CN109836385A - Tetrahydro chinolines N- oxidized derivatives and its preparation method and application - Google Patents

Tetrahydro chinolines N- oxidized derivatives and its preparation method and application Download PDF

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CN109836385A
CN109836385A CN201910270614.4A CN201910270614A CN109836385A CN 109836385 A CN109836385 A CN 109836385A CN 201910270614 A CN201910270614 A CN 201910270614A CN 109836385 A CN109836385 A CN 109836385A
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alkyl
base
naphthenic base
atom
compound
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CN109836385B (en
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孙长安
张晓瑜
陈刚胜
宗书敏
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansen Biological Medicine Technology Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansen Biological Medicine Technology Co Ltd
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Abstract

The present invention relates to tetrahydro chinolines N- oxidized derivatives and its preparation method and application.Specifically, be related to logical formula (I) compound represented, preparation method and the pharmaceutical composition containing the compound, and its as BRD4 inhibitor the related diseases such as treating cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS purposes.

Description

Tetrahydro chinolines N- oxidized derivatives and its preparation method and application
Technical field
The invention belongs to field of medicaments, and in particular to BRD4 inhibitor, preparation method and application.
Background technique
Tumour is to seriously endanger one of the major disease of human life, more than half occurs in developing country.It dislikes in China Property tumor incidence it is totally in rising trend, disease incidence is with average annual 3%~5% speed increase, it is contemplated that arrive the year two thousand twenty, China will There is the raw cancer of 4,000,000 human hairs, 3,000,000 people die of cancer, the main reason is that: aging, urbanization, industrialization and living habit Change.In Chinese Hospitals medication market, the steady-state growth always in recent years of the marketing scale of anti-tumor drug reaches for 2012 664.2 hundred million yuan, increase by 13.07% on a year-on-year basis, it is contemplated that by 2017, the market scale of anti-tumor drug was up to 1055.7 hundred million Member increases by 7.57% on a year-on-year basis.
Since malignant tumour is without limitation growth and infiltration, transfer, clinical three big conventional treatments (hands used now Art, radiation and chemotherapy) tumour cell can not be cut off or thoroughly killed completely, therefore often there is the phenomenon that metastases or recurrence. Tumor biotherapy is the new treatment that treatment and prevention of tumour is carried out using modern biotechnology and its Related product, because of it safely, effectively, The features such as adverse reaction is low becomes the 4th kind of mode of the oncotherapy after operation, radiotherapy, chemotherapy, by transferring host Natural immunology defense or give the very strong substance of naturally-produced targeting to obtain antitumor effect.
Bromine structural proteins 4 (BRD4) are bromine structural domain and super end structure (bromodomain and extraterminal Domain, BET) family member, BRD4 by recruiting different transcription regulaton factor, as Mediator, positive transcriptional extend because Sub- b (positive transcription elongation factor b, P-TEFb) adjusts the expression of target gene.As " adapter, reader " can be identified during entire mitosis for a kind of chromatin of wide expression in mammals In the protein binding to chromosome of acetylation, different chromatin modification albumen are raised, the expression of extensive controlling gene, thus Cell cycle regulation process, transcription, inflammation etc. play a significant role.Recent studies have shown that the expression of BRD4 is lacked of proper care Or dysfunction and testis nucleoprotein center line cancer (midline carcinoma with rearrangement of the Nuclear protein intestis gene, NMC), melanoma, acute myeloid leukemia, colon cancer, breast cancer etc. Occur related.BRD4shRNA or BET inhibitor can induce above-mentioned tumorigenic cell Cycle Arrest, apoptosis and cell differentiation, Show powerful anti-tumor activity.These discoveries show that BET albumen is expected to become that above-mentioned tumour even other tumours are new to be controlled Treat target spot.In addition, by tool compound JQ1 etc. the study found that the inhibitor of BRD4 is in virus infection, diabetes, metabolic A variety of diseases such as disease, liver diseases and senile dementia may have wide utilization.
BRD4 inhibitor has a good application prospect as drug in pharmaceuticals industry, there is presently no the drug of listing, In order to achieve the purpose that better therapeutic effect and meet the market demand, it is therefore desirable to be able to develop the high-efficiency low-toxicity of a new generation Selective BRD4 inhibitor.
Summary of the invention
The purpose of the present invention is to provide a kind of logical formula (I) compound represented, its stereoisomer, deuterated derivative or Its pharmaceutically acceptable salt, the compound structure are as follows:
Wherein:
R1Selected from hydrogen atom, D-atom, alkyl, deuteroalkyl, halogenated alkyl, naphthenic base, heterocycle；
RXSelected from hydrogen atom, D-atom, alkyl, deuteroalkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, ammonia Base, naphthenic base, heterocycle, aryl, heteroaryl ,-(CH2)nS(O)mRaOr-(CH2)nNRaS(O)mRb；
RaAnd RbIt is identical or different, and be each independently selected from hydrogen atom, D-atom, alkyl, deuteroalkyl, halogenated alkyl, Alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, naphthenic base, heterocycle, aryl, heteroaryl；
Wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are optionally further selected from deuterium Atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino；
M is 0, an integer of 1 or 2；And
The integer that n and q is 0,1,2,3,4 or 5.
In a preferred embodiment of the present invention scheme, the logical formula (I) compound represented, its alloisomerism Body, deuterated derivative or its pharmaceutically acceptable salt, shown in the structure such as general formula (IA):
Wherein:
R3、RYAnd RZIt is identical or different, and be each independently selected from selected from hydrogen atom, D-atom, C1-8Alkyl, C1-8It is deuterated Alkyl, C1-8Halogenated alkyl, C1-8Alkoxy, C1-8Halogenated alkoxy, halogen, amino, C3-8Naphthenic base, 3-12 circle heterocyclic ring base, 6- 12 yuan of aryl or 5-12 unit's heteroaryl ,-(CH2)nS(O)mRaOr-(CH2)nNRaS(O)mRb；The wherein C1-8Alkyl, C1-8Halogen Substituted alkyl, C3-8Naphthenic base, 3-12 circle heterocyclic ring base, 6-12 member aryl and 5-12 unit's heteroaryl optionally further by selected from D-atom, C1-8Alkyl, C1-8Halogenated alkyl, halogen, amino, oxo base, nitro, cyano, hydroxyl, C1-8Alkoxy, C1-8Halogenated alkoxy, C1-8Hydroxyalkyl, C3-8One or more substituent groups in naphthenic base, 3-12 circle heterocyclic ring base, 6-12 member aryl and 5-12 unit's heteroaryl It is replaced；
m、n、Ra、RbAs defined in logical formula (I).
In a preferred embodiment of the present invention, the R1Selected from C1-8Alkyl or cycloalkyl, preferably 5-6 member ring Alkyl or C1-3Alkyl；
R3、RYAnd RZIt is identical or different, and it is each independently selected from hydrogen ,-NHS (O)2Rc、C1-8Alkyl, C1-8Naphthenic base, C1-8 Heterocycle, C1-8Aryloxy group, amino, wherein the C1-8Alkyl, C1-8Naphthenic base, C1-8Heterocycle, C1-8Aryloxy group, amino are appointed Choosing is further selected from C1-3Alkyl, C1-3Hydroxyl substituted alkyl group, halogen, replaced one or more substituent groups in hydroxyl；
RcSelected from C1-3Alkyl, wherein the alkyl is optionally further replaced halogen.
In further preferred embodiment of the present invention, the R1Selected from cyclohexyl, methyl or ethyl；
R3、RYIt is identical or different, and it is each independently selected from-NHS (O)2CH2CH3、-NHS(O)2CH2CF3、C1-3Hydroxyl takes Substituted alkyl, cyclohexyl oxygroup, phenoxy group, piperidyl amino, wherein the cyclohexyl oxygroup, phenoxy group, piperidyl amino, appoint Choosing is further selected from C1-3Alkyl, C1-3Hydroxyl substituted alkyl group, halogen, replaced one or more substituent groups in hydroxyl；
RZSelected from hydrogen, cyclopropyl or piperidyl.
In the embodiment of the present invention still more preferably, the C1-3Hydroxyl substituted alkyl group is-C (OH) (CH3)2；
C1-3Alkyl is selected from methyl or ethyl；
Halogen is selected from fluorine, chlorine or bromine.
In a preferred embodiment of the present invention scheme, the logical formula (I) compound represented, its alloisomerism Body, deuterated derivative or its officinal salt, shown in the compound structure such as general formula (IB):
Wherein:
RUAnd RVIt is identical or different, and it is each independently selected from hydrogen atom or C1-6Alkyl or RU、RVForm a ring, ring Selected from C3-6Naphthenic base or C5-6Heterocycle；
RUAnd RVIt is preferred that methyl, preferred cyclopropyl when cyclic；
RWSelected from hydrogen atom, halogen, C1-6Alkyl, C1-6Halogenated alkyl or C1-6Hydroxyalkyl, preferably hydrogen atom, halogen, C1-3 Alkyl, C1-3Halogenated alkyl or C1-3Hydroxyalkyl, such as-C (CH3)2OH。
The integer that t is 0,1,2,3,4 or 5；
R1Selected from hydrogen atom, D-atom, C1-3Alkyl, C5-6Naphthenic base, C5-6Heterocycle.
In a preferred embodiment of the present invention scheme, the logical formula (I) compound represented, its alloisomerism Body, deuterated derivative or its pharmaceutically acceptable salt, shown in the compound structure such as general formula (IC):
Wherein:
M is selected from NH, oxygen atom or-OCH2, preferred oxygen atom；
Ring B is selected from C3-6Naphthenic base, C3-6Heterocycle or C5-6First aryl；It is preferred that C5-6Naphthenic base, C5-6Heterocycle or phenyl, Wherein C5-6Heterocycle is replaced by 1-2 containing N, O or S atom.
RBSelected from hydrogen atom, halogen, C1-6Alkyl, C1-6Halogenated alkyl or C1-6Hydroxyalkyl, preferably hydrogen atom, halogen, C1-3 Alkyl, C1-3Halogenated alkyl or C1-3Hydroxyalkyl, more preferable hydrogen atom, fluorine atom, methyl, ethyl or-C (CH3)2OH；
Y is selected from key or NH；
R4Selected from C1-6Alkyl, C3-6Naphthenic base or amino, preferably C1-3Alkyl, C5-6Naphthenic base or amino, more preferable ethyl And cyclopropyl；
RZSelected from hydrogen atom, C1-8Alkyl, C1-8Hydroxyalkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base or 5-8 unit's heteroaryl；It is excellent Select C1-8Alkyl, C3-8Naphthenic base and hydrogen atom；
The integer that r is 0,1,2,3,4 or 5；
R1Selected from hydrogen atom, D-atom, C1-3Alkyl, C5-6Naphthenic base, C5-6Heterocycle.
In a preferred embodiment of the present invention scheme, the logical formula (I) compound represented, its alloisomerism Body, deuterated derivative or its pharmaceutically acceptable salt, shown in the compound structure such as general formula (ID):
Wherein:
R1Selected from hydrogen atom, D-atom, C1-3Alkyl, C5-6Naphthenic base, C5-6Heterocycle；
M is selected from NH, oxygen atom or-OCH2, preferred oxygen atom；
Ring B is selected from C3-6Naphthenic base, C3-6Heterocycle or C5-6First aryl；It is preferred that C5-6Naphthenic base, C5-6Heterocycle or phenyl, Wherein C5-6Heterocycle is replaced by 1-2 containing N, O or S atom.
RBSelected from hydrogen atom, halogen, C1-6Alkyl, C1-6Halogenated alkyl or C1-6Hydroxyalkyl, preferably hydrogen atom, halogen, C1-3 Alkyl, C1-3Halogenated alkyl or C1-3Hydroxyalkyl, more preferable hydrogen atom, fluorine atom, methyl, ethyl or-C (CH3)2OH；
R5Independently selected from key or SO2R6、NHSO2R6、COH R7R8；
R6Selected from C1-6Alkyl, C3-6Naphthenic base or amino, preferably C1-3Alkyl, C5-6Naphthenic base or amino, more preferable ethyl And cyclopropyl；
R7Or R8Independently selected from hydrogen atom or C1-6Alkyl or R7、R8A ring is formed, ring is selected from C3-6Naphthenic base or C5-6 Heterocycle；
R7And R8It is preferred that methyl, preferred cyclopropyl when cyclic；
RZSelected from hydrogen atom, C1-8Alkyl, C1-8Hydroxyalkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base or 5-8 unit's heteroaryl；It is excellent Select C1-3Alkyl, C3-6Naphthenic base or hydrogen atom；
The integer that r is 0,1,2,3,4 or 5.
In a preferred embodiment of the present invention scheme, shown in formula (I) compound, its stereoisomer, deuterated spread out Biology or its pharmaceutically acceptable salt are selected from following compound:
In a preferred embodiment of the present invention scheme, a kind of intermediate (ID) is provided, structure is as follows:
In a preferred embodiment of the present invention scheme, provides and lead to formula (I) compound, its solid shown in a kind of prepare The preparation method of isomers, deuterated derivative or its pharmaceutically acceptable salt:
Wherein:
General formula (ID) obtains logical formula (I) compound after oxidizing；The preferred metachloroperbenzoic acid of oxidant,
R1、RXWith q as defined in logical formula (I).
In a preferred embodiment of the present invention scheme, a kind of intermediate (IE) is provided, structure is as follows:
In a preferred embodiment of the present invention scheme, provide that general formula shown in a kind of prepare (IC) compound, it is vertical The preparation method of body isomers, deuterated derivative or its pharmaceutically acceptable salt:
Wherein:
General formula (IE) obtains general formula (IC) compound after oxidizing；The preferred metachloroperbenzoic acid of oxidant；R1 As described in claim 1, R4, ring B, RB, M, Y, r and RZAs defined in general formula (IC).
In a preferred embodiment of the present invention scheme, a kind of intermediate (IF) is provided, structure is as follows:
In a preferred embodiment of the present invention scheme, provide that general formula shown in a kind of prepare (IC) compound, it is vertical The preparation method of body isomers, deuterated derivative or its pharmaceutically acceptable salt:
Wherein:
General formula (IF) is by ROH or RNH2Substitution obtains general formula (IC) compound；And RNH2When reaction, the preferred N- methyl of solvent Pyrrolidones；When with ROH reaction, solvent and the preferred n,N-Dimethylformamide of reactant and sodium hydride；
X is halogen；
R1、R4, ring B, RB, r and RZAs defined in general formula (IC).
