CN110066236A - 1H- azole derivatives, preparation method, pharmaceutical composition and application - Google Patents

1H- azole derivatives, preparation method, pharmaceutical composition and application Download PDF

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CN110066236A
CN110066236A CN201910043647.5A CN201910043647A CN110066236A CN 110066236 A CN110066236 A CN 110066236A CN 201910043647 A CN201910043647 A CN 201910043647A CN 110066236 A CN110066236 A CN 110066236A
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compound
cancer
derivatives
isomers
acceptable salt
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CN110066236B (en
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高大新
郭洪利
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Shanghai de Novo Pharmatech Co Ltd
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Abstract

The invention discloses a kind of 1H- azole derivatives, preparation method, pharmaceutical composition and applications.1H- azole derivatives (I), its isomers, prodrug, solvated compounds, hydrate, stable isotope derivatives or pharmaceutically acceptable salt of the invention has the following structure.1H- azole derivatives of the invention have good IDO1 inhibiting effect, can effectively treat, alleviate and/or prevent various related diseases, such as tumour, virus infection or autoimmune disease etc. due to caused by immunosupress.

Description

1H- azole derivatives, preparation method, pharmaceutical composition and application
Technical field
The present invention relates to a kind of 1H- azole derivatives, preparation method, pharmaceutical composition and applications.
Background technique
Indole amine 2,3-dioxygenase (IDO) is by some alternative activated macrophages and other immunity regulatory cells Immunological regulation enzyme caused by (being also used as destroying immune strategy by many tumours), is to be compiled in the mankind by IDO gene Code.Its effect is to decompose required L-Trp to kynurenin (kynurenine).The exhaustion of tryptophan and its metabolism produce Object will lead to the strong inhibition effect to immune response, cause the stopping of the growth of T cell, and the activation of blocking t cell induces T Apoptosis and the generation for increasing regulatory T cells.Inherent immunity has been asserted to kynurenine metabolism pathway by tryptophan Crucial with adaptive immunity adjusts access.
A large amount of preclinical study shows this immune tolerance approach in tumour immunity, autoimmunity, infection, transplanting row It is all activation in reprimand and allergy.An active weight for increasing the increment and transfer that are presently considered to be cancer of cancer cell IDO The factor wanted.Studies have shown that IDO makes tumor-specific cytotoxicity T lymphocyte functionally inactive or can no longer attack patient Cancer cell, in fact, many human cancers, such as prostate cancer, colorectal cancer, cancer of pancreas, cervix cancer, gastric cancer, ovary Cancer, the cancer of the brain, lung cancer etc., all overexpression mankind IDO.IDO inhibit can inhibition with reversing tumor to immune function of human body, from And generate a kind of effective antitumour immune response.Since IDO inhibitor can activate T cell to enhance the immune function of human body Can, IDO inhibitor has therapeutic effect, including drug resistance of tumor and repulsion, chronic infection, HIV infection and Chinese mugwort to many diseases Disease, autoimmune disease or illness, such as rheumatoid arthritis are grown, immune tolerance and prevention uterus fetus repel.IDO's Inhibitor can be used for treatment nerve or neuropsychiatric disease or obstacle, as depression (Protula et al., 2005, blood, 106:238290；Munn etc., 1998, scientific 281:11913).
A large amount of preclinical and clinical researches show to inhibit IDO that can enhance the immunocompetence of body, and significantly improve various The antitumor drug effect of chemotherapeutic agent and curative effect (C.J.D.Austin and to disease caused by other immunosupress L.M.Rendina, Drug Discovery Today 2014,1-9).IDO-/- mice gene knockouts are feasible, Er Qie little Mouse is healthy, it means that IDO inhibits that the serious toxicity generated by the mechanism of action may not be caused.
The IDO micromolecular inhibitor being currently being deployed treats and prevents above-mentioned disease relevant to IDO, for example, PCT Patent application WO99/29310 discloses the method for changing T cell mediated immunity, including by giving a certain amount of 1- methyl DL Tryptophan or p- (3 benzofuranyl)-DL-Alanine change the extracellular concentration of local tryptophan and tryptophan metabolism object (Munn, 1999).It is disclosed in WO2004/0234623 and is able to suppress indole amine 2,3-dioxygenase (IDO) active chemical combination Object；U.S. Patent application 2004/0234623 discloses one kind by taking IDO inhibitor and controlling in conjunction with other therapeutic modalities The method for treating cancer or infected patient.
Show IDO inhibitor to immunosupress, tumor suppression, chronic infection, virus infection packet in view of lot of experimental data Including HIV infection, autoimmune disease or disorder and intrauterine fetal rejection etc. has good treatment and prevention, therefore, most The good treatment method used by inhibiting IDO activity to reach inhibition tryptophan degradation.As the HIV suppressions such as malignant tumour or HIV T When cell, IDO inhibitor can be used for enhancing the activity of T cell.In addition, IDO chemistry has been studied clearer, and its X- ray crystal structure is also parsed, this facilitates the structure optimization for preferably using Structure-ba sed drug design and drug.IDO It is a very attractive target currently used for therapeutic intervention.
Summary of the invention
Technical problem to be solved by the present invention lies in, provide a kind of novel 1H- azole derivatives, preparation method, Pharmaceutical composition and application.1H- azole derivatives of the invention have good IDO inhibiting effect, can effectively treat, alleviate And/or prevention various related diseases due to caused by immunosupress, such as tumour, communicable disease and autoimmunity class disease Deng.
Although the activity disclosed by the invention such as formula (I) compound represented be by inhibiting IDO shows, It inhibits the active mechanism of IDO not yet thoroughly research, and is also not excluded for it with inhibition TDO (tryptophan 2,3- dioxygenase) A possibility that active.Therefore, relating to " IDO inhibitor " in the present invention may each comprise following meanings: IDO inhibitor, TDO suppression Preparation or IDO and TDO double inhibitors.
The present invention provides a kind of 1H- azole derivatives (I), its isomers, prodrug, stable isotope derivatives or medicine Acceptable salt on；
Wherein, R1、R2Or R3It is separately hydrogen, deuterium, halogen, hydroxyl, amino, cyano, sulfydryl, C1-6Alkyl, C1-6Alkane Oxygroup, C1-6Alkylthio group, halogenated C1-6Alkyl, halogenated C1-6Alkoxy ,-OC (O) R7、-C(O)OR7、-C(O)R7、-C(O)N (R7)2、-NHC(O)R7、-NHS(O)2R7、-S(O)0-2R7Or-S (O)2N(R7)2；
R4For C1-6Alkyl；
R5For deuterium, halogen, amino, cyano, nitro, C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, C2-6Alkenyl, C2-6Alkynyl ,-C (O) OR8、-C(O)R8、-C(O)N(R8)2、-NHC(O)R8, it is substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 unit's heteroaryl, substituted or unsubstituted C3-8First naphthenic base or substituted or unsubstituted 3-8 membered heterocycloalkyl；When the benzene Base, 5-6 unit's heteroaryl, C3-8When first naphthenic base or 3-8 membered heterocycloalkyl are substituted, optionally by 1~3 selected from halogen, Hydroxyl, amino, cyano, nitro, C1-3Alkyl, C1-3Alkoxy and halogenated C1-3The substituent group of alkoxy replaces at an arbitrary position；
R6For aryl or 5-10 unit's heteroaryl；The R6It is unsubstituted, or is selectively selected from hydroxyl, cyanogen by 1~3 Base, amino, C1-3Alkyl, C1-3The substituent group of alkoxy and halogen replaces at an arbitrary position；
R7For hydrogen or C1-6Alkyl；
R8For hydrogen or C1-6Alkyl.
The R1Preferably hydrogen, fluorine, chlorine, bromine, cyano, amino, methyl, formamido, methoxyl group, ethyoxyl, fluoroform Oxygroup or difluoro-methoxy.
The R1Preferably cyano, methoxyl group, trifluoromethoxy, formamido or difluoro-methoxy.
The R1More preferably methoxyl group, formamido or trifluoromethoxy.
The R2Preferably hydrogen, fluorine, chlorine, cyano, methyl or methoxy.
The R2More preferably hydrogen or methoxyl group.
The R3Preferably hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxyl group, ethyoxyl or trifluoromethoxy.
The R3More preferably hydrogen or methoxyl group.
The R4Preferably methyl, ethyl or isopropyl.
R5In, the substituted or unsubstituted 5-6 unit's heteroaryl is preferably substituted or unsubstituted pyridyl group, substitution or not Substituted pyrimidine radicals, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazole radicals, substituted or unsubstituted pyrrole radicals, Substituted or unsubstituted thiazolyl, substituted or unsubstituted 1,2,3- triazol radical or substituted or unsubstituted tetrazole base；When When the 5-6 membered heterocycloalkyl is substituted, the substituent group is as previously described.
R5In, the substituted or unsubstituted 5-6 unit's heteroaryl be more preferably substituted or unsubstituted pyrazolyl, substitution or Unsubstituted imidazole radicals, substituted or unsubstituted pyrrole radicals, substituted or unsubstituted 1,2,3- triazol radical or substitution do not take The tetrazole base in generation；When the 5-6 membered heterocycloalkyl is substituted, the substituent group is as previously described.
R5In, the substituted or unsubstituted 5-6 unit's heteroaryl is more preferably pyrazolyl, imidazole radicals, pyrrole radicals or four nitrogen Oxazolyl.
The R5Preferably deuterium, halogen, cyano ,-C (O) N (R8)2, it is substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 unit's heteroaryl；When the phenyl, 5-6 unit's heteroaryl be substituted when, optionally by 1~3 selected from halogen, hydroxyl or C1-3The substituent group of alkoxy replaces at an arbitrary position.
The R5Preferably halogen, cyano ,-C (O) N (R8)2, it is substituted or unsubstituted phenyl, 5 yuan substituted or unsubstituted Heteroaryl；When the phenyl, 5 unit's heteroaryls are substituted, halogen, hydroxyl or C optionally are selected from by 1~31-3Alcoxyl The substituent group of base replaces at an arbitrary position.
The R5Preferably deuterium, methyl, chlorine, bromine, iodine, cyano, amino, formamido,
The R5Preferably deuterium, methyl, chlorine, bromine, iodine, cyano, formamido,
The R6Preferably substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl group, substituted or unsubstituted N- Pyridine oxide base, substituted or unsubstituted quinolyl or substituted or unsubstituted isoquinolyl；The R6When being substituted, it may be selected Property by following 1~3 be selected from methyl, ethyl, methoxyl group, F, Cl, Br, I ,-OH ,-NH2It is substituted in arbitrarily with the substituent group of-CN Position.
The R6It is more preferably substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl group, substituted or unsubstituted Quinolyl or substituted or unsubstituted isoquinolyl；The R6When being substituted, the alternative substituent group that F is selected from by following 1 Replace at an arbitrary position.
The R6More preferably
The 1H- azole derivatives (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives Or pharmaceutically acceptable salt, general structure are preferably:
Wherein, R1、R2、R3、R4And R5It is defined as described above.
In some preferred embodiments, the R1For cyano, methoxyl group, trifluoromethoxy or difluoro-methoxy, R3For H.
In some preferred embodiments, the R4For methyl or isopropyl.
The 1H- azole derivatives (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives Or pharmaceutically acceptable salt, general structure are preferred are as follows:
Wherein, R1、R2、R3、R4、R5And R6It is defined as described above.
The 1H- azole derivatives (I), its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable Salt is most preferably following any structure:
The present invention also provides the 1H- azole derivatives (I), its isomers, prodrug, stable isotope derivatives or The preparation method of pharmaceutically acceptable salt, the method is as follows: in solvent, in the presence of alkali, by compound I-b and compound X- 1 carries out condensation reaction；
Wherein, R1、R2、R3、R4、R5And R6It is as defined above.
