CN109206360A - Carbazole amide derivatives or its salt and its preparation method and application - Google Patents

Carbazole amide derivatives or its salt and its preparation method and application Download PDF

Info

Publication number
CN109206360A
CN109206360A CN201810700432.1A CN201810700432A CN109206360A CN 109206360 A CN109206360 A CN 109206360A CN 201810700432 A CN201810700432 A CN 201810700432A CN 109206360 A CN109206360 A CN 109206360A
Authority
CN
China
Prior art keywords
alkyl
carbazole
added
ethyl
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201810700432.1A
Other languages
Chinese (zh)
Other versions
CN109206360B (en
Inventor
王永辉
黄亚飞
郁明诚
谢琼
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.)
Fudan University
Original Assignee
Fudan 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 Fudan University filed Critical Fudan University
Publication of CN109206360A publication Critical patent/CN109206360A/en
Application granted granted Critical
Publication of CN109206360B publication Critical patent/CN109206360B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles 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 ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention discloses the new carbazole amide derivatives with ROR γ t Active Regulation effect or its salt and preparation method thereof shown in a kind of general formula I, also disclose the carbazole amide derivatives or its salt preparation treat and the drug of ROR γ t related disease in purposes.Experimental result is shown, carbazole amide derivatives or its salt of the invention can effectively adjust ROR γ t protein receptor activity, to regulate and control the differentiation of Th17 cell and the generation of IL-17, it is further used as the therapeutic agent for the related disease that treatment ROR γ t is mediated, is particularly suitable for the related diseases such as treatment multiple sclerosis, rheumatoid arthritis, Collagen-induced Arthritis, psoriasis, inflammatory bowel disease, encephalomyelitis, clone's disease, asthma and various cancers.

