preferably comprises monocycle or condensed
Bicyclic aroma system contains 6 to 18 carbon atoms, preferably comprises from about 6 to about 12 carbon atoms.Suitable aryl includes
But it is not limited to phenyl, naphthalene, anthryl, tetralyl, fluorenyl, indanyl.Aryl can be optionally it is substituted or unsubstituted, when
When being substituted, substituent group can be on any workable tie point.
" heteroaryl " of the invention refers to the aryl that at least one carbon atom is substituted by hetero atom, by 5-20 atom structure
At being further preferably made of 5-12 atom, the hetero atom is O, S, N, and suitable heteroaryl preferably contains 1-18 carbon
Atom (i.e. C1-18), including but not limited to imidazole radicals, benzimidazolyl, imidazopyridyl, quinazoline ketone group, pyrrole radicals, miaow
Oxazolone base, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
Pyrimidine radicals, pyridyl group, pyrazinyl, pyridazinyl, pyrimido pyrazolyl, pyrimido imidazole radicals etc..Heteroaryl can be optional substitution
Or it is unsubstituted, when substituted, substituent group can be on any workable tie point.
" isomers " of the invention be there is identical molecular formula but in nature or on the key sequence of its atom or
Different compound on the space arrangement of its atom.Stereoisomer is its atom isomers different on space arrangement.That
This stereoisomer not being mirrored into is diastereomer and be the stereoisomer of mirror image of non-overlap is mutually enantiomer.When
When compound has asymmetric center, for example, it is bonded to four different groups, a pair of of enantiomer is possible.Mapping
Rule is sequenced characterized by the absolute configuration of its asymmetric center and through the R- and S- of Cahn and Prelog in body, or by dividing
The method of the plane of sub- rotatory polarization light is described and specifies as dextrorotation or left-handed (i.e. different respectively as (+) or (-)-
Structure body).Chipal compounds can be used as the presence of or mixtures thereof single enantiomer.The mixing of equal proportion comprising enantiomer
Object is referred to as " racemic mixture ".
" pharmaceutically acceptable salt " of the invention refers to the salt of the compounds of this invention, and this kind of salt is in the mammalian body
When have safety and validity, and have due bioactivity.
" solvate " of the invention refer in a conventional sense solute (such as salt of reactive compound, reactive compound) and
The compound that solvent (such as water) combination is formed.Solvent refers to the solvent of known to those of skill in the art or easy determination.Such as
Fruit is water, then solvate is commonly referred to as hydrate, for example, semihydrate, monohydrate, dihydrate, trihydrate or its
Substitution amount etc..
The internal effect of compound with chemical formula (I) can be partly by giving the chemical combination with chemical formula (I)
One or more metabolins for being formed after object in human body or animal body play.As described above, having the change of chemical formula (I)
The internal effect for closing object can also be metabolized to play via precursor compound (" prodrug ")." prodrug " of the invention refers in biology
Under physiological condition in body, due to reacting and converting the compound of the compound of an accepted way of doing sth (I) with enzyme, gastric acid etc., that is, pass through enzyme
Oxidation, reduction, hydrolysis etc. convert the compound of the compound of an accepted way of doing sth (I) and/or are converted to by hydrolysis of gastric acid etc. etc.
The compound etc. of the compound of formula (I).The compound with Formula I with carboxyl it is suitable it is pharmaceutically acceptable before
Medicine is the ester of such as its internal cleavable.The ester for wrapping the internal cleavable of the carboxylic compound with Formula I is for example
It is cracked in human body or animal body to generate the pharmaceutically acceptable ester of parent acid.Suitable for carboxyl can pharmaceutically connect
The ester received includes Arrcostab, such as methyl ester, ethyl ester and tertiary butyl ester, alkoxy methyl ester such as methoxymethyl ester;Alkane acyl
Oxygroup methyl ester, such as new pentane acyloxy ester;3- phthalidyl ester;Naphthenic base carbonyloxy group Arrcostab, such as cyclopenta carbonyl oxy-methyl ester and
1- cyclohexylcarbonyloxyethyl ester;2- oxo -1,3- dioxa cyclopentenyl (dioxolenyl) methyl ester, such as 5- methyl -2-
Oxo-1,3- Dioxol-4 -yl methyl ester;And alkoxy carbonyloxy group Arrcostab, such as methoxycarbonyl-oxymethyl ester
With 1- methoxycarbonyloxyethyl ester.The compound with Formula I with carboxyl it is suitable it is pharmaceutically acceptable before
Medicine is the amide of for example internal cleavable, such as N- alkylamide and N, N- dialkyl amide, such as N- methyl nitrosourea, N- ethyl acyl
Amine, N- propyl amides, N, N- dimethylformamide, N- ethyl-N-methyl or N, N- diethylamide.
Bioisostere (or abbreviation " isostere ") of the present invention is for defining wherein one or more atoms
(or atomic group) is by with those of replacing the displaced atom that atom has similar spatial and/or electronic characteristic with them
The term generally acknowledged generally in the art of drug analogue replaced (or atomic group).
