CN109836385B - Tetrahydroquinoline N-oxide derivative and preparation method and application thereof - Google Patents
Tetrahydroquinoline N-oxide derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to tetrahydroquinoline N-oxide derivatives, a preparation method and application thereof. In particular to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound serving as a BRD4 inhibitor in treating related diseases such as cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease, AIDS and the like.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a BRD4 inhibitor, and a preparation method and application thereof.
Background
Tumors are one of the major diseases that seriously harm human life, and more than half occur in developing countries. The incidence of malignant tumors in China generally tends to rise, the incidence is increased at a speed of 3% -5% per year, and 400 million people in China are expected to have cancer and 300 million people die of cancer by 2020, and the main reasons are that: aging, urbanization, industrialization and change of living habits. In the drug market of Chinese hospitals, the sales scale of the antitumor drugs is steadily increased in recent years, the sales scale of the antitumor drugs reaches 664.2 hundred million yuan in 2012 and is increased by 13.07 percent on a par, and the market scale of the antitumor drugs is estimated to reach 1055.7 hundred million yuan and is increased by 7.57 percent on a par by 2017.
Due to unlimited growth, infiltration and metastasis of malignant tumors, three conventional treatment methods (operation, radiotherapy and chemotherapy) clinically adopted at present cannot completely remove or completely kill tumor cells, so that the phenomenon of tumor metastasis or recurrence often occurs. The biological treatment of tumor is a new therapy for preventing and treating tumor by applying modern biotechnology and related products, is a fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy due to the characteristics of safety, effectiveness, low adverse reaction and the like, and obtains the anti-tumor effect by mobilizing the natural defense mechanism of a host or giving naturally-produced substances with strong targeting property.
Bromodomain and extra-terminal domain (BET) family members are bromodomain and BRD4, and BRD4 regulates expression of target genes by recruiting different transcriptional regulators, such as Mediator, positive transcriptional elongation factor b (P-TEFb). As a chromatin adaptor which is widely expressed in mammals, the chromatin adaptor can recognize acetylated proteins to be combined on chromosomes in the whole mitosis process, recruit different chromatin modifying proteins and widely regulate the expression of genes, thereby playing an important role in the aspects of regulating cell cycle process, transcription, inflammation and the like. Recent studies have shown that deregulated expression levels or dysfunction of BRD4 are associated with the development of testicular nuclear protein midline carcinomas (NMCs), melanomas, acute myeloid leukemias, colon cancer, breast cancer and the like. The BRD4shRNA or BET inhibitor can induce the tumorigenesis cell cycle arrest, apoptosis and cell differentiation, and shows strong antitumor activity. These findings indicate that the BET protein is expected to be a novel therapeutic target for the above-mentioned tumors and even other tumors. In addition, the research of a tool compound JQ1 and the like shows that the inhibitor of BRD4 can be widely applied to various diseases such as virus infection, diabetes, metabolic diseases, liver diseases, senile dementia and the like.
The BRD4 inhibitor has good application prospect in the pharmaceutical industry, no medicine on the market exists at present, and in order to achieve the purpose of better treatment effect and meet the market demand, a new generation of high-efficiency low-toxicity selective BRD4 inhibitor is hoped to be developed.
Disclosure of Invention
The invention aims to provide a compound shown as a general formula (I), a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
wherein:
R1selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups;
RXselected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nS(O)mRaOr is- (CH)2)nNRaS(O)mRb；
RaAnd RbThe same or different, and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaromatic groupA group;
wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium atoms, substituted or unsubstituted alkyl groups, halogens, hydroxyl groups, substituted or unsubstituted amino groups;
m is an integer of 0, 1 or 2; and is
n and q are integers of 0, 1,2,3, 4 or 5.
In a preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer, a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, has the structure represented by the general formula (IA):
wherein:
R3、RYand RZAre the same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Alkoxy radical, C1-8Haloalkoxy, halogen, amino, C3-8Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl or 5-12 membered heteroaryl, - (CH)2)nS(O)mRaOr- (CH)2)nNRaS(O)mRb(ii) a Wherein said C1-8Alkyl radical, C1-8Haloalkyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl and 5-12 membered heteroaryl optionally further substituted by a substituent selected from deuterium atom, C1-8Alkyl radical, C1-8Haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, C1-8Alkoxy radical, C1-8Haloalkoxy, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl and 5-12 membered heteroaryl;
m、n、Ra、Rbas defined in formula (I).
In a preferred embodiment of the inventionSaid R is1Is selected from C1-8Alkyl or cycloalkyl, preferably 5-to 6-membered cycloalkyl or C1-3An alkyl group;
R3、RYand RZAre the same or different and are each independently selected from hydrogen, -NHS (O)2Rc、C1-8Alkyl radical, C1-8Cycloalkyl radical, C1-8Heterocyclic group, C1-8Aryloxy, amino, wherein said C1-8Alkyl radical, C1-8Cycloalkyl radical, C1-8Heterocyclic group, C1-8Aryloxy, amino optionally further selected from C1-3Alkyl radical, C1-3Hydroxyl substituted alkyl, halogen, and one or more substituent groups of hydroxyl;
Rcis selected from C1-3Alkyl, wherein said alkyl is optionally further substituted with halo.
In a further preferred embodiment of the invention, R is1Selected from cyclohexyl, methyl or ethyl;
R3、RYare the same or different and are each independently selected from-NHS (O)2CH2CH3、-NHS(O)2CH2CF3、C1-3Hydroxy-substituted alkyl, cyclohexyloxy, phenoxy, piperidinylamino, wherein said cyclohexyloxy, phenoxy, piperidinylamino is optionally further selected from C1-3Alkyl radical, C1-3Hydroxyl substituted alkyl, halogen, and one or more substituent groups of hydroxyl;
RZselected from hydrogen, cyclopropyl or piperidinyl.
In a still further preferred embodiment of the present invention, said C1-3The hydroxy-substituted alkyl group is-C (OH) (CH)3)2；
C1-3The alkyl is selected from methyl or ethyl;
halogen is selected from fluorine, chlorine or bromine.
In a preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, has a structure represented by the general formula (IB):
wherein:
RUand RVAre the same or different and are each independently selected from a hydrogen atom or C1-6Alkyl, or RU、RVForm a ring selected from C3-6Cycloalkyl or C5-6A heterocyclic group;
RUand RVPreferably methyl, and preferably cyclopropyl when cyclized;
RWselected from hydrogen atoms, halogens, C1-6Alkyl radical, C1-6Haloalkyl or C1-6Hydroxyalkyl, preferably hydrogen atom, halogen, C1-3Alkyl radical, C1-3Haloalkyl or C1-3Hydroxyalkyl radicals, e.g. -C (CH)3)2OH。
t is an integer of 0, 1,2,3, 4 or 5;
R1selected from hydrogen atom, deuterium atom, C1-3Alkyl radical, C5-6Cycloalkyl radical, C5-6A heterocyclic group.
In a preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, has a structure represented by the general formula (IC):
wherein:
m is selected from NH, oxygen atom or-OCH2-, preferably an oxygen atom;
ring B is selected from C3-6Cycloalkyl radical, C3-6Heterocyclyl or C5-6A meta aryl group; preferably C5-6Cycloalkyl radical, C5-6Heterocyclyl or phenyl, in which C is5-6The heterocyclic ring is substituted with 1-2 atoms containing N, O or S atoms.
RBSelected from hydrogen atoms, halogens, C1-6Alkyl radical, C1-6Haloalkyl or C1-6Hydroxyalkyl, preferably hydrogen atom, halogen, C1-3Alkyl radical, C1-3Haloalkyl or C1-3Hydroxyalkyl group, more preferably hydrogen atom, fluorine atom, methyl group, ethyl group or-C (CH)3)2OH；
Y is selected from a bond or NH;
R4is selected from C1-6Alkyl radical, C3-6Cycloalkyl or amino, preferably C1-3Alkyl radical, C5-6Cycloalkyl or amino, more preferably ethyl and cyclopropyl;
RZselected from hydrogen atoms, C1-8Alkyl radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl; preferably C1-8Alkyl radical, C3-8Cycloalkyl and a hydrogen atom;
r is an integer of 0, 1,2,3, 4 or 5;
R1selected from hydrogen atom, deuterium atom, C1-3Alkyl radical, C5-6Cycloalkyl radical, C5-6A heterocyclic group.