Another aspect of the present invention relates to a kind of pharmaceutical compositions, change shown in each general formula containing treatment effective dose Close object, its stereoisomer, deuterated derivative or pharmaceutical salt and one or more pharmaceutically acceptable carriers.
The invention further relates to logical formula (I) compound represented, its stereoisomer, deuterated derivative or its is pharmaceutically acceptable Salt, or comprising its pharmaceutical composition preparation for prevent and/or Prevention as BRD4 inhibitor in treating cancer, inflammation Disease, AIDS drug in purposes.It is different that BRD4 inhibitor can be used for treating cancer, inflammation, chronic liver disease, diabetes, blood lipid The cardiovascular diseases, the disease of AIDS such as normal, cancer (including T cell leukaemia and colon cancer), inflammation disease and autoimmunity Property disease.
The invention further relates to logical formula (I) compound represented, its stereoisomer, deuterated derivative or its is pharmaceutically acceptable Salt and pharmaceutical composition are preparing the application in BRD4 inhibitor medicaments.
The invention further relates to logical formula (I) compound represented, its stereoisomer, deuterated derivative or its is pharmaceutically acceptable Salt and pharmaceutical composition are in cardiovascular diseases and AIDS such as preparation treating cancer, inflammation, chronic liver disease, diabetes, dyslipidemias Drug in application.
The invention further relates to a kind of sides of the disease of Prevention and/or Prevention the BRD4 pathological characteristics mediated Method comprising logical formula (I) compound represented, its stereoisomer, deuterated derivative for the treatment of effective dose are applied to patient Or its officinal salt and its pharmaceutical composition.BRD4 inhibitor can be used for treating cancer, inflammation, the disease of AIDS, these diseases The infection of the disease virus such as including AIDS, cancer (including T cell leukaemia and colon cancer), inflammation disease and autoimmune disease Disease.
Another aspect of the present invention is related to a kind of method for the treatment of cancer, and this method includes applying treatment effective dose to patient Logical formula (I) of the invention described in compound, its stereoisomer, deuterated derivative or its officinal salt.This method is shown Curative effect outstanding and less side effect out.
Another aspect of the present invention is related to a kind of method for treating inflammation, and this method includes applying treatment effective dose to patient Logical formula (I) of the invention described in compound, its stereoisomer, deuterated derivative or its officinal salt.This method is shown Curative effect outstanding and less side effect out.
Another aspect of the present invention is related to a kind of method for treating chronic liver disease, and this method includes that treatment is applied to patient effectively Compound, its stereoisomer, deuterated derivative or its officinal salt described in the logical formula (I) of the invention of dosage.This method Show curative effect outstanding and less side effect.
Above-described cancer can be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, brain Cancer, liver cancer, solid tumor, glioma, spongioblastoma, leukaemia, lymthoma, myeloma and non-small cell lung cancer； The chronic liver disease is selected from: primary harden (PBC), the dirty property xanthomatosis (CTX) of brain, primary sclerosing cholangitis (PSC), Drug induced cholestasia, intrahepatic cholestasis of pregnancy, parenteral absorption associated cholestasis (PNAC), bacterial overgrowth Or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver disease (NASH), the anti-host disease of liver transfer operation related Graft, live donor liver transfer operation regenerate, first Nature liver fibrosis, choledocholithiasis, granular hepatopathy, malignant tumour in or beyond liver, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or α1Primary antibody membrane proteolytic enzyme deficiency disease.
Detailed description of the invention
Unless stated to the contrary, the term used in the specification and in the claims has following meanings.
Term " alkyl " refers to saturated aliphatic hydrocarbons group, is the linear chain or branched chain group comprising 1 to 20 carbon atom, excellent Select the alkyl containing 1 to 8 carbon atom, the alkyl of more preferable 1 to 6 carbon atom, the alkyl of most more preferable 1 to 3 carbon atom. Non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1, 1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, N-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- Dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- bis- Methyl butyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl amyl group, 2, 4- dimethyl amyl group, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- Dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- bis- Methylhexyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethyl penta Base, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl amyl group, positive decyl, 3,3- diethyl Base hexyl, 2,2- diethylhexyl and its various branched isomers etc..Alkyl can be it is substituted or non-substituted, when being taken Dai Shi, substituent group can be substituted on any workable tie point, and the substituent group is preferably one or more following bases Group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyanogen Base, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, carboxyl or carboxylate.
Term " alkylidene " refers to that a hydrogen atom of alkyl is further substituted, such as: " methylene " refers to-CH2, it is " sub- Ethyl " refers to-(CH2)2, " propylidene " refer to-(CH2)3, " butylidene " refer to-(CH2)4Etc..Term " alkenyl " refers to by least by two A carbon atom and at least one carbon-to-carbon double bond composition alkyl as defined above, such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..Alkenyl can be substituted or non-substituted, and when substituted, substituent group is preferably one or more A following group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, Nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane sulphur Base.
Term " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring include 3 to 20 carbon atoms, preferably comprise 3 to 12 carbon atoms, more preferably include 3 to 6 carbon atoms.Monocyclic cycloalkyl it is non-limiting Example includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl Trialkenyl, cyclooctyl etc.；Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring, preferably cyclopropyl, cyclobutyl, hexamethylene Base, cyclopenta and suberyl.
Term " spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle, It can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more Preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spirocyclanes according to the number for sharing spiro-atom between ring and ring Base or more spiro cycloalkyl groups, preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 Member/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.
Term " cycloalkyl " refers to 5 to 20 yuan, each ring in system and the shared a pair adjoined of other rings in system The full carbon polycyclic moiety of carbon atom, wherein one or more rings can be containing one or more double bonds, but none ring has The pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into according to a group cyclic number double Ring, tricyclic, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl.
Term " bridge ring alkyl " refers to 5 to 20 yuan, and the full carbon that any two ring shares two carbon atoms being not directly connected is more Cyclic group, can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, it is excellent It is selected as bicyclic, tricyclic or Fourth Ring, is more selected as bicyclic or tricyclic.
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure Ring together is naphthenic base, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Naphthenic base can be Optionally replacing or non-substituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkane Base, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, Aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl or carboxylate.
Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 rings Atom, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not wrap The loop section of-O-O- ,-O-S- or-S-S- are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 It is hetero atom；It more preferably include 3 to 8 annular atoms；Most preferably comprise 3 to 8 annular atoms.The non-limiting reality of monocyclic heterocycles base Example includes pyrrolidinyl, imidazolidinyl, tetrahydrofuran base, tetrahydro-thienyl, glyoxalidine base, dihydrofuryl, pyrazoline Base, pyrrolin base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base, pyranose etc., preferably tetrahydrofuran Base and pyranose.Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring.
Term " spiro heterocyclic radical " refers to the multiring heterocyclic that an atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle Group, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom For carbon.It can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 Member, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiro heterocyclic radical, double according to the number for sharing spiro-atom between ring and ring Spiro heterocyclic radical or more spiro heterocyclic radicals, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 Member/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.
Term " condensed hetero ring base " refers to 5 to 20 yuan, each ring in system and the shared a pair adjoined of other rings in system The polycyclic heterocyclic group of atom, one or more rings can be containing one or more double bonds, but none ring is with completely total The pi-electron system of yoke, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe miscellaneous original of (wherein m is integer 0 to 2) Son, remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to a group cyclic number can be divided into it is bicyclic, Tricyclic, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero rings Base.
Heterocycle can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, carboxyl or carboxylate.
Term " aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared The ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, such as phenyl and naphthalene.More preferable phenyl.The aryl rings can be with It condenses on heteroaryl, heterocycle or cycloalkyl ring, wherein be aryl rings with the ring that precursor structure links together, it is unrestricted Property example includes:
Aryl can be substituted or non-substituted, and when substituted, substituent group is preferably one or more following groups, It is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid Ester group.
Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom selects From oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan, more preferably 5- or 6-membered, such as imidazole radicals, furyl, thienyl, thiophene Oxazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridyl group, pyrimidine radicals, thiadiazoles, pyrazinyl etc., preferably imidazole radicals, Pyrazolyl or pyrimidine radicals, thiazolyl；More select pyrazolyl.The heteroaryl ring can be condensed in aryl, heterocycle or naphthenic base On ring, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting example includes:
Heteroaryl can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl Or carboxylate.
Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), and wherein alkyl is as defined above. The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, penta oxygen of ring Base, cyclohexyloxy.Alkoxy can be optionally replacing or non-substituted, and when substituted, substituent group is preferably one or more A following group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, Nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane sulphur Base, carboxyl or carboxylate.
Term " halogenated alkyl " refers to the alkyl replaced by one or more halogens, and wherein alkyl is as defined above.
Term " halogenated alkoxy " refers to the alkoxy replaced by one or more halogens, and wherein alkoxy is as defined above.
Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.
Term " hydroxyl " refers to-OH group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " amino " refers to-NH2。
Term " cyano " refers to-CN.
Term " nitro " refers to-NO2。
Term " oxo base " refers to=O.
Term " carboxyl " refers to-C (O) OH.
Term " carboxylate " refers to-C (O) O (alkyl) or-C (O) O (naphthenic base), and wherein alkyl is as defined above.
Term " carboxylic acid halides " refers to the compound containing-C (O)-halogen group.
The different terms such as " X is selected from A, B or C ", " X is selected from A, B and C ", " X A, B or C ", " X A, B and C " are expressed Identical meaning, i.e. expression X can be any one or a few in A, B, C.
Hydrogen atom of the present invention can be replaced its isotope deuterium, in embodiment compound of the present invention Any hydrogen atom also can be replaced by D-atom.
" optional " or " optionally " mean event or environment described later can with but need not occur, which includes The occasion that the event or environment occur or do not occur.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically/pharmaceutical salt or The mixture and other components such as physiology/pharmaceutical carrier and excipient of pro-drug and other chemical constituents.Medicine The purpose of compositions is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
" officinal salt " refers to the salt of the compounds of this invention, has safety when this kind of salt is used in the mammalian body and has Effect property, and there is due bioactivity.
The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention adopts the following technical scheme:
The following general formula compound represented of the present invention, the system of its stereoisomer, deuterated derivative or its pharmaceutical salt Preparation Method, comprising the following steps:
Scheme one
It is that raw material obtains target general formula (A) compound through multistep reaction with general formula (A-1)；Wherein:
X、X1And X2It is identical or different, it is independently selected from halogen, preferably fluorine and bromine；
R4、RB, r definition defines such as general formula (IC).
Scheme two
It is that raw material obtains target general formula (B) compound through multistep reaction with general formula (B-1)；
Wherein:
X3And X4It is identical or different, it is independently selected from halogen, preferably fluorine and bromine；
R4、RB, r definition as described in general formula (IC).
Scheme three
It is that raw material obtains target general formula (C) compound through multistep reaction with general formula (C-1)；
Wherein:
X5、X6It is identical or different, it is independently selected from halogen, preferably fluorine and bromine.
Scheme four
It is that raw material obtains target general formula (D) compound through multistep reaction with general formula (D-1)；
Wherein:
X7And X8It is identical or different, it is independently selected from halogen, preferably fluorine and bromine；
RzDefinition is as described in general formula (IC).
Specific embodiment
The present invention is further described with reference to embodiments, but these embodiments not limit the scope of the present invention.
Embodiment
The structure of compound is by nuclear magnetic resonance (NMR) or mass spectrum (MS) come what is determined.The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, measurement solvent are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), it is inside designated as tetramethylsilane (TMS), chemical shift is with 10-6(ppm) it is provided as unit.
The measurement of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX)。
The measurement of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 × 4.6mm chromatography Column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini 150 × 4.6mm of C18 chromatographic column).
Kinases average inhibition and IC50The measurement of value is with NovoStar microplate reader (German BMG company).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.2mm, thin-layer chromatography isolate and purify product use specification be 0.4mm~ 0.5mm silica gel plate.
Column chromatography is generally carrier using 200~300 mesh silica gel of the Yantai Huanghai Sea.
Known starting material of the invention can be used or be synthesized according to methods known in the art, or can purchase certainly ABCR GmbH&Co.KG, Acros Organnics, Aldrich Chemical Company, splendid remote chemical science and technology (Accela ChemBio Inc), up to the companies such as auspicious chemicals.
In embodiment unless otherwise specified, reaction carries out under argon atmospher or nitrogen atmosphere.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects the argon gas or nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Parr 3916EKX type hydrogenation instrument and clear indigo plant QL-500 type hydrogen generator or HC2-SS Type hydrogenates instrument.
Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.
Microwave reaction uses 908860 type microwave reactor of CEM Discover-S.
In embodiment unless otherwise specified, the solution in reaction refers to aqueous solution.
In embodiment unless otherwise specified, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, and temperature range is 20 DEG C~30 DEG C.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), reacts the system of used solvent Have: A: methylene chloride and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, The volume ratio of solvent is different according to the polarity of compound and is adjusted.
The system of the solvent of the system and thin-layered chromatography of the eluant, eluent for the column chromatography that purifying compound uses includes: A: Methylene chloride and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, ethyl acetate and dichloromethane system, D: Petroleum ether and ethyl acetate system, E: the volume ratio of ethyl acetate, solvent is different according to the polarity of compound and is adjusted, A small amount of triethylamine and acid or alkaline reagent etc. can be added to be adjusted.
Intermediate one
N- (4- (2,4 difluorobenzene oxygroup) -3- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) phenyl) second Sulfonamide
Step 1: the preparation of the bromo- 1- of 2- (2,4 difluorobenzene oxygroup) -4- nitrobenzene
The fluoro- 4- nitrobenzene (14g, 107.7mmol) of the bromo- 1- of 2-, 2,4- difluorophenol (19.6g, 89.7mmol) are dissolved in In DMSO (100mL), cesium carbonate (35g, 17.7mmol) is added at room temperature, is then stirred 2 hours at 110 DEG C.In reaction solution It is added water (150mL), is then extracted with ethyl acetate (200mL*1), organic phase washes (100mL*1) with saturated common salt, anhydrous Sodium sulphate is dry, is then concentrated to give the bromo- 1- of 2- (2,4- difluoro phenoxy group) -4- nitrobenzene (32g, 86.16mmol, molar yield 84%).
