CN107793360A - Indoleamine 2,3 dioxygenase inhibitors and application - Google Patents

Indoleamine 2,3 dioxygenase inhibitors and application Download PDF

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CN107793360A
CN107793360A CN201710768867.5A CN201710768867A CN107793360A CN 107793360 A CN107793360 A CN 107793360A CN 201710768867 A CN201710768867 A CN 201710768867A CN 107793360 A CN107793360 A CN 107793360A
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hydroxyl
hydrogen
nitro
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CN107793360B (en
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吴永谦
杨民民
李进
王琳
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Yaojie Ankang (Nanjing) Technology Co.,Ltd.
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Transthera Bioscience Co Ltd
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Abstract

The invention belongs to pharmaceutical technology field, and in particular to compound, its pharmaceutically acceptable salt, isomers and prodrug shown in Formulas I, R1、R2、R3, X, m, n and ring A be defined as in the description；The invention further relates to these compound medicine preparations, pharmaceutical composition and its in indoleamine 2, therapeutical uses in the relevant disease of 3 dioxygenases (IDO) mediation, especially treat the tumor-specific immunity relevant with cancer to suppress, strengthen the validity of anti-cancer therapies.

Description

Indole amine 2,3-dioxygenase inhibitor and application
Technical field
The invention belongs to pharmaceutical technology field, is related to IDO (IDO) inhibitor compound, its pharmacy Upper acceptable salt or its isomers and its application, this kind of compound have efficient to IDO (IDO) With the inhibitory action of high selectivity, the treating correlative diseases of IDO mediation are can apply to.
Background technology
Tryptophan (Trp) is internal essential amino acid, in vivo for biosynthesis protein, nicotinic acid and neurotransmitter Serotonin (thrombocytin).IDO (IDO) is a kind of monomeric enzyme containing heme into the cell, extensively It is distributed in many tissues and cell of humans and animals.IDO can be catalyzed the indole ring oxicracking generation dog urinary ammonia of L-Trp The first step reaction of sour (kynurenine), the step is also crucial rate-limiting reaction.IDO is in low-level under body normal condition Expression, under morbid state, can detect its overexpression.IDO is in the nervous system disease (especially Alzheimer's disease And depression) pathogenesis in play vital effect.IDO also has Immune tolerance function, tumour cell, antigen IDO on presenting cell can induce immune tolerance of the T cell to tumour antigen.In addition, IDO also assist in chronic infection, The pathogenic processes such as HIV- infection, AIDS, autoimmune disease.Therefore, IDO has been found to be an important drug discovery target Mark, the exploitation of IDO inhibitor are badly in need of very much.
IDO mainly influences the function of brain by two kinds of mechanism, so as to cause the generation of the nervous system disease：(1) in inflammation When disease is reacted, by being metabolized tryptophan, the Tryptophan concentration of circulation is reduced, reduces, causes so that serotonine is horizontal It is depressed；(2) catalysis tryptophan, which follows kynurenine pathway metabolism, accumulates kynurenin and neurotoxicity quinolinic acid, so as to cause god Generation through systemic disease.Therefore, IDO inhibitor has in terms of the nervous system diseases such as treatment Alzheimer disease, depression Hold out broad prospects.
IDO also has become the very important small molecule regulation target spot of antitumor immunotherapy, and it is for immune system Regulation and control mainly include following several respects：(1) the high expression of IDO can cause the local tryptophan depletion of cell, because T cell is to color ammonia The exhaustion of acid is especially sensitive, therefore when Tryptophan concentration reduces, the propagation of T cell will be stagnated in the G1 phases.(2) IDO is relied on The tryptophan degradation of property causes the raising of kynurenine levels, induces the t cell proliferation of Mediated by Free Radicals.(3) dendron is raised Shape cell IDO expression strengthens the immunosupress that local modulation T cell (Treg) mediates by degrading local tryptophan, promotees Make peripheral immune tolerance of the body to tumour specific antigen.
At present, the blocking for immunologic test point also turns into one of available strategy of numerous activation antineoplastic immunes.It is immune Checkpoint refers to some inhibition signal paths present in immune system, by adjusting continuing for immune response in peripheral tissues Property and intensity avoid tissue damage, and participate in maintaining tolerance for autoantigen.Utilize the inhibition signal of immunologic test point It is the important mechanisms that tumour escapes immunologic cytotoxicity that path, which suppresses T cell activity,.Cell magazines have delivered one on April 7th, 2016 Entitled " the Combination Cancer Therapies with Immune Checkpoint Blockade " summary of a piece Article, introduce the cancer therapy that (checkpoint blockade) is blocked with reference to immunologic test point, it is indicated that combination is different Tradition or target on cancer therapy, the effect of effectively improving immune cancer therapy.It is above-mentioned also it has been noted that IDO As the very important small molecule regulation target spot of antitumor immunotherapy, therefore, exploitation IDO inhibitor and immunologic test point antibody Drug combination, the effect of playing targeting anti-tumor is cooperateed with, has become new R＆D direction.
At present, a series of development of IDO micromolecular inhibitors has also been carried out both at home and abroad, for treating or in advance Disease related anti-IDO.For example reported in patent WO99/29310 and utilize IDO inhibitor 1MT, 4- (3- Benzofuran)-DL-Alanine, 4- (3- benzothiophenes)-DL-Alanines and 6- nitros-L-Trp, it is cell-mediated to change T- Immunity, including change local cells outside tryptophan and tryptophan metabolism thing concentration.Patent WO2004/094409 is also reported Some specific compounds for having IDO inhibitory action of road.In patent US2004/0234623, it was recently reported that pressed down using a kind of IDO Preparation for treating cancer and infection.
But generally to suppress effect low for existing 2,3- dioxygenases (IDO) inhibitor, the double oxygenations of 2,3- are there is no at present Enzyme (IDO) inhibitor medicaments come out.In medicine is ground, more representational IDO inhibitor be Epacadostat (the II phases, Under Active Development) and NLG-919 (I phases, Under Active Development).Its structural formula is as follows It is shown：
The invention discloses a series of IDO inhibitors, are new and effective selective depressant, have good patent medicine Property, available for prevent and/or treat Alzheimer disease, the infection that the activation of cataract, cellular immunity is related, LADA disease The abnormal medicine of disease, AIDS, cancer, depression or tryptophan metabolism.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of Novel IDO inhibitor, and such compound has very to IDO Good inhibitory activity, possibility is provided for treatment of the IDO inhibitor as the disease mediated by IDO.The present invention will also solve Technical problem be to provide the application of above-mentioned IDO inhibitor.In order to solve the above technical problems, the technical solution adopted by the present invention is such as Under：The IDO inhibitor that scheme 1, formula I are represented, or its pharmaceutically acceptable salt isomers is with before Medicine：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl Amino, (C1-6Alkyl)2Amino, halo C1-6Alkyl, halo C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl sulphonyl, C1-6Alkyl-carbonyl-amino or C1-6Alkyl amino-carbonyl；
Work as R1For hydroxyl or carboxyl when, can with any group formed prodrug；R3Selected from hydrogen, hydroxyl, amino, cyano group, nitre Base or halogen atom；
Ring A is selected from optionally by 1~3 R63~8 yuan of cycloalkyl containing 0~3 O, S and/or N atom of substitution, 3~8 yuan Heterocyclic radical, 6~14 yuan of aromatic rings or 5~10 yuan of hetero-aromatic rings, wherein, the S atom in ring can optionally be oxidized to S (O) or S (O)2, C atoms in ring can optionally be oxidized to C (O)；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1~6Alkyl, C1-6Alkoxy, C1-6Alkyl Amino, (C1-6Alkyl)2Amino, halo C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl amino, C1-6Alkyl sulphonyl or 3~8 yuan of cycloalkyl, C1-6Alkyl-carbonyl or C1-6Alkyl sulfenyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、- CONHR5、-CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, halo C1-6Alkyl, (C1-6Alkane Base)2Amino, C1-6Alkyl-carbonyl-amino, C1-6Alkyl sulphonyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl C1-6Alkoxy, 3~8 yuan of cycloalkyl, 3~8 circle heterocycles bases, 6~14 yuan of aromatic ring yls, 5~10 unit's heteroaryls；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, carbonyl, carboxyl, C1-6Alkyl sulphonyl C1-6Alcoxyl Base, halo C1-6Alkyl or phenyl；
M represents 0,1,2 or 3；
N represents 1,2 or 3；
X is CH or N.
Scheme 2, the compound as described in scheme 1 or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl or trifluoromethyl；
Work as R1For hydroxyl when, can be with any group formation-OC (O) R ' ,-O (CH2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O)R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, amino, cyanogen Base, nitro, halogen atom, halo C1-6Alkyl, C1-6Alkyl, t 0,1 or 2；
R3Selected from halogen；
Ring A is selected from optionally by 1~3 R63~8 yuan of cycloalkyl of substitution, wherein, the C atoms in ring are optionally by oxygen Turn to C (O)；R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、- CONHR5、-CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, halo C1-6Alkyl, (C1-6Alkane Base)2Amino, C1-6Alkyl-carbonyl-amino, C1-6Alkyl sulphonyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl C1-6Alkoxy, 3~8 yuan of cycloalkyl, 3~8 circle heterocycles bases, phenyl, 5~6 unit's heteroaryls；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, carbonyl, carboxyl, trifluoromethyl or phenyl；
M represents 0,1,2 or 3；
N represents 1；
X is CH or N.
Scheme 3, compound as described in solution 1 and 2 or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, fluorine atom, chlorine atom or bromine atoms；
Work as R1For hydroxyl when, can be with any group formation-OC (O) R ' ,-O (CH2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O)R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, fluoroform Base, C1-6Alkyl, t 0,1 or 2；
R3Selected from halogen；
Ring A is selected from optionally by 1~3 R64~6 yuan of cycloalkyl of substitution, wherein, the C atoms in ring can be optionally oxidized For C (O)；R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、- CONHR5、-CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, phenyl, pyrimidine radicals, pyridine radicals；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, trifluoromethyl or phenyl；
M represents 0,1,2 or 3；
N choosings represent 1；
X is CH or N.
Scheme 4, the compound as described in scheme 3 or its pharmaceutically acceptable salt, isomers and prodrug：
R1Selected from hydrogen, hydroxyl or fluorine atom；
Work as R1For hydroxyl when, can be with any group formation-OC (O) R ' ,-O (CH2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O)R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, C1-6Alkane Base, t 0,1 or 2；
R3Selected from chlorine atom；
Ring A is selected from optionally by 1~3 R64~6 yuan of cycloalkyl of substitution；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、- CONHR5、-CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, phenyl, pyrimidine radicals, pyridine radicals；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, trifluoromethyl or phenyl；
M represents 0,1 or 2；
N represents 1；
X is CH.
Scheme 5, the compound as described in scheme 1 or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl or trifluoromethyl；
, can be with any group formation-OC (O) R ' ,-O (CH when R1 is hydroxyl2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O)R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, amino, cyanogen Base, nitro, halogen atom, halo C1-6Alkyl, C1-6Alkyl, t 0,1 or 2；R3Selected from halogen；
R3Selected from halogen；
Ring A is selected from optionally by 1~3 R6Substitution 6~14 yuan of aryl, 3~8 yuan containing 1~3 O, S and/or N atom Heterocyclic radical, 5~10 unit's heteroaryls containing 1~3 O, S and/or N atom, wherein, the S atom in ring can optionally be oxidized to S Or S (O) (O)2, nuclear carbon atom can optionally be oxidized to C (O)；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-N R4R5、-N(R4)COR5、-N(R4)CONHR5、- CONHR5、-CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, halo C1-6Alkyl, (C1-6Alkane Base)2Amino, C1-6Alkyl-carbonyl-amino, C1-6Alkyl sulphonyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl C1-6Alkoxy, 3~8 yuan of cycloalkyl, 3~8 circle heterocycles bases, phenyl, 5~6 unit's heteroaryls；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, carbonyl, carboxyl, trifluoromethyl or phenyl；
M represents 0,1,2 or 3；
N represents 1,2 or 3；
X is CH or N.
Scheme 6, the compound as described in scheme 5 or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl or trifluoromethyl；
Work as R1For hydroxyl when, can be with any group formation-OC (O) R ' ,-O (CH2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O)R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, fluoroform Base, C1-6Alkyl, t 0,1 or 2；R3Selected from halogen；
Ring A is selected from optionally by 1~3 R6Substituted phenyl, 4~6 circle heterocycles bases containing 1~3 O, S and/or N atom, Or 5~6 unit's heteroaryls containing 1~3 O, S and/or N atom；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、- CONHR5、-CON(R4)R5、-COR5；
R4、R5The independent C for being selected from hydrogen atom or optionally being substituted by 1-3 Q1-6Alkyl, phenyl, pyrimidine radicals, pyridine radicals,；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, carbonyl, carboxyl, trifluoromethyl or phenyl；
M represents 0,1 or 2；
N represents 1；
X is CH or N.