" crystallization " of the invention refer to its internal structure be in three-dimensional regularly repeat constituting atom (or its group) and
The solid of formation is different from the amorphous solid of the internal structure without this rule.
" pharmaceutical composition " of the invention refers to comprising any compound as described herein, including corresponding isomery
Protection form and one or more pharmaceutically acceptable of body, prodrug, solvate, pharmaceutically acceptable salt or its chemistry
The mixture of carrier.The purpose of Pharmaceutical composition is to promote the administration of compound on organism body.The composition is commonly used in system
It is standby to treat and/or prevent the drug by one or more kinase mediated diseases.
" pharmaceutically acceptable carrier " of the invention refer to obvious irritation is not caused to organism and do not interfere to
The bioactivity of compound and the carrier of property are given, all solvents, diluent or other excipient, dispersing agent, surface are included
Activating agent isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant etc..Unless any conventional carrier medium with
The compounds of this invention is incompatible.The some examples that can be used as pharmaceutically acceptable carrier include, but are not limited to carbohydrate, such as cream
Sugar, dextrose and saccharose;Starch, such as cornstarch and potato starch;Cellulose and its derivates, such as carboxymethyl cellulose
Sodium and cellulose and cellulose acetate;Malt, gelatin etc..
" excipient " of the invention, which refers to, to be added in Pharmaceutical composition with the further inert substance for promoting to give compound.
Excipient may include calcium carbonate, calcium phosphate, various saccharides and a plurality of types of starch, cellulose derivative, gelatin, plant
Oil, polyethylene glycol.
Of the invention " purposes in the drug for the treatment of and/or the relevant disease of prevention estrogen receptor " refer to can make it is female
The relevant disease of hormone receptor is improved, and growth, development and/or the transfer of the relevant disease of estrogen receptor, or drop are inhibited
The risk of the relevant disease of low estrogen receptor mainly gives treatment and/or prevention effective dose to required human or animal
The compound of the present invention is to inhibit, slow down or reverse growth, development or the expansion of the relevant disease of estrogen receptor in subject
It dissipates, improves the relevant disease of estrogen receptor, or reduce risk, the disease relevant to estrogen receptor
Including disease relevant to estrogen receptor alpha and disease relevant with erss, for example, with estrogen receptor dysfunction
Relevant cancer (such as osteocarcinoma, breast cancer, colorectal cancer, carcinoma of endometrium, prostate cancer, oophoroma and uterine cancer etc.) is put down
Sliding myomata (such as leiomyoma of uterus etc.), central nervous system (CNS) defect (such as alcoholism, migraine etc.), painstaking effort
Guard system defect (such as aortic aneurysm, myocardial infarction neurological susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease,
Hypertension etc.), hematological deficiencies (such as Deep vain thrombosis etc.), immune and inflammation disease (such as Graves disease, close
Save inflammation, multiple sclerosis, cirrhosis etc.), susceptibility infection (such as hepatitis B, chronic liver disease etc.), metabolic deficiency (such as bone
Density, cholestasis, hypospadia, obesity, osteoarthritis, sclerotin reduction, osteoporosis etc.), neurologically handicapped (such as Ah
Alzheimer's disease, Parkinson's disease, migraine, dizziness etc.), (such as anorexia nervosa, attention deficit are with more dynamic barriers for mental defect
Hinder (ADHD), dementia, major depressive disorder, mental disease etc.) and genetic defect (such as Menarcheal Age is abnormal, endometrium
Endometriosis, sterility etc.) etc..
Specific embodiment
Representative embodiment is protection model and is not intended to limit the present invention in order to better illustrate the present invention below
It encloses.Material used in the following embodiment is commercially available unless otherwise specified.