Step 2: the preparation of the bromo- 4- of 3- (2,4 difluorobenzene oxygroup) aniline
The bromo- 1- of 2- (2,4- difluoro phenoxy group) -4- nitrobenzene (29g, 88.4mmol) is dissolved in ethyl alcohol (160mL), tetrahydro Iron powder (24.7g, 442mmol), ammonium chloride (9.45g, 176.8mmol) is added in furans (160mL), water (56mL).It is warming up to It 100 DEG C, stirs 1.5 hours, is filtered through diatomite, filtrate removes solvent, methylene chloride (250mL) extraction is added, by organic phase Filtrate decompression removing methylene chloride after drying, filtering obtains the bromo- 4- phenoxybenzamine of 3- (22.0g, 73.37mmol, mole receipts Rate 83%).
MS m/z(ESI):300.1[M+H]+。
Step 3: the preparation of N- (the bromo- 4- of 3- (2,4 difluorobenzene oxygroup) phenyl) ethyl sulfonamide
The bromo- 4- phenoxybenzamine (10g, 33.44mmol) of 3- is dissolved in addition second sulphonyl under methylene chloride (80mL) ice bath Chlorine (5.52g, 43.48mmol), pyridine (5.28g, 66.88mmol), are stirred overnight at room temperature, organic phase hydrochloric acid (2M, 100mL* 2) it washes, water (100mL*2) is washed, and saturated salt solution (100mL) is washed, and anhydrous sodium sulfate is dry, and concentration rear pillar chromatographs (petroleum ether: second Acetoacetic ester=5:1) obtain compound N-(the bromo- 4- of 3- (2,4 difluorobenzene oxygroup) phenyl) ethyl sulfonamide (10.7g, 27.42mmol, molar yield 82%).
MS m/z(ESI):392.1.1[M+H]+。
Step 4: N- (4- (2,4 difluorobenzene oxygroup) -3- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) Phenyl) ethyl sulfonamide preparation
By N- (the bromo- 4- of 3- (2,4- difluoro phenoxy group) phenyl) ethyl sulfonamide (500mg, 1.28mmol), 4,4,4', 4', 5,5,5', 5'- prestox -2,2'- connection (1,3,2- bis- dislikes penta ring of boron) (648mg, 2.55mmol), 1,3,5,7- tetramethyl -6- Phenyl -2,4,8- trioxa -6- phosphinylidyne adamantane (37mg, 0.128mmol), tris(dibenzylideneacetone) dipalladium (35mg, 0.038mmol) and potassium acetate (275mg, 2.82mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (20mL).Reaction solution is at 80 DEG C of nitrogen protection Under, it reacts 12 hours, is then reacted 5 hours at 105 DEG C.Reaction solution is evaporated, crude product post separation (petroleum ether: ethyl acetate =5:1) obtain N- (4- (2,4 difluorobenzene oxygroup) phenyl) ethyl sulfonamide and N- (4- (2,4 difluorobenzene oxygroup) -3- (4,4,5, 5- tetramethyl -1,3,2- bis- dislike penta ring -2- base of boron) phenyl) and ethyl sulfonamide mixture (500mg), be directly used in next step.
MS m/z(ESI):440.1[M+H]+。
Intermediate two
2- methyl -4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -5,6,7,8- tetrahydroquinoline -3- sulphur Amine
Step 1: the preparation of the chloro- 5,6,7,8- tetrahydroquinoline -3- sulfonamide of 4-
By 1- (the chloro- 5,6,7,8- tetrahydroquinoline -3- base of 4-) ethyl ketone under the conditions of 60-70 DEG C of temperature of agitating and heating (20.97g, 100mmol) and glacial acetic acid are mixed to get sulfonation stoste, and sulfur trioxide gas is passed through into sulfonation stoste and carries out sulfonation Reaction, is recovered under reduced pressure glacial acetic acid and obtains sulfonated products；The agitating and heating condition for being kept for 60-70 DEG C of temperature, by sulfonated products and two The mixing of chlorine sulfoxide carries out chlorination reaction, and remaining thionyl chloride is recovered under reduced pressure and obtains chloro- 5,6,7,8- tetrahydroquinoline -3- sulphonyl of 4- Chlorine；Obtained sulfonic acid chloride product is added in the ammonium hydroxide that mass concentration is about 20%, is reacted under conditions of about 50 DEG C of temperature 3h；The sodium hydroxide solution that mass concentration is about 40% is added after the reaction was completed and adjusts pH to 6.2-7, crystallisation by cooling obtains 4- Chloro- 5,6,7,8- tetrahydroquinoline -3- sulfonamide (20.56g, 83mmol, molar yield 83%).
MS m/z(ESI):247.7[M+H]+。
Step 2: the preparation of the chloro- 3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation of 4-
By the chloro- 5,6,7,8- tetrahydroquinoline -3- sulfonamide (20.56g, 83mmol) of 4- and Phosphotungstic Acid Supported by Activated Carbon Agent (2.0g) mixing, stirring are added hydrogen peroxide (3.4g, 100mmol), and control reaction temperature is reacted at 55 DEG C, stir After reaction 3 hours, it is cooled to room temperature, obtains the chloro- 3- sulfoamido -5,6 of 4- after isolating Phosphotungstic Acid Supported by Activated Carbon agent, Solid (17.14g, 65mmol, molar yield 78.31%) is collected by filtration in 7,8- tetrahydroquinoline 1- oxidized solids.
MS m/z(ESI):263.7[M+H]+
Step 3: the preparation of the chloro- 3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation of the bromo- 4- of 2-
Benzoyl bromide (28.6g, 144mmol) is slowly dropped to the chloro- 3- sulfoamido -5,6 of 4-, 7,8- tetrahydroquinoline 1- In tetrahydrofuran (75mL) solution for aoxidizing (17.14g, 65mmol), the time about 1 hour, temperature was maintained at 25~40 DEG C. After being added dropwise, react at room temperature 2 hours.Reaction solution is neutralized with saturated solution of sodium bicarbonate, ethyl acetate (25mL*2) extraction, will Organic phase merges, and uses Na2SO4It is concentrated after drying.Crude product obtains the bromo- 4- of 2- through post separation (ethyl acetate: petroleum ether=1:10) Chloro- 3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- aoxidize (15.92g, 48.75mmol, molar yield 75%)
MS m/z(ESI):326.6[M+H]+。
Step 4: the preparation of 4- chloro-2-methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide
By the chloro- 3- sulfoamido -5,6 of the bromo- 4- of 2-, 7,8- tetrahydroquinoline 1- oxidation (15.92g, 48.75mmol) is dissolved in four [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (1.46g, 2mmol) is added in hydrogen furans (150mL), replaces nitrogen, Zinc methide (50mL, 1M toluene solution) is added dropwise under condition of ice bath, 80 DEG C of reactions are heated to after being added dropwise overnight, LC/MS Detect fully reacting.Water (400mL) is added into reaction solution, is extracted with ethyl acetate (300mL*1), organic phase saturated common salt Water (300mL*1) washing, it is dry with anhydrous sodium sulfate, after concentration with silica gel column chromatogram separating purification (petroleum ether: ethyl acetate= 9:1) obtain 4- chloro-2-methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (9.76g, 37.29mmol, molar yield 70.0%).
MS m/z(ESI):261.7[M+H]+。
Step 5: 2- methyl -4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -5,6,7,8- tetrahydro quinoline The preparation of quinoline -3- sulfonamide
By 4- chloro-2-methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (9.76g, 37.29mmol), 4,4,4', 4', 5, 5,5', 5'- prestox -2,2'- connection (1,3,2- bis- dislikes penta ring of boron) (15.2g, 60mmol), palladium acetate (0.28g, 1.26mmol), [1,1'- xenyl] -3- base dicyclohexyl phosphine (0.876g, 2.5mmol), potassium acetate (18.4g, It 187.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (100mL), replaces nitrogen, be heated to 100 DEG C and be stirred overnight, LC/MS detection reaction Completely.Water (200mL) is added into reaction solution, is extracted with ethyl acetate (200mL*1), organic phase saturated salt solution (200mL*1) washing, it is dry with anhydrous sodium sulfate, after concentration with silica gel column chromatogram separating purification (petroleum ether: ethyl acetate= 10:1) obtain 2- methyl -4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -5,6,7,8- tetrahydroquinoline -3- sulphur Amide (9.68g, 27.41mmol, yield 73.5%).
MS m/z(ESI):353.2[M+H]+。
Embodiment one
4- (2- (2,4 difluorobenzene oxygroup) -5- (second sulfophenyl) phenyl) -2- methyl -3- sulfoamido -5,6,7,8- four Hydrogen quinoline 1- oxidation
Step 1: 2,6- dimethyl -4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -5,6,7,8- four The preparation of hydrogen quinoline -3- sulfonamide
By the bromo- 2- methyl -5,6 of 4-, 7,8- tetrahydroquinoline -3- sulfonamide (3.062g, 10.0mmol), 4,4,4', 4', 5, 5,5', 5'- prestox -2,2'- connection (1,3,2- bis- dislikes penta ring of boron) (3.2g, 12.9mmol), [1,1'- bis- (diphenylphosphinos) Ferrocene] palladium chloride (0.393g, 0.54mmol), potassium acetate (1.6g, 16.12mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (15mL) replaces nitrogen, is heated to 85 DEG C and is stirred overnight, and LC/MS detects fully reacting.Water (50mL) is added into reaction solution, It is extracted with ethyl acetate (60mL), organic phase is washed with saturated salt solution (50mL*2), dries, filters concentration with anhydrous sodium sulfate Obtain 2- methyl -4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -5,6,7,8- tetrahydroquinoline -3- sulfonamide (3.373g, 9.57mmol molar yield 95.7%).
MS m/z(ESI):352.1[M+H]+。
Step 2: the preparation of 4- (the fluoro- 5- nitrobenzophenone of 2-) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide
By 2- methyl -4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -5,6,7,8- tetrahydroquinoline -3- Sulfonamide (3.373g, 9.57mmol), the fluoro- 4- nitrobenzene (2.09g, 9.55mmol) of the bromo- 1- of 2-, [1,1'- bis- (diphenylphosphines Base) ferrocene] palladium chloride (0.12g, 0.16mmol), potassium carbonate (2.26g, 16.35mmol) is dissolved in Isosorbide-5-Nitrae-dioxane The mixed solvent of (32mL) and water (8mL) replace nitrogen, are heated to 100 DEG C and are stirred overnight, and LC/MS detects fully reacting.To anti- Addition water (50mL) in liquid is answered, is extracted with ethyl acetate (80mL), organic phase is washed with saturated salt solution (50mL), with anhydrous sulphur Sour sodium uses silica gel column chromatogram separating purification (petroleum ether: ethyl acetate=1:1) to obtain 4- (the fluoro- 5- nitro of 2- after drying, filtering concentration Phenyl) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (2.73g, 7.47mmol, molar yield 78%).
MS m/z(ESI):365.1[M+H]+。
Step 3: 4- (2- (2,4 difluorobenzene oxygroup) -5- nitrobenzophenone) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulphur The preparation of amide
By 4- (the fluoro- 5- nitrobenzophenone of 2-) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (2.73g, 7.47mmol) and 2,4- difluorophenol (1.7g, 13.0mmol) be dissolved in dimethyl sulfoxide (10mL), by potassium carbonate (2.7g, It 19.5mmol) is added in above-mentioned solution, is heated to 100 DEG C and stirs 1 hour.Into reaction solution plus ethyl acetate (80mL) is extracted, Organic phase is washed with saturated sodium carbonate (50mL*2) and saturated salt solution (50mL), is dried, filtered and is concentrated to give with anhydrous sodium sulfate 4- (2- (2,4 difluorobenzene oxygroup) -5- nitrobenzophenone) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (3.13g, 6.58mmol, molar yield 88.1%)
MS m/z(ESI):475.5[M+H]+。
Step 4: 4- (5- amino -2- (2,4 difluorobenzene oxygroup) phenyl) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulphur The preparation of amide
By 4- (2- (2,4 difluorobenzene oxygroup) -5- nitrobenzophenone) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (3.13g, 6.57mmol) is dissolved in the mixed solvent of tetrahydrofuran (20mL), ethyl alcohol (10mL) and water (10mL), by iron powder (2.52g, 45.0mmol) and ammonium chloride (2.40g, 45.0mmol) are added in above-mentioned solution, are heated to 100 DEG C and stir 1 hour. Filtering, filtrate are extracted with ethyl acetate (80mL), and organic phase is washed with saturated salt solution (50mL), dry with anhydrous sodium sulfate, Filtering and concentrating obtains 4- (5- amino -2- (2,4 difluorobenzene oxygroup) phenyl) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (2.33g, 5.21mmol, molar yield 79.3%)
MS m/z(ESI):446.5[M+H]+。
Step 5: 4- (2-(2,4 difluorobenzene oxygroup)-5- (second sulfophenyl) phenyl)-2- methyl-7- tetrahydroquinoline-3- sulphur The preparation of amide
At room temperature, by 4- (2,4- difluoro phenoxy group) -3- (2,6- lutidines -4- base) aniline 4- (5- amino -2- (2,4- difluoro phenoxy group) phenyl) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (2.33g, 5.21mmol) and pyridine (5mL) is dissolved in methylene chloride (30mL), and ethyl chloride (2.01g, 15.63mmol) is then added drop-wise to reaction system In, it is stirred overnight at room temperature.After reaction, ethyl acetate (100mL) is added, is washed with saturated sodium bicarbonate solution (150mL*3) It washs, saturated salt solution (100mL) washing, organic phase is dried, filtered with anhydrous sodium sulfate, the crude product silicon after filtrate is spin-dried for Glue prepares plate and isolates and purifies to obtain 4- (2-(2,4 difluorobenzene oxygroup)-5- (second sulfophenyl) phenyl)-2- methyl-7- tetrahydro quinoline Quinoline -3- sulfonamide (1.77g, 3.29mmol, molar yield 63.2%).
MS m/z(ESI):538.6[M+H]+.
