CN108558848A - A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage - Google Patents

A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage Download PDF

Info

Publication number
CN108558848A
CN108558848A CN201810353541.0A CN201810353541A CN108558848A CN 108558848 A CN108558848 A CN 108558848A CN 201810353541 A CN201810353541 A CN 201810353541A CN 108558848 A CN108558848 A CN 108558848A
Authority
CN
China
Prior art keywords
methyl
cyano
formamido
pyrazoles
bithiophene
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.)
Pending
Application number
CN201810353541.0A
Other languages
Chinese (zh)
Inventor
陈益华
刘明耀
周文波
陈煌
胡盼
易正芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
East China Normal University
Original Assignee
East China Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by East China Normal University filed Critical East China Normal University
Priority to CN201810353541.0A priority Critical patent/CN108558848A/en
Publication of CN108558848A publication Critical patent/CN108558848A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pulmonology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of cycloalkane thiophthene derivative and its pharmaceutically acceptable salt, metabolite or prodrugs.The compound can be used as treatment and STAT3 and activate related disease treatment, including oophoroma, carcinoma of endometrium, cervical carcinoma, breast cancer, colon cancer, cancer of pancreas, lung cancer, the cancer of the brain, prostate cancer, kidney, liver cancer, carcinoma of urinary bladder, carcinoma of mouth, sarcoma, prostate cancer, Head and neck squamous cell carcinoma, glioma, melanoma, lymthoma, leukaemia and kidney fibrosis, pulmonary fibrosis, rheumatoid arthritis, hair growth, arthritis, psoriasis, lupus erythematosus, inflammatory lung disease and inflammatory bowel disease etc..