In a preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, has a structure represented by the general formula (ID):
wherein:
R1selected from hydrogen atom, deuterium atom, C1-3Alkyl radical, C5-6Cycloalkyl radical, C5-6A heterocyclic group;
m is selected from NH, oxygen atom or-OCH2-, preferably an oxygen atom;
ring B is selected from C3-6Cycloalkyl radical, C3-6Heterocyclyl or C5-6A meta aryl group; preferably C5-6Cycloalkyl radical, C5-6Heterocyclyl or phenyl, in which C is5-6The heterocyclic ring is substituted with 1-2 atoms containing N, O or S atoms.
RBSelected from hydrogen atoms, halogens, C1-6Alkyl radical, C1-6Haloalkyl or C1-6Hydroxyalkyl, preferably hydrogen atom, halogen, C1-3Alkyl radical, C1-3Haloalkyl or C1-3Hydroxyalkyl group, more preferably hydrogen atom, fluorine atom, methyl group, ethyl group or-C (CH)3)2OH；
R5Independently selected from a bond or SO2R6、NHSO2R6、COH R7R8；
R6Is selected from C1-6Alkyl radical, C3-6Cycloalkyl or amino, preferably C1-3Alkyl radical, C5-6Cycloalkyl or amino, more preferably ethyl and cyclopropyl;
R7or R8Independently selected from a hydrogen atom or C1-6Alkyl, or R7、R8Form a ring selected from C3-6Cycloalkyl or C5-6A heterocyclic group;
R7and R8Preferably methyl, and preferably cyclopropyl when cyclized;
RZselected from hydrogen atoms, C1-8Alkyl radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl; preferably C1-3Alkyl radical, C3-6A cycloalkyl group or a hydrogen atom;
r is an integer of 0, 1,2,3, 4 or 5.
In a preferred embodiment of the present invention, the compound of formula (I) as shown, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, is selected from the following compounds:
in a preferred embodiment of the present invention, there is provided an Intermediate (ID) having the structure:
in a preferred embodiment of the present invention, there is provided a process for preparing a compound of the general formula (I) shown below, a stereoisomer, a deuterated derivative thereof or a pharmaceutically acceptable salt thereof:
wherein:
oxidizing the general formula (ID) with an oxidant to obtain a compound of the general formula (I); the oxidizing agent is preferably m-chloroperoxybenzoic acid,
R1、RXand q is as defined in formula (I).
In a preferred embodiment of the present invention, there is provided an Intermediate (IE) having the structure:
in a preferred embodiment of the present invention, there is provided a method for preparing a compound of the general formula (IC) shown below, a stereoisomer, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof:
wherein:
oxidizing the general formula (IE) with an oxidizing agent to obtain a compound of a general formula (IC); the oxidizing agent is preferably m-chloroperoxybenzoic acid; r1R as in claim 14Ring B, RBM, Y, R and RZAs defined in formula (IC).
In a preferred embodiment of the present invention, there is provided an Intermediate (IF) having the structure:
in a preferred embodiment of the present invention, there is provided a method for preparing a compound of the general formula (IC) shown below, a stereoisomer, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof:
wherein:
the general formula (IF) is substituted by ROH or RNH2Substitution to give a compound of formula (IC); and RNH2During the reaction, the solvent is preferably N-methyl pyrrolidone; when reacting with ROH, the solvent and reactant are preferably N, N-dimethylformamide and sodium hydride;
x is halogen;
R1、R4ring B, RBR and RZAs defined in formula (IC).
Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of each formula, a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
The invention further relates to application of the compound shown in the general formula (I), a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound in preparation of medicines for preventing and/or treating and preventing BRD4 serving as an inhibitor in treatment of cancer, inflammation and AIDS. The BRD4 inhibitor can be used for treating cancer, inflammation, chronic liver disease, diabetes, cardiovascular diseases such as dyslipidemia, AIDS, cancer (including T cell leukemia and colon cancer), inflammatory diseases and autoimmune diseases.
The invention further relates to a compound shown in the general formula (I), a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, and application of a pharmaceutical composition in preparation of BRD4 inhibitor drugs.
The invention further relates to a compound shown in the general formula (I), a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, and application of a pharmaceutical composition in preparing medicaments for treating cancers, inflammations, chronic liver diseases, diabetes, dyslipidemia and other cardiovascular diseases and AIDS.
The present invention also relates to a method for the treatment and/or prophylaxis of diseases of pathological characteristics mediated by BRD4, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof. The BRD4 inhibitors are useful for treating cancer, inflammation, AIDS diseases including viral infections such as AIDS, cancer (including T cell leukemia and colon cancer), inflammatory diseases and autoimmune diseases.
Another aspect of the present invention relates to a method for treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer, a deuterated derivative thereof or a pharmaceutically acceptable salt thereof according to the present invention. The method has remarkable therapeutic effect and less side effects.
Another aspect of the present invention relates to a method for treating inflammation, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer, a deuterated derivative thereof or a pharmaceutically acceptable salt thereof according to the present invention. The method has remarkable therapeutic effect and less side effects.
Another aspect of the present invention relates to a method for treating chronic liver diseases, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer, a deuterated derivative thereof or a pharmaceutically acceptable salt thereof according to the present invention. The method has remarkable therapeutic effect and less side effects.
The above-mentioned cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma, myeloma and non-small cell lung cancer; said chronic liver disease is selected from: primary cirrhosis (PBC), brain xanthoma (CTX), Primary Sclerosing Cholecystitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, extra-intestinal absorption-related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic diseasesToxic hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver transplantation-associated graft-versus-host disease, liver transplantation regeneration of a live donor, congenital liver fibrosis, choledocholithiasis, granulation liver disease, intrahepatic or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha-disease1It is used for treating deficiency of membrane protease.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2)2-, "propylene" means- (CH)2)3-, "butylene" means- (CH)2)4-and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered.
The term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl.
The term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings.
The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2)The ring moiety of a heteroatom, but not comprising-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with tetrahydrofuranyl and pyranyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups.
The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferred is pyrazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "oxo" refers to ═ O.
The term "carboxy" refers to-C (O) OH.
The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl is as defined above.
The term "acyl halide" refers to a compound containing a group that is-C (O) -halogen.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Synthesis of the Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the invention relates to a preparation method of a compound shown as the following general formula, a stereoisomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, which comprises the following steps:
scheme one
Taking the general formula (A-1) as a raw material, and carrying out multi-step reaction to obtain a target compound with the general formula (A); wherein:
X、X1and X2Identical or different, each independently selected from halogen, preferably fluorine and bromine;
R4、RBand r is as defined for formula (IC).
Scheme two
Taking the general formula (B-1) as a raw material, and carrying out multi-step reaction to obtain a target compound of the general formula (B);
wherein:
X3and X4Identical or different, each independently selected from halogen, preferably fluorine and bromine;
R4、RBand r is as defined in formula (IC).
Scheme three
Taking the general formula (C-1) as a raw material, and carrying out multi-step reaction to obtain a target general formula (C) compound;
wherein:
X5、X6same or different, eachIndependently selected from halogen, preferably fluorine and bromine.
Scheme four
Taking the general formula (D-1) as a raw material, and carrying out multi-step reaction to obtain a target general formula (D) compound;
wherein:
X7and X8Identical or different, each independently selected from halogen, preferably fluorine and bromine;
Rzthe definition is described in the general formula (IC).
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS), chemical shift is 10-6(ppm) is given as a unit.
MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
Average inhibition rate of kinase and IC50The values were determined with a NovoStar microplate reader (BMG, Germany).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of Taiwan yellow sea as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organnics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.
In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
In the examples, the reaction temperature was room temperature unless otherwise specified.
The room temperature is the optimum reaction temperature, and the temperature range is 20-30 ℃.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.
The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include: a: dichloromethane 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 and solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acidic or basic reagent can be added for adjustment.
Intermediate one
N- (4- (2, 4-difluorophenoxy) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethanesulfonamide
The first step is the preparation of 2-bromo-1- (2, 4-difluorophenoxy) -4-nitrobenzene
2-bromo-1-fluoro-4-nitrobenzene (14g, 107.7mmol), 2, 4-difluorophenol (19.6g, 89.7mmol) were dissolved in DMSO (100mL), cesium carbonate (35g, 17.7mmol) was added at room temperature, and then stirred at 110 ℃ for 2 hours. The reaction mixture was added with water (150mL), extracted with ethyl acetate (200mL × 1), and the organic phase was washed with saturated brine (100mL × 1), dried over anhydrous sodium sulfate, and concentrated to give 2-bromo-1- (2, 4-difluorophenoxy) -4-nitrobenzene (32g, 86.16mmol, 84% molar yield).