Step 6: 4- (2- (2,4 difluorobenzene oxygroup)-5- (second sulfophenyl) phenyl) sulfonamide-5,6,7-2- methyl-3-, The preparation of 8- tetrahydroquinoline 1- oxidation
By 4- (2-(2,4 difluorobenzene oxygroup)-5- (second sulfophenyl) phenyl)-2- methyl-7- tetrahydroquinoline-3- sulfonamide (1.77g, 3.29mmol) is dissolved in tetrahydrofuran (30mL), is added metachloroperbenzoic acid (1.14g, 5.58mmol), room temperature is stirred It mixes 1 hour, LC/MS detects fully reacting.Ethyl acetate (100mL) is added into reaction solution, uses saturated sodium carbonate solution (100mL*2) washing, is then washed with saturated salt solution (100mL), dry with anhydrous sodium sulfate, prepares plate with silica gel after concentration It isolates and purifies (methylene chloride: methanol=10:1) and obtains 4- (2- (2,4 difluorobenzene oxygroup) -5- (second sulfophenyl) phenyl) -2- first Base -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- aoxidize (0.95g, 1.72mmol, molar yield 52.3%).
1H NMR(400MHz,CDCl3)δ:7.10(m,1H),6.98(m,1H),6.97(m,1H),6.95(m,1H),6.85 (m,1H),6.64(m,1H),4.0(s,1H),3.45(m,2H),2.91(s,3H),2.76(t,2H),2.55(t,2H),2.0 (s,1H),1.79(t,2H),1.79(t,2H),1.27(t,3H).
MS m/z(ESI):554.6[M+H]+。
Embodiment two
4- (2- (2,4 difluorobenzene oxygroup) -5- (second sulfophenyl) phenyl) -2- ethyl -3- sulfonamide -5,6,7,8- tetrahydro Quinoline 1- oxidation
With the bromo- 2- ethyl -5,6 of 4-, 7,8- tetrahydroquinoline -3- sulfonamide are starting material, and example one is applied in preparation step reference, Obtain 4- (2- (2,4 difluorobenzene oxygroup) -5- (second sulfophenyl) phenyl) -2- ethyl -3- sulfonamide -5,6,7,8- tetrahydroquinoline 1- It aoxidizes (1.21g, molar yield 50.2%).
1H NMR(400MHz,CDCl3)δ:7.10(m,1H),6.98(m,1H),6.97(m,1H),6.95(m,1H),6.85 (m,1H),6.64(m,1H),4.0(s,1H),3.45(m,2H),2.76(t,2H),2.59(m,2H),2.55(t,2H),2.0 (s,1H),1.79(t,2H),1.79(t,2H),1.27(t,3H),1.25(t,3H).
MS m/z(ESI):568.6[M+H]+。
Embodiment three
2- cyclohexyl-4- (2- (2,4 difluorobenzene oxygroup)-5- (ethyl sulfophenyl) phenyl) sulfoamido-5,6,7-3-, 8- tetrahydroquinoline 1- oxidation
With the bromo- 2- cyclohexyl -5,6 of 4-, 7,8- tetrahydroquinoline -3- sulfonamide are starting material, and example is applied in preparation step reference One, obtain 2- cyclohexyl -4- (2- (2,4- difluoro phenoxy group) -5- (ethyl sulfophenyl) phenyl) -3- sulfoamido -5,6,7,8- tetra- Hydrogen quinoline 1- aoxidizes (1.28g, molar yield 51.4%).
1H NMR(400MHz,CDCl3)δ:7.10(m,1H),6.98(m,1H),6.97(m,1H),6.95(m,1H),6.85 (m,1H),6.64(m,1H),4.0(s,1H),3.45(m,2H),2.76(t,2H),2.72(m,2H),2.55(t,2H),2.0 (s,1H),1.79(t,4H),1.86-1.61(m,4H),1.53-1.43(m,4H),1.49-1.47(m,2H).
MS m/z(ESI):622.7[M+H]+。
Example IV
2- cyclohexyl-4- (2- ((4- ethylcyclohexyl) oxygroup)-5- (ethanesulfonamide group) phenyl) sulfoamido-5-3-, 6,7,8- tetrahydroquinoline 1- oxidation
With the bromo- 2- cyclohexyl -5,6 of 4-, 7,8- tetrahydroquinoline -3- sulfonamide are starting material, are taken with 4- ethyl cyclohexanol Generation 2,4- difluorophenol, preparation step obtain 2- cyclohexyl -4- (2- ((4- ethylcyclohexyl) oxygroup) -5- (second referring to example one is applied Sulfoamido) phenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation (1.53g, molar yield 49.8%).
1H NMR(400MHz,CDCl3)δ:6.91(m,1H),6.80(m,1H),6.78(m,1H),4.0(s,1H),3.64 (m,1H),3.45(m,2H),2.76(t,2H),2.72(m,1H),2.55(t,2H),2.0(s,1H),1.95-1.70(m,4H), 1.86-1.61(m,4H),1.79(m,4H),1.53-1.43(m,4H),1.52-1.27(m,4H),1.49-1.47(m,2H), 1.43(m,1H),1.29(m,2H),1.27(t,3H),0.9(t,3H).
MS m/z(ESI):620.8[M+H]+。
Embodiment five
5,5,8,8-D-4- (2- (2,4- difluorophenyl oxygroup) -5- (ethyl sulfonamide base) phenyl) -3- sulfoamido -2- (methyl-d3) -5,6,7,8- tetrahydroquinoline 1- oxidation
Sodium hydride (7.2mg, 0.18mmol, 60%w/w) is added to 4- (2- (2,4- difluorophenyl oxygroup) -5- (ethyl Sulfoamido) phenyl) -2- methyl -3- sulfoamido -5,6, the deuterium of 7,8- tetrahydroquinoline 1- oxidation (49.91mg, 0.09mmol) For in methanol (1mL) solution.Reaction solution reacts 12 hours at 60 DEG C, adjusts pH with aqueous hydrochloric acid solution (1M) after being cooled to room temperature =5, after solvent is removed under reduced pressure, crude product uses the preparation (2- (2,4- difluorophenyl oxygroup)-of HPLC isolated 5,5,8,8-D-4- 5- (ethyl sulfonamide base) phenyl) -3- sulfoamido -2- (methyl-d3) -5,6,7,8- tetrahydroquinoline 1- oxidation (49.41mg, 0.06mmol, molar yield 69%).
1H NMR(400MHz,CDCl3)δ:7.10(m,1H),6.98(m,1H),6.97(m,1H),6.95(m,1H),6.85 (m,1H),6.64(m,1H),4.0(s,1H),3.45(m,2H),2.0(s,1H),1.6(s,4H),1.27(t,3H).
MS m/z(ESI):795.7[M+H]+。
Embodiment six
2- cyclohexyl -4- (2- (2,4 difluorobenzene oxygroup) -5- (2,2,2- trifluoromethyl sulfophenyl) phenyl) -3- sulfonamide Base -5,6,7,8- tetrahydroquinoline 1- oxidation
Step 1: 4- (2- (2,4 difluorobenzene oxygroup) -5- (trifluoroethyl sulfoamido) phenyl) -2- methyl -7- tetrahydro The preparation of quinoline -3- sulfonamide
With 4- (2,4 difluorobenzene oxygroup) -3- (2,6- lutidines -4- base) aniline 4- (5- amino -2- (2,4- difluoro Phenoxy group) phenyl) -2- methyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide are raw material, referring to the 5th step of example 1 is applied, with 2,2,2- Trifluoroethyl-sulfonic acid chloride replaces ethyl chloride to obtain 4- (2- (2,4 difluorobenzene oxygroup) -5- (trifluoroethyl sulfoamido) benzene Base) -2- methyl -7- tetrahydroquinoline -3- sulfonamide (86.7mg, molar yield 52.0%).
MS m/z(ESI):592.6[M+H]+。
Step 2: 4- (2- (2,4 difluorobenzene oxygroup) -5- (trifluoroethyl sulfoamido) phenyl) -2- methyl -7- tetrahydro The preparation of quinoline -3- sulfonamide 1- oxidation
With 4- (2- (2,4 difluorobenzene oxygroup) -5- (trifluoroethyl sulfoamido) phenyl) -2- methyl -7- tetrahydroquinoline - 3- sulfonamide is raw material, and reference applies example one, obtains 4- (2- (2,4- difluoro phenoxy group) -5- (trifluoroethyl sulfoamido) phenyl) - 2- methyl -7- tetrahydroquinoline -3- sulfonamide 1- aoxidizes (68.5mg, molar yield 53.6%).
1H NMR(400MHz,CDCl3)δ:7.10(m,1H),6.98(m,1H),6.97(m,1H),6.95(m,1H),6.85 (m,1H),6.64(m,1H),4.0(s,1H),3.93(s,2H),2.76(t,2H),2.72(m,1H),2.55(t,2H),2.0 (s,1H),1.86-1.61(m,4H),1.53-1.43(m,4H),1.49-1.47(m,2H),1.79(m,4H).
MS m/z(ESI):489.1[M+H]+。
Embodiment seven
2- cyclohexyl -4- (2- ((1- ethyl piperidine -4- base) amino) -5- (ethyl sulfonamide base) phenyl) -3- sulfonamide Base -5,6,7 8- tetrahydroquinoline 1- oxidation
Step 1: 2- cyclohexyl -4- (5- (ethyl sulfonamide base) -2- fluorophenyl) -5,6,7,8- tetrahydroquinoline -3- sulphonyl The preparation of amine
By N- (the bromo- 4- fluorophenyl of 3-) ethyl sulfonamide (0.8g, 2.84mmol), 2- cyclohexyl -4- (4,4,5,5- tetramethyls Base -1,3,2- bis- dislike penta ring -2- base of boron) -5,6,7,8- tetrahydroquinoline -3- sulfonamide (2.39g, 5.68mmol), [1,1'- is bis- (diphenylphosphino) ferrocene] palladium chloride (130mg, 0.18mmol), potassium carbonate (2.0g, 14.3mmol) is dissolved in Isosorbide-5-Nitrae-dioxy The in the mixed solvent of six rings (30mL) and water (10mL).Nitrogen is replaced, 80 DEG C is heated to and is stirred overnight, LC/MS detection has been reacted Entirely.Water (50mL) is added into reaction solution, is extracted with ethyl acetate (60mL), organic phase is washed with saturated salt solution (50mL*2) It washs, it is dry with anhydrous sodium sulfate, 2- hexamethylene is obtained with silica gel column chromatogram separating purification (petroleum ether: ethyl acetate=1:1) after concentration (0.95g, 1.92mmol's -5,6,7,8- tetrahydroquinoline -3- sulfonamide rub base -4- (5- (ethyl sulfonamide base) -2- fluorophenyl) That yield 67.6%).
MS m/z(ESI):496.6[M+H]+。
Step 2: 2- cyclohexyl -4- (5- (ethyl sulphonyl) -2- fluorophenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinolines The preparation of 1- oxidation
By 2- cyclohexyl -4- (5- (ethyl sulfonamide base) -2- fluorophenyl) -5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.95g, 1.92mmol) is dissolved in tetrahydrofuran (8mL), is added metachloroperbenzoic acid (0.50g, 2.88mmol), is stirred at room temperature 2 hours, LC/MS detected fully reacting.Ethyl acetate (50mL) is added into reaction solution, with saturated sodium carbonate solution (50mL*2) Washing, is then washed with saturated salt solution (50mL), dry with anhydrous sodium sulfate, prepares chromatographic separation and purification with silica gel after concentration (methylene chloride: methanol=10:1) 2- cyclohexyl -4- (5- (ethyl sulphonyl) -2- fluorophenyl) -3- sulfoamido -5,6,7,8- Tetrahydroquinoline 1- aoxidizes (0.72g, 1.41mmol, molar yield 73.2%).
MS m/z (ESI): 512.6 [M+H]+。
Step 3: 2- cyclohexyl -4- (2- ((1- ethyl piperidine -4- base) amino) -5- (ethyl sulfophenyl) phenyl) -3- sulphur The preparation of amide groups -5,6,7,8- tetrahydroquinoline 1- oxidation
By 2- cyclohexyl -4- (5- (ethyl sulphonyl) -2- fluorophenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxygen Change (0.72g, 1.41mmol) and 4- amino -1- ethyl piperidine (1.21g, 9.45mmol) is dissolved in N-Methyl pyrrolidone (10mL) is heated to 120 DEG C and is stirred overnight.Stop reaction, be cooled to room temperature, adds ethyl acetate (50mL) into reaction solution, have Machine is mutually washed with saturated salt solution (50mL), dry with anhydrous sodium sulfate, isolates and purifies (C18 with reversed-phase preparative chromatography after concentration Column, mobile phase (acetonitrile/water)) obtain 2- cyclohexyl -4- (2- ((1- ethyl piperidine -4- base) amino) -5- (ethyl sulfophenyl) benzene Base) -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation (0.31g, 0.50mmol, molar yield 35.7%).
1H NMR(400MHz,CDCl3)δ:6.67(m,1H),6.41(m,1H),6.37(m,1H),4.0(s,2H),3.45 (m,2H),3.01(m,2H),2.76(t,2H),2.72(m,1H),2.63(m,1H),2.55(t,2H),2.51-2.41(m, 4H),2.0(s,1H),1.86-1.61(m,4H),1.81-1.56(m,4H),1.79(m,4H),1.53-1.43(m,4H), 1.49-1.47(m,2H),1.27(t,3H),1.02(t,3H).
MS m/z(ESI):620.8[M+H]+。
Embodiment eight
2- cyclohexyl -4- (2- (2,4 difluorobenzene oxygroup) -5- (ethyl sulfonamide base) -4- (1H- pyrazol-1-yl) benzene Base) -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation
Step 1: the preparation of the iodo- 5- nitrobenzene of the bromo- 2- of 1- (2,4 difluorobenzene oxygroup) -4-
At room temperature, the iodo- 5- nitrobenzene (1.07g, 3.09mmol) of the fluoro- 4- of the bromo- 2- of 1- is dissolved in acetonitrile (20mL), so 2,4- difluorophenol (0.80g, 6.18mmol) and sodium carbonate (0.66g, 6.18mmol) are added in reaction solution afterwards, room temperature is stirred It mixes overnight.After reaction, reaction solution dilutes (40mL) with ethyl acetate, and organic phase is washed with saturated salt solution (10mL*2), Organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, and crude product uses column chromatography (pure petroleum ether is as mobile phase) and obtains 1- The bromo- 2- iodo- 5- nitrobenzene of (2,4- difluoro phenoxy group) -4- (0.53g, yellow solid, 1.16mmol, molar yield 37%).