Description

Carbazole amide derivatives or its salt and its preparation method and application
Technical field
The invention belongs to technical field of chemical medicine, it is related to having the new of general formula I that there is ROR γ t to adjust active click Azoles amide derivatives and preparation method thereof further relate to the purposes of this compounds for treating disease related with ROR γ t.
Background technique
Retinoic acid receptors related orphan receptor (retinoic acid recetor-related orphan Receptors, RORs), also known as NF1R belongs to a member of the transcription factor nuclear receptor superfamily of ligand-dependent.The Asia RORs man Race mainly includes ROR α, ROR β and ROR γ these three members.There are two different hypotypes by ROR γ: ROR γ 1 and ROR γ t (also referred to as ROR γ 2), wherein ROR γ 1 is distributed in skeletal muscle, thymus gland, testis, pancreas, prostate, heart and liver etc., and ROR γ t is only expressed in certain immunocytes.
Littman etc. reports ROR γ t for initial CD4 earliest+T cell differentiating into T h17 cell is required.Through antigen The Thp cell of stimulation is into Th17 cell differentiation procedure, the inducing expression under the Cytokines such as IL-6, IL-21 and TGF-β RORγt.The Thp cell separated from ROR γ t depleted mice, the ability broken up to Th17 cell strain are substantially reduced.This All show that ROR γ t is the key regulator for promoting Th17 cell differentiation a bit.
Th17 cell is one kind of helper T lymphocyte, can generate IL-17 and other pro-inflammatory cytokines.Th17 cell Crucial effect, such as experimental allergic encephalomyelitis have been played in many mouse Autoimmune Disease Models (EAE) and Collagen-induced Arthritis (CIA) animal model.In addition, including rheumatoid in some mankind's autoimmune diseases In property arthritis (RA), multiple sclerosis (MS), psoriasis (Psoriasis) and inflammatory bowel disease (IBD), can it detect The raising of IL-17 level.Th17 cell quantity found in the tissue and peripheral blood sample of autoimmune disease patient Increase.Therefore, the pathogenesis of Th17 cell or its cell factor IL-17 generated and inflammation and autoimmune disease has It is closely connected.
In January, 2015, by the monoclonal antibody for treating psoriasis by specific inhibition IL-17 of Novartis Co., Ltd's exploitation Cosentyx (Secukinumab/AIN457) has obtained FDA approval listing, this is first work in treatment psoriasis class pharmaceutical market Drug for IL-17.This also highlights importance of the IL-17 signal path in inflammatory disease, and illustrates and pass through ROR γ t inhibitor and influence IL-17 signal path and treat the Potential feasibility of inflammatory disease.
Therefore, ROR γ t can be used as the novel targets for the treatment of autoimmune disease drug, finds ROR γ t small molecule and adjusts The agent and treatment of inflammation and autoimmune disease for being used for ROR γ t mediation will be of great significance.
Tumour immunotherapy is the immune system by transferring body, enhances tumor microenvironment anti-tumor immunity, thus Control and killing tumor cell, its target are the immune systems of human body rather than directly against tumours.Immunotherapy of tumors is close It is concerned over year, is the focus of therapeutic field of tumor.It is reported that at present in some tumor types such as melanoma, non-small Powerful anti-tumor activity is illustrated in the treatment of cell lung cancer etc., and existing immunotherapy of tumors monoclonal antibody medicine obtains the U.S. FDA approval listing.Immunotherapy of tumors is chosen as due to its brilliant curative effect and novelty, in 2013 by " Science " magazine Year most important scientific breakthrough.Immunotherapy of tumors is expected to become the oncotherapy after operation, chemotherapy, radiotherapy, targeted therapy One innovation in field.
The discovery of existing research at present, Th17 cell is widely present in tumor tissues, however, about Th17 in tumor tissues In function but know nothing.2009, Dong Chen professor delivered an article on " Immunity ", and main parsing Th17 is thin Born of the same parents can promote cytotoxic T cell activation and play tumour immunity function, the study found that the mouse of IL-17A defect is easier to that lung occurs (a kind of cancer can be prevented effectively if taking T cell therapy to mouse with the T cell treatment of secretion IL-17A melanoma The generation of tumour, it is often more important that, under the auxiliary of IL-17A, Th17 cells show goes out therapeutic effect more stronger than Th1 cell, It is more to one's surprise, the CD8 of tumour-specific can be also effectively activated using Th17 cell therapy+T cell, wherein CD8+ T Cell is antitumor necessary cell, and studies have shown that Th17 cell can convene dendritic cells to enter tumor tissues, and can make CD8α+Dendritic cells gather in tumor tissues.In addition, the Chemokines CC CL20 of Th17 cell-stimulating tumor tissues.Total comes It says, Th17 cell can effectively facilitate the CD8 of tumour-specific+The activity of T cell, these new discoveries are opened up for immunotherapy of tumors The wide visual field.ROR γ t is expressed in certain immunocytes.Research report, Th17 cell specific expression ROR γ t, by ROR γ T activation can promote Th17 cell differentiation, and generate pro-inflammatory cytokine IL-17.It therefore, theoretically can be by activating ROR γ t increases Th17 cell differentiation, to promote the CD8 of tumour-specific+The activity of T cell plays tumour immunity function.
On June 9th, 2015, Celgene with rent before 82,500,000 plus 22,500,000 payments in the recent period with Lycera just to anticancer The T cell drug of disease is reached an agreement.2 months 2015, Lycera declaration obtained a large amount of evidences and has shown its oral ROR γ excitement Agent can improve the effect of T cell, can increase the generation of IL-17, promote Tc cell activation, so that cancer cell is exempted from stimulation Epidemic disease reaction, brings lasting kill tumour cell effect；In January, 2017, this drug have formally entered clinical phase experiment；The conjunction Make the great potential for sufficiently demonstrating ROR γ t agonist for tumour immunotherapy.
Therefore, ROR γ t can be used as the target spot of potential tumour immunotherapy, and find small molecule ROR γ t agonist simultaneously Being used for virology infection and treatment of cancer will be of great significance.
Summary of the invention
The present invention provides a kind of novel carbazole amide derivatives and its pharmaceutically acceptable salt with general formula I:
Wherein:
A indicates phenyl, heteroaryl, aliphatic heterocycle base or fatty naphthenic base；
B indicates phenyl or heteroaryl；
R1Optionally from hydrogen, halogen, cyano, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1- C6Alkyl, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl, C3-C6The C that oxygen or azacycloalkyl replace1-C6Alkyl, C1-C6Alkane The C that oxygroup, halogen replace1-C6Alkoxy, C3-C8The C that cycloalkyloxy, halogen replace3-C8Cycloalkyloxy, C3-C8Heterocycle alcoxyl Base, C1-C3The C that alkoxy replaces1-C3Alkyl, heterocycle, heterocyclic oxy group, C2-C6Alkenyl ,-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
R2Optionally from hydrogen, halogen, cyano, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1- C6Alkyl, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl, C1-C6The C that alkoxy, halogen replace1-C6Alkoxy, C1-C3Alkane The C that oxygroup replaces1-C3Alkyl, C2-C6Alkenyl ,-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C (O)NRa1Ra2；
R3Selected from hydrogen, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1-C3Alkyl, C3-C6Oxygen Or the C that azacycloalkyl replaces1-C3Alkyl, C3-C6Naphthenic base, C3-C6The C that oxygen or azacycloalkyl, phenyl replace1-C3Alkyl, The C that substituted-phenyl replaces1-C3The C that alkyl, heteroaryl replace1-C3The C that alkyl, substituted heteroaryl replace1-C3Alkyl；
R4Selected from hydrogen, C1-C3The C that alkyl, halogen replace1-C3Alkyl, C3-C6The C that naphthenic base replaces1-C3Alkyl, C3-C6Oxygen Or the C that azacycloalkyl replaces1-C3Alkyl, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl；
R5、R6It is each independently selected from hydrogen, hydroxyl, halogen, cyano, C1-C3Alkyl, hydroxyl or C1-C3What alkoxy replaced C1-C3The C that alkyl, halogen replace1-C3Alkyl, C1-C3The C that alkoxy, halogen replace1-C3Alkoxy, C3-C6Naphthenic base, C3-C6 Oxygen or azacycloalkyl, and R5、R6Also it can connect into C3-C6Ring；
R7Optionally from hydrogen, halogen, cyano, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1- C6Alkyl, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl, C1-C6The C that alkoxy, halogen replace1-C6Alkoxy, C1-C3Alkane The C that oxygroup replaces1-C3Alkyl, heterocycle, heterocyclic oxy group, C2-C6Alkenyl ,-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、- (CH2)nC(O)ORa、-C(O)NRa1Ra2；
Y is selected from covalent bond ,-NRa-、-O-、-CRa1Ra2-、-C(O)NRa-；
R8Selected from hydroxyl, C1-C6The C that alkyl, halogen replace1-C6Alkyl, hydroxyl or C1-C3The C that alkoxy replaces1-C3Alkane Base, C2-C6Alkenyl ,-(CH2)nNRa1Ra2、-NHC(O)CH3；
Z is selected from O, NRa；
Ra、Ra1、Ra2It is each independently selected from hydrogen, C1-C3The C that alkyl or halogen replace1-C3Alkyl；
M, r, t, n, s are each independently selected from any integer value in 0~2.
In some preferred embodiments, Y is covalent bond, and s is 1 and R6For H.
In some preferred embodiments, B is phenyl or hexa-atomic (or five yuan) heteroaryl, R4For H, r 0, Z be O or NH。
In some preferred embodiments, R7Optionally from hydrogen, halogen, cyano, hydroxyl, C1-C6Alkyl.
In some preferred embodiments, R8Selected from C1-C3Alkyl ,-NHCH3、-NH2、-NHC(O)CH3。
In some more preferably embodiments, the carbazole amide derivatives or its pharmaceutically acceptable salt have The structure of general formula I-A:
Wherein:
A indicates phenyl, heteroaryl, aliphatic heterocycle base or fatty naphthenic base；
B indicates phenyl or hexa-atomic (or five yuan) heteroaryl；
R1Optionally from hydrogen, halogen, cyano, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1- C6Alkyl, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl, C3-C6The C that oxygen or azacycloalkyl replace1-C6Alkyl, C1-C6Alkane The C that oxygroup, halogen replace1-C6Alkoxy, C3-C8The C that cycloalkyloxy, halogen replace3-C8Cycloalkyloxy, C3-C8Heterocycle alcoxyl Base, C1-C3The C that alkoxy replaces1-C3Alkyl, heterocycle, heterocyclic oxy group, C2-C6Alkenyl ,-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
R3Selected from hydrogen, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1-C3Alkyl, C3-C6Oxygen Or the C that azacycloalkyl replaces1-C3Alkyl, C3-C6Naphthenic base, C3-C6The C that oxygen or azacycloalkyl, phenyl replace1-C3Alkyl, The C that substituted-phenyl replaces1-C3The C that alkyl, heteroaryl replace1-C3The C that alkyl, substituted heteroaryl replace1-C3Alkyl；
R5Selected from hydrogen, hydroxyl, halogen, cyano, C1-C3Alkyl, hydroxyl or C1-C3The C that alkoxy replaces1-C3Alkyl, halogen Substituted C1-C3Alkyl, C1-C3The C that alkoxy, halogen replace1-C3Alkoxy, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl Base；
R7Optionally from hydrogen, halogen, cyano, hydroxyl, C1-C6Alkyl；
R8Selected from C1-C3Alkyl ,-NHCH3、-NH2、-NHC(O)CH3；
Z is selected from O, NH；
Ra、Ra1、Ra2It is each independently selected from hydrogen, C1-C3The C that alkyl or halogen replace1-C3Alkyl；
M, n, t are each independently selected from any integer value in 0~2.
Most preferably, carbazole amide derivatives or its salt provided by the invention include but is not limited to compound in detail below Example:
The present invention also provides a kind of methods for preparing the compounds of this invention, including following synthetic schemes:
Synthetic schemes 1:
Formulas I -1 reacts to obtain Formulas I -3 under the action of palladium acetate with Formulas I -2, and Formulas I -3 is closed under the action of palladium acetate and acetic acid Ring obtains Formulas I -4, and Formulas I -4 and halohydrocarbons reaction obtain Formulas I -5, and Formulas I -5 hydrolyzes to obtain Formulas I -6 in the presence of alkali, and Formulas I -6 contracts with benzylamine Close to obtain Formulas I-a.
Synthetic schemes 2:
Formulas I -1 reacts to obtain Formulas I -3 under the action of palladium acetate with Formulas I -2, and Formulas I -3 is closed under the action of palladium acetate and acetic acid Ring obtains Formulas I -4, and Formulas I -4 hydrolyzes to obtain Formulas I -7, and Formulas I -7 is condensed to obtain Formulas I -8 with benzylamine, and Formulas I -8 and halohydrocarbons reaction obtain Formulas I-b.
Unless otherwise indicated, meaning and the meaning phase in compound of Formula I of group described in above-mentioned synthetic schemes, term Together.
Above-mentioned synthetic schemes is the preparation method for listing part of compounds in the present invention, according to the known skill of this field Art, technical staff can also synthesize the compound of the present invention on the basis of above-mentioned synthetic schemes, using similar method.
" compound " of the present invention, including all stereoisomers, geometric isomer, tautomer and same position Element.
" compound " of the present invention, can be it is asymmetric, for example, having one or more stereoisomers.It removes Non- to be otherwise noted, all stereoisomers all include, such as enantiomter and diastereoisomer.Contain asymmetry in the present invention The compound of carbon atom can be separated with the pure form of optical activity or racemic form.The pure form of optical activity can To be synthesized from racemic mixture, or by using chiral raw material or chiral reagent.
" compound " of the present invention, further includes tautomeric forms.Tautomeric forms derive from a list Key exchanges with adjacent double bond and together with the migration of a proton.
The invention also includes the atoms of all isotopes, either in intermediate or last compound.The original of isotope Attached bag includes atomicity having the same but different quality number.For example, the isotope of hydrogen includes deuterium and tritium.
In the present invention, unless otherwise specified, term used has following meaning:
Term " halogen " refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
Term " cyano ", refers to-CN.
Term " hydroxyl ", refers to-OH.
Term " carboxyl ", refers to-COOH.
Term " alkyl " refers to the linear or branched saturated hydrocarbon group being made of carbon atom and hydrogen atom, such as C1-C20Alkane Base, preferably C1-C6Alkyl, such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including normal-butyl, isobutyl Base, sec-butyl or tert-butyl), amyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2- methylhexyl etc..The alkane Base can be it is non-substituted or replaced one or more substituent groups, substituent group include but is not limited to alkyl, alkoxy, Cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.
Term " naphthenic base " refers to the ring of the monocycle of all carbon, condensed, loop coil or bridged ring, such as cyclopropyl, cyclobutyl, ring Amyl, cyclopentenyl, cyclohexyl, spiral shell [3.4] octyl, two rings [3.1.1] hexyl.
Term " Heterocyclylalkyl " refers to the heteroatomic monocycle containing one or more N, O or S or condensed ring.Typically contain The heteroatomic 5-6 circle heterocyclic ring base of one or more N, O or S, such as Piperazino, morpholino base, piperidino, pyrrolidinyl And its derivative.
Term " aryl " refers to the full carbon monocycle or fused rings of the pi-electron system with total conjugated, usually has 6-14 Carbon atom preferably has 6-12 carbon atom, most preferably has 6 carbon atoms.Aryl can be it is non-substituted or by one or Replaced multiple substituent groups, substituent group includes but is not limited to alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, aralkyl Base, amino, halogen, sulfonyl, sulfinyl, phosphoryl.The example of non-substituted aryl include but is not limited to phenyl, naphthalene and Anthryl.
Term " heteroaryl " refers to the monocycle or fused rings of 5-12 annular atom, wherein being selected from the ring of N, O, S containing 1-4 Atom, remaining annular atom is C, and has π-electron system of total conjugated, including but not limited to pyrrole radicals, furyl, thiophene Base, imidazole radicals, oxazolyl, isoxazolyl, pyrazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, Triazolyl, nafoxidine base.Heteroaryl can be non-substituted or substituted, described substituent group include but is not limited to alkyl, Alkoxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl and heteroalicyclyl.
" treatment " means any treatment to disease in the mammalian body, comprising: (1) prevents disease, that is, cause clinic The symptom of disease does not develop；(2) inhibit disease, that is, prevent the development of clinical symptoms；(3) mitigate disease, that is, cause clinical symptoms Recession.
The present invention also provides a kind of pharmaceutical compositions, include foregoing compound or its pharmaceutically acceptable salt As active ingredient and one or more pharmaceutically acceptable carriers.
" pharmaceutical composition " of the present invention, refer to one or more the compound of the present invention or its salt in the art The preparation of the carrier for bioactive compound to be delivered to organism (such as people) usually received.The mesh of pharmaceutical composition Be to be conducive to organism drug delivery.
Term " pharmaceutically acceptable carrier " refers to active ingredient co-administered and is conducive to active ingredient administration Substance, including but not limited to State Food and Drug Administration license it is acceptable be used for human or animal (such as domestic animal) Any glidant, sweetener, diluent, preservative, dyestuff/colorant, flavoring reinforcing agent, surfactant, wetting agent, point Powder, disintegrating agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.For example including but be not limited to calcium carbonate, calcium phosphate, Various sugar and each kind of starch, cellulose derivative, gelatin, vegetable oil and polyethylene glycol.
Pharmaceutical composition of the present invention can be configured to solid-state, semisolid, liquid or gaseous state preparation, such as tablet, ball Agent, capsule, pulvis, granule, paste, emulsion, suspending agent, solution, suppository, injection, inhalant, gelling agent, microballoon And aerosol etc..
Pharmaceutical composition of the present invention can be manufactured using method well known in the art, such as conventional mixing method, molten Solution, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
The administration route of compound of the present invention or its pharmaceutically acceptable salt or its pharmaceutical composition, including but Be not limited to take orally, rectum, saturating mucous membrane, through enteral administration, or part, percutaneous, sucking, parenteral, sublingual, intravaginal, intranasally, eye It is interior, peritonaeum is interior, intramuscular, subcutaneous, intravenous administration.Preferred administration route is oral administration.
It, can be by the way that reactive compound and pharmaceutically acceptable carrier well known in the art be mixed for oral administration It closes, to prepare the pharmaceutical composition.These carriers can make the compound of the present invention be formulated into tablet, pill, pastille, sugar-coat Agent, capsule, liquid, gelling agent, slurry agent, suspending agent etc., for the oral administration to patient.For example, for being administered orally Pharmaceutical composition, can be used such as under type obtain tablet: active constituent is merged with one or more solid carriers, if need By gained granulating mixture, and a small amount of excipient processing resulting mixture or particle are added if necessary, to form tablet Or label.Label can be processed into conjunction with the optional coating material for being suitble to enteric and be more advantageous to organism (such as people) absorption Coated preparation form.
The present invention also provides a kind of foregoing compound or its pharmaceutically acceptable salt or in preparation ROR γ t Application in terms of receptor modulators.
The present invention additionally provides a kind of foregoing compound or its pharmaceutically acceptable salt or their medicine simultaneously Compositions are as ROR γ t receptor modulators in the drug that preparation is used to treat or prevent disease relevant to ROR γ t Purposes.
Preferably, aforementioned disease relevant to ROR γ t receptor is selected from multiple sclerosis, rheumatoid arthritis, collagen-induced Property arthritis, psoriasis, inflammatory bowel disease, encephalomyelitis, clone's disease, the diseases such as asthma and various cancers.Before cancer is preferred Column gland cancer, melanoma, non-small cell lung cancer etc..
The present invention provides a kind of carbazole amides compounds with general formula I feature.It has been investigated that such is changed Conjunction object can effectively adjust ROR γ t protein receptor and adjust the generation of IL-17 to regulate and control the differentiation of Th17 cell, can be used as and control Treat the therapeutic agent for the inflammation associated class disease that ROR γ t is mediated.
Specific embodiment
The following is specific embodiments of the present invention, is further described to technical solution of the present invention, but of the invention Protection scope be not limited to these examples.It is all to be included in this hair without departing substantially from the change of present inventive concept or equivalent substitute Within bright protection scope.
In target compound preparation method provided by the invention, column chromatography chromatogram uses Rushan sun desiccant Co., Ltd The silica gel (300-400 mesh) of production；Thin-layer chromatography uses GF254 (0.25 millimeter)；Nuclear magnetic resonance chromatography (NMR) uses Varian-400 nmr determination；Liquid matter is used in conjunction (LC/MS) and is joined using 6120 liquid matter of Agilent Technologi ESI Use instrument.
In addition, all operations for being related to oxidizable or facile hydrolysis raw material all carry out under nitrogen protection.Unless otherwise Illustrate, the raw material that the present invention uses all is marketable material, can directly use without being further purified.
Embodiment 1:9- ethyl-N- (4- (ethyl sulfone) phenyl) -9H- carbazole -3- formamide
9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
The synthesis of intermediate 1:9- ethyl -9H- carbazole -3- formic acid
The synthesis of step 1:4- phenyl amino phenyl methyl formate
Aniline (1.82g, 19.5mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (3.5g, 16.28mmol), potassium carbonate (6.72g, 49.4mmol), rac-BINAP (506mg, 0.81mmol), palladium acetate (218mg, 0.97mmol), toluene (10mL), 130 DEG C of heating of microwave are reacted 2 hours, and reaction is finished, and ethyl acetate is added to dilute, diatomite filtering, Decompression is spin-dried for solvent, and silica gel post separation (petroleum ether: ethyl acetate=10:1-5:1) obtains yellow solid product 3.5g, yield 94.6%.1H NMR (400MHz, CDCl3) δ 7.92 (d, J=8.5Hz, 2H), 7.34 (t, J=7.7Hz, 2H), 7.17 (d, J= 7.7Hz, 2H), 7.07 (t, J=7.3Hz, 1H), 6.99 (d, J=8.6Hz, 2H), 6.08 (s, 1H), 3.88 (s, 3H) .MS (ESI)m/z:228.1(MH+).
The synthesis of step 2:9H- carbazole -3- methyl formate
4- phenyl amino phenyl methyl formate (1.97g, 8.67mmol) is added into 100mL single port bottle, palladium acetate (2.14g, 9.56mmol), acetic acid (10mL), 120 DEG C of heating are reacted 1 hour, and reaction is finished, and decompression spins off acetic acid, then with ethyl acetate thick Product dissolution, mixes sample, silica gel post separation obtains yellow solid product 1.5g, yield 76.9%.MS(ESI)m/z:248.0(M+23).
The synthesis of step 3:9- ethyl -9H- carbazole -3- methyl formate
9H- carbazole -3- methyl formate (700mg, 3.11mmol) is added into 25mL single port bottle, anhydrous N, N- dimethyl methyl Ice bath stirring 5 minutes, NaH (245mg, 6.22mmol, 60%) then was added in amide (10mL), room temperature reaction 30 minutes, then It is added dropwise to bromoethane (678mg, 6.22mmol), reacts at room temperature 3 hours under ice cooling, 4, TLC detection raw material has reacted.Add Water quenching reaction, ethyl acetate (3 × 20mL) are washed (5 × 20mL), then saturated sodium-chloride washing, organic layer anhydrous slufuric acid Sodium dries, filters, and decompression spins off solvent and obtains yellow solid 700mg, yield 88.9%.
The synthesis of step 4:9- ethyl -9H- carbazole -3- formic acid
9- ethyl -9H- carbazole -3- methyl formate (690mg, 2.72mmol) is added into 25mL single port bottle, lithium hydroxide (344mg, 8.18mmol), ethyl alcohol (5mL), water (1mL), 80 DEG C of heating are reacted 3 hours, and TLC detection raw material has reacted, and use 2N Hydrochloric acid tune pH to 3, have white solid precipitation, filter, obtained solid is dried in vacuo to obtain white solid product 590mg, yield 80.4%.MS(ESI)m/z:240.1(MH+).
The synthesis of intermediate 2:4- (ethylsulfonyl) benzene methanamine
The synthesis of step 1:4- (ethylsulfonyl) benzonitrile
4- cyanobenzenesulfonyl chloride (1g, 4.97mmol) is added into 100mL single port bottle, water (15mL), sodium bicarbonate (835mg, 9.94mmol), sodium sulfite (689mg, 5.47mmol), 70 DEG C of reaction solution are stirred to react 4 hours, and decompression spins off molten Agent.Crude product uses n,N-Dimethylformamide (20mL) to dissolve again, is added iodoethane (1.2mL), and reaction solution continues 70 DEG C and stirs Mix reaction 4 hours.It is cooled to room temperature, is added water (30mL), ethyl acetate (3 × 30mL) extraction merges organic layer, and organic layer is used Saturated common salt water washing, anhydrous sodium sulfate dry, filter, and filtrate decompression is spin-dried for obtaining crude product, crude product purified by silica gel column (acetic acid second Ester: petroleum ether=1:4-1:2) separate to obtain yellow solid product 630mg, yield 65.0%.1H NMR (400MHz, CDCl3)δ 8.04 (d, J=8.5Hz, 2H), 7.89 (d, J=8.6Hz, 2H), 3.16 (q, J=7.4Hz, 2H), 1.30 (t, J=7.4Hz, 3H).
The synthesis of step 2:4- (ethylsulfonyl) benzene methanamine
4- (ethylsulfonyl) benzonitrile (630mg, 3.23mmol), methanol (10mL), Pd/ are added into 25mL single port bottle C (100mg, 10%).Reaction solution is stirred at room temperature 1 hour under an atmosphere of hydrogen, diatomite filtering, is spin-dried for solvent and obtains white solid production Object 500mg, yield 77.9%.1H NMR (400MHz, CDCl3) δ 7.86 (d, J=8.3Hz, 2H), 7.53 (d, J=8.2Hz, 2H), 3.99 (s, 2H), 3.10 (d, J=7.4Hz, 2H), 1.27 (t, J=7.4Hz, 3H)
The synthesis of compound 9- ethyl-N- (4- (ethyl sulfone) phenyl) -9H- carbazole -3- formamide
9- ethyl -9H- carbazole -3- formic acid (66mg, 0.26mmol) is added into single port bottle, 2- (7- azoThree nitrogen of benzo Azoles)-N, N, N ', N '-TetramethylureaHexafluorophosphoric acid ester (102mg, 0.26mmol), n,N-diisopropylethylamine (65mg, 0.52mmo1), 4- (ethylsulfonyl) benzene methanamine (50mg, 0.26mmol), methylene chloride (2mL), stirs 10h at room temperature.Instead After answering plus ethyl acetate dilutes, and successively uses saturated sodium chloride solution, water washing, and organic phase is dry with anhydrous sodium sulfate.Subtract Organic solvent is distilled off in pressure, with the isolated 9- ethyl-N- of silicagel column (4- (ethyl sulfone) phenyl) -9H- carbazole -3- formamide 70mg, yield 71%.1H NMR (400MHz, CD3OD) δ 8.70 (s, 1H), 8.15 (d, J=7.7Hz, 1H), 8.03 (d, J= 8.7Hz, 1H), 7.89 (d, J=8.3Hz, 2H), 7.66 (d, J=8.2Hz, 2H), 7.61-7.54 (m, 2H), 7.50 (t, J= 7.6Hz, 1H), 7.26 (t, J=7.3Hz, 1H), 4.75 (s, 2H), 4.47 (q, J=7.1Hz, 2H), 3.19 (q, J=7.4Hz, 2H), 1.42 (t, J=7.2Hz, 3H), 1.20 (t, J=7.4Hz, 3H) .MS (ESI) m/z:421.1 (MH+)
Embodiment 2:9- ethyl-N- (4- ethylsulfonyl) benzyl) -2,3,4,9- tetrahydro -1H- carbazole -6- formamides(9- Ethyl-N- (4- (ethylsulfonyl) benzyl) -2,3,4,9-tetrahydro-1H-carbazole-6- carboxamide)
Step 1:2, the synthesis of 3,4,9- tetrahydro -1H- carbazole -6- formic acid
4- hydrazino-benzoic acid (1g, 6.6mmol) is added into 25mL single port bottle, cyclohexanone (647mg, 6.6mmol), Isosorbide-5-Nitrae- Dioxane (10mL), concentrated hydrochloric acid (5mL), 120 DEG C of back flow reactions are stayed overnight, and have a large amount of solids to generate, filtering, obtained solid is put into Stirring 30 minutes, refilter, obtained solid is dried in vacuo to obtain brown solid 1.13g, yield 80.1% in water (10mL).MS (ESI)m/z:216.1(MH+).
The synthesis of -2,3,4,9- tetrahydro -1H- carbazole -6- formamide of step 2:N- (4- (ethylsulfonyl) benzyl)
2,3,4,9- tetrahydro -1H- carbazole -6- formic acid (169mg, 0.78mmol), 4- (ethyl are added into 25ml single port bottle Sulfonyl) benzene methanamine (130mg, 0.65mmol), HATU (296mg, 0.78mmol), n,N-diisopropylethylamine (302mg, 2.34mmol), methylene chloride (5mL), n,N-Dimethylformamide (1mL), overnight, TLC detection raw material has reacted for room temperature reaction It is complete.It is added methylene chloride (20mL), saturated ammonium chloride (30mL) washing, organic layer is spin-dried for obtaining crude product 230mg, is directly used in down Single step reaction.
The conjunction of -2,3,4,9- tetrahydro -1H- carbazole -6- formamide of step 3:9- ethyl-N- (4- (ethylsulfonyl) benzyl) At
N- (4- (ethylsulfonyl) benzyl) -2,3,4,9- tetrahydro -1H- carbazole -6- formyl is added into 25mL single port bottle Amine (130mg, 0.33mmol), anhydrous n,N-Dimethylformamide (3mL), ice bath stirring 5 minutes, then be added NaH (26mg, 0.66mmol, 60%), react at room temperature 30 minutes, iodoethane (103mg, 0.66mmol) be then added dropwise under ice bath, room temperature is anti- It answers 3 hours, TLC detection raw material has reacted.Add water quenching reaction, ethyl acetate (3 × 20mL) is washed (5 × 20mL), then satisfies It is washed with sodium chloride, organic layer anhydrous sodium sulfate dries, filters, and it depressurizes and is spin-dried for solvent, silica gel post separation (methylene chloride: methanol= 100:1) obtain yellow solid 80mg, yield 74.7%.1HNMR (400MHz, CD3OD) δ 8.02 (s, 1H), 7.85 (d, J= 8.1Hz, 2H), 7.65 (d, J=8.6Hz, 1H), 7.61 (d, J=8.1Hz, 2H), 7.35 (d, J=8.6Hz, 1H), 4.68 (s, 2H), 4.16-4.10 (m, 2H), 3.17 (q, J=7.4Hz, 2H), 2.73 (d, J=6.1Hz, 4H), 1.95 (d, J=5.5Hz, 2H), 1.87 (d, J=5.2Hz, 2H), 1.28 (t, J=7.1Hz, 3H), 1.19 (t, J=7.4Hz, 3H) .MS (ESI) m/z: 425.0(MH+).