Embodiment 1 (E) -3- (the fluoro- 4- of 3,5- bis- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,
10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid
The synthesis of step a 2- (1H- indol-3-yl) cyclopenta -1- ketone
In the mono- neck bottle of 100mL, indoles (1.98g, 16.9mmol) and dichloro cyclopentanone (2g, 16.9mmol) is added,
The dissolution of 35mL trifluoroethanol, is stirred at room temperature, and is added natrium carbonicum calcinatum (2.15g, 20.28mmol), maintaining the temperature, the reaction was continued
48h.After reaction, it successively filters, be concentrated, column chromatographs to obtain title product.ESI-Ms m/z:200.1[M+H]+。
The synthesis of step b 2- (1H- indol-3-yl) cyclopenta -1- amine
In the mono- neck bottle of 200mL, 2- (1H- indol-3-yl) cyclopenta -1- ketone (4.78g, 24.02mmol), 60mL is added
Methanol dissolution, weighs ammonium acetate (20.18g, 262mmol), sodium cyanoborohydride (1.67g, 26.42mmol) addition, and room temperature is stirred
Mix 48h.Then 50mL water is added in 2M HCl% tune pH to 2, concentrated solvent, the extraction of 40mL methylene chloride collects water phase, then use
4M sodium hydroxide solution tune pH to 12 is extracted with 3 × 60mL methylene chloride, merges organic phase, washing, saturated common salt washing are dense
Contract to obtain title product.ESI-Ms m/z:201.13[M+H]+。
The synthesis of the fluoro- 2- methyl-propyl trifluoromethayl sulfonic acid ester of step c 2-
In 250mL reaction flask, the fluoro- 2- methyl propyl- 1- alcohol (7.25g, 78.75mmol) of 2-, 2,6- dimethyl pyrazole is added
Pyridine (12.75mL, 110.25mmol), with sub-cooled after the dissolution of 60mL methylene chloride to -10 DEG C.By trifluoromethanesulfanhydride anhydride
(14.58mL, 86.75mmol) is added dropwise in above-mentioned reaction solution after being dissolved with 20mL methylene chloride, and drop finishes the reaction was continued 1h.Reaction
After, reaction solution is used respectively 2N hydrochloric acid (2 × 20mL), saturated sodium bicarbonate aqueous solution (2 × 20mL) and saturated salt solution
(2 × 20mL) washing, anhydrous sodium sulfate is dry, and methylene chloride is removed under reduced pressure and obtains title compound.ESI-Ms m/z:225.1[M+
H]+。
The synthesis of step d N- (the fluoro- 2- methyl-propyl of 2-) -2- (1H- indol-3-yl) cyclopenta -1- amine
In 250mL reaction flask, the addition fluoro- 2- methyl-propyl trifluoromethayl sulfonic acid ester of step c gains 2- (5g,
22.32mmol), 2- (1H- indol-3-yl) cyclopenta -1- amine (3.5g, 17.5mmol) and diisopropylethylamine (4.52g,
35mmol), it is dissolved with 50mL dioxane, argon gas protects lower 90 DEG C of reactions 2h, stops reaction, concentration, and column chromatographic purifying must be marked
Inscribe compound 1.7g.ESI-Ms m/z:275.19[M+H]+.Step e (E) -3- (4- carbonyl -3,5- difluorophenyl) propyl- 2- alkene
The synthesis of sour methyl esters
By the fluoro- 1- benzaldehyde (6.66g, 30mmol) of the bromo- 2,6- bis- of 4-, triethylamine (8.4mL, 60mmol), acid chloride
(0.34g, 1.5mmol) and trimethylphenyl phosphorus (1.0g, 3.2mmol) are dissolved in DMF (70mL), are de-gassed.Then
The reactant is simultaneously heated to 80 DEG C of lasting 4h by addition methyl acrylate (4.3mL, 45.0mmol).After cooling, by the mixture
It is added in water (300mL), and is extracted with ethyl acetate (2 × 400mL).Combined organic matter is used into 2N HCl in succession
(200mL) washing, then anhydrous sodium sulfate is dried and concentrated, which is obtained title compound.ESI-Ms
m/z:227.04[M+H]+。
Step f (E) -3- (the fluoro- 4- of 3,5- bis- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,10c-
Octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) methyl acrylate synthesis
In 100mL reaction flask, addition step d gains (300mg, 1.1mmol), (3,5- bis- is fluoro- by (E)-methyl -3-
4- Fonnylphenyl) methyl acrylate (251mg, 1.1mmol) and glacial acetic acid (0.6mL, 11mmol), it is molten to add toluene 25mL
Solution, 90 DEG C of reaction 6h, concentration of reaction solution, column chromatographic purifying obtain title compound.ESI-Ms m/z:483.2[M+H]+。
Step g (E) -3- (the fluoro- 4- of 3,5- bis- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,10c-
Octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid synthesis
Weigh step f gains (E) -3- (the fluoro- 4- of 3,5- bis- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a,