In the method as shown in reaction equation 1, the condition and step of the condensation reaction can be anti-for the condensation of this field routine The condition and step answered, following reaction condition specifically preferred according to the invention: the preferred methylene chloride of the solvent or N, N- dimethyl Formamide；The dosage of the solvent preferably 5~20mL/mmol compound I-b；The preferred N of the alkali, N- diisopropylethylamine or Triethylamine；Preferred 1:1~the 5:1 of molar ratio of the alkali and compound I-b；It, can also be to reactant to accelerate reaction speed The 4-dimethylaminopyridine of catalytic amount is added in system, the 4-dimethylaminopyridine and the molar ratio of compound I-b are preferred 0.05:1~0.2:1.Preferably 0~30 DEG C of the temperature of the reaction；Condensing agent in the condensation reaction is that this field is conventional Condensing agent, preferably 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, the condensing agent and compound I- Preferred 1:1~the 5:1 of the molar ratio of b.The reaction can be detected by TLC, as anti-when generally being disappeared using compound I-b The terminal answered, preferably 0.5~24 hour；It is described after reaction, can also by post-processing product be further purified, preferably wrap It includes following steps: after reaction system is quenched with ice water, being diluted with solvent, separate organic phase, organic phase is dry, has been removed under reduced pressure Solvent, residue general purification means, for example, silica gel column chromatography, Flash column chromatography or prep-HPLC purifying.Described The step of silica gel column chromatography, Flash column chromatography or prep-HPLC are purified and condition can in this field the step of general purification and Condition.
The preparation method of the compound I-b can be the conventional method of such reaction in this field, preferably include as follows Step: in solvent, compound I-a is subjected to deprotection reaction；
Wherein, Pg is carboxy protective group, preferably C1-6Alkyl, more preferably methyl or ethyl；R1、R2、R3、R4And R5 It is as defined above.
It, can be under acid condition or alkaline condition by compound I-a progress deprotection reaction in the method as shown in reaction equation 2 It carries out.The preferred hydrochloric acid of acid condition/alcohol system or hydrogen chloride/alcohol system, the alcohol are preferably methanol or ethyl alcohol.Alkaline condition In: the solvent can be the such common solvent of reaction in this field, preferred alcohol, methanol, tetrahydrofuran, water or ethyl alcohol, first Alcohol, tetrahydrofuran and any 2~4 kinds of the mixed solvent of water, more preferably ethanol/water mixed solvent, wherein the ethyl alcohol and Preferred 1:0.5~the 2:1 of the volume ratio of water.The dosage of the solvent does not influence the progress of reaction, preferably 5~15mL/ generally Mmol compound I-a.The alkali is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, more preferably sodium hydroxide, described The molar ratio of alkali and compound I-a are preferably 2:1~10:1, the water that under normal conditions can be first dissolved in alkali in admixture solvent In the aqueous solution of alkali is prepared.The preferred room temperature of the temperature of the deprotection reaction~solvent boiling, more preferably 30~80 ℃.The process of the reaction can be detected by TLC, as the terminal of reaction when generally being disappeared using compound I-a, preferably 10 minutes~2 hours.It is described after reaction, can also by post-processing product be further purified, preferably include following steps: It is concentrated under reduced pressure after removing organic solvent, residue is sufficiently acidified, obtained solid is filtered, obtain chemical combination after filter cake vacuum drying Object I-b.
The pharmaceutically acceptable salt of the 1H- azole derivatives (I) can be chemically synthesized by general.
Under normal circumstances, the preparation of salt can by free alkali or acid and equal chemical equivalents or excess acid (inorganic acid or Organic acid) or alkali (inorganic base or organic base) reacted in suitable solvent or solvent compositions be made.
The present invention also provides a kind of pharmaceutical compositions comprising the active component of therapeutically effective amount and can pharmaceutically connect The auxiliary material received；The active component includes 1H- azole derivatives (I), its isomers, prodrug, solvate, hydrate, stabilization Isotope derivatives and one of pharmaceutically acceptable salt or a variety of.
In described pharmaceutical composition, the active component may also include its of cancer, virus infection or autoimmune disease Its therapeutic agent.
In described pharmaceutical composition, the pharmaceutically acceptable auxiliary material may include pharmaceutically acceptable carrier, dilution Agent and/or excipient.
According to therapeutic purposes, pharmaceutical composition can be made to various types of administration unit dosage forms, such as tablet, pill, powder Agent, liquid, suspension, lotion, granule, capsule, suppository and injection (solution and suspension) etc., preferred liquid, suspension, cream Liquid, suppository and injection (solution and suspension) etc..
In order to shape the pharmaceutical composition of tablet form, it can be used this field any known and widely used figuration Agent.For example, carrier, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, avicel cellulose and silicon Acid etc.；Adhesive, such as water, ethyl alcohol, propyl alcohol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose Element, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dried starch, mosanom, agar powder and sea Band powder, sodium bicarbonate, calcium carbonate, the aliphatic ester of polyethylene sorbitan, lauryl sodium sulfate, stearic acid monoglycerides, Starch and lactose etc.；Disintegration inhibitor, such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil and fat；Adsorption enhancer, such as season Amine base and lauryl sodium sulfate etc.；Wetting agent, such as glycerol, starch；Adsorbent, such as starch, lactose, kaolin, bentonite With colloid silicic acid etc.；And lubricant, such as pure talcum, stearate, boric acid powder and polyethylene glycol etc..It can also be according to need Select common coated material be made sugar coated tablet, apply gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and Multilayer tablet.
In order to shape the pharmaceutical composition of pill, it can be used this field any of and widely used figuration Agent, for example, carrier, such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talcum powder etc.；Adhesive, such as Arabic tree Rubber powder, tragacanth gum powder, gelatin and ethyl alcohol etc.；Disintegrating agent, such as agar and Kelp Powder.
In order to shape the pharmaceutical composition of suppository form, it can be used this field any known and widely used inborn nature Agent, for example, polyethylene glycol, coconut oil, higher alcohol, the ester of higher alcohol, gelatin and semi-synthetic glyceride etc..
In order to prepare the pharmaceutical composition of injection form, (suitable chlorine can will be preferably added after solution or suspension liquid disinfectant Change sodium, glucose or glycerol etc.), it is made and the isotonic injection of blood.When preparing injection, it is possible to use in the art any Common carrier.For example, water, ethyl alcohol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy The aliphatic ester etc. of anhydro sorbitol.In addition, common lytic agent, buffer and analgesic etc. can also be added.
In the present invention, content of the composition in pharmaceutical composition, can be in a wide range without specifically limited It is selected, generally can be the 5~95% of mass percent, preferably mass percent 30~80%.
In the present invention, the medication of described pharmaceutical composition is not particularly limited.Can according to patient age, gender and its Its condition and symptom select the preparation of various dosage forms to be administered.For example, tablet, pill, solution, suspension, lotion, granule or Capsule oral administration；Injection can be administered alone, or mixed with injection conveying liquid (such as glucose solution and amino acid solution) Conjunction is injected intravenously；Suppository is to be administered into rectum.
The present invention also provides the 1H- azole derivatives (I), its isomers, prodrug, solvates, hydrate, stabilization Isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition inhibit in preparation indoleamine 2,3-dioxygenase Application in agent.The indole amine 2,3-dioxygenase inhibitor (IDO inhibitor), which refers to, can inhibit IDO activity or expression (abnormal movement or overexpression including IDO), and the immunosuppressive compound for reversing IDO- to mediate.The IDO inhibitor It can inhibit IDO.
The present invention also provides the 1H- azole derivatives (I), its isomers, prodrug, solvates, hydrate, stabilization Isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition in preparation stimulation T cell hyperproliferation agent Using.
The present invention also provides the 1H- azole derivatives (I), its isomers, prodrug, solvates, hydrate, stabilization Isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition in preparation treatment, alleviate and/or prevent by Yin Diindyl amine 2,3- dioxygenase mediate related disease drug in application.It is the 1H- azole derivatives (I), its isomers, preceding Medicine, solvate, hydrate, stable isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition may be used also Combine with the therapeutic agent and/or treatment method for treating cancer of one or more other types for treating, alleviate and/or Prevent the related disease mediated by indoleamine 2,3-dioxygenase.The related disease that 2, the 3- dioxygenase mediates refer to by 2,3- dioxygenases mediate immunosupress caused by disease, the disease can include: it is viral or it is other infection (such as: Skin infection, alimentary infection, urogenital infections, systemic infection etc.), cancer or autoimmune disease (such as: Rheumatoid arthritis, lupus erythematosus, psoriasis etc.).
The therapeutic agent for treating cancer of other types can be made into list with the 1H- azole derivatives (I) The therapeutic dosage forms of one administration, or it is taken up in order of priority the therapeutic dosage forms of administration.
The therapeutic agent and/or treatment method for treating cancer of other types may include but be not limited to: micro-pipe egg White inhibitor, alkylating agent, topological enzyme I/II inhibitor, platinum-like compounds, antimetabolitas, hormone and hormone analogs, letter Number transduction pathway inhibitors, angiogenesis inhibitors, targeted therapy (such as: special kinase inhibitor), immunotherapeutic agent, rush One of apoptosis agent, cell cycle signalling pathways inhibitor and radiotherapy are a variety of.
The Antitubulin may be selected from but not limited to: and vincaleukoblastinum series (such as: vincaleukoblastinum, vincristine, Changchun Rui Bin, eldisine), one of taxanes (docetaxel, taxol) and methanesulfonic acid eribulin or a variety of.
The alkylating agent may be selected from but not limited to: mustargen, ethylenimine derivatives, Loprazolam esters, nitrosourea and One of Triazenes are a variety of.
The topological enzyme I/II inhibitor may be selected from but not limited to: Irinotecan, topotecan, adriamycin and dexrazoxane One of or it is a variety of.
The platinum-like compounds may be selected from but not limited to: cis-platinum and/or carboplatin.
The antimetabolitas may be selected from but not limited to: antifol, pyrimidine analogue, purine analogue, adenosine Deaminase inhibitors, such as: methotrexate (MTX), 5 FU 5 fluorouracil, fluridine, cytarabine, Ismipur, 6- thioguanine, One of fludarabine phosphate, Pentostatin and gemcitabine are a variety of.
The immunotherapeutic agent may be selected from but not limited to: and anti-tumor vaccine (such as: synthetic peptide, DNA vaccination and recombination disease Poison), oncolytic virus, immunostimulation antibody, novel adjuvant, cytokine therapy (such as: IL2 and GM-CSF), chimeric antigen by One in body T cell cure (CAR-T), Small molecule immunodulators, tumor microenvironment regulator and anti-angiogenesis Kind is a variety of.The immunostimulation antibody may include but be not limited to: 1) inhibit the active protein antagonist of T cell (such as: exempt from Epidemic disease checkpoint inhibitor): CTLA4 (such as: ipilimumab and tremelimumab), PD-1 (such as: pembrolizumab And nivolumab), PD-L1 (such as: durvalumab, avelumab and atezolizumab), one of LAG3 and TIM3 Or it is a variety of；1) the active protein agonist of T cell is stimulated: in GITR, OX40, OX40L, 4-1BB (CD137), CD27 and CD40 It is one or more.
The signal transduction pathway inhibitor (STI) may be selected from but not limited to: BCR/ABL kinase inhibitor, epidermal growth Factor receptor inhibitor, her-2/neu acceptor inhibitor, AKT family kinase inhibitors, PI3K signal pathway inhibitor and thin Born of the same parents' cycle checkpoint inhibitors.
The angiogenesis inhibitors may be selected from but not limited to: VEGF/VEGFR signal pathway inhibitor, Src family kinase One of inhibitor, Src signal pathway inhibitor and c-Fes kinase inhibitor are a variety of.
The virus infection can include: by influenza, Hepatitis C Virus (HCV), human papilloma virus (HPV), huge Cell virus (CMV), epstein-Barr virus (EBV), poliovirus, varicella virus, Coxsack Infection caused by the virus such as virus or human immunodeficiency virus (HIV).
The cancer may include but be not limited to: osteocarcinoma, lung cancer, gastric cancer, colon cancer, cancer of pancreas, breast cancer, prostate Cancer, lung cancer, the cancer of the brain, oophoroma, bladder cancer, cervix cancer, carcinoma of testis, kidney, head and neck cancer, lymph cancer, leukaemia and cutaneum carcinoma One of or it is a variety of.