Description

A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of cycloalkane thiophthene derivative and preparation method thereof and doctor Medicine application, the application especially in preparing antitumor drug and autoimmune disease.
Background technology
Signal transduction and (the signal transducers and activators of of transcriptional activators 3 Transcription 3, STAT3) be the signal transduction that some cell factors and growth factor mediate transcription factor, just A series of often physiological functions such as intracellular regulation and control growth, proliferation, differentiation and apoptosis.Stat protein family includes 7 members： STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6, wherein STAT3 are overexpressed and are activated many pernicious Organization type tumour in high expression is presented, and play a driving role, wrap in the generation process to many solid tumors and blood tumor Containing oophoroma, carcinoma of endometrium, cervical carcinoma, breast cancer, colon cancer, cancer of pancreas, lung cancer, the cancer of the brain, prostate cancer, kidney, liver cancer, Carcinoma of urinary bladder, carcinoma of mouth, sarcoma, prostate cancer, Head and neck squamous cell carcinoma, glioma, melanoma, lymthoma and white blood Disease.
The molecular size range of STAT3 albumen is about 89~92kD, is made of 750~795 amino acid, which includes 6 A functional structure：N-terminal amino acid conserved sequence, helical region, DNA binding domain, bonding pad, SH2 structural domains and C-terminal transcription activating Area.As a kind of wide expression in each histiocytic transcription regulaton factor of people and mouse, STAT3 mainly by cell factor (such as IL-6) and growth factor (such as VEGF) induction JAK-STAT signal pathways and MAPK pathway activations.Cell factor or growth The factor forms dimer after being combined with corresponding receptor, so that cytoplasm JAKs is assembled, mutual phosphoric acid between neighbouring JAKs Change and be activated, to the tyrosine residue phosphorylation of catalytic receptor.By recruiting STAT3 monomers it is allowed to that tyrosine 705 occurs Position phosphorylation, pSTAT3 monomer form dimer across nuclear membrane from cytoplasm by being mutually distinguishable the SH2 structural domains of other side Transporte to cells core is simultaneously combined using its DNA binding domain with specific dna sequence in core, and the adjustment signal conduction in downstream is then started The transcriptional expression of key protein (Bc1)-X1, (Mcl-1), cyclinD1/D2 and c-Myc etc. grow to regulating cell, proliferation, Differentiation and apoptosis.
After STAT3 activation, the expression of cyclin and anti-apoptotic can be enhanced, to promote abnormal cell proliferation and swell Oncocyte anti-apoptotic ability can also express MMP2, MMP9 and VEGF to promote invasion and the thin vessels of tumour cell by activation Formation.In addition, the STAT3 of activation can improve the immune of tumour cell by adjusting the secretion of inflammatory factor and chemotactic factor (CF) Escape capability.Research confirms, STAT3 after activation mainly by adjusting tumour cell microenvironment (such as IL-12/IL-23 is unbalance), IL-12 secretions are caused to reduce and promote the generation of canceration；IL-23 is improved immune in tumor microenvironment by regulatory T-cell Inhibit molecular activity.
STAT3 is very important in addition to playing the role of in tumour, while the work of STAT3 is had also discovered in other diseases Change, the STAT3 of abnormal activation promotes the occurrence and development of disease.These diseases include kidney fibrosis, pulmonary fibrosis, rheumatoid Property arthritis, psoriasis, lupus erythematosus, inflammatory lung disease and inflammatory bowel disease.
Generation, the development of most of tumours are related to abnormal JAK-STAT3 signal pathways, this signal pathway is finally concentrated again It is activated in the STAT3 of transcription regulaton factor STAT3, aberrant continuation, leads to infinite multiplication, anti-apoptotic, invasion, the blood of tumour cell Pipe regenerates and escape immunosurveillance.Block STAT3, you can block abnormal tumor signal approach, therefore using STAT3 as target spot Inhibitor carry out the research and development for the treatment of cancer and also increasingly paid attention to by international bio businesses and institutions.Currently, many specificity STAT3 micromolecular inhibitors are found and are applied to oncotherapy research, wherein activity preferably Mechanism Study is relatively specific smaller Molecule STAT3 inhibitor is as follows.
By to the analysis of above-mentioned small molecule STAT3 inhibitor structures and clinical manifestation analysis, finding current small molecule STAT3 inhibitor has apparent defect：Wherein with STA-21, Cryptotanshinone, Stattic, BBI608 and JMC-9 For representative micromolecular inhibitor due to all contain quinones or class quinones structure, clinically show prodigious toxicity；In addition This kind of compound of a part of compound in part such as S3I-201, SH5-07 and BP-1-102 is mostly quasi- peptides, in vivo generation It thanks unstable, it is difficult to which exploitation enters clinic at clinical compounds, there is presently no report this small molecule STAT3 inhibitor and grinds Study carefully.Therefore this application involves a kind of novel specific small molecule STAT3 inhibitor, to solve to have small molecule at present The defect of STAT3 inhibitor, the clinical application for STAT3 micromolecular inhibitors provide better choice.
Invention content
In view of the deficiency of existing small molecule STAT3 inhibitor, the purpose of the present invention is to propose to a kind of novel cycloalkane and thiophenes Pheno derivative can be used as STAT3 inhibitor, be used for developing anti-tumor medicaments.
A kind of cycloalkane thiophthene derivative and its pharmaceutically acceptable salt, metabolite or prodrug, structure such as formula (I) shown in：
Wherein,
X is CH, N；
Y be C=O, C=S ,-C (O) NH- ,-C (O) O- ,-C (O) S- ,-C (S) NH- ,-C (S) O- ,-C (S) S-, NH, O, S；
M is 0~3；
Ar be the 5-6 member aromatic rings containing 0-3 N atom and 0-1 O or S atom, including phenyl ring, thiphene ring, furan nucleus, Pyrrole ring, thiazole ring,It is azoles ring, differentAzoles ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring；
R1For the substituent group on aromatic rings/aromatic heterocycle, it is selected from one or more of following groups：Halogen, hydroxyl, cyanogen Base, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 members heteroaryl are fragrant Base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5Substituent group take Generation, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, p 0,1 or 2；
R2For hydrogen, hydroxyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5, 5-6 members aromatic radical, 5-6 circle heterocyclic ring aromatic radicals；Optionally, the 5-6 members aromatic radical and 5-6 circle heterocyclic ring aromatic radicals are respectively only On the spot by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 Circle heterocyclic ring base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C (O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, p 0,1 Or 2.
In formula (I) of the present invention, when X is CH, shown in structure such as following formula (II)：
Wherein,
Y be C=O, C=S ,-C (O) NH- ,-C (O) O- ,-C (O) S- ,-C (S) NH- ,-C (S) O- ,-C (S) S-, NH, O, S；
M is 0~3；
Ar be the 5-6 member aromatic rings containing 0-3 N atom and 0-1 O or S atom, including phenyl ring, thiphene ring, furan nucleus, Pyrrole ring, thiazole ring,It is azoles ring, differentAzoles ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring；
R1Independently by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5Be each independently hydrogen or C1-4Alkyl, p 0,1 or 2；
R2For hydrogen, hydroxyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5, 5-6 members aromatic radical, 5-6 circle heterocyclic ring aromatic radicals；Optionally, the 5-6 members aromatic radical and 5-6 circle heterocyclic ring aromatic radicals are respectively only On the spot by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 Circle heterocyclic ring base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C (O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, p 0,1 Or 2.
In formula (I) of the present invention, when X is N atoms, and Y is carbonyl, shown in structure following (III)：
Wherein,
M is 0~3；
Ar be the 5-6 member aromatic rings containing 0-3 N atom and 0-1 O or S atom, including phenyl ring, thiphene ring, furan nucleus, Pyrrole ring, thiazole ring,It is azoles ring, differentAzoles ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring；
R1Independently by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5Be each independently hydrogen or C1-4Alkyl, p 0,1 or 2；
R2For hydrogen, hydroxyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5, 5-6 members aromatic radical, 5-6 circle heterocyclic ring aromatic radicals；Optionally, the 5-6 members aromatic radical and 5-6 circle heterocyclic ring aromatic radicals are respectively only On the spot by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 Circle heterocyclic ring base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C (O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, p 0,1 Or 2.
In formula (I) of the present invention, when X is N atoms, and Y is-C (O) NH-, shown in structure such as following formula (IV)：
Wherein,
M is 0~3；
Ar be the 5-6 member aromatic rings containing 0-3 N atom and 0-1 O or S atom, including phenyl ring, thiphene ring, furan nucleus, Pyrrole ring, thiazole ring,It is azoles ring, differentAzoles ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring；
R1Independently by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5Be each independently hydrogen or C1-4Alkyl, p 0,1 or 2；
R2For hydrogen, hydroxyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5, 5-6 members aromatic radical, 5-6 circle heterocyclic ring aromatic radicals；Optionally, the 5-6 members aromatic radical and 5-6 circle heterocyclic ring aromatic radicals are respectively only On the spot by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 Circle heterocyclic ring base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C (O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, p 0,1 Or 2.
Those skilled in the art is appreciated that the convention used according to this field, in the structural formula of the application,With In describing chemical bond, the chemical bond is part or the point that substituent group is connected with nuclear structure or skeleton.
As a result, throughout this manual, those skilled in the art can be to R described in compound shown in formula (I)-(IV)1 ~R2Group and its substituent group and X, Y, m, p and Ar selected, it is described in the embodiment of the present invention, steady to provide Compound or pharmaceutically acceptable salt thereof, hydrate, solvate, metabolite or prodrug shown in fixed formula (I)-(IV).
According to an embodiment of the invention, formula (I)-(IV) compound represented of the present invention or its is pharmaceutically acceptable Salt, hydrate, solvate, metabolite or prodrug, including:
4- cyano -5- (1- methyl -4- pyrazoles)-formamido-cyclobutyl [2,3] bithiophene
4- cyano -5- (1- methyl -4- pyrazoles)-formamido-cyclopenta [2,3] bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -4,5,6,7- tetrahydro benzo thiophene
4- cyano -5- (1- methyl -4- pyrazoles)-formamido-suberyl [2,3] bithiophene
4- cyano -5- (1- methyl -4- pyrazoles)-formamido-cyclooctyl [2,3] bithiophene
2- (1- first -4- pyrazoles)-formamido -3- cyano -4- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (1-H-4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6,6- dimethyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- propyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- phenyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethoxy carbonyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl 4- pyrazoles)-formamido -3- cyano -6- oxygen -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- hydroxyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6,2 '-[1,3] dioxolanes -4,5,6,7- tetrahydro benzos Thiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethoxy carbonyl -4,5,6,7- tetrahydrochysenes [2,3-c] piperazine Pyridine bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- tertbutyloxycarbonyl -4,5,6,7- tetrahydrochysenes [2,3-c] piperazine Pyridine bithiophene
2- (1- methyl -3- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl -5- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- methyl -4- imidazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2-(4-Azoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (4- thiazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2-benzamide base -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (2- pyridines)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (4- pyrimidines)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- hydrogen -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- (2- ethoxys) -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene
2- (1- (2- methoxy ethyls) -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophenes Pheno
2- (1- (2- (2- hydroxy ethoxies) ethyl -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydrochysenes Benzothiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- glycolyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- Methoxyacetyl -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (1- methylpyrazole -3- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (1- methylpyrazole -4- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (1- methylpyrazole -5- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (Azoles -4- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (thiazole -4- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methoxybenzothiophene -2- carbonyls) -4,5,6, 7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (benzothiophene -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methyl benzofuran -2- carbonyls) -4,5,6,7- Tetrahydrochysene [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- methylfuran -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (thiophene -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- chlorothiophene -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromine furans -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- chlorine furans -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene (implement 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromothiophene -2- carbonyls) -4,5, 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (4- bromothiophene -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromomethyl furans -2- carbonyls) -4,5,6,7- four Hydrogen [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (pyrrolidines -1- methylene) furans -2- carbonyls) - 4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (morpholine ring -1- methylene) furans -2- carbonyls) - 4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (4- methyl piperazine -1- methylene) furans -2- carbonyls Base) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (4- (2- ethoxys) piperazine -1- methylene) furans Mutter -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethylamino-s carbonyl -4,5,6,7- tetrahydrochysenes [2,3-c] piperazine Pyridine bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- anilinocarbonyl -4,5,6,7- tetrahydrochysenes [2,3-c] piperazine Pyridine bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- benzylamines acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines Bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- β phenyl ethylamines acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperazine Pyridine bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- phentermines acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperazine Pyridine bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (furans -2- methylene) aminoacyl -4,5,6,7- four Hydrogen [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- pyridine ethylamines acyl group) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (4- pyridine propylamine acyl group) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- are to Bretylium Tosylate acyl group -4,5,6,7- tetrahydrochysenes [2,3- C] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (to fluorophenethylamine acyl group) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- are to chlorophenethylamine acyl group -4,5,6,7- tetrahydrochysenes [2,3- C] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- neighbour's fluoroaniline acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- m-fluoroaniline acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- para-fluoroaniline acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- o-aminoanisole acyl group -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- m-anisidine acyl group -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- P-nethoxyaniline acyl group -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methyl formate aniline acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (o-Phenetidine acyl group) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (the chloro- 3- 5-trifluoromethylanilines acyl groups of 4-) -4,5,6, 7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ((2- pyridines amido) carbonyl) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methoxyl group -3- pyridines amine) acyl group -4,5,6,7- Tetrahydrochysene [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (4- methoxyl group -3- pyridines amine) acyl group -4,5,6,7- Tetrahydrochysene [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2,4- dimethoxyanilines acyl group) -4,5,6,7- four Hydrogen [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- (2- (tert-butoxycarbonylamino) ethyoxyl) aniline acyls Base) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- methoxyl groups -4- (2- (tert-butoxycarbonylamino) ethoxies Base) aniline acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (quinoline -8- amine acyl group) -4,5,6,7- tetrahydrochysenes [2,3- C] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (isoquinolin -8- amine acyl group) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2 methyl indole -3- ethyls) amine acyl group -4,5,6, 7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- methoxy-Indole -3- ethyls) amine acyl group -4,5, 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- fluoro indole -3- ethyls) amine acyl group -4,5,6,7- Tetrahydrochysene [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- chloro-indole -3- ethyls) amine acyl group -4,5,6,7- Tetrahydrochysene [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromo indole -3- ethyls) amine acyl group -4,5,6,7- Tetrahydrochysene [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (6- bromo indole -3- ethyls) amine acyl group -4,5,6,7- Tetrahydrochysene [2,3-c] piperidines bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (7- bromo indole -3- ethyls) amine acyl group -4,5,6,7- Tetrahydrochysene [2,3-c] piperidines bithiophene.
In term used in the present invention, C1-6Selected from C1、C2、C3、C4、C5And C6；C1-8Selected from C1、C2、C3、C4、C5、 C6、C7And C8；C2-8Selected from C2、C3、C4、C5、C6、C7And C8；C3-8Selected from C3、C4、C5、C6、C7And C8；C5-10Selected from C5、C6、C7、 C8、C9And C10.Term " pharmaceutically acceptable " of the present invention, be for those compounds, material, composition and/ Or for dosage form, they are suitable for contacting use with the tissue of human and animal within the scope of reliable medical judgment, and Not excessive toxicity, irritation, allergic reaction or other problems or complication match with rational interests/Hazard ratio.
Term " pharmaceutically acceptable salt " of the present invention refers to the salt of the compounds of this invention, by present invention discover that The compound and relative nontoxic with specified substituent acid or alkali prepare.
It, can be by pure solution or suitable lazy when in the compound of the present invention containing relatively acid functional group In property solvent base addition salts are obtained with the mode that the alkali of sufficient amount is contacted with the neutral form of this kind of compound.It is pharmaceutically acceptable Base addition salts include sodium, potassium, calcium, amine, organic amine or magnesium salts or similar salt.