4,5,6,10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) methyl acrylate (215mg,
0.45mmol) in 100mL single port bottle, tetrahydrofuran/methanol (10mL/5mL) dissolution instills 7.5M NaOH% solution
2h is stirred at room temperature in (0.5mL), and fully reacting is concentrated under reduced pressure, and instills 1M HCl%, adjusts pH value to 6.5,15mL water is added, with 3
The extraction of × 15mL ethyl acetate merges organic phase, concentration, and column, which chromatographs, is made title compound.1H-NMR(400MHz,DMSO-d6)
δ:12.17(s,1H),10.16(s,1H),7.55(s,1H),7.51-7.15(m,4H),7.18-7.16(d,1H),7.02-
6.92(m,1H),6.71-6.67(d,1H),5.20(s,1H),3.15-3.12(m,1H),2.39-2.28(m,1H),2.15-
2.13(m,1H),2.08(s,1H),1.91-1.77(m,1H),1.65-1.49(m,1H),1.15(s,2H),1.09(s,6H),
1.01(s,2H).ESI-Ms m/z:469.2[M+H]+。
Embodiment 2 (E) -3- (the fluoro- 4- of the chloro- 5- of 3- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,
10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid
Step a:(E) synthesis of -3- (the fluoro- 4- Fonnylphenyl of the chloro- 5- of 3-) methyl acrylate
In 100mL reaction flask, the fluoro- benzaldehyde of the chloro- 6- of the bromo- 2- of 4- (2.37g, 10mmol), methyl acrylate is added
(1.72g, 20mmol), three (adjacent toluene) phosphines (0.33g, 1.0mmol), acid chloride (0.13g, 0.5mmol) and triethylamine
(1.99g, 20mmol) is dissolved with 25mL DMF, and argon gas protects lower 80 DEG C of reactions 6h.After reaction.20mL ice water is added to stir
It mixes, is extracted with ethyl acetate, saturated sodium-chloride washing is concentrated under reduced pressure after anhydrous sodium sulfate is dry, and column chromatographic purifying obtains titled
Close object.ESI-Ms m/z:243.0[M+H]+。
Step b:(E) -3- (the fluoro- 4- of the chloro- 5- of 3- (and (5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,
10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid synthesis
By the method for step f-g in embodiment 1, with step d gains N- (the fluoro- 2- methyl-propyl of 2-) -2- (1H- indoles -
3- yl) cyclopenta -1- amine, embodiment 2 step a gains (E) -3- (the fluoro- 4- Fonnylphenyl of the chloro- 5- of 3-) methyl acrylate be
Title compound is made in raw material.1H-NMR(400MHz,DMSO-d6)δ:12.23(s,1H),10.38(s,1H),8.07(s,
1H),7.92-7.45(m,4H),7.01-6.92(m,2H),6.77-6.69(m,1H),5.41(s,1H),3.95-3.89(m,
1H),3.03-2.95(m,1H),2.18-1.93(m,1H),1.91-1.52(m,2H),1.65-1.49(m,1H),1.31-0.99
(m,10H).ESI-Ms m/z:485.2[M+H]+。
Embodiment 3 (E) -3- (the fluoro- 4- of 3- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,10c- eight
Hydrogen cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) -5- methoxyphenyl) acrylic acid
Preparation method is similar to the preparation method of embodiment 1, the difference is that by the fluoro- 1- benzaldehyde of bromo- 2, the 6- bis- of raw material 4-
The fluoro- 6- methoxybenzaldehyde of the bromo- 2- of 4- is replaced with, title compound is made.
1H-NMR(400MHz,DMSO-d6)δ:12.24(s,1H),10.23(s,1H),7.55-7.47(m,2H),7.29-
7.14(m,2H),7.06-7.03(m,1H),6.96-6.91(m,2H),6.68-6.64(d,1H),5.35(s,1H),3.91(s,
3H),2.89(m,1H),2.32-2.29(m,1H),2.20-1.91(m,2H),1.60-1.55(m,2H),1.36-1.17(m,
4H),1.08-1.01(m,6H).ESI-Ms m/z:481.3[M+H]+。
Embodiment 4 (E) -3- (the fluoro- 4- of 3,5- bis- (the fluoro- 4- of (5R) -9- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,
6,10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid
Preparation method is similar to the preparation method of embodiment 1, the difference is that indoles, which is replaced with the fluoro- indoles of 5-, is made title
Compound.
1H-NMR(400MHz,DMSO-d6)δ:12.50(s,1H),10.60(s,1H),7.22-7.0(m,5H),6.85-
6.80(dd,1H),6.50-6.45(d,1H),5.16(s,1H),3.94-3.35(m,1H),3.01-2.75(m,1H),2.39-
2.27(m,1H),2.35-2.27(m,1H),2.09-2.03(m,1H),1.82-1.75(m,1H),1.68-1.51(m,1H),
1.38-1.24(m,1H),1.13(s,2H),1.09-1.08(d,5H),1.01(s,1H).ESI-Ms m/z:487.2[M+H]+。
Embodiment 5 (E) -3- (the fluoro- 4- of 3- (the fluoro- 4- of (5R) -9- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,
10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) -5- methoxyphenyl) acrylic acid
Preparation method is similar to the preparation method of embodiment 1, unlike indoles replaced with into the fluoro- indoles of 5- and by 4-
The fluoro- 1- benzaldehyde of bromo- 2,6- bis- replaces with the fluoro- 6- methoxybenzaldehyde of the bromo- 2- of 4-, and title compound is made.