Embodiment 3:N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- formamide
N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
The synthesis of step 1:4- (phenyl amino) methyl benzoate
Under protection of argon gas, aniline (1.82g, 19.53mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (3.5g, 16.28mmol), palladium acetate (218mg, 0.97mmol), rac-BINAP (506mg, 0.81mmol), potassium carbonate (6.72g, 48.62mmol), toluene (10mL).It reacts 2 hours, is cooled to room temperature under the conditions of 160 DEG C of microwave.After reaction, Decompression is spin-dried for solvent, and methylene chloride is added and dilutes and filters.Organic phase be spin-dried for after be added water (15mL), with ethyl acetate (3 × It 30mL) extracts, saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation obtains Light tan solid 3.32g, yield 89.7%.MS(ESI)m/z:228.1(MH+).
The synthesis of step 2:9- hydrogen carbazole -3- methyl formate
Under protection of argon gas, into 100mL eggplant-shape bottle be added 4- (phenyl amino) methyl benzoate (3.32g, 15.58mmol), palladium acetate (3.84g, 17.1mmol), acetic acid (50mL).It is reacted 2 hours under 130 DEG C of condition of heating and stirring.Instead After answering, decompression is spin-dried for solvent, and methanol (40mL) dilution is added.Diatomite filtering.Water (15mL) is added after being spin-dried in organic phase, It is extracted with ethyl acetate (3 × 30mL), saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product. Column chromatography for separation obtains light tan solid 2.23g, yield 63.6%.MS (ESI) m/z:226.1 (MH+).
The synthesis of step 3:9- hydrogen carbazole -3- formic acid:
Into 25mL eggplant-shape bottle, it is added 9- hydrogen carbazole -3- methyl formate (50mg, 0.22mmol), potassium hydroxide solid (37mg, 0.67mmol), ethyl alcohol (2mL)/water (0.5mL) mixed liquor.It is reacted 2 hours under 100 DEG C of condition of heating and stirring.Reaction knot Ethyl alcohol is removed in Shu Hou, decompression rotation, and water supplement (2mL) is added dropwise 2N hydrochloric acid into reaction solution and is adjusted to reaction solution pH=2, it is seen that solid analysis Out.Decompression filters and obtains white solid, is eluted with a small amount of water, and methanol (10mL) dissolution, decompression is spin-dried for obtaining white solid 28mg, Yield 60.8%.MS (ESI) m/z:210.0 (M-1), 212.0 (MH+) step 4:N- (4- (ethyl sulfone) benzyl) -9H- carbazole - The synthesis of 3- formamide
It into 25mL eggplant-shape bottle, is added 9- hydrogen carbazole -3- formic acid (27mg, 0.128mmol), (7- aoxidizes three nitrogen of benzo to 2- Azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (55mg, 0.147mmol), n,N-diisopropylethylamine (25mg, 0.147mmol), 4-(ethylsulfonyl) benzene methanamine (29.3mg, 0.147mmol), methylene chloride (5mL).2 are reacted under stirring at normal temperature Hour.After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3x5mL), and organic phase is washed with saturated sodium-chloride (3x5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1: 1) white solid 19mg, yield 38.1%. are obtained1H NMR (400MHz, CD3OD) δ 8.68 (d, J=1.2Hz, 1H), 8.12 (d, J=7.8Hz, 1H), 7.96 (d, J=8.5,1.7Hz, 1H), 7.89 (d, J=8.3Hz, 2H), 7.67 (d, J=8.3Hz, 2H), 7.52-7.46 (m, 2H), 7.42 (t, J=7.7Hz, 1H), 7.22 (t, J=7.4Hz, 1H), 4.74 (s, 2H), 3.19 (q, J= 7.4Hz, 2H), 1.20 (t, J=7.4Hz, 3H) .MS (ESI) m/z:390.9 (M-1), MS (ESI) m/z:393.0 (MH+).
Embodiment 4:N- (4- (ethyl sulfone) benzyl) -9- methyl -9H- carbazole -3- formamide
N-(4-(ethylsulfonyl)benzyl)-9-methyl-9H-carbazole-3-carboxamide
The synthesis of step 1:9- methyl carbazole -3- methyl formate
Under ice bath, 9- hydrogen carbazole -3- methyl formate (200mg, 0.89mmol) is added into 25mL eggplant-shape bottle, sodium hydride (64mg, 2.67mmol), n,N-Dimethylformamide (3mL), removes ice bath stirring 30 minutes after charging.After 30 minutes, It is added dropwise iodomethane (380mg/248 μ L, 2.67mmol), reacts 3 hours.After reaction, saturated ammonium chloride solution is added Neutralization is quenched in (15mL).It is extracted with ethyl acetate (3 × 30mL), (5 × 10mL) is washed with water in organic phase, and saturated sodium-chloride is washed, nothing Aqueous sodium persulfate dries, filters, and decompression is spin-dried for obtaining crude product.Crude product use column chromatography (petroleum ether: ethyl acetate=10: 1) white solid 80mg, yield 39.6%. are obtained
The synthesis of step 2:9- methyl carbazole -3- formic acid
In 25mL eggplant-shape bottle, it is added 9- methyl carbazole -3- methyl formate (80mg, 0.335mmol), potassium hydroxide solid (56mg, 1.005mmol), ethyl alcohol (3mL)/water (0.75mL) mixed liquor.It is stirred to react under 100 DEG C of heating conditions 1 hour.Reaction After, ethyl alcohol is removed in decompression rotation, and 2N hydrochloric acid is added dropwise until reaction solution pH=2 into reaction solution, it is seen that solid in water supplement to 2mL It is precipitated.Decompression filters and obtains white solid, is eluted with a small amount of water, and obtained solid is dissolved with methanol (5mL), and decompression is spin-dried for obtaining white Color solid 65mg, yield 86.2%.
The synthesis of step 3:N- (4- (ethyl sulfone) benzyl) -9- methyl -9H- carbazole -3- formamide
It into 25mL eggplant-shape bottle, is added 9- methyl carbazole -3- formic acid (65mg, 0.29mmol), (7- aoxidizes three nitrogen of benzo to 2- Azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (130mg, 0.33mmol), n,N-diisopropylethylamine (65mg, 0.33mmol), (4- (ethylsulfonyl) phenyl) methylamine (65.7mg, 0.33mmol), methylene chloride (5mL).It is anti-under stirring at normal temperature It answers 2 hours, reactant reaction is complete.After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), organic (3 × 5mL) mutually is washed with saturated sodium-chloride, anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (stone Oily ether: ethyl acetate=1:1) obtain white solid 12mg, yield 10.2%.1H NMR (400MHz, CD3OD) δ 8.70 (s, 1H), 8.15 (d, J=7.7Hz, 1H), 8.04 (d, J=8.6,1.7Hz, 1H), 7.89 (d, J=8.4Hz, 2H), 7.67 (d, J =8.4Hz, 2H), 7.57 (t, J=7.9Hz, 2H), 7.51 (t, J=7.9Hz, 1H), 7.27 (t, J=6.7Hz, 1H), 4.75 (s, 2H), 3.92 (s, 3H), 3.20 (q, J=7.4Hz, 2H), 1.21 (t, J=7.4Hz, 3H) .MS (ESI) m/z:404.8 (M- 1), 407.0 (MH+)
Embodiment 5:- 9-n-propyl-9H- carbazole-3- formamide of N- (4- (ethyl sulfone) benzyl)
N-(4-(ethylsulfonyl)benzyl)-9-propyl-9H-carbazole-3-carboxamide
The synthesis of step 1:9- propyl carbazole:
Under ice bath, carbazole (500mg, 3.0mmol) is added into 25mL eggplant-shape bottle, sodium hydride (144mg, 6mmol), N, N- Dimethylformamide (8mL) removes ice bath and is stirred at room temperature 30 minutes after charging.After 30 minutes, N-Propyl Bromide (726mg/ is added dropwise 538 μ l, 6mmol), it reacts 3 hours.After reaction, saturated ammonium chloride solution (15mL) is added and neutralization is quenched.Use ethyl acetate (5 × 10mL) is washed with water in (3 × 30mL) extraction, organic phase, and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for Obtain crude product.Column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtains white solid 386mg, yield 61.6%.
The synthesis of step 2:9- propyl -3- carbazole formaldehyde:
Into 25mL eggplant-shape bottle, 9- propyl carbazole (386mg, 1.85mmol) is added under ice bath, phosphorus oxychloride (558mg/ 339.6mL, 3.70mmol), n,N-Dimethylformamide (8mL).It is stirred to react under 80 DEG C of heating conditions 4 hours.TLC detection is anti- Answer object fully reacting.It is cooled to room temperature.After reaction, ice water, 20% sodium hydrate aqueous solution tune pH to alkalinity, dichloro is added Methane extraction.Column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtains white solid 180mg, yield 41.1%.MS (ESI)m/z:238.1(MH+).
The synthesis of step 3:9- propyl -3- carbazole formic acid:
In 25mL eggplant-shape bottle, it is added 9- propyl -3- carbazole formaldehyde (180mg, 0.76mmol), potassium permanganate solution (168mg is dissolved in 3mL water), anhydrous magnesium sulfate (180mg, 1.52mmol).It is reacted 2 hours under stirring at normal temperature, reactant reaction Completely.After reaction, 1N hydrochloric acid solution is added and is adjusted to pH=2, extracted with ethyl acetate (3 × 5mL), organic phase saturation chlorine Change sodium and wash (3 × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: acetic acid Ethyl ester=1:1) obtain white solid 120mg, yield 62.4%.MS (ESI) m/z:251.9 (M-1)
The synthesis of-9-n-propyl-9H- carbazole-3- formamide of step 4:N- (4- (ethyl sulfone) benzyl):
It in 25mL eggplant-shape bottle, is added 9- propyl -3- carbazole formic acid (120mg, 0.47mmol), (7- aoxidizes three nitrogen of benzo to 2- Azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (207mg, 0.55mmol), n,N-diisopropylethylamine (70.4mg, 0.55mmol), 4- (ethylsulfonyl) benzene methanamine (108.5mg, 0.55mmol), methylene chloride (5mL).It was reacted under stirring at normal temperature Night, reactant reaction are complete.After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (5mL), organic phase saturation Sodium chloride washes (3 × 5mL), and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: second Acetoacetic ester=1:1) obtain white solid 2mg, yield 12.7%.1H NMR (400MHz, CD3OD) δ 8.67 (d, J=1.5Hz, 1H), 8.09 (d, J=7.8Hz, 1H), 7.99 (dd, J=8.6,1.8Hz, 1H), 7.83 (d, J=8.4Hz, 2H), 7.61 (d, J =8.4Hz, 2H), 7.54-7.41 (m, 3H), 7.24-7.17 (t, J=8.0Hz, 1H), 4.71 (s, 2H), 4.29 (t, J= 7.1Hz, 2H), 3.13 (q, J=7.4Hz, 2H), 1.84 (q, J=7.4Hz, 2H), 1.16 (t, J=7.4Hz, 3H), 0.89 (t, J=7.4Hz, 3H) .MS (ESI) m/z:432.9 (M-1), 435.0 (MH+)
Embodiment 6:- 9-isopropyl-9H- carbazole-3- formamide of N- (4- (ethyl sulfone) benzyl)
N-(4-(ethylsulfonyl)benzyl)-9-isopropyl-9H-carbazole-3-carboxamide
The synthesis of step 1:9- isopropylcarbazole -3- methyl formate
Under ice bath, 9- hydrogen carbazole -3- methyl formate (300mg, 1.33mmol) is added into 25mL eggplant-shape bottle, sodium hydride (96mg, 4mmol), n,N-Dimethylformamide (3mL), removes ice bath stirring 30 minutes after charging.After 30 minutes, it is added dropwise Bromo propane (488mg/373 μ L, 4mmol), reaction overnight.Monitoring overnight has new point generation and more raw material, adds 400 μ L bromo propane.It is control with 9- hydrogen carbazole -3- methyl formate after 5 hours, TLC detects (solvent: petroleum ether: acetic acid second Ester=5:1), reactant reacts completely.
After reaction, saturated ammonium chloride solution (15mL) is added and neutralization is quenched.It is extracted with ethyl acetate (3 × 30mL), (5 × 10mL) is washed with water in organic phase, and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column Chromatography (petroleum ether: ethyl acetate=10:1) obtains white solid 120mg, yield 54.0%.
The synthesis of step 2:9- isopropylcarbazole -3- formic acid
In 25mL eggplant-shape bottle, it is added 9- isopropylcarbazole -3- methyl formate (120mg, 0.45mmol), potassium hydroxide solid (75.5mg, 1.005mmol), ethyl alcohol (3mL)/water (0.75mL) mixed liquor.It is reacted 1 hour under 100 DEG C of condition of heating and stirring.Instead After answering, ethyl alcohol is removed in decompression rotation, and 2N hydrochloric acid is added dropwise until reaction solution pH=2 into reaction solution in water supplement to 2mL, it is seen that Gu Body is precipitated.Decompression filters and obtains white solid, is eluted with a small amount of water, and methanol (5mL) dissolution, decompression is spin-dried for obtaining white solid 110mg, yield 96.6%.
The synthesis of-9-isopropyl-9H- carbazole-3- formamide of step 3:N- (4- (ethyl sulfone) benzyl)
It in 25mL eggplant-shape bottle, is added 9- isopropylcarbazole -3- formic acid (110mg, 0.43mmol), (7- aoxidizes benzo three to 2- Nitrogen azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (196mg, 0.49mmol), n,N-diisopropylethylamine (98.5mg, 0.49mmol), (4- (ethylsulfonyl) phenyl) methylamine (100mg, 0.49mmol), methylene chloride (5mL).It is reacted under stirring at normal temperature 2 hours, after reaction, decompression was spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), and organic phase washes (3 with saturated sodium-chloride × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1: 1) white solid 68mg, yield 35.4%. are obtained1H NMR (400MHz, CD3OD) δ 8.70 (d, J=1.6Hz, 1H), 8.15 (d, J=7.8Hz, 1H), 8.00 (d, J=8.7,1.8Hz, 1H), 7.89 (d, J=8.3Hz, 2H), 7.67 (t, J=9.0Hz, 4H), 7.47 (t, J=7.3Hz, 1H), 7.24 (t, J=7.5Hz, 1H), 5.18-5.08 (m, 1H), 4.74 (s, 2H), 3.19 (q, J= 7.4Hz, 2H), 1.71 (d, J=7.0Hz, 6H), 1.20 (t, J=7.4Hz, 3H) .MS (ESI) m/z:446.8 (M-1), 448.9 (MH+).
Embodiment 7:- 9-isobutyl group-9H- carbazole-3- formamide of N- (4- (ethyl sulfone) benzyl)
N-(4-(ethylsulfonyl)benzyl)-9-isobutyl-9H-carbazole-3-carboxamide
The synthesis of step 1:9- isobutyl group carbazole -3- methyl formate
Under ice bath, 9- hydrogen carbazole -3- methyl formate (300mg, 1.33mmol) is added into 25mL eggplant-shape bottle, sodium hydride (64mg, 2.67mmol), n,N-Dimethylformamide (3mL), removes ice bath stirring 30 minutes after charging.After 30 minutes, It is added dropwise isobutane bromide (370mg/293 μ L, 2.67mmol), reaction overnight.Reaction 4 hours, it is complete that TLC detects reactant reaction Entirely.
After reaction, saturated ammonium chloride solution (15mL) is added and neutralization is quenched.It is extracted with ethyl acetate (3 × 30mL), (5 × 10mL) is washed with water in organic phase, and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column Chromatography (petroleum ether: ethyl acetate=10:1) obtains white solid 170mg, yield 45.5%.
The synthesis of step 2:9- isobutyl group carbazole -3- formic acid:
In 25mL eggplant-shape bottle, it is added 9- isobutyl group carbazole -3- methyl formate (170mg, 0.60mmol), potassium hydroxide solid (100.8mg, 1.8mmol), ethyl alcohol (3mL)/water (0.75mL) mixed liquor.It is reacted 2 hours under 100 DEG C of condition of heating and stirring.TLC Detect fully reacting.After reaction, it is cooled to room temperature, ethyl alcohol is removed in decompression rotation, and 2N is added dropwise into reaction solution for water supplement to 5mL Hydrochloric acid is until reaction solution pH=2, it is seen that solid is precipitated.Decompression filters and obtains white solid, is eluted with a small amount of water, methanol (5mL) Dissolution, decompression are spin-dried for obtaining white solid 114mg, yield 71.2%.
The synthesis of-9-isobutyl group-9H- carbazole-3- formamide of step 3:N- (4- (ethyl sulfone) benzyl)
It in 25mL eggplant-shape bottle, is added 9- isobutyl group carbazole -3- formic acid (114mg, 0.43mmol), (7- aoxidizes benzo three to 2- Nitrogen azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (186mg, 0.49mmol), n,N-diisopropylethylamine (64mg, 0.49mmol), 4- (ethylsulfonyl) benzene methanamine (98mg, 0.49mmol), methylene chloride (5mL).Reaction 2 is small under stirring at normal temperature When, after reaction, decompression is spin-dried for reaction solution, extracted with ethyl acetate (3 × 5mL), organic phase washed with saturated sodium-chloride (3 × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1:1) Obtain white solid 39mg, yield 20.2%.1H NMR (400MHz, CD3OD) δ 8.64 (d, J=1.5Hz, 1H), 8.09 (d, J =7.8Hz, 1H), 7.95 (d, J=8.7,1.8Hz, 1H), 7.82 (d, J=8.4Hz, 2H), 7.60 (d, J=8.3Hz, 2H), 7.50 (t, J=7.6Hz, 2H), 7.42 (t, J=7.6Hz, 1H), 7.19 (t, J=7.4Hz, 1H), 4.68 (s, 2H), 4.15 (d, J=7.5Hz, 2H), 3.12 (d, J=7.4Hz, 2H), 2.30 (m, 1H), 1.14 (t, J=7.4Hz, 3H), 0.90 (d, J= 6.7Hz, 6H) .MS (ESI) m/z:446.8 (M-1), 448.9 (MH+)
Embodiment 8:9- Cvclopropvlmethvl-N- (4- (ethylsulfonyl) benzene) -9H- carbazole -3- formamide
9-(cyclopropylmethyl)-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide
The synthesis of step 1:9- Cvclopropvlmethvl carbazole -3- methyl formate
Under ice bath, 9- hydrogen carbazole -3- methyl formate (200mg, 0.89mmol) is added into 25mL eggplant-shape bottle, sodium hydride (64mg, 2.67mmol), n,N-Dimethylformamide (3mL) remove ice bath and are stirred at room temperature 30 minutes after charging.30 minutes Afterwards, bromomethyl cyclopropane (360mg/259 μ L, 2.67mmol) is added dropwise, reacts at room temperature 10 hours,
After reaction, saturated ammonium chloride solution (15mL) is added and neutralization is quenched.It is extracted with ethyl acetate (3 × 30mL), (5 × 10mL) is washed with water in organic phase, and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column Chromatography (petroleum ether: ethyl acetate=10:1) obtains white solid 110mg, yield 44.3%.
The synthesis of step 2:9- Cvclopropvlmethvl carbazole -3- formic acid
In 25mL eggplant-shape bottle, it is added 9- Cvclopropvlmethvl carbazole -3- methyl formate (170mg, 0.60mmol), potassium hydroxide Solid (100.8mg, 1.8mmol), ethyl alcohol (3mL)/water (0.75mL) mixed liquor.Reaction 2 is small under 100 DEG C of condition of heating and stirring When.It is complete that TLC detects reactant reaction.After reaction, it is cooled to room temperature, ethyl alcohol is removed in decompression rotation, water supplement to 5mL, to anti- It answers and 2N hydrochloric acid is added dropwise in liquid until reaction solution pH=2, it is seen that solid is precipitated.Decompression filters and obtains white solid, is drenched with a small amount of water It washes, methanol (5mL) dissolution, decompression is spin-dried for obtaining white solid 64mg, yield 40.3%.
The synthesis of step 3:9- (Cvclopropvlmethvl)-N- (4- (ethylsulfonyl) benzene) -9H- carbazole -3- formamide
It in 25mL eggplant-shape bottle, is added 9- Cvclopropvlmethvl carbazole -3- formic acid (64mg, 0.24mmol), (7- aoxidizes benzo to 2- Triazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (107mg, 0.28mmol), n,N-diisopropylethylamine (36mg, 0.28mmol), 4- (ethylsulfonyl) benzene methanamine (48mg, 0.28mmol), methylene chloride (5mL).Reaction 11 is small under stirring at normal temperature When, after reaction, decompression is spin-dried for reaction solution, extracted with ethyl acetate (3 × 5mL), organic phase washed with saturated sodium-chloride (3 × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1:1) Obtain white solid 41mg, yield 38.3%.1H NMR (400MHz, CD3OD) δ 8.70 (d, J=1.3Hz, 1H), 8.14 (d, J =7.7Hz, 1H), 8.02 (d, J=8.6,1.7Hz, 1H), 7.88 (d, J=8.3Hz, 2H), 7.66 (d, J=8.3Hz, 2H), 7.59 (t, J=8.3Hz, 2H), 7.49 (t, J=7.7Hz, 1H), 7.25 (t, J=7.5Hz, 1H), 4.74 (s, 2H), 4.33 (d, J=6.6Hz, 2H), 3.18 (q, J=7.4Hz, 2H), 1.20 (t, J=7.4Hz, 3H), 0.52 (m, 2H), 0.45 (m, 2H) .MS (ESI) m/z:445.0 (M-1), 447.0 (MH+)
Embodiment 9:9- (cyclobutylmethyl)-N- (4- (ethylsulfonyl) benzene) -9H- carbazole -3- formamide
9-(cyclobutylmethyl)-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide
The synthesis of step 1:9- cyclobutylmethyl carbazole -3- methyl formate
Under ice bath, 9- hydrogen carbazole -3- methyl formate (300mg, 1.33mmol) is added into 25mL eggplant-shape bottle, sodium hydride (96mg, 4mmol), n,N-Dimethylformamide (3mL) remove ice bath and are stirred at room temperature 30 minutes after charging.After 30 minutes, It is added dropwise Bromomethylcyclobutane (596mg/450 μ L, 4mmol), reacts 3 hours, TLC detection unreacted is complete, and 100 (μ L) bromines are added Methyl cyclobutane continues stirring 10 hours, and reactant reacts completely.After reaction, saturated ammonium chloride solution (15mL) is added to quench It goes out neutralization.It is extracted with ethyl acetate (3 × 30mL), (5 × 10mL) is washed with water in organic phase, and saturated sodium-chloride is washed, anhydrous sodium sulfate It dries, filters, decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtains white solid 100mg, yield 25.7%.
The synthesis of step 2:9- cyclobutylmethyl carbazole -3- methyl formate
In 25mL eggplant-shape bottle, it is added 9- cyclobutylmethyl carbazole -3- methyl formate (100mg, 0.34mmol), potassium hydroxide Solid (100.8mg, 1.02mmol), ethyl alcohol (3mL)/water (0.75mL) mixed liquor.Reaction 2 is small under 100 DEG C of condition of heating and stirring When.TLC detects (solvent: methylene chloride: methanol=7:1), and reactant reaction is complete.After reaction, it is cooled to room temperature.Subtract Ethyl alcohol is removed in pressure rotation, adds liquid to 5mL, 2N hydrochloric acid is added dropwise until reaction solution pH=2 into reaction solution, it is seen that solid is precipitated.Subtract Pressure filters and obtains white solid, is eluted with a small amount of water, and methanol (5mL) dissolution, decompression is spin-dried for obtaining white solid 70mg, yield 73.8%.
The synthesis of step 3:9- (cyclobutylmethyl)-N- (4- (ethylsulfonyl) benzene) -9H- carbazole -3- formamide
It in 25mL eggplant-shape bottle, is added 9- cyclobutylmethyl carbazole -3- methyl formate (70mg, 0.25mmol), 2- (7- oxidation Benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (110mg, 0.29mmol), n,N-diisopropylethylamine (37mg, 0.29mmol), 4- (ethylsulfonyl) benzene methanamine (58mg, 0.29mmol), methylene chloride (5mL).It is anti-under stirring at normal temperature It answers 11 hours, it is complete that TLC detects reactant reaction.After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL) It takes, organic phase washes (3 × 5mL) with saturated sodium-chloride, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography Separation (petroleum ether: ethyl acetate=1:1) obtains white solid 67mg, yield 58.3%.1H NMR (400MHz, CD3OD)δ 8.70 (s, 1H), 8.15 (d, J=7.8Hz, 1H), 8.02 (d, J=8.6Hz, 1H), 7.90 (d, J=8.2Hz, 2H), 7.67 (d, J=8.2Hz, 2H), 7.60 (d, J=14.2,8.4Hz, 2H), 7.49 (t, J=7.6Hz, 1H), 7.26 (t, J=7.4Hz, 1H), 4.76 (d, J=4.5Hz, 2H), 4.44 (d, J=6.9Hz, 2H), 3.20 (q, J=7.4Hz, 2H), 2.97 (d, J= 7.0Hz, 1H), 1.99 (m, 3H), 1.90 (m, 3H), 1.21 (t, J=7.4Hz, 3H) .MS (ESI) m/z:461.0 (MH+)
Embodiment 10:9- benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- formamide
9-benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
The synthesis of step 1:9- benzyl carbazole -3- methyl formate
Under ice bath, 9- hydrogen carbazole -3- methyl formate (300mg, 1.33mmol) is added into 25mL eggplant-shape bottle, sodium hydride (96mg, 4mmol), n,N-Dimethylformamide (3mL) remove ice bath and are stirred at room temperature 30 minutes after charging.It separately takes simultaneously Benzyl bromine (684.16mg/475 μ L, 4mmol) is diluted with n,N-Dimethylformamide (1mL).After 30 minutes, the benzyl diluted is added dropwise Bromine/n,N-Dimethylformamide solution, reaction overnight.After reaction, saturated ammonium chloride solution (15mL) is added, with acetic acid second (5 × 10mL) is washed with water in ester (3 × 30mL) extraction, organic phase, and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, decompression rotation It is dry to obtain crude product.Column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtains yellow viscous liquid 170mg, yield 40.5%.MS the synthesis of (ESI) m/z:316.1 (MH+) step 2:9- benzyl carbazole -3- formic acid
In 25mL eggplant-shape bottle, it is added 9- benzyl carbazole -3- methyl formate (170mg, 0.549mmol), potassium hydroxide solid (90.7mg, 1.62mmol), ethyl alcohol (6mL)/water (1.5mL) mixed liquor.It is reacted 2 hours under 100 DEG C of condition of heating and stirring.Reaction After, ethyl alcohol is removed in decompression rotation, and 2N hydrochloric acid is added dropwise until reaction solution pH=2 into reaction solution, it is seen that a large amount of in water supplement to 5mL Solid is precipitated.Decompression suction filtration obtains white solid, is eluted with a small amount of water, and methanol (10mL) dissolution, decompression is spin-dried for obtaining white admittedly Body 136mg, yield 83.7%.MS (ESI) m/z:302.1 (MH+), 300.1 (M-1)
The synthesis of step 3:9- benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- formamide
It in 25mL eggplant-shape bottle, is added 9- benzyl carbazole -3- formic acid (136mg, 0.45mmol), (7- aoxidizes three nitrogen of benzo to 2- Azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (198mg, 0.52mmol), n,N-diisopropylethylamine (67mg, 0.52mmol), 4- (ethylsulfonyl) benzene methanamine (103mg, 0.52mmol), methylene chloride (5mL).Reaction 3 is small under stirring at normal temperature When.After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), organic phase washed with saturated sodium-chloride (3 × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1:1) Obtain white solid 158mg, yield 72.8%.1H NMR (400MHz, CD3OD) δ 8.74 (s, 1H), 8.19 (d, J=8.2Hz, 1H), 7.99 (d, J=8.6Hz, 1H), 7.89 (d, J=8.2Hz, 2H), 7.67 (d, J=8.2Hz, 2H), 7.56 (d, J= 8.7Hz, 1H), 7.51 (t, J=9.0Hz, 2H), 7.46 (d, J=8.2Hz, 1H), 7.29 (d, J=7.4Hz, 1H), 7.24 (d, J=7.8Hz, 2H), 7.14 (d, J=6.9Hz, 2H), 5.66 (s, 2H), 4.75 (s, 2H), 3.19 (q, J=7.2Hz, 2H), 1.20 (t, J=7.4Hz, 3H) .MS (ESI) m/z:480.8 (M-1), 483.0 (MH+)
Embodiment 11:(9- cyclohexyl methyl)-(4- (ethylsulfonyl) benzene) -9H- carbazole -3- formamide
9-(cyclohexylmethyl)-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide
The synthesis of step 1:9- cyclohexyl methyl carbazole -3- methyl formate
Under ice bath, 9- hydrogen carbazole -3- methyl formate (20 0mg, 0.89mmol) are added into 25mL eggplant-shape bottle, sodium hydride (64mg, 2.67mmol), n,N-Dimethylformamide (3mL), removes ice bath stirring 30 minutes after charging.After 30 minutes, It is added dropwise bromomethylcyclohexane (472mg/372 μ L, 2.67mmol), reacts 2 hours, TLC detection unreacted is complete, continues stirring 2 Hour, reactant reacts completely.After reaction, saturated ammonium chloride solution (15mL) is added and neutralization is quenched.With ethyl acetate (3 × 30mL) it extracts, (5 × 10mL) is washed with water in organic phase, and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for To crude product.Column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtains white solid 156mg, yield 54.6%.
The synthesis of step 2:9- cyclohexyl methyl carbazole -3- formic acid:
In 25mL eggplant-shape bottle, it is added 9- cyclohexyl methyl carbazole -3- methyl formate (130mg, 0.4mmol), potassium hydroxide Solid (68mg, 1.2mmol), ethyl alcohol (4mL)/water (1mL) mixed liquor.It is reacted 2 hours under 100 DEG C of condition of heating and stirring.
After reaction, ethyl alcohol is removed in decompression rotation, and 2N hydrochloric acid is added dropwise until reaction solution pH into reaction solution in water supplement to 5mL =2, it is seen that a large amount of solids are precipitated.Decompression filters and obtains white solid, is eluted with a small amount of water, methanol (10mL) dissolution, decompression rotation It is dry to obtain white solid 125mg, yield 100%.
Step 3:(9- cyclohexyl methyl)-(4- (ethylsulfonyl) benzene) -9H- carbazole -3- formamide synthesis
9- cyclohexyl methyl carbazole -3- formic acid (125mg, 0.41mmol) is added in 25mL eggplant-shape bottle, 2- (7- Oxybenzene And triazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (178mg, 0.47mmol), n,N-diisopropylethylamine (60mg, 0.47mmol), 4- (ethylsulfonyl) benzene methanamine (93mg, 0.47mmol), methylene chloride (5mL).It is reacted under stirring at normal temperature overnight, After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), organic phase washed with saturated sodium-chloride (3 × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1:1) Obtain white solid 16mg, yield 8.0%.1H NMR (400MHz, CDCl3) δ 8.61 (s, 1H), 8.12 (d, J=7.7Hz, 1H), 7.94 (d, J=8.6Hz, 1H), 7.87 (d, J=8.1Hz, 2H), 7.59 (d, J=8.2Hz, 2H), 7.51 (t, J= 7.5Hz, 1H), 7.43 (d, J=10.7Hz, 2H), 7.29 (d, J=7.6Hz, 1H), 6.76 (s, 1H), 4.82 (d, J= 5.7Hz, 2H), 4.14 (d, J=7.3Hz, 2H), 3.10 (q, J=7.4Hz, 2H), 2.00 (m, 1H), 1.66 (m, 10H), 1.28 (t, J=7.4Hz, 3H) .MS (ESI) m/z:486.9 (M-1), MS (ESI) m/z:489.3 (MH+)
Embodiment 12:9- ethyl-N- (4- (ethylsulfonyl) benzyl) -6- methyl -9H- carbazole -3- formamide
(9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-methyl-9H-carbazole-3- carboxamide)
The synthesis of step 1:4- ((4- aminomethyl phenyl) amino) methyl benzoate
4- methylaniline (1.07g, 10mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (2.58g, 12mmol), potassium carbonate (1.66g, 12mmol), rac-BINAP (310mg, 0.5mmol), palladium acetate (130mg, 0.6mmol), Toluene (5mL), 120 DEG C of heating of microwave are reacted 2 hours, and reaction is finished, and ethyl acetate is added to dilute, and diatomite filtering, decompression is spin-dried for molten Agent, silica gel post separation (petroleum ether: ethyl acetate=10:1) obtain yellow solid product 1.45g, yield 68.4%.1H NMR (400MHz, DMSO) δ 8.64 (s, 1H), 7.75 (d, J=8.8Hz, 2H), 7.12 (d, J=8.2Hz, 2H), 7.06 (d, J= 8.4Hz, 2H), 6.96 (d, J=8.8Hz, 2H), 3.75 (s, 3H), 2.24 (s, 3H) .MS (ESI) m/z:242.1 (MH+)
The synthesis of step 2:6- methyl -9H- carbazole -3- methyl formate
4- ((4- aminomethyl phenyl) amino) methyl benzoate (600mg, 3mmol), palladium acetate are added into 100mL single port bottle (555mg, 3.3mmol), acetic acid (30mL), 120 DEG C of heating are reacted 2 hours, and reaction is finished, and decompression is spin-dried for acetic acid, then with acetic acid second Ester dissolves crude product, and silica gel post separation (petroleum ether: ethyl acetate=10:1) obtains yellow solid product 180mg, yield 30.2%%.1H NMR (400MHz, CDCl3) δ 8.78 (s, 1H), 8.22 (s, 1H), 8.11 (d, J=8.6Hz, 1H), 7.92 (s, 1H), 7.41 (d, J=8.5Hz, 1H), 7.35 (d, J=8.2Hz, 1H), 7.28 (d, J=8.2Hz, 1H), 3.97 (s, 3H), 2.54 (s, 4H)
The synthesis of step 3:6- methyl -9- ethyl -9H- carbazole -3- methyl formate
6- methyl -9H- carbazole -3- methyl formate (180mg, 0.75mmol) is added into 25mL single port bottle, anhydrous N, N- Dimethylformamide (5mL) ice bath stirring 5 minutes, is then added NaH (90mg, 2.56mmol, 60%), reacts at room temperature 30 points Then clock is added dropwise to bromoethane (279mg, 2.56mmol) under ice bath, react at room temperature 3 hours, and TLC detection raw material has reacted It is complete.Add water quenching reaction, ethyl acetate (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, organic layer anhydrous slufuric acid Sodium dries, filters, and decompression is spin-dried for solvent and obtains crude product 200mg, is directly used in and reacts in next step.
The synthesis of step 4:6- methyl -9- ethyl -9H- carbazole -3- formic acid