The autoimmune disease may include but be not limited to: rheumatoid arthritis, systemic lupus erythematosus, mixing Property connective tissue disease (MCTD), system chorionitis (including: CREST syndrome), dermatomyositis, nodular vasculitis, nephrosis (packet Include: empsyxis nephrotic syndrome, acute glomerulonephritis, primary membranoproliferative glomerulonephtitis etc.), endocrine related disease (including: type-1 diabetes mellitus, sexual gland insufficiency, pernicious anaemia, hyperthyroidism etc.), hepatopathy (include: primary biliary Property cirrhosis, autoimmune cholangitis, oneself immunity hepatitis, primary sclerotic cholangitis etc.) and since infection causes One of autoimmune response (such as: AIDS, malaria etc.) or a variety of.
The present invention also provides a kind of with the 1H- azole derivatives (I), its isomers, prodrug, solvate, hydration Tryptophan degradation in object, stable isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition inhibition system Method comprising following steps: by give mammalian therapeutic it is a effective amount of as formula (I) compound represented inhibit lactation The degradation of tryptophan in animal body；The system is to express tissue, mammal or the cell tissue of IDO.
The mammal, preferably people.
In the present invention, when with substituent group be bonded display in connection ring two atoms be bonded intersect when, then in this way The bonding any bonding annular atom on ring of substituent group.
Unless otherwise indicated, the following term occurred in description of the invention and claims has the meaning that
Term " alkyl " refers to saturated straight chain or branched hydrocarbyl comprising 1-20 carbon atom, preferably 1~10 carbon atom, More preferable 1~8,1~6 or 1~4 carbon atom, the representative example of alkyl includes but is not limited to: methyl, ethyl, n-propyl, Isopropyl, normal-butyl, sec-butyl, tert-butyl, isobutyl group, amyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4- dimethyl-penten Base, 2,2,4- tri-methyl-amyls, undecyl, dodecyl and their various isomers etc..
Term " naphthenic base " refers to the saturation comprising 3-20 carbon atom or part unsaturated (comprising 1 or 2 double bond) One or more cyclic groups.It is preferred that 3-10 unit monocycle alkyl, more preferable 3-8 unit monocycle alkyl, such as: cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, suberyl, cyclooctyl, cyclodecyl, cyclo-dodecyl, cyclohexenyl group.The naphthenic base can be by any on ring Carbon atom chain be connected on parent molecule.
Term " Heterocyclylalkyl " refers to by carbon atom and the saturation or part insatiable hunger that form selected from hetero atoms such as nitrogen, oxygen or sulphur The non-aromatic cyclic radical of the 3-20 member of (including 1 or 2 double bond), this cyclic group can be monocycle or bicyclic radicals, at this In invention, hetero atom number preferably 1,2,3 or 4 in Heterocyclylalkyl, nitrogen, carbon or the sulphur atom in Heterocyclylalkyl are optionally by oxygen Change.Nitrogen-atoms can optionally further be replaced by other groups and form tertiary amine or quaternary ammonium salt." Heterocyclylalkyl " preferably 3-10 member is single Ring Heterocyclylalkyl, more preferable 3-8 unit monocycle Heterocyclylalkyl.Such as: it is '-aziridino, tetrahydrofuran -2- base, morpholine -4- base, thio Morpholine -4- base, thiomorpholine-S-oxide -4- base, piperidin-1-yl, N- Alkylpiperidine -4- base, pyrrolidin-1-yl, N- alkyl Pyrrolidin-2-yl, piperazine -1- base, 4- alkyl piperazine -1- base etc..The Heterocyclylalkyl can pass through annular atom arbitrary on ring It is linked on parent molecule.Above-mentioned annular atom refers in particular to the carbon atom and/or nitrogen-atoms of composition ring skeleton.
Term " aryl " refers to any stable 6-20 unit monocycle or Ppolynuclear aromatic group, such as: phenyl, naphthalene, four Hydrogen naphthalene, indanyl or xenyl etc..
Term " heteroaryl " refers to that the carbon atom at least one ring is formed by the hetero atom displacement selected from nitrogen, oxygen or sulphur Aromatic group, can be 5-7 unit monocycle structure or 7-12 membered bicyclic structure, preferably 5-6 unit's heteroaryl.In the present invention, Hetero atom number preferably 1,2 or 3, including but not limited to: pyridyl group, pyrimidine radicals, (2H) -one of pyridazine -3 base, furyl, thiophene Base, thiazolyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,4- triazol radical, 1,2,3- triazol radical, tetrazole base, indazolyl, iso indazolyl, quinolyl, isoquinolyl etc..
Term " alkenyl " refers to the alkenyl with 2-6 carbon atom, including vinyl, acrylic, cyclobutenyl, 2- methyl fourth Alkenyl and cyclohexenyl group.The alkenyl can be substituted.
Term " alkynyl " refers to the straight chain containing at least one triple carbon-carbon bonds, branch or cyclic hydrocarbon group.Wherein may exist Preferably there are 1 triple carbon-carbon bonds in 1-3 triple carbon-carbon bonds.Term " C2-6Alkynyl " refers to the alkynyl with 2-6 carbon atom, including Acetenyl, propinyl, butynyl and 3- methylbutynyl.
Term " alkoxy " refers to has the carbon atom number purpose cyclic annular or acyclic alkyl groups by what oxygen bridge connected, packet Containing alkyl oxy, cycloalkyl oxy and Heterocyclylalkyl oxygroup." alkoxy " includes abovementioned alkyl, Heterocyclylalkyl and cycloalkanes as a result, The definition of base.
Term " alkylthio group " refers to has the carbon atom number purpose cyclic annular or acyclic alkyl groups by what sulphur bridge connected, packet Alkyl sulfide base, cycloalkylsulfanyl and Heterocyclylalkyl sulfenyl." alkylthio group " includes abovementioned alkyl, Heterocyclylalkyl and cycloalkanes as a result, The definition of base.
Term " halogen " indicates fluorine, chlorine, bromine or iodine.
Term " halogenated alkyl " refers to the alkyl arbitrarily replaced by halogen.As a result, " halogenated alkyl " include the above halogen and The definition of alkyl.
Term " halogenated alkoxy " refers to the alkoxy arbitrarily replaced by halogen.More than " halogenated alkoxy " include as a result, The definition of halogen and alkoxy.
Term " formamido " refers to-C (O) NH2。
Term " hydroxyl " refers to-OH.
Term " sulfydryl " refers to-SH.
Term " amino " refers to-NH2。
Term " cyano " refers to-CN.
Term " nitro " refers to-NO2。
" room temperature " of the present invention refers to 15-30 DEG C.
The isotope substitutive derivative include: in Formulas I arbitrary hydrogen atom replaced by 1-5 D-atom it is same The isotope substitutive derivative or formula that arbitrary carbon atom is replaced by 1-3 14 atom of carbon in the plain substitutive derivative in position, Formulas I The isotope substitutive derivative that arbitrary oxygen atom is replaced by 1-3 18 atom of oxygen in I.
" prodrug ", which refers to, is converted into original activity compound after compound is metabolized in vivo.Typically say, it is preceding Medicine is that perhaps specific activity parent compound activity is small but can provide convenient operation, is administered or improve generation for inert matter Thank to characteristic.
" pharmaceutically acceptable salt " of the present invention is in Berge, et al., " Pharmaceutically Acceptable salts ", J.Pharm.Sci., 66,1-19 are discussed in (1977), and for Pharmaceutical Chemist be it is aobvious and Be clear to, the salt is substantially avirulent, and pharmacokinetic property needed for capable of providing, palatability, absorption, distribution, Metabolism or excretion etc..Compound of the present invention can have acidic-group, basic group or amphiprotic group, typically pharmaceutically Acceptable salt includes the salt that compound and acid reaction are prepared through the invention, such as: hydrochloride, hydrobromate, sulfuric acid Salt, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphoric acid Salt, pyrophosphate, nitrate, acetate, propionate, caprate, caprylate, formates, acrylates, isobutyrate, caproic acid Salt, enanthate, oxalates, malonate, succinate, suberate, benzoate, methyl benzoic acid salt, phthalic acid Salt, maleate, mesylate, tosilate, (D, L)-tartaric acid, citric acid, maleic acid, (D, L)-malic acid are rich Horse acid, succinic acid, succinate, lactate, fluoroform sulphonate, naphthalene -1- sulfonate, mandelate, acetonate, stearic acid Salt, ascorbate, salicylate.When the compounds of this invention contains acidic-group, pharmaceutically acceptable salt can be with It include: alkali metal salt, such as sodium or sylvite；Alkali salt, such as calcium or magnesium salts；Organic alkali salt, for example, with ammonia, alkyl ammonia The salt of the formation such as class, hydroxy alkyl Ammonia, amino acid (lysine, arginine), N-METHYL-ALPHA-L-GLUCOSAMINE.
" isomers " of the present invention refer to formula of the invention (I) compound can have asymmetric center and racemic modification, Racemic mixture and single diastereoisomer, all these isomers, including stereoisomer, geometric isomer include In the present invention.In the present invention, compound of formula I or its salt in the form of stereomeric (for example, its contain it is one or more not Symmetric carbon atom) in the presence of, individual stereoisomer (enantiomter and diastereoisomer) and their mixture It is included within the scope of the invention.The independent isomers of the compound or salt that are indicated the invention also includes Formulas I, and with wherein one The mixture of the isomers of a or multiple chiral centers reversion.Scope of the invention include that the mixture of stereoisomer, and The enantiomter or enantiomter of purifying/diastereoisomer enrichment mixture.The present invention includes all enantiomerisms The mixture of the stereoisomer of body and all possible various combination of non-corresponding isomers.The present invention includes institute defined above There are the whole combinations and subset of the stereoisomer of specific group.The invention also includes compound of formula I or the geometrical isomerisms of its salt Body, the geometric isomer include cis-trans-isomer.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably Example.
The reagents and materials used in the present invention are commercially available.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.
The structure of all compounds of the present invention can by nuclear magnetic resonance (1H NMR) and/or Mass Spectrometer Method (MS) identification.
1H nmr chemical is displaced (δ) with PPM record (10-6).NMR is carried out by Bruker AVANCE-400 spectrometer.It closes Suitable solvent is deuterated chloroform (CDCl3), deuterated methanol (MeOD-d4), deuterated dimethyl sulfoxide (DMSO-d6), tetramethylsilane is made For internal standard (TMS).
Low resolution mass spectrometry (MS) is measured by Agilent 1200HPLC/6120 mass spectrograph, using XBridge C18,4.6 × 50mm, 3.5 μm, one: 80-5% solvent A of condition of gradient elution1With 20-95% solvent B1(1.8 minutes), then 95% solvent B1With 5% solvent A1(3 minutes or more), percentage are the percentage by volume that a certain solvent accounts for total solvent volume.Solvent A1: The aqueous solution of 0.01% trifluoroacetic acid (TFA)；Solvent B1: the acetonitrile solution of 0.01% trifluoroacetic acid；Percentage accounts for molten for solute The percentage by volume of liquid.Two: 80-5% solvent A of condition of gradient elution2With 20-95% solvent B2(1.5 minutes), then 95% is molten Agent B2With 5% solvent A2(2 minutes or more), percentage are the percentage by volume that a certain solvent accounts for total solvent volume.Solvent A2: The aqueous solution of the ammonium hydrogen carbonate of 10mM；Solvent B2: acetonitrile.
All compounds of the present invention can pass through high performance liquid chromatograph, silica gel column chromatography, thin layer silica gel plate, fast selector Separation.
Fast selector (Flash column chromatography) (flash system/CheetahTM) use Agela Technologies MP200, matching used splitter are Flash columm Silica-CS (80g), Cat No.CS140080-0。
High performance liquid chromatograph (prep-HPLC) uses Shimadzu LC-20 preparative liquid chromatography, Detection wavelength: 214nm& 254nm；Flow velocity: 9.0mL/ minutes.Chromatographic column are as follows: waters xbridge Pre C18,10um, 19mm × 260mm.Elute item Part: the mobile phase A of condition 1:65~70% and 35~30% Mobile phase Bs；The mobile phase A of condition 2:25~75% and 75~25% flowings Phase B；The mobile phase A of condition 3:20~70% and 80~30% Mobile phase Bs.Solvent A: the aqueous solution of 10mM ammonium hydrogen carbonate；Solvent B: Acetonitrile.