It, can be by pure solution or suitable inertia when in the compound of the present invention containing relatively alkaline functional group In solvent acid-addition salts are obtained with the mode that the acid of sufficient amount is contacted with the neutral form of this kind of compound.It is pharmaceutically acceptable The implementation of acid-addition salts includes inorganic acid salt, and the inorganic acid salt includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate Root, phosphoric acid, one hydrogen radical of phosphoric acid, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, it is described Organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, breast Acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；Further include The salt of amino acid (such as arginine), and such as glucuronic acid organic acid salt.Certain specific compounds of the present invention Containing acid and alkalinity functional group, so as to be converted into any alkali or acid-addition salts.
Preferably, make alkali or acid contact in a usual manner, then detach parent compound, thus the neutral shape of raw compounds again Formula.The forms of the parent fo of compound and its various salt is the difference is that certain physical properties, such as in polar solvent Different solubility.
" pharmaceutically acceptable salt " used in the present invention belongs to the derivative of the compounds of this invention, wherein by with acid The parent compound is modified at salt or with alkali at the mode of salt.The example of pharmaceutically acceptable salt includes：Base such as amine Inorganic salts or organic salt, acid group such as carboxylic acid the salt etc. that is formed of alkali metal or organic acid.Pharmaceutically acceptable salt includes The quaternary amine of conventional avirulent salt or parent compound, such as nontoxic inorganic acid or organic acid are formed by salt.
The conventional avirulent salt that inorganic acid and organic acid are derived from including those, the inorganic acid or organic acid choosing From Aspirin, 2- ethylenehydrinsulfonic acids, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, lemon Lemon acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid, salt Acid, hydroiodic acid eye, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, first Alkyl sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, poly galacturonic, propionic acid, salicylic acid, stearic acid, Asia Acetic acid, succinic acid, sulfamic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.
The pharmaceutically acceptable salt of the present invention can pass through conventional chemical side by the parent compound containing acid group or base Method synthesizes.Under normal circumstances, the preparation method of such salt is：In the mixture of water or organic solvent or both, via trip It is reacted with the alkali appropriate of stoichiometry or acid to prepare from these compounds of acid or alkali form.It is generally preferable that ether, acetic acid The non-aqueous medias such as ethyl ester, ethyl alcohol, isopropanol or acetonitrile.
In addition to the form of salt, there is also prodrug forms for compound provided by the present invention.The compound that the present invention is described Prodrug be easy in physiological conditions occur chemical change to be converted to the compound of the present invention.It can convert in vivo to provide Any compound of bioactive substance (i.e. compound shown in formula (I)~(IV)) be in the scope and spirit of the present invention before Medicine.For example, the compound containing carboxyl can hydrolyzable ester on physiology, by hydrolyze in vivo the formula of having obtained ((I)~ (IV)) compound itself shown in and serve as prodrug.The prodrug is preferably administered orally, this is because hydrolysis is led in many cases To occur under the influence of digestive ferment.When ester itself is active or hydrolysis occurs in blood, parenteral administration can be used. In addition, pro-drug can be transformed into the compound of the present invention in environment by chemistry or biochemical method in vivo.
Certain compounds of the present invention can have asymmetric carbon atom (optical centre) or double bond.It is racemic modification, non-right Isomers, geometric isomer and single isomers is reflected to be included within the scope of the present invention.
The compound of the present invention may exist specific geometry or stereoisomer form.It is contemplated by the invention that all is this kind of Compound, including cis and trans isomer, (-)-and (+)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomery Body and its racemic mixture and other mixtures, such as enantiomter or the mixture of diastereoisomer enrichment, own These mixtures are within the scope of the present invention.Other asymmetric carbon atom may be present in the substituent groups such as alkyl.It is all These isomers and their mixture, are included within the scope of the present invention.
The compound of the present invention can include the original of unnatural proportions on one or more atoms for constituting the compound Daughter isotope.For example, compound isotopically labelled can be used, such as deuterium (2H), tritium (3H), iodine-125 (125I) or C-14 (14C).This The transformation of all isotopics of the compound of invention is included in whether no matter radiation within the scope of the present invention.
Term " excipient " of the present invention typically refers to carrier, dilution required for configuration drug composition effective Agent and/or medium.
For drug or pharmacologically active agents, term " effective quantity " of the present invention or " therapeutically effective amount " are Refer to enough dosages of drug that is nontoxic but can achieving the desired results or medicament.For the peroral dosage form in the present invention, composition In order to achieve the desired results when a kind of " effective quantity " of middle active material refers to another active material combination in the composition The dosage needed.A effective amount of determination varies with each individual, and depends on age and the ordinary circumstance of receptor, also depends on specific active matter Matter, suitable effective quantity can be determined by those skilled in the art according to routine test in case.
Term " active constituent " of the present invention, " therapeutic agent ", " active material " or " activating agent " refers to a kind ofization Entity is learned, it can effective therapeutic purpose disorder, disease or illness.
Term " substituted " of the present invention refers to that any one or more hydrogen atoms in specific atoms are taken Replace for base, include the variant of heavy hydrogen and hydrogen, as long as the compound after the valence state of specific atoms is normal and substitution is steady Fixed.Mean that two hydrogen atoms are substituted (i.e. when C=O) when substituent group is ketone group.Ketone substitution will not occur directly in fragrance On base.Term " arbitrary substituted " of the present invention refers to that can be substituted, and can not also be substituted, unless otherwise rule Calmly, the type and number of substituent group can be arbitrary on the basis of may be implemented in chemistry.
When any variable (such as R) occurs in the composition of compound or structure more than primary, in every case Under definition be all independent.Thus, for example, if a group is replaced by 0-2 R, the group can be arbitrarily At most replaced by two R, and R in each case is independent option.In addition, the group of substituent group and/or its variant It closes and is only just allowed in the case where such combination will produce stable compound.When one of variable is selected from list When key, indicate that two groups of its connection are to be connected directly, for example when L represents singly-bound in A-L-Z indicates that the structure is actually A-Z。
In the context of the present invention, all terms " alkyl " being related to or " alkane " or " alkyl group " can be handed over here Use is changed, wherein the alkyl can optionally be replaced by the substituent group that one or more present invention describe.Some embodiment party In case, alkyl group contains 1-8 carbon atom；In other embodiments, alkyl group contains 1-6 carbon atom；Other In embodiment, alkyl group contains 1-4 carbon atom.The example of alkyl group includes, but is not limited to：Methyl (Me ,- CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n- Bu、-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tertiary butyl (t-Bu、-C(CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyls (- CH (CH3)CH2CH2CH3) 3- amyls (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl- 1- butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH3CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3))、2- Methyl -2- amyls (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyls (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- penta Base (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyls (- C (CH3)(CH2CH3)2), 2- methyl -3- amyls (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3-3- dimethyl -2- butyl (- CH (CH3) C(CH3)3), n-heptyl, n-octyl etc..
Term " alkoxy " of the present invention indicates that alkyl group is connected by oxygen atom with molecule rest part, Middle alkyl group has meaning as described in the present invention.Unless otherwise detailed instructions, it is former to contain 1-6 carbon for the alkoxy grp Son.The example of alkoxy base includes, but is not limited to：Methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-OCH2CH3), the third oxygen Base (n-PrO ,-OCH2CH2CH3), isopropoxy (i-PrO ,-OCH (CH3)2), n-butoxy (n-BuO ,-OCH2CH2CH2CH3)、 Isobutoxy (i-BuO ,-OCH2CH(CH3)2), sec-butoxy (s-BuO ,-OCH (CH3)CH2CH3), tert-butoxy (t-BuO ,- OC(CH3)3), n-pentyloxy (- OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3)CH2CH2CH3) 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- butoxy (- OCH (CH3)CH(CH3)2)、 3- methyl-1s-butoxy (- OCH2CH2CH(CH3)2), 2-methyl-1-butene oxygroup (- OCH3CH(CH3)CH2CH3), positive hexyloxy (- OCH2CH2CH2CH2CH2CH3) etc..
Term " naphthenic base " of the present invention indicates containing 3-8 carbon atom, monovalent or multivalence saturation monocycle, Bicyclic or three-ring system, wherein the substituent group institute that the group of naphthene base can be described optionally by one or more present invention Substitution.In some embodiments, naphthenic base includes 3-8 carbon atom.Such example includes, but are not limited to：Cyclopropyl, ring Butyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl etc..
Term " halogen " of the present invention refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " alkoxyamino " of the present invention includes " N- alkoxyaminos " and " N, N- alkoxyamino ", wherein ammonia Base group is separately replaced by one or two alkyl group.Wherein, alkyl group has and contains as described in the present invention Justice.Suitable alkoxyamino group can be single alkoxyamino or dialkoxy amino, and such example includes, but is not limited to： N- methylaminos, N- ethylamino-s, isopropylamino, the third amino, tertiary fourth amino, n-butyl amine base, 1- methylpropylaminos, n-pentyl ammonia Base, n-hexyl amino, N, N- dimethylaminos, N, TMSDEA N diethylamine base etc..
Term " C of the present invention1-6Acyl group " refers to R-C (=O)-, and wherein R is C1-6Alkyl, C1-6Alkyl has such as Meaning of the present invention.
Term " alkoxy morpholine " of the present invention refers to the morpholinyl being substituted with one or more alkyl groups.
Term " C of the present invention1-6Acyl piperazine " refers to by one or more C1-6The piperazinyl of acyl group substitution.
Term " hydroxyl C of the present invention1-6Alkyl piperazine " refers to the C replaced by one or more hydroxyls1-6Alkyl Substituted piperazinyl.
Term " alkylaminopiperidine base " of the present invention refers to the amino substitution being substituted with one or more alkyl groups Piperidyl.
Term "comprising" of the present invention is open language, that is, includes the content specified by the present invention, but do not arrange Except otherwise content.
Reaction dissolvent is not particularly limited used in each reaction step of the present invention, any to a certain extent It dissolves starting material and the solvent of reaction is not inhibited to be included in the present invention.In addition, many similar changes of this field, etc. With replacement, or equivalent and described in the invention solvent, the different proportion of solvent combination and solvent combination is accordingly to be regarded as the present invention Scope.
According to the second aspect of the invention, the present invention, which proposes, a kind of preparing cycloalkane bithiophene shown in formula (I)-(IV) and spreads out The method of biology.The universal synthesis method of such compound is first to synthesize -3 cyano thiophene derivative of 2- amino, then passes through one Serial reaction is formed by connecting with -3 cyano thiophene derivative of intermediate 2-amino.
According to an embodiment of the invention, the present invention provides a kind of method preparing compound shown in formula (I)-(IV), is logical Cross what following synthetic route (1) was prepared：
Route (1)；
Wherein, R1, R2, X, Y, m, A be as defined herein.
The inventors discovered that can fast and effeciently prepare formula (I)-(IV) institute using the synthetic method of implementation column of the present invention Show compound, and short, environmental-friendly, target product the yield of synthetic route and purity are higher, raw material is easy to get, operates and post-processes Simply, it is suitble to industrialized production.
According to the third aspect of the present invention, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition contains The aforesaid compound of therapeutic dose.
Described pharmaceutical composition includes cycloalkane thiophthene derivative and its pharmaceutically acceptable salt, metabolite or preceding Medicine.
Described pharmaceutical composition is at least one following：
Inhibit the tool compound of signal transduction and transcriptional activators 3 (STAT3)；
The pharmaceutical composition of disease that treatment STAT3 activation causes or regulates and controls；
The pharmaceutical composition of cancer that treatment STAT3 activation causes or regulates and controls；
Inhibit the tool compound of cancer cell multiplication and migration caused by STAT3 activation.
" pharmaceutical composition " indicate containing one or more compounds of the present invention or its physiologically/it is pharmaceutical The mixture or other components such as physiological saline/pharmaceutical load of salt, metabolite or pro-drug and other chemical constituents Body and excipient.The purpose of pharmaceutical composition is the administration promoted to organism, and life is played in turn conducive to the absorption of active constituent Object activity.
According to a particular embodiment of the invention, which contains chemical combination shown in foregoing formula (I)-(IV) Object.According to an embodiment of the invention, described pharmaceutical composition is for inhibiting STAT3；Inhibit the phosphorylation and downstream gene of STAT3 Expression；Treatment prevents the cancer that STAT3 is mediated；The cancer is that malignant tumour includes oophoroma, carcinoma of endometrium, palace Neck cancer, breast cancer, colon cancer, cancer of pancreas, lung cancer, the cancer of the brain, kidney, liver cancer, sarcoma, prostate cancer, Head and neck squamous cell carcinoma, god Through glioma, melanoma, lymthoma and leukaemia.Described pharmaceutical composition can be additionally used in caused by p-STAT3 overexpressions Other diseases；The disease be autoimmune disease include kidney fibrosis, pulmonary fibrosis, rheumatoid arthritis, psoriasis, Lupus erythematosus, inflammatory lung disease and inflammatory bowel disease etc..
According to an embodiment of the invention, described pharmaceutical composition further comprises that second medicament, the second medicament are different In compound noted earlier and for treatment or pre- anti-cancer, kidney fibrosis, pulmonary fibrosis, rheumatoid arthritis, silver Consider disease, lupus erythematosus, inflammatory lung disease and inflammatory bowel disease etc. to be worth doing.According to an embodiment of the invention, second medicament and formula (I)-(IV) institute Show the combination of compound so that described pharmaceutical composition is more efficiently used to inhibit STAT3, and for treating or preventing Cancer, kidney fibrosis, pulmonary fibrosis, rheumatoid arthritis, psoriasis, lupus erythematosus, inflammatory lung disease and inflammatory bowel disease etc..
According to a particular embodiment of the invention, pharmaceutical composition further include pharmaceutically acceptable carrier, excipient, Diluent, adjuvant, medium or combinations thereof.
According to a particular embodiment of the invention, pharmaceutical composition in tablet, capsule, injection, powder-injection, pulvis, syrup, Solution shape, suspension or aerosol.It is possible thereby to significantly improve the applicability of the pharmaceutical composition.And the above-mentioned implementation of the present invention The pharmaceutical composition of example can reside in the carrier of suitable solid or liquid or dilution neutralize it is suitable for injecting or dripping In the disinfecting container of note.
The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to the customary preparation methods of pharmaceutical field.The present invention's Compound and pharmaceutical composition can to mammal Clinical practice, including humans and animals, can by mouth, nose, skin, lung or The approach of gastrointestinal tract etc. is administered.No matter use which kind of instructions of taking, personal optimal dose should according to specific therapeutic scheme and It is fixed.It is to gradually increase dosage until finding most suitable dosage since low dose under normal conditions.Most preferred administration way Diameter is oral or percutaneous drug delivery.
According to the fourth aspect of the invention, the present invention proposes foregoing compound, prepared by foregoing method The purposes of obtained compound or foregoing pharmaceutical composition in medicine preparation.
According to a particular embodiment of the invention, the drug is at least one following：As STAT3 inhibitor, it is used for Treatment or pre- anti-cancer, kidney fibrosis, pulmonary fibrosis, rheumatoid arthritis, psoriasis, lupus erythematosus, inflammatory lung disease and Inflammatory bowel disease etc..
Specific example according to the present invention, compound has apparent knot to STAT3 shown in formula (I)-(IV) of the present invention Cooperation is used, and activity is significantly better than positive control BP-1-102.
According to example of the present invention, compound shown in formula (I)-(IV) of the present invention can to the proliferation of a variety of cancer cells and Migration has apparent inhibiting effect.
According to example of the present invention, compound shows good metabolic stability shown in formula (I)-(IV) of the present invention, Important evidence is provided for further clinical research.
According to example of the present invention, compound shown in formula (I)-(IV) of the present invention can in vivo to the growth of tumour and Transfer has an apparent inhibiting effect, and apparent is better than positive control BP-1-102.
Therefore, drug of the present invention can be effectively as STAT3 inhibitor, for treating a kind of or one kind with STAT3 Related disease is activated, the disease includes oophoroma, carcinoma of endometrium, cervical carcinoma, breast cancer, colon cancer, cancer of pancreas, lung Cancer, the cancer of the brain, kidney, liver cancer, sarcoma, prostate cancer, Head and neck squamous cell carcinoma, glioma, melanoma, lymthoma and white Blood disease, kidney fibrosis, pulmonary fibrosis, rheumatoid arthritis, psoriasis, lupus erythematosus, inflammatory lung disease and inflammatory bowel disease etc..
The beneficial effects of the present invention are：Cycloalkane thiophthene derivative of the present invention as STAT3 inhibitor (compound shown in formula (I)-(IV)) is used as STAT3 inhibitor, has good clinical application and medical usage.
Description of the drawings
Fig. 1 .STAT3 inhibitor 7r inhibits the growth (1A) of osteosarcoma and inhibits the transfer (1B) to lung in vivo.