6- methyl -9- ethyl -9H- carbazole -3- methyl formate (200mg, 0.75mmol) is added into 25mL single port bottle, hydrogen Lithia (94mg, 2.25mmol), ethyl alcohol (5mL), water (1mL), 90 DEG C are reacted 2 hours, and TLC detection raw material has reacted, and are used The hydrochloric acid tune pH to 3 of 2N has white solid precipitation, and filtering is dried in vacuo to obtain white solid product 180mg, two step yields 94.7%.MS(ESI)m/z:254.1(MH+).
The synthesis of step 5:9- ethyl-N- (4- (ethylsulfonyl) benzyl) -6- methyl -9H- carbazole -3- formamide
6- methyl -9- ethyl -9H- carbazole -3- formic acid (65mg, 0.26mmol) is added into 25mL single port bottle, 4- (ethyl Sulfonyl) benzene methanamine (61mg, 0.31mmol), HATU (117mg, 0.31mmol), n,N-diisopropylethylamine (100mg, 0.78mmol), methylene chloride (2mL), overnight, TLC detection raw material has reacted for room temperature reaction.It is added methylene chloride (20mL), Saturated ammonium chloride (30mL) washing, organic layer are spin-dried for obtaining crude product, crude product purified by silica gel post separation (petroleum ether: ethyl acetate= 2:1-1:1), white solid product 77mg, yield 69.4% are obtained.1H NMR (400MHz, CDCl3) δ 8.62 (s, 1H), 7.96 (dd, J=8.6,1.3Hz, 1H), 7.87 (s, 1H), 7.74 (d, J=8.2Hz, 2H), 7.48 (d, J=8.2Hz, 2H), 7.35 (d, J=8.6Hz, 1H), 7.32-7.27 (m, 3H), 4.74 (d, J=5.9Hz, 2H), 4.32 (q, J=7.2Hz, 2H), 3.05 (q, J=7.4Hz, 2H), 2.49 (s, 3H), 1.39 (t, J=7.2Hz, 3H), 1.24 (d, J=7.4Hz, 4H) .MS (ESI) m/ z:435.2(MH+)。
Embodiment 13:9- ethyl-N- (4- (ethylsulfonyl) benzyl) -6- methoxyl group -9H- carbazole -3- formamide
(9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-methoxy-9H-carbazole-3- carboxamide)
The synthesis of step 1:4- ((4- methoxyphenyl) amino) methyl benzoate
4- aminoanisole (1.23g, 10mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (2.58g, 12mmol), potassium carbonate (1.66g, 12mmol), rac-BINAP (310mg, 0.5mmol), palladium acetate (130mg, 0.6mmol), Toluene (10mL), 120 DEG C of heating of microwave are reacted 1 hour, and reaction is finished, and ethyl acetate is added to dilute, and diatomite filtering, decompression is spin-dried for molten Agent, silica gel post separation (petroleum ether: ethyl acetate=10:1-5:1) obtain yellow solid product 1.3g, yield 50.6%.1H NMR (400MHz, DMSO) δ 8.51 (s, 1H), 7.72 (d, J=8.7Hz, 2H), 7.10 (d, J=8.8Hz, 2H), 6.91 (d, J= 8.9Hz, 2H), 6.85 (d, J=8.8Hz, 2H), 3.74 (s, 3H), 3.72 (s, 3H)
The synthesis of step 2:6- methoxyl group -9H- carbazole -3- methyl formate
4- ((4- methoxyphenyl) amino) methyl benzoate (512mg, 2mmol), acetic acid are added into 100mL single port bottle Palladium (444mg, 4.4mmol), acetic acid (30mL), 120 DEG C of heating are reacted 2 hours, and reaction is finished, and decompression is spin-dried for acetic acid, then uses acetic acid Ethyl ester dissolves crude product, and silica gel post separation (petroleum ether: ethyl acetate=10:1) obtains yellow solid product 210mg, yield 41.3%.1H NMR (400MHz, CDCl3) δ 8.78 (s, 1H), 8.19 (s, 1H), 8.11 (dd, J=8.5,1.5Hz, 1H), 7.60 (d, J=2.3Hz, 1H), 7.41 (d, J=8.5Hz, 1H), 7.36 (d, J=8.8Hz, 1H), 7.10 (dd, J=8.8, 2.5Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H)
The synthesis of step 3:6- methoxyl group -9- ethyl -9H- carbazole -3- methyl formate
6- methoxyl group -9H- carbazole -3- methyl formate (210mg, 0.82mmol) is added into 25mL single port bottle, anhydrous N, Ice bath stirring 5 minutes, NaH (99mg, 2.47mmol, 60%) then is added, room temperature reaction 30 in dinethylformamide (5mL) Minute, it is then added dropwise to bromoethane (269mg, 2.47mmol), reacts at room temperature 3 hours under ice bath, TLC detection raw material has reacted It is complete.Add water quenching reaction, ethyl acetate (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, the anhydrous sulphur of organic layer Sour sodium dries, filters, and decompression is spin-dried for solvent and obtains crude product 120mg, is directly used in and reacts in next step.
The synthesis of step 4:6- methoxyl group -9- ethyl -9H- carbazole -3- formic acid
6- methoxyl group -9- ethyl -9H- carbazole -3- methyl formate (120mg, 0.42mmol) is added into 25mL single port bottle, Lithium hydroxide (53mg, 1.26mmol), ethyl alcohol (5mL), water (1mL), 90 DEG C are reacted 2 hours, and TLC detection raw material has reacted, With the hydrochloric acid tune pH to 3 of 2N, there is white solid precipitation, filters, be dried in vacuo to obtain white solid product 110mg, two step yields 49.7%.MS(ESI)m/z:270.1(MH+).
Step 5:The synthesis of 9- ethyl-N- (4- (ethylsulfonyl) benzyl) -6- methoxyl group -9H- carbazole -3- formamide
6- methoxyl group -9- ethyl -9H- carbazole -3- formic acid (100mg, 0.37mmol) is added into 25mL single port bottle, 4- (ethylsulfonyl) benzene methanamine (89mg, 0.45mmol), HATU (171mg, 0.45mmol), n,N-diisopropylethylamine (143mg, 1.11mmol), methylene chloride (5mL), overnight, TLC detection raw material has reacted for room temperature reaction.Methylene chloride is added (20mL), saturated ammonium chloride (30mL) washing, organic layer are spin-dried for obtaining crude product, crude product purified by silica gel post separation (petroleum ether: acetic acid Ethyl ester=1:1-1:2), obtain white solid product 140mg, yield 83.8%.1H NMR (400MHz, CDCl3) δ 8.59 (s, 1H), 7.92 (d, J=8.5Hz, 1H), 7.85-7.76 (m, 2H), 7.59 (d, J=2.3Hz, 1H), 7.53 (t, J=9.3Hz, 2H), 7.37 (d, J=8.3Hz, 1H), 7.33 (d, J=9.0Hz, 1H), 7.14 (dd, J=8.8,2.4Hz, 1H), 4.78 (t, J= 5.8Hz, 2H), 4.34 (dd, J=13.5,6.5Hz, 2H), 3.90 (q, J=7.1Hz, 2H), 3.08 (q, J=7.3Hz, 2H), 1.41 (t, J=7.1Hz, 3H), 1.26 (t, J=7.3Hz, 3H) .MS (ESI) m/z:451.2 (MH+).
Embodiment 14:The fluoro- 9H- carbazole -3- formamide of 9- ethyl-N- (4- (ethylsulfonyl) benzyl) -6-
(9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-fluoro-9H-carbazole-3- carboxamide)
The synthesis of step 1:4- ((4- fluorophenyl) amino) methyl benzoate
4- fluoroaniline (1.18g, 10mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (2.58g, 12mmol), potassium carbonate (1.66g, 12mmol), rac-BINAP (310mg, 0.5mmol), palladium acetate (130mg, 0.6mmol), Toluene (10mL), 120 DEG C of heating of microwave are reacted 1 hour, and reaction is finished, and ethyl acetate is added to dilute, and diatomite filtering, decompression is spin-dried for molten Agent, silica gel post separation (petroleum ether: ethyl acetate=10:1-5:1), obtains yellow solid product 1.0g, yield 41.7%.MS (ESI)m/z:253.0(MH+).
The synthesis of the fluoro- 9H- carbazole -3- methyl formate of step 2:6-
4- ((4- fluorophenyl) amino) methyl benzoate (600mg, 2.45mmol), acetic acid are added into 100mL single port bottle Palladium (603mg, 2.69mmol), acetic acid (5mL), 120 DEG C of heating are reacted 2 hours, and reaction is finished, and decompression is spin-dried for acetic acid, then uses acetic acid Ethyl ester dissolves crude product, and silica gel post separation (petroleum ether: ethyl acetate=10:1-5:1) obtains yellow solid product 350mg, produces Rate 58.8%.1H NMR (400MHz, CDCL3) δ 8.76 (s, 1H), 8.30 (s, 1H), 8.14 (d, J=8.6Hz, 1H), 7.77 (dd, J=8.6,2.0Hz, 1H), 7.43 (d, J=8.6Hz, 1H), 7.38 (dd, J=8.8,4.2Hz, 1H), 7.20 (td, J= 9.0,2.3Hz, 1H), 3.98 (s, 3H)
The synthesis of the fluorine-based -9- ethyl -9H- carbazole -3- methyl formate of step 3:6-
The fluoro- 9H- carbazole -3- methyl formate (200mg, 0.82mmol) of 6-, anhydrous N, N- bis- are added into 25mL single port bottle Methylformamide (5mL) ice bath stirring 5 minutes, is then added NaH (99mg, 2.47mmol, 60%), reacts at room temperature 30 minutes, Then it is added dropwise to bromoethane (269mg, 2.47mmol), reacts at room temperature 3 hours under ice bath, TLC detection raw material has reacted.Add Water quenching reaction, ethyl acetate (3 × 20mL) extraction, is washed (5 × 20mL), then saturated sodium-chloride is washed, organic layer anhydrous slufuric acid Sodium dries, filters, and decompression is spin-dried for solvent and obtains crude product 220mg, is directly used in and reacts in next step.1H NMR (400MHz, CDCl3)δ 8.77 (s, 1H), 8.18 (dd, J=8.7,1.6Hz, 1H), 7.79 (dd, J=8.7,2.5Hz, 1H), 7.42-7.38 (m, 1H), 7.35 (dd, J=8.9,4.2Hz, 1H), 7.23 (dd, J=8.9,2.5Hz, 1H), 4.37 (t, J=7.2Hz, 2H), 3.97 (s, 3H), 1.45 (t, J=7.2Hz, 3H)
The synthesis of the fluoro- 9- ethyl -9H- carbazole -3- formic acid of step 4:6-
The fluoro- 9- ethyl -9H- carbazole -3- methyl formate (200mg, 0.74mmol) of 6-, hydrogen-oxygen are added into 25mL single port bottle Change lithium (93mg, 2.21mmol), ethyl alcohol (5mL), water (1mL), 90 DEG C are reacted 1 hour, and TLC detection raw material has reacted, and use 2N Hydrochloric acid tune pH to 3, have white solid precipitation, filter, be dried in vacuo to obtain white solid product 160mg, two step yields 43.2%. MS(ESI)m/z:258.1(MH+).
The synthesis of the fluoro- 9H- carbazole -3- formamide of step 5:9- ethyl-N- (4- (ethylsulfonyl) benzyl) -6-
The fluoro- 9- ethyl -9H- carbazole -3- formic acid (80mg, 0.31mmol) of 6-, 4- (ethyl sulphur are added into 25mL single port bottle Acyl group) benzene methanamine (74mg, 0.37mmol), HATU (141mg, 0.37mmol), n,N-diisopropylethylamine (120mg, 0.93mmol), methylene chloride (5mL), overnight, TLC detection raw material has reacted for room temperature reaction.It is added methylene chloride (20mL), Saturated ammonium chloride (30mL) washing, organic layer are spin-dried for obtaining crude product, crude product purified by silica gel post separation (petroleum ether: ethyl acetate= 1:1-1:2), white solid product 53mg, yield 83.8% are obtained.1H NMR (400MHz, CDCl3) δ 8.56 (s, 1H), 7.97 (d, J=8.7Hz, 1H), 7.87 (d, J=8.2Hz, 2H), 7.77 (dd, J=8.6,2.4Hz, 1H), 7.58 (d, J=8.2Hz, 2H), 7.43 (d, J=8.5Hz, 1H), 7.36 (dd, J=8.8,4.1Hz, 1H), 7.25-7.22 (m, 1H), 4.82 (d, J= 5.7Hz, 2H), 4.37 (t, J=7.2Hz, 2H), 3.10 (q, J=7.4Hz, 2H), 1.44 (t, J=7.2Hz, 3H), 1.27 (t, J=7.5Hz, 3H) .MS (ESI) m/z:439.0 (MH+).
Embodiment 15:The chloro- 9- ethyl-N- of 6- (4- (ethylsulfonyl) benzyl) -9H- carbazole -3- formamide
(6-chloro-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide)
The synthesis of step 1:4- ((4- chlorphenyl) amino) methyl benzoate
4- chloroaniline (500mg, 3.9mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (1.01g, 4.68mmol), potassium carbonate (1.6g, 11.7mmol), rac-BINAP (121mg, 0.20mmol), palladium acetate (52mg, 0.23mmol), toluene (10mL), 130 DEG C of heating of microwave are reacted 1.5 hours, and reaction is finished, and adds ethyl acetate to dilute, diatomite mistake Filter, decompression are spin-dried for solvent, and silica gel post separation (petroleum ether: ethyl acetate=4:1) obtains yellow solid product 700mg, yield 68.4%.1H NMR (400MHz, CDCl3) δ 7.92 (d, J=8.7Hz, 2H), 7.29 (d, J=8.7Hz, 2H), 7.10 (d, J= 8.7Hz, 2H), 6.96 (d, J=8.7Hz, 2H), 3.88 (s, 3H) .MS (ESI) m/z:262.0 (MH+)
The synthesis of the chloro- 9H- carbazole -3- methyl formate of step 2:6-
4- ((4- chlorphenyl) amino) methyl benzoate (200mg, 0.76mmol), acetic acid are added into 100mL single port bottle Palladium (188mg, 0.84mmol), acetic acid (5mL), 130 DEG C of heating are reacted 1 hour, and reaction is finished, and decompression is spin-dried for acetic acid, then uses acetic acid Ethyl ester dissolves crude product, mixes sample, and silica gel post separation (petroleum ether: ethyl acetate=4:1) obtains yellow solid product 160mg, produces Rate 82.4%%.1H NMR (400MHz, DMSO) δ 11.85 (s, 1H), 8.85 (s, 1H), 8.40 (d, J=1.8Hz, 1H), 8.03 (dd, J=8.6,1.6Hz, 1H), 7.55 (t, J=8.6Hz, 2H), 7.44 (dd, J=8.6,2.1Hz, 1H), 3.87 (s, 3H).MS(ESI)m/z:257.9(M-1).
The synthesis of the chloro- 9- ethyl -9H- carbazole -3- methyl formate of step 3:6-
The chloro- 9H- carbazole -3- methyl formate (150mg, 0.58mmol) of 6-, anhydrous N, N- bis- are added into 25mL single port bottle Methylformamide (3mL) ice bath stirring 5 minutes, is then added NaH (69mg, 1.73mmol, 60%), reacts at room temperature 30 minutes, Then it is added dropwise to bromoethane (189mg, 1.73mmol), reacts at room temperature 3 hours under ice bath, TLC detection raw material has reacted.Add Water quenching reaction, ethyl acetate (3 × 20mL) extraction, is washed (5 × 20mL), then saturated sodium-chloride is washed, organic layer anhydrous slufuric acid Sodium dries, filters, and decompression is spin-dried for solvent and obtains crude product, and silicagel column (petroleum ether: ethyl acetate=10:1) separates to obtain yellow solid 65mg, yield 39.4%.
The synthesis of the chloro- 9- ethyl -9H- carbazole -3- formic acid of step 4:6-
The chloro- 9- ethyl -9H- carbazole -3- methyl formate (65mg, 0.23mmol) of 6-, hydrogen-oxygen are added into 25mL single port bottle Change lithium (28mg, 0.69mmol), ethyl alcohol (5mL), water (1mL), 90 DEG C are reacted 3 hours, and TLC detection raw material has reacted, and use 2N Hydrochloric acid tune pH to 3, have white solid precipitation, filter, be dried in vacuo to obtain white solid product 60mg, yield 96.7%.
The synthesis of the chloro- 9- ethyl-N- of step 5:6- (4- (ethylsulfonyl) benzyl) -9H- carbazole -3- formamide
The chloro- 9- ethyl -9H- carbazole -3- formic acid (60mg, 0.22mmol) of 6-, 4- (ethyl sulphur are added into 25mL single port bottle Acyl group) benzene methanamine (52mg, 0.26mmol), HATU (99mg, 0.26mmol), n,N-diisopropylethylamine (85mg, 0.66mmol), methylene chloride (2mL), overnight, TLC detection raw material has reacted for n,N-Dimethylformamide (2mL) room temperature reaction It is complete.It is added methylene chloride (20mL), saturated ammonium chloride (30mL) washing, organic layer is spin-dried for solvent and obtains crude product, crude product silicon Rubber column gel column separates (petroleum ether: ethyl acetate=1:1-1:2), obtains white solid product 70mg, yield 77.8%%.1H NMR (400MHz, DMSO) δ 9.11 (t, J=5.9Hz, 1H), 8.80 (s, 1H), 8.26 (d, J=1.9Hz, 1H), 8.09-8.02 (m, 1H), 7.84 (d, J=8.3Hz, 2H), 7.70 (dd, J=8.7,3.3Hz, 2H), 7.61 (d, J=8.3Hz, 2H), 7.50 (dd, J=8.7,2.0Hz, 1H), 4.63 (d, J=5.8Hz, 2H), 4.47 (q, J=6.9Hz, 2H), 3.24 (t, J=7.4Hz, 2H), 1.29 (t, J=7.1Hz, 3H), 1.07 (t, J=7.4Hz, 3H) .MS (ESI) m/z:454.9 (MH+)
Embodiment 16:6- cyano -9- ethyl-N- (4- (ethylsulfonyl) benzyl) -9H- carbazole -3- formamide
(6-cyano-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide)
The synthesis of step 1:4- ((4- cyano-phenyl) amino) methyl benzoate
Under protection of argon gas, 4- cyano-aniline (566mg, 4.80mmol) is added into 25mL microwave tube, 4- bromobenzoic acid Methyl esters (1g, 4.67mmol), palladium acetate (52mg, 0.23mmol), rac-BINAP (506mg, 0.81mmol), cesium carbonate (6.72g, 48.62mmol), toluene (10mL).Reacted 3 hours under the conditions of 160 DEG C of microwave, after be cooled to room temperature.Reaction terminates Afterwards, decompression is spin-dried for solvent, and methylene chloride is added and dilutes and filters.Water (15mL) is added after being spin-dried in organic phase, uses ethyl acetate (30mL X 3) extraction, saturated sodium-chloride are washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (mobile phase: petroleum ether: ethyl acetate=5:1) obtains white solid 400mg, yield 34.0%.MS (ESI) m/z:253.1 (MH+), 251.0 (M-1)
The synthesis of step 2:6- cyano -9- hydrogen carbazole -3- methyl formate
Under protection of argon gas, into 100mL eggplant-shape bottle be added 4- ((4- cyano-phenyl) amino) methyl benzoate (360mg, 1.43mmol), palladium acetate (350mg, 1.57mmol), acetic acid (8mL).It is reacted 45 minutes under 130 DEG C of condition of heating and stirring.Reaction After, decompression is spin-dried for solvent, is added methanol dilution (40mL).Suspension is filtered with diatomite.Organic phase is added after being spin-dried for Water (15mL) is extracted with ethyl acetate (3 × 30mL), and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for To crude product.Column chromatography for separation obtains yellow solid 70mg, yield 19.7%.MS (ESI) m/z:251.1 (MH+), 248.9 (M- 1).
The synthesis of step 3:6- cyano -9- ethyl carbazole -3- methyl formate
Under ice bath, 6- cyano -9- hydrogen carbazole -3- methyl formate (70mg, 0.28mmol) is added into 25mL eggplant-shape bottle, hydrogen Change sodium (20.3mg, 0.85mmol), n,N-Dimethylformamide (2mL), reacts at room temperature 30 minutes, be then added dropwise under ice bath Bromoethane (31mg, 0.28mmol), removes ice bath stirring 30 minutes after charging.After reaction, saturated ammonium chloride is added Neutralization is quenched in solution (5mL).(5 × 10mL) is washed with water in ethyl acetate (3 × 10mL) extraction, organic phase, and saturated sodium-chloride is washed, nothing Aqueous sodium persulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (eluant, eluent: petroleum ether: ethyl acetate=7:1), Obtain white solid 80mg, yield 100%.MS (ESI) m/z:279.1 (MH+)
The synthesis of step 4:6- cyano -9- ethyl carbazole -3- formic acid
In 25mL eggplant-shape bottle, it is added 6- cyano -9- ethyl carbazole -3- methyl formate (80mg, 0.29mmol), 20% hydrogen-oxygen Change sodium solution (173 μ L), ethyl alcohol (3mL)/water (0.75mL) mixed liquor.It is reacted 2 hours under 50 DEG C of condition of heating and stirring.Reaction knot Ethyl alcohol is removed in Shu Hou, decompression rotation, and 2N hydrochloric acid is added dropwise until reaction solution pH=2 into reaction solution in water supplement to 5mL, it is seen that solid analysis Out.Decompression filters and obtains white solid, is eluted with a small amount of water, and methanol (10mL) dissolution, decompression is spin-dried for obtaining white solid 36mg, Yield 47%.MS (ESI) m/z:263.0 (M-1), 265.1 (MH+)
The synthesis of step 5:6- cyano -9- ethyl-N- (4- (ethylsulfonyl) benzyl) -9H- carbazole -3- formamide
In 25mL eggplant-shape bottle, it is added 6- cyano -9- ethyl carbazole -3- formic acid (36mg, 0.14mmol), 2- (7- Oxybenzene And triazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (60mg, 0.16mmol), n,N-diisopropylethylamine (20mg, 0.16mmol), 4- (ethylsulfonyl) benzene methanamine (31mg, 0.16mmol), methylene chloride (3mL).It is reacted under stirring at normal temperature overnight, After reaction, decompression be spin-dried for reaction solution, with ethyl acetate (3 × 5mL) extract, organic phase with saturated sodium-chloride wash (3 × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Prepare plate separation (solvent: petroleum ether: ethyl acetate =1:1) obtain white solid 3mg, yield 4.8%.1H NMR (400MHz, CDCl3) δ 8.63 (s, 1H), 8.40 (s, 1H), 8.08 (t, J=8.1Hz, 2H), 7.87 (d, J=8.2Hz, 2H), 7.75 (d, J=8.7Hz, 1H), 7.59 (d, J=8.3Hz, 2H), 7.50 (t, J=8.1Hz, 2H), 6.90 (s, 1H), 4.83 (d, J=5.9Hz, 2H), 4.43 (q, J=7.4Hz, 2H), 3.10 (q, J=7.4Hz, 2H), 1.48 (t, J=7.4Hz, 3H), 1.28 (t, J=7.4Hz, 3H) .MS (ESI) m/z:443.9 (M-1), 446.2 (MH+)
Embodiment 17:5- ethyl-N- (4- (ethylsulfonyl) benzyl) -5H- pyrido [3,2-b] indoles -8- formamide
(5-ethyl-N- (4- (ethylsulfonyl) benzyl) -5H-pyrido [3,2-b] indole-8- carboxamide)
The synthesis of step 1:4- ((2- chloropyridine -3- base) amino) ethyl benzoate
The addition chloro- 3- iodine pyridine (1g, 4.2mmol) of 2- into microwave tube, 4-aminobenzoic acid ethyl ester (830mg, 5mmol), palladium acetate (56mg, 0.25mmol), cesium carbonate (4.1g, 12.6mmol), rac-BINAP (130mg, 0.21mmol), Toluene (15mL), nitrogen are bubbled 5 minutes, then react 1.5 hours for 140 DEG C of microwave.Saturated ammonium chloride (20mL) washing, decompression are steamed Dry solvent.Silica gel post separation (petroleum ether: ethyl acetate=5:1-4:1), obtains colorless oil 260mg, yield 22.6%.1H NMR (400MHz, CDCl3) δ 8.05-7.93 (m, 3H), 7.69 (d, J=7.9Hz, 1H), 7.18 (dd, J=8.0,4.6Hz, 1H), 7.12 (d, J=8.7Hz, 2H), 6.35 (s, 1H), 4.35 (t, J=7.1Hz, 2H), 1.38 (t, J=7.1Hz, 3H)
The synthesis of step 2:5H- pyrido [3,2-b] indoles -8- Ethyl formate
4- ((2- chloropyridine -3- base) benzocaine (400mg, 1.45mmol), three hydrations are added into microwave tube Sodium acetate (247mg, 3.63mmol), PdCl2(PPh3)2(105mg, 0.15mmol), n,N-dimethylacetamide (10mL), nitrogen It gas bell 5 minutes, then reacts 1.5 hours for 140 DEG C of microwave.Reaction is finished, and is added water (20mL), ethyl acetate (3 × 10mL) extraction, Merge organic layer, saturated sodium-chloride (3 × 20mL) washing, evaporated under reduced pressure solvent obtains crude product, crude product purified by silica gel post separation (stone Oily ether: ethyl acetate=4:1-2:1), obtain yellow solid 220mg, yield 63.9%.1H NMR (400MHz, CDCl3)δ9.12 (s, 1H), 8.98 (s, 1H), 8.62 (dd, J=4.7,1.1Hz, 1H), 8.23 (dd, J=8.6,1.6Hz, 1H), 7.78 (dd, J =8.2,1.1Hz, 1H), 7.48 (d, J=8.6Hz, 1H), 7.37 (dd, J=8.2,4.7Hz, 1H), 4.39 (q, J=7.1Hz, 2H), 1.43-1.36 (m, 3H)
The synthesis of step 3:5- ethyl -5H- pyrido [3,2-b] indoles -8- Ethyl formate
5H- pyrido [3,2-b] indoles -8- Ethyl formate (220mg, 0.97mmol), nothing are added into 25mL single port bottle Ice bath stirring 5 minutes, NaH (116mg, 12.9mmol, 60%) then is added, room temperature is anti-in water n,N-Dimethylformamide (5mL) It answers 30 minutes, is then added dropwise under ice bath bromoethane (316mg, 2.9mmol), reacted at room temperature 2 hours, TLC has detected raw material It has reacted.Add water quenching reaction, ethyl acetate (3 × 20mL) extraction is washed (5 × 20mL), then saturated sodium-chloride is washed, organic layer Anhydrous sodium sulfate dries, filters, and decompression is spin-dried for solvent and obtains crude product, is directly used in and reacts in next step.
The synthesis of step 4:5- ethyl -5H- pyrido [3,2-b] indoles -8- formic acid
5- ethyl -5H- pyrido [3,2-b] indoles -8- Ethyl formate, lithium hydroxide are added into 25mL single port bottle (112mg, 2.76mmol), ethyl alcohol (5mL), water (1mL), 90 DEG C of heating are reacted 2 hours, and TLC detection raw material has reacted, and use 2N Hydrochloric acid tune pH to 3, have white solid precipitation, filter, be dried in vacuo to obtain white solid product 150mg, two step yields 68.2%. MS(ESI)m/z:241.1(MH+).
The conjunction of step 5:5- ethyl-N- (4- (ethylsulfonyl) benzyl) -5H- pyrido [3,2-b] indoles -8- formamide At
5- ethyl -5H- pyrido [3,2-b] indoles -8- formic acid (100mg, 0.29mmol) is added into 25mL single port bottle, 4- (ethylsulfonyl) benzene methanamine (70mg, 0.35mmol), HATU (133mg, 0.35mmol), n,N-diisopropylethylamine (112mg, 0.87mmol), methylene chloride (5mL), overnight, TLC detects raw material for n,N-Dimethylformamide (1mL) room temperature reaction It has reacted.It is added methylene chloride (20mL), saturated ammonium chloride (30mL) washing, organic layer is spin-dried for obtaining crude product, and crude product is used Silica gel post separation (petroleum ether: ethyl acetate=2:1), obtains white solid product 40mg, yield 22.8%.1H NMR (400MHz, CDCl3) δ 8.79 (s, 1H), 8.54 (d, J=4.6Hz, 1H), 8.23 (dd, J=8.7,1.7Hz, 1H), 7.85 (d, J= 8.3Hz, 2H), 7.76 (d, J=8.3Hz, 1H), 7.56 (d, J=8.2Hz, 2H), 7.53 (d, J=8.7Hz, 1H), 7.42 (dd, J=8.3,4.7Hz, 1H), 7.15 (s, 1H), 4.78 (d, J=5.9Hz, 2H), 4.40 (q, J=7.3Hz, 3H), 3.10 (q, J=7.4Hz, 3H), 1.46 (t, J=7.2Hz, 3H), 1.28 (d, J=7.4Hz, 4H) .MS (ESI) m/z:422.2 (MH +)。
Embodiment 18:9- ethyl-N- ((5- (ethylsulfonyl) pyridine -2- base) methyl) -9H- carbazole -3- formamide
(9-ethyl-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-9H-carbazole-3- carboxamide)
The synthesis of step 1:5- (ethylmercapto group) -2- pyridine carbonitrile
5- bromo-2-pyridyl formonitrile HCN (940mg, 5.14mmol) is added into 50mL single port bottle, ethyl mercaptan (505mg, 6.01mmol), potassium carbonate (981mg, 7.11mmol), NMP (10mL).Reaction is stirred at room temperature overnight.It is added water (20mL), acetic acid Ethyl ester (3 × 30mL) extraction, organic layer are spin-dried for obtaining product 5- (ethylmercapto group) -2- pyridine carbonitrile 900mg, yield 100%.MS (ESI)m/z:165.1(MH+)。
The synthesis of step 2:5- (ethylsulfonyl) -2- pyridine carbonitrile
5- (ethylmercapto group) -2- pyridine carbonitrile (800mg, 4.88mmol) is added into 25mL single port bottle, methylene chloride (20mL), ice bath are mixed 10 minutes, and mCPBA (1.84g, 10.7mmol) is added portionwise in reaction solution, and then room temperature reaction is stayed overnight, It being washed with the sodium carbonate liquor of 2N, organic layer is spin-dried for, and silica gel post separation (petroleum ether: ethyl acetate=2:1-1:1) obtains 900mg, Yield 90.0%.1H NMR (400MHz, CDCl3) δ 9.18 (d, J=1.2Hz, 1H), 8.37 (dd, J=8.0,1.8Hz, 1H), 7.93 (d, J=8.0Hz, 1H), 3.21 (q, J=7.4Hz, 2H), 1.34 (t, J=7.4Hz, 3H) .MS (ESI) m/z:197.1 (MH+).
Step 3:(5- (ethylsulfonyl)-pyridine -2- base) methylamine synthesis
5- (ethylsulfonyl) -2- pyridine carbonitrile (200mg, 1mmol) is added into 25mL single port bottle, methanol (10mL), Pd/C (100mg, 10%).Reaction solution is stirred at room temperature 30 minutes under an atmosphere of hydrogen, diatomite filtering, be spin-dried for solvent obtain it is white solid Body product 110mg, yield 53.9%.MS(ESI)m/z:201.1(MH+).
The synthesis of step 4:9- ethyl-N- ((5- (ethylsulfonyl) pyridine -2- base) methyl) -9H- carbazole -3- formamide
Method is the same as embodiment 1,9- ethyl -9H- carbazole -3- formic acid (80mg, 0.33mmol), 5- ethyl sulfone -2- pyridine first Amine (82mg, 0.37mmol), HATU (141mg, 0.37mmol), n,N-diisopropylethylamine (129mg, 0.99mmol), dichloro Methane (5mL).Obtain white solid product 24mg, yield 17.0%.1H NMR(400MHz,CD3OD3) δ 8.99 (d, J=1.7Hz, 1H), 8.73 (d, J=1.1Hz, 1H), 8.26 (dd, J=8.3,2.2Hz, 1H), 8.15 (d, J=7.8Hz, 1H), 8.05 (dd, J=8.6,1.6Hz, 1H), 7.68 (d, J=8.3Hz, 1H), 7.61-7.53 (m, 2H), 7.50 (t, J=7.6Hz, 1H), 7.25 (t, J=7.4Hz, 1H), 4.85 (s, 2H), 4.46 (q, J=7.1Hz, 2H), 3.26 (t, J=7.4Hz, 2H), 1.41 (t, J= 7.2Hz, 3H), 1.24 (t, J=7.4Hz, 3H) .MS (ESI) m/z:423.1 (MH+)
Embodiment 19:9- ethyl-N- (4- (methyl sulphonyl) benzyl) -9H- carbazole -3- formamide
(9-ethyl-N-(4-(methylsulfonyl)benzyl)-9H-carbazole-3-carboxamide)
9- ethyl -9H- carbazole -3- formic acid (80mg, 0.33mmol) is added into 25mL single port bottle, 4- methylsulfonyl benzene methanamine (82mg, 0.37mmol), HATU (141mg, 0.37mmol), n,N-diisopropylethylamine (129mg, 0.99mmol), dichloromethane Alkane (5mL), overnight, TLC detection raw material has reacted for room temperature reaction.It is added methylene chloride (20mL), saturated ammonium chloride (30mL) Washing, organic layer are spin-dried for obtaining crude product, and crude product purified by silica gel post separation (petroleum ether: ethyl acetate=2:1-1:1) obtains white solid Body product 66mg, yield 48.5%.1H NMR (400MHz, DMSO) δ 9.15 (t, J=5.8Hz, 1H), 8.75 (s, 1H), 8.17 (d, J=7.7Hz, 1H), 8.07-8.00 (m, 1H), 7.88 (d, J=8.3Hz, 2H), 7.70-7.62 (m, 2H), 7.60 (d, J =8.3Hz, 2H), 7.49 (t, J=7.7Hz, 1H), 7.24 (t, J=7.4Hz, 1H), 4.62 (d, J=5.8Hz, 2H), 4.47 (q, J=7.0Hz, 2H), 3.17 (s, 3H), 1.31 (t, J=7.1Hz, 3H) .MS (ESI) m/z:407.0 (MH+)
Embodiment 20:9- ethyl-N- (4- (the third sulfonyl) benzyl) -9H- carbazole -3- formamide
9-ethyl-N-(4-(propylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
The synthesis of step 1:4- (the third sulfonyl) benzonitrile
4- cyanobenzenesulfonyl chloride (1g, 4.97mmol) is added into 100 (mL) single port bottles, water (15mL), sodium bicarbonate (835mg, 9.94mmol), sodium sulfite (689mg, 5.47mmol), 70 DEG C of reaction solution are stirred to react 4 hours, and decompression spins off molten Agent.Crude product uses n,N-Dimethylformamide (20mL) to dissolve again, is added iodopropane (1.1mL), and reaction solution continues 70 DEG C and stirs Mix reaction 4 hours.It is cooled to room temperature, is added water (30mL), ethyl acetate (3 × 30mL) extraction merges organic layer, and organic layer is used Saturated common salt water washing, anhydrous sodium sulfate dry, filter, and filtrate decompression is spin-dried for obtaining crude product, crude product purified by silica gel post separation (second Acetoacetic ester: petroleum ether=1:4-1:2), obtain yellow solid product 520mg, yield 50.1%.
The synthesis of step 2:4- (the third sulfonyl) benzene methanamine
4- (sulfonyl propyl base) benzonitrile (520mg, 2.49mmol), methanol (10mL), palladium are added into 25mL single port bottle Carbon (100mg, 10%).Reaction solution is stirred at room temperature 2 hours under an atmosphere of hydrogen, and diatomite filtering is spin-dried for solvent, column chromatography for separation (petroleum ether: ethyl acetate=1:1), obtains white solid white solid product 120mg, yield 22.6%.
The synthesis of step 3:9- ethyl-N- (4- (the third sulfonyl) benzyl) -9H- carbazole -3- formamide
In 25mL eggplant-shape bottle, 4- (the third sulfonyl) benzene methanamine (100mg, 0.47mmol) is added, (7- aoxidizes three nitrogen of benzo to 2- Azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (178mg, 0.47mmol), n,N-diisopropylethylamine (60mg, 0.47mmol), -9 hydrogen of 9- ethyl-carbazole -3- formic acid (98mg, 0.41mmol), methylene chloride (5mL).It is reacted under stirring at normal temperature Overnight, after reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), and organic phase washes (3 with saturated sodium-chloride × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1: 1) white solid 82mg, yield 40.2%., are obtained1H NMR (400MHz, CDCl3) δ 8.63 (s, 1H), 8.12 (d, J= 7.8Hz, 1H), 7.97 (d, J=8.6Hz, 1H), 7.82 (d, J=8.1Hz, 2H), 7.55 (d, J=8.2Hz, 2H), 7.51 (d, J=7.9Hz, 1H), 7.47-7.40 (t, J=7.9Hz, 2H), 7.28 (d, J=7.3Hz, 1H), 6.93 (s, 1H), 4.80 (d, J =5.6Hz, 2H), 4.38 (t, J=7.2Hz, 2H), 3.08-3.00 (m, 2H), 1.72 (t, J=7.9Hz, 2H), 1.45 (t, J =7.2Hz, 3H), 0.97 (t, J=7.4Hz, 3H) .MS (ESI) m/z:432.9 (M-1), 435.2 (MH+)
Embodiment 21:9- ethyl-N- (4- (N- Methylsulfamoyl) benzoyl) -9H- carbazole -3- formamide
(9-ethyl-N-(4-(N-methylsulfamoyl)benzyl)-9H-carbazole-3-carboxamide)
The synthesis of step 1:4- (amino methyl)-N- methyl benzenesulfonamide
Methylamine water solution (15mL, 25%w/v) is added into 50mL eggplant-shape bottle, 4- is added portionwise in acetone (5mL) at room temperature Cyanobenzenesulfonyl chloride (1g, 4.96mmol) stirs 2 hours.Reaction is finished, and is diluted with water, is extracted with ethyl acetate 3 times, is associated with Machine phase is spin-dried for, dries to obtain white solid 1g, is directly used in next step.MS(ESI)m/z:197.1(MH+).
The synthesis of step 2:4- (amino methyl)-N- methyl benzenesulfonamide
Raney's nickel (250mg) is added into 25mL eggplant-shape bottle, 4- cyano-N-methyl benzsulfamide (250mg), methanol (3mL), 28% ammonia (12 drop), tetrahydrofuran (24 drop) under atmosphere of hydrogen, stir 2 hours at room temperature.Reaction is finished, and filtering subtracts Pressure is spin-dried for organic solvent and obtains viscous liquid (120mg, yield 47%.MS(ESI)m/z:201.1(MH+).
The synthesis of step 3:9- ethyl-N- (4- (N- Methylsulfamoyl) benzoyl) -9H- carbazole -3- formamide
Method is the same as embodiment 1,9- ethyl -9H- carbazole -3- formic acid (52mg, 0.22mmol), 4- (amino methyl)-N- first Base benzsulfamide (36mg, 0.18mmol), HATU (84mg, 0.22mmol), n,N-diisopropylethylamine (70mg, 0.54mmol) It is dissolved in methylene chloride (4mL).Obtain white solid product 44mg, yield 31.2%.1H NMR (400MHz, DMSO) δ 9.12 (t, J=6.0Hz, 1H), 8.76 (s, 1H), 8.17 (d, J=7.7Hz, 1H), 8.04 (d, J=8.6Hz, 1H), 7.73 (d, J= 8.2Hz, 2H), 7.70-7.62 (m, 2H), 7.55 (d, J=8.1Hz, 2H), 7.49 (t, J=7.7Hz, 1H), 7.40 (q, J= 4.8Hz, 1H), 7.24 (t, J=7.5Hz, 1H), 4.60 (d, J=5.8Hz, 2H), 4.47 (q, J=6.9Hz, 2H), 2.37 (d, J=5.0Hz, 3H), 1.31 (t, J=7.0Hz, 3H) .MS (ESI) m/z:422.1 (MH+)