Thin layer silica gel plate is Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate.Column chromatography generally uses the Yantai Huanghai Sea 200-300 mesh silica gel is as carrier.
All compounds of the present invention can be analyzed by Ultra Performance Liquid Chromatography instrument, Ultra Performance Liquid Chromatography instrument (UPLC) Use Waters ACQUITY Hclass platform, chromatographic column are as follows: Waters ACQUITY UPLC BEH Shield RP18 2.1mm*100mm, 1.7 μm, mobile phase A: acetonitrile, Mobile phase B: 5mm potassium dihydrogen phosphate aqueous solution is (extremely with phosphoric acid tune pH value 2.5).The gradient elution time 15 minutes, flow velocity: 0.4mL/min, Detection wavelength: 214nm&254nm；Column temperature: 40 DEG C；Sample volume 1 μL；Condition of gradient elution is as follows:
Time (minute) Flow velocity phase A (%) Flow velocity phase B (%)
0.00 10 90
5.00 40 60
7.00 90 10
13.00 90 10
13.10 10 90
15.00 10 90
Embodiment 1: the synthesis of compound 1.6
Step 1: phosphine acyl acetic acid three ethyl (6.2g, 27.6mmol) is dissolved in anhydrous tetrahydro furan (100mL), it is cold But it to -40 DEG C, is added portionwise potassium tert-butoxide (3.4g, 29.9mmol), -40 DEG C of reaction system are stirred 10 minutes, are then slowly risen Temperature continues stirring 10 minutes to 0 DEG C.System is cooled to -40 DEG C later, is added 4- phenyl cyclohexanone (4.0g, 23.0mmol) Tetrahydrofuran (5mL) solution.Reaction system is warmed to room temperature naturally and is stirred overnight.Saturated aqueous ammonium chloride is added to be quenched instead It answers, mixture is extracted with ethyl acetate (100mL × 3), merges organic phase, and with saturated common salt water washing, anhydrous sodium sulfate is dry, Solvent is distilled off in filtering, filtrate decompression, and obtained residue is purified with silica gel column chromatography (petrol ether/ethyl acetate=5/1) Obtaining compound 1.1, (5.0g, yield: 89%) being colorless oil.
Step 2: compound 1.1 (5.0g, 20.5mmol) is dissolved in methanol (100mL), addition Pd/C (5%, 200mg).Then reaction system is replaced with hydrogen and is stirred overnight three times and under nitrogen atmosphere (hydrogen balloon).Filtering, filter cake first Solvent is distilled off in alcohol washing, filtrate decompression, and obtaining compound 1.2, (5.0g, yield: 99%) being white solid.
Step 3: compound 1.2 (2.0g, 8.12mmol) is dissolved in the mixed solvent (15mL/ of tetrahydrofuran and water In 5mL), a hydronium(ion) lithia (1.4g, 32.5mmol) is added.Then reaction system is stirred 3 hours at 50 DEG C.Use salt It is 1~2 that acid solution (2.0M), which adjusts pH, there is solid precipitation, is filtered, and filter cake is washed with water, and (1.4g is produced dry compound 1.3 Rate: 79%) being white solid.
Step 4: compound 1.3 (1.0g, 4.59mmol) being dissolved in methylene chloride (15mL), oxalyl chloride is added (2.9g, 22.9mmol) and two drop n,N-Dimethylformamide.After reaction system is stirred at room temperature 30 minutes, vacuum distillation removes molten In acetone by residue dissolution, and the aqueous sodium azide of saturation is added in agent.Then reaction system is stirred at room temperature 1 hour.Add water, with ethyl acetate (50mL × 3) extract, merge organic phase, and use saturated common salt water washing, anhydrous sodium sulfate do Dry, solvent is distilled off in filtering, filtrate decompression, and obtained residue is pure with silica gel column chromatography (petrol ether/ethyl acetate=4/1) Change compound 1.4 (0.9g, yield: 81%) be white solid.
Step 5: into toluene (20mL) solution of compound 1.4 (800mg, 3.29mmol) be added the tert-butyl alcohol (1.2g, 16.5mmol).By reaction system return stirring 3 hours, vacuum distillation removed solvent, adds water, be extracted with ethyl acetate (50mL × 2), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate dries, filters, and solvent is distilled off in filtrate decompression, obtains Residue purifies to obtain compound 1.5 (800mg, yield: 84%) to be white with silica gel column chromatography (petrol ether/ethyl acetate=3/1) Color solid.
Step 6: the methanol hydrochloride solution (4.0M, 20mL) of compound 1.5 (800mg, 2.77mmol) is heated to 40 DEG C, Stirring 3 hours, vacuum distillation remove solvent, and obtained residue petroleum ether obtains (4- phenylcyclohexyl) methylamine hydrochloric acid (compound 1.6,600mg, yield: 96%) being white solid to salt.
Embodiment 2: the synthesis of compound 2.5
Step 1: under nitrogen protection, by Isosorbide-5-Nitrae-dioxa-spiral shell [4,5] decyl- 7- alkene -8- pinacol borate (4.87g, 18.3mmol), the chloro- 6- fluorine quinoline (3.0g, 16.6mmol) of 4-, potassium carbonate (6.87g, 49.8mmol) and [1,1'- bis- (hexichol Base phosphino-) ferrocene] palladium chloride (0.61g, 0.83mmol) water/dioxane (65/6mL) mixture return stirring mistake Then night reaction solution is concentrated, and be extracted with ethyl acetate, and organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated, residue Compound 2.1 (3.2g, yield: 68%) solid for white are obtained with Flash column chromatography (petrol ether/ethyl acetate=1/1) purifying Body.
Step 2: into methanol (50mL) solution of compound 2.1 (3.2g, 11.2mmol) be added Pd/C (640mg, 20%), which is stirred overnight at room temperature under nitrogen atmosphere (hydrogen balloon).Then reaction system is filtered to remove Pd/C, Filtrate is concentrated to get compound 2.2, and (3.1g, yield: 97%) being light yellow oil.
Step 3: the hydrochloric acid solution (4.0M, 30mL) of compound 2.2 (3.0g, 10.4mmol) and methanol (20mL) are mixed Object is stirred overnight at 35 DEG C.Then reaction system is concentrated under reduced pressure, residue 6N sodium hydrate aqueous solution tune pH value=9, Mixture is extracted with ethyl acetate, and organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated, and residue chromatographs (stone with Flash column Oily ether/ethyl acetate=4/1~3/7) purifying obtain compound 2.3 (2.1g, yield: 84%) be white solid.
Step 4: under condition of ice bath, to compound 2.3 (2.0g, 8.19mmol) and to Methyl benzenesulfonyl methyl isocyanide In the glycol dimethyl ether (20mL) and ethyl alcohol (2mL) mixture solution of (2.1g, 10.7mmol) be added potassium tert-butoxide (2.75g, 24.5mmol).Reaction system is stirred overnight at room temperature, and with aqueous ammonium chloride solution quenching reaction, then uses ethyl acetate (3 × 30mL) Extraction, isolates organic phase.Organic phase saturated common salt water washing, filtering, filtrate decompression concentration.Residue Flash column layer Analysis (methylene chloride/methanol=19/1) purifying obtains compound 2.4, and (1.2g, yield: 57%) being colorless oil.
Step 5: under condition of ice bath, to nitrogen protection under compound 2.4 (1.0g, 3.93mmol) tetrahydrofuran The tetrahydrofuran solution (7.87mmol, 2.5M) of Lithium Aluminium Hydride is added in (20mL) solution, then reaction system is stirred at room temperature 2 hours are mixed, water (1mL), 15% sodium hydrate aqueous solution (1mL) and water (3mL) are then separately added into reaction system and is quenched Go out the reaction, after filtering by reaction solution be concentrated to get (4- (6- fluorine quinolyl-4) cyclohexyl) methylamine (compound 2.5,720mg, Yield: 72%) being yellow oil.m/z:[M+H]+259.0。
Embodiment 3: the synthesis of compound 2.6
With the synthetic method of compound 2.5, the chloro- 6- fluorine quinoline of 4- in step 1 is replaced with into chloro- 2, the 6- dimethyl pyrazole of 4- Pyridine obtains (4- (2,6- lutidines -4- base) cyclohexyl) methylamine (compound 2.6).m/z:[M+H]+219.0。
Embodiment 4: the synthesis of compound 2.5a/2.5b
The Flash column of compound 2.4 is chromatographed into the lesser chemical combination of (petrol ether/ethyl acetate=3/1) isolated polarity The object 2.4a and biggish compound 2.4b of polarity.It is that starting material obtains with compound 2.4a with the synthetic method of compound 2.5 Compound 2.5a；It is that starting material obtains compound 2.5b with compound 2.4b.
Embodiment 5: the synthesis of compound 3.3
Step 1: compound 2.6 (436mg, 2.0mmol), triethylamine (303mg, 3.0mmol) and di-tert-butyl dicarbonate Methylene chloride (15mL) solution of (480mg, 2.2mmol) is stirred at room temperature 2 hours.TLC detects fully reacting.Decompression boils off Solvent, residue silica gel column chromatography (petrol ether/ethyl acetate=10/1~4/1) purifying obtains compound 3.1, and (420mg is produced Rate: 66%) being colorless oil.
Step 2: compound 3.1 (400mg, 1.26mmol) is dissolved in methylene chloride (15mL), metachloroperbenzoic acid (282mg, 1.64mmol) is added in reaction system, which is stirred at room temperature 2 hours, is added water (50mL), mixing Object is extracted with methylene chloride (50mL × 2).Merge organic phase, washed with saturated common salt, after organic phase anhydrous sodium sulfate drying It is concentrated under reduced pressure.Residue silica gel column chromatography (petrol ether/ethyl acetate=4/1~1/1) purifying obtains compound 3.2 (260mg, yield: 62%) being white solid.
Step 3: compound 3.2 (260mg, 0.78mmol) is dissolved in hydrogen chloride methanol solution (7M, 10mL), the reaction 2 hours are stirred at room temperature in system, and filtrate decompression is concentrated to get 4- (4- (aminomethyl) cyclohexyl) -2,6- lutidines oxygen Compound (compound 3.3,170mg, 93%) is brown oil.m/z:[M+H]+235.0。
Embodiment 6: the synthesis of compound 10.3
Step 1: to the acetone (50mL) of compound 2- trifluoromethoxy benzoyl acetic acid methyl esters (3.15g, 12.0mmol) Potassium carbonate (3.32g, 24.4mmol) and bromo acetone (2.47g, 18.0mmol) are added portionwise in solution, reaction system is heated to Reaction solution is cooled to room temperature, is poured into water, be then extracted with ethyl acetate after stirring 3 hours by reflux.Organic phase is separated, is had Machine is mutually dry with anhydrous magnesium sulfate.Filtering, filtrate concentration.Residue silica gel column chromatography purifies (petrol ether/ethyl acetate=4/ 1) obtaining compound 10.1, (1.0g, yield: 26%) being faint yellow solid.
Step 2: under nitrogen protection, second is added into ethyl alcohol (20mL) solution of compound 10.1 (800mg, 2.51mmol) Sour ammonium (582mg, 7.54mmol), reaction system are heated to flowing back, and after stirring 3 hours, reaction solution are cooled to room temperature, water is poured into In, then it is extracted with ethyl acetate.Organic phase is separated, organic phase is dry with anhydrous magnesium sulfate.Filtering, filtrate concentration.Residue With silica gel column chromatography purify (petrol ether/ethyl acetate=4/1) obtain compound 10.2 (305mg, yield: 41%) to be faint yellow Solid.