Preferred compounds of the invention, its pharmaceutically acceptable salt or its stereoisomer are：
The medicine system of the compounds of this invention or its pharmaceutically acceptable salt, isomers and prodrug is also claimed in the present invention Agent, it is characterised in that include one or more pharmaceutical carriers.
The medicine group of the compounds of this invention or its pharmaceutically acceptable salt, isomers and prodrug is also claimed in the present invention Compound, it is characterised in that further comprising one or more second therapeutically active agents.
The second described therapeutically active agent is antimetabolite, growth factor receptor inhibitors, has silk classification inhibitor, be antitumor sharp Plain class, alkylating agents, metal class, topoisomerase enzyme inhibitor, hormone drug, immunomodulator, tumor suppressor gene, Theratope, The antibody and small-molecule drug of immunologic test point or immunotherapy of tumors correlation.
Described immunologic test the point antibody or small-molecule drug related to tumour immunity, may be selected from death protein PD-1 inhibitor, programmed death ligand albumen PD-L1 inhibitor, Cytotoxic T lymphocyte-associated antigen CTLA-4 inhibitor, Antibody drug is coupled ADC medicines, T cell immune globulin bletilla mucin domain albumen Tim-3 inhibitor, lymphocyte activation base Because of -3 molecule L AG-3 inhibitor, killer cell immunoglobulin-like receptors KIR inhibitor.
The compounds of this invention or its pharmaceutically acceptable salt is also claimed in the present invention, isomers and prodrug is controlled in preparation Treat the application in the medicine of the disease of IDO mediations.
The disease of described IDO mediations is communicable disease, the nervous system disease, cancer or non-cancerous proliferative diseases. The communicable disease is included by influenza virus, HCV (HCV), HPV (HPV), cytomegalovirus (CMV), epstein-barr virus (EBV), poliovirus, varicellazoster virus, Coxsackie virus, human immunodeficiency virus (HIV) disease caused by virus infection；The nervous system disease includes：Alzheimer's disease, depression；Described cancer Including lung cancer, dermoid cancer, carcinoma of urinary bladder, stomach cancer, oophoroma, peritoneal cancer, breast cancer, breast ductal cancer, head and neck cancer, son Endometrial carcinoma, carcinoma of corpus uteri, the carcinoma of the rectum, liver cancer, kidney, carcinoma of renal pelvis, the cancer of the esophagus, adenocarcinoma of esophagus, glioma, prostate cancer, Thyroid cancer, female reproductive system cancer, carcinoma in situ, lymthoma, neurofibromatosis, osteocarcinoma, cutaneum carcinoma, the cancer of the brain, colon cancer, Carcinoma of testis, gastrointestinal stromal tumor, carcinoma of mouth, pharynx cancer, Huppert's disease, leukaemia, NHL, big intestinal villus gland Knurl, melanoma, cytoma and sarcoma, RAEB.
Detailed description of the invention
" halogen " of the present invention refers to fluorine, chlorine, bromine, iodine etc., preferably fluorine atom, chlorine atom.
" oxo " of the present invention refers to that any carbon atom in substituent structure can be replaced by "-C (O)-"；If contain Hetero atom, its hetero atom can form oxide, such asCan quiltReplace, such as any ring S be optionally oxidized to S (O) or S(O)2。
" halo " of the present invention refers to that any carbon atom in substituent can be by one or more identical or different Halogen substitutes." halogen " as defined hereinabove.
" C of the present invention1-6Alkyl " refers to the hydrocarbon part containing 1~6 carbon atom and removes straight chain derived from a hydrogen atom Or the alkyl of side chain, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, different Amyl group, 2- methyl butyls, neopentyl, 1- ethyl propyls, n-hexyl, isohesyl, 4- methyl amyls, 3- methyl amyls, 2- methyl Amyl group, 1- methyl amyls, 3,3- dimethylbutyls, 2,2- dimethylbutyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 1,3- dimethylbutyls, 2,3- dimethylbutyls, 2- ethyl-butyls and 1- methyl -2- methyl-propyls etc.." the C1-4Alkyl " refers to Examples detailed above containing 1~4 carbon atom.
" C of the present invention1-6Alkyl-carbonyl-amino ", " C1-6Alkyl amino-carbonyl ", " C1-6Alkyl sulphonyl " is difference Refer to C1-6Alkyl-C (O)-NH-, C1-6Alkyl-NH-C (O)-, C1-6Alkyl-S (O)2-；" the C1-6Alkyl " as defined hereinabove, Preferably " C1-4Alkyl ".
" C of the present invention1-6Alkoxy " refers to " C defined hereinabove1-6Alkyl " passes through oxygen atom and parent molecule The group of part connection, i.e. " C1-6Alkyl-O- " groups, such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy, uncle Butoxy, n-pentyloxy, neopentyl oxygen and positive hexyloxy etc..Described " C1-4Alkoxy " refers to upper containing 1~4 carbon atom State example, i.e. " C1-4Alkyl-O- " groups.
" cycloalkyl " of the present invention, refer to monocyclic cycloalkyl, bicyclic cycloalkyl system either polycyclic naphthene base system System.Single loop system is the cycloalkyl group containing 3 to 8 carbon atoms, and these groups can be with saturation or unsaturation but be not aromatics. Monocyclic examples include but is not limited to：Cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl, cyclooctane base, ring Cyclobutenyl, cyclopentenyl, cyclohexenyl group, 1,4- cyclohexadienyls, cycloheptenyl, 1,4- cycloheptadiene base, cyclo-octene base, 1,5- Cyclo-octadiene base etc..Bicyclic cycloalkyl system is bridge joint or the monocyclic ring that is spirally connected or and the bicyclic ring that connects.In the monocyclic ring of bridge joint Containing monocyclic cycloalkyl ring, wherein two non-adjacent carbon atoms of monocyclic ring are by the alkylidene between one to three extra carbon atom Bridging connects that (i.e. ,-(CH2) the bridge joint group of w- forms, wherein w are 1,2 or 3).The representative example of bicyclic system is included but not It is limited to bicyclic [3.1.1] heptane, bicyclic [2.2.1] heptane, bicyclic [2.2.2] octane, bicyclic [3.2.2] nonane, bicyclic [3.3.1] nonane and bicyclic [4.2.1] nonane.Condensed-bicyclic alkyl ring system includes and is fused to phenyl, monocyclic cycloalkyl, list The monocyclic cycloalkyl ring of ring cycloalkenyl group, monocyclic heterocycles base or bicyclic heteroaryl.The bicyclic cycloalkyl of fusion, passes through monocyclic cycloalkyl Any carbon atom contained in ring is connected to parent molecule class.Group of naphthene base by one as independent oxo base or sulfenyl or Two group selectivity substitutions.
" heterocyclic radical " of the present invention refer to any carbon atom in " cycloalkyl " can by selected from oxygen, sulphur, nitrogen hetero atom Substitution, preferably 1~3 hetero atom, while can be by oxo including carbon atom, nitrogen-atoms and sulphur atom.
" heterocyclic radical ", refer to monocyclic heterocycles base, bicyclic heterocycle based system or multiring heterocyclic system, including saturation, part The heterocyclic radical of saturation, but do not include aromatic ring." 3-8 " first saturated heterocyclyl, the example include but is not limited to aziridine base, oxygen Heterocycle propyl, thiirane base, azetidinyl, oxa- azetidinyl, Thietane base, tetrahydrofuran base, Nafoxidine base, tetrahydro-thienyl, imidazolidinyl, pyrazolidinyl, 1,2- oxazoles alkyl, 1,3- oxazoles alkyl, 1,2- thiazolidines Base, 1,3- thiazolidinyls, tetrahydrochysene -2H- pyranoses, tetrahydrochysene -2H- thiapyrans base, piperidyl, piperazinyl, morpholinyl, 1,4- dioxas Cyclohexyl, 1,4- thioxane bases；" 3-8 " first fractional saturation heterocyclic radical, the example include but is not limited to 4,5- dihydros Isoxazolyl, 4,5- dihydro-oxazoles base, 2,5- dihydro-oxazoles base, 2,3- dihydro-oxazoles base, 3,4- dihydro-2 h-pyrroles base, 2,3- Dihydro -1H- pyrrole radicals, 2,5- dihydro -1H- imidazole radicals, 4,5- dihydro -1H- imidazole radicals, 4,5- dihydro-1 h-pyrazoles base, 4,5- Dihydro -3H- pyrazolyls, 4,5- dihydro-thiazolyls, 2,5- dihydro-thiazolyls, 2H- pyranoses, 4H- pyranoses, 2H- thiapyrans base, 4H- thiapyrans base, 2,3,4,5- tetrahydro pyridyls, 1,2- Yi oxazinyls, 1,4- Yi oxazinyls or 6H-1,3- oxazinyls etc..It is bicyclic Heterocycle is the monocyclic heterocycles for being fused to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic type heteroaromatic or bicyclic heteroaryl.It is logical double Any carbon atom or any nitrogen-atoms contained in the monocyclic heterocycles part of member ring systems, bicyclic heterocycle are connected to parent molecule class. The representative example of bicyclic heterocyclic radical includes but is not limited to 2,3- Dihydrobenzofuranes -2- bases, 2,3- dihydro benzo furyls -3- Base, indoline -1- bases, indoline -2- bases, indoline 3- bases, the base of 2,3 dihydrobenzo thiophene -2, octahydro -1H- indoles Base, octahydro benzofuranyl.Heterocyclic radical is substituted by one or two group selectivity as independent oxo base or sulfenyl. In some embodiments, bicyclic heterocyclic radical is monocyclic cycloalkyl, 5 yuan or 6 unit monocycle cycloalkenyl groups, 5 for being fused to phenyl ring, 5 yuan or 6 yuan 5 yuan or 6 unit monocycle heterocyclic rings of member or 6 unit monocycle heterocyclic radicals or 5 yuan or 6 unit monocycle heteroaryls, it is characterised in that bicyclic miscellaneous Ring group is substituted by one or two group selectivity as independent oxo base or sulfenyl.
Term used herein " thick and " includes bridge joint, is spirally connected and and connects three kinds of connected modes to form bicyclic or polycyclic system System.
" 6~14 yuan of aryl ", refer to the cyclic aromatic group containing 6~14 carbon atoms, including " 6-8 unit monocycles virtue Base ", such as phenyl, cyclo-octene base etc.；Including " 8~14 yuan of fused ring aryls ", such as pentalene, naphthalene, phenanthrene etc..Art used herein Language " aryl " refers in phenyl (that is, monocyclic aryl) or aromatics bicyclic system containing at least one phenyl ring or comprises only carbon atom Bicyclic system.Bicyclic aryl can be azulenyl, naphthyl or be fused to monocyclic cycloalkyl, monocyclic cycloalkenyl or monocyclic heterocycles Phenyl.Bicyclic aryl is former by any carbon atom contained by the phenyl moiety of bicyclic system or with any carbon of naphthyl or Azulene ring Son is attached in parent molecule class.The fusion monocyclic cycloalkyl or monocyclic heterocycles base section of bicyclic aryl are by one or two oxo base And/or thia group selectivity substitution.
Term " heteroaryl " used herein refers to bicyclic heteroaryl or bicyclic system containing at least one hetero-aromatic ring.It is monocyclic Heteroaryl can be one 5 yuan or 6 yuan of rings.5 yuan of rings are by two double bonds and one, two, three or four nitrogen-atoms and one Individual oxygen atom or sulphur atom composition.6 yuan of rings are made up of three double bonds and one, two, three or four nitrogen-atoms.5 yuan or 6 yuan Heteroaryl is connected to parent molecule class by any carbon atom or nitrogen-atoms contained in heteroaryl.The representative of monocyclic heteroaryl Property example includes but are not limited to furyl, imidazole radicals, isoxazolyl, thiazolyl, isothiazolyl, oxadiazoles base, oxazolyl, different Oxazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrazolyl, pyrrole radicals, tetrazole radical, thiadiazolyl group, thiazolyl, thiophene Base, triazolyl and triazine radical.Bicyclic heteroaryl is by being fused to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycles base or list The bicyclic heteroaryl composition of ring heteroaryl.The cycloalkyl or heterocyclyl moieties of the bicyclic heteroaryl of fusion are by by as separate oxygen generation One or two of base or sulfenyl group selectivity substitute.When bicyclic heteroaryl contains cycloalkyl, cycloalkenyl group or the heterocycle of fusion During basic ring, then bicyclic heteroaryl is contained by the monocyclic heteroaryl moiety of bicyclic system any carbon atom or nitrogen-atoms are connected to Parent molecule class.When bicyclic heteroaryl is to be fused to the bicyclic heteroaryl of phenyl ring or bicyclic heteroaryl, bicyclic heteroaryl passes through Any carbon atom or nitrogen-atoms in bicyclic system are connected to parent molecule class.The representative example of bicyclic heteroaryl is included but not It is limited to benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazole base, Ben Bing Evil thiadiazolyl groups (benzoxathiadiazolyl, benzothiazolyl), cinnolines base, 5,6 EEDQ -2- bases, 5,6- dihydro-isoquinoline -1- bases, Furopyridyl (furopyridinyl), indazolyl, indyl, isoquinolyl, naphthyridines base, purine radicals, quinolyl, 5,6, 7,8- tetrahydroquinoline -2- bases, 5,6,7,8- tetrahydric quinoline groups, 5,6,7,8- tetrahydroquinoline -4- bases, 5,6,7,8- Tetrahydroisoquinoli-s Quinoline -1- bases, thienopyridine base (thienopyridinyl), 4,5,6,7- tetrahydrochysenes simultaneously [c] [1,2,5] oxadiazoles and 6,7 dihydros And [c] [1,2,5] oxadiazoles -4 (5H) ketone group.In certain embodiments, fused bicyclic heteroaryl group be fused to benzyl ring, 5 yuan Or 6 unit monocycle cycloalkyl, 5 yuan or 6 unit monocycle cycloalkenyl groups, 5 yuan or 6 unit monocycle formula heterocyclic radicals or 5 yuan or 6 unit monocycle heteroaryls 5 yuan or 6 unit monocycle hetero-aromatic rings, wherein the cycloalkyl condensed, cycloalkenyl group and heterocyclic radical are by one as independent oxo base or sulfenyl Individual or two group selectivity substitutions.