Embodiment 22:9- (Cvclopropvlmethvl)-N- (4- (methyl sulphonyl) benzyl) -9H- carbazole -3- formamide
(9-(cyclopropylmethyl)-N-(4-(methylsulfonyl)benzyl)-9H-carbazole-3- carboxamide)
9- (Cvclopropvlmethvl) -9H- carbazole -3- formic acid (80mg, 0.30mmol), 4- methyl sulfone are added into 25mL single port bottle Base benzene methanamine (74mg, 0.33mmol), HATU (125mg, 0.33mmol), n,N-diisopropylethylamine (116mg, 0.90mmol), methylene chloride (5mL), overnight, TLC detection raw material has reacted for room temperature reaction.It is added methylene chloride (20mL), Saturated ammonium chloride (30mL) washing, organic layer are spin-dried for obtaining crude product, crude product purified by silica gel post separation (petroleum ether: ethyl acetate= 2:1-1:1), white solid product 75mg, yield 57.7% are obtained.1H NMR (400MHz, CDCl3) δ 8.61 (s, 1H), 8.12 (d, J=7.7Hz, 1H), 7.95 (d, J=8.4Hz, 1H), 7.91 (d, J=8.2Hz, 2H), 7.59 (d, J=8.2Hz, 2H), 7.55-7.49 (m, 1H), 7.49-7.42 (m, 2H), 7.29 (d, J=6.9Hz, 1H), 6.82 (s, 1H), 4.81 (d, J= 5.8Hz, 2H), 4.26 (d, J=6.5Hz, 2H), 3.04 (s, 3H), 1.33 (s, 2H), 0.56 (d, J=7.7Hz, 2H), 0.41 (d, J=5.2Hz, 2H) .MS (ESI) m/z:433.0 (MH+)
Embodiment 23:9- (Cvclopropvlmethvl)-N- ((5- (ethylsulfonyl) pyridine -2- base) methyl) -9H- carbazole -3- Formamide
(9-(cyclopropylmethyl)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-9H- carbazole-3-carboxamide)
Method is the same as embodiment 1,9- (Cvclopropvlmethvl) -9H- carbazole -3- formic acid (80mg, 0.30mmol), 5- ethyl sulfone - 2- pyridyl-methanamine (66mg, 0.33mmol), HATU (125mg, 0.33mmol), n,N-diisopropylethylamine (116mg, 0.90mmol), methylene chloride (5mL).Obtain white solid 10mg, yield 17.4%.1H NMR (400MHz, CD3OD) δ 8.98 (s, 1H), 8.72 (s, 1H), 8.24 (d, J=8.2Hz, 1H), 8.14 (d, J=7.7Hz, 1H), 8.03 (d, J=8.5Hz, 1H), 7.68 (d, J=8.2Hz, 1H), 7.62-7.53 (m, 2H), 7.49 (d, J=7.3Hz, 1H), 7.25 (t, J=7.4Hz, 1H), 4.84 (s, 2H), 4.31 (d, J=6.5Hz, 2H), 3.26 (dd, J=14.9,7.5Hz, 2H), 1.34 (d, J=7.0Hz, 1H), 1.22 (d, J=7.4Hz, 4H), 0.51 (d, J=7.8Hz, 2H), 0.43 (d, J=4.5Hz, 2H) .MS (ESI) m/z:448.0 (MH+).
Embodiment 24:9- (Cvclopropvlmethvl)-N- (4- (N- Methylsulfamoyl) benzoyl) -9H- carbazole -3- formyl Amine(9-(cyclopropylmethyl)-N-(4-(N-methylsulfamoyl)benzyl)-9H-carbazole-3- carboxamide)
Method is the same as embodiment 1,9- (Cvclopropvlmethvl) -9H- carbazole -3- formic acid (58mg, 0.22mmol), 4- (amino first Base)-N- methyl benzenesulfonamide (36mg, 0.18mmol), HATU (84mg, 0.22mmol), n,N-diisopropylethylamine (70mg, 0.54mmol), methylene chloride (4mL).Obtain white solid 39mg, yield 28.9%.1H NMR (400MHz, DMSO) δ 9.13 (s, 1H), 8.76 (s, 1H), 8.17 (d, J=7.9Hz, 1H), 8.03 (d, J=8.6Hz, 1H), 7.72 (dd, J=16.9,8.6Hz, 4H), 7.56 (d, J=8.3Hz, 2H), 7.49 (t, J=7.6Hz, 1H), 7.41 (d, J=5.0Hz, 1H), 7.25 (t, J= 7.4Hz, 1H), 4.61 (d, J=5.9Hz, 2H), 4.36 (d, J=6.8Hz, 2H), 2.38 (d, J=5.0Hz, 3H), 1.29 (s, 2H), 0.44 (d, J=7.5Hz, 4H) .MS (ESI) m/z:448.0 (MH+)
Embodiment 25:N- (4- (ethylsulfonyl) benzyl) -9- phenethyl -9H- carbazole -3- formamide
(N-(4-(ethylsulfonyl)benzyl)-9-phenethyl-9H-carbazole-3-carboxamide)
The synthesis of step 1:9- phenethyl -9H- carbazole -3- methyl formate
9H- carbazole -3- methyl formate (300mg, 1.33mmol) is added into 25mL single port bottle, anhydrous N, N- dimethyl methyl Amide (10mL) ice bath stirring 5 minutes, is then added NaH (160mg, 4mmol, 60%), reacts at room temperature 30 minutes, then exist It is added dropwise to (2- bromoethyl) benzene (736mg, 4mmol) under ice bath, reacts at room temperature 3 hours, TLC detection raw material has reacted.Add water quenching It goes out reaction, ethyl acetate (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, and organic layer anhydrous sodium sulfate is dry, mistake Filter, decompression are spin-dried for solvent and obtain yellow solid 140mg, yield 32.0%.
The synthesis of step 2:9- phenethyl -9H- carbazole -3- formic acid
9- phenethyl -9H- carbazole -3- methyl formate (140mg, 0.43mmol) is added into 25mL single port bottle, hydroxide Potassium (72mg, 1.29mmol), ethyl alcohol (4mL), water (1mL), 80 DEG C are reacted 1 hour, and TLC detection raw material has reacted, with 2N's Hydrochloric acid tune pH to 3 has white solid precipitation, and filtering is dried in vacuo to obtain white solid product 100mg, yield 75.6%.
The synthesis of step 3:N- (4- (ethylsulfonyl) benzyl) -9- phenethyl -9H- carbazole -3- formamide
9- phenethyl -9H- carbazole -3- formic acid (100mg, 0.32mmol) is added into 25mL single port bottle, 2- (7- azoBenzene And triazole)-N, N, N ', N '-TetramethylureaHexafluorophosphoric acid ester (138mg, 0.36mmol), n,N-diisopropylethylamine (47mg, 0.36mmo1), 4- (ethyl sulfone) benzene methanamine (73mg, 0.36mmol), methylene chloride (5mL), stirs 10h at room temperature.It has reacted It is subject to ethyl acetate dilution after finishing, successively uses saturated sodium chloride solution, water washing, organic phase is dry with anhydrous sodium sulfate.Decompression Organic solvent is distilled off, with the isolated 9- phenethyl-N- of silicagel column (4- (ethyl sulfone) phenyl) -9H- carbazole -3- amide 90mg, yield 57.2%.1H NMR (400MHz, CDCl3) δ 8.59 (s, 1H), 8.12 (d, J=7.9Hz, 1H), 7.87 (d, J= 8.2Hz, 3H), 7.59 (d, J=8.0Hz, 2H), 7.48 (t, J=7.6Hz, 1H), 7.36 (d, J=8.1Hz, 1H), 7.31- 7.26 (m, 2H), 7.21 (t, J=7.6Hz, 3H), 7.11 (d, J=6.3Hz, 2H), 6.73 (brs, 1H), 4.81 (d, J= 5.7Hz, 2H), 4.54 (t, J=7.4Hz, 2H), 3.21-3.01 (m, 4H), 1.27 (t, J=7.5Hz, 3H)
Embodiment 26:N- (4- (ethyl sulfone) benzyl) -9- (4- (trifluoromethyl) phenethyl) -9H- carbazole -3- amide
N-(4-(ethylsulfonyl)benzyl)-9-(4-(trifluoromethyl)phenethyl)-9H- carbazole-3-carboxamide
The synthesis of step 1:9- (4- (trifluoromethyl) phenethyl) carbazole -3- methyl formate
Under ice bath, 9- hydrogen carbazole -3- methyl formate (150mg, 0.67mmol) is added into 25mL eggplant-shape bottle, cesium carbonate (261mg, 0.8mmol), n,N-Dimethylformamide (10mL), potassium iodide (11mg, 0.078mmol) remove after charging Ice bath stirring 30 minutes.It after 30 minutes, is added dropwise 4- (trifluoromethyl) phenethyl bromide (261mg/174 μ L, 0.8mmol), reaction 9 is small When, TLC detects (solvent: petroleum ether: ethyl acetate=10:1), end of reaction.After reaction, water (20mL) is added to be quenched It neutralizes.It is extracted with ethyl acetate (3 × 10mL), (5 × 10mL) is washed with water in organic phase, and saturated sodium-chloride is washed, and anhydrous sodium sulfate is dry Dry, filtering, decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=20:1) obtains colourless oil liquid 32mg, yield 12.0%.
The synthesis of step 2:9- (4- (trifluoromethyl) phenethyl) carbazole -3- formic acid
In 25mL eggplant-shape bottle, addition 9- (4- (trifluoromethyl) phenethyl) carbazole -3- methyl formate (32mg, 0.08mmol), a hydronium(ion) lithia solid (9.67mg, 0.24mmol), ethyl alcohol (2mL)/water (0.5mL) mixed liquor.60℃ It is reacted 3 hours under condition of heating and stirring.After reaction, ethyl alcohol is removed in decompression rotation, and 2N is added dropwise into reaction solution for water supplement to 5mL Hydrochloric acid is until reaction solution pH=3, it is seen that a large amount of solids are precipitated.With ethyl acetate (3 × 10mL) extract, organic phase be washed with water (5 × 10mL), saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product, and decompression filters and obtains yellow oil Shape object 17mg, yield 56.2%.
The synthesis of compound N-(4- (ethyl sulfone) benzyl) -9- (4- (trifluoromethyl) phenethyl) -9H- carbazole -3- amide
9- (4- (trifluoromethyl) phenethyl) carbazole -3- formic acid (17mg, 0.045mmol) is added in 25mL eggplant-shape bottle, 2- (7- aoxidizes benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (21mg, 0.054mmol), N, N- diisopropyl Base ethamine (21mg, 0.054mmol), (4- (ethylsulfonyl) phenyl) methylamine (11mg, 0.054mmol), methylene chloride (2mL). It is reacted under stirring at normal temperature overnight, after reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), and organic phase is used Saturated sodium-chloride washes (3 × 5mL), and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Prepare plate separation (petroleum Ether: ethyl acetate=1:2) obtain white solid 15mg, yield 59.0%.1H NMR(400MHz,CDCl3)δ8.63(s,1H), 8.10 (d, J=7.7Hz, 1H), 7.87 (d, J=7.7Hz, 1H), 7.81 (d, J=8.0Hz, 2H), 7.54 (d, J=8.0Hz, 2H), 7.44 (d, J=7.8Hz, 3H), 7.29 (d, J=8.1Hz, 2H), 7.20 (d, J=8.1Hz, 1H), 7.16 (d, J= 7.8Hz, 2H), 6.96 (brs, 1H), 4.79 (d, J=5.0Hz, 2H), 4.55 (t, J=6.8Hz, 2H), 3.19 (t, J= 6.8Hz, 2H), 3.09 (q, J=7.5Hz, 2H), 1.27 (d, J=7.5Hz, 3H)
Embodiment 27:9- (2- trifluoromethyl) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9-(2-trifluoromethyl)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole- 3-carboxamide
The synthesis of step 1:9- (2- trifluoromethyl) benzyl -9H- carbazole -3- methyl formate
9H- carbazole -3- methyl formate (100mg, 0.44mmol) is added into 25mL single port bottle, anhydrous N, N- dimethyl methyl Amide (3mL) ice bath stirring 5 minutes, is then added sodium hydride (53.8mg, 1.32mmol, 60%), reacts at room temperature 30 minutes. 2- (trifluoromethyl) benzyl bromine (0.2mL, 1.32mmol) is added dropwise to after 30 minutes under ice cooling, 4, is reacted at room temperature 1 hour, TLC Detection raw material has reacted.Add water quenching reaction, ethyl acetate (3 × 10mL) extraction, saturated sodium-chloride is washed, and organic layer is with anhydrous Sodium sulphate dries, filters, and decompression spins off solvent, and column chromatographs (petroleum ether: ethyl acetate=5:1) and obtains crude product 100mg, yield 59.3%.
The synthesis of step 2:9- (2- trifluoromethyl) benzyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 9- (2- trifluoromethyl) benzyl -9H- carbazole -3- methyl formate (100mg, 0.26mmol), potassium hydroxide (43.68mg, 0.78mmol), water (1mL), ethyl alcohol adds to solid and is completely dissolved, and 90 DEG C of heating are anti- It answers 1 hour, TLC detection raw material has reacted, and 65 DEG C remove ethyl alcohol under reduced pressure, with the hydrochloric acid tune pH to 3 of 2N, there is solid precipitation, takes out Solid, ethyl acetate (5mL) dissolution are filtered to obtain, evaporating solvent under reduced pressure obtains solid product 130mg.MS-ESI (m/z): 370 [M+H ]+.
The synthesis of compound 9- (2- trifluoromethyl) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9- (2- trifluoromethyl) benzyl -9H- carbazole -3- formic acid (130mg, 0.35mmol) is added into 25mL single port bottle, 2- (7- azoBenzotriazole)-N, N, N ', N '-TetramethylureaHexafluorophosphoric acid ester (149mg, 0.392mmol), N, N- diisopropyl Base ethamine 10d, (4- (ethyl sulfone) phenyl) methylamine (78mg, 0.392mmol), methylene chloride (4mL) are stirred overnight at room temperature. After completion of the reaction, reaction solution is spin-dried for, and washing is primary, ethyl acetate extraction, saturated sodium chloride solution washing, the anhydrous sulphur of organic phase Sour sodium is dry.Vacuum distillation removes organic solvent, and column chromatography for separation (petroleum ether: ethyl acetate=1:2) obtains white solid 104mg, yield 54%.1H-NMR (400MHz, CDCl3) δ 8.69 (s, 1H), 8.19 (d, J=7.5Hz, 1H), 7.90 (d, J= 7.5Hz, 1H), 7.88 (d, J=7.9Hz, 2H), 7.77 (d, J=7.6Hz, 1H), 7.59 (d, J=7.9Hz, 2H), 7.48 (t, J=7.8Hz, 1H), 7.35 (s, 1H), 7.32 (t, J=7.7Hz, 3H), 7.23 (d, J=7.3Hz, 1H), 6.79 (s, 1H), 6.50 (d, J=7.4Hz, 1H), 5.75 (s, 2H), 4.83 (s, 2H), 3.11 (q, J=7.5Hz, 2H), 1.27 (t, J= 7.5Hz,3H).
Embodiment 28:9- (3- trifluoromethyl) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9-(3-trifluoromethyl)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole- 3-carboxamide
The synthesis of step 1:9- (3- trifluoromethyl) benzyl -9H- carbazole -3- methyl formate
9H- carbazole -3- methyl formate (50mg, 0.22mmol) is added into 25mL single port bottle, anhydrous N, N- dimethyl methyl Amide (3mL) ice bath stirring 5 minutes, is then added sodium hydride (26.4mg, 0.66mmol, 60%), reacts at room temperature 30 minutes, Then it is added dropwise to 3- (trifluoromethyl) benzyl bromine (0.1mL, 0.66mmol) under ice cooling, 4, reacts at room temperature 1 hour, TLC detection Raw material has reacted.Add water quenching reaction, ethyl acetate (3 × 10mL) extraction, saturated sodium-chloride is washed, organic layer anhydrous slufuric acid Sodium dries, filters, and decompression spins off solvent, and column chromatographs (petroleum ether: ethyl acetate=5:1) and obtains crude product 203mg.
The synthesis of step 2:9- (2- trifluoromethyl) benzyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 9- (3- trifluoromethyl) benzyl -9H- carbazole -3- methyl formate (203mg, 0.53mmol), potassium hydroxide (89.04mg, 1.59mmol), water (1mL), ethyl alcohol adds to solid and is completely dissolved, and 90 DEG C of heating are anti- It answers 1 hour, TLC detection raw material has reacted, and 65 DEG C remove ethyl alcohol under reduced pressure, with the hydrochloric acid tune pH to 3 of 2N, there is solid precipitation, takes out Solid, ethyl acetate (5mL) dissolution are filtered to obtain, evaporating solvent under reduced pressure obtains solid product 155mg, yield 79.3%.MS-ESI(m/ Z): 370 [M+H]+.
The synthesis of compound 9- (3- trifluoromethyl) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9- (3- trifluoromethyl) benzyl -9H- carbazole -3- formic acid (155mg, 0.42mmol) is added into 25mL single port bottle, 2- (7- azoBenzotriazole)-N, N, N ', N '-TetramethylureaHexafluorophosphoric acid ester (178.6mg, 0.47mmol), N, N- bis- are different Propylethylamine 10d, (4- (ethyl sulfone) phenyl) methylamine (93.53mg, 0.47mmol), methylene chloride (4mL) are stirred at room temperature Night.After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), organic phase washed with saturated sodium-chloride (3 × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1:2) Obtain white solid 83.5mg, yield 36%.1H-NMR:(400MHz, CDCl3) δ 8.66 (s, 1H), 8.01 (d, J=7.7Hz, 1H), 7.90 (d, J=8.6Hz, 1H), 7.80 (t, J=5.9Hz, 1H), 7.65 (s, 1H), 7.63 (s, 1H), 7.40 (d, J= 8.4Hz, 3H), 7.36 (d, J=7.8Hz, 1H), 7.23 (s, 1H), 7.22 (s, 1H), 7.20 (d, J=2.9Hz, 1H), 7.17 (d, J=7.4Hz, 1H), 7.05 (d, J=7.7Hz, 1H), 5.44 (s, 2H), 4.65 (d, J=5.8Hz, 2H), 2.96 (q, J= 7.4Hz, 2H), 1.12 (t, J=7.4Hz, 3H)
Embodiment 29:9- (4- trifluoromethyl) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9-(4-trifluoromethyl)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole- 3-carboxamide
The synthesis of step 1:9- (4- trifluoromethyl) benzyl -9H- carbazole -3- methyl formate
9H- carbazole -3- methyl formate (50mg, 0.22mmol) is added into 25mL single port bottle, anhydrous N, N- dimethyl methyl Amide (3mL) ice bath stirring 5 minutes, is then added sodium hydride (26.4mg, 0.66mmol, 60%), reacts at room temperature 30 minutes, Then it is added dropwise to 4- (trifluoromethyl) benzyl bromine (0.1mL, 0.66mmol) under ice cooling, 4, reacts at room temperature 1 hour, TLC detection Raw material has reacted.Add water quenching reaction, ethyl acetate (3 × 10mL) extraction, saturated sodium-chloride is washed, organic layer anhydrous slufuric acid Sodium dries, filters, and decompression spins off solvent, and column chromatographs (petroleum ether: ethyl acetate=5:1) and obtains crude product 170mg.
The synthesis of step 2:9- (4- trifluoromethyl) benzyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 9- (4- trifluoromethyl) benzyl -9H- carbazole -3- methyl formate (170mg, 0.44mmol), potassium hydroxide (73.92mg, 1.32mmol), water (1mL), ethyl alcohol adds to solid and is completely dissolved, and 90 DEG C of heating are anti- It answers 1 hour, TLC detection raw material has reacted, and 65 DEG C remove ethyl alcohol under reduced pressure, with the hydrochloric acid tune pH to 3 of 2N, there is solid precipitation, takes out Solid, ethyl acetate (5mL) dissolution are filtered to obtain, evaporating solvent under reduced pressure obtains solid product 79mg, yield 45.5%.MS-ESI(m/ Z): 370 [M+H]+
The synthesis of compound 9- (4- trifluoromethyl) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9- (4- trifluoromethyl) benzyl -9H- carbazole -3- formic acid (74mg, 0.2mmol), 2- are added into 25mL single port bottle (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (85.12mg, 0.224mmol), N, N- diisopropyl Base ethamine 10d, (4- (ethyl sulfone) phenyl) methylamine (44.576mg, 0.224mmol), methylene chloride (4mL) are stirred at room temperature Night.After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), organic phase washed with saturated sodium-chloride (3 × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1:2) Obtain solid 47mg, yield 43%.1H NMR(400MHz,CDCl3) δ 8.67 (s, 1H), 8.17 (d, J=8.0Hz, 1H), 7.92 (d, J=8.6Hz, 1H), 7.87 (d, J=8.0Hz, 2H), 7.58 (d, J=8.0Hz, 2H), 7.52 (d, J=8.5Hz, 2H), 7.48 (d, J=7.3Hz, 1H), 7.35 (d, J=8.5Hz, 2H), 7.32 (d, J=7.3Hz, 1H), 7.20 (d, J=7.9Hz, 2H), 6.78 (brs, 1H), 5.60 (s, 2H), 4.82 (d, J=5.6Hz, 2H), 3.10 (q, J=7.4Hz, 2H), 1.28 (t, J =7.4Hz, 3H)
Embodiment 30:9- (2- isopropoxy) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9-(2-isopropoxy)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide
The synthesis of step 1:2- (isopropoxy) benzyl alcohol
2-hydroxybenzyl alcohol (2g, 16.12mmol) is added into 50mL eggplant-shape bottle, ethyl alcohol (12mL), potassium carbonate (6.68g, 65 DEG C 48.39mmol) are heated to, bromo propane (2.86mL, 30.65mmol) is added after 10min, the reaction was continued, is condensed back to Stream, overnight.TLC (petroleum ether: ethyl acetate=3:1) monitoring, reacts completely.Suction filtered through kieselguhr, revolving, it is orange red to obtain crude product Oily liquids 2.78g.
The synthesis of step 2:2- (isopropoxy) benzyl bromine
2- (isopropoxy) benzyl alcohol (2.7mg, 16.27mmol) is added into 50mL eggplant-shape bottle, dichloro is added under ice bath Methane (20mL), phosphorus tribromide (1.16mL, 12.20mmol) add recession and remove ice bath, system lighter.After reacting 2h, TLC (petroleum ether: ethyl acetate=3:1) monitoring, fully reacting, saturated sodium bicarbonate solution are quenched to solution in colourless, dichloro Methane (3 × 10mL) extraction, saturated salt solution (3 × 40mL) are spin-dried for, and obtain crude product light orange oily liquids 4g.MS-ESI(m/ Z): 230 [M+H]+.
The synthesis of step 3:9- (2- isopropoxy) benzyl -9H- carbazole -3- methyl formate
9H- carbazole -3- methyl formate (50mg, 0.22mmol) is added into 25mL single port bottle, anhydrous N, N- dimethyl methyl Amide (3mL) ice bath stirring 5 minutes, is then added sodium hydride (26.4mg, 0.66mmol, 60%), reacts at room temperature 30 minutes, Then it is added dropwise to 2- (isopropoxy) benzyl bromine (151.14mg, 0.66mmol) under ice cooling, 4, reacts at room temperature 1 hour, TLC inspection Raw material is surveyed to have reacted.Add water quenching reaction, ethyl acetate (3 × 10mL) extraction, saturated sodium-chloride is washed, the anhydrous sulphur of organic layer Sour sodium dries, filters, and decompression spins off solvent, and column chromatographs (petroleum ether: ethyl acetate=5:1) and obtains colourless liquid 156.7mg.
The synthesis of step 4:9- (2- isopropoxy) benzyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 9- (2- isopropoxy) benzyl -9H- carbazole -3- methyl formate (156.7mg, 0.42mmol), potassium hydroxide (70.56mg, 1.26mmol), water (1mL), ethyl alcohol adds to solid and is completely dissolved, and 90 DEG C of heating are anti- It answers 1 hour, TLC detection raw material has reacted, and 65 DEG C remove ethyl alcohol under reduced pressure, with the hydrochloric acid tune pH to 3 of 2N, there is solid precipitation, takes out Solid, ethyl acetate dissolution are filtered to obtain, evaporating solvent under reduced pressure obtains solid product 188.4mg.MS-ESI (m/z): 360 [M+H]+.
The synthesis of compound 9- (2- isopropoxy) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
Into 25mL single port bottle be added 9- (2- isopropoxy) benzyl -9H- carbazole -3- formic acid (188.4mg, 0.525mmol), 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (223mg, 0.588mmol), n,N-diisopropylethylamine 20d, (4- (ethyl sulfone) phenyl) methylamine (117mg, 0.588mmol), methylene chloride (4mL), is stirred overnight at room temperature.After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), organic phase (3 × 5mL) is washed with saturated sodium-chloride, anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum Ether: ethyl acetate=1:2) obtain white solid 147.4mg, yield 51%.1H-NMR:(400MHz,CDCl3)δ8.53(s, 1H), 8.04 (d, J=6.9Hz, 1H), 7.48 (d, J=8.1Hz, 2H), 7.35 (s, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 6.81 (d, J=7.9Hz, 1H), 6.63 (s, 1H), 6.56 (t, J=7.4Hz, 1H), 6.47 (t, J=7.4Hz, 1H), 5.42 (s, 2H), 4.71 (s, 2H), 4.50-4.60 (m, 1H), 2.99 (q, J=7.4Hz, 2H), 1.24-1.28 (m, 6H), 1.16 (t, J=7.4Hz, 3H)
Embodiment 31:9- (3- isopropoxy) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9-(3-isopropoxy)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide
The synthesis of step 1:3- (isopropoxy) toluene
3- methylphenol (0.97mL, 9.26mmol) is added into 50mL eggplant-shape bottle, ethyl alcohol (12mL), potassium carbonate (3.83g, 27.78mmol) is heated to 60 DEG C, and bromo propane (1.65mL, 17.6mmol) is added after 10min, and the reaction was continued, It is condensed back, overnight.TLC (petroleum ether: ethyl acetate=9:1) monitoring, reacts, suction filtered through kieselguhr completely, and revolving obtains crude product Orange/red oil 1.36g.MS-ESI (m/z): 151 [M+H]+
The synthesis of step 2:3- (isopropoxy) benzyl bromine
In 50mL eggplant-shape bottle be added 3- (isopropoxy) toluene (500mg, 3.33mmol), be dissolved in 8mL carbon tetrachloride, first plus Enter azodiisobutyronitrile (119.7mg, 0.73mmol), then N-bromosuccinimide (712mg, 4mmol) is added portionwise, heats To 90 DEG C, it is condensed back.After reacting 6h, TLC (petroleum ether: ethyl acetate=2mL:1 drop) monitoring, fully reacting, diatomite pumping Filter, methylene chloride dissolved solid, 70 DEG C of revolvings obtain crude product pale yellowish oil liquid 1.046g.MS-ESI (m/z): 230 [M+ H]+.
The synthesis of step 3:9- (3- isopropoxy) benzyl -9H- carbazole -3- methyl formate
9H- carbazole -3- methyl formate (30mg, 0.13mmol) is added into 25mL single port bottle, anhydrous N, N- dimethyl methyl Amide (3mL) ice bath stirring 5 minutes, is then added sodium hydride (15.6mg, 0.39mmol, 60%), reacts at room temperature 30 minutes, Then it is added dropwise to 3- (isopropoxy) benzyl bromine (89.31mg, 0.39mmol) under ice cooling, 4, reacts at room temperature 1 hour, has reacted Finish.Add water quenching reaction, ethyl acetate (3 × 10mL) extraction, saturated sodium-chloride is washed, and organic layer is dry with anhydrous sodium sulfate, mistake Filter, decompression spin off solvent, obtain crude product 100mg.
The synthesis of step 6:9- (3- isopropoxy) benzyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 9- (3- isopropoxy) benzyl -9H- carbazole -3- methyl formate (100mg, 0.26mmol), potassium hydroxide (43.68mg, 0.78mmol), water (1mL), ethyl alcohol adds to solid and is completely dissolved, and 90 DEG C of heating are anti- It answers 1 hour, TLC detection raw material has reacted, and 65 DEG C remove ethyl alcohol under reduced pressure, with the hydrochloric acid tune pH to 3 of 2N, there is solid precipitation, takes out Solid, ethyl acetate (5mL) dissolution are filtered to obtain, evaporating solvent under reduced pressure obtains solid product 61mg, yield 65.4%.MS-ESI(m/ Z): 360 [M+H]+.
The synthesis of compound 9- (3 isopropoxy) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9- (3- isopropoxy) benzyl -9H- carbazole -3- formic acid (61mg, 0.17mmol), 2- are added into 25mL single port bottle (7- azoBenzotriazole)-N, N, N ', N '-TetramethylureaHexafluorophosphoric acid ester (72.2mg, 0.19mmol), N, N- diisopropyl Ethamine 20d, (4- (ethyl sulfone) phenyl) methylamine (37.81mg, 0.19mmol), methylene chloride (4mL) are stirred overnight at room temperature. After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), organic phase washed with saturated sodium-chloride (3 × 5mL), anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum ether: ethyl acetate=1:2) Obtain colourless oil liquid 45mg, yield 48%.1H-NMR:(400MHz, CDCl3) δ 8.70 (s, 1H), 8.11 (d, J= 7.6Hz, 1H), 7.94 (d, J=8.4Hz, 1H), 7.73 (d, J=7.9Hz, 2H), 7.47 (d, J=7.6Hz, 3H), 7.40 (s, 1H), 7.36 (t, J=7.6Hz, 2H), 7.16 (t, J=7.8Hz, 1H), 6.76 (d, J=8.0Hz, 1H), 6.66 (d, J= 7.4Hz, 1H), 6.64 (s, 1H), 5.45 (s, 2H), 4.74 (s, 2H), 3.06 (q, J=7.1Hz, 2H), 1.24 (d, J= 6.0Hz,9H).
Embodiment 32:9- (4- isopropoxy) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
9-(4-isopropoxy)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide
The synthesis of step 1:4- (isopropoxy) benzyl alcohol
4- salicylic alcohol (1g, 8mmol) is added into 50mL eggplant-shape bottle, ethyl alcohol (12mL), potassium carbonate (3.3g, 65 DEG C 24mmol) are heated to, bromo propane (1.43mL, 15.2mmol) is added after 10min, the reaction was continued, is condensed back, mistake Night.TLC (PE:EA=3:1) monitoring, reacts, suction filtered through kieselguhr completely, and revolving obtains crude product orange/red oil 1.34g. MS-ESI (m/z): 167 [M+H]+.
The synthesis of step 2:4- (isopropoxy) benzyl bromine
4- (isopropoxy) benzyl alcohol (500mg, 3mmol) is added into 50mL eggplant-shape bottle, methylene chloride is added under ice bath (6mL), phosphorus tribromide (0.2mL, 2.25mmol) add recession and remove ice bath, system lighter.After reacting 2h, TLC (PE:EA =3:1) monitoring, fully reacting.Saturated sodium bicarbonate solution is quenched to solution in colourless, suction filtered through kieselguhr, methylene chloride dissolution Solid, 70 DEG C of revolvings, obtains crude product light orange oily liquids 614.3mg, yield 89.4%.MS-ESI (m/z): 230 [M+H]+.
The synthesis of step 3:9- (4- isopropoxy) benzyl -9H- carbazole -3- methyl formate
9H- carbazole -3- methyl formate (50mg, 0.22mmol) is added into 25mL single port bottle, anhydrous N, N- dimethyl methyl Amide (3mL) ice bath stirring 5 minutes, is then added sodium hydride (26.4mg, 0.66mmol, 60%), reacts at room temperature 30 minutes, It is added dropwise to 4- (isopropoxy) benzyl bromine (151.14mg, 0.66mmol) under ice cooling, 4, reacts at room temperature 1 hour, TLC detection is former Material has reacted.Add water quenching reaction, ethyl acetate (3 × 10mL) extraction, saturated sodium-chloride is washed, organic layer anhydrous sodium sulfate It dries, filters, decompression spins off solvent, obtains crude product 188mg.
The synthesis of step 4:9- (4- isopropoxy) benzyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 9- (4- isopropoxy) benzyl -9H- carbazole -3- methyl formate (188mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol), water (1mL), ethyl alcohol adds to solid and is completely dissolved, and 90 DEG C of heating reactions 1 are small When, TLC detection raw material has reacted, and 65 DEG C remove ethyl alcohol under reduced pressure, with the hydrochloric acid tune pH to 3 of 2N, have solid precipitation, filter solid Body, ethyl acetate dissolution, evaporating solvent under reduced pressure obtain solid product 136.9mg, yield 76.3%.MS-ESI (m/z): 360 [M+ H]+.
The synthesis of compound 9- (4- isopropoxy) benzyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
Into 25mL single port bottle be added 9- (4- isopropoxy) benzyl -9H- carbazole -3- formic acid (136.9mg, 0.38mmol), 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (163.4mg, 0.43mmol), n,N-diisopropylethylamine 20d, (4- (ethyl sulfone) phenyl) methylamine (85.57mg, 0.43mmol), methylene chloride (4mL), is stirred overnight at room temperature.After reaction, decompression is spin-dried for reaction solution, is extracted with ethyl acetate (3 × 5mL), organic phase (3 × 5mL) is washed with saturated sodium-chloride, anhydrous sodium sulfate dries, filters, and decompression is spin-dried for obtaining crude product.Column chromatography for separation (petroleum Ether: ethyl acetate=1:2) obtain colourless oil liquid 118mg, yield 56%.1H-NMR:(400MHz,CDCl3)δ8.65(d,J =7.4Hz, 1H), 8.14 (t, J=7.7Hz, 1H), 7.91 (t, J=7.9Hz, 1H), 7.84 (t, J=8.0Hz, 2H), 7.56 (t, J=7.8Hz, 2H), 7.48 (d, J=7.4Hz, 1H), 7.41 (q, J=7.7Hz, 2H), 7.31 (t, J=7.3Hz, 1H), 7.04 (t, J=8.0Hz, 2H), 6.94 (d, J=6.2Hz, 1H), 6.76 (t, J=8.1Hz, 2H), 5.46 (d, J=7.6Hz, 2H), 4.42-4.50 (m, 1H), 3.08 (q, J=7.2Hz, 2H), 1.27 (d, J=6.1Hz, 9H)
Embodiment 33:9- ethyl-N- (4- (ethyl sulfone) benzyl) -6- (trifluoromethoxy) -9H- carbazole -3- amide
9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-(trifluoromethoxy)-9H- carbazole-3-carboxamide
The synthesis of step 1:4- ((4- Trifluoromethoxyphen-l) amino) methyl benzoate
4- trifluoro-methoxyaniline (2.3g, 13mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (3.44g, 16mmol), potassium carbonate (2.21g, 16mmol), rac-BINAP (405mg, 0.65mmol), palladium acetate (290mg, 1.3mmol), Toluene (10mL), 130 DEG C of heating of microwave are reacted 1 hour, and reaction is finished, and ethyl acetate (10mL) is added to dilute, diatomite filtering, decompression It is spin-dried for solvent, column chromatography for separation (petroleum ether: ethyl acetate=20:1-10:1) obtains purple solid product 870mg, yield 21.5%.1H NMR (400MHz, CDCl3) δ 7.93 (d, J=8.6Hz, 2H), 7.18 (d, J=1.8Hz, 4H), 6.99 (d, J= 8.7Hz, 2H), 3.88 (s, 3H) .MS-ESI (m/z): 312.1 [M+H]+step 2:6- trifluoromethoxy -9H- carbazole -3- formic acid The synthesis of methyl esters
Into 50mL single port bottle be added 4- ((4- Trifluoromethoxyphen-l) amino) methyl benzoate (550mg, 1.8mmol), palladium acetate (450mg, 2mmol), acetic acid (20mL), 120 DEG C of heating are reacted 2 hours, and reaction is finished, and decompression is spin-dried for second Acid, ethyl acetate (10mL) dissolution, column chromatography (petroleum ether: ethyl acetate=10:1) separate to obtain yellow solid product 330mg, produce Rate 60.4%.1H NMR (400MHz, CDCl3) δ 8.80 (s, 1H), 8.42 (s, 1H), 8.17 (d, J=8.4Hz, 1H), 7.98 (s, 1H), 7.48-7.43 (m, 2H), 7.34 (d, J=8.9Hz, 1H), 3.98 (d, J=1.4Hz, 3H) .MS-ESI (m/z): 310.1[M+H]+
The synthesis of step 3:6- trifluoromethoxy -9- ethyl -9H- carbazole -3- methyl formate