Step 3: being mixed to the methanol (4.0mL) and tetrahydrofuran (4.0mL) of compound 10.2 (370mg, 1.24mmol) The aqueous solution (1.0mL) of a hydronium(ion) lithia (260mg, 6.19mmol) is added in solution.Reaction system stirs at 80 DEG C It 16 hours, then cools to room temperature, dilutes (20mL) with ice water, resulting solid filtering, filter cake is washed with ice water, and vacuum is dry Obtained after dry 5- methyl -2- (2- (trifluoromethoxy) phenyl) -1H- pyrroles -3- carboxylic acid (compound 10.3,290mg, yield: It 82%) is faint yellow solid.m/z:[M+H]+286.0。
Embodiment 7: the synthesis of compound 10.4~10.8
With the synthetic method of compound 10.3,2- trifluoromethoxy benzoyl acetic acid methyl esters is replaced with into the benzene accordingly replaced Formyl acetic acid ethyl ester or substituted methyl benzoylacetate obtain compound 10.4~10.8:
Compound number R1 R1a R1b Title
10.4 H H Methoxyl group 5- methyl -2- (2- methoxyphenyl) -1H- pyrroles's -3- carboxylic acid
10.5 H Methoxyl group H 5- methyl -2- (3- methoxyphenyl) -1H- pyrroles's -3- carboxylic acid
10.6 H H -CN 2- (2- cyano-phenyl) -5- methyl-1 H- pyrroles's -3- carboxylic acid
10.7 H H -OCHF2 2- (2- (difluoro-methoxy) phenyl) -5- methyl-1 H- pyrroles's -3- carboxylic acid
10.8 H H -C(O)NH2 2- (2- Carbamoylphenyl) -5- methyl-1 H- pyrroles's -3- carboxylic acid
Embodiment 8: the synthesis of compound 11.1
Under the conditions of ice-water bath, bromine is slowly added dropwise into acetonitrile (20mL) solution of compound 10.3 (520mg, 2.73mmol) Change the acetonitrile solution of copper (610mg, 2.73mmol).Reaction mixture is stirred overnight at this temperature.Reaction solution ice water (20mL) dilution, ethyl acetate (50mL) extraction, is washed after merging organic phase with saturated salt solution (30mL), and anhydrous sodium sulfate is dry Dry, filtering, concentration, residue chromatograph (petrol ether/ethyl acetate=2/1) with Flash column and isolate and purify to obtain the bromo- 5- first of 4- Base -2- (2- (trifluoromethoxy) phenyl) -1H- pyrroles -3- carboxylic acid (compound 11.1,550mg, yield: 83%) solid for brown Body.
Embodiment 9: the synthesis of compound 11.2
Compound 10.6 (100.0mg, 0.44mmol) is dissolved in n,N-Dimethylformamide (4mL), under ice-water bath It is added N- chlorosuccinimide (86.0mg, 0.48mmol), reaction system stirs 0.5 hour at this temperature.Then it is added Water (4mL), obtained mixture are extracted with ethyl acetate (20mL × 2), organic phase saturated common salt water washing, anhydrous sodium sulfate Dry, filtering, filtrate decompression are concentrated to get the bromo- 2- of 4- (2- cyano-phenyl) -5- methyl-1 H- pyrroles's -3- carboxylic acid (compound 11.2,80mg, yield: 60%) being lavender solid.
Embodiment 10: the synthesis of compound 11.3~11.5
With the synthetic method of compound 11.2, compound 10.6 is replaced with 10.4,10.7 or 10.8 and obtains compound 11.3~11.5:
Compound number Starting material Product title
11.3 10.4 The bromo- 2- of 4- (2- methoxyphenyl) -5- methyl-1 H- pyrroles's -3- carboxylic acid
11.4 10.7 The bromo- 2- of 4- (2- (difluoro-methoxy) phenyl) -5- methyl-1 H- pyrroles's -3- carboxylic acid
11.5 10.8 4- bromo- 2- (Carbamoylphenyl) -5- methyl-1 H- pyrroles's -3- carboxylic acid
Embodiment 11: the synthesis of compound 11.6
Compound 10.6 (100.0mg, 0.44mmol) is dissolved in n,N-Dimethylformamide (4mL), under ice-water bath It is added N- chlorosuccinimide (65.0mg, 0.49mmol), reaction system stirs 2 hours at this temperature.Then to reaction Water (4mL) is added in system, and is extracted with ethyl acetate (20mL × 2), separates organic phase, organic phase is washed with saturated common salt It washs, anhydrous sodium sulfate is dry, filters, and filtrate decompression is concentrated to get the chloro- 2- of 4- (2- cyano-phenyl) -5- methyl-1 H- pyrroles -3- (compound 11.6,90mg, yield: 78%) being yellow oil to carboxylic acid.
Embodiment 12: the synthesis of compound 11.7
With the synthetic method of compound 11.6, compound 10.6 is replaced with 10.5 and obtains 4- chloro- 2- (3- methoxybenzene Base) -5- methyl-1 H- pyrroles -3- carboxylic acid (compound 11.7).
Embodiment 13: the synthesis of compound 12.4
Step 1: being that starting material closes with by 3- methoxybenzoyl methyl acetate according to the synthetic method of compound 10.2 At compound 12.1.By compound 12.1 (1.0g, 4.08mmol), the N of N- bromo-succinimide (0.94g, 5.3mmol), It is stirred at room temperature 10 minutes in dinethylformamide (20mL) solution.Reaction solution is quenched with water (100mL), and ethyl acetate is added (500mL) extraction, organic layer are concentrated under reduced pressure, and residue chromatographs (petrol ether/ethyl acetate=7/1) purifyingization with Flash column Closing object 12.2, (0.85g, yield: 65%) being yellow oil.
Step 2: by compound 12.2 (180mg, 0.55mmol), cuprous cyanide (248mg, 2.78mmol) is dissolved in N- first In base pyrrolidones (12mL), reaction mixture reacts 40 minutes at 150 DEG C of microwave.Reaction solution is quenched with water (100mL), is added Ethyl acetate (50mL) extraction, organic layer are concentrated under reduced pressure, and residue Flash column chromatographs (petrol ether/ethyl acetate=2/1) and purifies Obtaining compound 12.3, (0.12g, yield: 81%) being gray solid.
Step 3: by compound 12.3 (120mg, 0.44mmol), the methanol of potassium hydroxide (125mg, 2.21mmol) (6mL) and water (6mL/6mL) mixed solution stir 10 hours at 80 DEG C.It is 2-3 that reaction solution, which is transferred to pH with HCl (1.0M), is added Ethyl acetate (120mL) extraction, organic phase saturated common salt water washing are concentrated under reduced pressure to give 4- cyano -2- (3- methoxybenzene Base) (compound 12.4,90mg, yield: 80%) being gray solid to -5- methyl-1 H- pyrroles -3- carboxylic acid.
Embodiment 14: the synthesis of compound 12.5
By compound 12.2 (380mg, 1.17mmol), lithium hydroxide monohydrate (230mg, 5.48mmol) is dissolved in first In alcohol and water (15mL/15mL), stirred 20 hours at 70 DEG C of reaction mixture.It is 2-3 that reaction solution hydrochloric acid (1M), which adjusts pH, is added Enter ethyl acetate (120mL) extraction, with brine It, organic layer is concentrated under reduced pressure to give the bromo- 2- of 4- (3- methoxyphenyl) -5- (compound 12.5,215mg, yield: 60%) being yellow solid to methyl-1 H- pyrroles -3- carboxylic acid.
Embodiment 15: the synthesis of compound 13.2
Step 1: dividing into the glycol dimethyl ether and water (9mL/3mL) solution of compound 12.2 (200mg, 0.62mmol) It Jia Ru not sodium carbonate (130mg, 1.23mmol), 3- pyridine boronic acid (152mg, 1.23mmol) and Pd (dppf) Cl2(45mg, 0.062mmol).90 DEG C of reaction system are reacted 3 hours, rear ethyl acetate (2 × 50mL) extraction are quenched with water, after merging organic phase It dried, filtered, be concentrated under reduced pressure with saturated common salt water washing, anhydrous sodium sulfate, residue chromatographs (petroleum ether/acetic acid with flash column Ethyl ester=1/4) purifying obtain compound 13.1 (300mg) be yellow liquid.m/z:[M+H]+323.1。
Step 2: compound 13.1 (240mg, 0.92mmol) and potassium hydroxide (210mg, 3.72mmol) are dissolved in methanol In (10mL) and water (5mL), reaction system stirs 20 hours at 80 DEG C.PH to 3~4, ethyl acetate extraction are adjusted with hydrochloric acid (3M) It takes (30mL × 3), anhydrous sodium sulfate is dry, filters, and filtrate decompression is concentrated to get 2- (3- methoxyphenyl) -5- methyl -4- (pyrrole Pyridine -3- base) (compound 13.2,60mg, two step yields: 31%) being gray solid to -1H- pyrroles -3- carboxylic acid.m/z:[M+H]+ 309.1。
Embodiment 16: the synthesis of compound 14.1
Compound 10.3 (215mg, 0.75mmol) is dissolved in tetrahydrofuran (10mL), is slowly added dropwise under condition of ice bath N- N-iodosuccinimide (216mg, 0.98mmol).Reaction system stirs 2 hours at 0 DEG C, TLC (petrol ether/ethyl acetate =4/1) 10.3 fully reacting of raw material is shown.Then it is concentrated under reduced pressure and removes solvent, crude product is dissolved with ethyl acetate (10mL), is used Hydrochloric acid (1M) acidification, ethyl acetate extract (10mL × 3), merge organic phase and are dried, filtered with anhydrous sodium sulfate, filtrate decompression Concentration.Residue Flash column chromatographs (petrol ether/ethyl acetate=4/1~1/1) purifying and obtains the iodo- 5- methyl -2- (2- of 4- (trifluoromethoxy) phenyl) (compound 14.1,170mg, yield: 55%) being white solid to -1H- pyrroles -3- carboxylic acid.
Embodiment 17: the synthesis of compound 15.2
Step 1: under condition of ice bath, adding into nitromethane (10mL) solution of compound 10.2 (299mg, 1.0mmol) Enter acetic anhydride (122mg, 1.2mmol) and concentrated nitric acid (81mg, 1.3mmol), after 2 hours, ice water solution is added to reactant In system, the pH=7 of reaction system is adjusted with potassium carbonate powder, is then extracted, is isolated organic with ethyl acetate (3 × 50mL) Phase.Organic phase saturated common salt water washing, filtering, filtrate decompression concentration, residue chromatograph (petroleum ether/acetic acid second with Flash column Ester=10/1) purifying obtain compound 15.1 (190mg, yield: 55%) be yellow solid.
Step 2: to compound 15.1 (190mg, 0.57mmol) methanol (20mL) and water (5ml) mixed solution in plus Entering lithium hydroxide monohydrate (0.41g, 10mmol), reaction system stirs 12 hours at 80 DEG C, it is cooled to room temperature, filtering, PH=3, filtering are adjusted with hydrochloric acid (6M) after filtrate concentration, filter cake is washed with water, and then 45 DEG C of vacuum drying obtain 5- in 10 hours Methyl -4- nitro -2- (2- (trifluoromethoxy) phenyl) -1H- pyrroles -3- carboxylic acid (compound 15.2,120mg, yield: 66%) For yellow solid.
Embodiment 18: the synthesis of compound 1-1-1 and 1-1-2
Compound 11.1 (480mg, 1.32mmol), compound 2.5 (341mg, 1.32mmol) and 1- (3- dimethylamino third Base) -3- ethyl-carbodiimide hydrochloride (EDCI) (304mg, 1.58mmol) mixing after be suspended in methylene chloride (30mL), delay It is slow that n,N-diisopropylethylamine (DIEPA) (512mg, 3.96mmol) and 4-dimethylaminopyridine (16mg, 0.13mmol) is added. After reaction system is stirred at room temperature overnight, (50mL) reaction is quenched with ice water, and separated after being diluted with methylene chloride (30mL) Machine phase, organic phase are washed with saturated salt solution (25mL), and anhydrous sodium sulfate dries, filters, and filtrate decompression is concentrated to get compound Compound 1-1 Flash column is chromatographed (petrol ether/ethyl acetate=1/1) purifying and obtains the biggish compound 1- of polarity by 1-1 1-1 (26.1mg, single spatial configuration) and the lesser compound 1-1-2 of polarity (25.5mg, single spatial configuration), is white Solid.m/z:[M+H]+603.9；1-1-1, UPLC RT=7.830min；1H NMR(400MHz,DMSO-d6):δ11.54(s, 1H), 8.81 (d, J=4.4Hz, 1H), 8.09 (dd, J=6.0Hz, J=9.2Hz, 1H), 7.94 (dd, J=2.4Hz, J= 10.8Hz, 1H), 7.67 (dt, J=2.4Hz, J=8.8Hz, 1H), 7.52-7.36 (m, 6H), 3.33-3.28 (m, 3H), 2.19 (s,3H),1.94-1.92(m,1H),1.74-1.62(m,8H)；1-1-2, UPLC RT=7.729min；1H NMR(400MHz, DMSO-d6): δ 11.54 (s, 1H), 8.81 (d, J=4.8Hz, 1H), 8.09 (dd, J=6.0Hz, J=9.2Hz, 1H), 7.94 (dd, J=2.8Hz, J=11.2Hz, 1H), 7.67 (dt, J=2.8Hz, J=9.2Hz, 1H), 7.53-7.37 (m, 6H), 3.24 (t, J=11.6Hz, 1H), 3.04 (t, J=6.0Hz, 2H), 2.20 (s, 3H), 1.86 (d, J=11.6Hz, 2H), 1.76 (d, J =10.8Hz, 2H), 1.52-1.43 (m, 3H), 1.26-1.18 (m, 2H).