Step 2: the preparation of 1- bromo- 4- cyclopropyl -2- (2,4 difluorobenzene oxygroup) -5- nitrobenzene
At room temperature, by the iodo- 5- nitrobenzene (0.53g, 1.16mmol) of the bromo- 2- of 1- (2,4- difluoro phenoxy group) -4-, cyclopropyl Boric acid (0.15g, 1.74mmol), potassium phosphate (0.49g, 2.32mol) and [1,1'- bis- (diphenylphosphino) ferrocene] dichloride Palladium (0.085g, 0.13mmol) is dissolved in anhydrous dioxane (10mL), and nitrogen is replaced three times, is heated to 90 DEG C, reaction 14 Hour.After reaction, reaction solution dilutes (30mL) with ethyl acetate, and diatomite filtering, diatomite is with ethyl acetate (20mL) Washing, organic phase wash (10mL*2) with saturated brine, and anhydrous sodium sulfate dries, filters, and is spin-dried for, and crude product uses column chromatography (pure petroleum ether is as mobile phase) obtains 1- bromo- 4- cyclopropyl -2- (2,4 difluorobenzene oxygroup) -5- nitrobenzene (0.35g, yellow Solid, 0.95mmol, molar yield 82%).
Step 3: the preparation of 5- bromo- 2- cyclopropyl -4- (2,4 difluorobenzene oxygroup) aniline
At room temperature, by the bromo- 4- cyclopropyl -2- of 1- (2,4- difluoro phenoxy group) -5- nitrobenzene (0.15g, 0.41mmol) and Two hydrations stannous chloride (0.26g, 1.13mol) are dissolved in ethyl alcohol (10mL) and water (0.5mL), are stirred at room temperature 14 hours.Instead After answering, ethyl alcohol is spin-dried under reduced pressure, be added into residue ice water (15mL) and sodium hydrate aqueous solution (2N, 15mL), water phase is extracted with ethyl acetate (15mL*3), merges organic phase, organic phase saturated common salt water washing (15mL*3), nothing Aqueous sodium persulfate dries, filters, and is spin-dried for, and crude product obtains the bromo- 2- cyclopropyl -4- of 5- with plate separation (PE:EA:V/V:1:1) is prepared (2,4- difluoro phenoxy group) aniline (0.08g, 0.24mmol, molar yield 58%).
MS m/z(ESI):340.0,342.0[M+H]+.
Step 4: the preparation of N- (5- bromo- 2- cyclopropyl -4- (2,4 difluorobenzene oxygroup) phenyl) ethyl sulfonamide
At room temperature, by the bromo- 2- cyclopropyl -4- of 5- (2,4- difluoro phenoxy group) aniline (0.08g, 0.24mmol) and pyridine (0.037g, 0.47mmol) is dissolved in methylene chloride (10mL), and then ethyl chloride (0.06g, 0.47mmol) is added dropwise Into reaction system, 50 DEG C are heated to, is reacted four hours.After reaction, methylene chloride is spin-dried for, crude product ethyl acetate (30mL) dissolution, organic phase are washed with saturated sodium bicarbonate solution (15mL*3), saturated common salt water washing (10mL*2), organic phase It is dried, filtered, is spin-dried for anhydrous sodium sulfate, crude product obtains N- (5- with plate separation (petroleum ether: ethyl acetate=3:1) is prepared Bromo- 2- cyclopropyl -4- (2,4- difluoro phenoxy group) phenyl) ethyl sulfonamide (0.07g, white solid, 0.16mmol, molar yield 70%).
MS m/z(ESI):432.0,434.0[M+H]+.
Step 5: 2- cyclohexyl -4- (4- cyclopropyl -2- (2,4 difluorobenzene oxygroup) -5- (ethyl sulfophenyl) phenyl) -5, The preparation of 6,7,8- tetrahydroquinoline -3- sulfonamide
At room temperature, by N- (the bromo- 2- cyclopropyl -4- of 5- (2,4- difluoro phenoxy group) phenyl) ethyl sulfonamide (0.06g, 0.14mmol), 2- cyclohexyl -4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -5,6,7,8- tetrahydroquinoline - 3- sulfonamide (0.042g, 0.28mmol), potassium carbonate (0.12g, 0.28mmol) and [bis- (diphenylphosphino) ferrocene of 1,1'-] Palladium chloride (0.01g, 0.014mmol) is dissolved in dioxane (4mL) and water (1mL), and nitrogen is replaced three times, is heated to It 100 DEG C, reacts four hours.After reaction, it is cooled to room temperature.Reaction solution is diluted with ethyl acetate (20mL), diatomite filtering, Diatomite is washed with ethyl acetate (20mL), merges organic phase, and organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, Filtering, is spin-dried for, and crude product obtains 2- cyclohexyl -4- (4- cyclopropyl -2- with plate separation (petroleum ether: ethyl acetate=3:1) is prepared (2,4 difluorobenzene oxygroup) -5- (ethyl sulfophenyl) phenyl) -5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.07g, faint yellow oil Shape object, 0.11mmol, molar yield 76.3%).
MS m/z(ESI):646.7[M+H]+.
Step 6: 2- cyclohexyl -4- (4- cyclopropyl -2- (2,4 difluorobenzene oxygroup) -5- (ethanesulfonamide group) phenyl) -5, The preparation of 6,7,8- tetrahydroquinoline -3- sulfonamide 1- oxidation
Under ice bath, by 2- cyclohexyl -4- (4- cyclopropyl -2- (2,4- difluoro phenoxy group) -5- (ethanesulfonamide group) phenyl) - 5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.07g, 0.11mmol) are dissolved in methylene chloride (5mL), then by m-chloro peroxide Benzoic acid (85%, 0.033g, 0.16mmol) is added in reaction solution, reacts half an hour.After reaction, reaction solution dichloro Methane (20mL) dilution, organic phase are washed (10mL*3) with saturated sodium bicarbonate solution, saturated common salt water washing (10mL*2), Organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, isolated 2- cyclohexyl -4- (the 4- ring of crude product reversed-phase preparative chromatography Propyl -2- (2,4 difluorobenzene oxygroup) -5- (ethanesulfonamide group) phenyl) -5,6,7,8- tetrahydroquinoline -3- sulfonamide 1- oxidation (0.038g, white solid, 0.057mmol, molar yield 51.6%).
1H NMR(400MHz,CDCl3)δ:7.10(m,1H),7.04(m,1H),6.97(m,1H),6.77(m,1H),6.64 (m,1H),4.0(s,1H),3.45(m,2H),2.76(t,2H),2.72(m,1H),2.55(t,2H),2.0(s,1H),1.86- 1.61(m,4H),1.79(m,4H),1.50(m,1H),1.53-1.43(m,4H),1.49-1.47(m,2H),1.27(t,3H), 1.24-0.99(m,4H).
MS m/z(ESI):662.8[M+H]+.
Embodiment nine
2- cyclohexyl -4- (2- (2,4 difluorobenzene oxygroup) -5- (ethanesulfonamide group) -4- (piperidin-4-yl) phenyl) -3- sulphur Amide groups -5,6,7,8- tetrahydroquinoline 1- oxidation
Step 1: tert-butyl 4- (the bromo- 5- of 4- (2,4 difluorobenzene oxygroup) -2- nitrobenzophenone) -3,6- dihydropyridine -1 The preparation of (2H)-carboxylate
At room temperature, by the iodo- 5- nitrobenzene (0.20g, 0.44mmol) of the bromo- 2- of 1- (2,4- difluoro phenoxy group) -4-, tert- fourth Base 4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -3,6- dihydropyridine -1 (2H)-carboxylate (0.16g, 0.53mmol), potassium phosphate (0.19g, 0.88mol) and [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (0.032g, It 0.044mmol) is dissolved in anhydrous dioxane (10mL), nitrogen is replaced three times, is heated to 90 DEG C, is reacted 14 hours.Reaction After, reaction solution dilutes (30mL) with ethyl acetate, and diatomite filtering, diatomite is washed (20mL) with ethyl acetate, organic Saturated common salt water washing (10mL*3) mutually is used, anhydrous sodium sulfate dries, filters, and is spin-dried for, and crude product uses column chromatography (petroleum Ether: ethyl acetate=3:1) obtain tert-butyl 4- (the bromo- 5- of 4- (2,4 difluorobenzene oxygroup) -2- nitrobenzophenone) -3,6- dihydro pyrrole Pyridine -1 (2H)-carboxylate (0.125g, faint yellow solid, 0.24mmol, molar yield 55.6%).
MS m/z(ESI):511.0,513.0。
Step 2: 4- (4- (1- (tertbutyloxycarbonyl) -1,2,3,6- tetrahydropyridine -4- base) -2- (2,4 difluorobenzene oxygen Base) -5- nitrobenzophenone) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide preparation
At room temperature, by tert-butyl 4- (the bromo- 5- of 4- (2,4- difluoro phenoxy group)) -2- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-carboxylate (0.12g, 0.23mmol), (4,4,5,5- tetramethyls -1,3,2- bis- dislike penta ring -2- of boron to 2- cyclohexyl -4- Base) -5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.071g, 0.47mmol), potassium carbonate (0.065g, 0.47mmol) and [1, Bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (0.017g, 0.023mmol) is dissolved in dioxane (6mL) and water In (2mL), nitrogen is replaced three times, is heated to 90 DEG C, is reacted 14 hours.After reaction, it is cooled to room temperature.Reaction solution second Acetoacetic ester (20mL) dilution, diatomite filtering, diatomite are washed (20mL) with ethyl acetate, use saturated common salt after merging organic phase Water washing (10mL*3), anhydrous sodium sulfate dries, filters, and is spin-dried for, crude product with prepare plate separation (petroleum ether: ethyl acetate= 1:1) obtain 4- (4- (1- (tertbutyloxycarbonyl) -1,2,3,6- tetrahydropyridine -4- base) -2- (2,4 difluorobenzene oxygroup) -5- nitro Phenyl) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.109g, colorless oil, 0.15mmol, molar yields 65.2%).
MS m/z(ESI):725.8[M+H]+.
Step 3: 4- (5- amino -4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2,4 difluorobenzene oxygroup) benzene Base) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide preparation
At room temperature, by 4- (4- (1- (tertbutyloxycarbonyl) -1,2,3,6- tetrahydropyridine -4- bases) -2- (2,4- difluorobenzene oxygen Base) -5- nitrobenzophenone) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.073g, 0.10mmol) are dissolved in tetrahydro In furans (5mL), then palladium carbon (0.010g) is added thereto, is stirred at room temperature under an atmosphere of hydrogen 14 hours.Reaction terminates Afterwards, filtering removal palladium carbon, is spin-dried for obtaining crude product 4- (5- amino -4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2,4- bis- Fluorophenoxy) phenyl) -2- cyclohexyl -5,6, (0.056g, crude product are directly used in next 7,8- tetrahydroquinoline -3- sulfonamide Step).
MS m/z(ESI):697.8[M+H]+.
Step 4: 4- (4- (1- (tertbutyloxycarbonyl) piperidin-4-yl) -2- (2,4 difluorobenzene oxygroup) -5- (ethyl sulfonamide Base) phenyl) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide preparation
At room temperature, by 4- (5- amino -4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2,4- difluoro phenoxy group) benzene Base) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.056g, 0.08mmol) and pyridine (0.026g, It 0.32mmol) is dissolved in methylene chloride (5mL), ethyl chloride (0.025g, 0.20mmol) is then added drop-wise to reactant In system, react at room temperature 14 hours.After reaction, reaction solution is diluted with methylene chloride (20mL), organic phase unsaturated carbonate Hydrogen sodium solution (15mL*3) washing, saturated common salt water washing (10mL*3), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, Crude product obtains 4- (4- (1- (tertbutyloxycarbonyl) piperidin-4-yl) -2- with plate separation (petroleum ether: ethyl acetate=1:1) is prepared (2,4 difluorobenzene oxygroup) -5- (ethanesulfonamide group) phenyl) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.029g, colorless oil, 0.037mmol, molar yield 46.8%).
MS m/z(ESI):789.9[M+H]+.
Step 5: 4- (4- (1- (tertbutyloxycarbonyl) piperidin-4-yl) -2- (2,4 difluorobenzene oxygroup) -5- (ethyl sulfonamide Base) phenyl) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide 1- oxidation preparation
At room temperature, by 4- (4- (1- (tertbutyloxycarbonyl) piperidin-4-yl) -2- (2,4- difluoro phenoxy group) -5- (second sulphonyl Amido) phenyl) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.029g, 0.037mmol) is dissolved in methylene chloride In (5mL), then metachloroperbenzoic acid (85%, 0.010g, 0.050mmol) is added in reaction solution, is reacted one hour. After reaction, reaction solution is diluted with methylene chloride (20mL), and organic phase washs (10mL*3) with saturated sodium bicarbonate solution, is satisfied With brine It (10mL*3), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, and crude product 4- (4- (1- (uncle is obtained Butoxy carbonyl) piperidin-4-yl) -2- (2,4 difluorobenzene oxygroup) -5- (ethanesulfonamide group) phenyl) -2- cyclohexyl -5,6,7,8- Tetrahydroquinoline -3- sulfonamide 1- aoxidizes (0.025g, 0.031mmol molar yield 83%).
MS m/z(ESI):805.9[M+H]+.
Step 6: 2- cyclohexyl -4- (2- (2,4 difluorobenzene oxygroup) -5- (ethanesulfonamide group) -4- (piperidyl -4- base) Phenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation preparation
Under ice bath, by 4- (4- (1- (tertbutyloxycarbonyl) piperidin-4-yl) -2- (2,4- difluoro phenoxy group) -5- (second sulphonyl Amido) phenyl) -2- cyclohexyl -5,6,7,8- tetrahydroquinoline -3- sulfonamide 1- oxidation (0.025g, 0.031mmol) be dissolved in two In chloromethanes (3mL), then trifluoroacetic acid (0.3mL) is added drop-wise in reaction system, is reacted at room temperature one hour.Reaction terminates Afterwards, methylene chloride is spin-dried for, crude product ethyl acetate dissolves (20mL), and organic phase is washed with saturated sodium bicarbonate solution (10mL*3), saturated common salt water washing (10mL*3), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, crude product reverse phase Preparation chromatographic isolation obtains 2- cyclohexyl -4- (2- (2,4 difluorobenzene oxygroup) -5- (ethanesulfonamide group) -4- (piperidyl -4- base) Phenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation (0.008g, white solid, 0.011mmol, molar yield 34.8%).