1H-NMR(400MHz,DMSO-d6)δ:12.48(s,1H),10.35(s,1H),7.59-7.55(d,1H),7.31
(s,1H),7.20-7.07(m,3H),6.82-6.80(m,1H),6.70-6.66(d,1H),5.35(s,1H),3.91(s,3H),
3.41-3.37(t,2H),2.89-2.86(t,1H),2.38-2.26(t,1H),2.07-2.01(m,1H),1.92-1.71(m,
2H),1.59-1.52(m,2H),1.41-1.21(m,1H),1.09-1.01(q,6H).ESI-Ms m/z:499.3[M+H]+。
ER level activity rating of 1 Compound ira vitro of experimental example based on cellular level
1. experimental material
Reagent:Phosphate buffer (DPBS), trypan blue, PolarScreen ER Alpha competitor Assay,
Purchased from Invitrogen company;
Fetal calf serum (FBS), pancreatin, DMEM, Pen .- Strep (Pen/Strep) are purchased from GIBCO company;
Dimethyl sulfoxide (DMSO), active carbon, Formaldehyde solution are purchased from Sigma company;
MCF-7 cell is purchased from ATCC;
Estrogen Receptor α (D8H8) Rabbit mAb is purchased from CST company;
Goat anti-Rabbit IgG(H+L)Secondary Antibody(Alexa
488conjugate), it is purchased from Thermo company;
Tween 20 is purchased from EIA GRADE company.
Instrument:Biohazard Safety Equipment, CO2Incubator is purchased from Thermo Scientific company;
Centrifuge is purchased from Eppendorf company;
Cell counter is purchased from Invitrogen company;
Inverted microscope is purchased from Olympus company;
Multiflow is purchased from BioTeck company;
Turbine mixer is purchased from IKA company;
Envision is purchased from Perkin Elmer company.
2. experimental method
2.1. the preparation of cell culture fluid and compound
The preparation of Charcoal-stripped FBS:It weighs 1g active carbon and is mixed with 4 DEG C of 50mL fetal calf serum and passed through afterwards for 24 hours
0.22 μM of membrane filtration degerming, it is spare;
Cell culture fluid is prepared:The Pen .- Strep of 50mL FBS, 5mL are added in the DMEM of 445mL, mixed
It is spare.Charcoal-stripped FBS is used when cell culture fluid is prepared.
Compound prepares:After the compound of the present invention of above embodiments preparation is configured to 100mM with DMSO, successively dilute
To 10nM, 3.33nM, 1.11nM, 0.37nM, 0.123nM, 0.041nM, 0.014nM, 0.0045nM, 0.0015nM,
0.0005nM。
2.2. inoculating cell
10mL DPBS is added in the cell reject culture solution of logarithmic growth phase in T75 Tissue Culture Flask to wash once.It adds
2mL trypsin digestion cell, 37 DEG C are placed 2 minutes, and microscopically observation most cells shape is rounded, and the cell training of 5mL is added
Nutrient solution terminates digestion, and pipette is blown and beaten repeatedly, cell dissociation got off, cell suspension is made, then adds 10mL cell culture fluid,
It is counted after mixing;It is diluted to 1500 cells/40 μ L cell suspension, is spread cell into 384 hole cells with Multiflow instrument
Culture plate, 40 holes μ L/;Equilibrium at room temperature 20min is placed in 37 DEG C of cell incubators and cultivates for 24 hours.
Plus compound 2.3.
Compound is added in tissue culture plate with Acho instrument, DMSO final concentration 0.3%;Room temperature 1000rpm centrifugation
1min is placed in 37 DEG C of cell incubators and cultivates for 24 hours.
2.4. immunofluorescence experiment
Cell culture medium is sucked out, PBS is washed cell 1 time, with final concentration of 3.7% paraformaldehyde solution (PBS dilution) room
The fixed cell 20min of temperature;PBS is washed cell 2 times, permeates 1h with final concentration of 0.5% Tween-20 (PBS dilution) room temperature;With
PBS-T (in PBS containing 0.05% Tween-20) is washed cell 2 times, and Estrogen Receptor is added in ER level measurement
α (D8H8) Rabbit mAb dilution (1:1000, diluted with the milk in PBS-T containing 1%), it is incubated at room temperature 1.5h;PBS-T
It washes cell 3 times, Goat anti-Rabbit IgG (H+L) Secondary Antibody dilution (1 is added:1000, use PBS
In diluted containing 1% milk) Hochest 33342 of 2 μ g/mL, be incubated at room temperature 40min;PBS-T is washed cell 3 times, and PBS is washed
Cell 2 times;The ratio of Acumen reading ER positive signal value and nuclear signal value.
Table 1
It can be seen that the compound of the present invention had had the ER level based on cellular level from the above experimental result
Inhibitory activity promises to be the higher cancer therapeutic agent of curative effect very much.
The evaluation of 2 Compound ira vitro cell activity of experimental example
1. experimental material
Test-compound:The compound of the present invention of above embodiments preparation, each compound are configured to 10mM with DMSO,
Then successively 3 times be diluted to 100.00nM, 33.33nM, 11.11nM, 3.70nM, 1.23nM, 0.41nM, 0.14nM,
0.045nM、0.015nM。
Breast cancer cell line mcf-7 is purchased from company of Nanjing Keygen Biotech.
Reagent:MEM, FBS, Trypsin-EDTA, Penicillin-Streptomycin, it is public purchased from U.S. GIBCO
Department;Luminescent Cell Viability Assay Kit is purchased from U.S. Progema company;
Paclitaxel is purchased from Sichuan Tai Chi drugmaker.