" pharmaceutically acceptable salt " of formula I refers to the addition salts and solvation of pharmaceutically useful bronsted lowry acids and bases bronsted lowry Thing.Such officinal salt includes such as following sour salt：Hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluene Sulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acid (such as acetic acid, HOOC- (CH2) n-COOH (wherein n is 0~4)) etc..Nontoxic pharmaceutical base addition salts include the salt of such as following alkali：Sodium, potassium, calcium, Ammonium etc..Those skilled in the art know a variety of nontoxic pharmaceutically acceptable addition salts.
" stereoisomer " of formula I refers to, when compound of formula I has asymmetric carbon atom, to produce Enantiomter；When compound has carbon-carbon double bond or cyclic structure, cis-trans-isomer can be produced；When compound exist ketone or During oxime, dynamic isomer can be produced, the enantiomters of all compound of formula I, diastereoisomer, racemization isomers, along anti- Isomers, dynamic isomer, geometric isomer, epimer and its mixture, are included in the scope of the invention.
" prodrug " of formula I refers to the change that active compound can be converted under physiological condition or by solvolysis Compound, when patient is administered, prodrug can be inactive, but it is converted into the active compound compound of activity in vivo.When this When invention formula (I) compound has hydroxyl, prodrug can be formed with suitable group.
Embodiment
Embodiment 1：The synthesis of compound 14
SM2 (106mg, 1.07mmol, 1.0eq) is dissolved in dichloromethane (20mL), addition SM1 (168mg, 1.07mmol, 1.0eq) and magnesium sulfate (1.00g), resulting mixture react 13 hours at ambient temperature.Filtering, is obtained To filtrate be spin-dried for obtaining crude product 14-1, without further purification, directly progress next step reaction.
Crude product 14-1 is dissolved in ethanol (15mL), adds potassium carbonate (296mg, 2.14mmol, 2.0eq) and methylbenzene sulphur Acyl methyl isocyanide (250mg, 1.28mmol, 1.2eq), resulting 1 hour of mixture heating reflux reaction.It will react also cold But environment temperature is arrived, adds water (30mL), is extracted with ethyl acetate (30mL), is dried with anhydrous magnesium sulfate, decompression is spin-dried for obtaining Crude product washed with PE/EA=5/1 (20mL), obtain compound 14,250mg, yield 84%.
1HNMR：10.06 (s, 1H), 7.72 (s, 1H), 7.27-7.30 (m, 1H), 7.17 (d, J=2.68Hz, 1H), 6.95 (d, J=8.68Hz, 1H), 6.85 (s, 1H), 3.81 (d, J=7.72Hz, 2H), 1.98-2.02 (m, 1H), 1.39- 1.46(m,6H),1.01-1.04(m,2H).
Embodiment 2：The synthesis of compound 26
SM2 (2.98g, 13.05mmol, 1.0eq) is dissolved in 30mL DCM, addition DIPEA (5.90g, 45.68mmol, 3.5eq), CBzCl (3.34g, 19.58mmol, 1.5eq) is slowly added dropwise, adds (15 DEG C) reaction 20h of room temperature.TLC detection reactions Completely, dry reaction liquid is directly concentrated, adds a small amount of DCM systems sand, PE：EA=3:1 column chromatography, obtain compound 26-1, white solid 5.0g (contains a small amount of solvent), yield：In terms of 100%.
26-1 (5.0g, 13.05mol, 1.0eq) is dissolved in 50mL DCM, adds HCl/ dioxane solutions (30mL), add (15 DEG C) reaction 3d of room temperature.TLC display reactions are complete, concentrate dry reaction liquid, obtain compound 26-2, and white is solid Body 3.90g, yield：In terms of 100%
Compound 26-2 (3.4g, 11.4mmol, 1.0eq) is dissolved in 30mL water, adjusted with 2M wet chemical PH is more than 9, DCM extractions (50mL*3), and saturated sodium-chloride water solution is washed (50mL*1), and anhydrous magnesium sulfate is dried, and filtering and concentrating is done, Obtain yellow oil 2.53g.The product (232mg, 0.88mmol, 1.0eq) of separate out is taken, is dissolved in DCM (15mL), is added TEA (312mg, 3.08mmol, 3.5eq), chlorobenzoyl chloride (186mg, 1.32mmol, 1.5eq), add (15 DEG C) reactions of room temperature 1d.TLC detection reactions, add 10mL water, the lemon acid elution (20mL*1) of organic phase 10%, saturated nacl aqueous solution is washed (30mL*1), anhydrous magnesium sulfate dry filter concentration system is husky, DCM：MeOH=50:1 column chromatography, obtain compound 2-3, yellow oily Thing 223mg, yield：69.25%
Compound 26-3 (223mg, 0.61mmol, 1.0eq) is dissolved in 20mL methanol, adds Pd/C (120mg), room Warm (15 DEG C), hydrogen balloon reaction 5h, are filtered, and filtrate concentration is dry, obtains compound 26-4, yellow oil 134mg, yield： 95.04%
Synthesis of the compound 26-5 synthetic method with compound 14-1；
The synthesis of compound 26 obtains compound 26, yellow solid, 50.0mg with the synthesis of compound 1.
1HNMR：10.09 (s, 1H), 8.03 (d, J=7.08Hz, 1H), 7.77-7.79 (m, 2H), 7.70 (s, 1H), 7.42-7.53 (m, 3H), 7.27-7.30 (m, 1H), 7.18 (d, J=2.68Hz, 1H), 6.95 (d, J=8.72Hz, 1H), 6.88 (s, 1H), 3.87 (d, J=7.52Hz, 2H), 1.56-1.60 (m, 3H), 1.41-1.44 (m, 2H), 1.21-1.28 (m, 5H).
Embodiment 3：The synthesis of compound 27
Take SM4 (158mg, 0.60mmol, 1.0eq) to be dissolved in THF (20mL), add TEA (182mg, 1.80mmol, 3.0eq), benzene sulfonyl chloride (106mg, 0.6mmol, 1.0eq), (15 DEG C) reaction 1d of room temperature are added.TLC is detected, and is spin-dried for reaction solution, Frozen water 20mL, EA extraction (30mL*2) is added, saturated sodium-chloride is washed (30mL*2), and anhydrous magnesium sulfate is dried, filtering, concentration system Sand, PE：EA=3:1---EA column chromatographies, obtain compound 27-1, yellow oil 169mg, yield：69.83%.
Synthesis of the compound 27-2 synthetic method with compound 26-4；The compound 27-3 same compound of synthetic method 14-1 synthesis；The synthesis of compound 27 obtains compound 27, yellow solid, 48.8mg with the synthesis of Compound Compound 14.
1HNMR：10.06(s,1H),7.77-7.79(m,2H),7.54-7.67(m,5H),7.27-7.30(m,1H), 7.15 (d, J=2.68Hz, 1H), 6.95 (d, J=8.68Hz, 1H), 6.84 (s, 1H), 3.75 (d, J=7.32Hz, 2H), 3.08(m,1H),1.08-1.46(m,9H).
Embodiment 4：The synthesis of compound 29
SM4 (280mg, 1.07mmol, 1.0eq) is dissolved in DCM (20mL), addition TEA (379mg, 3.75mmol, 3.5eq), methylcarbamyl chloride (151mg, 1.61mmol, 1.5eq), (15 DEG C) reaction 20h of room temperature are added.Frozen water 10mL is added, Liquid separation, the citric acid solution of organic phase 10% are washed (20mL*1), and saturated sodium-chloride is washed (20mL*1), and anhydrous magnesium sulfate dry filter is dense Contracting is dry, obtains compound 29-1 (crude product), yellow oil 300mg, yield：87.72%.
Synthesis of the compound 29-2 synthesis with compound 26-4；Conjunction of the compound 29-3 synthesis with compound 14-1 Into；The synthesis with synthesis with compound 14 of compound 29, obtains compound 29, faint yellow solid 10.0mg.
1HNMR：10.09 (s, 1H), 7.73 (s, 1H), 7.28-7.31 (m, 1H), 7.18 (d, J=2.72Hz, 1H), 6.95 (d, J=8.68Hz, 1H), 6.87 (s, 1H), 5.77-5.80 (m, 1H), 5.55 (d, J=4.76Hz, 1H), 3.77 (d, J =7.4Hz, 2H), 3.56 (s, 1H), 0.96-1.51 (m, 9H)
Embodiment 5：The synthesis of compound 30
SM4 (211mg, 0.80mmol, 1.0eq) is dissolved in DCM (20mL), addition TEA (283mg, 2.8mmol, 3.5eq), mesyl chloride (137mg, 1.2mmol, 1.5eq), (15 DEG C) reaction 20h of room temperature are added.Add 10mL water, organic phase 10% lemon pickling (20mL*1), saturated sodium-chloride are washed (20mL*1), and anhydrous magnesium sulfate is dried, filtering, and filtrate concentration is dry, obtains Compound 30-1, yellow oil crude product, direct plunge into next step, yield：In terms of 100%.Compound 30-2 synthesis assimilation Compound 26-4 synthesis；Synthesis of the compound 30-3 synthesis with compound 14-1；The synthesis of compound 30 is the same as compound 14 Synthesis.
1HNMR：10.06 (s, 1H), 7.68 (s, 1H), 7.28-7.31 (m, 1H), 7.17 (d, J=2.68Hz, 1H), 6.95 (d, J=8.68Hz, 1H), 6.85-6.88 (m, 2H), 3.78 (d, J=7.44Hz, 2H), 2.84 (s, 3H), 1.11- 1.51(m,10H).
Embodiment 6：The synthesis of compound 32
By SM4 (225mg, 0.86mmol, 1.0eq), be dissolved in THF (20mL), add phenyl isocyanate (151mg, 1.27mmol, 1.5eq), add (15 DEG C) reaction 20h of room temperature.TLC detection reactions terminate, and add EA (50mL), 0.5M hydrochloric acid Wash (50mL*1), saturated sodium bicarbonate is washed (50mL*1), and saturated sodium-chloride is washed (50mL*1), and anhydrous magnesium sulfate is dried, and filtering is dense Contracting is dry, and filtrate concentration system is husky, PE：EA=3:1---1:1 column chromatography, obtain compound 32-1, white solid 258mg, yield： 78.66%.
Synthesis of the compound 32-2 synthesis with compound 26-4；Conjunction of the compound 32-3 synthesis with compound 14-1 Into；The synthesis of compound 32 obtains compound 6, yellow solid, 30mg with the synthesis of compound 14.
1HNMR：10.11(s,1H),8.27(s,1H),7.76(s,1H),7.28-7.35(m,3H),7.18-7.22(m, 3H), 6.95 (d, J=8.68Hz, 1H), 6.85-6.89 (m, 2H), 6.17 (d, J=7.52Hz, 1H), 3.81 (d, J= 7.40Hz,2H),3.70(s,1H),1.00-1.56(m,9H).
Embodiment 7：The synthesis of compound 40
SM7 (20.00g, 183.2mmol, 1.0eq) and Boc2O (48.00g, 220.0mmol, 1.2eq) are dissolved in THF In (200mL), the DMAP of catalytic amount is added, adds TEA (38ml, 275.0mmol, 1.5eq), the mixture of gained is in environment temperature The lower reaction 16h of degree.Reaction solution concentration is dry, and with water and PE/EA=1/1 processing, organic phase washed once with saturated lemon, satisfy With NaCl once, the crude product of gained adds PE, stands crystallization, and the solid of generation is collected by filtration, and obtains compound 40-1, light Yellow solid, 23.00g, yield：60%
Compound 40-1 (23.00g, 110.0mmol, 1.0eq) is dissolved in THF (100mL), the NaOH for adding 1N is water-soluble Liquid (200mL), the mixture of gained react 5h at 40 DEG C.With EA extractions once, aqueous phase is retained.Aqueous phase adjusts pH with watery hydrochloric acid =3-4, EA are extracted, and saturated sodium-chloride washed once, anhydrous sodium sulfate drying, and being concentrated under reduced pressure dry obtains solid.Solid PE：EA Recrystallization, obtains compound 40-2, faint yellow solid, 15.00g, yield：60%；
Compound 40-2 (15.00g, 66mmol, 1.0eq) is dissolved in methanol (100mL), adds the 10% of catalytic amount Pd/C, (15-20 DEG C) of room temperature reacts 16h to the mixture of gained under an atmosphere of hydrogen.Filter away catalyst, filtrate decompression concentration It is dry, obtain crude product 40-3, colorless oil, 15.00g, yield：In terms of 100%, direct plungeed into next step without purifying.