1H NMR(400MHz,CDCl3)δ:7.10(m,1H),7.04(m,1H),6.97(m,1H),6.77(m,1H),6.64 (m,1H),4.0(s,1H),3.45(m,2H),2.79-2.69(m,4H),2.78(m,1H),2.76(t,2H),2.72(m,1H), 2.55(t,2H),2.0(s,2H),1.92-1.67(m,4H),1.86-1.61(m,4H),1.79(m,4H),1.53-1.43(m, 4H),1.49-1.47(m,2H),1.27(t,3H).
MS m/z(ESI):705.8[M+H]+.
Embodiment ten
2- cyclohexyl-4- (2- (2,4 difluorobenzene oxygroup)-5- (2- hydroxy propane-2- base) phenyl) sulfoamido-5-3-, 6,7,8- tetrahydroquinoline 1- oxide
Step 1: the preparation of 2,4 difluorobenzene phenol
At -78 DEG C of nitrogen protection, n-BuLi (11mL, 17.7mmol, 1.6M) is instilled into bromo- 2, the 4- difluorobenzene of 1- In tetrahydrofuran (30mL) solution of (3g, 15.5mmol).Reaction solution stirs 30 minutes at -78 DEG C of nitrogen protection, then boron Sour trimethyl (1.84g, 17.7mmol).After being added dropwise to complete, reaction solution is slowly raised to room temperature, stirs 12 hours.At -15 DEG C, Hydrogen peroxide (24mL, 30%w/w) solution of sodium hydroxide (0.88g, 22mmol) is added drop-wise in reaction solution.After being added dropwise to complete, Reaction solution stirs 3 hours at room temperature, and reaction solution is quenched with aqueous hydrochloric acid solution (1M), and adjusts pH=1.Ethyl acetate (75mL*2) Extraction, saturated common salt water washing (100mL*3), organic phase drying are evaporated to obtain crude product.Through column separation (petroleum ether: acetic acid second Ester=5:1) obtain 2,4- difluorophenol (1.80g, 13.87mmol, molar yield 89.5%).
1H NMR(400MHz,DMSO-d6) (s, the 6H) of δ: 8.12 (br, 1H), 6.74 (d, J=9.3Hz, 2H), 2.14
MS m/z(ESI):130.09[M+H]+.
Step 2: the preparation of the bromo- 4- of methyl 3- (2,4 difluorobenzene oxygroup) benzoic ether
By cesium carbonate, ((3.1g, 9.6mmol) is added to 2,4- difluorophenol (0.83g, 6.4mmol) and the bromo- 4- of methyl 3- In dimethyl sulfoxide (10mL) solution of fluorobenzene acid esters (1.57g, 6.7mmol).Reaction solution stirs 12 hours at 80 DEG C, cooling To room temperature, water (50mL) then is added, ethyl acetate (50mL*2) extraction.Organic phase is washed with saturated salt solution (25mL*4), Drying is evaporated to obtain crude product.Crude product obtains the bromo- 4- of methyl 3- (2,4- bis- through column separation (petroleum ether: ethyl acetate=20:1) Fluorophenoxy) benzoic ether (1.58g, 4.61mmol, molar yield 72%).
MS m/z(ESI):341.1[M+H]+.
1H NMR(400MHz,DMSO-d6) δ: 8.28-8.16 (m, 1H), 7.90-7.79 (m, 1H), 7.11 (d, J= 9.1Hz, 2H), 6.52 (d, J=8.6Hz, 1H), 3.85 (s, 3H), 2.05 (s, 6H)
Step 3: the preparation of 2- (the bromo- 4- of 3- (2,4 difluorobenzene oxygroup) phenyl) propane -2- alcohol
At 0 DEG C of nitrogen protection, by methyl-magnesium-bromide (13.83mL, 13.83mmol, 1M) instill the bromo- 4- of methyl 3- (2, 4- difluoro phenoxy group) benzoic ether (1.58g, 4.61mmol) tetrahydrofuran (30mL) solution in.Reaction solution is in nitrogen protection Under be stirred at room temperature 10 hours, then use saturated ammonium chloride quenching reaction.Ethyl acetate (75mL*2) extraction, saturated common salt water washing (100mL*3), organic phase drying are evaporated to obtain crude product.Through column separation (petroleum ether: ethyl acetate=5:1), obtaining 2-, (3- is bromo- 4- (2,4- difluoro phenoxy group) phenyl) propane -2- alcohol (1.50g, 4.38mmol, molar yield 95%).
1H NMR(400MHz,DMSO-d6) δ: 7.75 (d, J=2.2Hz, 1H), 7.28 (dd, J=8.6,2.2Hz, 1H), 7.06 (d, J=9.1Hz, 2H), 6.29 (d, J=8.6Hz, 1H), 2.05 (s, 6H), 1.40 (s, 6H)
MS m/z(ESI):343.2[M+H]+.
Step 4: 2- cyclohexyl -4- (2- (2,4 difluorobenzene oxygroup) -5- (2- hydroxy propane -2- base) phenyl) -3- sulphonyl The preparation of amido -5,6,7,8- tetrahydroquinoline
Tris(dibenzylideneacetone) dipalladium (7.7mg, 8.4umol) is added to 2- (the bromo- 4- of 3- (2,4- difluoro phenoxy group) Phenyl) propane -2- alcohol (96.1mg, 0.28mmol), (4,4,5,5- tetramethyls -1,3,2- bis- dislike penta ring of boron-to 2- cyclohexyl -4- 2- yl) -5,6,7,8- tetrahydroquinoline -3- sulfonamide (102.3mg, 0.28mmol), 1,3,5,7- tetramethyl -6- phenyl -2,4, The dioxane (8mL) of 8- trioxa -6- phosphinylidyne adamantane (8.2mg, 28 μm of ol) and potassium phosphate (118mg, 0.56mmol) and In the mixture of water (2mL).Reaction solution stirs 12 hours at 60 DEG C.Reaction solution is cooled to room temperature, ethyl acetate (30mL*2) Extraction, saturated salt solution (30mL*2) washing, organic phase drying are evaporated to obtain crude product.Crude product prepare plate separation (petroleum ether: Ethyl acetate=2:1) obtain 2- cyclohexyl -4- (2- (2,4 difluorobenzene oxygroup) -5- (2- hydroxy propane -2- base) phenyl) -3- Sulfoamido -5,6,7,8- tetrahydroquinolines (122.7mg, 0.22mmol, molar yield 77.2%).
MS m/z(ESI):557.7[M+H]+。
Step 5: 2- cyclohexyl -4- (2- (2,4 difluorobenzene oxygroup) -5- (2- hydroxy propane -2- base) phenyl) -3- sulphonyl The preparation of amido -5,6,7,8- tetrahydroquinoline 1- oxidation
Metachloroperbenzoic acid (62mg, 0.31mmol, 85%w/w) is added to 2- cyclohexyl -4- (2- (2,4- difluoros Phenoxy group) -5- (2- hydroxy propane -2- base) phenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinolines (122.7mg, In methylene chloride (5mL) solution 0.22mmol).Room temperature reaction 20 minutes, methylene chloride extraction, saturated sodium bicarbonate washing, Organic phase is dry to be evaporated to obtain crude product, and crude product is through preparing the isolated 2- cyclohexyl -4- of HPLC (2- (2,4- difluoro phenoxy group) - 5- (2- hydroxy propane -2- base) phenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation (82.03mg, 0.143mmol, Molar yield 65%).
1H NMR(400MHz,CDCl3)δ:7.88(m,1H),7.13(m,1H),7.10(m,1H),6.97(m,1H),6.64 (m,1H),3.65(s,1H),2.76(t,2H),2.72(m,1H),2.55(t,2H),2.0(s,2H),1.86-1.61(m,4H), 1.79(m,4H),1.53-1.43(m,4H),1.49-1.47(m,2H),1.30(s,6H).
MS m/z(ESI):573.6[M+H]+。
Embodiment 11
2- cyclohexyl -4- (5- (the fluoro- 2,6- dimethyl phenoxy of 4-) -2- (2- hydroxy propane -2- base) phenyl) -3- sulphonyl The preparation of amido -5,6,7,8- tetrahydroquinoline 1- oxidation
Step 1: the preparation of 1- (the bromo- 4- of 3- (the fluoro- 2,6- dimethyl phenoxy of 4-) phenyl) ethyl ketone
At room temperature, by 2,6- dimethyl -4- fluorophenol (1.86g, 13.3mmol), 1- (the bromo- 4- fluorophenyl of 3-) ethane -1- Ketone (4.33g, 19.95mmol) and potassium carbonate (3.68g, 26.6mmol) are dissolved in n,N-dimethylacetamide (40mL), are added Heat is reacted 14 hours, is cooled to room temperature to 80 DEG C, and reaction solution is diluted with ethyl acetate (50mL), with saturated common salt water washing (3* 10mL), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, crude product purified by silica gel column chromatography separating purification (petroleum ether: acetic acid Ethyl ester=20:1) obtain 1- (the bromo- 4- of 3- (fluoro- 2, the 6- dimethyl phenoxy of 4-) phenyl) ethyl ketone (4.33g, yellow oil, 12.85mmol, molar yield 96.6%).
Step 2: the preparation of 2- (the bromo- 4- of 3- (the fluoro- 2,6- dimethyl phenoxy of 4-) phenyl) propane -2- alcohol
It is under ice bath that 1- (the bromo- 4- of 3- (fluoro- 2, the 6- dimethyl phenoxy of 4-) phenyl) ethyl ketone (0.60g, 1.78mmol) is molten Solution in anhydrous tetrahydro furan (5mL), replace nitrogen, then by methyl-magnesium-bromide diethyl ether solution (3.0M, 0.85mL, It 2.56mmol) is added drop-wise in reaction system, is stirred under ice bath, then react at room temperature 3 hours, saturated ammonium chloride solution is then added dropwise (20mL) quenching reaction, then (3*15mL) is extracted with ethyl acetate, brine It (2*10mL) is used after organic phase is merged, is had Machine is mutually dried, filtered with anhydrous sodium sulfate, is spin-dried for, crude product purified by silica gel column chromatography separating purification (petroleum ether: ethyl acetate=7: 1) obtain 2- (the bromo- 4- of 3- (fluoro- 2, the 6- dimethyl phenoxy of 4-) phenyl) propane -2- alcohol (0.32g, colorless oil, 0.91mmol, molar yield 51.2%).
Step 3: 2- cyclohexyl -4- (5- (the fluoro- 2,6- dimethyl phenoxy of 4-) -2- (2- hydroxy propane -2- base) benzene Base) -3- sulfoamido -5,6,7,8- tetrahydroquinoline preparation
At room temperature, by 2- (the bromo- 4- of 3- (fluoro- 2, the 6- dimethyl phenoxy of 4-) phenyl) propane -2- alcohol (0.029g, 0.083mol), tris(dibenzylideneacetone) dipalladium (0.006g, 0.0083mmol), sodium carbonate (0.018g, 0.165mmol) and 1,3,5,7- tetramethyl -6- phenyl -2,4,8- trioxa -6- phosphinylidyne adamantane (0.005g, 0.0165mmol) are dissolved in tetrahydro In the in the mixed solvent (4mL:1mL) of furans and water, replace nitrogen, be heated to 60 DEG C, then by 2- cyclohexyl -4- (4,4,5, 5- tetramethyl -1,3,2- bis- dislike penta ring -2- base of boron) -5,6,7,8- tetrahydroquinoline -3- sulfonamide (0.030g, 0.083mmol) Tetrahydrofuran (2mL) solution is added drop-wise in reaction system, is reacted 14 hours, is cooled to room temperature, reaction solution is diluted with ethyl acetate (30mL), filtering, with saturated common salt water washing (2*10mL), organic phase is dried, filtered organic phase with anhydrous sodium sulfate, is spin-dried for, Crude product purified by silica gel prepares the isolated 2- cyclohexyl -4- of plate (5- (the fluoro- 2,6- dimethyl phenoxy of 4-) -2- (2- hydroxyl third Alkane -2- base) phenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinolines (white solid, 0.017g, 0.030mmol, molar yield 35.8%).
MS m/z (ESI): 567.7 [M+H]+。
Step 4: 2- cyclohexyl -4- (5- (the fluoro- 2,6- dimethyl phenoxy of 4-) -2- (2- hydroxy propane -2- base) benzene Base) -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation preparation
Metachloroperbenzoic acid (62mg, 0.31mmol, 85%w/w) is added to 2- cyclohexyl -4- (5- (4- fluoro- 2,6- Dimethyl phenoxy) -2- (2- hydroxy propane -2- base) phenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinolines (141.93mg, In methylene chloride (5mL) solution 0.25mmol).Room temperature reaction 20 minutes, methylene chloride extraction, saturated sodium bicarbonate washing, Organic phase is dry to be evaporated to obtain crude product, and crude product is through preparing the isolated 2- cyclohexyl -4- of HPLC (5- (fluoro- 2, the 6- dimethyl benzene of 4- Oxygroup) -2- (2- hydroxy propane -2- base) phenyl) -3- sulfoamido -5,6,7,8- tetrahydroquinoline 1- oxidation (95.14mg, 0.163mmol, molar yield 65%).
1H NMR(400MHz,CDCl3)δ:7.44(m,1H),7.38(m,1H),7.29(m,1H),6.54(m,1H),3.65 (s,1H),2.76(t,2H),2.72(m,1H),2.55(t,2H),2.15(m,6H),2.0(s,2H),1.86-1.61(m,4H), 1.79(m,4H),1.53-1.43(m,4H),1.49-1.47(m,2H),1.30(s,6H).