6- trifluoromethoxy -9H- carbazole -3- methyl formate (200mg, 0.65mmol) is added into 25mL single port bottle, nothing Ice bath stirring 5 minutes, sodium hydride (40mg, 1mmol, 60%) then is added, room temperature is anti-in water n,N-Dimethylformamide (5mL) It answers 30 minutes, is then added dropwise under ice bath bromoethane (110mg, 1mmol), reacted at room temperature 3 hours, it is anti-that TLC detects raw material It has answered.Add water quenching reaction, ethyl acetate (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, the anhydrous sulphur of organic layer Sour sodium dries, filters, and decompression is spin-dried for solvent, and column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtains yellow solid product 116mg, yield 53.2%.
The synthesis of step 4:6- trifluoromethoxy -9- ethyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 6- trifluoromethoxy -9- ethyl -9H- carbazole -3- methyl formate (116mg, 0.34mmol), lithium hydroxide (45mg, 1.07mmol), ethyl alcohol (5mL), water (1mL), 90 DEG C are reacted 2 hours, and TLC detects raw material It has been reacted that, with the hydrochloric acid tune pH to 3 of 2N, there is white solid precipitation, filtered, be dried in vacuo to obtain white solid product 102mg, produced Rate 91.8%.
The synthesis of compound 9- ethyl-N- (4- (ethyl sulfone) benzyl) -6- (trifluoromethoxy) -9H- carbazole -3- amide
6- trifluoromethoxy -9- ethyl -9H- carbazole -3- formic acid (102mg, 0.32mmol) is added into 25mL single port bottle, (4- (ethylsulfonyl) phenyl) methylamine (78mg, 0.39mmol), 2- (7- aoxidizes benzotriazole)-N, N, N ', N '-tetramethylurea Hexafluorophosphoric acid ester (150mg, 0.39mmol), n,N-diisopropylethylamine (124mg, 0.96mmol), methylene chloride (5mL), room Overnight, TLC detection raw material has reacted for temperature reaction.It is added methylene chloride (20mL), saturated ammonium chloride (30mL) washing, organic layer It is spin-dried for obtaining crude product, column chromatography for separation (petroleum ether: ethyl acetate=1:1-1:1.5) obtains white solid product 75mg, yield 47.1%.1H NMR (400MHz, CDCl3) δ 8.60 (s, 1H), 8.02 (d, J=8.8Hz, 1H), 7.98 (s, 1H), 7.86 (d, J =7.9Hz, 2H), 7.58 (d, J=7.9Hz, 2H), 7.47 (d, J=8.5Hz, 1H), 7.43 (d, J=8.6Hz, 1H), 7.39 (d, J=9.2Hz, 1H), 6.86 (s, 1H), 4.83 (d, J=6.1Hz, 2H), 4.44-4.37 (q, J=7.2Hz, 2H), 3.11 (q, J=7.4Hz, 2H), 1.46 (t, J=7.4Hz, 3H), 1.28 (t, J=8.4Hz, 3H) .MS-ESI (m/z): 505.1 [M+ H]+。
Embodiment 34:9- ethyl-N- (4- (ethyl sulfone) benzyl) -6- isopropoxy -9H- carbazole -3- amide
9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-isopropoxy-9H-carbazole-3- carboxamide
The synthesis of step 1:4-isopropoxy nitrobenzene
P-nitrophenol (1g, 7.2mmol) is added into 50mL single port bottle, 2- N-Propyl Bromide (1.33mg, 10.8mmol), carbon Sour potassium (1.49g, 10.8mmol), n,N-Dimethylformamide (10mL), 120 DEG C of heating are reacted 1 hour, and reaction is finished.Acetic acid second Ester (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, and organic layer anhydrous sodium sulfate dries, filters, and decompression is spin-dried for molten Agent, column chromatography for separation (petroleum ether: ethyl acetate=100:1-50:1) obtain solid product 1.2g, yield 96.2%.1H NMR (400MHz, CDCl3) δ 8.19 (dd, J=9.2,2.4Hz, 2H), 6.92 (dd, J=9.2,2.4Hz, 2H), 4.66 (d, J= 6.2Hz, 1H), 1.39 (dd, J=6.2,2.2Hz, 6H)
The synthesis of step 2:4- isopropoxy aniline
4-isopropoxy the nitrobenzenes (1.2g, 6.6mmol) of addition into 50mL single port bottle, two hydration dichloro stannous (4.5g, 20mmol), concentrated hydrochloric acid (0.5mL), ethyl alcohol (15mL), 60 DEG C of heating are reacted 10 hours, and reaction is finished.Ethyl acetate (3 × 20mL), Saturated sodium-chloride is washed, and organic layer anhydrous sodium sulfate dries, filters, and decompression is spin-dried for solvent, column chromatography for separation (petroleum ether: acetic acid second Ester=20:1) obtain solid product 670mg, yield 66.9%.
The synthesis of step 3:4- ((4- isopropyl phenyl) amino) methyl benzoate
4- isopropoxy aniline (670mg, 4.4mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (1.14g, 5.3mmol), potassium carbonate (730mg, 5.3mmol), rac-BINAP (137mg, 0.22mmol), palladium acetate (100mg, 0.44mmol), toluene (10mL), 130 DEG C of heating of microwave are reacted 1 hour, and reaction is finished, and ethyl acetate is added to dilute, diatomite filtering, Decompression is spin-dried for solvent, and column chromatography for separation (petroleum ether: ethyl acetate=20:1-10:1) obtains purple solid product 420mg, yield 33.2%.MS-ESI(m/z):286.2[M+H]+
The synthesis of step 4:6- isopropoxy -9H- carbazole -3- methyl formate
4- ((4- isopropyl phenyl) amino) methyl benzoate (420mg, 1.5mmol) is added into 50mL single port bottle, Palladium acetate (360mg, 1.6mmol), acetic acid (20mL), 120 DEG C of heating are reacted 3 hours, and reaction is finished, and decompression is spin-dried for acetic acid, acetic acid Ethyl ester (5mL) dissolution, column chromatography (petroleum ether: ethyl acetate=10:1) separate to obtain yellow solid product 170mg, yield 40.7%.1H NMR (400MHz, CDCl3) δ 8.76 (s, 1H), 8.25 (s, 1H), 8.10 (d, J=8.6Hz, 1H), 7.62 (s, 1H), 7.40 (d, J=8.6Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 7.08 (d, J=8.7Hz, 1H), 4.61 (d, J= 6.4Hz, 1H), 3.97 (s, 3H), 1.40 (d, J=6.1Hz, 6H) .MS-ESI (m/z): 284.2 [M+H]+
The synthesis of step 5:6- isopropoxy -9- ethyl -9H- carbazole -3- methyl formate
6- isopropoxy -9H- carbazole -3- methyl formate (170mg, 0.6mmol) is added into 25mL single port bottle, anhydrous N, Ice bath stirring 5 minutes, sodium hydride (72mg, 1.8mmol, 60%) then is added, room temperature reaction in dinethylformamide (5mL) It 30 minutes, is then added dropwise to bromoethane (196mg, 1.8mmol), reacts at room temperature 3 hours under ice bath, it is anti-that TLC detects raw material It has answered.Add water quenching reaction, ethyl acetate (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, the anhydrous sulphur of organic layer Sour sodium dries, filters, and decompression is spin-dried for solvent and obtains crude product 190mg, is directly used in and reacts in next step.
The synthesis of step 6:6- isopropoxy -9- ethyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 6- isopropoxy -9- ethyl -9H- carbazole -3- methyl formate (190mg, 0.6mmol), lithium hydroxide (76mg, 1.8mmol), ethyl alcohol (5mL), water (1mL), 90 DEG C are reacted 2 hours, and TLC has detected raw material It has been reacted that, with the hydrochloric acid tune pH to 3 of 2N, there is white solid precipitation, filtered, be dried in vacuo to obtain white solid product 164mg, two steps Yield 91.9%.MS-ESI(m/z):298.2[M+H]+.
The synthesis of compound 9- ethyl-N- (4- (ethyl sulfone) benzyl) -6- isopropoxy -9H- carbazole -3- amide
6- isopropoxy -9- ethyl -9H- carbazole -3- formic acid (164mg, 0.55mmol) is added into 25mL single port bottle, (4- (ethylsulfonyl) phenyl) methylamine (132mg, 0.66mmol), 2- (7- aoxidizes benzotriazole)-N, N, N ', N '-tetramethyl Urea hexafluorophosphoric acid ester (252mg, 0.66mmol), n,N-diisopropylethylamine (210mg, 1.65mmol), methylene chloride (5mL), Room temperature reaction 2 hours, TLC detection raw material have reacted.It is added methylene chloride (20mL), saturated ammonium chloride (30mL) washing has Machine layer is spin-dried for obtaining crude product, and column chromatography for separation (petroleum ether: ethyl acetate=1:1) obtains white solid product 200mg, yield 75.8%.1H NMR (400MHz, CDCl3) δ 8.58 (d, J=1.8Hz, 1H), 7.93 (dd, J=8.6,1.8Hz, 1H), 7.84 (d, J=8.1Hz, 2H), 7.63 (d, J=2.5Hz, 1H), 7.57 (d, J=8.0Hz, 2H), 7.38 (d, J=8.6Hz, 1H), 7.33 (d, J=8.8Hz, 1H), 6.92 (s, 1H), 4.80 (d, J=5.3Hz, 2H), 4.54-4.64 (m, 1H), 4.35 (q, J= 7.4Hz, 2H), 3.09 (q, J=7.4Hz, 2H), 1.43 (t, J=3.2Hz, 3H), 1.38 (d, J=5.9Hz, 6H), 1.4 (t, J =3.3Hz, 3H) .MS-ESI (m/z): 479.4 [M+H]+.
Embodiment 35:6- pentamethylene oxygroup 9- ethyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
6-cyclopentyloxy-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide
The synthesis of step 1:4-pentamethylene oxygroup nitrobenzene
P-nitrophenol (3g, 21.6mmol) is added into 50mL single port bottle, 1- bromine pentamethylene (4.82g, 32.3mmol), Potassium carbonate (4.47g, 32.3mmol), n,N-Dimethylformamide (10mL), 120 DEG C of heating are reacted 1 hour, and reaction is finished.Acetic acid Ethyl ester (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, and organic layer anhydrous sodium sulfate dries, filters, and decompression is spin-dried for Solvent, column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtain solid product 4.4g, yield 98.5%.1H NMR (400MHz, CDCl3) δ 8.22-8.13 (m, 2H), 6.91 (d, J=9.0Hz, 2H), 4.85 (dd, J=6.1,2.9Hz, 1H), 1.97–1.64(m,8H).
The synthesis of step 2:4- pentamethylene oxygroup aniline
4-cyclopentyloxy the nitrobenzenes (2g, 9.7mmol) of addition into 50mL single port bottle, two hydration dichloro stannous (6.5g, 29mmol), concentrated hydrochloric acid (0.5mL), ethyl alcohol (15mL), 60 DEG C of heating are reacted 5 hours, and reaction is finished.Ethyl acetate (3 × 20mL), Saturated sodium-chloride is washed, and organic layer anhydrous sodium sulfate dries, filters, and decompression is spin-dried for solvent, column chromatography for separation (petroleum ether: acetic acid second Ester=20:1) obtain solid product 1.6g, yield 62.5%.
The synthesis of step 3:4- ((4- pentamethylene phenyl) amino) methyl benzoate
4- isoamoxy aniline (1.6g, 9mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (2.32g, 10.8mmol), potassium carbonate (1.49g, 10.8mmol), rac-BINAP (280mg, 0.45mmol), palladium acetate (202mg, 0.9mmol), toluene (10mL), 130 DEG C of heating of microwave are reacted 1 hour, and reaction is finished, and ethyl acetate is added to dilute, diatomite filtering, Decompression is spin-dried for solvent, and column chromatography for separation (petroleum ether: ethyl acetate=20:1-10:1) obtains solid product 690mg, yield 24.6%.
The synthesis of step 4:6- pentamethylene oxygroup -9H- carbazole -3- methyl formate
Into 50mL single port bottle be added 4- ((4- pentamethylene phenyl) amino) methyl benzoate (690mg, 2.22mmol), palladium acetate (548mg, 2.44mmol), acetic acid (20mL), 120 DEG C of heating are reacted 3 hours, and reaction is finished, decompression rotation Dry acetic acid, ethyl acetate (10mL) dissolution, column chromatography (petroleum ether: ethyl acetate=3:1) separate to obtain solid product 330mg, produce Rate 48.1%.1H NMR (400MHz, CDCl3) δ 8.76 (s, 1H), 8.21 (s, 1H), 8.10 (d, J=8.5Hz, 1H), 7.58 (d, J=2.3Hz, 1H), 7.40 (d, J=8.6Hz, 1H), 7.34 (d, J=8.6Hz, 1H), 7.08-7.04 (m, 1H), 4.88 (s,1H),3.97(s,3H),2.09–1.83(m,8H).MS-ESI(m/z):310.2[M+H]+
The synthesis of step 5:6- pentamethylene oxygroup -9- ethyl -9H- carbazole -3- methyl formate
6- pentamethylene oxygroup -9H- carbazole -3- methyl formate (200mg, 0.65mmol) is added into 25mL single port bottle, nothing Ice bath stirring 5 minutes, sodium hydride (78mg, 1.95mmol, 60%) then is added, room temperature in water n,N-Dimethylformamide (5mL) Reaction 30 minutes, is then added dropwise under ice bath bromoethane (212mg, 1.95mmol), reacts at room temperature 3 hours, and TLC detects raw material It has reacted.Add water quenching reaction, ethyl acetate (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, organic layer without Aqueous sodium persulfate dries, filters, and decompression is spin-dried for solvent, and column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtains solid product 214mg, yield 98.0%.MS-ESI(m/z):338.4[M+H]+
The synthesis of step 6:6- pentamethylene oxygroup -9- ethyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 6- pentamethylene oxygroup -9- ethyl -9H- carbazole -3- methyl formate (214mg, 0.63mmol), lithium hydroxide (80mg, 1.9mmol), ethyl alcohol (5mL), water (1mL), 90 DEG C are reacted 2 hours, and TLC detects raw material It has been reacted that, with the hydrochloric acid tune pH to 3 of 2N, there is white solid precipitation, filtered, be dried in vacuo to obtain solid product 146mg, yield 71.2%.MS-ESI(m/z):324.3[M+H]+.
The conjunction of compound 6- pentamethylene oxygroup -9- ethyl-N- (4- (ethylsulfonyl) benzyl) -9H- carbazole -3- formamide At
6- pentamethylene oxygroup -9- ethyl -9H- carbazole -3- formic acid (146mg, 0.45mmol) is added into 25mL single port bottle, (4- (ethylsulfonyl) phenyl) methylamine (108mg, 0.54mmol), 2- (7- aoxidizes benzotriazole)-N, N, N ', N '-tetramethyl Urea hexafluorophosphoric acid ester (206mg, 0.54mmol), n,N-diisopropylethylamine (172mg, 1.35mmol), methylene chloride (5mL), Room temperature reaction 2 hours, TLC detection raw material have reacted.It is added methylene chloride (20mL), saturated ammonium chloride (30mL) washing has Machine layer is spin-dried for obtaining crude product, and column chromatography for separation (petroleum ether: ethyl acetate=1:1) obtains white solid product 200mg, yield 47.1%.1H NMR (400MHz, CDCl3) δ 8.59 (s, 1H), 7.89 (d, J=23.4Hz, 3H), 7.59 (s, 3H), 7.36 (dd, J=15.4,8.0Hz, 2H), 7.13 (d, J=8.4Hz, 1H), 6.83 (s, 1H), 4.86 (s, 1H), 4.82 (s, 2H), 4.36(s,2H),3.11(s,2H),2.08–1.77(m,8H),1.61(s,3H),1.43(s,3H).MS-ESI(m/z):505.3 [M+H]+。
Embodiment 36:6- dimethyl aminomethyl 9- ethyl-N- (4- (ethylsulfonyl) benzyl) -9H- carbazole -3- amide
6-((dimethylamino)methyl)-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H- carbazole-3-carboxamide
The synthesis of step 1:4- ((4- aminomethyl phenyl) amino) methyl benzoate
4- methylaniline (500mg, 4.7mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (1.2g, 5.6mmol), potassium carbonate (0.77g, 5.6mmol), rac-BINAP (143mg, 0.23mmol), palladium acetate (105mg, 0.47mmol), toluene (10mL), 130 DEG C of heating of microwave are reacted 1 hour, and reaction is finished, and ethyl acetate is added to dilute, diatomite filtering, Decompression is spin-dried for solvent, and column chromatography for separation (petroleum ether: ethyl acetate=20:1) obtains solid product 724mg, yield 64.3%.
The synthesis of step 2:6- methyl -9H- carbazole -3- methyl formate
4- ((4- aminomethyl phenyl) amino) methyl benzoate (724mg, 3.0mmol), acetic acid are added into 50mL single port bottle Palladium (740mg, 3.3mmol), acetic acid (20mL), 120 DEG C of heating are reacted 2 hours, and reaction is finished, and decompression is spin-dried for acetic acid, ethyl acetate (10mL) dissolution, column chromatography (petroleum ether: ethyl acetate=10:1) separate to obtain yellow solid product 610mg, yield 62.5%.
The synthesis of step 3:6- methyl -9- ethyl -9H- carbazole -3- methyl formate
6- methyl -9H- carbazole -3- methyl formate (610mg, 2.55mmol) is added into 25mL single port bottle, anhydrous N, N- Dimethylformamide (5mL) ice bath stirring 5 minutes, is then added NaH (152mg, 3.8mmol, 60%), reacts at room temperature 30 points Then clock is added dropwise to bromoethane (413mg, 3.8mmol) under ice bath, react at room temperature 3 hours, and TLC detection raw material has reacted. Add water quenching reaction, ethyl acetate (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, organic layer anhydrous sodium sulfate It drying, filtering, decompression is spin-dried for solvent, and column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtains yellow solid product 330mg, Yield 36.6%.
The synthesis of step 4:6- bromomethyl -9- ethyl -9H- carbazole -3- methyl formate
6- methyl -9- ethyl -9H- carbazole -3- methyl formate (220mg, 0.37mmol) is added into 25mL single port bottle, N- Bromosuccinimide (80mg, 0.45mmol), azodiisobutyronitrile (6mg, 0.04mmol), carbon tetrachloride (2mL), nitrogen are protected Shield, 90 DEG C are reacted 2 hours, and TLC detection raw material has reacted, and decompression is spin-dried for solvent and obtains crude product, is directly used in and reacts in next step.
The synthesis of step 5:6- dimethylamine methyl -9- ethyl -9H- carbazole -3- methyl formate
Into 25mL single port bottle be added 6- bromomethyl -9- ethyl -9H- carbazole -3- methyl formate (102mg, 0.32mmol), dimethylamine (78mg, 0.39mmol), methylene chloride (150mg, 0.39mmol)) room temperature reaction 2 hours, TLC inspection Raw material is surveyed to have reacted.Decompression is spin-dried for solvent and obtains crude product, is directly used in and reacts in next step.MS-ESI(m/z):311.4[M+H] +
The synthesis of step 6:6- dimethyl aminomethyl -9- ethyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 6- dimethylamine methyl -9- ethyl -9H- carbazole -3- methyl formate (200mg, 0.65mmol), potassium hydroxide (53mg, 1.26mmol), ethyl alcohol (5mL), water (2 drop), 90 DEG C are reacted 2 hours, and TLC detects raw material It has reacted.Decompression is spin-dried for solvent and obtains crude product, is directly used in and reacts in next step.MS-ESI(m/z):297.4[M+H]+
The synthesis of compound 6- dimethyl aminomethyl -9- ethyl-N- (4- (ethylsulfonyl) benzyl) -9H- carbazole -3- amide
6- dimethyl aminomethyl -9- ethyl -9H- carbazole -3- formic acid (100mg, 0.37mmol) is added into 25mL single port bottle, 4- ethyl sulfone benzene methanamine (89mg, 0.45mmol), HATU (171mg, 0.45mmol), n,N-diisopropylethylamine (143mg, 1.11mmol), methylene chloride (5mL), overnight, TLC detection raw material has reacted for room temperature reaction.It is added methylene chloride (20mL), Saturated ammonium chloride (30mL) washing, organic layer are spin-dried for obtaining crude product, column chromatography for separation (petroleum ether: ethyl acetate=1:1-1:2) Obtain white solid product 140mg, yield 83.8%.1H NMR (400MHz, CDCl3)δ8.67(s,1H),8.43(s,1H),8.11 (d, J=8.6Hz, 1H), 7.87 (d, J=7.7Hz, 2H), 7.70 (d, J=8.4Hz, 1H), 7.61 (d, J=7.9Hz, 2H), 7.48 (d, J=8.2Hz, 2H), 4.82 (s, 2H), 4.41 (d, J=7.5Hz, 2H), 4.33 (s, 2H), 3.13-3.08 (m, 2H), 2.78 (s, 6H), 1.47 (d, J=7.1Hz, 3H), 1.30 (d, J=8.1Hz, 3H)
Embodiment 37:6- hexamethylene alkoxy 9- ethyl-N- (4- (ethyl sulfone) benzyl) -9H- carbazole -3- amide
6-(cyclohexyloxy)-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3- carboxamide
The synthesis of step 1:4-hexamethylene alkoxyl nitrobenzene
1- hydroxycyclohexan (1.5g, 14.98mmol) is added into 50mL single port bottle, n,N-Dimethylformamide (20mL) ice bath stirring 5 minutes, is added sodium hydride (900mg, 22.46mmol, 60%) under ice bath, reacts at room temperature 30 minutes.Ice It is added dropwise under bath to fluoronitrobenzene (2.59g, 17.97mmol), is reacted at room temperature 3 hours, reaction is finished.Ethyl acetate (3 × 20mL), It washes (5 × 20mL), then saturated sodium-chloride is washed, organic layer anhydrous sodium sulfate dries, filters, and decompression is spin-dried for solvent, column chromatography point Red liquid product 1.8g, yield 54.3% are obtained from (petroleum ether: ethyl acetate=40:1).
The synthesis of step 2:4- hexamethylene alkoxyl aniline
4-cyclohexyloxy nitrobenzenes (570mg, 2.58mmol) are added into 25mL single port bottle, palladium carbon hydrogenation catalyst is dense Hydrochloric acid (5 drop), methanol (5mL) reacts at room temperature 1 hour, and reaction is finished.Filtering, decompression are spin-dried for solvent, obtain brown solid 264.5mg, yield 53.7% are directly used in and react in next step.
The synthesis of step 3:4- ((4- hexamethylene alkoxyl phenyl) amino) methyl benzoate
4- hexamethylene alkoxyl aniline (264.5mg, 1.38mmol) is added into 25mL microwave tube, 4- methyl-bromobenzoate (356.1mg, 1.66mmol), potassium carbonate (571.32mg, 4.14mmol), rac-BINAP (42.96mg, 0.069mmol), vinegar Sour palladium (15.49mg, 0.069mmol), toluene (10mL), 130 DEG C of heating of microwave are reacted 1 hour, and reaction is finished, and adds ethyl acetate dilute It releases, diatomite filtering, decompression is spin-dried for solvent, and column chromatography for separation (petroleum ether: ethyl acetate=20:1-10:1) obtains white solid and produces Object 254mg, yield 56.6%.MS-ESI(m/z):326.3[M+H]+.
The synthesis of step 4:6- hexamethylene alkoxy -9H- carbazole -3- methyl formate
Into 50mL single port bottle be added 4- ((4- hexamethylene alkoxyl phenyl) amino) methyl benzoate (117mg, 0.36mmol), palladium acetate (89mg, 0.40mmol), acetic acid (3mL), 120 DEG C of heating are reacted 9 hours, and reaction is finished, and decompression is spin-dried for Acetic acid, ethyl acetate (4mL) dissolution, column chromatography (petroleum ether: ethyl acetate=10:1) separate to obtain solid product 64mg, yield 54.7%.MS-ESI(m/z):324.2[M+H]+.
The synthesis of step 5:6- hexamethylene alkoxy -9- ethyl -9H- carbazole -3- methyl formate
6- hexamethylene alkoxy -9H- carbazole -3- methyl formate (62.1mg, 0.19mmol) is added into 25mL single port bottle, nothing Ice bath stirring 5 minutes, sodium hydride (23mg, 0.58mmol, 60%) then is added, room temperature in water n,N-Dimethylformamide (5mL) Reaction 30 minutes, is then added dropwise under ice bath iodoethane (90mg, 0.58mmol), reacts at room temperature 3 hours, and TLC detects raw material It has reacted.Add water quenching reaction, ethyl acetate (3 × 20mL) is washed (5 × 20mL), then saturated sodium-chloride is washed, organic layer without Aqueous sodium persulfate dries, filters, and decompression is spin-dried for solvent, and column chromatography for separation (petroleum ether: ethyl acetate=10:1) obtains solid product 55mg, yield 83.4%.
The synthesis of step 6:6- hexamethylene alkoxy -9- ethyl -9H- carbazole -3- formic acid
Into 25mL single port bottle be added 6- hexamethylene alkoxy -9- ethyl -9H- carbazole -3- methyl formate (55mg, 0.16mmol), potassium hydroxide (26.88mg, 0.48mmol), ethyl alcohol (4mL), water (1mL), 90 DEG C are reacted 2 hours, TLC detection Raw material has reacted, and with the hydrochloric acid tune pH to 3 of 2N, there is white solid precipitation, and filtering is dried in vacuo to obtain solid product 62.1mg. MS-ESI(m/z):338.4[M+H]+.
The conjunction of compound 6- hexamethylene alkoxy -9- ethyl-N- (4- (ethylsulfonyl) benzyl) -9H- carbazole -3- formamide At
6- hexamethylene alkoxy -9- ethyl -9H- carbazole -3- formic acid (55mg, 0.16mmol) is added into 25mL single port bottle, (4- (ethylsulfonyl) phenyl) methylamine (39mg, 0.20mmol), 2- (7- aoxidizes benzotriazole)-N, N, N ', N '-tetramethylurea Hexafluorophosphoric acid ester (74mg, 0.20mmol), n,N-diisopropylethylamine (23mg, 0.20mmol), methylene chloride (3mL), room temperature Reaction 2 hours, TLC detection raw material have reacted.It is added methylene chloride (20mL), saturated ammonium chloride (10mL) washing, organic layer It is spin-dried for obtaining crude product, column chromatography for separation (petroleum ether: ethyl acetate=1:1) obtains white solid product 26mg, yield 31.3% .MS-ESI(m/z):519。2[M+H]+.1H NMR(400MHz,CDCl3) δ 8.61 (s, 1H), 7.94 (d, J=8.5Hz, 1H), 7.74 (d, J=7.8Hz, 2H), 7.64 (s, 1H), 7.49 (d, J=7.8Hz, 2H), 7.33 (d, J=9.9Hz, 1H), 7.30 (d, J=9.9Hz, 1H), 7.25 (brs, 1H), 7.14 (d, J=8.5Hz, 1H), 4.75 (d, J=5.5Hz, 2H), 4.31 (q, J =7.2Hz, 2H), 4.31-4.22 (m, 1H), 3.06 (q, J=7.2Hz, 2H), 2.02 (s, 2H), 1.80 (s, 2H), 1.62- 1.52 (m, 3H), 1.41 (d, J=7.0Hz, 2H), 1.38 (d, J=7.0Hz, 2H), 1.35 (d, J=7.3Hz, 2H), 1.23 (t, J=7.4Hz, 3H)
Embodiment 38: inhibitory activity (FRET method) of the external test compound to ROR γ receptor:
Part of compounds of the invention is tested using fluorescence resonance energy transfer (FRET) to measure compound to ROR γ The inhibitory activity of protein receptor.The inhibitory activity uses half inhibiting rate (IC50) this index indicates.
Experimental method:
The preparation of 1.ROR γ basis buffer
Prepare 100mL basis buffer, 10mLDTT is added, is uniformly mixed spare.
2. the preparation of compound solution
Compound is that 7.5mM plays 3 times of dilutions, 10 concentration.
The preparation of 3 protein solution mixtures
A. the SA-APC solution for preparing B-ROR the γ LBD and 20nM of 40nM, is uniformly mixed, incubation at room temperature 15 minutes, then 400nM biotin is added, is uniformly mixed, is incubated at room temperature 10 minutes.
B. the SA-eu solution for preparing the Bioin-SRC1 and 10nM of 40nM, is uniformly mixed, incubation at room temperature 15 minutes, then 200nM biotin is added, is uniformly mixed, is incubated at room temperature 10 minutes.
C. above-mentioned two mixed solution 1:1 is mixed, is incubated at room temperature 5 minutes.
D. 0.1 μM of substitution agonist N- (the chloro- 6- fluorophenyl of 2-)-N- ((20- methoxyl group-is added in every hole in 384 orifice plates [1,10- xenyl] -4- replaces) methyl) benzsulfamide, 25 μ LB-ROR γ LBD/SA-APC and Bioin-SRC1/SA-eu are mixed Liquid and test-compound are closed, 1000rpm is centrifuged 1 minute, is incubated for 1 hour at room temperature.It is read on Envision micropore board detector Access evidence, calculates IC50Value.Measurement result is shown in Table one.
The ROR γ inhibitory activity measurement result of one embodiment compound of table
·IC50Value is the average value of independent experiment at least twice
+++ indicate IC50≤500nM；++ indicate 500nM < IC50≤5000nM；+ indicate IC50Range is 5000nM < IC50 ≤50000nM。
Experimental result: majority of compounds of the present invention has preferable inhibitory activity to ROR γ protein receptor.
Embodiment 39:Agonist activity (dual FRET method) of the external test compound to ROR γ receptor
Part of compounds of the invention is tested using fluorescence resonance energy transfer (dual FRET) to measure compound pair The agonist activity of ROR γ protein receptor.The agonist activity uses half activation rate (EC50) and maximum activation rate (%) index carry out table Show.
Experimental method:
The preparation of 1.ROR γ basis buffer
Prepare 100mL basis buffer, 10mL DTT is added, is uniformly mixed spare.
2. the preparation of compound solution
Compound is that 7.5mM plays 3 times of dilutions, 10 concentration.
3. the preparation of protein solution mixture
A. the SA-APC solution for preparing B-ROR the γ LBD and 20nM of 40nM, is uniformly mixed, incubation at room temperature 15 minutes, then 400nM biotin is added, is uniformly mixed, is incubated at room temperature 10 minutes.
B. the SA-eu solution for preparing the Bioin-SRC1 and 10nM of 40nM, is uniformly mixed, incubation at room temperature 15 minutes, then 200nM biotin is added, is uniformly mixed, is incubated at room temperature 10 minutes.
C. above-mentioned two mixed solution 1:1 is mixed, is incubated at room temperature 5 minutes.
D. in 384 orifice plates every hole be added 25 μ L B-ROR γ LBD/SA-APC and Bioin-SRC1/SA-eu mixed liquors and Test-compound, 1000rpm are centrifuged 1 minute, are incubated for 1 hour at room temperature.Data are read on Envision micropore board detector, Calculate EC50Value and maximum activation rate (%).Measurement result is shown in Table two.
The ROR γ agonist activity of two embodiment compound of table measures
+++ indicate EC50<10nM；++ indicate 10nM≤EC50<100nM；+ indicate 100nM≤EC50<5000nM.+++ table Show maximum activation rate (%) > 100；++ indicate maximum activation rate (%)≤100
Experimental result: the compound that the present invention tests has preferable exciting ability to ROR γ protein receptor.
Embodiment 40: external test compound is to EL4 cell IL-17 Inhibition test:
Experimental method: the mouse lymph lymphoma EL4 cell of ROR γ t plasmid will have been transfected in 37 DEG C, carbon dioxide content 5% It is cultivated under environment, while compound is added, the formation efficiency of 24 hours post analysis IL-17 α；PMA is added before collecting cell 50ng/mL, ionomycin 500ng/mL are stimulated 4 hours, with the ratio of the method for cell inner dyeing and flow cytometer detection IL-17 Example；Simultaneously with the method for Live/Dead Cell Dye (Invitrogen) dyeing, the survival rate of cell is analyzed, judges drug pair Whether cell is toxic, measures the inhibiting rate that compound generates IL-17 in various concentration to EL4 cell, calculates IC50Value.It surveys Surely three be the results are shown in Table.
The measurement of three EL4 cell IL-17 Inhibition test of table
+++ indicate 1 μM≤IC50<2μM；++ indicate 2 μM≤IC50<3μM；+ indicate IC50≥3μM。
Experimental result: part of compounds of the present invention has the preferable ability for inhibiting EL4 cell to generate IL-17.
Embodiment 41:Mouse Th17 cell differentiation measures single concentration point inhibiting rate experiment
Experimental method: separating mouse spleen CD4+T cell and by cell differentiation to Th17.CD4+T cell is in anti-CD3 (0.25 μ g/mL), anti-CD28 (1 μ g/mL), anti-IL4 (2 μ g/mL), anti-IFN- γ (2 μ g/mL), TGF-β (5ng/ ML), cultivated under IL6 (20ng/mL) environment, while the compound that concentration is 0.3 μM, the differentiation of 96 hours post analysis Th17 is added Efficiency.PMA 50ng/mL is added before collecting cell, ionomycin 500ng/mL is stimulated 4 hours, thin with cell inner dyeing and streaming The ratio of the method detection IL-17 of born of the same parents' instrument.The method that we use Live/Dead Cell Dye (Invitrogen) dyeing simultaneously, The survival rate for analyzing cell, judges whether drug is toxic to cell, and in the case where concentration is 0.3 μM, compound is thin to Th17 for measurement The inhibiting rate of born of the same parents' generation IL-17 ability.Measurement result shows that the compound of the present invention has preferable point for inhibiting Th17 cell The ability (as shown in Table 4) changed and IL-17 is inhibited to generate.
Four, mouse Th17 cell differentiation of table measures single concentration point inhibiting rate experimental result
+++ indicate inhibiting rate > 40%；++ indicate inhibiting rate between 20% to 40%；+ indicate inhibiting rate < 20%.
Experimental result: part of compounds of the present invention has the preferable ability for inhibiting Th17 cell to generate IL-17.
Embodiment 42:The experiment of Mouse Liver Microsomes metabolic stability
Incubation system includes microsome, confactor, PBS, and 37 DEG C incubate 3min in advance, and substrate starting reaction is added.It is reacting Start 0,1,5,10,15,20,30,60min sampling, the appropriate object that terminates is added and terminates reaction.Sample treatment (n=3): each adduction Internal standard is fitted, high speed centrifugation after vortex is taken supernatant, detected using HPLC-MS/MS to substrate.The time point peak 0min face Product is used as 100%.The peak area of other times is converted to percentage surplus, the natural logrithm of the percentage surplus at each time point It maps to incubation time, linear regression, which is asked, calculates slope (- k), then presses intrinsic clearance (CLint)=(k × incubation liquid Product)/hepatomicrosome quality, calculate CLint(mL·min-1·mg-1) and Compound half-life (T1/2, min).As a result it can be shown in Table Five.
Five, Mouse Liver Microsomes metabolic stability experimental result of table