The second step is the preparation of 3-bromo-4- (2, 4-difluorophenoxy) aniline
2-bromo-1- (2, 4-difluorophenoxy) -4-nitrobenzene (29g, 88.4mmol) was dissolved in ethanol (160mL), tetrahydrofuran (160mL), water (56mL), and iron powder (24.7g, 442mmol), ammonium chloride (9.45g, 176.8mmol) were added. Heating to 100 deg.C, stirring for 1.5 hr, filtering with diatomaceous earth, removing solvent from the filtrate, extracting with dichloromethane (250mL), drying the organic phase, and removing dichloromethane from the filtered filtrate under reduced pressure to obtain 3-bromo-4-phenoxyaniline (22.0g, 73.37mmol, 83% molar yield).
MS m/z(ESI):300.1[M+H]+。
The third step is the preparation of N- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide
3-bromo-4-phenoxyaniline (10g, 33.44mmol) was dissolved in dichloromethane (80mL) under ice bath, ethanesulfonyl chloride (5.52g, 43.48mmol), pyridine (5.28g, 66.88mmol) and stirred at room temperature overnight, and the organic phase was washed with hydrochloric acid (2M, 100mL × 2), water (100mL × 2), saturated brine (100mL), dried over anhydrous sodium sulfate and concentrated by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the compound N- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (10.7g,27.42mmol, 82% molar yield).
MS m/z(ESI):392.1.1[M+H]+。
The fourth step: preparation of N- (4- (2, 4-difluorophenoxy) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethanesulfonamide
N- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (500mg, 1.28mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolan) (648mg, 2.55mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantadine (37mg, 0.128mmol), tris (dibenzylideneacetone) dipalladium (35mg, 0.038mmol) and potassium acetate (275mg, 2.82mmol) were dissolved in 1, 4-dioxane (20 mL). The reaction solution was reacted at 80 ℃ for 12 hours under nitrogen protection, and then at 105 ℃ for 5 hours. The reaction mixture was evaporated to dryness, and a crude product was separated by column chromatography (petroleum ether: ethyl acetate: 5:1) to obtain a mixture (500mg) of N- (4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide and N- (4- (2, 4-difluorophenoxy) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethanesulfonamide, which was used directly in the next step.
MS m/z(ESI):440.1[M+H]+。
Intermediate II
2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide
The first step is as follows: preparation of 4-chloro-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide
Mixing 1- (4-chloro-5, 6,7, 8-tetrahydroquinolin-3-yl) ethanone (20.97g,100mmol) and glacial acetic acid under the stirring and heating conditions at the temperature of 60-70 ℃ to obtain a sulfonation stock solution, introducing sulfur trioxide gas into the sulfonation stock solution to perform a sulfonation reaction, and recovering the glacial acetic acid under reduced pressure to obtain a sulfonation product; keeping the temperature at 60-70 ℃, stirring and heating, mixing the sulfonated product with thionyl chloride for chlorination reaction, and recovering the residual thionyl chloride under reduced pressure to obtain 4-chloro-5, 6,7, 8-tetrahydroquinoline-3-sulfonyl chloride; adding the obtained sulfonyl chloride product into ammonia water with the mass concentration of about 20%, and reacting for 3h at the temperature of about 50 ℃; after the reaction is finished, sodium hydroxide solution with the mass concentration of about 40% is added to adjust the pH value to 6.2-7, and the mixture is cooled and crystallized to obtain 4-chloro-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (20.56g,83mmol, 83 percent of molar yield).
MS m/z(ESI):247.7[M+H]+。
The second step is that: preparation of 4-chloro-3-sulfonamido-5, 6,7, 8-tetrahydroquinoline 1-oxidation
Mixing 4-chloro-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (20.56g,83mmol) and an activated carbon supported phosphotungstic acid catalyst (2.0g), stirring, adding hydrogen peroxide (3.4g,100mmol), controlling the reaction temperature at 55 ℃ for reaction, stirring for reaction for 3 hours, cooling to room temperature, separating the activated carbon supported phosphotungstic acid catalyst to obtain 4-chloro-3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxidized solid, and filtering to collect the solid (17.14g, 65mmol, molar yield 78.31%).
MS m/z(ESI):263.7[M+H]+
The third step: preparation of 2-bromo-4-chloro-3-sulfonamido-5, 6,7, 8-tetrahydroquinoline 1-oxidation
Benzoyl bromide (28.6g, 144mmol) was slowly added dropwise to a solution of 4-chloro-3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide (17.14g, 65mmol) in tetrahydrofuran (75mL) for about 1 hour at a temperature of 25-40 ℃. After the completion of the dropwise addition, the reaction was carried out at room temperature for 2 hours. The reaction was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (25mL × 2), the organic phases combined and Na added2SO4Drying and concentrating. The crude product was isolated by column (ethyl acetate: petroleum ether ═ 1:10) to give 2-bromo-4-chloro-3-sulfonamido-5, 6,7, 8-tetrahydroquinoline 1-oxide (15.92g, 48.75mmol, 75% molar yield)
MS m/z(ESI):326.6[M+H]+。
The fourth step: preparation of 4-chloro-2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide
Dissolving 2-bromo-4-chloro-3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide (15.92g, 48.75mmol) in tetrahydrofuran (150mL), adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.46g,2mmol), replacing nitrogen, dropwise adding dimethylzinc (50mL, 1M toluene solution) under ice bath conditions, heating to 80 ℃ after dropwise adding, reacting overnight, and detecting complete reaction by LC/MS. Water (400mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300mL × 1), and the organic phase was washed with saturated brine (300mL × 1), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 9:1) to 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]+。
The fifth step: preparation of 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide
4-chloro-2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (9.76g, 37.29mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2 '-bis (1,3, 2-dioxaborolane) (15.2g, 60mmol), palladium acetate (0.28g, 1.26mmol), [1,1' -biphenyl ] -3-yl dicyclohexyl phosphane (0.876g, 2.5mmol), potassium acetate (18.4g, 187.6mmol) were dissolved in 1, 4-dioxane (100mL), nitrogen was replaced, heating to 100 ℃ was stirred overnight, and the reaction was detected to be complete by LC/MS. Water (200mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (200mL × 1), and the organic phase was washed with saturated brine (200mL × 1), dried over anhydrous sodium sulfate, and concentrated and then purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (9.68g, 27.41mmol, yield 73.5%).
MS m/z(ESI):353.2[M+H]+。
Example one
4- (2- (2, 4-Difluorophenoxy) -5- (ethylsulfanylamino) phenyl) -2-methyl-3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxide
First step preparation of 2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide
4-bromo-2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (3.062g, 10.0mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2 '-bis (1,3, 2-dioxaborolan) (3.2g, 12.9mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.393g, 0.54mmol), potassium acetate (1.6g, 16.12mmol) were dissolved in 1, 4-dioxane (15mL), nitrogen was replaced, heated to 85 ℃ and stirred overnight, and the reaction was detected by LC/MS to be complete. Water (50mL) was added to the reaction mixture, extracted with ethyl acetate (60mL), and the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (3.373g,9.57mmol, 95.7% molar yield).
MS m/z(ESI):352.1[M+H]+。
The second step is the preparation of 4- (2-fluoro-5-nitrophenyl) -2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide
2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (3.373g,9.57mmol), 2-bromo-1-fluoro-4-nitrobenzene (2.09g, 9.55mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.12g, 0.16mmol), potassium carbonate (2.26g,16.35mmol) were dissolved in a mixed solvent of 1, 4-dioxane (32mL) and water (8mL), nitrogen was replaced, heating was carried out to 100 ℃ and stirring was carried out overnight, and the reaction was detected to be complete by LC/MS. Water (50mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80mL), and the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give 4- (2-fluoro-5-nitrophenyl) -2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (2.73g, 7.47mmol, molar yield 78%).