2. experimental method
2.1. cell inoculation
The MCF-7 for cultivating amplification is cells trypsinised, is resuspended and is counted using fresh culture.By the thin of resuspension
Born of the same parents adjust to 2 × 104A cell/mL, and 96 porocyte culture plates are added, 100 μ L, each two multiple holes of concentration are added in every hole.In
37 DEG C, 5%CO2Under the conditions of be incubated for for 24 hours.
Plus compound 2.2.
Compound is configured to 200 × working solution with DMSO, is diluted to 2 × working solution with culture solution, retransfers 100 μ L in fact
It verifies, in 37 DEG C, 5%CO2Under the conditions of be incubated for 96h.
2.3. fluorescence reading
50 μ L are added to gaging hole Luminescent Cell Viability Assay
Buffer, and gently shake up.After ten minutes, it is placed on Envison and reads fluorescence reading, and calculate cell survival rate (cell
Survive (%)), calculation formula is cell survive (%)=(Com-Min)/(Max-Min), and wherein Max is blank pair
According to the reading of group, Min is the reading of cell-free control group, and Com is the reading of compound processing group, and data are handled through XLfit, is intended
Close to obtain IC50, experimental result is shown in Table 2.
Table 2
From the above experiment as can be seen that the compound of the present invention shows good suppression to MCF-7 breast cancer cell
System activity, promises to be breast cancer treatment agent very much.
Pharmacokinetic Evaluation in 3 compound body of experimental example
Test-compound:The compound of the present invention of above embodiments preparation, each compound solvent (2%
Solutol, 98% physiological saline) it is formulated as oral test sample 2mg/kg, intravenous test sample 1mg/kg.
Balb/c mouse ties up experimental animal Co., Ltd of tonneau China purchased from Beijing.
Mouse oral is with 2mg/kg, after intravenous is with 1mg/kg single-dose, respectively at 2min, 5min, 15min, 30min,
1h, 2h, 6h, 10h take a blood sample from orbital venous plexus for 24 hours, after centrifuging and taking plasma treatment, are detected, will be measured using LC-MS/MS
The blood concentration at each time point be depicted as pharmaceutical concentration-time curve, and calculate pharmacokinetic parameter.Experimental result is shown in Table
3。
Table 3
Test-compound | T1/2(h) | Cmax(ng/mL) | AUC(h*ng/mL) | F (%) |
Embodiment 1 | 0.9 | 143.2 | 187.6 | 45.6 |
Embodiment 2 | 2.5 | 288.8 | 142.5 | 68.9 |
Embodiment 3 | 2.6 | 211.0 | 685.4 | 48.7 |
Embodiment 4 | 4.3 | 267.8 | 2022.2 | 100.1 |
Embodiment 5 | 3.2 | 321.0 | 1573.5 | 72.4 |
The experimental results showed that, the compound of the present invention has good exposed amount, oral bio benefit in Mice Body above
Expenditure is high, can be used for being administered orally.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair
The present invention can be carry out various modifications and be changed under the premise of bright spirit and scope.Interest field of the invention is not limited to
Detailed description made by above, and claims should be belonged to.
Claims (10)
1. a kind of general formula I compound represented or its isomers, pharmaceutically acceptable salt, solvate, crystallization or prodrug,
Wherein,
X1、X2、X4, each X3Separately it is selected from C (R1R2)、N(R3), O, S, sulfone and sulfoxide, wherein R1、R2Separately select
From hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl,
Cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos,
Alkenyl, alkynyl, naphthenic base, heterocycle, heteroaryl and aryl;Or R1、R2Carbon atom connected to it is formed together carbonyl;R3Choosing
From hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxy alkyl, alkenyl, alkynyl, naphthenic base,
Heterocycle, heteroaryl and aryl, the group can by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl,
Alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkyl aminos, cycloalkanes
Base, heterocycle, aryl and heteroaryl replace;
R4Selected from hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxy alkyl, alkenyl, alkynyl,
Naphthenic base, heterocycle, heteroaryl and aryl, the group can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxyls
Base alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkyl ammonia
Base, naphthenic base, heterocycle, aryl and heteroaryl replace;
R5Selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitre
Base, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkane
Base amino, alkenyl, alkynyl and naphthenic base;
Each R6, each R7Separately it is selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, haloalkoxy
Base, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl,
Alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base and boric acid;
Y is selected from alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroarylalkoxy, alkyl amino, ring
It is alkalkylamino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, naphthenic base, heterocycle, aryl, miscellaneous
Aryl, alkenyl and alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroarylalkoxy
Base, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, naphthenic base,
Heterocycle, aryl, heteroaryl, alkenyl and alkynyl can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxyl alkane
Base, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino,
Alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base, heterocycle and oxo group take
Generation;With
M, n, o are each independently 1,2,3 or 4.