Compound 40-3 (15.00g, 65.5mmol, 1.0eq) is dissolved in THF (100mL), thoroughly cooled down with frozen water, point Criticize and add solid CDI (10.61g, 65.5mmol, 1.0eq), the mixture of gained reacts 4h at ambient temperature.It is thorough with frozen water Bottom cools down, and adds solid NaBH4 (5.00g, 131.0mmol, 1.0eq), MeOH (20mL) is added dropwise, the mixture of gained is in environment At a temperature of react 16h.Reaction solution is quenched with saturated ammonium chloride, EA extractions.Organic phase is washed twice with the citric acid of saturation, saturation Once, anhydrous sodium sulfate drying, the crude product being concentrated under reduced pressure to give carries out column chromatography (200-300 mesh silica gel, PE/ to NaCl EA=3/1), compound 40-4, white solid, 5.70g, yield are obtained：50%
By compound 40-4 (5.70g, 26.5mmol, 1.0eq) and carbon tetrabromide (10.50g, 31.8mmol, 1.2eq), It is dissolved in DCM (100mL), is cooled down with frozen water, triphenylphosphine (8.33g, 31.8mmol, 1.2eq), the mixing of gained is added portionwise Thing reacts 16h at ambient temperature.Reaction solution is concentrated under reduced pressure, the crude product of gained carries out column chromatography (200-300 mesh silica gel, PE/ EA=20/1), compound 40-5, pale yellow oil, 6.50g, yield are obtained：88%；
Compound 40-5 (6.5g, 23.4mmol, 1.0eq) and imidazoles (4.78g, 70.2mmol, 3.0eq) are dissolved in acetone (50mL), the mixture of gained are heated to back flow reaction 3d, and point plate compound 8-5 is still complete without reaction, is handled.Will Reaction solution concentration is dry, is diluted with EA and water, separates organic phase.Organic phase is washed once respectively with water and saturated sodium-chloride, anhydrous sulphur Sour sodium is dried, and the crude product for depressurizing to obtain carries out column chromatography (200-300 mesh silica gel, DCM/MeOH=30/1), obtains compound 40- 6, position pale yellow oil, 2.7g, yield：44%；
Synthesis of the compound 40-7 synthesis with compound 39-3；
Synthesis of the compound 40-8 synthesis with compound 39-4；
Compound 40-8 is dissolved in DCM (20mL), added in HCl Isosorbide-5-Nitrae-dioxane solution, the mixture of gained 2h is reacted at ambient temperature.Reaction solution is directly concentrated dry, be dissolved in DMF, obtain chemical combination 40-9 DMF solution, be directly used in down Single step reaction, yield：In terms of 100%；
Compound 40-9 (81mg, 0.26mmol, 1.0eq) is dissolved in DMF (3mL), add TEA (0.1mL, 0.78mmol, 3.0eq), the mixture of gained reacts 10min at ambient temperature, adds phenyl isocyanate (46mg, 0.40mmol, 1.5eq), The mixture of gained reacts 16h at ambient temperature.Reaction solution, DCM extractions is diluted with water, the crude product for being evaporated under reduced pressure to obtain is carried out Column chromatography (DCM/MeOH=30/1), obtains compound 40, is faint yellow solid, 30.0mg, yield：29%.
Embodiment 8：The synthesis of compound 50：
The synthetic route of compound 50 is using SM9 as raw material, the synthesis of reference compound 40, obtains compound 50, is white Color solid, altogether 15.6mg.
1HNMR：8.84 (s, 1H), 7.77 (s, 1H), 7.64 (d, 2H, J=8.8Hz), 7.41-7.53 (m, 5H), 7.08 (s, 1H), 6.51 (d, 1H, J=7.9Hz), 4.08 (d, 2H, 6.0Hz), 3.88-3.92 (m, 1H), 2.15-2.19 (m, 3H), 1.47-1.52(m,2H)。
Embodiment 9：The synthesis of compound 58
The synthesis of compound 58 is using SM10 as initiation material, the synthetic route of reference compound 14, obtains compound 58, For faint yellow solid 245mg, yield：74.24%.
1HNMR：10.16(s,1H),7.79(s,1H),7.20-7.26(m,4H),6.90-6.99(m,5H),5.15(s, 2H).
Embodiment 10：The synthesis of compound 61
Synthetic route is as follows：
Compound 61-1 synthesis is using SM11 as initiation material, reference compound 14-1 synthetic route；
The synthesis of compound 61-2 synthesized reference compound 14；
By compound 61-2 (75mg, 0.23mmol, 1.0eq)), it is dissolved in 8mL, addition CDI (89mg, 0.55mmol, 2.4eq), back flow reaction 4h is heated to, is cooled to room temperature (10 DEG C), adds methylamine alcohol solution (2ML), reacts at room temperature 20h.TLC Display reaction is complete, adds 0.5g silica gel, sand processed, DCM：MeOH=20:1, column chromatography obtains compound 61, is faint yellow solid 6.2mg, yield：7.85%.
1HNMR：10.17 (s, 1H), 8.36 (d, J=4.60Hz, 1H), 7.82 (s, 1H), 7.69 (d, J=8.2Hz, 2H), 7.39 (s, 1H), 7.22-7.25 (m, 1H), 7.02 (d, J=2.64Hz, 1H), 6.92-6.98 (m, 4H), 5.21 (s, 2H), 2.75 (d, J=4.52Hz, 1H).
Embodiment 11：The synthesis of compound 62
The synthesis of compound 62 is using SM12 as initiation material, the synthesis of reference compound 14, obtains compound 62, for Huang Color solid, 102mg, yield：33.33%.
1HNMR：10.12 (s, 1H), 7.78 (s, 1H), 7.48 (s, 1H), 7.29-7.32 (m, 1H), 7.21 (d, J= 2.64Hz, 1H), 6.96 (d, J=8.72Hz, 1H), 6.88 (s, 1H), 3.95 (d, J=7.68Hz, 2H), 3.09-3.14 (m, 1H),2.76-2.80(m,1H),2.55-2.59(m,1H),2.04-2.10(m,1H),1.74-1.80(m,1H).
Embodiment 12：The synthesis of compound 65
Compound 65-1 synthesis is the reference compound 14-1 synthetic route using SM13 as initiation material；
Compound 65-2 synthesis is the synthetic route of reference compound 14 using compound 65-1 as initiation material；
Compound 65-2 (737mg, 1.95mmol, 1.0eq) is dissolved in 3DCM (30mL), it is molten to add HCl/ dioxane Liquid (5mL), add 17 DEG C of reaction 20h.TLC detection reactions are complete, and concentration is dry, obtains 65-3, is off-white powder 621.0mg, Yield：In terms of 100%.
Compound 65-3 (150.0mg, 0.48mmol, 1.0eq) is dissolved in THF (15mL), adds DIPEA (620.0mg, 2.4mmol, 5.0eq), acetic anhydride (245mg, 4.8mmol, 10.0eq), room temperature (17 DEG C of reaction 3h.TLC reacts Completely, dry reaction liquid is concentrated, adds frozen water 30mL, EA extraction (30mL*3), saturated sodium-chloride washes (50mL*3), anhydrous magnesium sulfate Dry, filtering, filtrate concentration is dry, obtains compound 65-4, is yellow oil 48mg, yield：27.59%
Compound 65-4 (48mg, 0.13mmol, 1.0eq) is dissolved in MeOH (15mL), adds K2CO3(36.0mg, 0.26mmol, 2.0eq), (17 DEG C) reaction 3h of room temperature.Dry reaction liquid is concentrated, adds 30mL water, the regulation of 1M hydrochloric acid pH=6, DCM Extract (30mL*2), anhydrous magnesium sulfate is dried, filtering, and filtrate concentration adds 0.5g silica gel sand, DCM：MeOH=10:1 post layer Analysis, obtains compound 65, is white solid, 1.6mg, yield：3.81%
1HNMR：10.14 (s, 1H), 7.84 (d, J=12.76Hz, 1H), 7.29-7.32 (m, 1H), 7.20-7.24 (m, 1H), 6.93-6.98 (m, 2H), 3.96 (d, J=7.48Hz, 2H), 2.50-3.23 (m, 4H), 2.27-2.42 (m, 2H), 1.67-1.80(m,4H),1.34-1.49(m,2H).
Embodiment 13：1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) - The synthesis (compound 74) of 3- (4- cyano-phenyls) urea
Step 1:The synthesis of ((cis) -4- (methylol) cyclohexyl) t-butyl carbamate:
((cis) -4- aminocyclohexyls) methoxide hydrochlorate (20.0g, 0.121mol) is added in DCM (30mL), added Triethylamine (32g, 0.316mol), it is slowly added dropwise into di-tert-butyl dicarbonate (32g, 0.147mol), is stirred overnight at room temperature.LC- MS is monitored without starting material left, is concentrated under reduced pressure, crude product is through silica gel column chromatography (PE:EA=30:1) (cis) -4- (hydroxyl first is separated Base) cyclohexyl) t-butyl carbamate (28g, yield 96%).
Step 2:The synthesis of ((cis) -4- ((tertbutyloxycarbonyl) amino) cyclohexyl) methylmethanesulfonate ester:
Intermediate ((cis) -4- (methylol) cyclohexyl) t-butyl carbamate (20.0g, 87.33mmol) is dissolved in In DCM (300mL), add triethylamine (13.21g, 0.131mol), ice bath to 0 DEG C, be added dropwise mesyl chloride (11.99g, 0.105mol), 1h is reacted.LC-MS monitorings add water quenching to go out, dichloromethane extracts, organic phase saturated aqueous common salt without starting material left Wash, be concentrated to give ((cis) -4- ((tertbutyloxycarbonyl) amino) cyclohexyl) methylmethanesulfonate ester (26g crude products).
Step 3:The synthesis of ((cis) -4- (azido methyl) cyclohexyl) t-butyl carbamate:
Intermediate ((cis) -4- ((tertbutyloxycarbonyl) amino) cyclohexyl) methylmethanesulfonate ester (26.0g crude products) is molten In DMF (300mL), Sodium azide (6.39g, 98mmol) is added, is heated to 80 DEG C of stirring 5h.LC-MS is monitored without starting material left, Reaction solution is poured into water (300mL), ethyl acetate (300mL) extraction, merges organic phase, is washed with water (3 × 4mL), saturation food Salt is washed, and anhydrous sodium sulfate drying, is concentrated to give ((cis) -4- (azido methyl) cyclohexyl) t-butyl carbamate (26.0g Crude product).Step 4:The synthesis of ((cis) -4- (amino methyl) cyclohexyl) t-butyl carbamate:
Intermediate ((cis) -4- (azido methyl) cyclohexyl) t-butyl carbamate (26.0g crude products) is dissolved in THF/H2In O (100mL), triphenylphosphine (27.02g, 103mmol) is added, is warming up to 60 DEG C, reacts 1.5h, TLC monitoring reactions Completely.Reaction solution is directly concentrated under reduced pressure, and adds DCM, anhydrous sodium sulfate drying, filters, concentration, crude product is through silica gel column chromatography (DCM:MeOH=20:1~10:1) purify ((cis) -4- (amino methyl) cyclohexyl) t-butyl carbamate (10.0g, Yield:3 steps 50.1%).
Step 5:The conjunction of ((cis) -4- ((((benzyloxy) carbonyl) amino) methyl) cyclohexyl) t-butyl carbamate Into:
((cis) -4- (amino methyl) cyclohexyl) t-butyl carbamate (10.0g, 43.8mmol) is dissolved in DCM In (20mL), ice bath is cooled to 0 DEG C, adds DIPEA (19.8g, 153mol) and benzyl chloroformate (8.9g, 52.17mmol), delays It is slow to be warmed to room temperature overnight.TLC monitoring reactions are complete, and saturated sodium bicarbonate aqueous solution (10mL) is added into reaction solution, liquid separation, is had Machine is mutually washed with saturated sodium-chloride (10mL), washing, and saturated common salt washing, anhydrous magnesium sulfate is dried, and is filtered, and concentration, crude product is through silicon Plastic column chromatography separates (PE:EA=10:1~3:1) white gummy solid ((cis) -4- ((((benzyloxy) carbonyl) amino) is obtained Methyl) cyclohexyl) t-butyl carbamate (11.0g, yield:70%).