MS m/z(ESI):365.1[M+H]+。
The third step is the preparation of 4- (2- (2, 4-difluorophenoxy) -5-nitrophenyl) -2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide
4- (2-fluoro-5-nitrophenyl) -2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (2.73g, 7.47mmol) and 2, 4-difluorophenol (1.7g, 13.0mmol) were dissolved in dimethyl sulfoxide (10mL), and potassium carbonate (2.7g, 19.5mmol) was added to the solution, which was heated to 100 ℃ and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate (80mL), and the organic phase was washed with saturated sodium carbonate (50mL × 2) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 4- (2- (2, 4-difluorophenoxy) -5-nitrophenyl) -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]+。
The fourth step is the preparation of 4- (5-amino-2- (2, 4-difluorophenoxy) phenyl) -2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide
4- (2- (2, 4-Difluorophenoxy) -5-nitrophenyl) -2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (3.13g,6.57mmol) was dissolved in a mixed solvent of tetrahydrofuran (20mL), ethanol (10mL) and water (10mL), iron powder (2.52g, 45.0mmol) and ammonium chloride (2.40g, 45.0mmol) were added to the above solution, and the mixture was heated to 100 ℃ and stirred for 1 hour. Filtration was carried out, the filtrate was extracted with ethyl acetate (80mL), and the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 4- (5-amino-2- (2, 4-difluorophenoxy) 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]+。
The fifth step is the preparation of 4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfanyl) phenyl) -2-methyl-7-tetrahydroquinoline-3-sulfonamide
4- (2, 4-Difluorophenoxy) -3- (2, 6-dimethylpyridin-4-yl) aniline 4- (5-amino-2- (2, 4-difluorophenoxy) phenyl) -2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (2.33g, 5.21mmol) and pyridine (5mL) were dissolved in dichloromethane (30mL) at room temperature, and ethylsulfonyl chloride (2.01g,15.63mmol) was added dropwise to the reaction system, and stirred at room temperature overnight. After completion of the reaction, ethyl acetate (100mL) was added, and the mixture was washed with a saturated sodium bicarbonate solution (150mL × 3), a saturated brine (100mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product obtained by drying the filtrate was isolated and purified by silica gel plate preparation to obtain 4- (2- (2, 4-difluorophenoxy) -5- (ethanesulfonamido) phenyl) -2-methyl-7-tetrahydroquinoline-3-sulfonamide (1.77g, 3.29mmol, molar yield 63.2%).
MS m/z(ESI):538.6[M+H]+.
Sixthly, preparing 4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfanyl) phenyl) -2-methyl-3-sulfonamide-5, 6,7, 8-tetrahydroquinoline by 1-oxidation
4- (2- (2, 4-Difluorophenoxy) -5- (ethylsulfanylamino) phenyl) -2-methyl-7-tetrahydroquinoline-3-sulfonamide (1.77g, 3.29mmol) was dissolved in tetrahydrofuran (30mL), m-chloroperoxybenzoic acid (1.14g,5.58mmol) was added, the mixture was stirred at room temperature for 1 hour, and LC/MS checked for completion of the reaction. To the reaction mixture was added ethyl acetate (100mL), washed with saturated sodium carbonate solution (100mL × 2), then with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel preparation plate (dichloromethane: methanol: 10:1) to obtain 4- (2- (2, 4-difluorophenoxy) -5- (ethanesulfonamido) phenyl) -2-methyl-3-sulfonamido-5, 6,7, 8-tetrahydroquinoline 1-oxide (0.95g,1.72mmol, 52.3% molar yield).
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]+。
Example two
4- (2- (2, 4-Difluorophenoxy) -5- (ethylsulfanyl) phenyl) -2-ethyl-3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide
Preparation procedure reference example one using 4-bromo-2-ethyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide as starting material gave 4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfanylamino) phenyl) -2-ethyl-3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxo (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]+。
EXAMPLE III
2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfonamido) phenyl) -3-sulfonamido-5, 6,7, 8-tetrahydroquinoline 1-oxide
Preparation procedure reference example one using 4-bromo-2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide as starting material gave 2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfonamido) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide (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 four
2-cyclohexyl-4- (2- ((4-ethylcyclohexyl) oxy) -5- (ethanesulfonamide) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide
Preparation of 2-cyclohexyl-4- (2- ((4-ethylcyclohexyl) oxy) -5- (ethanesulfonamide) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide (1.53g, molar yield 49.8%) using 4-bromo-2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide as starting material and 4-ethylcyclohexanol instead of 2, 4-difluorophenol.
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]+。
EXAMPLE five
5,5,8,8-D-4- (2- (2, 4-difluorophenyloxy) -5- (ethylsulfonylamino) phenyl) -3-sulfonylamino-2- (methyl-D3) -5,6,7, 8-tetrahydroquinoline 1-oxide
Sodium hydride (7.2mg, 0.18mmol, 60% w/w) was added to a solution of 4- (2- (2, 4-difluorophenyloxy) -5- (ethylsulfonamide) phenyl) -2-methyl-3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxidized (49.91mg, 0.09mmol) in deuterated methanol (1 mL). The reaction mixture was reacted at 60 ℃ for 12 hours, cooled to room temperature, adjusted to pH 5 with aqueous hydrochloric acid (1M), and the solvent was removed under reduced pressure, and the crude product was isolated by preparative HPLC to give 5,5,8,8-D-4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfonamido) phenyl) -3-sulfonamido-2- (methyl-D3) -5,6,7, 8-tetrahydroquinoline 1-oxide (49.41mg, 0.06mmol, 69% molar yield).
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]+。
EXAMPLE six
2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (2,2, 2-trifluoromethylsulfanylamino) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxidation
First step preparation of 4- (2- (2, 4-Difluorophenoxy) -5- (trifluoroethylsulfonylamino) phenyl) -2-methyl-7-tetrahydroquinoline-3-sulfonamide
Starting from 4- (2, 4-difluorophenoxy) -3- (2, 6-dimethylpyridin-4-yl) aniline 4- (5-amino-2- (2, 4-difluorophenoxy) phenyl) -2-methyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide, reference was made to the fifth step of the example, substituting ethylsulfonyl chloride with 2,2, 2-trifluoroethyl-sulfonyl chloride to give 4- (2- (2, 4-difluorophenoxy) -5- (trifluoroethylsulfonylamino) phenyl) -2-methyl-7-tetrahydroquinoline-3-sulfonamide (86.7mg, 52.0% molar yield).
MS m/z(ESI):592.6[M+H]+。
Second step preparation of 4- (2- (2, 4-difluorophenoxy) -5- (trifluoroethylsulfonylamino) phenyl) -2-methyl-7-tetrahydroquinoline-3-sulfonamide 1-oxidation
Starting from 4- (2- (2, 4-difluorophenoxy) -5- (trifluoroethylsulfonylamino) phenyl) -2-methyl-7-tetrahydroquinoline-3-sulfonamide, 1-oxo-4- (2- (2, 4-difluorophenoxy) -5- (trifluoroethylsulfonylamino) phenyl) -2-methyl-7-tetrahydroquinoline-3-sulfonamide (68.5mg, molar yield 53.6%) was obtained according to example one.
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]+。
EXAMPLE seven
2-cyclohexyl-4- (2- ((1-ethylpiperidin-4-yl) amino) -5- (ethylsulfonylamino) phenyl) -3-sulfonylamino-5, 6, 78-tetrahydroquinoline 1-oxidation
First step preparation of 2-cyclohexyl-4- (5- (ethylsulfonamido) -2-fluorophenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide
N- (3-bromo-4-fluorophenyl) ethanesulfonamide (0.8g, 2.84mmol), 2-cyclohexyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (2.39g, 5.68mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (130mg, 0.18mmol), and potassium carbonate (2.0g, 14.3mmol) were dissolved in a mixed solvent of 1, 4-dioxane (30mL) and water (10 mL). The reaction was completed by replacing nitrogen, heating to 80 ℃ and stirring overnight and LC/MS detection. Water (50mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60mL), and the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 1) to give 2-cyclohexyl-4- (5- (ethylsulfonamido) -2-fluorophenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (0.95g, 1.92mmol, molar yield 67.6%).
MS m/z(ESI):496.6[M+H]+。
The second step is the preparation of 2-cyclohexyl-4- (5- (ethylsulfonyl) -2-fluorophenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxidation
2-cyclohexyl-4- (5- (ethylsulfonamido) -2-fluorophenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (0.95g, 1.92mmol) was dissolved in tetrahydrofuran (8mL), m-chloroperoxybenzoic acid (0.50g,2.88mmol) was added, the mixture was stirred at room temperature for 2 hours, and LC/MS checked for completion of the reaction. To the reaction mixture was added ethyl acetate (50mL), washed with saturated sodium carbonate solution (50mL × 2), then with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative silica gel chromatography (dichloromethane: methanol ═ 10:1) to give 2-cyclohexyl-4- (5- (ethylsulfonyl) -2-fluorophenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide (0.72g, 1.41mmol, molar yield 73.2%).