Embodiment 19: the synthesis of compound 1-2-1 and 1-2-2
Cuprous cyanide is added into N-Methyl pyrrolidone (2.5mL) solution of compound 1-1-1 (30mg, 0.05mmol) (22mg, 0.25mmol).Microwave reaction 40 minutes at 150 DEG C of reaction mixture with water (25mL) diluting reaction system, and uses second Acetoacetic ester extraction.Organic phase is washed with saturated salt solution (30mL), and anhydrous sodium sulfate is dry, filters, and concentration, residue is used Flash column chromatography (petrol ether/ethyl acetate=1/1) purifying obtains compound 1-2-1, and (8.8mg, yield: 32%) being off-white color Solid.
It is that starting material synthesizes compound 1-2- with compound 1-1-2 (30mg) using the synthetic method of compound 1-2-1 2 (14.5mg, yield: 53%) be off-white powder.m/z:[M+H]+550.9；1-2-1, UPLC RT=7.140min；1H NMR (400MHz,DMSO-d6): δ 12.08 (s, 1H), 8.81 (d, J=4.4Hz, 1H), 8.09 (dd, J=6.0Hz, J=9.2Hz, 1H), 7.95 (dd, J=2.4Hz, J=10.8Hz, 1H), 7.67 (dt, J=2.8Hz, J=8.8Hz, 1H), 7.57-7.41 (m, 6H),3.33-3.27(m,3H),2.37(s,3H),1.90-1.88(m,1H),1.72-1.62(m,8H)；1-2-2,UPLC RT =7.974min；1H NMR(400MHz,DMSO-d6): δ 12.08 (s, 1H), 8.81 (d, J=4.0Hz, 1H), 8.09 (dd, J= 6.0Hz, J=8.4Hz, 1H), 7.93 (d, J=9.6Hz, 1H), 7.67 (t, J=7.6Hz, 1H), 7.59-7.45 (m, 6H), 3.24 (t, J=12.8Hz, 1H), 3.06-3.03 (m, 2H), 2.38 (s, 3H), 1.86 (d, J=11.2Hz, 2H), 1.73 (d, J =10.8Hz, 2H), 1.52-1.432 (m, 3H), 1.25-1.16 (m, 2H).
Embodiment 20: the synthesis of compound 1-3-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 11.6 and 2.5a reacts to obtain chemical combination Object 1-3-1.UPLC RT=6.057min；m/z:[M+H]+501.0；1H NMR(400MHz,DMSO-d6):δ11.36(s,1H), 8.82 (d, J=4.0Hz, 1H), 8.11-8.09 (m, 1H), 8.08-8.07 (m, 1H), 7.69-7.66 (m, 1H), 7.53-7.43 (m,2H),7.25-7.12(m,2H),6.58(s,1H),3.32-3.28(m,3H),2.08(s,3H),1.75-1.33(m,9H)。
Embodiment 21: the synthesis of compound 1-4-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 12.4 and 2.5a reacts to obtain chemical combination Object 1-4-1.UPLC RT=6.850min；m/z:[M+H]+497.1；1H NMR(400MHz,DMSO-d6):δ11.99(s,1H), 8.83 (d, J=4.4Hz, 1H), 8.12-8.07 (m, 2H), 7.98 (dd, J=2.8,11.2Hz, 1H), 7.99-7.96 (m, 1H), 7.49 (d, J=4.8Hz, 1H), 7.32 (t, J=7.6Hz, 1H), 7.14-7.11 (m, 2H), 6.89 (dd, J=1.6, 8.0Hz,1H),3.77(s,3H),3.38-3.34(m,3H),2.37(s,3H),1.97(br.s,1H),1.78-1.65(m, 8H)。
Embodiment 22: the synthesis of compound 1-5-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 11.2 and 2.5a reacts to obtain chemical combination Object 1-5-1.UPLC RT=7.372min；m/z:[M+H]+544.8；1H NMR(400MHz,DMSO-d6):δ11.93(s,1H), 8.83 (d, J=4.4Hz, 1H), 8.43-8.38 (m, 1H), 8.12-8.08 (m, 1H), 7.99-7.95 (m, 1H), 7.77-7.65 (m,1H),7.61-7.54(m,2H),7.48-7.45(m,1H),6.54(s,1H),3.30-3.28(m,3H),2.09(s,3H), 2.00-1.93(m,1H),1.79-1.52(m,8H)。
Embodiment 23: the synthesis of compound 1-7-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 12.5 and 2.5a reacts to obtain chemical combination Object 1-7-1.m/z:[M+H]+551.9；1H NMR(400MHz,DMSO-d6): δ 11.45 (s, 1H), 8.84 (d, J=4.8Hz, 1H), 8.11-8.04 (m, 2H), 7.98 (dd, J=10.8,2.8Hz, 1H), 7.70-7.65 (m, 1H), 7.49 (d, J= 4.8Hz,1H),7.28-7.24(m,1H),7.10-7.08(m,2H),6.82-6.79(m,1H),3.74(s,3H),3.37- 3.33(m,3H),2.20(s,3H),2.01(br.s,1H),1.76-1.65(m,8H)。
Embodiment 24: the synthesis of compound 1-8-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 11.4 and 2.5a reacts to obtain chemical combination Object 1-8-1.UPLC RT=7.468min；m/z:[M+H]+585.9；1H NMR(400MHz,DMSO-d6):δ11.42(s,1H), 8.98 (d, J=4.8Hz, 1H), 8.16-8.11 (m, 1H), 8.08-8.02 (m, 1H), 7.79-7.71 (m, 1H), 7.58-7.55 (m, 1H), 7.50-7.44 (m, 1H), 7.41-7.35 (m, 2H), 7.28-7.21 (m, 2H), 7.02 (t, J=74.0Hz, 1H), 3.33-3.25(m,3H),2.18(s,3H),1.94-1.89(m,1H),1.77-1.57(m,8H)。
Embodiment 25: the synthesis of compound 1-9-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 11.5 and 2.5a reacts to obtain chemical combination Object 1-9-1.UPLC RT=5.924min；m/z:[M+H]+563.2；1H NMR(400MHz,DMSO-d6):δ11.41(s,1H), 8.82 (d, J=4.8Hz, 1H), 8.63 (t, J=5.6Hz, 1H), 8.10-8.07 (m, 1H), 7.98-7.94 (m, 1H), 7.69- 7.64(m,1H),7.54-7.41(m,4H),7.23-7.12(m,3H),3.29-3.25(m,3H),2.08(s,3H),1.73- 1.59(m,7H),1.46-1.42(m,2H)。
Embodiment 26: the synthesis of compound 1-10-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 14.1 and 2.5a reacts to obtain chemical combination Object 1-10-1.UPLC RT=7.435min；m/z:[M+H]+651.9；1H NMR(400MHz,CD3OD):δ8.65-8.63(d,J =8.0Hz, 1H), 7.98-7.95 (m, 1H), 7.77-7.74 (m, 1H), 7.50-7.41 (m, 3H), 7.36-7.23 (m, 3H), 3.37-3.34 (d, J=12.0Hz, 2H), 3.25-3.22 (m, 1H), 2.23 (s, 3H), 1.93 (m, 1H), 1.75-1.63 (m, 8H)。
Embodiment 27: the synthesis of compound 1-11-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 11.7 and 2.5a reacts to obtain chemical combination Object 1-11-1.UPLC RT=7.324min；m/z:[M+H]+506.0；1H NMR(400MHz,MeOD-d4): δ 8.77 (d, J= 4.8Hz, 1H), 8.09 (dd, J=5.6, J=9.2Hz, 1H), 7.88 (dd, J=2.8, J=10.8Hz, 1H), 7.56-7.63 (m, 2H), 7.25-7.29 (m, 1H), 7.07-7.09 (m, 2H), 6.82-6.85 (m, 1H), 3.79 (s, 3H), 3.52 (d, J= 8.0Hz,2H),3.37-3.39(m,1H),2.24(s,3H),2.10(s,1H),1.78-1.91(m,8H)。
Embodiment 28: the synthesis of compound 1-12-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 15.2 and 2.5a reacts to obtain chemical combination Object 1-12-1.m/z:[M+H]+571.0。
Embodiment 29: the synthesis of compound 2-1-1
It is that starting material reacts to obtain compound 2-1 with compound 1.6 and 10.4 using the synthetic method of compound 1-1, Compound 2-1 is obtained into the biggish compound 2- of polarity through silica gel column chromatography separation (petrol ether/ethyl acetate=3/1~1/1) 1a (8.3mg, single spatial configuration) and the lesser compound 2-1b of polarity (11.1mg, single spatial configuration) is that white is solid Body.