MS m/z(ESI):583.7[M+H]+。
Embodiment 12
2- cyclohexyl -4- (2- (the fluoro- 2,6- dimethyl phenoxy of 4-) -5- (2- hydroxy propane) phenyl) -3- sulfoamido - The preparation of 5,6,7,8- tetrahydroquinoline 1- oxidation
Step 1: the preparation of the fluoro- 2,6- xylenol of 4-
At -78 DEG C of nitrogen protection, n-BuLi (11mL, 17.7mmol, 1.6M) is instilled into fluoro- 1, the 3- bis- of the bromo- 5- of 2- In tetrahydrofuran (30mL) solution of methylbenzene (3g, 14.8mmol).Reaction solution stirs 30 minutes at -78 DEG C of nitrogen protection, Then trimethylborate (1.84g, 17.7mmol).After being added dropwise to complete, reaction solution is slowly raised to room temperature, stirs 12 hours.- 15 At DEG C, hydrogen peroxide (24mL, 30%w/w) solution of sodium hydroxide (0.88g, 22mmol) is added drop-wise in reaction solution.It drips Cheng Hou, reaction solution stir 3 hours at room temperature, and reaction solution is quenched with aqueous hydrochloric acid solution (1M), and adjusts pH=1.Ethyl acetate (75mL*2) extraction, saturated common salt water washing (100mL*3), organic phase drying are evaporated to obtain crude product.Through column separation (petroleum Ether: ethyl acetate=5:1) obtain fluoro- 2, the 6- xylenol of 4- (1.8g, 12.73mmol, molar yield 86%).
1H NMR(400MHz,DMSO-d6) (s, the 6H) of δ: 8.12 (br, 1H), 6.74 (d, J=9.3Hz, 2H), 2.14
MS m/z(ESI):140.2[M+H]+。
Step 2: the preparation of the bromo- 4- of methyl 3- (the fluoro- 2,6- dimethyl phenoxy of 4-) benzoic ether
Cesium carbonate (3.1g, 9.6mmol) is added to fluoro- 2, the 6- xylenol (0.9g, 6.4mmol) of 4- and methyl 3- In dimethyl sulfoxide (10mL) solution of bromo- 4- fluorobenzene acid esters (1.57g, 6.7mmol).It is small that reaction solution stirs 12 at 80 DEG C When, it is cooled to room temperature, water (50mL) then is added, ethyl acetate (50mL*2) extraction.Organic phase saturated salt solution (25mL* 4) it washs, drying is evaporated to obtain crude product.Crude product obtains the bromo- 4- of methyl 3- through column separation (petroleum ether: ethyl acetate=20:1) (fluoro- 2, the 6- dimethyl phenoxy of 4-) benzoic ether (1.4g, 3.97mmol, molar yield 62%).
1H NMR(400MHz,DMSO-d6) δ: 8.28-8.16 (m, 1H), 7.90-7.79 (m, 1H), 7.11 (d, J= 9.1Hz, 2H), 6.52 (d, J=8.6Hz, 1H), 3.85 (s, 3H), 2.05 (s, 6H)
MS m/z(ESI):353.2[M+H]+。
Step 3: the preparation of 2- (the bromo- 4- of 3- (the fluoro- 2,6- dimethyl phenoxy of 4-) phenyl) propane -2- alcohol
At 0 DEG C of nitrogen protection, methyl-magnesium-bromide (11.9mL, 11.9mmol, 1M) is instilled the bromo- 4- of methyl 3-, and (4- is fluoro- 2,6- dimethyl phenoxies) benzoic ether (1.4g, 4.0mmol) tetrahydrofuran (30mL) solution in.Reaction solution is in nitrogen protection Under be stirred at room temperature 10 hours, then use saturated ammonium chloride quenching reaction.Ethyl acetate (75mL*2) extraction, saturated common salt water washing (100mL*3), organic phase drying are evaporated to obtain crude product.Through column separation (petroleum ether: ethyl acetate=5:1), obtaining 2-, (3- is bromo- 4- (fluoro- 2, the 6- dimethyl phenoxy of 4-) phenyl) propane -2- alcohol (1.3g, 3.72mmol, molar yield 93%).
1H NMR(400MHz,DMSO-d6) δ: 7.75 (d, J=2.2Hz, 1H), 7.28 (dd, J=8.6,2.2Hz, 1H), 7.06 (d, J=9.1Hz, 2H), 6.29 (d, J=8.6Hz, 1H), 2.05 (s, 6H), 1.40 (s, 6H)
MS m/z(ESI):353.2[M+H]+。
Step 4: 2- cyclohexyl -4- (2- (the fluoro- 2,6- dimethyl phenoxy of 4-) -5- (2- hydroxy propane -2- base) benzene Base) -5,6,7,8- tetrahydroquinoline -3- sulfonamide preparation
Tris(dibenzylideneacetone) dipalladium (7.7mg, 8.4umol) is added to methyl 2- (the bromo- 4- of 3- (fluoro- 2, the 6- bis- of 4- Methylphenoxy) phenyl) propane -2- alcohol (98.90mg, 0.28mmol), 2- cyclohexyl -4- (4,4,5,5- tetramethyls -1,3,2- Two dislike penta ring -2- base of boron) -5,6,7,8- tetrahydroquinoline -3- sulfonamide (102.3mg, 0.28mmol), 1,3,5,7- tetramethyl - 6- phenyl -2,4, the dioxy of 8- trioxa -6- phosphinylidyne adamantane (8.2mg, 28 μm of ol) and potassium phosphate (118mg, 0.56mmol) In the mixture of six rings (8mL) and water (2mL).Reaction solution stirs 12 hours at 60 DEG C.Reaction solution is cooled to room temperature, acetic acid second Ester (30mL*2) extraction, saturated salt solution (30mL*2) washing, organic phase drying are evaporated to obtain crude product.Crude product carries out preparing plate point 2- cyclohexyl -4- (2- (the fluoro- 2,6- dimethyl phenoxy of 4-) -5- (2- hydroxyl third is obtained from (petroleum ether: ethyl acetate=2:1) Alkane -2- base) phenyl) -5,6,7,8- tetrahydroquinoline -3- sulfonamide (119mg, 0.21mmol, yield 73.6%).
MS m/z(ESI):567.7[M+H]+。
Step 5: 2- cyclohexyl -4- (2- (the fluoro- 2,6- dimethyl phenoxy of 4-) -5- (2- hydroxy propane -2- base) benzene Base) -5,6,7,8- tetrahydroquinoline -3- sulfonamide 1- oxidation preparation
Metachloroperbenzoic acid (62mg, 0.31mmol, 85%w/w) is added to 2- cyclohexyl -4- (2- (4- fluoro- 2,6- Dimethyl phenoxy) -5- (2- hydroxy propane -2- base) phenyl) -5,6,7,8- tetrahydroquinoline -3- sulfonic acid (130.57mg, In methylene chloride (10mL) solution 0.23mmol).Room temperature reaction 20 minutes, methylene chloride extraction, saturated sodium bicarbonate washing, Organic phase is dry to be evaporated to obtain crude product, and crude product is through preparing the isolated 2- cyclohexyl -4- of HPLC (2- (fluoro- 2, the 6- dimethyl benzene of 4- Oxygroup) -5- (2- hydroxy propane -2- base) phenyl) -5,6,7,8- tetrahydroquinoline -3- sulfonamide 1- oxidation (46.7mg, 0.08mmol, molar yield 34.5%).
1H NMR(400MHz,CDCl3)δ:7.88(m,1H),7.48(m,1H),7.13(m,1H),6.54(m,2H), 3.65(s,1H),2.76(t,2H),2.72(m,1H),2.55(t,2H),2.15(m,6H),2.0(s,1H),1.86-1.61(m, 4H),1.79(m,4H),1.53-1.43(m,4H),1.49-1.47(m,2H),1.30(s,6H).
MS m/z(ESI):583.7[M+H]+。
Embodiment 13
2- cyclohexyl -4- (2- (the chloro- 2,6- dimethyl phenoxy of 4-) -5- (2- hydroxy propane -2- base) phenyl) -5,6,7, The preparation of 8- tetrahydroquinoline -3- sulfonamide 1- oxidation
With fluoro- 2, the 6- xylenol of 4- for raw material, preparation step reference implementation example 12 obtains product 2- cyclohexyl- 4- (2- (the chloro- 2,6- dimethyl phenoxy of 4-) -5- (2- hydroxy propane -2- base) phenyl) -5,6,7,8- tetrahydroquinoline -3- sulphonyl Amine 1- aoxidizes (molar yield 36.2%).
1H NMR(400MHz,CDCl3)δ:7.88(m,1H),7.48(m,1H),7.13(m,1H),7.20(m,2H), 3.65(s,1H),2.76(t,2H),2.72(m,1H),2.55(t,2H),2.15(m,6H),2.0(s,1H),1.86-1.61(m, 4H),1.79(m,4H),1.53-1.43(m,4H),1.49-1.47(m,2H),1.30(s,6H).
MS m/z(ESI):600.2[M+H]+。
Embodiment 14
2- cyclohexyl -4- (2- (the bromo- 2,6- dimethyl phenoxy of 4-) -5- (2- hydroxy propane -2- base) phenyl) -5,6,7, The preparation of 8- tetrahydroquinoline -3- sulfonamide 1- oxidation
With bromo- 2, the 6- xylenol of 4- for raw material, preparation step reference implementation example 12 obtains product 2- cyclohexyl- 4- (2- (the bromo- 2,6- dimethyl phenoxy of 4-) -5- (2- hydroxy propane -2- base) phenyl) -5,6,7,8- tetrahydroquinoline -3- sulphonyl Amine 1- aoxidizes (molar yield 34.2%).
1H NMR(400MHz,CDCl3)δ:7.88(m,1H),7.48(m,1H),7.13(m,1H),7.15(m,2H), 3.65(s,1H),2.76(t,2H),2.72(m,1H),2.55(t,2H),2.15(m,6H),2.0(s,1H),1.86-1.61(m, 4H),1.79(m,4H),1.53-1.43(m,4H),1.49-1.47(m,2H),1.30(s,6H).
MS m/z(ESI):644.6[M+H]+。
Embodiment 15
2- cyclohexyl-4- (5-(2- hydroxy propane-2- base)-2- (4-(2- hydroxy propane-2- base)-2,6- dimethyl benzene oxygen Base) phenyl) -3- sulfonamide -5,6,7,8- tetrahydroquinoline 1- oxidation preparation
With 4-(2- hydroxy propane-2- base)-2,6- xylenols for raw material, preparation step reference implementation example 12 is obtained To product 2- cyclohexyl -4- (5- (2- hydroxy propane -2- base) -2- (4- (2- hydroxy propane -2- base) -2,6- dimethyl benzene oxygen Base) phenyl) -3- sulfonamide -5,6,7,8- tetrahydroquinoline 1- oxidation (molar yield 36.9%).
1H NMR(400MHz,CDCl3)δ:7.88(m,1H),7.48(m,1H),7.13(m,1H),7.00(m,2H), 3.65(s,2H),2.76(t,2H),2.72(m,1H),2.55(t,2H),2.15(m,6H),2.0(s,1H),1.86-1.61(m, 4H),1.79(m,4H),1.53-1.43(m,4H),1.49-1.47(m,2H),1.30(s,12H).
MS m/z(ESI):623.8[M+H]+。
Biological assessment
Below in conjunction with test case further describe explanation the present invention, but these embodiments be not meant as limiting it is of the invention Range.
Test case 1, the compounds of this invention combine active measurement to BRD4
BRD4 combination active testing is tested by the following method.
The compound that this method is used to measure in the present invention combines active inhibiting effect to BRD4.
Experimental procedure
In order to test influence of the compound to BRD4 in conjunction with acetylated protein, this experiment is turned using fluorescence resonance energy The inhibiting effect of the method test compound to BRD4 and acetylation substrate binding activity of (TR-FRET) is moved, and obtains compound Active half-inhibitory concentration IC is combined to BRD450。
Specific experiment operation is as follows:
1,1~5 μ L BRD4 enzyme solutions, the final concentration of 1~20nM of enzyme are added in 384 orifice plates；
2, the good compound solution of 1~5 μ L gradient dilution is added；
3, it includes 2~50nM of acetylation substrate polypeptide final concentration that 1~5 μ L Substrate cocktail, which is added,；
4, it is incubated at room temperature 0.5~3 hour；
5,10 μ L EDTA and the detection liquid containing labelled antibody is added, is incubated at room temperature 1 hour；
6, microplate reader measures the 665nm fluorescence signal value of each plate hole；
7, inhibiting rate is calculated by fluorescence signal value；
8, the IC of compound is obtained by curve matching according to the inhibiting rate of various concentration50。
Compound combines activity to be measured by above test BRD4 in the present invention, the IC measured50Value is shown in Table 1.
Compound is to BRD4 combination activity suppression IC in 1 present invention of table50
Embodiment number IC50(nM) Embodiment number IC50(nM)
1 0.18 9 0.30
2 0.11 10 0.24
3 0.19 11 0.38
4 0.27 12 0.25
5 0.35 13 0.36
6 0.19 14 0.62
7 0.15 15 0.11
8 0.26 / /
Conclusion: the compounds of this invention significantly inhibits BRD4 combination activity.
Test case 2, test compound test BRD4BD1 or BD2 combination activity suppression
Experiment purpose: the purpose of the test case be measurement the present invention in compound to BRD4BD1 or BD2 combine it is active Inhibiting effect.
Laboratory apparatus: centrifuge (5810R) is purchased from Eppendorf company, and pipettor is public purchased from Eppendorf or Rainin Department, microplate reader are purchased from U.S. BioTek company, model SynergyH1 global function microplate reader.
Experimental method: in order to test influence of the compound to BRD4BD1 or BD2 in conjunction with acetylated protein, this experiment It is living to BRD4BD1 or BD2 and acetylation Binding Capacity using the method test compound of fluorescence resonance energy transfer (TR-FRET) Property inhibiting effect, and obtain compound to BRD4BD1 or BD2 combine active half-inhibitory concentration IC50。
Specific experiment operation is as follows:
1,1~5 μ L BRD4BD1 or BD2 enzyme (being purchased from BPS Bioscience) solution is added in 384 orifice plates, enzyme is dense eventually Degree is 1~20nM；
2, the good compound solution of 1~5 μ L gradient dilution is added；
3, be added 1~5 μ L Substrate cocktail include acetylation substrate polypeptide (be purchased from BPS Bioscience) final concentration 2~ 50nM；
4, it is incubated at room temperature 0.5~3 hour；
5,10 μ L EDTA and the detection liquid (being purchased from Cisbio) containing labelled antibody are added, are incubated at room temperature 1 hour；
6, microplate reader measures the 665nm fluorescence signal value of each plate hole；
7, inhibiting rate is calculated by fluorescence signal value；
8, the IC of compound is obtained by curve matching according to the inhibiting rate of various concentration50。
Compound combines activity to be measured by above test BRD4BD1 or BD2 in the present invention, the IC measured50 Value is shown in Table 2.