Step 6:The synthesis of benzyl (((cis) -4- aminocyclohexyls) methyl) carbamate:
By ((cis) -4- ((((benzyloxy) carbonyl) amino) methyl) cyclohexyl) t-butyl carbamate (1.0g, 2.76mmol) it is added in the dioxane solution (10mL) of hydrogen chloride, stirs 1h, reaction solution is directly concentrated under reduced pressure to obtain benzyl (((cis) -4- aminocyclohexyls) methyl) carbamate (1.1g crude products).
Step 7:The conjunction of benzyl (((cis) -4- (3- (4- cyano-phenyls) urea groups) cyclohexyl) methyl) carbamate Into:
Benzyl (((cis) -4- aminocyclohexyls) methyl) carbamate (1.1g crude products) is added to DCM (20mL) In, ice bath is cooled to 0 DEG C, adds triethylamine (636.3mg, 6.29mmol), addition is different to cyano group benzene after 30min is stirred at 0 DEG C Cyanate (726mg, 5.04mmol), is slowly increased to ambient temperature overnight.TLC monitoring reactions are complete, and reaction solution concentration, crude product is through silica gel Column chromatography for separation (PE:EA=10:1~3:1) white gummy solid benzyl (((cis) -4- (3- (4- cyano-phenyls) ureas are obtained Base) cyclohexyl) methyl) carbamate (800mg, 2 step yields:71.3%).
Step 8:The synthesis of 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- cyano-phenyls) urea:
By benzyl (((cis) -4- (3- (4- cyano-phenyls) urea groups) cyclohexyl) methyl) carbamate (400.0mg, 0.985mmol) it is dissolved in MeOH (10mL), adds Pd/C (20.0mg), three times, room temperature reaction is overnight for replacing hydrogen.TLC is monitored Reaction is complete, and suction filtered through kieselguhr, filtrate decompression is concentrated to give yellowish solid 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- Cyano-phenyl) urea (350mg crude products).
Step 9:1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (4- cyano group Phenyl) urea synthesis:
1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- cyano-phenyls) urea (350mg crude products) is dissolved in dichloromethane The in the mixed solvent of alkane and ethanol (10/1,11mL), add 5- chlorine-2-hydroxyls benzaldehyde (201.5mg, 1.29mmol) and sulfuric acid Magnesium (600mg, 5.0mmol), is stirred overnight at 20 DEG C.TLC monitoring reactions are complete, filter, it is ((suitable that filtrate decompression is concentrated to give 1- Formula) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (4- cyano-phenyls) urea (410.0mg crude products)
Step 10:1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- The synthesis of (4- cyano-phenyls) urea:
By 1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (4- cyano-phenyls) Urea is dissolved in ethanol (10mL), add to Methyl benzenesulfonyl methyl isocyanide (293mg, 1.5mmol) and potassium carbonate (345.53mg, 2.5mmol), it is heated to reflux 5h.TLC monitoring reactions are complete, and reaction solution concentration, crude product separates (DCM through silica gel column chromatography:MeOH =30:1~10:1) obtain 1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) - 3- (4- cyano-phenyls) urea (114.0mg).
1HNMR(400MHz,DMSO-d6)δ(ppm):10.06(s,1H),8.78(s,1H),7.22(s,1H),7.65- 7.63(d,2H),7.53-7.51(m,2H),7.30-7.28(m,1H),7.19-7.18(d,1H),6.97-6.95(d,1H), 6.86(s,1H),6.38-6.36(d,1H),3.81-3.79(d,2H),3.69(s,1H),1.56-1.27(m,7H),1.03(s, 2H).
Molecular formula:C24H24ClN5O2, molecular weight:449.94, the LC-MS [M+H of (Pos, m/z)=450+].
Embodiment 14：1- ((cis) -3- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) - The synthesis (compound 75) of 3- (4- cyano-phenyls) urea
Step 1:The conjunction of ((cis) -3- ((((benzyloxy) carbonyl) amino) methyl) cyclobutyl) t-butyl carbamate Into:
((cis) -3- (amino methyl) cyclobutyl) t-butyl carbamate (1.45g, 7.24mmol) is dissolved in DCM In (15mL), ice bath is cooled to 0 DEG C, adds DIPEA (2.6g, 20.1mmol), added at 0 DEG C benzyl chloroformate (1.45g, Ambient temperature overnight 8.5mmol) is slowly increased to, TLC monitoring reactions are complete.Saturated sodium bicarbonate (10mL) is added into reaction solution, point Liquid, organic phase are washed with saturated sodium-chloride (10mL), washing, and saturated common salt washing, anhydrous magnesium sulfate is dried, and is filtered, concentration, crude product (PE is separated through silica gel column chromatography:EA=10:1~3:1) white gummy solid ((cis) -3- ((((benzyloxy) carbonyl) is obtained Amino) methyl) cyclobutyl) t-butyl carbamate (1.6g, yield:66.1%).
Step 2:The synthesis of benzyl (((cis) -3- Aminocyclobutyls) methyl) carbamate:
By ((cis) -3- ((((benzyloxy) carbonyl) amino) methyl) cyclobutyl) t-butyl carbamate (1.6g, 4.78mmol) it is added in the dioxane solution (10mL) of hydrogen chloride, stirs 1h.Reaction solution is directly concentrated under reduced pressure to obtain benzyl (((cis) -3- Aminocyclobutyls) methyl) carbamate (1.3g crude products).
Step 3:The conjunction of benzyl (((cis) -3- (3- (4- cyano-phenyls) urea groups) cyclobutyl) methyl) carbamate Into:
Benzyl (((cis) -3- Aminocyclobutyls) methyl) carbamate (1.3g crude products) is added to DCM (10mL) In, ice bath is cooled to 0 DEG C, adds triethylamine (760mg, 7.52mmol), is added after stirring 30min to cyano group phenylisocyanate (860mg, 5.97mmol), is slowly increased to ambient temperature overnight.TLC monitoring reactions are complete, and reaction solution concentration, crude product is through silica gel column chromatography Separate (PE:EA=10:1~3:1) white gummy solid benzyl (((cis) -3- (3- (4- cyano-phenyls) urea groups) ring fourth is obtained Base) methyl) carbamate (400mg, yield:22.1%).
Step 4:The synthesis of 1- ((cis) -3- (amino methyl) cyclobutyl) -3- (4- cyano-phenyls) urea:
By benzyl (((cis) -3- (3- (4- cyano-phenyls) urea groups) cyclobutyl) methyl) carbamate (400.0mg, 1.06mmol) it is dissolved in MeOH (10mL), adds Pd/C (25mg), three times, room temperature reaction is overnight for replacing hydrogen.TLC monitorings are anti- Should be complete, for reaction solution through suction filtered through kieselguhr, filtrate decompression is concentrated to give yellowish solid 1- ((cis) -3- (amino methyl) ring fourths Base) -3- (4- cyano-phenyls) urea (0.5g crude products).
Step 5:1- ((cis) -3- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclobutyl) -3- (4- cyano group Phenyl) urea synthesis:
1- ((cis) -3- (amino methyl) cyclobutyl) -3- (4- cyano-phenyls) urea (210mg crude products) is dissolved in dichloromethane In the in the mixed solvent of alkane and ethanol (10/1,11mL), 5- chlorine-2-hydroxyls benzaldehyde (135mg, 0.86mmol) and sulfuric acid are added Magnesium (600mg, 5.0mmol), is stirred overnight at 20 DEG C.TLC monitoring reactions are complete, filter, it is ((suitable that filtrate decompression is concentrated to give 1- Formula) -3- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclobutyl) -3- (4- cyano-phenyls) urea (300.0mg crude products).
Step 6:1- ((cis) -3- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- The synthesis of (4- cyano-phenyls) urea:
By 1- ((cis) -3- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclobutyl) -3- (4- cyano-phenyls) Urea (300.0mg crude products) is dissolved in ethanol (10mL), is added to Methyl benzenesulfonyl methyl isocyanide (228mg, 1.17mmol), carbonic acid Potassium (270mg, 1.95mmol), is heated to reflux 5h, and TLC monitoring reactions are complete.Reaction solution concentrates, and crude product separates through silica gel column chromatography (DCM:MeOH=30:1~10:1) purifying obtains 1- ((cis) -3- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) Methyl) cyclohexyl) -3- (4- cyano-phenyls) urea (120.0mg, yield:63.9%).
1HNMR(400MHz,DMSO-d6)δ(ppm):10.06(s,1H),8.81(s,1H),7.68-7.63(t,3H), 7.53-7.51(d,2H),7.30-7.28(m,1H),7.18-7.17(d,1H),6.97-6.95(d,1H),6.86(s,1H), 6.51-6.49(d,1H),3.91-3.87(t,3H),2.15-2.07(m,3H),1.47-1.42(m,2H).
Molecular formula:C22H20ClN5O2, molecular weight:421.89, the LC-MS [M+H of (Pos, m/z)=422+].
Embodiment 15：1- ((cis) -4- ((5- (3- chlorphenyls) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- (4- ammonia Base phenyl) urea synthesis (compound 77)
Step 1:The synthesis of ((cis) -4- (bromomethyl) cyclohexyl) t-butyl carbamate:
By ((cis) -4- (methylol) cyclohexyl) t-butyl carbamate (8.0g, 34.89mmol, 1.0eq) and tetrabromo Change carbon (13.88g, 41.86mmol, 1.2eq) and be dissolved in DCM (200mL), be cooled with an ice bath, triphenylphosphine is added portionwise (10.98g, 41.86mmol, 1.2eq), the mixture of gained are raised to (15 DEG C) reaction 16h of room temperature.TLC monitoring reactions are complete, will Reaction solution directly concentrates, and the crude product of gained is through silica gel column chromatography (PE:EA=20:1~10:1) purifying obtains ((cis) -4- (bromines Methyl) cyclohexyl) t-butyl carbamate (8.63g, yield:84.6%).
Step 2:The synthesis of ((cis) -4- ((1H- imidazoles -1- bases) methyl) cyclohexyl) t-butyl carbamate:
By ((cis) -4- (bromomethyl) cyclohexyl) t-butyl carbamate (8.63g, 29.53mmol, 1.0eq) and miaow Azoles (10.05g, 147.66mmol, 5.0eq) is added in acetone (50mL), and the mixture of gained is heated to flowing back, and reacts 16h, TLC monitoring reactions are complete.Reaction solution is concentrated under reduced pressure, is diluted with water, DCM extractions, anhydrous magnesium sulfate is dried, is concentrated under reduced pressure, institute The crude product obtained carries out silica gel column chromatography (DCM/MeOH=20/1) and obtains faint yellow solid ((cis) -4- ((1H- imidazoles -1- bases) first Base) cyclohexyl) t-butyl carbamate (2.08g, yield:45%).
Step 3:The synthesis of ((cis) -4- ((the bromo- 1H- imidazoles -1- bases of 5-) methyl) cyclohexyl) t-butyl carbamate:
By ((cis) -4- ((1H- imidazoles -1- bases) methyl) cyclohexyl) t-butyl carbamate (2.08g, 7.44mmol, 1.0eq), DCM (100mL) is dissolved in, is cooled down with ice-water bath, the DCM of C5H6Br2N2O2 (1.06g, 3.72mmol, 0.51eq) is added dropwise (100mL) solution, resulting mixture are raised to room temperature reaction 12h.TLC monitoring reactions are complete, by the thio sulphur of reaction solution saturation Sour sodium is quenched, and with anhydrous sodium sulfate drying, is concentrated under reduced pressure, and crude product is through silica gel column chromatography (DCM:MeOH=100:1~60:1) To ((cis) -4- ((the bromo- 1H- imidazoles -1- bases of 5-) methyl) cyclohexyl) t-butyl carbamate (600.0mg, yield 22.5%).
Step 4:((cis) -4- ((5- (3- chlorphenyls) -1H- imidazoles -1- bases) methyl) cyclohexyl) tertiary fourth of carbamic acid The synthesis of ester:
By ((cis) -4- ((the bromo- 1H- imidazoles -1- bases of 5-) methyl) cyclohexyl) t-butyl carbamate (500mg, 1.4mmol, 1.0eq) and a chlorophenylboronic acid (262.7mg, 1.68mmol, 1.2eq) be dissolved in THF (10mL), add potassium phosphate Water (3mL) solution of (580.5mg, 4.2mmol, 3.0eq) and the PdCl of catalytic amount2(PPh3)2(30.73mg, 0.07mmol), The mixture of gained is heated to flowing back under nitrogen protection, reacts 6h.TLC monitoring reactions are complete, and reaction solution is concentrated, uses saturation Sodium carbonate and EA dilutions, liquid separation, organic phase washed once with saturated sodium-chloride, anhydrous sodium sulfate drying, be concentrated under reduced pressure, crude product warp Silica gel column chromatography (DCM:MeOH=100:1~40:1) ((cis) -4- ((5- (3- chlorphenyls) -1H- imidazoles -1- bases) first is obtained Base) cyclohexyl) t-butyl carbamate (500mg, yield:92%).