Compound 2-1a (50mg, 0.12mmol) is dissolved in n,N-Dimethylformamide (20mL), is delayed under ice-water bath It is slow that N- chlorosuccinimide (20mg, 0.15mmol) is added.After reaction mixture stirs 3 hours at 0 DEG C, ice water is used (20mL) dilution, ethyl acetate (30mL) extraction, is washed after merging organic phase with saturated salt solution (30mL), and anhydrous sodium sulfate is dry Dry, filtering, filtrate decompression concentration, residue Flash column chromatograph (petrol ether/ethyl acetate=3/1) purifying and obtain compound (9.4mg, yield: 17%) being off-white powder to 2-1-1.UPLC RT=8.162min；m/z:[M+H]+437.2；1H NMR (400MHz,DMSO-d6):δ11.09(s,1H),7.38-7.35(m,1H),7.31-7.26(m,6H),7.18-7.14(m, 1H), 7.04 (d, J=8.4Hz, 1H), 6.95-6.91 (m, 1H), 3.74 (s, 3H), 3.33-3.31 (m, 1H), 3.22 (t, J= 7.2Hz,2H),2.16(s,3H),1.80-1.77(m,1H),1.65-1.44(m,8H)。
Embodiment 30: the synthesis of compound 2-2-1 and 2-2-2
With the synthetic method of compound 1-1, compound 2.5 is replaced with into compound 1.6 and obtains compound 2-2,2-2 is used Flash column chromatography (petrol ether/ethyl acetate=1/1) purifying obtains the biggish compound 2-2-1 of polarity (single spatial configuration) It is white solid with the lesser compound 2-2-2 of polarity (single spatial configuration).m/z:[M+H]+535.2。
Embodiment 31: the synthesis of compound 2-3-1 and 2-3-2
With the synthetic method of compound 1-1, compound 2-3 is obtained with compound 11.3 and the reaction of compound 1.6, by 2-3 The biggish compound 2-3-1 of polarity (single solid structure is obtained with Flash column chromatography (petrol ether/ethyl acetate=1/1) purifying Type) and the lesser compound 2-3-2 of polarity (single spatial configuration), it is white solid.m/z:[M+H]+482.9；2-3-2, UPLC RT=8.146min；1H NMR(400MHz,DMSO-d6): δ 11.17 (s, 1H), 7.36 (t, J=5.6Hz, 1H), 7.32-7.22 (m, 6H), 7.16 (t, J=6.8Hz, 1H), 7.04 (d, J=8.4Hz, 1H), 6.93 (t, J=7.2Hz, 1H), 3.75 (s, 3H), 3.21 (t, J=7.2Hz, 2H), 2.52-2.50 (m, 1H), 2.17 (s, 3H), 1.79 (br.s, 1H), 1.66- 1.47(m,8H)。
Embodiment 32: the synthesis of compound 2-4-2
It is starting material synthesis compound 2-4-2 with compound 2-3-2 using the synthetic method of compound 1-2-1.UPLC RT=7.802min；m/z:[M+H]+428.1；1H NMR(400MHz,DMSO-d6):δ11.75(s,1H),7.41-7.37(m, 1H), 7.73-7.10 (m, 8H), 6.99 (t, J=7.6Hz, 1H), 3.33-3.31 (m, 1H), 3.20 (t, J=6.8Hz, 2H), 2.34(s,3H),1.72(br.s,1H),1.62-1.46(m,8H)。
Embodiment 33: the synthesis of compound 2-5-1 and 2-5-2
With the synthetic method of compound 1-1, compound 2-5 is obtained with compound 11.6 and the reaction of compound 1.6, by 2-5 With prep-HPLC (condition 2) purifying obtain compound 2-5-1 (appearance time: 17.5~18.2 minutes, single spatial configuration) and Compound 2-5-2 (appearance time: 18.3~19.0 minutes, single spatial configuration), it is white solid.2-5-1, UPLC RT =7.487min；1H NMR(400MHz,DMSO-d6):δ11.43(s,1H),8.70-8.67(m,1H),7.53-7.40(m, 3H), 7.33-7.27 (m, 2H), 7.21-7.15 (m, 4H), 3.03 (t, J=6.4Hz, 2H), 2.40-2.34 (m, 1H), 2.10 (s, 3H), 1.73 (d, J=10.8Hz, 2H), 1.48 (d, J=12.0Hz, 2H), 1.36-1.19 (m, 3H), 0.91-0.81 (m, 2H)；2-5-2, UPLC RT=7.552min；1H NMR(400MHz,DMSO-d6):δ11.35(s,1H),8.61-8.58(m, 1H), 7.52-7.40 (m, 3H), 7.30-7.26 (m, 2H), 7.22-7.10 (m, 4H), 3.19 (t, J=6.0Hz, 2H), 2.09 (s,3H),1.63-1.24(m,10H)。
Embodiment 34: the synthesis of compound 3-1-2
By compound 2-2-2 (161mg, 0.30mmol), pyridine -3- boric acid (55mg, 0.45mmol), Pd (dppf) Cl2 (22mg, 0.03mmol) and sodium carbonate (95mg, 0.90mmol) are dissolved in water (2.0mL) and Isosorbide-5-Nitrae-dioxane (5.0mL). Reaction mixture is concentrated under reduced pressure after flowing back under nitrogen atmosphere 3 hours, residue with Flash column chromatograph (petrol ether/ethyl acetate= 1/1) purifying obtain compound 3-1-2 (20.7mg, yield: 13%) be faint yellow solid.UPLC RT=7.448min；m/z: [M+H]+534.0；1H NMR(400MHz,DMSO-d6): δ 11.31 (s, 1H), 8.52 (d, J=1.6Hz, 1H), 8.40 (dd, J =1.6,4.8Hz, 1H), 7.71-7.68 (m, 1H), 7.59 (dd, J=1.6,7.2Hz, 1H), 7.46-7.13 (m, 10H), 3.08 (t, J=7.2Hz, 2H), 2.51-2.45 (m, 1H), 2.26 (s, 3H), 1.53 (br.s, 1H), 1.46-1.24 (m, 8H).
Embodiment 35: the synthesis of compound 4-1-1
With the synthetic method of compound 3-1-2, compound 2-2-2 is replaced with into compound 1-1-1 and obtains compound 4-1- 1.UPLC RT=6.238min；m/z:[M+H]+603.2；1H NMR(400MHz,DMSO-d6):δ11.33(s,1H),8.80 (d, J=4.4Hz, 1H), 8.53 (s, 1H), 8.40 (d, J=4.4Hz, 1H), 8.08 (dd, J=5.6,9.6Hz, 1H), 7.92 (dd, J=2.4,10.8Hz, 1H), 7.73-7.59 (m, 3H), 7.45-7.30 (m, 6H), 3.33-3.30 (m, 1H), 3.16 (t, J=6.8Hz, 2H), 2.27 (s, 3H), 1.75 (br.s, 1H), 1.62-1.39 (m, 8H).
Embodiment 36: the synthesis of compound 4-2-1
With the synthetic method of compound 3-1-2, with the fluoro- 5- hydroxyphenyl boronic acid reaction of compound 1-1-1 and 3- Close object 4-2-1.UPLC RT=7.331min；m/z:[M+H]+636.1；1H NMR(400MHz,DMSO-d6):δ11.20(s, 1H), 9.75 (s, 1H), 8.80 (d, J=4.8Hz, 1H), 8.08 (dd, J=6.0,9.6Hz, 1H), 7.93 (dd, J=2.8, 11.2Hz, 1H), 7.69-7.58 (m, 2H), 7.43-7.36 (m, 4H), 7.23 (t, J=6.0Hz, 1H), 6.58-6.52 (m, 2H), 6.42-6.38 (m, 1H), 3.29-3.26 (m, 1H), 3.17 (t, J=6.8Hz, 2H), 2.24 (s, 3H), 1.78 (br.s, 1H),1.64-1.44(m,8H)。
Embodiment 37: the synthesis of compound 4-3-1
With the synthetic method of compound 3-1-2, with compound 1-1-1 and 3, the fluoro- 5- methoxyphenyl-boronic acid of 4- bis- reacts Obtain compound 4-3-1.UPLC RT=7.701min；m/z:[M+H]+668.2；1H NMR(400MHz,DMSO-d6):δ 11.26 (s, 1H), 8.80 (d, J=4.4Hz, 1H), 8.08 (dd, J=6.0,9.2Hz, 1H), 7.93 (dd, J=2.4, 10.8Hz,1H),7.69-7.64(m,1H),7.60-7.57(m,1H),7.44-7.31(m,5H),6.94-6.86(m,2H), 3.87 (s, 3H), 3.33-3.27 (m, 1H), 3.17 (t, J=6.8Hz, 2H), 2.27 (s, 3H), 1.76 (br.s, 1H), 1.63- 1.42(m,8H)。
Embodiment 38: the synthesis of compound 4-4-1
Under the conditions of ice-water bath, Boron tribromide-dichloromethane solution (0.90mL, 0.90mmol) is slowly dropped to compound In methylene chloride (30mL) solution of 4-3-1 (120mg, 0.18mmol).Reaction mixture stirs 5 hours at 0 DEG C, then uses Saturated sodium bicarbonate aqueous solution (30mL) quenching reaction, obtained mixture are extracted with dichloromethane (30mL × 3), merge organic Xiang Hou is washed with saturated salt solution (30mL), and anhydrous sodium sulfate dries, filters, filtrate decompression concentration, residue prep- HPLC (condition 1) purifying obtains compound 4-4-1, and (19.3mg, yield: 16%) being white solid.UPLC RT=7.466min； m/z:[M+H]+654.2；1H NMR(400MHz,DMSO-d6): δ 11.22 (s, 1H), 10.20 (br.s, 1H), 8.80 (d, J= 4.4Hz, 1H), 8.08 (dd, J=6.0,10.4Hz, 1H), 7.93 (dd, J=2.4,9.2Hz, 1H), 7.69-7.64 (m, 1H), 7.59-7.58(m,1H),7.42-7.37(m,4H),7.27-7.24(m,1H),6.75-6.68(m,2H),3.33-3.27(m, 1H), 3.17 (t, J=6.8Hz, 2H), 2.23 (s, 3H), 1.77 (br.s, 1H), 1.64-1.45 (m, 8H).
Embodiment 39: the synthesis of compound 4-5-1
With the synthetic method of compound 1-1, compound 11.1 is replaced with into compound 13.2 and 2.5a reacts to obtain chemical combination Object 4-5-1.UPLC RT=4.997min；m/z:[M+H]+549.2；1H NMR(400MHz,DMSO-d6):δ11.31(s,1H), 8.82 (d, J=4.8Hz, 1H), 8.54-8.53 (m, 1H), 8.40-8.38 (m, 1H), 8.10-8.07 (m, 1H), 7.98-7.92 (m,2H),7.71-7.64(m,2H),7.45-7.43(m,1H),7.37-7.39(m,1H),7.29-7.25(m,1H),7.19- 7.15(m,2H),6.81-6.78(m,1H),3.75(s,3H),3.27-3.21(m,3H),2.28(s,3H),1.83(br.s, 1H),1.66-1.43(m,8H)。
Embodiment 40: the synthesis of compound 5-1-1
Microwave is anti-at 150 DEG C after compound 1-1-1 (60mg, 0.1mmol) and 1H- pyrazoles (68mg, 1.0mmol) are mixed It answers 1 hour.Reaction mixture directly obtains compound 5-1-1 with prep-HPLC (condition 1) purifying after being cooled to room temperature (5.5mg, yield: 9%) being white solid.UPLC RT=7.218min；m/z:[M+H]+592.0；1H NMR(400MHz, DMSO-d6): δ 11.58 (s, 1H), 8.79 (d, J=4.0Hz, 1H), 8.08 (dd, J=6.4,8.8Hz, 1H), 7.97 (s, 1H), 7.93 (d, J=10.4Hz, 1H), 7.75 (s, 1H), 7.66 (t, J=6.8Hz, 1H), 7.55-7.39 (m, 6H), 6.47 (s,1H),3.34-3.32(m,1H),3.22-3.20(m,2H),2.09(s,3H),1.68-1.42(m,9H)。
Embodiment 41: the synthesis of compound 5-2-1
With the synthetic method of compound 5-1-1,1H- pyrazoles is replaced with into 1H-1,2,3- triazoles obtain compound 5-2- 1.UPLC RT=6.683min；m/z:[M+H]+593.0；1H NMR(400MHz,DMSO-d6):δ11.73(s,1H),8.79 (d, J=4.4Hz, 1H), 8.34 (s, 1H), 8.08 (dd, J=6.0,9.2Hz, 1H), 7.92 (dd, J=2.8,10.8Hz, 1H), 7.87 (s, 1H), 7.69-7.59 (m, 2H), 7.50-7.40 (m, 4H), 7.17 (t, J=5.6Hz, 1H), 3.30-3.31 (m, 1H), 3.15 (t, J=6.4Hz, 2H), 2.12 (s, 3H), 1.67 (br.s, 1H), 1.59-1.53 (m, 6H), 1.59-1.38 (m,2H)。
Embodiment 42: the synthesis of compound 5-3-1
With the synthetic method of compound 5-1-1,1H- pyrazoles is replaced with into 1H- tetrazole and obtains compound 5-3-1.UPLC RT=6.908min；m/z:[M+H]+593.8；1H NMR(400MHz,DMSO-d6):δ11.88(s,1H),9.11(s,1H), 8.79 (d, J=4.4Hz, 1H), 8.08 (dd, J=2.0,9.6Hz, 1H), 7.94-7.92 (m, 1H), 7.69-7.62 (m, 2H), 7.54-7.33 (m, 5H), 3.34-3.32 (m, 1H), 3.15 (t, J=5.2Hz, 2H), 2.12 (s, 3H), 1.73 (br.s, 1H), 1.60-1.45(m,8H)。
Embodiment 43: the synthesis of compound 6-1-1
It is starting material synthesis compound 6-1-1 with compound 1-8-1 using the synthetic method of compound 1-2-1.UPLC RT=6.662min；m/z:[M+H]+533.0；1H NMR(400MHz,DMSO-d6): δ 11.97 (s, 1H), 8.81 (d, J= 4.4Hz,1H),8.12-8.06(m,1H),7.97-7.92(m,1H),7.70-7.62(m,1H),7.50-7.42(m,4H), 7.33-7.21 (m, 2H), 7.07 (t, J=73.6Hz, 1H), 3.36-3.25 (m, 3H), 2.36 (s, 3H), 1.92-1.84 (m, 1H),1.76-1.57(m,8H)。
Embodiment 44: the synthesis of compound 6-2-1
Compound 1-2-1 (50mg, 0.09mmol) is dissolved in the concentrated sulfuric acid (2mL), 70 DEG C are stirred 16 hours.Reaction solution It pours into ice water, adjusts pH=8 with sodium carbonate, obtained mixture is extracted with ethyl acetate, and separates organic phase and with anhydrous sulphur Sour sodium dries, filters, filtrate is concentrated, and residue is separated with prep-HPLC (condition 1), and obtaining compound 6-2-1, (2.5mg is produced Rate: 5%) being white solid.UPLC RT=6.711min；m/z:[M+H]+568.9；1H NMR(400MHz,CD3OD):δ 8.77-8.76 (d, J=4.0Hz, 1H), 8.11 (m, 1H), 7.87-7.85 (d, J=8.0Hz, 1H), 7.58-7.40 (m, 6H), 3.40-3.38(m,2H),3.32(m,1H),2.52(s,3H),1.77-1.62(m,9H)。
Embodiment 45: the synthesis of compound 7-1-1