Claims (16)

1. carbazole amide derivatives or its pharmaceutically acceptable salt shown in general formula I,
Wherein:
A indicates phenyl, heteroaryl, aliphatic heterocycle base or fatty naphthenic base；
B indicates phenyl or heteroaryl；
R1Optionally from hydrogen, halogen, cyano, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1-C6Alkane Base, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl, C3-C6The C that oxygen or azacycloalkyl replace1-C6Alkyl, C1-C6Alcoxyl The C that base, halogen replace1-C6Alkoxy, C3-C8The C that cycloalkyloxy, halogen replace3-C8Cycloalkyloxy, C3-C8Heterocyclylalkoxy groups, C1-C3The C that alkoxy replaces1-C3Alkyl, heterocycle, heterocyclic oxy group, C2-C6Alkenyl ,-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
R2Optionally from hydrogen, halogen, cyano, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1-C6Alkane Base, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl, C3-C6The C that oxygen or azacycloalkyl replace1-C6Alkyl, C1-C6Alcoxyl The C that base, halogen replace1-C6Alkoxy, C1-C3The C that alkoxy replaces1-C3Alkyl, C2-C6Alkenyl ,-(CH2)nOH、-C(O)Ra、- (CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
R3Selected from hydrogen, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1-C3Alkyl, C3-C6Oxygen or nitrogen The C that Heterocyclylalkyl replaces1-C3Alkyl, C3-C6Naphthenic base, C3-C6The C that oxygen or azacycloalkyl, phenyl replace1-C3Alkyl, substitution The C that phenyl replaces1-C3The C that alkyl, heteroaryl replace1-C3The C that alkyl, substituted heteroaryl replace1-C3Alkyl；
R4Selected from hydrogen, C1-C3The C that alkyl, halogen replace1-C3Alkyl, C3-C6The C that naphthenic base replaces1-C3Alkyl, C3-C6Oxygen or nitrogen The C that Heterocyclylalkyl replaces1-C3Alkyl, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl；
R5、R6It is each independently selected from hydrogen, hydroxyl, halogen, cyano, C1-C3Alkyl, hydroxyl or C1-C3The C that alkoxy replaces1-C3 The C that alkyl, halogen replace1-C3Alkyl, C1-C3The C that alkoxy, halogen replace1-C3Alkoxy, C3-C6Naphthenic base, C3-C6Oxygen or Azacycloalkyl, and R5、R6Also it can connect into C3-C6Ring；
R7Optionally from hydrogen, halogen, cyano, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1-C6Alkane Base, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl, C1-C6The C that alkoxy, halogen replace1-C6Alkoxy, C1-C3Alkoxy Substituted C1-C3Alkyl, heterocycle, heterocyclic oxy group, C2-C6Alkenyl ,-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
Y is selected from covalent bond ,-NRa-、-O-、-CRa1Ra2-、-C(O)NRa-；
R8Selected from hydroxyl, C1-C6The C that alkyl, halogen replace1-C6Alkyl, hydroxyl or C1-C3The C that alkoxy replaces1-C3Alkyl, C2- C6Alkenyl ,-(CH2)nNRa1Ra2、-NHC(O)CH3；
Z is selected from O, NRa；
Ra、Ra1、Ra2It is each independently selected from hydrogen, C1-C3The C that alkyl or halogen replace1-C3Alkyl；
M, r, t, n, s are each independently selected from any integer value in 0~2.
2. carbazole amide derivatives according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that Y is total Valence link.
3. -2 described in any item carbazole amide derivatives or its pharmaceutically acceptable salt according to claim 1, feature It is that s is 1.
4. carbazole amide derivatives according to claim 1-3 or its pharmaceutically acceptable salt, feature It is R6For hydrogen.
5. carbazole amide derivatives according to claim 1-4 or its pharmaceutically acceptable salt, feature It is that B is phenyl or hexa-atomic (or five yuan) heteroaryl.
6. carbazole amide derivatives according to claim 1-5 or its pharmaceutically acceptable salt, feature It is R4For hydrogen.
7. carbazole amide derivatives according to claim 1-6 or its pharmaceutically acceptable salt, feature It is that r is 0.
8. carbazole amide derivatives according to claim 1-7 or its pharmaceutically acceptable salt, feature It is that Z is O or NH.
9. carbazole amide derivatives according to claim 1-8 or its pharmaceutically acceptable salt, feature It is: R7Optionally from hydrogen, halogen, cyano, hydroxyl, C1-C6Alkyl.
10. -9 described in any item carbazole amide derivatives or its pharmaceutically acceptable salt according to claim 1, feature It is: R8Selected from C1-C3Alkyl ,-NHCH3、-NH2、-NHC(O)CH3。
11. -10 described in any item carbazole amide derivatives or its pharmaceutically acceptable salt according to claim 1, special Sign is, the carbazole amide derivatives or its pharmaceutically acceptable salt have the structure of general formula I-A:
Wherein:
A indicates phenyl, heteroaryl, aliphatic heterocycle base or fatty naphthenic base；
B indicates phenyl or hexa-atomic (or five yuan) heteroaryl；
R1Optionally from hydrogen, halogen, cyano, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1-C6Alkane Base, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl, C3-C6The C that oxygen or azacycloalkyl replace1-C6Alkyl, C1-C6Alcoxyl The C that base, halogen replace1-C6Alkoxy, C3-C8The C that cycloalkyloxy, halogen replace3-C8Cycloalkyloxy, C3-C8Heterocyclylalkoxy groups, C1-C3The C that alkoxy replaces1-C3Alkyl, heterocycle, heterocyclic oxy group, C2-C6Alkenyl ,-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
R3Selected from hydrogen, C1-C6The C that alkyl, halogen replace1-C6Alkyl, C3-C6The C that naphthenic base replaces1-C3Alkyl, C3-C6Oxygen or nitrogen The C that Heterocyclylalkyl replaces1-C3Alkyl, C3-C6Naphthenic base, C3-C6The C that oxygen or azacycloalkyl, phenyl replace1-C3Alkyl, substitution The C that phenyl replaces1-C3The C that alkyl, heteroaryl replace1-C3The C that alkyl, substituted heteroaryl replace1-C3Alkyl；
R5Selected from hydrogen, hydroxyl, halogen, cyano, C1-C3Alkyl, hydroxyl or C1-C3The C that alkoxy replaces1-C3Alkyl, halogen replace C1-C3Alkyl, C1-C3The C that alkoxy, halogen replace1-C3Alkoxy, C3-C6Naphthenic base, C3-C6Oxygen or azacycloalkyl；
R7Optionally from hydrogen, halogen, cyano, hydroxyl, C1-C6Alkyl；
R8Selected from C1-C3Alkyl ,-NHCH3、-NH2、-NHC(O)CH3；
Z is selected from O, NH；
Ra、Ra1、Ra2It is each independently selected from hydrogen, C1-C3The C that alkyl or halogen replace1-C3Alkyl；
M, n, t are each independently selected from any integer value in 0~2.
12. -11 described in any item carbazole amide derivatives or its pharmaceutically acceptable salt according to claim 1, special Sign is, is selected from following compound:
13. a kind of pharmaceutical composition as ROR γ t receptor modulators includes the chemical combination as described in claim any one of 1-12 Object or its pharmaceutically acceptable salt are as active ingredient and one or more pharmaceutically acceptable carriers.
14. compound or its pharmaceutically acceptable salt are in preparation ROR γ t regulation as described in claim any one of 1-12 Application in agent.
15. compound or its pharmaceutically acceptable salt are being prepared for treating or preventing as described in claim any one of 1-12 Purposes in the drug of disease relevant to ROR γ t receptor.
16. purposes as claimed in claim 15, it is characterised in that: the disease is selected from multiple sclerosis, rheumatoid arthrosis Inflammation, Collagen-induced Arthritis, psoriasis, inflammatory bowel disease, encephalomyelitis, clone's disease, asthma and various cancers etc..Cancer It is preferred that prostate cancer, melanoma, non-small cell lung cancer etc..
CN201810700432.1A 2017-07-01 2018-06-29 Carbazole amide derivative or salt thereof, and preparation method and application thereof Active CN109206360B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2017105292546 2017-07-01
CN201710529254 2017-07-01