Therapeutic effects of Fig. 2 .STAT3 inhibitor 5p and 7r to psoriasis.
Fig. 3 .STAT3 inhibitor 5p and 7r promote the growth of hair.
Specific implementation mode
The conjunction of embodiment 1-14- cyano -5- (1- methyl -4- pyrazoles)-formamido-cyclobutyl [2,3] bithiophene (1a) At.
Target product 1a-1e, 2a-2j are as shown in formula 1-1, by cyclobutanone (or other cyclanones), malononitrile, solid-state sulphur It is dissolved in DMF with proline, reaction in 10 hours is stirred at 60 DEG C and is finished；Reaction solution is slowly dropped in the ice water of stirring, Crude product containing intermediate 2-amino -3- cyano-thiophene derivatives intermediates is largely precipitated, by filtering, drying and purifying Afterwards；The intermediate, 1- methylpyrazole -4- carboxylic acids, the chloro- 1- methyl pyridinium iodides of 2- and DMAP are dissolved in dichloromethane, The lower dropwise addition triethylamine of stirring, which is then heated to, to be refluxed overnight, and obtains target product 1a-1e, 2a-2j.
The synthesis step of formula 1-1 1a-1e, 2a-2j
Weigh cyclobutanone (210mg, 3.0mmol), malononitrile (218mg, 3.3mmol), sulphur (144mg, 4.5mmol) and L- Proline (35mg, 0.3mmol) is dissolved in 5 milliliters of DMF, is stirred to react at 60 c 10 hours；It will reaction after cooling Liquid is slowly dropped in the water of stirring, by solid filtering, the drying of precipitation, obtains intermediate 4- cyanogen after purification by column chromatography Base -5- Amino-cyclobutyls [2,3] bithiophene (261mg, 53%).By 4- cyano -5- Amino-cyclobutyls [2,3] bithiophene (261mg, 1.6mmol), 1- methylpyrazole -4- carboxylic acids (202mg, 1.6mmol), the chloro- 1- methyl pyridinium iodides of 2- (409mg, It 1.6mmol) is dissolved in 10 milliliters of dichloromethane with DMAP (39mg, 0.32mmol), triethylamine is slowly added dropwise in stirring It (0.89ml, 6.4mmol) and is heated to reflux 4 hours, 4- cyano -5- (1- methyl -4- pyrazoles)-formamide is obtained after column chromatography Base-cyclobutyl [2,3] bithiophene (1a, 223mg, 54%).1H NMR(500MHz,DMSO)δ11.49(s,1H),8.49(s, 1H),8.05(s,1H),3.90(s,3H),3.08-3.02(m,1H),2.96-2.89(m,1H),2.86-2.80(m,1H), 2.78-2.72(m,1H).
The conjunction of embodiment 1-2 4- cyano -5- (1- methyl -4- pyrazoles)-formamido-cyclopenta [2,3] bithiophene (1b) At.
Using prepare compound 1a same procedures, cyclobutanone is changed to cyclopentanone, finally obtains 1b, yield 67%.1H NMR (500MHz, DMSO) δ 11.32 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 3.91 (s, 3H), 2.85 (t, J= 6.5Hz, 2H), 2.75 (t, J=6.4Hz, 2H), 2.40-2.36 (m, 2H)
Embodiment 1-3 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -4,5,6,7- tetrahydro benzos thiophene (1c) Synthesis.
Using prepare compound 1a same procedures, cyclobutanone is changed to cyclohexanone, finally obtains 1c, yield 63%.1H NMR(500MHz,DMSO)δ11.31(s,1H),8.44(s,1H),8.05(s,1H),3.90(s,3H),2.61-2.60(m, 2H),2.51-2.50(m,2H),1.76-1.75(m,4H).
The conjunction of embodiment 1-4 4- cyano -5- (1- methyl -4- pyrazoles)-formamido-suberyl [2,3] bithiophene (1d) At.
Using prepare compound 1a same procedures, cyclobutanone is changed to cycloheptanone and obtains 1d, yield 57%.1H NMR (500MHz,DMSO)δ11.23(s,1H),8.43(s,1H),8.03(s,1H),3.90(s,3H),2.72-2.67(m,4H), 1.82-1.81(s,2H),1.61-1.60(m,4H).
The conjunction of embodiment 1-5 4- cyano -5- (1- methyl -4- pyrazoles)-formamido-cyclooctyl [2,3] bithiophene (1e) At.
Using prepare compound 1a same procedures, cyclobutanone is changed to cyclooctanone and obtains 1e, yield 64%.1H NMR (500MHz, DMSO) δ 11.29 (s, 1H), 8.44 (s, 1H), 8.04 (s, 1H), 3.91 (s, 3H), 2.76 (t, J=5.6Hz, 2H), 2.68 (t, J=5.8Hz, 2H), 1.60-1.59 (m, 4H), 1.25-1.23 (m, 4H)
Embodiment 1-6 2- (1- first -4- pyrazoles)-formamido -3- cyano -4- methyl -4,5,6,7- tetrahydro benzo thiophene The synthesis of (2a).
Using prepare compound 1a same procedures, cyclobutanone is changed to 1- methyl cyclohexanones and obtains 2a, yield 37%.1H NMR(500MHz,DMSO)δ11.25(s,1H),8.43(s,1H),8.04(s,1H),3.91(s,3H),2.86-2.85(m, 1H),2.65-2.62(m,1H),2.57-2.55(m,1H),1.80-1.76(m,3H),1.60-1.59(m,1H),1.23(d,J =6.8Hz, 3H)
Embodiment 1-7 2- (1-H-4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene The synthesis of (2b).
Using prepare compound 1a same procedures, cyclobutanone is changed to 4- methyl cyclohexanones and finally obtains 2b, yield 58%.1H NMR(500MHz,DMSO)δ11.32(s,1H),8.44(s,1H),8.04(s,1H),3.90(s,3H),2.73- 2.69(m,1H),2.60-2.57(m,1H),2.53-2.52(m,1H),2.23-2.18(m,1H),1.97-1.84(m,2H), 1.42-1.34 (m, 1H), 1.03 (d, J=6.5Hz, 3H)
Embodiment 1-8 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6,6- dimethyl -4,5,6,7- tetrahydrochysene benzene The synthesis of bithiophene (2c).
Using prepare compound 1a same procedures, cyclobutanone is changed to 4,4- dimethylcyclohexanons and obtains 2c, yield 58%.1H NMR(500MHz,DMSO)δ11.32(s,1H),8.44(s,1H),8.05(s,1H),3.90(s,3H),2.57– 2.50 (m, 2H), 2.40 (s, 2H), 1.53 (t, J=6.4Hz, 2H), 0.96 (s, 6H)
Embodiment 1-9 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethyl -4,5,6,7- tetrahydro benzo thiophenes The synthesis of pheno (2d).
Using prepare compound 1a same procedures, cyclobutanone is changed to 4- ethyl cyclohexanones and obtains 2d, yield 63%.1H NMR(500MHz,DMSO)δ11.31(s,1H),8.44(s,1H),8.04(s,1H),3.90(s,3H),2.76-2.73(m, 1H),2.61-2.58(m,1H),2.50-2.49(m,1H),2.24-2.19(m,1H),1.93-1.90(m,1H),1.63-1.62 (m, 1H), 1.37-1.35 (m, 3H), 0.93 (t, J=7.1Hz, 3H)
Embodiment 1-10 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- propyl -4,5,6,7- tetrahydro benzos The synthesis of thiophene (2e).
Using prepare compound 1a same procedures, cyclobutanone is changed to 4- propylcyclohexanones and obtains 2e, yield 64%.1H NMR(500MHz,DMSO)δ11.31(s,1H),8.44(s,1H),8.05(s,1H),3.91(s,3H),2.76-2.72(m, 1H),2.61-2.57(m,1H),2.24-2.19(m,1H),1.92-1.89(m,1H),1.74-1.73(m,1H),1.40-1.35 (m, 5H), 0.90 (t, J=6.6Hz, 3H)
Embodiment 1-11 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- phenyl -4,5,6,7- tetrahydro benzos The synthesis of thiophene (2f).
Using prepare compound 1a same procedures, cyclobutanone is changed to 4- phenyl cyclohexanones and obtains 2f, yield 71%.1H NMR(500MHz,DMSO)δ11.38(s,1H),8.45(s,1H),8.06(s,1H),7.33-7.32(m,4H),7.24-7.22 (m,1H),3.91(s,3H),3.00-2.99(m,1H),2.93-2.89(m,1H),2.76-2.73(m,1H),2.71-2.67 (m,2H),2.05-2.03(m,1H),1.99-1.90(m,1H).
Embodiment 1-12 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethoxy carbonyls -4,5,6,7- four The synthesis of hydrogen benzothiophene (2g)
Using prepare compound 1a same procedures, cyclobutanone is changed to, 2g, yield are obtained to cyclohexanone Ethyl formate 67%.1H NMR(500MHz,DMSO)δ11.38(s,1H),8.45(s,1H),8.05(s,1H),4.12-4.09(m,2H), 3.90(s,3H),2.90-2.74(m,3H),2.62.59(m,2H),2.15-2.13(m,1H),1.84-1.81(m,1H),1.20 (t, J=7.1Hz, 3H)
Embodiment 1-13 2- (1- methyl 4- pyrazoles)-formamido -3- cyano -6- oxygen -4,5,6,7- tetrahydro benzo thiophene The synthesis of (2h).
Using prepare compound 1a same procedures, cyclobutanone is changed to Isosorbide-5-Nitrae-cyclohexanedione and obtains 2h, yield 69%.1H NMR(500MHz,DMSO)δ11.50(s,1H),8.47(s,1H),8.07(s,1H),3.91(s,3H),3.54(s,2H),2.93 (t, J=6.5Hz, 2H), 2.63 (t, J=6.7Hz, 2H)
Embodiment 1-14 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- hydroxyl -4,5,6,7- tetrahydro benzos The synthesis of thiophene (2i).
Using prepare compound 1a same procedures, cyclobutanone is changed to 4- hydroxy-cyclohexanones and obtains 2i, yield 41%.1H NMR(500MHz,DMSO)δ11.32(s,1H),8.44(s,1H),8.05(s,1H),4.94(s,1H),4.00-3.99(m, 1H),3.90(s,3H),2.86-2.83(m,1H),2.64-2.61(m,1H),2.52.50(m,2H),1.88-1.86(m,1H), 1.73-1.70(m,1H).
Embodiment 1-15 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6,2 '-[1,3] dioxolanes -4,5, The synthesis of 6,7- tetrahydro benzos thiophene (2j).
Using prepare compound 1a same procedures, cyclobutanone is changed to Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal and is obtained 2j, yield 71%.1HNMR(500MHz,DMSO)δ11.51(s,1H),8.47(s,1H),8.06(s,1H),6.17-6.14(m, 1H), 5.75-5.73 (m, 1H), 4.75 (s, 1H), 4.64 (s, 1H), 3.91 (s, 3H), 3.85 (d, J=5.7Hz, 2H), 2.68-2.62(m,2H),1.26-1.23(m,2H).
Embodiment 1-16 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethoxy carbonyls -4,5,6,7- four The synthesis of hydrogen [2,3-c] piperidines bithiophene (2k).
Using prepare compound 1a same procedures, cyclobutanone is changed to N- carbethoxyl group -4- piperidones and obtains 2k, yield 56%.1HNMR(500MHz,DMSO)δ11.50(s,1H),8.46(s,1H),8.06(s,1H),4.51-4.50(m,2H), 4.09-4.08(m,2H),3.91(s,3H),3.67-3.66(m,2H),2.62-2.61(m,2H),1.21-1.20(m,3H).
Embodiment 1-17 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- tertbutyloxycarbonyls -4,5,6,7- four The synthesis of hydrogen [2,3-c] piperidines bithiophene (2l).
Using prepare compound 1a same procedures, cyclobutanone is changed to N- tertbutyloxycarbonyl -4- piperidones and obtains 2l, produced Rate 89%.1HNMR(500MHz,DMSO)δ11.49(s,1H),8.47(s,1H),8.06(s,1H),4.46(s,2H),3.91 (s, 3H), 3.62 (t, J=5.3Hz, 2H), 2.60-2.59 (m, 2H), 1.42 (s, 9H)
Embodiment 1-18 2- (1- methyl -3- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzos The synthesis of thiophene (3a).
3a-3h synthesis steps are dissolved in DMF as shown in formula 1-2, by p-methylcyclohexanol, malononitrile, solid-state sulphur and proline In, reaction in 10 hours is stirred at 60 DEG C to be finished；Reaction solution is slowly dropped in the ice water of stirring, intermediate 2- ammonia is contained The crude product of base -3- cyano-thiophene derivatives intermediates is largely precipitated, by filtering, drying and after purification；By the intermediate, The chloro- 1- methyl pyridinium iodides of various commercialized carboxylic acids, 2- and DMAP are dissolved in dichloromethane, and triethylamine is added dropwise under stiring It is then heated to and is refluxed overnight, obtain target product 3a-3h.
The synthesis step of formula 1-2 3a-3h
Using prepare compound 2b same procedures, 1- methylpyrazole -4- carboxylic acids are changed to 1- methylpyrazole-3-carboxyl acids most After obtain 3a, yield 54%.1HNMR(500MHz,DMSO)δ10.95(s,1H),7.90(s,1H),6.83(s,1H),3.99 (s,3H),2.74-2.71(m,1H),2.60-2.57(m,2H),2.24-2.19(m,1H),1.86-1.85(m,2H),1.39- 1.38 (m, 1H), 1.03 (d, J=5.3Hz, 3H)
Embodiment 1-19 2- (1- methyl -5- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzos The synthesis of thiophene (3b).
Using prepare compound 2b same procedures, 1- methylpyrazole -4- carboxylic acids are changed to 1- methylpyrazole -5- carboxylic acids most After obtain 3b, yield 47%.1H NMR (500MHz, DMSO) δ 11.65 (s, 1H), 7.57 (d, J=2.1Hz, 1H), 7.13 (d, J=2.1Hz, 1H), 4.08 (s, 3H), 2.77-2.73 (m, 1H), 2.63-2.60 (m, 1H), 2.57-2.51 (m, 1H), 2.26- 2.21 (m, 1H), 1.88-1.86 (m, 2H), 1.43-1.35 (m, 1H), 1.04 (d, J=6.5Hz, 3H)
Embodiment 1-20 2- (1- methyl -4- imidazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzos The synthesis of thiophene (3c).
Using prepare compound 2b same procedures, 1- methylpyrazole -4- carboxylic acids are changed to 1- methylimidazole -4- carboxylic acids most After obtain 3c, yield 61%.1HNMR(500MHz,DMSO)δ10.52(s,1H),7.96(s,1H),7.84(s,1H),3.75 (s,3H),2.74-2.69(m,1H),2.60-2.57(m,1H),2.54-2.51(m,1H),2.23-2.18(m,1H),1.86- 1.84 (m, 2H), 1.41-1.33 (m, 1H), 1.03 (d, J=6.5Hz, 3H)
Embodiment 1-21 2- (4-Azoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzos thiophene (3d) Synthesis.
Using prepare compound 2b same procedures, 1- methylpyrazole -4- carboxylic acids are changed toAzoles -4- carboxylic acids finally obtain 3d, yield 43%.1H NMR (500MHz, DMSO) δ 11.26 (s, 1H), 8.94 (d, J=0.9Hz, 1H), 8.68 (d, J= 0.9Hz,1H),2.76-2.72(m,1H),2.61-2.59(m,1H),2.55-2.50(m,1H),2.25-2.20(m,1H), 1.87-1.85 (m, 2H), 1.40-1.35 (m, 1H), 1.03 (d, J=6.6Hz, 3H)
Embodiment 1-22 2- (4- thiazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzos thiophene (3e) Synthesis.
Using prepare compound 2b same procedures, 1- methylpyrazole -4- carboxylic acids are changed to thiazole -4-carboxylic acid and are finally obtained 3e, yield 48%.1HNMR(500MHz,DMSO)δ11.16(s,1H),9.32(s,1H),8.65(s,1H),2.76-2.72(m, 1H),2.62-2.59(m,1H),2.56-2.51(m,1H),2.25-2.20(m,1H),1.87-1.85(m,2H),1.42-1.34 (m, 1H), 1.03 (d, J=6.5Hz, 3H)
The synthesis of embodiment 1-23 2-benzamide base -3- cyano -6- methyl -4,5,6,7- tetrahydro benzos thiophene (3f).
Using prepare compound 2b same procedures, 1- methylpyrazole -4- carboxylic acids are changed to benzoic acid and finally obtain 3f, produced Rate 78%.1H NMR (500MHz, DMSO) δ 11.72 (s, 1H), 7.95 (d, J=7.2Hz, 2H), 7.64 (dd, J=7.4, 7.4Hz, 1H), 7.56 (dd, J=7.8,7.4Hz, 2H), 2.75-2.71 (m, 1H), 2.62-2.59 (m, 1H), 2.56-2.52 (m, 1H), 2.25-2.19 (m, 1H), 1.87-1.85 (m, 2H), 1.42-1.34 (m, 1H), 1.03 (d, J=6.5Hz, 3H)
Embodiment 1-24 2- (2- pyridines)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzos thiophene (3g) Synthesis.
Using prepare compound 2b same procedures, 1- methylpyrazole -4- carboxylic acids are changed to 2- pyridine carboxylic acids and are finally obtained 3g, yield 64%.1H NMR (500MHz, DMSO) δ 11.32 (s, 1H), 8.80 (d, J=4.2Hz, 1H), 8.17 (d, J= 7.8Hz, 1H), 8.11 (dd, J=7.8,7.6Hz, 1H), 7.75 (dd, J=7.5,7.4Hz, 1H), 2.78-2.74 (m, 1H), 2.63-2.60(m,1H),2.58-2.54(m,1H),2.27-2.22(m,1H),1.88-1.85(m,2H),1.43-1.33(m, 1H), 1.04 (d, J=6.5Hz, 3H)
Embodiment 1-25 2- (4- pyrimidines)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzos thiophene (3h) Synthesis.
Using prepare compound 2b same procedures, 1- methylpyrazole -4- carboxylic acids are changed to pyrimidine -4- formic acid and are finally obtained 3h, yield 45%.1HNMR (500MHz, DMSO) δ 11.63 (s, 1H), 9.49 (s, 1H), 9.17 (d, J=5.0Hz, 1H), 8.14 (d, J=4.9Hz, 1H), 2.77 (dd, J=16.3,4.4Hz, 1H), 2.60 (dd, J=31.4,12.1Hz, 2H), 2.26 (dd, J=16.1,9.8Hz, 1H), 1.87 (d, J=7.9Hz, 2H), 1.39 (dt, J=11.0,6.2Hz, 1H), 1.04 (d, J =6.5Hz, 3H)
Embodiment 1-26 2- (1- hydrogen -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophenes The synthesis of pheno (4a).
Using prepare compound 2b same procedures, it is last that 1- methylpyrazole -4- carboxylic acids are changed to 1H- pyrazoles -4- carboxylic acids Obtain 4a, yield 37%.1H NMR(500MHz,DMSO)δ13.39(s,1H),11.29(s,1H),8.49(s,1H),8.09 (s,1H),2.74-2.70(m,1H),2.61-2.53(m,2H),2.24-2.18(m,1H),1.87-1.85(m,2H),1.42- 1.34 (m, 1H), 1.03 (d, J=6.4Hz, 3H)
Embodiment 1-27 2- (1- (2- ethoxys) -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- four The synthesis of hydrogen benzothiophene (4b).
4b-4d synthesis steps are as shown in formula 1-3, using the method synthetic intermediate 4a of formula 1-3, then by 4a and K2CO3It is molten In acetone, bromide is slowly added dropwise under stiring, is then heated to reflux 3 hours and obtains target product 4b-4d.
The synthesis step of pyrazoles substitutive derivative on formula 1-3 2- (1- hydrogen -4- pyrazoles)-formamido -3- cyano-thiophenes
By intermediate 4a (286mg, 1.0mmol) and K2CO3(415mg, 3.0mmol) is dissolved in 5 milliliters of acetone, is being stirred Under bromoethanol (0.11ml, 1.5mmol) is slowly added dropwise, in heating reflux reaction 3 hours；By extraction, column chromatography obtains 4b (178mg, 54%).1H NMR (500MHz, DMSO) δ 11.33 (s, 1H), 8.48 (s, 1H), 8.06 (s, 1H), 4.98 (t, J= 5.1Hz, 1H), 4.21 (t, J=5.1Hz, 2H), 3.76-3.75 (m, 2H), 2.74-2.70 (m, 2H), 2.61-2.58 (m, 2H), 2.24-2.18 (m, 1H), 1.87-1.85 (m, 2H), 1.42-1.34 (m, 1H), 1.04 (d, J=6.3Hz, 3H)
Embodiment 1-28 2- (1- (2- methoxy ethyls) -4- pyrazoles)-methyl -4,5,6 formamido -3- cyano -6-, The synthesis of 7- tetrahydro benzos thiophene (4c).
Using prepare compound 4b same procedures, bromoethanol is changed to bromo-ethyl-methyl ether and obtains 4c, yield 43%.1H NMR (500MHz, DMSO) δ 11.34 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 4.34 (t, J=5.1Hz, 2H), 3.71 (t, J=5.1Hz, 2H), 3.24 (s, 3H), 2.74-2.70 (m, 1H), 2.61-2.53 (m, 2H), 2.23-2.18 (m, 1H), 1.87-1.85 (m, 2H), 1.41-1.35 (m, 1H), 1.03 (d, J=6.5Hz, 3H)
Embodiment 1-29 2- (1- (2- (2- hydroxy ethoxies) ethyl -4- pyrazoles)-methyl -4 formamido -3- cyano -6-, The synthesis of 5,6,7- tetrahydro benzos thiophene (4d).
Using prepare compound 4b same procedures, bromoethanol is changed to 2- (2- bromine oxethyls) ethyl alcohol and obtains 4d, yield 38%.1H NMR(500MHz,DMSO)δ11.33(s,1H),8.48(s,1H),8.08(s,1H),4.61-4.58(m,1H), 4.33 (t, J=5.0Hz, 2H), 3.80 (t, J=5.0Hz, 2H), 3.72-3.70 (m, 1H), 3.68-3.66 (m, 1H), 3.51- 3.50(m,1H),3.47-3.46(m,2H),3.43-3.52(m,1H),2.61-2.58(m,2H),2.23-2.18(m,1H), 1.87-1.85 (m, 2H), 1.42-1.34 (m, 1H), 1.03 (d, J=6.3Hz, 3H)
Embodiment 1-30 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- glycolyls) -4,5,6,7- The synthesis of tetrahydrochysene [2,3-c] piperidines bithiophene (5a).
5a-5r synthesis steps are as shown in 1-4, using the method synthetic intermediate 2m of formula 1-1, then by R4COOH、 EDC.HCl and HOBt are dissolved in DMF, are stirred under ice bath 15 minutes and 2m is then added, then reacted 3 hours under room temperature and obtain target Product 5a-5r.
The synthesis step of piperidines acyl substituted derivative on formula 1-4 2- amido -3- cyano-piperidin bithiophenes
Intermediate 2l (387mg, 1.0mmol) is dissolved in 10 milliliters of dichloromethane, 4N is slowly added dropwise under ice bath 1 milliliter of Isosorbide-5-Nitrae-dioxane solution of HCl gases is stirred overnight under room temperature, and solvent evaporated obtains 2- (1- methyl -4- pyrazoles) - Formamido -3- cyano -6- hydrogen -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines and thiophene (2m) 287mg, yield 100%；By glycolic (114mg, 1.5mmol), EDC.HCl (383mg, 2.0mmol) and HOBt (196mg, 1.7mmol) are dissolved in 5 milliliters of DMF, instead 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- glycolyls) -4,5,6,7- tetrahydrochysenes are added after answering 30 minutes [2,3-c] piperidines bithiophene (2m) (287mg, 1.0mmol), the reaction was continued 3 hours, and extraction, column chromatography obtains 5a, and yield is 42%.1H NMR(500MHz,DMSO)δ11.51(s,1H),8.46(s,1H),8.06(s,1H),4.75(s,1H),4.59- 4.53(m,2H),4.21-4.14(m,2H),3.91(s,3H),3.78-3.65(m,2H),2.69-2.60(m,2H).
Embodiment 1-31 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- Methoxyacetyls -4,5,6,7- The synthesis of tetrahydrochysene [2,3-c] piperidines bithiophene (5b).
Using prepare compound 5a same procedures, glycolic is changed to methoxyacetic acid and obtains 5b, yield 62%.1H NMR(500MHz,DMSO)δ11.51(s,1H),8.46(s,1H),8.06(s,1H),4.57(s,2H),4.20-4.14(m, 2H),3.91(s,3H),3.76-3.67(m,2H),3.32(s,3H),2.69-2.59(m,2H).
Embodiment 1-32 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (1- methylpyrazole -3- carbonyls) -4, The synthesis of 5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5c).
Using prepare compound 5a same procedures, glycolic is changed to 1- methylpyrazole -3- formic acid and obtains 5c, yield 73%.1H NMR(500MHz,DMSO)δ11.49(s,1H),8.46(s,1H),8.06(s,1H),7.78(s,1H),6.59(s, 1H),5.08-4.11(m,2H),4.15(s,2H),3.91(s,6H),2.73-2.71(m,2H).
Embodiment 1-33 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (1- methylpyrazole -4- carbonyls) -4, The synthesis of 5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5d).
Using prepare compound 5a same procedures, glycolic is changed to 1- methylpyrazole -4- formic acid and obtains 5d, yield 74%.1H NMR(500MHz,DMSO)δ11.48(s,1H),8.46(s,1H),8.14(s,1H),8.06(s,1H),7.74(s, 1H),4.72(s,2H),3.91(s,3H),3.87-3.86(m,5H),2.73-2.72(m,2H).
Embodiment 1-34 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (1- methylpyrazole -5- carbonyls) -4, The synthesis of 5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5e).
Using prepare compound 5a same procedures, glycolic is changed to 1- methylpyrazole -5- formic acid and obtains 5e, yield 80%.1H NMR(500MHz,DMSO)δ11.51(s,1H),8.46(s,1H),8.06(s,1H),7.51(s,1H),6.60(s, 1H),4.73(s,2H),3.91(s,3H),3.86(s,3H),3.77-3.76(m,2H),2.75-2.74(m,2H).
Embodiment 1-35 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (Azoles -4- carbonyls) -4,5,6,7- The synthesis of tetrahydrochysene [2,3-c] piperidines bithiophene (5f).
Using prepare compound 5a same procedures, glycolic is changed toAzoles -4- formic acid obtains 5f, yield 59%.1H NMR(500MHz,DMSO)δ11.53(s,1H),9.22(s,1H),8.47(s,1H),8.26(s,1H),8.07(s,1H), 4.88-4.76(m,2H),3.92-3.91(m,5H),2.75-2.74(m,2H).
Embodiment 1-36 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (thiazole -4- carbonyls) -4,5,6,7- The synthesis of tetrahydrochysene [2,3-c] piperidines bithiophene (5g).
Using prepare compound 5a same procedures, glycolic is changed to 4-thiazolecarboxylic acid and obtains 5g, yield 61%.1H NMR(500MHz,DMSO)δ11.53(s,1H),8.64(s,1H),8.55(s,1H),8.46(s,1H),8.06(s,1H), 5.02-4.71(m,2H),4.11-3.91(m,5H),2.76-2.75(m,2H).
Embodiment 1-37 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methoxybenzothiophene -2- carbonyls Base) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5h) synthesis.