MS m/z(ESI)：512.6[M+H]+。
The third step is the preparation of 2-cyclohexyl-4- (2- ((1-ethylpiperidin-4-yl) amino) -5- (ethylsulfonamido) phenyl) -3-sulfonamido-5, 6,7, 8-tetrahydroquinoline 1-oxidation
2-cyclohexyl-4- (5- (ethylsulfonyl) -2-fluorophenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide (0.72g, 1.41mmol) and 4-amino-1-ethylpiperidine (1.21g, 9.45mmol) were dissolved in N-methylpyrrolidone (10mL), heated to 120 ℃ and stirred overnight. The reaction was stopped, cooled to room temperature, ethyl acetate (50mL) was added to the reaction mixture, and the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase preparative chromatography (C18 column, mobile phase (acetonitrile/water)) to give 2-cyclohexyl-4- (2- ((1-ethylpiperidin-4-yl) amino) -5- (ethylsulfanyl) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide (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]+。
Example eight
2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (ethylsulfonylamino) -4- (1H-pyrazol-1-yl) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxide
The first step is the preparation of 1-bromo-2- (2, 4-difluorophenoxy) -4-iodo-5-nitrobenzene
1-bromo-2-fluoro-4-iodo-5-nitrobenzene (1.07g,3.09mmol) was dissolved in acetonitrile (20mL) at room temperature, and then 2, 4-difluorophenol (0.80g,6.18mmol) and sodium carbonate (0.66g,6.18mmol) were added to the reaction solution, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate (40mL), the organic phase was washed with saturated brine (10mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spinning, and the crude product was separated by column chromatography (pure petroleum ether as mobile phase) to give 1-bromo-2- (2, 4-difluorophenoxy) -4-iodo-5-nitrobenzene (0.53g, yellow solid, 1.16mmol, molar yield 37%).
The second step is the preparation of 1-bromo-4-cyclopropyl-2- (2, 4-difluorophenoxy) -5-nitrobenzene
1-bromo-2- (2, 4-difluorophenoxy) -4-iodo-5-nitrobenzene (0.53g,1.16mmol), cyclopropylboronic acid (0.15g,1.74mmol), potassium phosphate (0.49g,2.32mol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.085g,0.13mmol) were dissolved in anhydrous dioxane (10mL) at room temperature, replaced with nitrogen three times, heated to 90 ℃ and reacted for 14 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (30mL), filtered through celite, the celite was washed with ethyl acetate (20mL), the organic phase was washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by column chromatography (pure petroleum ether as mobile phase) to give 1-bromo-4-cyclopropyl-2- (2, 4-difluorophenoxy) -5-nitrobenzene (0.35g, yellow solid, 0.95mmol, molar yield 82%).
The third step is the preparation of 5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) aniline
1-bromo-4-cyclopropyl-2- (2, 4-difluorophenoxy) -5-nitrobenzene (0.15g,0.41mmol) and tin dichloride dihydrate (0.26g,1.13mol) were dissolved in ethanol (10mL) and water (0.5mL) at room temperature and stirred at room temperature for 14 hours. After completion of the reaction, ethanol was dried under reduced pressure, ice water (15mL) and aqueous sodium hydroxide solution (2N,15mL) were added to the residue, the aqueous phase was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, the organic phase was washed with saturated brine (15 mL. times.3), dried over anhydrous sodium sulfate, filtered, dried, and the crude product was separated with a preparative plate (PE: EA: V/V:1:1) to give 5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) aniline (0.08g,0.24mmol, 58% molar yield).
MS m/z(ESI):340.0,342.0[M+H]+.
The fourth step is the preparation of N- (5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide
5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) aniline (0.08g,0.24mmol) and pyridine (0.037g,0.47mmol) were dissolved in dichloromethane (10mL) at room temperature, and ethylsulfonyl chloride (0.06g,0.47mmol) was added dropwise to the reaction system, heated to 50 ℃ and reacted for four hours. After the reaction was complete, the dichloromethane was dried, the crude product was dissolved in ethyl acetate (30mL), the organic phase was washed with saturated sodium bicarbonate solution (15mL x 3), saturated brine (10mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, dried and the crude product was isolated with a preparative plate (petroleum ether: ethyl acetate: 3:1) to give N- (5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (0.07g, white solid, 0.16mmol, 70% molar yield).
MS m/z(ESI):432.0,434.0[M+H]+.
The fifth step is the preparation of 2-cyclohexyl-4- (4-cyclopropyl-2- (2, 4-difluorophenoxy) -5- (ethylsulfanyl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide
N- (5-bromo-2-cyclopropyl-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide (0.06g,0.14mmol), 2-cyclohexyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (0.042g,0.28mmol), potassium carbonate (0.12g,0.28mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.01g,0.014mmol) were dissolved in dioxane (4mL) and water (1mL) at room temperature, replaced with nitrogen three times, heated to 100 ℃ and reacted for four hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with ethyl acetate (20mL), filtered through celite, the celite was washed with ethyl acetate (20mL), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated on a preparation plate (petroleum ether: ethyl acetate ═ 3:1) to give 2-cyclohexyl-4- (4-cyclopropyl-2- (2, 4-difluorophenoxy) -5- (ethylsulfanylamino) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (0.07g, pale yellow oil, 0.11mmol, 76.3% molar yield).
MS m/z(ESI):646.7[M+H]+.
The sixth step is the preparation of 1-oxidation of 2-cyclohexyl-4- (4-cyclopropyl-2- (2, 4-difluorophenoxy) -5- (ethanesulfonamide) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide
2-cyclohexyl-4- (4-cyclopropyl-2- (2, 4-difluorophenoxy) -5- (ethanesulfonamide) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (0.07g, 0.11mmol) was dissolved in dichloromethane (5mL) under ice-cooling, and m-chloroperoxybenzoic acid (85%, 0.033g,0.16mmol) was added to the reaction mixture and reacted for half an hour. After the reaction was completed, the reaction solution was diluted with dichloromethane (20mL), the organic phase was washed with saturated sodium bicarbonate solution (10mL x 3), saturated brine (10mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by reverse phase preparative chromatography to give 2-cyclohexyl-4- (4-cyclopropyl-2- (2, 4-difluorophenoxy) -5- (ethanesulfonamide) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxide (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]+.
Example nine
2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (ethanesulfonylamino) -4- (piperidin-4-yl) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxide
The first step is as follows: preparation of tert-butyl 4- (4-bromo-5- (2, 4-difluorophenoxy) -2-nitrophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate
1-bromo-2- (2, 4-difluorophenoxy) -4-iodo-5-nitrobenzene (0.20g,0.44mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (0.16g,0.53mmol), potassium phosphate (0.19g,0.88mol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.032g,0.044mmol) were dissolved in anhydrous dioxane (10mL) at room temperature, replaced with nitrogen three times, heated to 90 ℃ and reacted for 14 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (30mL), filtered through celite, the celite was washed with ethyl acetate (20mL), the organic phase was washed with saturated brine (10mL × 3), dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give tert-butyl 4- (4-bromo-5- (2, 4-difluorophenoxy) -2-nitrophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (0.125g, pale yellow solid, 0.24mmol, molar yield 55.6%).
MS m/z(ESI):511.0,513.0。
The second step is that: preparation of 4- (4- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2- (2, 4-difluorophenoxy) -5-nitrophenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide
Tert-butyl 4- (4-bromo-5- (2, 4-difluorophenoxy)) -2-nitrophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (0.12g,0.23mmol), 2-cyclohexyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (0.071g,0.47mmol), potassium carbonate (0.065g,0.47mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.017g,0.023mmol) were dissolved in dioxane (6mL) and water (2mL) at room temperature, replaced with nitrogen three times, heated to 90 ℃ and reacted for fourteen hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with ethyl acetate (20mL), filtered through celite, the celite was washed with ethyl acetate (20mL), the organic phases were combined and washed with brine (10mL × 3), dried over anhydrous sodium sulfate, filtered, spun to dryness, and the crude product was separated on a preparative plate (petroleum ether: ethyl acetate 1:1) to give 4- (4- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2- (2, 4-difluorophenoxy) -5-nitrophenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (0.109g, colorless oil, 0.15mmol, molar yield 65.2%).
MS m/z(ESI):725.8[M+H]+.
The third step: preparation of 4- (5-amino-4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2, 4-difluorophenoxy) phenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide
4- (4- (1- (tert-Butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2- (2, 4-difluorophenoxy) -5-nitrophenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (0.073g, 0.10mmol) was dissolved in tetrahydrofuran (5mL) at room temperature, and palladium on carbon (0.010g) was added thereto, followed by stirring at room temperature for fourteen hours under a hydrogen atmosphere. After the reaction was completed, palladium on carbon was removed by filtration, and the crude product, 4- (5-amino-4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2, 4-difluorophenoxy) phenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (0.056g, crude product was used in the next step as it was) was obtained by spin-drying.
MS m/z(ESI):697.8[M+H]+.
The fourth step: preparation of 4- (4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2, 4-difluorophenoxy) -5- (ethanesulfonylamino) phenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide
4- (5-amino-4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2, 4-difluorophenoxy) phenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (0.056g,0.08mmol) and pyridine (0.026g,0.32mmol) were dissolved in dichloromethane (5mL) at room temperature, and ethylsulfonyl chloride (0.025g,0.20mmol) was added dropwise to the reaction system and reacted at room temperature for fourteen hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (20mL), the organic phase was washed with saturated sodium bicarbonate solution (15mL × 3), saturated brine (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated with a preparation plate (petroleum ether: ethyl acetate ═ 1:1) to give 4- (4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2, 4-difluorophenoxy) -5- (ethanesulfonamide) 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]+.