2. compound according to claim 1 or its isomers, pharmaceutically acceptable salt, solvate, crystallization or preceding
Medicine, wherein X1、X2, each X3It is C (R1R2), X4For N (R3), O, S, sulfone or sulfoxide.
3. compound according to claim 1 or its isomers, pharmaceutically acceptable salt, solvate, crystallization or preceding
Medicine, wherein R1、R2Separately it is selected from hydrogen, halogen, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6Alcoxyl
Base, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxyl, cyano, amino, list C1-6Alkyl amino, C1-6Alkyl acyl
Amino, C1-6Alkyl acyl, aminoacyl, C1-6Alkylaminoacyl, double C1-6Alkyl amino, C2-10Alkenyl, C2-10Alkynyl, C3-10
Naphthenic base, C1-10Heterocycle, C6-18Aryl and C1-18Heteroaryl;Or R1、R2Carbon atom connected to it is formed together carbonyl;R3Choosing
From hydrogen, C1-10Alkyl acyl, aminoacyl, C1-10Alkylaminoacyl, C1-10Alkyl, halogenated C1-10Alkyl, hydroxyl C1-10Alkyl,
C2-10Alkenyl, C2-10Alkynyl, C3-10Naphthenic base, C1-10Heterocycle, C6-18Aryl and C1-18Heteroaryl, the group can be by one
Or multiple halogens, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxylic
Base, cyano, amino, alkyl monosubstituted amino, double alkyl aminos, naphthenic base, heterocycle, aryl and heteroaryl replace.
4. -3 described in any item compounds or its isomers, pharmaceutically acceptable salt, solvation according to claim 1
Object, crystallization or prodrug, wherein R4Selected from hydrogen, C1-10Alkyl acyl, aminoacyl, C1-10Alkylaminoacyl, C1-10Alkyl, halogen
For C1-10Alkyl, hydroxyl C1-10Alkyl, C2-10Alkenyl, C2-10Alkynyl, C3-10Naphthenic base, C1-10Heterocycle, C6-18Aryl and C1-18It is miscellaneous
Aryl, the group can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, haloalkoxies
Base, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkyl aminos, naphthenic base, heterocycle, aryl and
Heteroaryl replaces;R5Selected from hydrogen, halogen, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6It is alkoxy, halogenated
C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxyl, cyano, amino, list C1-6Alkyl amino, C1-6Alkyl acylamino, C1-6
Alkyl acyl, aminoacyl, C1-6Alkylaminoacyl, double C1-6Alkyl amino, C2-10Alkenyl, C2-10Alkynyl and C3-10Naphthenic base.
5. -4 described in any item compounds or its isomers, pharmaceutically acceptable salt, solvation according to claim 1
Object, crystallization or prodrug, wherein each R6, each R7Separately it is selected from hydrogen, halogen, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl
C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxyl, cyano, amino, list C1-6Alkyl ammonia
Base, C1-6Alkyl acylamino, C1-6Alkyl acyl, aminoacyl, C1-6Alkylaminoacyl, double C1-6Alkyl amino, C2-10Alkene
Base, C2-10Alkynyl, C3-10Naphthenic base and boric acid.
6. -5 described in any item compounds or its isomers, pharmaceutically acceptable salt, solvation according to claim 1
Object, crystallization or prodrug, wherein Y is selected from C1-6Alkoxy, C3-10Naphthenic base C1-6Alkoxy, C1-10Heterocycle C1-6Alkoxy, C6-18
Aryl C1-6Alkoxy, C1-18Heteroaryl C1-6Alkoxy, C1-6Alkyl amino, C3-10Naphthenic base C1-6Alkyl amino, C1-10Heterocycle
C1-6Alkyl amino, C6-18Aryl C1-6Alkyl amino, C1-18Heteroaryl C1-6Alkyl amino, C3-10Naphthenic base, C1-10Heterocycle,
C6-18Aryl, C1-18Heteroaryl, C2-10Alkenyl and C2-10Alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy,
Alkoxy aryl, heteroarylalkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino,
Heteroaryl alkyl amino, naphthenic base, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can by one or more halogens, hydroxyl,
C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, nitro, carboxylic
Base, cyano, amino, list C1-6Alkyl amino, C1-6Alkyl acylamino, C1-6Alkyl acyl, aminoacyl, C1-6Alkyl amino acyl
Base, double C1-6Alkyl amino, C2-10Alkenyl, C2-10Alkynyl, C1-10Heterocycle, C3-10Naphthenic base and carbonyl replace.
7. -6 described in any item compounds or its isomers, pharmaceutically acceptable salt, solvation according to claim 1
Object, crystallization or prodrug, formula of I have the structure of following general formula Ia,
Wherein R4, each R6, each R7, m, n such as -6 formula of I according to claim 1 define.
8. compound according to claim 1 or its isomers, pharmaceutically acceptable salt, solvate, crystallization or preceding
Medicine, wherein the compound is compound selected from the following:
9. a kind of pharmaceutical composition, it includes described in any item compounds of claim 1 to 8 or its isomers, pharmaceutically
Acceptable salt, solvate, crystallization or prodrug and pharmaceutical acceptable carrier.