To compound 1-12-1 (50mg, 0.08mmol) ethyl alcohol (10mL) and water (5mL) mixed solution in zinc is added The aqueous ammonium chloride solution (3mL) of powder (52mg, 0.8mmol) and saturation, the reaction system stir 3 hours at 50 DEG C, filter, filter Liquid separates organic phase after being diluted with methylene chloride (30mL), and organic phase is washed with saturated salt solution (25mL), and anhydrous sodium sulfate is dry Dry, filtering, concentration, residue chromatograph (methylene chloride/methanol=10/1) with Flash column and isolate and purify to obtain compound 7-1-1 (20mg, yield: 46%) being white solid.UPLC RT=4.567min；m/z:[M+H]+540.9；1H NMR(400MHz, CD3OD): δ 8.64 (d, J=4.8Hz, 1H), 7.97 (dd, J=5.2,9.2Hz, 1H), 7.76 (dd, J=2.8,10.4Hz, 1H), 7.26-7.50 (m, 6H), 3.30 (d, J=7.6Hz, 2H), 3.21-3.24 (m, 1H), 2.07 (s, 3H), 1.42-1.76 (m,9H)。
Embodiment 46: the synthesis of compound 8-1-1 and 8-1-2
With the synthetic method of compound 1-1, compound 8-1 is obtained with compound 14.1 and the reaction of compound 3.3, by 8-1 With prep-HPLC (condition 3) purifying obtain compound 8-1-1 (appearance time: 18.4~19.1 minutes, single spatial configuration) and Compound 8-1-2 (appearance time: 19.6~20.2 minutes, single spatial configuration), it is white solid.m/z:[M+H]+ 627.8；8-1-1, UPLC RT=7.235min；1H NMR(400MHz,CD3OD):δ7.53-7.55(m,1H),7.36-7.47 (m, 3H), 7.30 (s, 2H), 3.15 (d, J=6.4Hz, 2H), 2.54 (s, 6H), 2.48-2.52 (m, 1H), 2.30 (s, 3H), 1.84-1.90(m,4H),1.40-1.59(m,3H),1.05-1.15(m,2H)；8-1-2, UPLC RT=7.289min；1H NMR(400MHz,CD3OD): δ 7.52-7.55 (m, 1H), 7.36-7.46 (m, 3H), 7.34 (s, 2H), 3.39 (d, J= 68.0Hz,2H),2.61-2.66(m,1H),2.54(s,6H),2.30(s,3H),1.91-1.95(m,1H),1.58-1.81(m, 8H)。
Biological test embodiment: the measurement of IDO bioactivity
Embodiment 1: the IDO inhibitory activity based on HeLa cell tests (IC50)
HeLa cell strain source: ATCC additionally incorporates fetal bovine serum (10% with MEM/EBSS fluid nutrient medium culture FBS), Pen .- Strep (100,000U/L), nonessential amino acid (0.1mM), Sodium Pyruvate (Na-pyruvate) (1.0mM).Cell keeps 37 DEG C, 95% humidity and 5% carbon dioxide in incubator.Altogether with gamma interferon (IFN γ) Incubation makes it express IDO, makes it in the medium can be by tryptophan metabolism N- formylkynurenine.Specific experiment method is such as Under:
HeLa cell is planted in 96 orifice plates with the amount of 25,000 cells/wells, the culture medium of 100 μ l is contained in every hole, Next with the test compound of IFN γ and certain concentration (10 μM of concentration range are arrived 1nM, be its in conventional medium most Volume is overnight for 200 μ L) inducing cell afterwards, so that it is expressed people and recombinates IDO.Followed by incubation, by supernatant liquor (140 μ L) It is transferred in 96 orifice plates, 6.1N TCA (10 μ L) is added and continues to be incubated for 30 minutes at 50 DEG C afterwards, the N- formyl dog for generating IDO Urinary ammonia acid is fully hydrolyzed as kynurenin.Reaction solution is centrifuged 10 minutes under 2500rpm revolving speed later, removes solid precipitating Supernatant is transferred in another 96 orifice plate by object with 100 holes μ L/ later, and 2% (w/v) 4- (N, N- bis- of 100 μ L is added Methylamino) benzaldehyde acetum.It is incubated at room temperature 10 minutes, the solution that kynurenin generates yellow can be with using enzyme Mark instrument (TECAN Infinite M1000Pro) records its absorbance having at 480nm.
The suppression percentage of each concentration of untested compound is made to be measured with reference to comparative evaluation with 0.1% DMSO blank solution The reduction amount of kynurenin determines in chemical combination objects system, data Graph Pad4 are obtained by nonlinear regression IC50Value.
1H- azole derivatives active testing result of the present invention is as shown in the table:
Ref.A (positive control) is embodiment 239 disclosed in Chinese patent application CN2015800603285, chemical name Claim: N- ((R) -1- ((1s, 4S) -4- (6- fluorine quinolyl-4) cyclohexyl) ethyl) -4- (5- methoxypyridine -2- base) benzene first Amide.

Claims (14)

1. a kind of 1H- azole derivatives (I), its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable Salt；
Wherein, R1、R2Or R3It is separately hydrogen, deuterium, halogen, hydroxyl, amino, cyano, sulfydryl, C1-6Alkyl, C1-6Alcoxyl Base, C1-6Alkylthio group, halogenated C1-6Alkyl, halogenated C1-6Alkoxy ,-OC (O) R7、-C(O)OR7、-C(O)R7、-C(O)N(R7)2、- NHC(O)R7、-NHS(O)2R7、-S(O)0-2R7Or-S (O)2N(R7)2；
R4For C1-6Alkyl；
R5For deuterium, halogen, amino, cyano, nitro, C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, C2-6Alkenyl, C2-6Alkynes Base ,-C (O) OR8、-C(O)R8、-C(O)N(R8)2、-NHC(O)R8, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 Unit's heteroaryl, substituted or unsubstituted C3-8First naphthenic base or substituted or unsubstituted 3-8 membered heterocycloalkyl；When the phenyl, 5- 6 unit's heteroaryls, C3-8First naphthenic base can 3-8 membered heterocycloalkyl when being substituted, optionally by 1~3 selected from halogen, hydroxyl, Amino, cyano, C1-3Alkyl, C1-3Alkoxy and halogenated C1-3The substituent group of alkoxy replaces at an arbitrary position；
R6For aryl or 5-10 unit's heteroaryl；The R6It is unsubstituted, or is selectively selected from hydroxyl, cyano, ammonia by 1~3 Base, C1-3Alkyl, C1-3The substituent group of alkoxy and halogen replaces at an arbitrary position；
R7For hydrogen or C1-6Alkyl；
R8For hydrogen or C1-6Alkyl.
2. 1H- azole derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or medicine Acceptable salt on, which is characterized in that R1For cyano, methoxyl group, trifluoromethoxy or difluoro-methoxy；
And/or R2For hydrogen, fluorine, chlorine, cyano, methyl or methoxy；
And/or R3For hydrogen；
And/or R4For methyl, ethyl or isopropyl；
And/or R5For deuterium, methyl, chlorine, bromine, iodine, cyano, formamido,
And/or R6For
3. 1H- azole derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or medicine Acceptable salt on, which is characterized in that its general structure are as follows:
Wherein, R1、R2、R3、R4And R5Definition it is as described in claim 1.
4. 1H- azole derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or medicine Acceptable salt on, which is characterized in that its general structure is following any:
Wherein, R1、R2、R3、R4、R5And R6Definition it is as described in claim 1.
5. 1H- azole derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or medicine Acceptable salt on, it is characterised in that: if formula (I) compound represented is following any structure:
6. 1H- azole derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or medicine Acceptable salt on, wherein the preparation method of the compound as shown in formula (I) is following method:
In solvent, in the presence of alkali, compound I-b and compound X-1 is subjected to condensation reaction and obtains the chemical combination as shown in formula (I) Object；
Wherein, R1、R2、R3、R4、R5And R6Definition it is as described in claim 1.
7. a kind of pharmaceutical composition comprising the active component of therapeutically effective amount and pharmaceutically acceptable auxiliary material；The work Property component includes 1H- azole derivatives (I) as claimed in any one of claims 1 to 5, its isomers, prodrug, stable same position Plain derivative or pharmaceutically acceptable salt.
8. pharmaceutical composition as claimed in claim 7, it is characterised in that: in described pharmaceutical composition, the active component is also Other therapeutic agents including cancer, virus infection or autoimmune disease；
And/or in described pharmaceutical composition, the pharmaceutically acceptable auxiliary material includes pharmaceutically acceptable carrier, dilution Agent and/or excipient.
9. 1H- azole derivatives (I) as claimed in any one of claims 1 to 5, its isomers, prodrug, stable isotope derivative method Biology or pharmaceutically acceptable salt, or as claim 7 or 8 described pharmaceutical compositions are preparing indoleamine 2,3-dioxygenase Application in inhibitor.
10. 1H- azole derivatives (I) as claimed in any one of claims 1 to 5, its isomers, prodrug, stable isotope Derivative or pharmaceutically acceptable salt, or as claim 7 or 8 described pharmaceutical compositions are preparing stimulation T cell proliferation medicine Application in object.
11. 1H- azole derivatives (I) as claimed in any one of claims 1 to 5, its isomers, prodrug, stable isotope Derivative or pharmaceutically acceptable salt, or such as claim 7 or 8 described pharmaceutical compositions in preparation treatment, alleviate and/or pre- Application in the drug of the anti-related disease mediated by indoleamine 2,3-dioxygenase.
12. application as claimed in claim 11, it is characterised in that: the 1H- azole derivatives (I), its isomers, preceding Medicine, stable isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition and one or more other types The therapeutic agent and/or treatment method for treating cancer be used in combination；The treatment for treating cancer of other types Agent and/or treatment method are Antitubulin, alkylating agent, topological enzyme I/II inhibitor, platinum-like compounds, anti-metabolism medicine Object, hormone and hormone analogs, signal transduction pathway inhibitor, angiogenesis inhibitors, targeted therapy, immunotherapeutic agent, rush One of apoptosis agent, cell cycle signalling pathways inhibitor and radiotherapy are a variety of.
13. application as claimed in claim 11, it is characterised in that: the related disease packet that 2, the 3- dioxygenase mediates It includes: virus infection, cancer or autoimmune disease.
14. application as claimed in claim 13, it is characterised in that: the cancer be osteocarcinoma, liver cancer, cancer of the esophagus, carcinoma of mouth, Gastric cancer, colorectal cancer, cancer of pancreas, breast cancer, prostate cancer, lung cancer, the cancer of the brain, oophoroma, bladder cancer, cervix cancer, carcinoma of testis, One of kidney, head and neck cancer, lymph cancer, leukaemia and cutaneum carcinoma are a variety of；The autoimmune disease is rheumatoid Property arthritis, systemic lupus erythematosus, mixed connective tissue disease, system chorionitis, dermatomyositis, nodular vasculitis, nephrosis, Endocrine related disease, hepatopathy, psoriasis and due to one of autoimmune response caused by infection or a variety of；The virus Infection is by influenza, Hepatitis C Virus, human papilloma virus, cytomegalovirus, epstein-Barr virus, spinal cord One of poliovirus, varicella virus, Coxsackie virus and human immunodeficiency virus are a variety of caused Infection.
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