The fifth step: preparation of 4- (4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2, 4-difluorophenoxy) -5- (ethanesulfonylamino) phenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxide
4- (4- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2- (2, 4-difluorophenoxy) -5- (ethanesulfonamide) phenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide (0.029g,0.037mmol) was dissolved in dichloromethane (5mL) at room temperature, and then m-chloroperoxybenzoic acid (85%, 0.010g,0.050mmol) was added to the reaction solution and reacted for one hour. After completion of the reaction, the reaction mixture was diluted with dichloromethane (20mL), the organic phase was washed with saturated sodium bicarbonate solution (10mL x 3), saturated brine (10mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give a crude product, 4- (4- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (2, 4-difluorophenoxy) -5- (ethanesulfonamide) phenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxide (0.025g, 0.031mmol, 83% molar yield).
MS m/z(ESI):805.9[M+H]+.
And a sixth step: preparation of 2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (ethanesulfonylamino) -4- (piperidinyl-4-yl) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxide
4- (4- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2- (2, 4-difluorophenoxy) -5- (ethanesulfonamide) phenyl) -2-cyclohexyl-5, 6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxide (0.025g, 0.031mmol) was dissolved in methylene chloride (3mL) under ice-cooling, and trifluoroacetic acid (0.3mL) was added dropwise to the reaction system and reacted at room temperature for one hour. After the reaction was complete, the dichloromethane was dried, the crude product was dissolved in ethyl acetate (20mL), the organic phase was washed with saturated sodium bicarbonate solution (10mL x 3), saturated brine (10mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, dried, and the crude product was isolated by reverse phase preparative chromatography to give 2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (ethanesulfonamide) -4- (piperidinyl-4-yl) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide (0.008g, white solid, 0.011mmol, 34.8% molar yield).
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]+.
Example ten
2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxide
The first step is as follows: preparation of 2, 4-difluorophenol
N-butyllithium (11mL, 17.7mmol, 1.6M) was added dropwise to a solution of 1-bromo-2, 4-difluorobenzene (3g, 15.5mmol) in tetrahydrofuran (30mL) at-78 deg.C under nitrogen. The reaction was stirred under nitrogen-78 ℃ for 30 minutes and then trimethyl borate (1.84g, 17.7mmol) was added. After completion of the dropwise addition, the reaction solution was slowly warmed to room temperature and stirred for 12 hours. A solution of sodium hydroxide (0.88g, 22mmol) in hydrogen peroxide (24mL, 30% w/w) was added dropwise to the reaction mixture at-15 ℃. After completion of the dropwise addition, the reaction solution was stirred at room temperature for 3 hours, quenched with aqueous hydrochloric acid (1M), and adjusted to pH 1. Ethyl acetate (75mL × 2) was extracted, washed with saturated brine (100mL × 3), and the organic phase was dried and evaporated to dryness to give a crude product. Column separation (petroleum ether: ethyl acetate ═ 5:1) afforded 2, 4-difluorophenol (1.80g, 13.87mmol, 89.5% molar yield).
1H NMR(400MHz,DMSO-d6)δ:8.12(br,1H),6.74(d,J＝9.3Hz,2H),2.14(s,6H).
MS m/z(ESI):130.09[M+H]+.
The second step is that: preparation of methyl 3-bromo-4- (2, 4-difluorophenoxy) benzoate
Cesium carbonate ((3.1g, 9.6mmol) was added to a solution of 2, 4-difluorophenol (0.83g, 6.4mmol) and methyl 3-bromo-4-fluorophenyl ester (1.57g, 6.7mmol) in dimethylsulfoxide (10 mL.) the reaction solution was stirred at 80 ℃ for 12 hours, cooled to room temperature, then water (50mL) was added, ethyl acetate (50mL x 2) was extracted the organic phase was washed with saturated brine (25mL x 4), dried and evaporated to dryness to give crude product which was subjected to column separation (petroleum ether: ethyl acetate ═ 20:1) to give methyl 3-bromo-4- (2, 4-difluorophenoxy) benzoate (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).
The third step: preparation of 2- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) propan-2-ol
Methyl magnesium bromide (13.83mL, 13.83mmol, 1M) was added dropwise to a solution of methyl 3-bromo-4- (2, 4-difluorophenoxy) benzoate (1.58g, 4.61mmol) in tetrahydrofuran (30mL) at 0 ℃ under nitrogen. The reaction was stirred at room temperature for 10 hours under nitrogen, and then quenched with saturated ammonium chloride. Ethyl acetate (75mL × 2) was extracted, washed with saturated brine (100mL × 3), and the organic phase was dried and evaporated to dryness to give a crude product. Column separation (petroleum ether: ethyl acetate ═ 5:1) gave 2- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) propan-2-ol (1.50g, 4.38mmol, 95% molar yield).
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]+.
The fourth step: preparation of 2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline
Tris (dibenzylideneacetone) dipalladium (7.7mg, 8.4umol) was added to a mixture of 2- (3-bromo-4- (2, 4-difluorophenoxy) phenyl) propan-2-ol (96.1mg, 0.28mmol), 2-cyclohexyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (102.3mg, 0.28mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane (8.2mg, 28 μmol) and potassium phosphate (118mg, 0.56mmol) in dioxane (8mL) and water (2 mL). The reaction solution was stirred at 60 ℃ for 12 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (30mL × 2), washed with saturated brine (30mL × 2), and dried to dryness to obtain a crude product. Crude product was isolated by preparative plate chromatography (petroleum ether: ethyl acetate ═ 2:1) to give 2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -3-sulfonamido-5, 6,7, 8-tetrahydroquinoline (122.7mg, 0.22mmol, 77.2% molar yield).
MS m/z(ESI):557.7[M+H]+。
The fifth step: preparation of 2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxide
M-chloroperoxybenzoic acid (62mg, 0.31mmol, 85% w/w) was added to a solution of 2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline (122.7mg, 0.22mmol) in dichloromethane (5 mL). The reaction was carried out at room temperature for 20 minutes, extracted with dichloromethane, washed with saturated sodium bicarbonate, dried and evaporated to dryness to obtain a crude product, which was separated by preparative HPLC to give 2-cyclohexyl-4- (2- (2, 4-difluorophenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -3-sulfonamido-5, 6,7, 8-tetrahydroquinoline 1-oxide (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]+。
EXAMPLE eleven
Preparation of 2-cyclohexyl-4- (5- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxide
The first step is as follows: preparation of 1- (3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) phenyl) ethanone
2, 6-dimethyl-4-fluorophenol (1.86g, 13.3mmol), 1- (3-bromo-4-fluorophenyl) ethan-1-one (4.33g, 19.95mmol) and potassium carbonate (3.68g, 26.6mmol) were dissolved in N, N-dimethylacetamide (40mL) at room temperature, heated to 80 ℃ and reacted for 14 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50mL), washed with saturated brine (3 × 10mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give 1- (3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) phenyl) ethanone (4.33g, yellow oil, 12.85mmol, 96.6% molar yield).
The second step is that: preparation of 2- (3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) phenyl) propan-2-ol
Dissolving 1- (3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) phenyl) ethanone (0.60g, 1.78mmol) in anhydrous tetrahydrofuran (5mL) under ice bath, replacing nitrogen, then adding methyl magnesium bromide diethyl ether solution (3.0M, 0.85mL, 2.56mmol) dropwise into the reaction system, stirring under ice bath, then reacting at room temperature for 3 hours, then adding saturated ammonium chloride solution (20mL) dropwise to quench the reaction, then extracting with ethyl acetate (3 x 15mL), combining the organic phases, washing with brine (2 x 10mL), drying the organic phases with anhydrous sodium sulfate, filtering, spin-drying, separating and purifying the crude product by silica gel column chromatography (petroleum ether: ethyl acetate ═ 7: 1) to obtain 2- (3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) phenyl) propan-2-ol (0.32 g), colorless oil, 0.91mmol, 51.2% molar yield).