Publications (2)

Publication Number Publication Date
CN109206360A true CN109206360A (en) 2019-01-15
CN109206360B CN109206360B (en) 2022-05-17

Family

ID=64949721

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810700432.1A Active CN109206360B (en) 2017-07-01 2018-06-29 Carbazole amide derivative or salt thereof, and preparation method and application thereof

Country Status (2)

Country Link
CN (1) CN109206360B (en)
WO (1) WO2019007284A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023232870A1 (en) 2022-05-31 2023-12-07 Immunic Ag Rorg/rorgt modulators for the treatment of virus infections like covid-19

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014773A1 (en) * 1992-12-21 1994-07-07 Smithkline Beecham Plc Tetrahydrocarbazole derivatives as 5-ht1-like agonists
CN105940002A (en) * 2014-02-03 2016-09-14 生命医药公司 Dihydropyrrolopyridine inhibitors of ROR-gamma
CN106061947A (en) * 2014-01-06 2016-10-26 百时美施贵宝公司 Cyclohexyl sulfone ror [gamma] modulators
CN106232582A (en) * 2014-04-16 2016-12-14 格兰马克药品股份有限公司 Aryl and heteroaryl ether compound as ROR gamma modulators

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014773A1 (en) * 1992-12-21 1994-07-07 Smithkline Beecham Plc Tetrahydrocarbazole derivatives as 5-ht1-like agonists
CN106061947A (en) * 2014-01-06 2016-10-26 百时美施贵宝公司 Cyclohexyl sulfone ror [gamma] modulators
CN105940002A (en) * 2014-02-03 2016-09-14 生命医药公司 Dihydropyrrolopyridine inhibitors of ROR-gamma
CN106232582A (en) * 2014-04-16 2016-12-14 格兰马克药品股份有限公司 Aryl and heteroaryl ether compound as ROR gamma modulators

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
YAFEI HUANG ET AL.: "Discovery of carbazole carboxamides as novel RORgt inverse agonists", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
来源：AURORA FINE CHEMICALS等提供的产品目录: "STN检索报告", 《数据库REGISTRY（在线）》 *

Also Published As

Publication number Publication date
WO2019007284A1 (en) 2019-01-10
CN109206360B (en) 2022-05-17

Similar Documents

Publication Publication Date Title
JP7026196B2 (en) RET inhibitor
CN106536503B (en) A kind of tyrosine kinase inhibitor and application thereof
WO2020177653A1 (en) Pyrazine derivative and application thereof in inhibiting shp2
CN110156786A (en) Pyrimido cycle compound and its preparation method and application
CN110016025A (en) A kind of immunomodulator
CN105612153B (en) Substituted heterocyclic sulfonamide compound as TRPA1 conditioning agents
TWI729047B (en) Inhibitors of bruton&#39;s tyrosine kinase and methods of their use
WO2016127074A1 (en) 2-(pyridin-3-yl)-pyrimidine derivatives as ret inhibitors
KR20160132041A (en) Azaspiro derivatives as trpm8 antagonists
CN113321654B (en) Fused pyridones as kinase inhibitors
CN111867585A (en) Oxadiazole transient receptor potential channel inhibitors
CN105524068A (en) Azabicyclo derivatives, preparation methods thereof, and pharmaceutical applications thereof
CN111032644A (en) Diarylthiohydantoin compounds useful as androgen receptor antagonists
CN110461838A (en) Oxadiazoles transient receptor potential channel inhibitor
CN108699006A (en) 3- ((miscellaneous -) aryl) -8- amino -2- oxo -1,3- aza-spiros-&amp;#91;4.5&amp;#93;Decane derivative
CN109476628A (en) Sulfonyl cyclic alkyl amides compound as TRPA1 regulator
WO2019137201A1 (en) Heteroarylo tetrahydropyridine compound and preparation method, pharmaceutical composition, and application thereof
CN105884695B (en) Heterocyclic derivatives species tyrosine kinase inhibitor
CN108863850B (en) Biaryl compound and preparation method and application thereof
CN108699005A (en) 3- (carboxy ethyl) -8- amino -2- oxo -1,3- aza-spiros-&amp;#91;4.5&amp;#93;Decane derivative
CN109476640B (en) Bicyclic proline compounds
CN109206346A (en) Tertiary amine analog derivative or its salt and its preparation method and application
CN109206360A (en) Carbazole amide derivatives or its salt and its preparation method and application
CN107176956B (en) A kind of IDO inhibitor compound, Pharmaceutical composition, purposes
CN110294742A (en) And ring class ASK1 inhibitor and its application

Legal Events

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