Using prepare compound 5a same procedure, glycolic is changed to 3- methoxybenzothiophene -2- carboxylic acids and obtains 5h, Yield 39%.1HNMR (500MHz, DMSO) δ 11.54 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 8.02 (d, J= 6.8Hz, 1H), 7.86 (d, J=8.3Hz, 1H), 7.51-7.46 (m, 2H), 4.73 (s, 2H), 3.91 (s, 3H), 3.77 (s, 2H),2.72-2.71(m,2H),2.38(s,3H).
Embodiment 1-38 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (benzothiophene -2- carbonyls) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5i).
Using prepare compound 5a same procedures, glycolic is changed to benzothiophene -2- carboxylic acids and obtains 5i, yield 56%.1H NMR(500MHz,DMSO)δ11.58(s,1H),8.38(s,1H),8.04-7.96(m,3H),7.87(s,1H), 7.47-7.46(m,2H),4.80(s,2H),3.96-3.95(m,2H),3.90(s,3H),2.80-2.79(m,2H).
Embodiment 1-39 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methyl benzofuran -2- carbonyls Base) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5j) synthesis.
Using prepare compound 5a same procedures, glycolic is changed to 3- methyl benzofuran -2- carboxylic acids and obtains 5j, produced Rate 71%.1HNMR (500MHz, DMSO) δ 11.54 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.73 (d, J=7.6Hz, 1H), 7.64 (d, J=6.0Hz, 1H), 7.46 (t, J=7.8,7.6Hz, 1H), 7.35 (t, J=7.5,7.4Hz, 1H), 4.78 (s,2H),3.91-3.90(m,5H),2.79-2.78(m,2H),2.37(s,3H).
Embodiment 1-40 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- methylfuran -2- carbonyls) -4, The synthesis of 5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5k).
Using prepare compound 5a same procedures, glycolic is changed to 5- methylfuran -2- formic acid and obtains 5k, yield 63%.1H NMR(500MHz,DMSO)δ11.52(s,1H),8.47(s,1H),8.06(s,1H),6.98(s,1H),6.28(s, 1H),4.77-4.76(m,2H),3.91-3.90(m,5H),2.75-2.74(m,2H),2.35(s,3H).
Embodiment 1-41 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (thiophene -2- carbonyls) -4,5,6,7- The synthesis of tetrahydrochysene [2,3-c] piperidines bithiophene (5l).
Using prepare compound 5a same procedures, glycolic is changed to thiophene -2-carboxylic acid and obtains 5l, yield 67%.1H NMR (500MHz, DMSO) δ 11.56 (s, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.80 (d, J=4.7Hz, 1H), 7.54 (d, J=3.9Hz, 1H), 7.17 (dd, J=3.9,4.0Hz, 1H), 4.75 (s, 2H), 3.90-3.89 (m, 5H), 2.75-2.74 (m,2H).
Embodiment 1-42 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- chlorothiophene -2- carbonyls) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5m).
Using prepare compound 5a same procedures, glycolic is changed to 5- chlorothiophene -2- formic acid and obtains 5m, yield 71%.1H NMR(500MHz,DMSO)δ11.53(s,1H),8.47(s,1H),8.06(s,1H),7.46(s,1H),7.20(s, 1H),4.78(s,2H),3.91-3.90(m,5H),2.77-2.76(m,2H).
Embodiment 1-43 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromine furans -2- carbonyls) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5n).
Using prepare compound 5a same procedures, glycolic is changed to 5- bromothiophene -2- carboxylic acids and obtains 5n, yield 48%.1H NMR(500MHz,DMSO)δ11.53(s,1H),8.47(s,1H),8.07(s,1H),7.41(s,1H),7.30(s, 1H),4.77(s,2H),3.91-3.90(m,5H),2.76-2.75(m,2H).
Embodiment 1-44 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- chlorine furans -2- carbonyls) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5o).
Using prepare compound 5a same procedures, glycolic is changed to 5- chlorine furans -2- formic acid and obtains 5o, yield 72%.1H NMR (500MHz, DMSO) δ 11.57 (s, 1H), 8.14 (s, 1H), 7.82 (s, 1H), 7.16 (d, J=3.3Hz, 1H), 6.70 (d, J=3.3Hz, 1H), 4.66-4.65 (m, 2H), 3.90-3.89 (m, 2H), 3.86 (s, 3H), 2.73-2.64 (m,2H).
Embodiment 1-45 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromothiophene -2- carbonyls) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5p).
Using prepare compound 5a same procedures, glycolic is changed to 5- bromine furans -2- carboxylic acids and obtains 5p, yield 51%.1H NMR (500MHz, DMSO) δ 11.53 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.13 (d, J=2.9Hz, 1H), 6.80 (d, J=3.2Hz, 1H), 4.76 (s, 2H), 3.92-3.91 (m, 5H), 2.76-2.75 (m, 2H)
Embodiment 1-46 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (4- bromothiophene -2- carbonyls) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5q).
Using prepare compound 5a same procedures, glycolic is changed to 5- bromine furans -2- carboxylic acids and obtains 5q, yield 54%.1H NMR(500MHz,DMSO)δ11.53(s,1H),8.47(s,1H),8.14(s,1H),8.07(s,1H),7.28(s, 1H),4.74(s,2H),3.91-3.90(m,5H),2.77-2.76(m,2H).
Embodiment 1-47 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromomethyl furans -2- carbonyls) - The synthesis of 4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (5r).
Using prepare compound 5a same procedures, glycolic is changed to 5- bromomethyl furans -2- carboxylic acids and obtains 5r, yield 39%.1H NMR (500MHz, DMSO) δ 11.51 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.05 (d, J=3.3Hz, 1H), 6.72 (d, J=3.3Hz, 1H), 5.75 (s, 1H), 4.84 (s, 1H), 4.77 (s, 2H), 3.94-3.93 (m, 2H), 3.91 (s,3H),2.77-2.76(m,2H).
Embodiment 1-48 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (pyrrolidines -1- methylene) furans Mutter -2- carbonyls) synthesis of -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (6a).
6a-6d synthesis steps are as shown in formula 1-5, using the method synthetic intermediate 5r of formula 1-4, then by R5NH2With K2CO3It is dissolved in acetone, is added slowly with stirring 5r, then normal-temperature reaction obtains target product 6a-6d in 3 hours.
The synthesis step of furan nucleus substitutive derivative on formula 1-5 2- amido -3- cyano-piperidin bithiophenes
By nafoxidine (214mg, 3.0mmol) and K2CO3(415mg, 3.0mmol) is dissolved in 5 milliliters of acetone, is being stirred Under be slowly added to 5r (474mg, 1.0mmol), at normal temperatures react 3 hours；By extraction, column chromatography obtain 6a (316mg, 68%).It takes1HNMR (500MHz, DMSO) δ 11.19 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.03 (d, J=3.1Hz, 1H), 6.52 (d, J=3.0Hz, 1H), 4.77 (s, 2H), 3.94 (s, 2H), 3.91 (s, 3H), 3.84-3.83 (m, 2H), 2.75-2.74(m,2H),2.65-2.64(m,4H),1.74-1.73(m,4H).
Embodiment 1-49 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (morpholine ring -1- methylene) furans Mutter -2- carbonyls) synthesis of -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (6b).
Using prepare compound 6a same procedures, nafoxidine is changed to morpholine and obtains 6b, yield 79%.1H NMR (500MHz, DMSO) δ 11.54 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.03 (d, J=3.4Hz, 1H), 6.49 (d, J =3.3Hz, 1H), 4.78 (s, 2H), 3.92-3.91 (m, 5H), 3.59-3.57 (m, 6H), 2.76-2.75 (m, 2H), 2.42- 2.41(m,4H).
Embodiment 1-50 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (4- methyl piperazine -1- methylenes Base) furans -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (6c) synthesis.
Using prepare compound 6a same procedures, nafoxidine is changed to 4- methyl piperazines and obtains 6c, yield 62%.1H NMR (500MHz, DMSO) δ 11.11 (s, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.02 (d, J=3.3Hz, 1H), 6.47 (d, J=3.3Hz, 1H), 4.75 (s, 2H), 3.92-3.90 (m, 5H), 3.33-3.32 (m, 6H), 2.75-2.74 (m, 2H), 2.44-2.43(m,4H),2.21(s,3H).
Embodiment 1-51 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (4- (2- ethoxys) piperazines - 1- methylene) furans -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (6d) synthesis.
Using prepare compound 6a same procedures, nafoxidine is changed to 4- hydroxyethyl piperazines and obtains 6d, yield 54% 。1H NMR (500MHz, DMSO) δ 11.45 (s, 1H), 8.43 (s, 1H), 8.04 (s, 1H), 7.02 (d, J=3.3Hz, 1H), 6.46 (d, J=3.2Hz, 1H), 5.75 (s, 1H), 4.75 (s, 2H), 3.93 (s, 2H), 3.90 (s, 3H), 3.49-3.48 (m, 2H),3.33-3.32(m,2H),2.75-2.74(m,2H),2.45-2.44(m,10H).
Embodiment 1-52 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethylamino- carbonyls -4,5,6,7- four The synthesis of hydrogen [2,3-c] piperidines bithiophene (7a).
7a-7u, 8a-8h and 9a-9g synthesis step are as shown in formula 1-6.Using the method synthetic intermediate 2m of formula 1-1, so Afterwards by R-NH2It is dissolved in dichloromethane with CDI, is stirred under room temperature 15 minutes and 2m and triethylamine is then added, the reaction was continued overnight Obtain target product 7a-7u, 8a-8h and 9a-9g.
The synthesis step of piperidines ureas substitutive derivative on formula 1-6 2- amido -3- cyano-piperidin bithiophenes
By 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- hydrogen -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines and thiophene Pheno (287mg, 1.0mmol) is dissolved in 5 milliliters of dichloromethane, be slowly added dropwise ethyl isocyanate (0.12ml, 1.5mmol) and Triethylamine (0.42ml, 3.0mmol) reacts 3 hours under room temperature, and column chromatography obtains 7a, yield 87%.1H NMR(500MHz, DMSO)δ11.47(s,1H),8.45(s,1H),8.05(s,1H),6.66(s,1H),4.43(s,2H),3.91(s,3H), 3.61-3.60(m,2H),3.06-3.05(m,2H),2.56-2.55(m,2H),1.02-1.01(m,3H).
Embodiment 1-53 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- anilinocarbonyls -4,5,6,7- four The synthesis of hydrogen [2,3-c] piperidines bithiophene (7b).
Aniline (186mg, 2.0mmol) and N, N'- carbonyl dimidazoles (324mg, 2.0mmol) are dissolved in 10 milliliters of dichloros In methane, it is stirred to react under room temperature 30 minutes；Then by 2- (1- methyl -4- pyrazoles)-hydrogen -4,5 formamido -3- cyano -6-, 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (287mg, 1.0mmol) be added reaction solution in and be slowly added dropwise triethylamine (0.56ml, 4.0mmol), it is reacted overnight under room temperature, column chromatography obtains 7b, yield 52%.1H NMR(500MHz,DMSO)δ11.52(s, 1H), 8.67 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.46 (d, J=7.9Hz, 2H), 7.24 (t, J=7.7Hz, 2H), 6.95 (t, J=7.2Hz, 1H), 4.60-4.59 (m, 2H), 3.91 (s, 3H), 3.79-3.78 (m, 2H), 2.68-2.67 (m, 2H).
Embodiment 1-54 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- benzylamine acyl group -4,5,6,7- tetrahydrochysenes The synthesis of [2,3-c] piperidines bithiophene (7c).
Using prepare compound 7b same procedures, aniline is changed to benzylamine and obtains 7c, yield 61%.1HNMR (500MHz, DMSO) δ 11.49 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.31-7.28 (m, 3H), 7.25 (d, J= 7.1Hz, 2H), 7.20 (dd, J=7.0,7.0Hz, 1H), 4.49 (s, 2H), 4.26 (d, J=5.5Hz, 2H), 3.91 (s, 3H), 3.68 (t, J=5.3Hz, 2H), 2.60-2.59 (m, 2H)
Embodiment 1-55 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- β phenyl ethylamine acyl groups -4,5,6,7- four The synthesis of hydrogen [2,3-c] piperidines bithiophene (7d).
Using prepare compound 7b same procedures, aniline is changed to 2- phenyl ethylamines and obtains 7d, yield 57%.1H NMR (500MHz,DMSO)δ11.50(s,1H),8.46(s,1H),8.06(s,1H),7.28-7.25(m,2H),7.19-7.16(m, 3H), 6.80 (dd, J=5.4,5.3Hz, 1H), 4.44 (s, 2H), 3.91 (s, 3H), 3.61 (t, J=5.6Hz, 2H), 3.27- 3.23 (m, 2H), 2.74-2.71 (m, 2H), 2.53 (t, J=5.5Hz, 2H)
Embodiment 1-56 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- phentermine acyl groups -4,5,6,7- four The synthesis of hydrogen [2,3-c] piperidines bithiophene (7e).
Using prepare compound 7b same procedures, aniline is changed to phenyl -4- butylamine and obtains 7e, yield 63%.1H NMR(500MHz,DMSO)δ11.50(s,1H),8.46(s,1H),8.06(s,1H),7.27-7.24(m,2H),7.17-7.15 (m,3H),6.67(s,1H),4.43(s,2H),3.91(s,3H),3.62-3.61(m,2H),3.07-3.05(m,2H),2.56- 2.55(m,4H),1.55-1.52(m,2H),1.43-1.41(m,2H).
Embodiment 1-57 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (furans -2- methylene) aminoacyl - The synthesis of 4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7f).
Using prepare compound 7b same procedures, aniline is changed to 2- furylamines and obtains 7f, yield 65%.1H NMR (500MHz, DMSO) δ 11.49 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.54 (s, 1H), 7.20 (dd, J=5.3, 5.1Hz, 1H), 6.36 (s, 1H), 6.18 (d, J=5.1Hz, 1H), 4.47 (s, 2H), 4.24 (d, J=5.3Hz, 2H), 3.91 (s, 3H), 3.65 (t, J=5.2Hz, 2H), 2.58-2.57 (m, 2H)
Embodiment 1-58 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- pyridine ethylamines acyl group) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7g).
Using prepare compound 7b same procedures, aniline is changed to 2- (2- aminoethyls) pyridine and obtains 7g, yield 47% 。1H NMR (500MHz, DMSO) δ 11.53 (s, 1H), 8.48-8.46 (m, 2H), 8.06 (s, 1H), 7.66 (dd, J=7.0, 6.5Hz,1H),7.20-7.19(m,2H),6.81(s,1H),4.43(s,2H),3.91(s,3H),3.60-3.59(m,2H), 3.41-3.37 (m, 2H), 2.88 (t, J=7.3Hz, 2H), 2.54-2.5 (m, 2H)
Embodiment 1-59 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- pyridine ethylamines acyl group) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7h).
Using prepare compound 7b same procedures, aniline is changed to 2 thiophene ethyl amine and obtains 7h, yield 52%.1H NMR (500MHz, DMSO) δ 11.49 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.31 (d, J=4.8Hz, 1H), 6.94-6.89 (m, 2H), 6.84 (s, 1H), 4.45 (s, 2H), 3.91 (s, 3H), 3.62 (s, 2H), 3.29-3.27 (m, 2H), 2.94 (t, J= 7.0Hz,2H),2.57-2.56(m,2H).
Embodiment 1-60 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (4- pyridine propylamine acyl group) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7i).
Using prepare compound 7b same procedures, aniline is changed to 4- pyridine propylamine and obtains 7i, yield 48%.1H NMR (500MHz,DMSO)δ11.49(s,1H),8.46-8.43(m,3H),8.06(s,1H),7.23-7.22(m,2H),6.73(s, 1H), 4.44 (s, 2H), 3.91 (s, 3H), 3.62 (s, 2H), 3.07 (d, J=5.7Hz, 2H), 2.59-2.58 (m, 4H), 1.75-1.72(m,2H).
Embodiment 1-61 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- to Bretylium Tosylate acyl group -4,5,6, The synthesis of 7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7j).
Using prepare compound 7b same procedures, aniline is changed to 4- Bretylium Tosylates and obtains 7j, yield 54%.1H NMR (500MHz,DMSO)δ11.47(s,1H),8.46(s,1H),8.07(s,1H),7.49-7.48(m,2H),7.33(s,1H), 7.22-7.21(m,2H),4.49(s,2H),4.22(s,2H),3.91(s,3H),3.68-3.67(m,2H),2.60-2.59(m, 2H).
Embodiment 1-62 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (to fluorophenethylamine acyl group) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7k).
Using prepare compound 7b same procedures, aniline is changed to 4- fluorophenethylamines and obtains 7k, yield 55%.1H NMR (500MHz,DMSO)δ11.49(s,1H),8.46(s,1H),8.06(s,1H),7.19(m,2H),7.05(m,2H),6.78 (dd, J=5.0,4.9Hz, 1H), 4.43 (s, 2H), 3.91 (s, 3H), 3.60 (t, J=5.2Hz, 2H), 3.26-3.22 (m, 2H), 2.71 (t, J=7.2Hz, 2H), 2.54-2.53 (m, 2H)
Embodiment 1-63 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- to chlorophenethylamine acyl group -4,5,6, The synthesis of 7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7l).
Using prepare compound 7b same procedures, aniline is changed to 4- chlorophenethylamines and obtains 7l, yield 61%.1H NMR (500MHz, DMSO) δ 11.50 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.30 (d, J=8.4Hz, 2H), 7.19 (d, J =8.4Hz, 2H), 6.78 (t, J=5.4Hz, 1H), 4.43 (s, 2H), 3.91 (s, 3H), 3.60 (t, J=5.6Hz, 2H), 3.27-3.23 (m, 2H), 2.72 (t, J=7.2Hz, 2H), 2.54-2.51 (m, 3H)
Embodiment 1-64 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- neighbour's fluoroaniline acyl groups -4,5,6,7- The synthesis of tetrahydrochysene [2,3-c] piperidines bithiophene (7m).
Using prepare compound 7b same procedures, aniline is changed to 2- fluoroanilines and obtains 7m, yield 57%.1H NMR (500MHz,DMSO)δ11.16(s,1H),8.50-8.46(m,2H),8.06(s,1H),7.42(s,1H),7.19-7.17(m, 1H),7.13-7.12(m,2H),4.59(s,2H),3.91(s,3H),3.79-3.78(m,2H),2.68-2.67(m,2H).
Embodiment 1-65 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- m-fluoroaniline acyl groups -4,5,6,7- The synthesis of tetrahydrochysene [2,3-c] piperidines bithiophene (7n).
Using prepare compound 7b same procedures, aniline is changed to 4- fluoroanilines and obtains 7n, yield 64%.1H NMR (500MHz,DMSO)δ11.56(s,1H),8.88(s,1H),8.47(s,1H),8.07(s,1H),7.45-7.43(m,1H), 7.27-7.26(m,2H),6.76(s,1H),4.61(s,2H),3.91(s,3H),3.79-3.78(m,2H),2.69-2.68(m, 2H).
Embodiment 1-66 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- para-fluoroaniline acyl groups -4,5,6,7- The synthesis of tetrahydrochysene [2,3-c] piperidines bithiophene (7o).
Using prepare compound 7b same procedures, aniline is changed to 4- fluoroanilines and obtains 7o, yield 60%.1H NMR (500MHz,DMSO)δ11.52(s,1H),8.71(s,1H),8.47(s,1H),8.07(s,1H),7.47-7.46(m,2H), 7.10-7.06(m,2H),4.60-4.59(m,2H),3.91(s,3H),3.78-3.77(m,2H),2.67-2.66(m,2H).
Embodiment 1-67 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- o-aminoanisoles acyl group -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7p).
Using prepare compound 7b same procedures, aniline is changed to 2- aminoanisoles and obtains 7p, yield 42%.1H NMR(500MHz,DMSO)δ11.52(s,1H),8.47(s,1H),8.07(s,1H),7.87(s,1H),7.57-7.55(m, 1H),7.01-7.00(m,2H),6.88-6.87(m,1H),4.59(s,2H),3.91(s,3H),3.81-3.76(m,5H), 2.68-2.67(m,2H).
Embodiment 1-68 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- m-anisidines acyl group -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7q).
Using prepare compound 7b same procedures, aniline is changed to 3- aminoanisoles and obtains 7q, yield 51%.1H NMR(500MHz,DMSO)δ11.53(s,1H),8.65(s,1H),8.47(s,1H),8.07(s,1H),7.15-7.07(m, 3H),6.53(s,1H),4.60(s,2H),3.91(s,3H),3.78-3.77(m,2H),3.71(s,3H),2.68-2.67(m, 2H).
Embodiment 1-69 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- P-nethoxyaniline acyl group -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7r).
Using prepare compound 7b same procedures, aniline is changed to 4- aminoanisoles and obtains 7r, yield 52%.1H NMR (500MHz, DMSO) δ 11.51 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.34 (d, J= 8.9Hz, 2H), 6.83 (d, J=8.9Hz, 2H), 4.58 (s, 2H), 3.91 (s, 3H), 3.77 (t, J=5.4Hz, 2H), 3.70 (s,3H),2.667-2.66(m,2H).
Embodiment 1-70 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methyl formate aniline acyl group) - The synthesis of 4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7s).
Using prepare compound 7b same procedures, aniline is changed to 3- Methyl anthranilates and obtains 7s, yield 54% 。1H NMR(500MHz,DMSO)δ11.55(s,1H),8.93(s,1H),8.47(s,1H),8.13(s,1H),8.07(s,1H), 7.80 (d, J=7.3Hz, 1H), 7.55 (d, J=7.3Hz, 1H), 7.39 (dd, J=7.7,7.3Hz, 1H), 4.62 (s, 2H), 3.91(s,3H),3.84(s,3H),3.81-3.80(m,2H),2.69-2.68(m,2H).
Embodiment 1-71 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (o-Phenetidine acyl group) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7t).
Using prepare compound 7b same procedures, aniline is changed to 2- phenetidines and obtains 7t, yield 51%.1H NMR (500MHz, DMSO) δ 11.52 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.85 (s, 1H), 7.56 (d, J= 7.8Hz, 1H), 7.03-6.97 (m, 2H), 6.87 (dd, J=7.6,7.5Hz, 1H), 4.59 (s, 2H), 4.04 (q, J= 6.8Hz, 2H), 3.91 (s, 3H), 3.77 (t, J=5.2Hz, 2H), 2.70-2.69 (m, 2H), 1.33 (t, J=6.8Hz, 3H)
Embodiment 1-72 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (the chloro- 3- 5-trifluoromethylanilines acyls of 4- Base) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (7u) synthesis.
Using prepare compound 7b same procedures, aniline is changed to 3- trifluoromethyl -4- chloroanilines and obtains 7u, yield 39%.1H NMR(500MHz,DMSO)δ11.54(s,1H),9.11(s,1H),8.47(s,1H),8.07-8.05(m,2H), 7.82 (d, J=7.9Hz, 1H), 7.59 (d, J=8.6Hz, 1H), 4.62 (s, 2H), 3.91 (s, 3H), 3.81-3.80 (m, 2H),2.70-2.69(m,2H).
Embodiment 1-73 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ((2- pyridines amido) carbonyl) -4, The synthesis of 5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (8a).
Using prepare compound 7b same procedures, aniline is changed to 2-aminopyridine and obtains 8a, yield 57%.1H NMR (500MHz,DMSO)δ11.44(s,1H),9.37(s,1H),8.46(s,1H),8.25(s,1H),8.06(s,1H),7.78- 7.69(m,2H),6.99(s,1H),4.62-4.60(m,2H),3.91(s,3H),3.81-3.80(m,2H),2.68-2.67(m, 2H).
Embodiment 1-74 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methoxyl group -3- pyridines amine) acyl The synthesis of base -4,5,6,7- tetrahydrochysene [2,3-c] piperidines bithiophenes (8b).
Using prepare compound 7b same procedures, aniline is changed to 3- amino -2- methoxypyridines and obtains 8b, yield 37%.1H NMR(500MHz,DMSO)δ11.52(s,1H),8.47(s,1H),8.07(s,1H),8.02(s,1H),7.90- 7.89(m,1H),7.86-7.85(m,1H),6.95-6.93(m,1H),4.60(s,2H),3.91(s,3H),3.90(s,3H), 3.77 (t, J=5.5Hz, 2H), 2.69-2.68 (m, 2H)
Embodiment 1-75 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (4- methoxyl group -3- pyridines amine) acyl The synthesis of base -4,5,6,7- tetrahydrochysene [2,3-c] piperidines bithiophenes (8c).
Using prepare compound 7b same procedures, aniline is changed to 4- amino -3-Methoxy Pyridine and obtains 8c, yield 39%.1H NMR (500MHz, DMSO) δ 11.53 (s, 1H), 8.47 (s, 1H), 8.44 (s, 1H), 8.22 (d, J=5.5Hz, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 7.07 (d, J=5.5Hz, 1H), 4.59 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.78 (t, J=5.3Hz, 2H), 2.68-2.67 (m, 2H)
Embodiment 1-76 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2,4- dimethoxyaniline acyls Base) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (8d) synthesis.