Step 5:The synthesis of (cis) -4- ((5- (3- chlorphenyls) -1H- imidazoles -1- bases) methyl) hexamethylene -1- amine:
By ((cis) -4- ((5- (3- chlorphenyls) -1H- imidazoles -1- bases) methyl) cyclohexyl) t-butyl carbamate (500mg, 1.54mmol, 1.0eq) is dissolved in MeOH (10mL), adds hydrogen chloride saturation Isosorbide-5-Nitrae-dioxane solution (10mL), (15-20 DEG C) reaction 4h of mixture room temperature of gained.TLC monitoring reactions are complete, are concentrated under reduced pressure, and crude product is dissolved with water, DCM extractions Once, aqueous phase adjusts pH=10 with the NaOH aqueous solution, DCM extractions, organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure (suitable Formula) -4- ((5- (3- chlorphenyls) -1H- imidazoles -1- bases) methyl) hexamethylene -1- amine (500.0mg).
Step 6:1- ((cis) -4- ((5- (3- chlorphenyls) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- (4- amino Phenyl) urea synthesis:
By (cis) -4- ((5- (3- chlorphenyls) -1H- imidazoles -1- bases) methyl) hexamethylene -1- amine (250mg, 0.77mmol, 1.0eq) it is dissolved in DMF (10mL), add triethylamine (233.3mg, 2.31mmol, 3.0eq) and phenyl isocyanate (133mg, 0.924mmol, 1.2eq), the mixture of gained react 16h under room temperature (15-20 DEG C).TLC monitoring reactions are complete, Saturated sodium carbonate solution, EA extractions are added into reaction solution, organic phase saturated sodium-chloride washed once, anhydrous sodium sulfate drying, It is concentrated under reduced pressure, the crude product of gained is through silica gel column chromatography (DCM/MeOH=100:1~20:1) purify white solid 1- is ((suitable Formula) -4- ((5- (3- chlorphenyls) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- (4- aminophenyls) urea (120mg, yield: 33%)
1HNMR(400MHz,DMSO-d6)δ(ppm):8.79(s,1H),7.79(s,1H),7.66-7.63(d,2H), 7.53-7.45(m,5H),7.08(s,1H),6.38-6.36(d,1H),3.99-3.97(d,2H),3.68(s,1H),1.54- 1.27(m,7H),1.069(s,2H).
Molecular formula:C24H24ClN5O, molecular weight:433.94, the LC-MS [M+H of (Pos, m/z)=434+]
Embodiment 16：1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) - The synthesis (compound 83) of 3- (3- cyano-phenyls) urea
Step 1：The synthesis of (((cis) -4- aminocyclohexyls) methyl) benzyq carbamate hydrochloride:
By ((cis) -4- ((((benzyloxy) carbonyl) amino) methyl) cyclohexyl) t-butyl carbamate (1.0g, 2.76mmol) it is dissolved in methanol (10mL), is cooled to 0 DEG C, is slowly added dropwise in the ethanol solution (3mL) of hydrogen chloride, room temperature is stirred Mix overnight.TLC detection reactions are complete, and reaction solution is directly concentrated under reduced pressure to obtain benzyl (((cis) -4- aminocyclohexyls) methyl) Carbamate hydrochloride (750mg, yield:91%).
Step 2:The synthesis of (((cis) -4- (3- (3- cyano-phenyls) urea groups) cyclohexyl) methyl) benzyq carbamate:
(((cis) -4- aminocyclohexyls) methyl) benzyq carbamate hydrochloride (400mg, 1.34mmol) is dissolved in DCM and DMF mixed solvent (3:1,16mL) in, isocyanic acid m-cyano phenyl ester (232mg, 1.61mmol) and triethylamine are added (406.8mg, 4.02mmol), is stirred overnight at room temperature.TLC detection reactions are complete, add saturated aqueous ammonium chloride (10mL), second Acetoacetic ester extracts (3 × 20mL), merges organic phase, anhydrous sodium sulfate drying, concentration, crude product addition dichloromethane (10mL), mistake Filter obtain white solid (((cis) -4- (3- (3- cyano-phenyls) urea groups) cyclohexyl) methyl) benzyq carbamate (366mg, Yield:67.3%).
Step 3:The synthesis of 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (3- cyano-phenyls) urea:
By (((cis) -4- (3- (3- cyano-phenyls) urea groups) cyclohexyl) methyl) benzyq carbamate (150.0mg, 0.369mmol) it is dissolved in MeOH (10mL), adds Pd/C (7.0mg), replacing hydrogen three times, reacts at room temperature 4 hours.TLC is monitored Reaction is complete, and suction filtered through kieselguhr, filtrate decompression is concentrated to give 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (3- cyano group benzene Base) urea (45mg, yield:45%).
Step 4:1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (3- cyano group Phenyl) urea synthesis:
1- ((cis) -4- (amino methyl) cyclohexyl) -3- (3- cyano-phenyls) ureas (45mg, 0.165mmol) are dissolved in The in the mixed solvent of dichloromethane and ethanol (4/1,5mL), add 5- chlorine-2-hydroxyls benzaldehyde (25.9mg, 0.165mmol) and Magnesium sulfate (200mg, 1.6mmol), is stirred overnight at room temperature.TLC monitoring reactions are complete, and reaction solution filters, filtrate decompression concentration Obtain 1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (3- cyano-phenyls) urea (60.5mg, yield:88%).
Step 5:1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- The synthesis of (3- cyano-phenyls) urea:
By 1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (3- cyano-phenyls) Urea (60.5mg, 0.147mmol) is dissolved in ethanol (3mL), is added to Methyl benzenesulfonyl methyl isocyanide (42.9mg, 0.22mmol) With potassium carbonate (50.8mg, 0.368mmol), 80 DEG C of reaction 5h are heated to.TLC monitoring reactions are complete, reaction solution concentration, add second Acetoacetic ester (15mL) and water (10mL), liquid separation, aqueous phase are extracted with ethyl acetate (2 × 15mL), merge organic phase, anhydrous magnesium sulfate Dry, filter, concentration, crude product separates (DCM through silica gel column chromatography:MeOH=100:1~20:1) grey powder solid is obtained 1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- (3- cyano-phenyls) urea (15.9mg, yield:24%).
1HNMR(400MHz,DMSO-d6)δ(ppm):10.07(s,1H),8.61(d,1H),7.90(d,1H),7.53- 7.51(m,1H),7.43-7.39(m,1H),7.32-7.27(m,2H),7.19-7.18(d,1H),6.97-6.95(d,1H), 6.86(s,1H),6.34-6.32(d,1H),3.81-3.79(d,2H),3.68(m,1H),1.55-1.26(m,7H),1.10- 1.02(m,2H).
Molecular formula:C24H24ClN5O2, molecular weight:449.94, the LC-MS [M+H of (Pos, m/z)=451+].
Embodiment 17：1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) - The synthesis (compound 84) of 3- (4- trifluoromethyls) urea
Step 1:The conjunction of (((cis) -4- (3- (4- trifluoromethyls) urea groups) cyclohexyl) methyl) benzyq carbamate Into:
(((cis) -4- aminocyclohexyls) methyl) benzyq carbamate hydrochloride (407mg, 1.36mmol) is dissolved in In DCM (16mL), add 4- trifluoromethyls phenylisocyanate (304.8mg, 1.63mmol) and triethylamine (493.9mg, 4.89mmol), it is stirred overnight at room temperature.TLC detection reactions are complete, add saturated aqueous ammonium chloride (15mL), liquid separation, and aqueous phase is used DCM extracts (2 × 20mL), merges organic phase, washes (10mL), and saturated common salt washing (10mL), anhydrous magnesium sulfate is dried, dense Contracting, crude product separate (DCM through silica gel column chromatography:MeOH=200:1~150:1) white solid (((cis) -4- (3- (4- are obtained Trifluoromethyl) urea groups) cyclohexyl) methyl) benzyq carbamate (300mg, yield:55.9%).
Step 2:The synthesis of 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- trifluoromethyls) urea:
By (((cis) -4- (3- (4- trifluoromethyls) urea groups) cyclohexyl) methyl) benzyq carbamate (150.0mg, 0.38mmol) is dissolved in MeOH (10mL), adds Pd/C (7.0mg), three times, room temperature reaction 5 is small for replacing hydrogen When.TLC monitoring reactions are complete, and suction filtered through kieselguhr, filtrate decompression is concentrated to give 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- trifluoromethyls) urea (47.7mg, yield:48%).
Step 3:1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (4- trifluoros Aminomethyl phenyl) urea synthesis:
By 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- trifluoromethyls) urea (47.7mg, 0.18mmol) Be dissolved in the in the mixed solvent (4/1,5mL) of dichloromethane and ethanol, add 5- chlorine-2-hydroxyls benzaldehyde (28.2mg, 0.18mmol) with magnesium sulfate (200mg, 1.6mmol), it is stirred overnight at room temperature.TLC monitoring reactions are complete, add water (15mL), Liquid separation, aqueous phase are extracted (2 × 10mL) with DCM, merge organic phase, and anhydrous magnesium sulfate is dried, and filtering, is concentrated to give 1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (4- trifluoromethyls) urea (34mg, yield: 47.2%).
Step 4:1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- The synthesis of (4- trifluoromethyls) urea:
By 1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (4- trifluoromethyls Phenyl) urea (33.4mg, 0.085mmol) is dissolved in ethanol (2mL), add to Methyl benzenesulfonyl methyl isocyanide (25.0mg, 0.128mmol) and potassium carbonate (29.3mg, 0.213mmol), heating reflux reaction.TLC monitoring reactions are complete, reaction solution concentration, Add ethyl acetate (10mL) and water (10mL), liquid separation, aqueous phase are extracted with ethyl acetate (2 × 10mL), merge organic phase, it is anhydrous Magnesium sulfate is dried, and is filtered, and concentration, crude product separates (DCM through silica gel column chromatography:MeOH=100:1~20:1) gray solid is obtained 1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- (4- trifluoromethylbenzenes Base) urea (23.1mg, yield:24%).
1HNMR(400MHz,DMSO-d6)δ(ppm):10.08(s,1H),8.69(d,1H),7.75(d,1H),7.55- 7.54(m,4H),7.30-7.28(m,1H),7.19-7.18(d,1H),6.96-6.94(m,1H),6.86(s,1H),6.32- 6.30(d,1H),3.81-3.79(d,2H),3.68(m,1H),1.56-1.26(m,7H),1.10-1.02(m,2H).
Molecular formula:C24H24ClF3N4O2, molecular weight:492.93, the LC-MS [M+H of (Pos, m/z)=494+].
Embodiment 18：1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) - The synthesis (compound 85) of 3- (4- (methyl sulphonyl) phenyl) urea
Step 1:The conjunction of (((cis) -4- (3- (4- methyl mercaptos phenyl) urea groups) cyclohexyl) methyl) benzyq carbamate Into:
(((cis) -4- aminocyclohexyls) methyl) benzyq carbamate hydrochloride (730mg, 2.45mmol) is dissolved in In DCM (30mL), add 4- methylthio phenyls isocyanates (485.9mg, 2.94mmol) and triethylamine (742.3mg, 7.35mmol), it is stirred at room temperature.TLC detection reactions are complete, add saturated aqueous ammonium chloride (20mL), liquid separation, aqueous phase DCM Extract (2 × 20mL), merge organic phase, wash (20mL), saturated common salt washing (20mL), concentration, crude product is through silica gel column chromatography Separate (DCM:MeOH=200:1~150:1) white solid (((cis) -4- (3- (4- methyl mercaptos phenyl) urea groups) hexamethylene is obtained Base) methyl) benzyq carbamate (607mg, yield:58.0%).
Step 2:(((cis) -4- (3- (4- (methyl sulphonyl) phenyl) urea groups) cyclohexyl) methyl) benzyq carbamate Synthesis:
By (((cis) -4- (3- (4- methyl mercaptos phenyl) urea groups) cyclohexyl) methyl) benzyq carbamate (200.0mg, 0.468mmol) it is dissolved in MeOH (20mL) and water (12mL), Oxone (431.6mg, 0.702mmol) is slowly added under ice bath, Reaction 2 hours.TLC monitoring reactions are complete, add ammoniacal liquor and adjust pH value to neutrality, add water (20mL) to dilute, ethyl acetate extraction (3 × 10mL), organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, crude product is through silica gel column chromatography (DCM:MeOH= 100:1~70:1) (((cis) -4- (3- (4- (methyl sulphonyl) phenyl) urea groups) cyclohexyl) methyl) carbamic acid is separated Benzyl ester (195.5mg, yield:90.6%).