The third step: preparation of 2-cyclohexyl-4- (5- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline
2- (3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) phenyl) propan-2-ol (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-phosphoadamantane (0.005g, 0.0165mmol) were dissolved in a mixed solvent of tetrahydrofuran and water (4mL:1mL) at room temperature, nitrogen was replaced, heating was performed to 60 ℃, and then 2-cyclohexyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (0.030g, 0.083mmol) of tetrahydrofuran (2mL) was added dropwise to the reaction system, the reaction was carried out for 14 hours, cooled to room temperature, the reaction solution was diluted with ethyl acetate (30mL), filtered, the organic phase was washed with saturated brine (2 x 10mL), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was isolated on a silica gel preparation plate to give 2-cyclohexyl-4- (5- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline (white solid, 0.017g, 0.030mmol, molar yield 35.8%).
MS m/z(ESI)：567.7[M+H]+。
The fourth step: preparation of 2-cyclohexyl-4- (5- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxide
M-chloroperoxybenzoic acid (62mg, 0.31mmol, 85% w/w) was added to a solution of 2-cyclohexyl-4- (5- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline (141.93mg, 0.25mmol) in dichloromethane (5 mL). Reaction at room temperature for 20 minutes, extraction with dichloromethane, washing with saturated sodium bicarbonate, drying of the organic phase to dryness to give a crude product, which was separated by preparative HPLC to give 2-cyclohexyl-4- (5- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxide (95.14mg, 0.163mmol, 65% molar yield).
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]+。
Example twelve
Preparation of 2-cyclohexyl-4- (2- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropane) phenyl) -3-sulfonylamino-5, 6,7, 8-tetrahydroquinoline 1-oxide
The first step is as follows: preparation of 4-fluoro-2, 6-dimethylphenol
N-butyllithium (11mL, 17.7mmol, 1.6M) was added dropwise to a solution of 2-bromo-5-fluoro-1, 3-dimethylbenzene (3g, 14.8mmol) in tetrahydrofuran (30mL) at-78 ℃ under nitrogen. The reaction was stirred under nitrogen-78 ℃ for 30 minutes and then trimethyl borate (1.84g, 17.7mmol) was added. After completion of the dropwise addition, the reaction solution was slowly warmed to room temperature and stirred for 12 hours. A solution of sodium hydroxide (0.88g, 22mmol) in hydrogen peroxide (24mL, 30% w/w) was added dropwise to the reaction mixture at-15 ℃. After completion of the dropwise addition, the reaction solution was stirred at room temperature for 3 hours, quenched with aqueous hydrochloric acid (1M), and adjusted to pH 1. Ethyl acetate (75mL × 2) was extracted, washed with saturated brine (100mL × 3), and the organic phase was dried and evaporated to dryness to give a crude product. Column separation (petroleum ether: ethyl acetate ═ 5:1) afforded 4-fluoro-2, 6-dimethylphenol (1.8g, 12.73mmol, molar yield 86%).
1H NMR(400MHz,DMSO-d6)δ:8.12(br,1H),6.74(d,J＝9.3Hz,2H),2.14(s,6H).
MS m/z(ESI):140.2[M+H]+。
The second step is that: preparation of methyl 3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) benzoate
Cesium carbonate (3.1g, 9.6mmol) was added to a solution of 4-fluoro-2, 6-dimethylphenol (0.9g, 6.4mmol) and methyl 3-bromo-4-fluoroacrylate (1.57g, 6.7mmol) in dimethylsulfoxide (10 mL). The reaction mixture was stirred at 80 ℃ for 12 hours, cooled to room temperature, and then extracted with water (50mL) and ethyl acetate (50mL × 2). The organic phase was washed with saturated brine (25mL 4), dried and evaporated to dryness to give the crude product. The crude product was isolated by column (petroleum ether: ethyl acetate ═ 20:1) to give methyl 3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) benzoate (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]+。
The third step: preparation of 2- (3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) phenyl) propan-2-ol
Methyl magnesium bromide (11.9mL, 11.9mmol, 1M) was added dropwise to a solution of methyl 3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) benzoate (1.4g, 4.0mmol) in tetrahydrofuran (30mL) at 0 ℃ under nitrogen blanket. The reaction was stirred at room temperature for 10 hours under nitrogen, and then quenched with saturated ammonium chloride. Ethyl acetate (75mL × 2) was extracted, washed with saturated brine (100mL × 3), and the organic phase was dried and evaporated to dryness to give a crude product. Column separation (petroleum ether: ethyl acetate ═ 5:1) gave 2- (3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) phenyl) propan-2-ol (1.3g, 3.72mmol, 93% molar yield).
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]+。
The fourth step: preparation of 2-cyclohexyl-4- (2- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide
Tris (dibenzylideneacetone) dipalladium (7.7mg, 8.4umol) was added to methyl 2- (3-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) phenyl) propan-2-ol (98.90mg, 0.28mmol), 2-cyclohexyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (102.3mg, 0.28mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane (8.2mg, 28. mu. mol) and potassium phosphate (118mg, 0.56mmol) in a mixture of dioxane (8mL) and water (2 mL). The reaction solution was stirred at 60 ℃ for 12 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (30mL × 2), washed with saturated brine (30mL × 2), and dried to dryness to obtain a crude product. Crude product was isolated by preparative plate chromatography (petroleum ether: ethyl acetate ═ 2:1) to give 2-cyclohexyl-4- (2- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide (119mg, 0.21mmol, 73.6% yield).
MS m/z(ESI):567.7[M+H]+。
The fifth step: preparation of 2-cyclohexyl-4- (2- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxidation
M-chloroperoxybenzoic acid (62mg, 0.31mmol, 85% w/w) was added to a solution of 2-cyclohexyl-4- (2- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonic acid (130.57mg, 0.23mmol) in dichloromethane (10 mL). The reaction was carried out at room temperature for 20 minutes, extracted with dichloromethane, washed with saturated sodium bicarbonate, dried and evaporated to dryness to obtain a crude product, which was separated by preparative HPLC to give 2-cyclohexyl-4- (2- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxide (46.7mg, 0.08mmol, 34.5% molar yield).
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]+。
EXAMPLE thirteen
Preparation of 2-cyclohexyl-4- (2- (4-chloro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxidation
Preparation procedure reference example twelve, starting from 4-fluoro-2, 6-dimethylphenol, gave the product 2-cyclohexyl-4- (2- (4-chloro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxidized (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]+。
Example fourteen
Preparation of 2-cyclohexyl-4- (2- (4-bromo-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxidation
Preparation procedure reference example twelve, starting from 4-bromo-2, 6-dimethylphenol, gave the product 2-cyclohexyl-4- (2- (4-bromo-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5,6,7, 8-tetrahydroquinoline-3-sulfonamide 1-oxidized (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]+。
Example fifteen
Preparation of 2-cyclohexyl-4- (5- (2-hydroxypropan-2-yl) -2- (4- (2-hydroxypropan-2-yl) -2, 6-dimethylphenoxy) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxidation
Preparation procedure reference example twelve, starting from 4- (2-hydroxypropan-2-yl) -2, 6-dimethylphenol, gave the product 2-cyclohexyl-4- (5- (2-hydroxypropan-2-yl) -2- (4- (2-hydroxypropan-2-yl) -2, 6-dimethylphenoxy) phenyl) -3-sulfonamide-5, 6,7, 8-tetrahydroquinoline 1-oxidized (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 evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 determination of BRD4 binding Activity of Compounds of the present invention
BRD4 binding activity assay was tested by the following method.
This method was used to determine the inhibitory effect of the compounds of the present invention on BRD4 binding activity.
Experimental procedure
To test the effect of compounds on the binding of BRD4 to acetylated proteins, the inhibition of BRD4 binding to acetylated substrates was tested using fluorescence resonance energy transfer (TR-FRET) andthe median inhibitory concentration IC of the compound on the binding activity of BRD4 was determined50。
The specific experimental operations were as follows:
1. adding 1-5 mul BRD4 enzyme solution into a 384-well plate, wherein the final enzyme concentration is 1-20 nM;
2. adding 1-5 mu L of the compound solution diluted in a gradient manner;
3. adding 1-5 mu L of substrate mixed solution containing acetylated substrate polypeptide with the final concentration of 2-50 nM;
4. incubating for 0.5-3 hours at room temperature;
5. adding 10 mu L of EDTA and detection solution containing a labeled antibody, and incubating for 1 hour at room temperature;
6. the enzyme-linked immunosorbent assay measures the 665nm fluorescence signal value of each plate hole;
7. calculating the inhibition rate through the fluorescence signal value;
8. obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations50。
The BRD4 binding activity of the compounds of the invention was determined by the above assay, and the IC measured50The values are shown in Table 1.
TABLE 1 inhibition of BRD4 binding Activity IC by the Compounds of the invention50
| Example numbering | IC50(nM) | Example numbering | 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 | / | / |
And (4) conclusion: the compound of the invention has obvious inhibition effect on BRD4 binding activity.