Using prepare compound 7b same procedures, aniline is changed to 2,4- dimethoxyanilines and obtains 8d, yield 38% 。1H NMR (500MHz, DMSO) δ 11.54 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 7.26 (d, J= 8.6Hz,1H),6.59-6.57(m,1H),6.46-6.44(m,1H),4.56(s,2H),3.91(s,3H),3.76(s,3H), 3.74(s,3H),3.73-3.72(m,2H),2.66-2.65(m,2H).
Embodiment 1-77 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- (2- (tert-butoxycarbonylamino) second Oxygroup) aniline acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (8e) synthesis.
Using prepare compound 7b same procedures, aniline is changed to 2- (2- (tert-butoxycarbonylamino) ethyoxyl) aniline and is obtained To 8e, yield 58%.1H NMR(500MHz,DMSO)δ11.52(s,1H),8.47(s,1H),8.07(s,1H),7.88(s, 1H), 7.71 (d, J=7.7Hz, 1H), 7.11-7.10 (m, 1H), 6.97-6.96 (m, 2H), 6.88-6.87 (m, 1H), 4.63 (s,2H),3.99(s,2H),3.91(s,3H),3.80-3.79(m,2H),3.37-3.35(m,2H),2.71-2.70(m,2H), 1.37(s,9H).
Embodiment 1-78 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- methoxyl groups -4- (2- (tertiary fourth oxygen Amide groups) ethyoxyl) aniline acyl group) and -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (8f) synthesis.
Using prepare compound 7b same procedures, aniline is changed to 2- methoxyl groups -4- (2- (tert-butoxycarbonylamino) ethoxies Base) aniline obtains 8f, yield 47%.1H NMR(500MHz,DMSO)δ11.60(s,1H),8.47(s,1H),8.07(s,1H), 7.81 (s, 1H), 7.25 (d, J=8.6Hz, 1H), 7.02-7.00 (m, 1H), 6.58 (s, 1H), 6.45 (d, J=8.6Hz, 1H), 4.55 (s, 2H), 3.93 (t, J=5.8Hz, 2H), 3.91 (s, 3H), 3.76 (s, 3H), 3.74 (t, J=5.6Hz, 2H), 3.29-3.26(m,2H),2.66-2.65(m,2H),1.38(s,9H).
Embodiment 1-79 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (quinoline -8- amine acyl group) -4,5,6, The synthesis of 7- tetrahydrochysenes [2,3-c] piperidines bithiophene (8g).
Using prepare compound 7b same procedures, aniline is changed to 8- aminoquinolines and obtains 8g, yield 51%.1H NMR (500MHz,DMSO)δ11.53(s,1H),9.43(s,1H),8.93(s,1H),8.47-8.39(m,3H),8.07(s,1H), 7.63-7.57(m,3H),4.74(s,2H),3.91(s,3H),3.88-3.87(m,2H),2.78-2.77(m,2H).
Embodiment 1-80 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (isoquinolin -8- amine acyl group) -4,5, The synthesis of 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene (8h).
Using prepare compound 7b same procedures, aniline is changed to 8- aminoisoquinolines and obtains 8h, yield 59%.1H NMR (500MHz, DMSO) δ 11.43 (s, 1H), 9.68 (s, 1H), 9.55 (s, 1H), 8.56 (d, J=4.9Hz, 1H), 8.46 (s, 1H), 8.23 (dd, J=6.9,6.9Hz, 1H), 8.09-8.06 (m, 1H), 7.84 (d, J=4.5Hz, 1H), 7.78-7.75 (m, 1H), 7.68 (d, J=7.5Hz, 1H), 7.53 (s, 1H), 7.07 (s, 1H), 4.68 (s, 2H), 3.91 (s, 3H), 3.75- 3.74(m,2H),2.81-2.80(s,2H).
Embodiment 1-81 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2 methyl indole -3- ethyls) amine The synthesis of acyl group -4,5,6,7- tetrahydrochysene [2,3-c] piperidines bithiophenes (9a).
Using prepare compound 7b same procedures, aniline is changed to 2- methyltryptamines and obtains 9a, yield 63%.1H NMR (500MHz, DMSO) δ 11.54 (s, 1H), 10.70 (s, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 7.41 (d, J=7.7Hz, 1H), 7.21 (d, J=7.9Hz, 1H), 6.95 (dd, J=7.7,7.4Hz, 1H), 6.88-6.84 (m, 2H), 4.45 (s, 2H), 3.91 (s, 3H), 3.62 (t, J=5.2Hz, 2H), 3.18-3.15 (m, 2H), 2.76 (t, J=7.3Hz, 2H), 2.54-2.53 (m,2H),2.28(s,3H).
Embodiment 1-82 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- methoxy-Indole -3- ethyls) The synthesis of amine acyl group -4,5,6,7- tetrahydrochysene [2,3-c] piperidines bithiophenes (9b).
Using prepare compound 7b same procedures, aniline is changed to 5- methoxytryptamines and obtains 9b, yield 49%.1H NMR (500MHz, DMSO) δ 11.46 (s, 1H), 10.59 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.21 (d, J= 8.7Hz, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 6.80 (s, 1H), 6.71 (d, J=8.6Hz, 1H), 4.46 (s, 2H), 3.91(s,3H),3.74(s,3H),3.63(s,2H),3.17(s,2H),2.82-2.79(m,2H),2.56(s,2H).
Embodiment 1-83 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- fluoro indole -3- ethyls) amine acyl The synthesis of base -4,5,6,7- tetrahydrochysene [2,3-c] piperidines bithiophenes (9c).
Using prepare compound 7b same procedures, aniline is changed to 5- flutamines and obtains 9c, yield 46%.1H NMR (500MHz,DMSO)δ11.47(s,1H),10.87(s,1H),8.46(s,1H),8.07(s,1H),7.33-7.28(m,2H), 7.22 (s, 1H), 6.90-6.87 (m, 1H), 6.82 (dd, J=5.0,4.9Hz, 1H), 4.46 (s, 2H), 3.92 (s, 3H), 3.64 (t, J=5.2Hz, 2H), 3.31-3.30 (m, 2H), 2.81 (t, J=7.3Hz, 2H), 2.57 (m, 2H)
Embodiment 1-84 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- chloro-indole -3- ethyls) amine acyl The synthesis of base -4,5,6,7- tetrahydrochysene [2,3-c] piperidines bithiophenes (9d).
Using prepare compound 7b same procedures, aniline is changed to 5- chloramines and obtains 9d, yield 51%.1H NMR (500MHz,DMSO)δ11.49(s,1H),10.98(s,1H),8.46(s,1H),8.06(s,1H),7.57(s,1H),7.34 (d, J=8.5Hz, 1H), 7.21 (s, 1H), 7.04 (d, J=8.5Hz, 1H), 6.81 (s, 1H), 4.45 (s, 2H), 3.91 (s, 3H),3.63(s,2H),3.17-3.16(m,2H),2.83-2.81(m,2H),2.56(m,2H).
Embodiment 1-85 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromo indole -3- ethyls) amine acyl The synthesis of base -4,5,6,7- tetrahydrochysene [2,3-c] piperidines bithiophenes (9e).
Using prepare compound 7b same procedures, aniline is changed to 5- bromoamines and obtains 9e, yield 47%.1H NMR (500MHz,DMSO)δ11.50(s,1H),11.01(s,1H),8.46(s,1H),8.06(s,1H),7.72(s,1H),7.31- 7.29 (m, 1H), 7.21-7.20 (m, 1H), 7.17-7.15 (m, 1H), 6.83 (t, J=5.4Hz, 1H), 4.45 (s, 2H), 3.91 (s, 3H), 3.63 (t, J=5.5Hz, 2H), 3.30-3.26 (m, 2H), 2.81 (t, J=7.4Hz, 2H), 2.57-2.56 (s,2H).
Embodiment 1-86 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (6- bromo indole -3- ethyls) amine acyl The synthesis of base -4,5,6,7- tetrahydrochysene [2,3-c] piperidines bithiophenes (9f).
Using prepare compound 7b same procedures, aniline is changed to 6- bromoamines and obtains 9f, yield 32%.1H NMR (500MHz,DMSO)δ11.54(s,1H),10.96(s,1H),8.47(s,1H),8.07(s,1H),7.48(s,1H),7.17 (s, 1H), 7.06 (d, J=8.4Hz, 1H), 6.88-6.86 (m, 1H), 4.45 (s, 2H), 3.91 (s, 3H), 3.62 (t, J= 5.3Hz, 2H), 3.29 (t, J=6.7Hz, 2H), 2.81 (t, J=7.4Hz, 2H), 2.55-2.54 (m, 2H)
Embodiment 1-87 2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (7- bromo indole -3- ethyls) amine acyl The synthesis of base -4,5,6,7- tetrahydrochysene [2,3-c] piperidines bithiophenes (9g).
Using prepare compound 7b same procedures, aniline is changed to 7- bromoamines and obtains 9g, yield 52%.1H NMR (500MHz, DMSO) δ 11.45 (s, 1H), 11.00 (d, J=4.9Hz, 2H), 8.45 (s, 1H), 8.05 (s, 1H), 7.55 (d, J =7.8Hz, 1H), 7.26 (m, 1H), 7.19 (s, 1H), 6.93-6.88 (m, 1H), 6.80 (s, 1H), 4.44 (s, 2H), 3.90 (s,3H),3.61-3.60(m,2H),3.27-3.26(m,2H),2.85-2.83(m,2H),2.54-2.53(m,2H).
Compound and STAT3 shown in 2 formula of embodiment ((I)-(IV)) combination activity, to STAT3 transcriptional repression activities with And the measurement to osteosarcoma 143B and liver cancer Huh-7 cell-proliferation activities.
Compound and the combination activity of STAT3 shown in formula ((I)-(IV)) use surface plasma resonance technology (Surface Plasmon Resonance technology, SPR) measuring is sun with STAT3 inhibitor BP-1-102 and Stattic Property control, wherein BP-1-102 SPR experiment in KD=1.79 μM, Stattic SPR experiment in KD=31.03 μM.SPR skills Art is based on the cutting edge technology of ligand and analyte effect on SPR detection bio-sensing chips (Biosensor chip), with tradition Means compare, and SPR has outstanding advantages of being not necessarily to that sample is marked, can monitor in real time, high sensitivity.Oversea laboratories are logical It crosses the technology and has detected STAT3 full-length proteins and its micromolecular inhibitor BP-1-102 combination situations, external KDValue is 504nM, we equally carry out SPR experiments with the compound and STAT3 albumen, the experimental results showed that, the two has good combination, And there is good concentration dependent, obtain KDIt it is 1.79 μM, with document report KDValue is close.
Compound and the combination activity of STAT3 shown in formula ((I)-(IV)) are also simultaneously with fluorescence polarization experiment (FP) test. STAT3 (127-722 amino acids) recombinant protein that we purify, this section remain the binding ability of STAT3 SH2domain, The simultaneously synthesizing fluorescent polypeptide 5-carboxyXuorescein-GpYLPQTV- that can be specifically bound with STAT3 SH2 domain NH2 is tested for fluorescence polarization, which is：When fluorescent molecular is excited by linearly polarized light, if molecule exists Be stimulated period and (lasted about for 4 nanoseconds for fluorescein) remains stationary, and transmitting light will be located at same plane of polarization.If by In excitation period, molecule, which is rotated or turned over, deviates this plane, and transmitting light will be positioned at the plane of polarization different from exciting light.Due to us The fluorescent polypeptide molecule amount very little of label, in the presence of it is in the form of unbonded STAT3, the movement occurred after excitation is big, hair Penetrate light relative to excitation optical plane will depolarizing, the polarized light signal detected is relatively low.When fluorescent polypeptide is attached to STAT3 When, since overall molecule amount becomes larger, the movement occurred when exciting is minimum, and transmitting light polarization optical signal is strong, we are as base The variation that rear polarizer optical signal is added to evaluate drug for plinth judges whether untested compound affects STAT3 and its The combination of SH2domian specific polypeptides determines that untested compound whether there is with STAT3 from side and binds directly effect.
P T Gunning＆M W Deininger professors seminar in 2015 reports BP-1-102 and is tested in fluorescence polarization (FP) the competitive binding activity that it is measured in STAT3 SH2 structural domains is 23.2 ± 5.9 μM, we are with the similarly side of experiment Method measures BP-1-102 and STAT3 SH2 structural domain inhibitory activity IC50Value is 32.12 μM, consistent with document report.In addition we Representative compound 9e and STAT3 SH2 structural domain inhibitory activity IC in -3 cyano thiophene derivative of 2- amino of oneself synthesis50 Value is 10.46 μM, is better than positive compound BP-1-102.
Compound shown in formula ((I)-(IV)) tests the transcriptional repression activity of STAT3 with luciferase (luciferase) It measures.STAT3 plays important signal transduction effect in the cell, is responsible for extracellular signal being transmitted to nucleus, pass through Induce the effect effect of target gene transcriptional expression biostimulation.We in vitro by build STAT3 Reporter Systems come into Row its transcriptional activity research.We are that STAT3 specific bindings DNA element sequence is inserted into PGL4.17 reporter genes first On carrier, it can be specifically bound in DNA element sequence to drive reporter gene luciferase after STAT3 activation (luciferase) expression, luciferase can be catalyzed its substrate luciferin and send out fluorescence, by detecting the intensity of fluorescence just The degree of Androgen Receptor Activation can be detected；Renila internal reference reporter genes carry renilla luciferase, can express sea pansy fluorescence Plain enzyme can determine whether the transfection efficiency of every group of cell is consistent by the plasmid, while IL-6 or OSM conducts will also be added STAT3 specific activation agent improves specificity and the sensitivity of reporter gene detection with this, and IL-6 or OSM are to Renila Internal reference reporter plasmid does not influence.It is intracellular that we with this transfect 293T simultaneously to plasmid, then uses untested compound Processing a period of time, then measure readings, you can be used for influence of the screening compounds to STAT3 transcriptional activities.
P T Gunning＆M W Deininger professors seminar reports BP-1-102 in luciferase simultaneously within 2015 (luciferase) about 20 μM or so of its activity is measured in testing, we measure BP-1-102 with same test method and live Property is consistent with document report.In addition its work of representative compound 9e in -3 cyano thiophene derivative of 2- amino of our oneself synthesis Property be 10 μM or so, be better than positive compound BP-1-102.
Compound shown in formula ((I)-(IV)) measures cancer cell multiplication inhibitory activity MTS methods.Cell proliferation experiment is thin Born of the same parents' proliferation experiment is tested using MTS, and MTS experiments are a kind of methods with colorimetric method indirect determination living cells quantity.MTS is one The newly synthesized tetrazole compound of kind, by being reduced into orange-yellow first by the succinate dehydrogenase in living cells mitochondrial The quantity of a ceremonial jade-ladle, used in libation, light absorption value and living cells that reduzate is measured at 490nm is proportional, to reflect cell viability situation.This Experiment can be used for evaluating the influence of compounds on pancreatic cancer cell multiplication, to judge compounds on pancreatic cancer cell multiplication Inhibiting effect and calculation of half inhibitory concentration (IC50)。
Each cell is uniformly inoculated into 96 orifice plates with the density in 5 × 103/hole, per 100 μ L of hole, in 37 DEG C of constant incubators After middle placement 24 hours, corresponding culture medium is added in control group, and experimental group gives the compound of various concentration, drug-treated 48 It is taken out after hour and observes cell state under the microscope, be protected from light every hole and 20 μ LMTS are added, avoid light place is 37 after mixing DEG C constant incubator reads absorbance value with being measured at microplate reader 490nm, until the OD value ranges of control group are between 0.8-1.2, It tests in triplicate, IC50It is calculated with GraphPad5 Prism softwares.
The bioactivity of compound of the present invention is measured by testing above, what compound of the present invention measured IC50Value experimental result is shown in Table 1.Wherein activity value is the IC of " A " representation compound50Value is less than 0.1 μM；Activity value represents for " B " The IC of compound50Value is 0.1-1 μM；Activity value is the IC of " C " representation compound50Value is 1-10 μM, and activity value represents for " D " The IC of compound50Value is more than 10 μM.
Chemical combination microbic activity list shown in 1 formula of table ((I)-(IV))
Inhibitory activity of the 3 STAT3 inhibitor 5p of embodiment to different cancer cells.
We test STAT3 inhibitor 5P to bone tumour, liver cancer, kidney, breast cancer, colon cancer, oophoroma, gastric cancer Antiproliferative effect the results are shown in Table shown in 2：
Inhibitory activity of the 2 STAT3 inhibitor 5P of table to different cancer cells
4 STAT3 inhibitor 7r of embodiment inhibits the growth and transfer of osteosarcoma.
We devise animal model of the osteosarcoma shin bone to Lung metastases, with STAT3 inhibitor BP-1-102 for the positiveization Object is closed, dosage is that 20mg/kg is injected intraperitoneally once every other day, while 7r dosages are 10mg/kg and 20mg/kg abdomens every other day Chamber injection is primary.Continue in administration surrounding, the results are shown in Figure 1.
Experimental result show 7r can dose-dependent inhibition osteosarcoma growth in situ, 7r exists compared with BP-1-102 It can achieve the effect that BP-1-102 20mg/kg dosages groups (Figure 1A) under the dosage of 10mg/kg；And inhibiting to lung 7r also shows same effect in the effect of transfer, 7r almost inhibited under the dosage of 20mg/kg osteosarcoma to The transfer (Figure 1B) of lung.
Therapeutic effects of the 5 STAT3 inhibitor 5p and 7r of embodiment to psoriasis
Imiquimod (IMQ) is used as the artificial synthesized agonists of TLR-7/8, is commonly used for treatment caused by papillomavirus Human reproduction's device wart.Psoriasiform skin can be induced by TLR-7/8 activation and inflammatory cell infiltration, imiquimod Local treatment Skin inflammation；Mechanism is proved the similitude with mankind's psoriasis in the Mice Body of imiquimod processing：Common cell factor letter Number access depends on IL-17/IL-23 axis, frequently as mankind's psoriasis induced animal model jointly.
In all experiments, using 8 to 11 week C57BL/6 mouse (being purchased from Shanghai Si Laike Bioisystech Co., Ltd), Raise the SPF grade animal houses in East China Normal University's Animal Research Center.With containing 5%IMQ (the bright glad limited public affairs of medicine company in Sichuan Department) continuous 5 days of 62.5mg Aldara emulsifiable pastes processing shaving daily mouse back skin.In experiment, 50 μ l Aldara breasts Cream is mixed with final concentration of 500 μM of 5p and 7r (in DMSO solution).For the severity for the skin of back inflammation that scores, it is based on Clinical psorasis area and severity index (PASI) develop objective scoring system, in addition to for mouse model, whole Impacted skin area is not considered in body scoring.Erythema, the scales of skin that peel off and thickens independent scoring 0 to 4：0, nothing；1, slightly；2, temperature With；3, mark；4, it will be apparent that.It is scored erythema level using the score-sheet with red stain.Accumulation scoring (erythema Mark-on degree, which adds, to be thickened) it is used as the measurement (scoring 0-12) of severity of inflammation.
During this investigation it turned out, we are research shows that STAT3 micromolecular inhibitors 5p (500 μM) and 7r (500 μM) presses down strongly Psoriasis sample scytitis in the mouse of imiquimod (IMQ) induction processed.The erythema of daily scoring skin of back, fouling and thickness Degree.It calculates and depicts accumulation scoring, in addition, the parameter of the 6th day scytitis (erythema, the scales of skin that peel off and thickness) describes respectively, Every group of 3 mouse.Statistically significant difference (p≤0.05) indicates.We show that STAT3 micromolecular inhibitors 5p and 7r are locally controlled Treating reduces the skin hyperplasia of IMQ inductions, the expression (Fig. 2) of pro-inflammatory mediator in inflammatory mononuclear cells infiltration and mouse skin.
Implementation column 6 STAT3 inhibitor 5p and 7r promote the growth of hair
Hair follicle cultured in vitro scale-model investigation is not only to carry out hair follicle cell biological study, hair follicle growth regulation and control, hair follicle weight The basis with researchs such as hair follicle drug screenings is built, and the in vitro culture of free hair follicle can control influence factor, be conducive to hair The research of the long regulatory mechanism of Tibetan household slave.Have more document reports and has carried out relative medicine or the factor using the culture of in vitro hair follicle Promote the verification of hair growth.In addition to this, domestic and foreign scholars mainly use the evaluation study for promoting the drug of hair growth at present Internal and external two kinds of experimental methods, and what experiment in vitro mainly used is that the in vitro hair follicle organ of animal is cultivated, then Evaluate the variation of pretherapy and post-treatment hair follicle growth.Due to human hair hair follicle source difficulty, and mouse antenna hair follicle is larger, is easy to divide From age of mouse is easy to control, and experimental result is stablized.So we select C57BL/6 mouse antenna hair follicles to promoting hair growth drug Carry out the screening of organ level.
The C57BL/6 mouse --- taking off both sides beard with scissors and tweezers --- suitable for week old are chosen with 75% alcohol Disinfection, pbs rinse --- be under the microscope stripped out each individual hair follicle, cleared up --- selection and are in growth period Hair follicle cultivated.At regular intervals, it measures hair shaft and upholds length, finally carry out statistical analysis.
As a result showing (Fig. 3), we can promote the growth of hair by organ level discovery stat3 inhibitor 5p and 7r. Especially drug 7r promotees hair growth with * * * explicitlies on cultured in vitro hair follicle organ level compared with control groups Difference, and compared with positive drug Ruxolitinib, also there is the difference of * *.
The present invention protects content to be not limited to above example.Without departing from the spirit and scope of the invention, this field Technical staff it is conceivable that variation and advantage be all included in the present invention, and with appended claims be protection model It encloses.