Step 3:The synthesis of 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- (methyl sulphonyl) phenyl) urea:
By (((cis) -4- (3- (4- (methyl sulphonyl) phenyl) urea groups) cyclohexyl) methyl) benzyq carbamate (144mg, 0.31mmol) is dissolved in DCM and MeOH mixed solvents (1:1,10mL) in, Pd/C (10mg), replacing hydrogen three are added It is secondary, react at room temperature 5 hours.TLC monitoring reactions are complete, and suction filtered through kieselguhr, filtrate decompression is concentrated to give 1- ((cis) -4- (amino first Base) cyclohexyl) -3- (4- (methyl sulphonyl) phenyl) urea (93.7mg, yield:93%).
Step 4:1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (4- (methyl Sulfonyl) phenyl) urea synthesis:
By 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- (methyl sulphonyl) phenyl) urea (93.7mg, The in the mixed solvent (4/1,15mL) of dichloromethane and ethanol 0.29mmol) is dissolved in, adds 5- chlorine-2-hydroxyl benzaldehydes (45.1mg, 0.29mmol) and magnesium sulfate (350mg, 2.7mmol), is stirred overnight at room temperature.TLC monitoring reactions are complete, filtering, It is concentrated to give 1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (4- (methyl sulphonyl) Phenyl) urea (90.3mg, yield:62.5%).
Step 5:1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- The synthesis of (4- (methyl sulphonyl) phenyl) urea:
By 1- ((cis) -4- (((5- chlorine-2-hydroxyls benzylidene) amino) methyl) cyclohexyl) -3- (4- (sulfonyloxy methyls Base) phenyl) urea (90.3mg, 0.19mmol) is dissolved in ethanol (5mL), add to Methyl benzenesulfonyl methyl isocyanide (56.6mg, 0.29mmol) and potassium carbonate (66.4mg, 0.48mmol), heating reflux reaction.TLC monitoring reactions are complete, reaction solution concentration, add Enter ethyl acetate (30mL) and water (30mL), liquid separation, aqueous phase is extracted with ethyl acetate (2 × 20mL), merges organic phase, washing (20mL), anhydrous magnesium sulfate are dried, and are filtered, and concentration, crude product separates (DCM through silica gel column chromatography:MeOH=50:1~20:1) To faint yellow solid 1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- (4- (methyl sulphonyl) phenyl) urea (21mg, yield:22.1%).
1HNMR(400MHz,DMSO-d6)δ(ppm):10.08(s,1H),8.80(d,1H),7.75-7.72(m,3H), 7.58-7.56(m,2H),7.30-7.27(m,1H),7.19-7.18(d,1H),6.97-6.94(m,1H),6.86(s,1H), 6.37-6.35(d,1H),3.81-3.79(d,2H),3.70-3.68(m,1H),3.12(s,3H),1.56-1.26(m,7H), 1.10-1.02(m,2H).
Molecular formula:C24H27ClN4O4S, molecular weight:503.01, the LC-MS [M+H of (Pos, m/z)=503.1+].
Embodiment 19：1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) - The synthesis (compound 87) of 3- (4- (2- (methyl sulphonyl) ethyoxyl) phenyl) urea
Step 1：The synthesis of methyl (2- (4-nitrophenoxy) ethyl) sulfane
The fluoro- 4- nitrobenzene (5.6g, 39.6mmol, 1.0eq) of raw material 1- are dissolved in tetrahydrofuran (40mL), nitrogen is protected Shield, is cooled to 0 DEG C or so, is added sodium hydride (60%) (4.6g, 118.8mmol, 3.0eq) into system in batches, is added 0 DEG C stirring 1 hour, be added dropwise 2- methyl mercaptos ethanol (4.3g, 46.2mmol, 1.2eq) tetrahydrofuran solution (10mL), add by Edge up to being stirred at room temperature 7 hours, TLC monitoring reactions are complete.Reaction solution is slowly instilled in cold water (50mL), use dichloromethane (100 × 3mL) is extracted, organic phase anhydrous sodium sulfate drying, is filtered, and filtrate is concentrated to give methyl (2- (4-nitrophenoxy) Ethyl) sulfane (5.1g, yield:61.4%).
Step 2：The synthesis of 4- (2- (methyl mercapto) ethyoxyl) aniline
Methyl (2- (4-nitrophenoxy) ethyl) sulfane (2.0g, 9.3mmol, 1.0eq) is dissolved in ethanol (20mL) In saturated aqueous ammonium chloride (15mL) mixed solution, lower addition iron powder (5.2g, 93mmol, 10.0eq) is stirred, is finished, 70 DEG C heated overnight at reflux.TLC display reactions are complete, are cooled to room temperature, suction filtered through kieselguhr, filtrate decompression concentration, add water (60mL), Extracted, organic phase anhydrous sodium sulfate drying, filtered with dichloromethane (150 × 3mL), filtrate concentration, crude product is through silica gel column chromatography Separate (petroleum ether:Ethyl acetate=50:1~20:1) 4- (2- (methyl mercapto) ethyoxyl) aniline (1.13g, yield is obtained: 64.7%).
Step 3：Benzyl (((cis) -4- (3- (4- (2- (methyl mercapto) ethyoxyl) phenyl) urea groups) cyclohexyl) methyl) ammonia The synthesis of carbamate
Solid triphosgene (888.7mg, 3.0mmol, 0.5eq) is dissolved in dichloromethane (6mL), 0 is cooled under stirring DEG C, the dichloromethane solution (4mL) of 4- (2- (methyl mercapto) ethyoxyl) aniline is added dropwise in stirring after 10 minutes, finish, 0 DEG C of stirring 2 Hour.TLC display reactions are complete, and triethylamine and (((cis) -4- aminocyclohexyls) methyl) ammonia are slowly added dropwise at this temperature The dichloromethane solution (10mL) of base benzyl formate, is finished, and 0 DEG C is stirred 3 hours, adds water (20mL), dichloromethane (60 × 3mL) Extraction, organic phase anhydrous sodium sulfate drying, filter, filtrate concentration, crude product separates (dichloromethane through silica gel column chromatography:Methanol= 250:1~200:1) benzyl (((cis) -4- (3- (4- (2- (methyl mercapto) ethyoxyl) phenyl) urea groups) cyclohexyl) first is obtained Base) carbamate (1.21g, yield:42.8%).
Step 4：1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- (2- (methyl mercapto) ethyoxyl) phenyl) urea Synthesis
By benzyl (((cis) -4- (3- (4- (2- (methyl mercapto) ethyoxyl) phenyl) urea groups) cyclohexyl) methyl) amino first Acid esters (1.20g, 2.5mmol, 1.0eq) is dissolved in acetonitrile (6mL), and stirring and dissolving after being added dropwise Iodotrimethylsilane at room temperature (1.25g, 6.2mmol, 2.5eq), drop finish, are stirred overnight at room temperature.TLC display reactions are complete, and triethylamine is added into system (632.4mg, 6.24mmol, 2.5eq), is finished, and stirs half an hour at room temperature.System is concentrated, adds saturated sodium bicarbonate water Solution (50mL), extracted with dichloromethane (150 × 3mL), organic phase anhydrous sodium sulfate drying, concentration, crude product is through silica gel column layer Analysis separation (dichloromethane:Methanol==50:1~10:1) 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- (2- are obtained (methyl mercapto) ethyoxyl) phenyl) urea (645.1mg, yield:76.4%).
Step 5：1- ((cis) -4- (((5- chlorine-2-hydroxyls benzal) amino) methyl) cyclohexyl) -3- (4- (2- (first Sulfenyl) ethyoxyl) phenyl) and urea synthesis
By 1- ((cis) -4- (amino methyl) cyclohexyl) -3- (4- (2- (methyl mercapto) ethyoxyl) phenyl) urea (645.1mg, 1.91mmol, 1.0eq) is dissolved in the mixed solution of dichloromethane (8mL) and ethanol (1mL), stirs lower room temperature It is lower addition anhydrous magnesium sulfate (3.4g, 28.65mmol, 10.0eq) and 5- chlorine-2-hydroxyls benzaldehyde (598.0mg, 3.82mmol, 2.0eq), finish, be stirred overnight at room temperature.TLC display reactions are complete, filtering, and filtrate concentration, crude product separates through silica gel column chromatography (dichloromethane:Methanol=250:1~200:1), isolated 1- ((cis) -4- (((5- chlorine-2-hydroxyls benzal) amino) Methyl) cyclohexyl) -3- (4- (2- (methyl mercapto) ethyoxyl) phenyl) urea (831.1mg, yield 91.4%).
Step 6：1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- The synthesis of (4- (2- (methyl mercapto) ethyoxyl) phenyl) urea
By 1- ((cis) -4- (((5- chlorine-2-hydroxyls benzal) amino) methyl) cyclohexyl) -3- (4- (2- (methyl mercapto) Ethyoxyl) phenyl) urea (826.4mg, 1.73mmol, 1.0eq) is dissolved in ethanol (16mL), lower addition potassium carbonate is stirred at room temperature (599.8mg, 4.34mmol, 2.5eq) and to Methyl benzenesulfonyl methyl isocyanide (508.4mg, 2.60mmol, 1.5eq), finish, 70 DEG C are heated to reflux being stirred overnight.TLC display reactions are complete, and system temperature filters after being down to room temperature, and filtrate concentration, crude product is through silicon Plastic column chromatography separates (dichloromethane:Methanol=250:1~90:1) 1- ((cis) -4- ((5- (5- chlorine-2-hydroxyl benzene is obtained Base) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- (4- (2- (methyl mercapto) ethyoxyl) phenyl) urea (475.7mg, yield: 53.1%).
Step 7：1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- The synthesis of (4- (2- (methyl sulphonyl) ethyoxyl) phenyl) urea
By 1- ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- (4- (2- (methyl mercapto) ethyoxyl) phenyl) urea (475.7mg, 0.92mmol, 1.0eq) is dissolved in dichloromethane (10mL), under stirring Be cooled to 0 DEG C stirring 20 minutes after metachloroperbenzoic acid (425.6mg, 2.46mmol, 2.0eq) is added portionwise, finish, gradually It is warmed to room temperature and is stirred overnight.TLC display reactions are complete, and saturated aqueous sodium thiosulfate (20mL), stirring are added into system Extracted, organic phase anhydrous sodium sulfate drying, filtered with dichloromethane (60 × 3mL) after 30 minutes, filtrate decompression concentration, crude product is used Methyl tertiary butyl ether(MTBE) (5mL) is beaten, and is filtered, and solid separates (dichloromethane through silica gel column chromatography:Methanol=10:1) 1- is obtained ((cis) -4- ((5- (5- chlorine-2-hydroxyls phenyl) -1H- imidazoles -1- bases) methyl) cyclohexyl) -3- (4- (2- (sulfonyloxy methyls Base) ethyoxyl) phenyl) urea (47.2mg, yield:9.3%).
1HNMR(400MHz,DMSO-d6)δ(ppm):10.06(s,1H),8.10(s,1H),7.71(s,1H),7.25- 7.29(m,2H),7.18(s,1H),6.94-6.96(m,1H),6.83-6.86(s,2H),6.06(s,1H),4.24-4.27(m, 2H),3.78-3.80(m,2H),3.66(s,1H),3.55-3.58(m,2H),3.05(s,3H),0.99-1.54(m,8H).
Molecular formula:C26H31ClN4O5S molecular weight:547.07LC-MS (Neg, m/z)=547.2 [M+H+].
The synthetic method of other compounds of the invention, it is referred to above-described embodiment progress.
Biological Examples：Part of compounds in the present invention is tested to IDO1 the enzyme activities in vitro
According to following embodiments, the present invention may be better understood.It is however, as it will be easily appreciated by one skilled in the art that real Apply the content described by example and be merely to illustrate the present invention, without should be also without limitation on sheet described in detail in claims Invention.The effect of same, available for treatment or prevent the relevant disease mediated by IDO.
Tester：Shown in compound in the present invention, its structure and preparation method see above.