Test example 2 test Compounds inhibitory Activity on BRD4BD1 or BD2
Purpose of the experiment: the purpose of this test example was to determine the inhibitory effect of the compounds of the present invention on the binding activity of BRD4BD1 or BD 2.
An experimental instrument: the centrifuge (5810R) is purchased from Eppendorf company, the pipettor is purchased from Eppendorf or Rainin company, and the microplate reader is purchased from BioTek company in the United states and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps: to test the effect of compounds on the binding of BRD4BD1 or BD2 to acetylated proteins, the inhibition of BRD4BD1 or BD2 to acetylated substrates was tested using the fluorescence resonance energy transfer (TR-FRET) method and the half inhibitory concentration IC of the compound on BRD4BD1 or BD2 binding activity was determined50。
The specific experimental operations were as follows:
1. adding 1-5 μ L of BRD4BD1 or BD2 enzyme (from BPS Bioscience) solution into a 384-well plate, wherein the final concentration of the enzyme is 1-20 nM;
2. adding 1-5 mu L of the compound solution diluted in a gradient manner;
3. adding 1-5 μ L of substrate mixture containing acetylated substrate polypeptide (from BPS Bioscience) at a final concentration of 2-50 nM;
4. incubating for 0.5-3 hours at room temperature;
5. add 10. mu.L EDTA and labeled antibody containing assay (purchased from Cisbio) and incubate for 1 hour at room temperature;
6. the enzyme-linked immunosorbent assay measures the 665nm fluorescence signal value of each plate hole;
7. calculating the inhibition rate through the fluorescence signal value;
8. obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations50。
The binding activity of the compounds of the present invention to BRD4BD1 or BD2 was determined by the above assay, and the IC was determined50The values are shown in Table 2.
TABLE 2 inhibition of BRD4BD1 or BD2 binding Activity by Compounds of the invention IC50
And (4) conclusion: the compound has obvious inhibition effect on the binding activity of BRD4BD2, has no obvious inhibition activity on BRD4BD1, and shows good selective inhibition effect.
Test example 3 Effect of the Compounds of the present invention on the proliferative Activity of leukemia cells MV4-11
The effect of the compounds on the proliferative activity of leukemia cells MV4-11 was tested by the following method.
This method was used to determine the effect of the compounds of the invention on the proliferative activity of leukemia cells MV 4-11.
The experiment adopts a CellTiter-Glo method to test the inhibition effect of the compound on the proliferation of MV4-11 cells and obtains the half inhibition concentration IC of the compound for inhibiting the cell proliferation activity50。
The experimental steps are as follows:
1. inoculating 50-100 mu L of MV4-11 cell suspension with the density of 1-5 x 10 in a 96-well cell culture plate4cells/mL, the plates were incubated in an incubator for 16-24 hours (37 ℃ C., 5% CO)2)。
2. To the cells of the plate, solutions of the test compounds at different concentrations were added in a gradient and the plate was incubated in an incubator for 72 hours (37 ℃ C., 5% CO)2)。
3. 50-100. mu.L of CellTiter-Glo reagent was added to each well, shaken for 10 minutes, and allowed to stand at room temperature for 10 minutes.
4. The microplate reader measures the chemiluminescence signal value of each plate.
5. The inhibition rate was calculated from the chemiluminescence signal value.
6. Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations50。
Assay for the proliferative Activity of Compounds of the invention on leukemia cells MV4-11, IC determined50The values are shown in Table 3.
TABLE 3 inhibition of the proliferative Activity of the Compounds of the invention on leukemia cells MV4-11 IC50
| Example numbering | IC50(nM) | Example numbering | 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 example 4 PK assay test of the Compound of the present invention on mice
The mouse pharmacokinetic experiments of the preferred embodiment of the invention were performed using Balb/c mice (Shanghai Jitsie laboratory animals Co., Ltd.).
The administration mode comprises the following steps: single administration by gavage
Administration dose: 5 mg/10 ml/kg
The preparation prescription is as follows: 0.5% CMC-Na and 1% Tween 80, ultrasonic dissolving
Sampling points are as follows: 0.5, 1,2, 4, 6, 8 and 24 hours after administration
Sample treatment:
collecting blood in vein of 0.1mL, placing in K2Centrifuging the plasma in an EDTA test tube at the room temperature of 1000-3000 Xg for 5-20 min, and storing the plasma at-80 ℃.
Adding 160 mul acetonitrile into 40 mul of the plasma sample for precipitation, mixing, and centrifuging for 5-20 minutes at 500-2000 Xg.
Taking 100 mu L of the treated supernatant solution for LC/MS/MS analysis to analyze the concentration of the compound to be detected, and using an LC/MS/MS analysis instrument: AB Sciex API 4000.
Liquid phase conditions: shimadzu LC-20AD pump
A chromatographic column: phenomenex Gemiu 5 mu m C1850X 4.6mm
Mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile
Flow rate: 0.8mL/min
Pharmacokinetics:
the main parameters were calculated by WinNonlin 6.1, and the mouse pharmacokinetic experiment results are shown in Table 4
Table 4 PK experiment of the Compounds of the invention on mice
As can be seen from the results of the mouse pharmacokinetic experiments in the table: the compounds of the examples of the invention show good metabolic properties, exposure AUC and maximum blood concentration CmaxAll performed well.
Claims (10)
1. A compound shown as a general formula (ID), a deuterated derivative or a pharmaceutically acceptable salt thereof has the following structure:
wherein:
R1selected from hydrogen atom, deuterium atom, C1-3Alkyl radical, C5-6A cycloalkyl group;
m is selected from NH or oxygen atom;
ring B is selected from C5-6Cycloalkyl radical, C5-6Heterocyclyl or phenyl;
RBselected from hydrogen atoms, halogens, C1-3Alkyl radical, C1-3Haloalkyl or C1-3A hydroxyalkyl group;
R5selected from NHSO2R6、COHR7R8；
R6Is selected from C1-3An alkyl group;
R7and R8Independently selected from methyl;
RZis selected from C3-6A cycloalkyl group or a hydrogen atom;
r is an integer of 0, 1,2,3, 4 or 5.
2. The compound of formula (ID), deuterated derivative or pharmaceutically-acceptable salt thereof as claimed in claim 1 wherein R isBSelected from a hydrogen atom, a fluorine atom, a methyl group, an ethyl group or-C (CH)3)2OH。
3. The compound of formula (ID), deuterated derivative or pharmaceutically-acceptable salt thereof as claimed in claim 1 wherein R is6Selected from ethyl.
4. The compound, deuterated derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the structure shown in formula (IB):
wherein:
RUand RVIs methyl;
RWselected from hydrogen atoms, halogens, C1-3Alkyl radical, C1-3Haloalkyl or-C (CH)3)2OH；
t is an integer of 0, 1,2,3, 4 or 5;
R1is selected from C5-6Cycloalkyl or C1-3An alkyl group.
5. The compound, deuterated derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the structure according to formula (IC):
wherein:
m is selected from NH or oxygen atom;
ring B is selected from C5-6A cycloalkyl group;
RBselected from fluorine atoms;
y is selected from NH;
R4is selected from ethyl;
RZselected from hydrogen atoms;
r is an integer of 0, 1,2,3, 4 or 5.
6. A compound or deuterated derivative or pharmaceutically acceptable salt thereof, wherein the compound has the structure:
7. the process for the preparation of a compound of formula (IC), a deuterated derivative or a pharmaceutically acceptable salt thereof as claimed in claim 5, comprising the step of oxidizing a compound of formula (IE) with an oxidizing agent to obtain a compound of formula (IC):
wherein:
the oxidant is m-chloroperoxybenzoic acid;
R1r as in claim 14Ring B, RBM, Y, R and RZAs claimed in claim 5.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (ID), a deuterated derivative or a pharmaceutically acceptable salt thereof as set forth in any one of claims 1-5 and one or more pharmaceutically acceptable carriers.
9. Use of a compound of general formula (ID), a deuterated derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 or a pharmaceutical composition according to claim 8 for the preparation of a BRD4 inhibitor medicament.
10. Use of a compound, deuterated derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 or a pharmaceutical composition according to claim 8 as a BRD4 inhibitor for the manufacture of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS; wherein the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, glioma, glioblastoma, leukemia, lymphoma, myeloma; the chronic liver disease is selected from primary sclerosis, brain tendon xanthoma, primary sclerosing cholecystitis, drug-induced cholestasis, intrahepatic cholestasis of pregnancy, extra-intestinal absorption-related cholestasis, bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver transplantation-related graft-versus-host disease, live donor liver transplantation regeneration, congenital liver fibrosis, choledocholithiasis, granulation liver disease, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha-alpha disease1It is used for treating deficiency of membrane protease.
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