Compound is to BRD4BD1 or BD2 combination activity suppression IC in 2 present invention of table50
Conclusion: the compounds of this invention significantly inhibits BRD4BD2 combination activity, to BRD4BD1 without significant Inhibitory activity shows good selective inhibitory.
The influence of test case 3, the compounds of this invention to leukaemia cell's MV4-11 proliferation activity
Influence of the compound to leukaemia cell's MV4-11 proliferation activity is tested by the following method.
This method is used to measure influence of the compound to leukaemia cell's MV4-11 proliferation activity in the present invention.
This experiment tests compound to the inhibiting effect of MV4-11 cell Proliferation using the method for CellTiter-Glo, and Show that compound inhibits the half-inhibitory concentration IC of cell-proliferation activity50。
Experimental procedure:
1, the MV4-11 cell suspension of 50~100 μ L is inoculated in 96 porocyte culture plates, density is 1~5*104Cell/ ML, by culture plate in incubator culture 16~24 hours (37 DEG C, 5%CO2)。
2, the testing compound solution of the various concentration of gradient dilution is added into culture plate cell, culture plate is being cultivated Case be incubated for 72 hours (37 DEG C, 5%CO2)。
3,50~100 μ L CellTiter-Glo reagents are added in every hole, and vibrate 10 minutes, are stored at room temperature 10 minutes.
4, microplate reader measures the chemiluminescence signal value of each plate.
5, inhibiting rate is calculated by chemiluminescence signal value.
6, the IC of compound is obtained by curve matching according to the inhibiting rate of various concentration50。
Compound is measured the test of leukaemia cell's MV4-11 proliferation activity in the present invention, the IC measured50Value is shown in Table 3.
Compound inhibits IC to leukaemia cell's MV4-11 proliferation activity in 3 present invention of table50
Embodiment number IC50(nM) Embodiment number IC50(nM)
1 0.39 9 0.22
2 0.48 10 0.38
3 0.57 11 0.47
4 0.71 12 0.52
5 0.46 13 0.63
6 0.55 14 0.35
7 0.40 15 0.60
8 0.23 / /
Test case 4, the compounds of this invention analyze test to the PK of mouse
The mouse pharmacokinetics test of the preferred embodiment of the present invention is using (the Shanghai Jie Sijie experiment of Balb/c mouse Company of Animals Ltd.) it carries out.
Administration mode: single oral gavage administration
Dosage: 5 milligrams/10 ml/kgs
Preparation prescription: 0.5%CMC-Na and 1%Tween 80, ultrasonic dissolution
Sample point: 0.5 after administration, 1,2,4,6,8 and 24 hours
Sample treatment:
Venous blood collection 0.1mL, is placed in K2In EDTA test tube, 1000~3000 × g of room temperature is centrifuged 5~20min separated plasma, It is saved in -80 DEG C.
160 μ L acetonitrile precipitations are added in 40 μ L of plasma sample, and 500~2000 × g is centrifuged 5~20 minutes after mixing.
100 μ L of supernatant solution after processing is taken to carry out the concentration that LC/MS/MS analyzes untested compound, LC/MS/MS analyzer Device: AB Sciex API 4000.
Liquid-phase condition: Shimadzu LC-20AD pump
Chromatographic column: 5 μm of 50 × 4.6mm of C18 of phenomenex Gemiu
Mobile phase: A liquid is 0.1% aqueous formic acid, and B liquid is acetonitrile
Flow velocity: 0.8mL/min
Pharmacokinetics:
Major parameter is calculated with WinNonlin 6.1, and small raticide generation, experimental result is shown in the following table 4
4 the compounds of this invention of table tests the PK of mouse
Small raticide is for experimental result it can be seen that compound of the embodiment of the present invention shows good metabolic from table Matter, exposed amount AUC and maximum plasma concentration CmaxAll performance is good.

Claims (14)

1. a kind of logical formula (I) compound represented, its stereoisomer, deuterated derivative or its pharmaceutically-acceptable salts, knot Structure is as follows:
Wherein:
R1Selected from hydrogen atom, D-atom, alkyl, deuteroalkyl, halogenated alkyl, naphthenic base, heterocycle；
RXSelected from hydrogen atom, D-atom, alkyl, deuteroalkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, ring Alkyl, heterocycle, aryl, aryloxy group, heteroaryl ,-(CH2)nS(O)mRaOr-(CH2)nNRaS(O)mRb；
RaAnd RbIt is identical or different, and it is each independently selected from hydrogen atom, D-atom, alkyl, deuteroalkyl, halogenated alkyl, alcoxyl Base, halogenated alkoxy, halogen, amino, nitro, hydroxyl, naphthenic base, heterocycle, aryl or heteroaryl；
Wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl optionally further by selected from D-atom, Substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino one or more substituent groups replaced；
M is 0, an integer of 1 or 2；And
The integer that n and q is 0,1,2,3,4 or 5.
2. logical formula (I) compound represented, its stereoisomer, deuterated derivative or its pharmacy according to claim 1 Upper acceptable salt, which is characterized in that shown in the compound structure such as general formula (IA):
Wherein:
R3、RYAnd RZIt is identical or different, and it is each independently selected from hydrogen atom, D-atom, C1-8Alkyl, C1-8Deuteroalkyl, C1-8 Halogenated alkyl, C1-8Alkoxy, C1-8Aryloxy group, C1-8Halogenated alkoxy, halogen, amino, C3-8Naphthenic base, 3-12 circle heterocyclic ring base, 6-12 member aryl or 5-12 unit's heteroaryl ,-(CH2)nS(O)mRaOr-(CH2)nNRaS(O)mRb；The wherein C1-8Alkyl, C1-8 Halogenated alkyl, C3-8Naphthenic base, 3-12 circle heterocyclic ring base, 6-12 member aryl and 5-12 unit's heteroaryl are optionally further by former selected from deuterium Son, C1-8Alkyl, C1-8Halogenated alkyl, halogen, amino, oxo base, nitro, cyano, hydroxyl, C1-8Alkoxy, C1-8Haloalkoxy Base, C1-8Hydroxyalkyl, C3-8One or more of naphthenic base, 3-12 circle heterocyclic ring base, 6-12 member aryl and 5-12 unit's heteroaryl take Replaced Dai Ji；
R1、m、n、Ra、RbAs described in claim 1.
3. logical formula (I) compound represented, its stereoisomer, deuterated derivative or its pharmacy according to claim 1 Upper acceptable salt, which is characterized in that shown in the compound structure such as general formula (ID):
Wherein:
R1Selected from hydrogen atom, D-atom, C1-3Alkyl, C5-6Naphthenic base, C5-6Heterocycle；
M is selected from NH, oxygen atom or-OCH2, preferred oxygen atom；
Ring B is selected from C3-6Naphthenic base, C3-6Heterocycle or C5-6First aryl；It is preferred that C5-6Naphthenic base, C5-6Heterocycle or phenyl, wherein C5-6Heterocycle is replaced by 1-2 containing N, O or S atom；
RBSelected from hydrogen atom, halogen, C1-6Alkyl, C1-6Halogenated alkyl or C1-6Hydroxyalkyl, preferably hydrogen atom, halogen, C1-3Alkyl, C1-3Halogenated alkyl or C1-3Hydroxyalkyl, more preferable hydrogen atom, fluorine atom, methyl, ethyl or-C (CH3)2OH；
R5Independently selected from key or SO2 R6、NHSO2 R6、CHOH R7 R8；
R6Selected from C1-6Alkyl, C3-6Naphthenic base or amino, preferably C1-3Alkyl, C5-6Naphthenic base or amino, more preferable ethyl and cyclopropyl Base；
R7Or R8Independently selected from hydrogen atom or C1-6Alkyl or R7、R8A ring is formed, ring is selected from C3-6Naphthenic base or C5-6Heterocycle Base；
R7And R8It is preferred that methyl, preferred cyclopropyl when cyclic；
RZSelected from hydrogen atom, C1-8Alkyl, C1-8Hydroxyalkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base or 5-8 unit's heteroaryl；It is preferred that C1-3 Alkyl, C3-6Naphthenic base or hydrogen atom；
The integer that r is 0,1,2,3,4 or 5.
4. logical formula (I) compound represented, its stereoisomer, deuterated derivative or its pharmacy according to claim 1 Upper acceptable salt, which is characterized in that shown in the compound structure such as general formula (IB):
Wherein:
RUAnd RVIt is identical or different, and it is each independently selected from hydrogen atom or C1-6Alkyl or RU、RVA ring is formed, ring is selected from C3-6Naphthenic base or C5-6Heterocycle；
RUAnd RVIt is preferred that methyl, preferred cyclopropyl when cyclic；
RWSelected from hydrogen atom, halogen, C1-6Alkyl, C1-6Halogenated alkyl or-C (CH3)2OH；
The integer that t is 0,1,2,3,4 or 5；
R1Selected from C5-6Naphthenic base or C1-3Alkyl.
5. logical formula (I) compound represented, its stereoisomer, deuterated derivative or its pharmacy according to claim 1 Upper acceptable salt, which is characterized in that shown in the compound structure such as general formula (IC):
Wherein:
M is selected from NH, oxygen atom or-OCH2, preferred oxygen atom；
Ring B is selected from C3-6Naphthenic base or C5-6First aryl；
RBSelected from hydrogen atom, halogen or C1-6Alkyl, preferably fluorine atom；
Y is selected from key or NH；
R4Selected from C1-6Alkyl, C3-6Naphthenic base or amino, preferably are selected from ethyl and cyclopropyl；
RZSelected from hydrogen atom, C1-8Alkyl, C1-8Hydroxyalkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base or 5-8 unit's heteroaryl；It is preferred that C1-8 Alkyl, C3-8Naphthenic base and hydrogen atom；
The integer that r is 0,1,2,3,4 or 5.
6. logical formula (I) compound represented, its stereoisomer, deuterated derivative or its pharmacy according to claim 2 Upper acceptable salt, which is characterized in that the R1Selected from C1-8Alkyl or cycloalkyl, preferably 5-6 member naphthenic base or C1-3Alkyl；
R3、RYAnd RZIt is identical or different, and it is each independently selected from hydrogen ,-NHS (O)2Rc、C1-8Alkyl, C1-8Naphthenic base, C1-8Heterocycle Base, C1-8Aryloxy group, amino, wherein the C1-8Alkyl, C1-8Naphthenic base, C1-8Heterocycle, C1-8Aryloxy group, amino optionally into One step is selected from C1-3Alkyl, C1-3Hydroxyl substituted alkyl group, halogen, replaced one or more substituent groups in hydroxyl:
RcSelected from C1-3Alkyl, wherein the alkyl is optionally further replaced halogen.
7. logical formula (I) compound represented, its stereoisomer, deuterated derivative or its pharmacy according to claim 6 Upper acceptable salt, which is characterized in that the R1Selected from cyclohexyl, methyl or ethyl；
R3、RYIt is identical or different, and it is each independently selected from-NHS (O)2CH2CH3、-NHS(O)2CH2CF3、C1-3Hydroxyl replaces alkane Base, cyclohexyl oxygroup, phenoxy group, piperidyl amino, wherein the cyclohexyl oxygroup, phenoxy group, piperidyl amino, optionally into One step is selected from C1-3Alkyl, C1-3Hydroxyl substituted alkyl group, halogen, replaced one or more substituent groups in hydroxyl；
RZSelected from hydrogen, cyclopropyl or piperidyl.
8. logical formula (I) compound represented, its stereoisomer, deuterated derivative or its pharmacy according to claim 7 Upper acceptable salt, which is characterized in that the C1-3Hydroxyl substituted alkyl group is-C (OH) (CH3)2；
C1-3Alkyl is selected from methyl or ethyl；
Halogen is selected from fluorine, chlorine or bromine.
9. lead to formula (I) shown in any according to claim 1~8) compound, its stereoisomer, deuterated derivative or its medicine Acceptable salt on, which is characterized in that be selected from following compound:
10. the preparation method of logical formula (I) compound, its stereoisomer, deuterated derivative or its pharmaceutically acceptable salt, tool Body step is that general formula (ID) obtains logical formula (I) compound after oxidizing,
Wherein:
The preferred metachloroperbenzoic acid of oxidant,
R1、RXIt is as described in claim 1 with q.
Its preparation side of general formula 11. (IC) compound, its stereoisomer, deuterated derivative or its pharmaceutically acceptable salt Method, the specific steps are general formula (IE) obtains general formula (IC) compound after oxidizing:
Wherein:
The preferred metachloroperbenzoic acid of oxidant；
R1As described in claim 1, R4, ring B, RB, M, Y, r and RZAs claimed in claim 5.
12. a kind of Pharmaceutical composition comprising lead to formula (I) chemical combination shown in the claim 1~9 for the treatment of effective dose is any Object, its stereoisomer, deuterated derivative or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable loads Body.
13. leading to formula (I) compound, its stereoisomer, deuterated derivative or its medicine shown in any according to claim 1~9 Pharmaceutical composition described in acceptable salt or claim 12 is preparing the application in BRD4 inhibitor medicaments on.
14. according to claim 1~9 described in any item compounds, its stereoisomer, deuterated derivative or its pharmaceutically may be used Pharmaceutical composition described in the salt or claim 12 of receiving is in preparation treating cancer, inflammation, chronic liver disease, diabetes, painstaking effort Application in the drug of pipe disease and AIDS；Wherein the cancer be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, The carcinoma of the rectum, cancer of pancreas, the cancer of the brain, liver cancer, solid tumor, glioma, spongioblastoma, leukaemia, lymthoma, myeloma And non-small cell lung cancer；The chronic liver disease be selected from primary hardening, the dirty property xanthomatosis of brain, primary sclerosing cholangitis, Drug induced cholestasia, intrahepatic cholestasis of pregnancy, parenteral absorption associated cholestasis, bacterial overgrowth or purulence blood Disease cholestasia, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, non-alcoholic Steatohepatitis, the anti-host disease of liver transfer operation related Graft, live donor liver transfer operation regeneration, congenital hepatic fibrosis, choledochus knot Stone, granular hepatopathy, malignant tumour, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's disease in or beyond liver Disease, hemochromatosis or α1Primary antibody membrane proteolytic enzyme deficiency disease.
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