Method of testing：IDO1 the enzyme activity tests are carried out using Tecan Infinite 200Pro multi-function microplate readers
1, compound plate prepares
A) 96 orifice plate, 10 dosage groups, 3 times are serially diluted, and DMSO is added per hole, and maximum concentration is that (2 is micro- by 2mM or 1mM Liter/hole, 100 times of dilutions of stoste)
B) 48 microlitres of 50mM kaliumphosphate buffers (pH=6.5), 25 times of dilution stostes are added, and mix (4 times of work Liquid)
2, by adding following reagent preparing experiment solution (substrate mixing)
A) 1.95 microlitres of 0.5M kaliumphosphate buffers (pH=6.5) (in 19.5 microlitres), final concentration 50mM
B) 3 microlitres of 0.2M ascorbic acid (in 30 microlitres), final concentration 20mM
C) 0.6 microlitre of 0.5mM methylene blues (in 30 microlitres), the micromole of final concentration 10
D) 0.6 microlitre of 5mg/ml catalase (in 30 microlitres), the mcg/ml of final concentration 100
E) 1.5 microlitres of 20mM L-tryptophans (in 30 microlitres), the micromole of final concentration 1000
F) 11.85 microlitres of water, substrate mixture volume are 19.5 microlitres
3, in 50mM kaliumphosphate buffer (pH=6.5) dilution IDO1 enzymes to 40 mcg/mls, the microgram of final concentration 4/ Milliliter
4,3 microlitres of IDO1 dilutions (40 mcg/ml) are added in 384 orifice plates, and 3 microlitre 1 is added in negative control hole Kaliumphosphate buffer (pH=6.5) again
5, in 384 orifice plates, 7.5 microlitres of compounds are added per hole and 7.5 microlitres of 4% DMSO 1 times of potassium phosphate delays Fliud flushing (pH=6.5)
6, centrifuged 1 minute under the conditions of 800 revs/min, room temperature is shaken 5 minutes, then is incubated 5 minutes
7, in 384 orifice plates, 19.5 microlitres of substrate mixtures (30 microlitres of reaction system) are added per hole
8, centrifuged 1 minute under the conditions of 800 revs/min, room temperature is shaken 5 minutes, then is incubated 1 hour under 37 degree
9, add 6 microlitres of 1M sodium hydroxide solution
10, centrifuge 1 minute, shake 5 minutes, be incubated 20 minutes under 60 degree
11, room temperature cooling, with TECAN Infinite f 200pro, reading is tested under the conditions of Ex340nm, Em495nm As a result it is as shown in table 1：
Table 1：The external zymetology inhibitory activity of part of compounds in the present invention
Compound IDO1 inhibitory activity (IC50,nM)
Compound 14 48
Compound 26 25
Compound 27 51
Compound 28 28
Compound 29 19
Compound 30 29
Compound 31 31
Compound 32 14
Compound 33 30
Compound 39 2
Compound 40 3
Compound 43 21
Compound 45 25
Compound 50 21
Compound 51 14
Compound 73 16
Compound 74 8
Compound 75 16
Compound 76 30
Compound 77 10
Compound 83 19
Compound 84 20
Compound 85 19
Compound 87 24
From the experimental result of table 1, compound of the invention has good suppression to IDO IDO1 System activity, illustrates that the compounds of this invention has preferable clinical practice potentiality.

Claims (12)

1. the IDO inhibitor that formula I is represented, or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, (C1-6Alkyl)2Amino, halo C1-6Alkyl, halo C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl sulphonyl, C1-6Alkane Base carbonylamino or C1-6Alkyl amino-carbonyl；
Work as R1For hydroxyl or carboxyl when, can with any group formed prodrug；
R3Selected from hydrogen, hydroxyl, amino, cyano group, nitro or halogen atom；
Ring A is selected from optionally by 1~3 R63~8 yuan of cycloalkyl, 3~8 circle heterocycles containing 0~3 O, S and/or N atom of substitution Base, 6~14 yuan of aromatic rings or 5~10 yuan of hetero-aromatic rings, wherein, the S atom in ring can optionally be oxidized to S (O) or S (O)2, in ring C atoms can optionally be oxidized to C (O)；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1~6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, (C1-6Alkyl)2Amino, halo C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl amino, C1-6Alkyl sulphonyl or 3~8 First cycloalkyl, C1-6Alkyl-carbonyl or C1-6Alkyl sulfenyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、-CONHR5、- CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, halo C1-6Alkyl, (C1-6Alkyl)2Ammonia Base, C1-6Alkyl-carbonyl-amino, C1-6Alkyl sulphonyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl C1-6Alkoxy, 3~8 yuan Cycloalkyl, 3~8 circle heterocycles bases, 6~14 yuan of aromatic ring yls, 5~10 unit's heteroaryls；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, carbonyl, carboxyl, C1-6Alkyl sulphonyl C1-6Alkoxy, Halo C1-6Alkyl or phenyl；
M represents 0,1,2 or 3；
N represents 1,2 or 3；
X is CH or N.
2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl or trifluoromethyl；
Work as R1For hydroxyl when, can be with any group formation-OC (O) R ' ,-O (CH2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O) R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, amino, cyano group, nitre Base, halogen atom, halo C1-6Alkyl, C1-6Alkyl, t 0,1 or 2；
R3Selected from halogen；
Ring A is selected from optionally by 1~3 R63~8 yuan of cycloalkyl of substitution, wherein, the C atoms in ring are optionally oxidized to C (O)；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、-CONHR5、- CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, halo C1-6Alkyl, (C1-6Alkyl)2Ammonia Base, C1-6Alkyl-carbonyl-amino, C1-6Alkyl sulphonyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl C1-6Alkoxy, 3~8 yuan Cycloalkyl, 3~8 circle heterocycles bases, phenyl, 5~6 unit's heteroaryls；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, carbonyl, carboxyl, trifluoromethyl or phenyl；
M represents 0,1,2 or 3；
N represents 1；
X is CH or N.
3. compound as claimed in claim 2 or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, fluorine atom, chlorine atom or bromine atoms；
Work as R1For hydroxyl when, can be with any group formation-OC (O) R ' ,-O (CH2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O) R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, trifluoromethyl, C1-6 Alkyl, t 0,1 or 2；
R3Selected from halogen；
Ring A is selected from optionally by 1~3 R64~6 yuan of cycloalkyl of substitution, wherein, the C atoms in ring can optionally be oxidized to C (O)；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、-CONHR5、- CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, phenyl, pyrimidine radicals, pyridine radicals；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, trifluoromethyl or phenyl；
M represents 0,1,2 or 3；
N choosings represent 1；
X is CH or N.
4. compound as claimed in claim 3 or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl or fluorine atom；
Work as R1For hydroxyl when, can be with any group formation-OC (O) R ' ,-O (CH2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O) R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, C1-6Alkyl, t 0, 1 or 2；
R3Selected from chlorine atom；
Ring A is selected from optionally by 1~3 R64~6 yuan of cycloalkyl of substitution；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、-CONHR5、- CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, phenyl, pyrimidine radicals, pyridine radicals；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, trifluoromethyl or phenyl；
M represents 0,1 or 2；
N represents 1；
X is CH.
5. compound as claimed in claim 1 or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl or trifluoromethyl；
Work as R1For hydroxyl when, can be with any group formation-OC (O) R ' ,-O (CH2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O) R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, amino, cyano group, nitre Base, halogen atom, halo C1-6Alkyl, C1-6Alkyl, t 0,1 or 2；R3Selected from halogen；
R3Selected from halogen；
Ring A is selected from optionally by 1~3 R66~14 yuan of aryl of substitution, 3~8 circle heterocycles containing 1~3 O, S and/or N atom Base, 5~10 unit's heteroaryls containing 1~3 O, S and/or N atom, wherein, the S atom in ring can optionally be oxidized to S (O) or S (O)2, nuclear carbon atom can optionally be oxidized to C (O)；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-N R4R5、-N(R4)COR5、-N(R4)CONHR5、- CONHR5、-CON(R4)R5、-COR5；
R4、R5Independent is selected from hydrogen atom, or the C optionally substituted by 1-3 Q1-6Alkyl, halo C1-6Alkyl, (C1-6Alkyl)2Ammonia Base, C1-6Alkyl-carbonyl-amino, C1-6Alkyl sulphonyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl C1-6Alkoxy, 3~8 yuan Cycloalkyl, 3~8 circle heterocycles bases, phenyl, 5~6 unit's heteroaryls；
Q independences are selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, carbonyl, carboxyl, trifluoromethyl or phenyl；
M represents 0,1,2 or 3；
N represents 1,2 or 3；
X is CH or N.
6. compound as claimed in claim 5 or its pharmaceutically acceptable salt, isomers and prodrug：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl or trifluoromethyl；
Work as R1For hydroxyl when, can be with any group formation-OC (O) R ' ,-O (CH2)tR’、-O(CH2)tOR’、-O(CH2)tOC(O) R’、-O(CH2)tThe prodrug of OP (O) (OR ') (OR ') form, each R ' are independently selected from hydrogen, hydroxyl, trifluoromethyl, C1-6 Alkyl, t 0,1 or 2；R3Selected from halogen；
Ring A is selected from optionally by 1~3 R6Substituted phenyl, 4~6 circle heterocycles bases containing 1~3 O, S and/or N atom or containing 1 5~6 unit's heteroaryls of~3 O, S and/or N atoms；
R6Selected from hydrogen, hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, trifluoromethyl or methyl；
Each R2It is independently selected from following group：
(1) hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, carboxyl, trifluoromethyl, C1-6Alkyl；
(2)-SO2R4、-N(R4)SO2R5、-N(R4)SO2N(R4)R5、-NR4R5、-N(R4)COR5、-N(R4)CONHR5、-CONHR5、- CON(R4)R5、-COR5；
R4、R5The independent C for being selected from hydrogen atom or optionally being substituted by 1-3 Q1-6Alkyl, phenyl, pyrimidine radicals, pyridine radicals,；Q is independent Be selected from hydrogen, halogen, cyano group, amino, hydroxyl, nitro, carbonyl, carboxyl, trifluoromethyl or phenyl；
M represents 0,1 or 2；
N represents 1；
X is CH or N.
7. compound or its pharmaceutically acceptable salt, isomers and prodrug as described in any one of claim 1~6, it is special Sign is that its structural formula is one of following arbitrary structures formula：
8. the medicine containing the compound described in any one of claim 1~7 or its pharmaceutically acceptable salt, isomers and prodrug Thing preparation, it is characterised in that include one or more pharmaceutical carriers.
9. the medicine containing the compound described in any one of claim 1~7 or its pharmaceutically acceptable salt, isomers and prodrug Compositions, it is characterised in that be comprising one or more second therapeutically active agents, the second described therapeutically active agent further Antimetabolite, growth factor receptor inhibitors, there are silk classification inhibitor, antitumor steroids, alkylating agents, metal class, topoisomerase Enzyme inhibitor, hormone drug, immunomodulator, tumor suppressor gene, Theratope, immunologic test point or immunotherapy of tumors are related Antibody and small-molecule drug.
10. immunologic test point described in claim 9 antibody or small-molecule drug related to tumour immunity, may be selected from procedural Death protein PD-1 inhibitor, programmed death ligand albumen PD-L1 inhibitor, Cytotoxic T lymphocyte-associated antigen CTLA- 4 inhibitor, antibody drug coupling ADC medicines, T cell immune globulin bletilla mucin domain albumen Tim-3 inhibitor, lymphocyte The molecule L AG-3 inhibitor of activating gene -3, killer cell immunoglobulin-like receptors KIR inhibitor.
11. the compound or its its pharmaceutically acceptable salt, isomers and prodrug described in any one of claim 1~7 are being made Application in the medicine of the disease of standby treatment IDO mediations.
12. application according to claim 11, it is characterised in that the disease of described IDO mediations is communicable disease, god Through systemic disease, cancer or non-cancerous proliferative diseases；Wherein, the communicable disease is included by influenza virus, hepatitis C Viral (HCV), HPV (HPV), cytomegalovirus (CMV), epstein-barr virus (EBV), poliovirus, varicella The caused disease of herpes zoster virus, Coxsackie virus, human immunodeficiency virus (HIV) virus infection；The nervous system Disease includes：Alzheimer's disease, depression；Described cancer includes lung cancer, dermoid cancer, carcinoma of urinary bladder, stomach cancer, ovum Nest cancer, peritoneal cancer, breast cancer, breast ductal cancer, head and neck cancer, carcinoma of endometrium, carcinoma of corpus uteri, the carcinoma of the rectum, liver cancer, kidney, renal plevis Cancer, the cancer of the esophagus, adenocarcinoma of esophagus, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymph It is knurl, neurofibromatosis, osteocarcinoma, cutaneum carcinoma, the cancer of the brain, colon cancer, carcinoma of testis, gastrointestinal stromal tumor, carcinoma of mouth, pharynx cancer, multiple Property myeloma, leukaemia, NHL, big intestinal villus adenoma, melanoma, cytoma and sarcoma, myelosis are different Normal syndrome.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109674788A (en) * 2019-01-18 2019-04-26 中国医学科学院基础医学研究所 Carboxyltriazole combines the purposes in antitumor with IDO1 inhibitor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102083429A (en) * 2008-04-24 2011-06-01 新联基因股份公司 Ido inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102083429A (en) * 2008-04-24 2011-06-01 新联基因股份公司 Ido inhibitors

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
-: "1368420-88-5/rn", 《STN REGISTRY》 *
-: "1552274-18-6/rn", 《STN REGISTRY》 *
-: "1860910-98-0/rn", 《STN REGISTRY》 *
-: "1979307-66-8/rn", 《STN REGISTRY》 *
SANJEEV KUMAR 等: "Structure Based Development of Phenylimidazole-Derived Inhibitors of Indoleamine 2,3-Dioxygenase", 《J. MED. CHEM.》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109674788A (en) * 2019-01-18 2019-04-26 中国医学科学院基础医学研究所 Carboxyltriazole combines the purposes in antitumor with IDO1 inhibitor
CN109674788B (en) * 2019-01-18 2022-01-18 广东银珠医药科技有限公司 Application of carboxyamidotriazole and IDO1 inhibitor combination in resisting tumors

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