10. the described in any item compounds or its isomers, pharmaceutically acceptable salt, solvate, knot of claim 1-8
Brilliant or prodrug or pharmaceutical composition as claimed in claim 9 are being prepared for treating and/or preventing the relevant disease of estrogen receptor
Application in the drug of disease.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710320628 | 2017-05-09 | ||
CN2017103206283 | 2017-05-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108864080A true CN108864080A (en) | 2018-11-23 |
CN108864080B CN108864080B (en) | 2021-10-15 |
Family
ID=64327474
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810429737.3A Active CN108864080B (en) | 2017-05-09 | 2018-05-08 | Tetracyclic compounds as selective estrogen receptor down-regulating agents and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108864080B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021254471A1 (en) * | 2020-06-19 | 2021-12-23 | InventisBio Co., Ltd. | Oral formulations and uses thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010138659A1 (en) * | 2009-05-27 | 2010-12-02 | Ptc Therapeutics, Inc. | Methods for treating brain tumors |
WO2010138652A4 (en) * | 2009-05-27 | 2011-01-27 | Ptc Therapeutics, Inc. | Methods for treating kaposi sarcoma |
CN105229004A (en) * | 2013-05-28 | 2016-01-06 | 阿斯利康(瑞典)有限公司 | Compound |
CN106167488A (en) * | 2009-05-27 | 2016-11-30 | Ptc医疗公司 | Treatment cancer and the method for non-neoplastic conditions |
-
2018
- 2018-05-08 CN CN201810429737.3A patent/CN108864080B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010138659A1 (en) * | 2009-05-27 | 2010-12-02 | Ptc Therapeutics, Inc. | Methods for treating brain tumors |
WO2010138652A4 (en) * | 2009-05-27 | 2011-01-27 | Ptc Therapeutics, Inc. | Methods for treating kaposi sarcoma |
CN106167488A (en) * | 2009-05-27 | 2016-11-30 | Ptc医疗公司 | Treatment cancer and the method for non-neoplastic conditions |
CN105229004A (en) * | 2013-05-28 | 2016-01-06 | 阿斯利康(瑞典)有限公司 | Compound |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021254471A1 (en) * | 2020-06-19 | 2021-12-23 | InventisBio Co., Ltd. | Oral formulations and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
CN108864080B (en) | 2021-10-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106518946A (en) | Sulfonylurea derivative and pharmaceutical composition and application thereof | |
KR20190003572A (en) | Benzazepine derivatives, their preparation, drug compositions and applications | |
CN110494141A (en) | Pharmaceutical composition containing substituted polycyclic Pyridione derivatives and its prodrug | |
CN108329311B (en) | Tricyclic compound as selective estrogen receptor down-regulator and application thereof | |
CN103204838B (en) | The synthesis of polyhydroxy Benzofurantone compound and its antitumor action | |
CN104926788B (en) | Substituted piperidine analog derivative, the pharmaceutical composition containing it and its application in antitumor | |
CN108218868A (en) | Multi-kinase inhibitor compound, its crystal form and purposes | |
CN106831824A (en) | Pyrrolopyridines and its application containing naphthyridones structure | |
JP2021501215A (en) | Amino-substituted nitrogen-containing condensed ring compound, its preparation method and use | |
CN105085383B (en) | 5 methyl 2 (1H) Pyridione derivatives and its production and use | |
CN107814798A (en) | 3 substitutional crylic acid class compounds and its production and use | |
CN104230952A (en) | Compound containing pyrimidine skeleton, and preparation method and use of compound | |
CN104926814B (en) | Matrine derivative and application thereof | |
CN108299420A (en) | Five cyclics alternatively adjusted under property estrogen receptor and its application | |
TW202033520A (en) | Fused ring derivatives used as fgfr4 inhibitors | |
CN109988201A (en) | Glucoside compound, preparation method, composition, application and intermediate | |
CN108864080A (en) | Four cyclics alternatively adjusted under property estrogen receptor and its application | |
CN112384508B (en) | Tricyclic ASK1 inhibitor and application thereof | |
CN108218874A (en) | A kind of phosphodiesterase inhibitors and application thereof | |
CN105130884B (en) | 5 methyl 2 (1H) Pyridione derivatives and its production and use | |
CN107973788A (en) | BBI608 derivatives and its preparation and purposes | |
KR102606167B1 (en) | Fluorine-containing substituted benzothiophene compounds, pharmaceutical compositions and applications thereof | |
CN113444074B (en) | Compound with EGFR (epidermal growth factor receptor) and Wnt dual inhibition effects as well as preparation method and application thereof | |
CN107892691A (en) | 2,8,9 3 substitution 9H purine compounds and its salt and application | |
CN106810549A (en) | Contain 7 azaindoles of dihydrogen dazin structure and its application |
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 |