Claims (11)

1. a kind of cycloalkane thiophthene derivative and its pharmaceutically acceptable salt, metabolite or prodrug, which is characterized in that institute It states shown in cycloalkane thiophthene derivative such as following formula (I)：
Wherein,
X is CH or N；
Y is C=O, C=S ,-C (O) NH- ,-C (O) O- ,-C (O) S- ,-C (S) NH- ,-C (S) O- ,-C (S) S-, NH, O, S；
M is 0~3；
Ar is the 5-6 member aromatic rings containing 0-3 N atom and 0-1 O or S atom, including phenyl ring, thiphene ring, furan nucleus, pyrroles Ring, thiazole ring,It is azoles ring, differentAzoles ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring；
R1For the substituent group on aromatic rings/aromatic heterocycle, it is selected from one or more of following groups：Halogen, hydroxyl, cyano, nitre Base, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5, wherein R3、R4、R5Respectively From independently being hydrogen or C1-4Alkyl, p 0,1 or 2；
R2For hydrogen, hydroxyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 First heteroaryl perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5、5-6 First aromatic radical, 5-6 circle heterocyclic ring aromatic radicals, optionally, the 5-6 members aromatic radical and 5-6 circle heterocyclic rings aromatic radical each independently by One or more is selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings Base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、- NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, p 0,1 or 2.
2. cycloalkane thiophthene derivative according to claim 1 and its pharmaceutically acceptable salt, metabolite or preceding Medicine, which is characterized in that when X is CH, shown in the cycloalkane thiophthene derivative such as following formula (II)：
Wherein,
Y is C=O, C=S ,-C (O) NH- ,-C (O) O- ,-C (O) S- ,-C (S) NH- ,-C (S) O- ,-C (S) S-, NH, O, S；
M is 0~3；
Ar is the 5-6 member aromatic rings containing 0-3 N atom and 0-1 O or S atom, including phenyl ring, thiphene ring, furan nucleus, pyrroles Ring, thiazole ring,It is azoles ring, differentAzoles ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring；
R1Independently by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Ring Alkyl, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C (O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, P is 0,1 or 2；
R2For hydrogen, hydroxyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 First heteroaryl perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5、5-6 First aromatic radical, 5-6 circle heterocyclic ring aromatic radicals, optionally, the 5-6 members aromatic radical and 5-6 circle heterocyclic rings aromatic radical each independently by One or more is selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings Base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、- NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, p 0,1 or 2.
3. cycloalkane thiophthene derivative according to claim 1 and its pharmaceutically acceptable salt, metabolite or preceding Medicine, which is characterized in that when X is N atoms, and Y is carbonyl, shown in the cycloalkane thiophthene derivative such as following formula (III)：
Wherein,
M is 0~3；
Ar is the 5-6 member aromatic rings containing 0-3 N atom and 0-1 O or S atom, including phenyl ring, thiphene ring, furan nucleus, pyrroles Ring, thiazole ring,It is azoles ring, differentAzoles ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring；
R1Independently by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Ring Alkyl, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C (O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, P is 0,1 or 2；
R2For hydrogen, hydroxyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 First heteroaryl perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5、5-6 First aromatic radical, 5-6 circle heterocyclic ring aromatic radicals, optionally, the 5-6 members aromatic radical and 5-6 circle heterocyclic rings aromatic radical each independently by One or more is selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings Base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、- NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, p 0,1 or 2.
4. cycloalkane thiophthene derivative according to claim 1 and its pharmaceutically acceptable salt, metabolite or preceding Medicine, which is characterized in that when X is N atoms, and Y is-C (O) NH-, shown in the cycloalkane thiophthene derivative such as following formula (IV)：
Wherein,
M is 0~3；
Ar is the 5-6 member aromatic rings containing 0-3 N atom and 0-1 O or S atom, including phenyl ring, thiphene ring, furan nucleus, pyrroles Ring, thiazole ring,It is azoles ring, differentAzoles ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring；
R1Independently by one or more selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Ring Alkyl, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C (O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, P is 0,1 or 2；
R2For hydrogen, hydroxyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, C5-10Aromatic radical, 5-10 First heteroaryl perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、-NR4R5Or-C (O) NR5、5-6 First aromatic radical, 5-6 circle heterocyclic ring aromatic radicals, optionally, the 5-6 members aromatic radical and 5-6 circle heterocyclic rings aromatic radical each independently by One or more is selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings Base, C5-10Aromatic radical, 5-10 member heteroaryls perfume base, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR3、-C(O)R3、-C(O)OR3、- NR4R5Or-C (O) NR5Substituent group substitution, wherein R3、R4、R5It is each independently hydrogen or C1-4Alkyl, p 0,1 or 2.
5. a kind of any one of them cycloalkane thiophthene derivative according to claim 1-4 and its pharmaceutically acceptable Salt, metabolite or prodrug, which is characterized in that including：
4- cyano -5- (1- methyl -4- pyrazoles)-formamido-cyclobutyl [2,3] bithiophene；
4- cyano -5- (1- methyl -4- pyrazoles)-formamido-cyclopenta [2,3] bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -4,5,6,7- tetrahydro benzo thiophene；
4- cyano -5- (1- methyl -4- pyrazoles)-formamido-suberyl [2,3] bithiophene；
4- cyano -5- (1- methyl -4- pyrazoles)-formamido-cyclooctyl [2,3] bithiophene；
2- (1- first -4- pyrazoles)-formamido -3- cyano -4- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1-H-4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6,6- dimethyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- propyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- phenyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethoxy carbonyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl 4- pyrazoles)-formamido -3- cyano -6- oxygen -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- hydroxyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6,2 '-[1,3] dioxolanes -4,5,6,7- tetrahydro benzo thiophenes Pheno；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethoxy carbonyl -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines is simultaneously Thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- tertbutyloxycarbonyl -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines is simultaneously Thiophene；
2- (1- methyl -3- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl -5- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- methyl -4- imidazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2-(4-Azoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (4- thiazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2-benzamide base -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (2- pyridines)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (4- pyrimidines)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- hydrogen -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- (2- ethoxys) -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- (2- methoxy ethyls) -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzo thiophene；
2- (1- (2- (2- hydroxy ethoxies) ethyl -4- pyrazoles)-formamido -3- cyano -6- methyl -4,5,6,7- tetrahydro benzos Thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- glycolyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines Bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- Methoxyacetyl -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines Bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (1- methylpyrazole -3- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3- C] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (1- methylpyrazole -4- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3- C] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (1- methylpyrazole -5- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3- C] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (Azoles -4- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines Bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (thiazole -4- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines Bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methoxybenzothiophene -2- carbonyls) -4,5,6,7- four Hydrogen [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (benzothiophene -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methyl benzofuran -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- methylfuran -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3- C] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (thiophene -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines Bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- chlorothiophene -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromine furans -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- chlorine furans -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromothiophene -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (4- bromothiophene -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromomethyl furans -2- carbonyls) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (pyrrolidines -1- methylene) furans -2- carbonyls) -4,5, 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (morpholine ring -1- methylene) furans -2- carbonyls) -4,5, 6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (4- methyl piperazine -1- methylene) furans -2- carbonyls) - 4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- (4- (2- ethoxys) piperazine -1- methylene) furans -2- Carbonyl) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ethylamino-s carbonyl -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines is simultaneously Thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- anilinocarbonyl -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines is simultaneously Thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- benzylamines acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines and thiophene Pheno；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- β phenyl ethylamines acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines is simultaneously Thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- phentermines acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines is simultaneously Thiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (furans -2- methylene) aminoacyl -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- pyridine ethylamines acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (4- pyridine propylamine acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- are to Bretylium Tosylate acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperazine Pyridine bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (to fluorophenethylamine acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- are to chlorophenethylamine acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperazine Pyridine bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- neighbour's fluoroaniline acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines Bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- m-fluoroanilines acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines Bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- para-fluoroaniline acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines Bithiophene
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- o-aminoanisole acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- m-anisidine acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- P-nethoxyaniline acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methyl formate aniline acyl group) -4,5,6,7- tetrahydrochysenes [2, 3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (o-Phenetidine acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (the chloro- 3- 5-trifluoromethylanilines acyl groups of 4-) -4,5,6,7- four Hydrogen [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- ((2- pyridines amido) carbonyl) -4,5,6,7- tetrahydrochysenes [2,3- C] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (3- methoxyl group -3- pyridines amine) acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (4- methoxyl group -3- pyridines amine) acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2,4- dimethoxyanilines acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- (2- (tert-butoxycarbonylamino) ethyoxyl) aniline acyl group) - 4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2- methoxyl groups -4- (2- (tert-butoxycarbonylamino) ethyoxyl) Aniline acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (quinoline -8- amine acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] piperazine Pyridine bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (isoquinolin -8- amine acyl group) -4,5,6,7- tetrahydrochysenes [2,3-c] Piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (2 methyl indole -3- ethyls) amine acyl group -4,5,6,7- four Hydrogen [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- methoxy-Indole -3- ethyls) amine acyl group -4,5,6,7- Tetrahydrochysene [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- fluoro indole -3- ethyls) amine acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- chloro-indole -3- ethyls) amine acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (5- bromo indole -3- ethyls) amine acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (6- bromo indole -3- ethyls) amine acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene；
2- (1- methyl -4- pyrazoles)-formamido -3- cyano -6- (7- bromo indole -3- ethyls) amine acyl group -4,5,6,7- tetrahydrochysenes [2,3-c] piperidines bithiophene.
6. one kind including any one of them cycloalkane thiophthene derivative of claim 1-5 and its pharmaceutically acceptable The pharmaceutical composition of salt, metabolite or prodrug.
7. a kind of such as any one of them cycloalkane thiophthene derivative of claim 1-5 and its pharmaceutically acceptable salt, The application of metabolite or prodrug or pharmaceutical composition according to claim 6 in preparing STAT3 inhibitor.
8. a kind of such as any one of them cycloalkane thiophthene derivative of claim 1-5 and its pharmaceutically acceptable salt, Metabolite or prodrug or pharmaceutical composition according to claim 6 are preparing prevention and/or are treating what STAT3 was mediated Application in disease medicament, wherein the disease includes oophoroma, carcinoma of endometrium, cervical carcinoma, breast cancer, colon cancer, pancreas Cancer, lung cancer, the cancer of the brain, kidney, liver cancer, carcinoma of urinary bladder, carcinoma of mouth, sarcoma, prostate cancer, Head and neck squamous cell carcinoma, glioma, Melanoma, lymthoma, leukaemia, kidney fibrosis, pulmonary fibrosis, rheumatoid arthritis, hair growth, arthritis, silver bits Disease, lupus erythematosus, inflammatory lung disease and inflammatory bowel disease.
9. a kind of such as any one of them cycloalkane thiophthene derivative of claim 1-5 and its pharmaceutically acceptable salt, Metabolite or prodrug or pharmaceutical composition according to claim 6 are preparing prevention and/or are treating what STAT3 was mediated Application in cancer drug, wherein the cancer be malignant tumour include oophoroma, carcinoma of endometrium, cervical carcinoma, breast cancer, Colon cancer, cancer of pancreas, lung cancer, the cancer of the brain, kidney, liver cancer, carcinoma of urinary bladder, carcinoma of mouth, sarcoma, prostate cancer, Head and neck squamous cell carcinoma, Glioma, melanoma, lymthoma and leukaemia.
10. a kind of such as any one of them cycloalkane thiophthene derivative of claim 1-5 and its pharmaceutically acceptable salt, Metabolite or prodrug or pharmaceutical composition according to claim 6 are preparing prevention and/or treatment autoimmune disease Application in medicine, wherein the autoimmune disease includes kidney fibrosis, pulmonary fibrosis, rheumatoid arthritis, hair It grows, arthritis, psoriasis, lupus erythematosus, inflammatory lung disease and inflammatory bowel disease.
11. a kind of such as any one of them cycloalkane thiophthene derivative of claim 1-5 and its pharmaceutically acceptable salt, Metabolite or prodrug or pharmaceutical composition according to claim 6 have apparent combination to STAT3.
CN201810353541.0A 2018-04-19 2018-04-19 A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage Pending CN108558848A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810353541.0A CN108558848A (en) 2018-04-19 2018-04-19 A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810353541.0A CN108558848A (en) 2018-04-19 2018-04-19 A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage

Publications (1)

Publication Number Publication Date
CN108558848A true CN108558848A (en) 2018-09-21

Family

ID=63535847

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810353541.0A Pending CN108558848A (en) 2018-04-19 2018-04-19 A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage

Country Status (1)

Country Link
CN (1) CN108558848A (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108309975A (en) * 2018-05-02 2018-07-24 华东师范大学 Micromolecular compound WB460 is preparing the application in treating pancreatic cancer drug
WO2019173437A1 (en) * 2018-03-06 2019-09-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Positive allosteric modulators of dopamine 1 receptor and method of use thereof
WO2020200154A1 (en) * 2019-03-30 2020-10-08 上海凌达生物医药有限公司 A class of thiophene fused n-heterocyclies, preparation method and use
CN111909167A (en) * 2019-05-07 2020-11-10 华东师范大学 Novel piperidinothiophene derivative and application thereof in preparing medicine for treating psoriasis
CN112516145A (en) * 2019-09-19 2021-03-19 华东师范大学 Application of small molecular compound WK369 in preparation of medicines for treating ovarian cancer
CN113318103A (en) * 2020-02-28 2021-08-31 华东师范大学 Application of small molecular compound YJ-5-41 in preparation of anti-gastric cancer drugs
WO2022200580A1 (en) * 2021-03-26 2022-09-29 Chiesi Farmaceutici S.P.A. Tetrahydrothieno pyridine derivatives as ddrs inhibitors
WO2022200578A1 (en) * 2021-03-26 2022-09-29 Chiesi Farmaceutici S.P.A. Tetrahydrothieno pyridine derivatives as ddrs inhibitors
RU2810078C1 (en) * 2023-03-31 2023-12-21 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" POTASSIUM 2-(4-BROMOPHENYL)-6-OXO-4-(PHENYLIMINO)-1,6-CYANO-1-((4-CYANO-3-TETRAHYDROBENZO[b]THIOPHEN-4,5,6,7-YL)AMINO)-2-ETOXYHEXA-2,4-DIENE-3-OLATE WITH ANALGESIC ACTIVITY

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7517986B2 (en) * 2004-06-04 2009-04-14 4Sc Ag Tetrahydropyridothiophenes for use in the treatment of cancer
US7714134B2 (en) * 2004-06-11 2010-05-11 4Sc Ag Compounds and use of tetrahydropyridothiophenes
CN104844563A (en) * 2015-03-31 2015-08-19 苏州大学 Targeting STAT3 inhibitor and application thereof
KR101633453B1 (en) * 2015-06-17 2016-06-24 한국과학기술연구원 Novel Tetrahydrothieno[2,3-c]pyridine derivatives as mGluR1 and/or mGluR5 antagonists
CN108191885A (en) * 2018-01-29 2018-06-22 华东师范大学 A kind of piperidines bithiophene micromolecular organic compound and its application

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7517986B2 (en) * 2004-06-04 2009-04-14 4Sc Ag Tetrahydropyridothiophenes for use in the treatment of cancer
US7714134B2 (en) * 2004-06-11 2010-05-11 4Sc Ag Compounds and use of tetrahydropyridothiophenes
CN104844563A (en) * 2015-03-31 2015-08-19 苏州大学 Targeting STAT3 inhibitor and application thereof
KR101633453B1 (en) * 2015-06-17 2016-06-24 한국과학기술연구원 Novel Tetrahydrothieno[2,3-c]pyridine derivatives as mGluR1 and/or mGluR5 antagonists
CN108191885A (en) * 2018-01-29 2018-06-22 华东师范大学 A kind of piperidines bithiophene micromolecular organic compound and its application

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MINA NAM ET AL.: "Discovery and biological evaluation of tetrahydrothieno[2,3-c]pyridine derivatives as selective metabotropic glutamate receptor 1 antagonists for the potential treatment of neuropathic pain", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
STN: "RN号为919849-09-5、919840-91-8等的化合物", 《STNEXT》 *
STN: "RN号分别为1005651-30-8、1005674-22-5、1005703-73-0 、1005552-21-5、 1234944-99-0、1492724-19-2、331869-86-4、940637-89-8、1291527-21-3的化合物", 《STNEXT》 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019173437A1 (en) * 2018-03-06 2019-09-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Positive allosteric modulators of dopamine 1 receptor and method of use thereof
CN108309975A (en) * 2018-05-02 2018-07-24 华东师范大学 Micromolecular compound WB460 is preparing the application in treating pancreatic cancer drug
WO2020200154A1 (en) * 2019-03-30 2020-10-08 上海凌达生物医药有限公司 A class of thiophene fused n-heterocyclies, preparation method and use
CN111763217A (en) * 2019-03-30 2020-10-13 上海凌达生物医药有限公司 Thieno-nitrogen heterocyclic compound, preparation method and application
CN111909167A (en) * 2019-05-07 2020-11-10 华东师范大学 Novel piperidinothiophene derivative and application thereof in preparing medicine for treating psoriasis
CN111909167B (en) * 2019-05-07 2021-11-19 华东师范大学 Piperidinothiophene derivative and application thereof in preparation of medicine for treating psoriasis
CN112516145A (en) * 2019-09-19 2021-03-19 华东师范大学 Application of small molecular compound WK369 in preparation of medicines for treating ovarian cancer
CN113318103A (en) * 2020-02-28 2021-08-31 华东师范大学 Application of small molecular compound YJ-5-41 in preparation of anti-gastric cancer drugs
WO2022200580A1 (en) * 2021-03-26 2022-09-29 Chiesi Farmaceutici S.P.A. Tetrahydrothieno pyridine derivatives as ddrs inhibitors
WO2022200578A1 (en) * 2021-03-26 2022-09-29 Chiesi Farmaceutici S.P.A. Tetrahydrothieno pyridine derivatives as ddrs inhibitors
RU2810078C1 (en) * 2023-03-31 2023-12-21 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" POTASSIUM 2-(4-BROMOPHENYL)-6-OXO-4-(PHENYLIMINO)-1,6-CYANO-1-((4-CYANO-3-TETRAHYDROBENZO[b]THIOPHEN-4,5,6,7-YL)AMINO)-2-ETOXYHEXA-2,4-DIENE-3-OLATE WITH ANALGESIC ACTIVITY

Similar Documents

Publication Publication Date Title
CN108558848A (en) A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage
CN104968647B (en) Acid amides as sodium channel modulators
CN105026373B (en) Pyridine keto-amide as sodium channel modulators
CN102271682B (en) Be used for the treatment of the P2X of pain 3receptor antagonist
CN103635458B (en) TRPV1 antagonist
CN105683157B (en) Sulfonamides as sodium channel modulators
CN104797555B (en) The benzamide and its application method of N substitutions
CN102471347B (en) The enantiomer of spiral shell-oxindole compounds and the purposes as therapeutical agent thereof
JP6556154B2 (en) Isoquinoline derivatives and uses thereof
CN107382859B (en) The crystal habit of prolyl hydroxylase inhibitors
TWI331034B (en) Inhibitors of cyclin-dependent kinases and their use
CN104334527B (en) Sulfonamide compounds and uses as tnap inhibitors
CN108395452A (en) The prodrug of pyridine keto-amide as sodium channel modulators
CN102942520B (en) P38 map kinase inhibitors
CN109071459A (en) PPAR agonist, compound, pharmaceutical composition and their application method
CN101160285A (en) Substituted sulfonylaminoarylmethyl cyclopropanecarboxamide as vr1 receptor antagonists
CN107434779A (en) Notch signal pathway inhibitors and its purposes in treatment of cancer
JP6152227B2 (en) New triazolo-pyridine compounds
BRPI0608653A2 (en) compound or a pharmaceutically acceptable salt thereof, pharmaceutical composition, and use of a compound or salt thereof
CN102448937A (en) Aryl Substituted Carboxamide Derivatives As Calcium Or Sodium Channel Blockers
TW200409756A (en) Novel compounds
CN107007587A (en) For inducing chondrogenetic Compounds and methods for
WO2010135976A1 (en) 1-(substituted benzyl)-5-trifluoromethyl-2-(1h) pyridone compounds and their salts, their preparation methods and use thereof
TWI250152B (en) N,N-substituted cyclic amine compounds used as calcium antagonizer
JP2007509158A (en) 3- (4-Aminophenyl) thienopyrimid-4-one derivatives as MCHR1 antagonists for treating obesity, diabetes, depression and anxiety

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
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20180921