CN110156656A

CN110156656A - Five yuan of heteroaromatic ring derivatives, preparation method, pharmaceutical composition and application

Info

Publication number: CN110156656A
Application number: CN201910062130.0A
Authority: CN
Inventors: 高大新; 杨伟; 李国成
Original assignee: Shanghai de Novo Pharmatech Co Ltd
Current assignee: Shanghai de Novo Pharmatech Co Ltd
Priority date: 2018-02-13
Filing date: 2019-01-23
Publication date: 2019-08-23
Anticipated expiration: 2039-01-23
Also published as: CN110156656B

Abstract

The invention discloses five yuan of heteroaromatic ring derivatives, preparation method, pharmaceutical composition and applications.Five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable salt of the invention has the following structure.Five yuan of heteroaromatic ring derivatives of the invention have good IDO 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

Five yuan of heteroaromatic ring derivatives, preparation method, pharmaceutical composition and application

Technical field

The present invention relates to a kind of five yuan of heteroaromatic ring 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 quinary heteroaromatic ring derivative, its preparation side Method, pharmaceutical composition and application.Five yuan of heteroaromatic ring derivatives of the invention have good IDO inhibiting effect, can effectively control It treats, alleviate and/or prevention various related diseases due to caused by immunosupress, such as tumour, communicable disease and itself exempt from Epidemic disease class disease etc..

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 five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope derivatives Or pharmaceutically acceptable salt；

Wherein, A ring is pyrrole ring, also, X, Y, Z are selected from following combination:

1) X is NR₁, Y CR₂It is CR with Z₃；

2) X is CR₂, Y NR₁It is CR with Z₃；

3) X is CR₃, Y CR₂It is NR with Z₁；Or

4) X is CR₃, Y NR₁It is CR with Z₂；

Alternatively, A ring is imidazole ring, also, X, Y, Z are selected from following combination:

5) X is NR₁, Y CR₂It is N with Z；Or

6) X is N, Y CR₂It is NR with Z₁；

L is CH₂、CH(CH₃)、C(CH₃)₂Or CH₂CH₂；

U and V is separately selected from N or CR₄；

Cy is phenyl ring or 5-10 member hetero-aromatic ring, and the Cy is unsubstituted or is further selected from halogen, C by 1~4_1-6Alkane Base, C_1-6Alkoxy, C_1-6Alkylthio group, halogenated C_1-6Alkyl, halogenated C_1-6Alkoxy, C_2-6Alkynyl, C_2-6Alkenyl, C_3-6Naphthenic base ,- OH、-SH、-CN、-NO₂、-OC(O)R_a、-OC(O)OR_b、-OC(O)N(R_b)₂、-C(O)OR_b、-C(O)R_a、-C(O)N(R_b)₂、- NR_bC(O)R_a、-N(R_b)₂、-NR_bC(O)R_a、-S(O)_0-2R_aWith-S (O)₂N(R_b)₂One of or a variety of substituent groups replace it is in office Meaning position；

R be substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl or Substituted or unsubstituted heteroaryl；When the R is the naphthenic base replaced, substituted Heterocyclylalkyl, substituted aryl or is replaced Heteroaryl when can be by following 1~3 R^AGroup replaces at an arbitrary position :-CN ,-OR_a、-C(O)N(R_b)₂、-OC(O)R_a、-OC (O)OR_b、-OC(O)N(R_b)₂、-C(O)OR_b、-C(O)R_a、-C(O)N(R_b)₂、-N(R_b)₂、-NR_bC(O)R_a、-NR_bC(O)OR_a、- NR_bC(O)N(R_b)₂、-NR_bC(O)N(R_b)₂、-NR_bS(O)₂R_a、-NR_bS(O)₂N(R_b)₂、-S(O)_0-2R_a、-S(O)₂N(R_b)₂, halogen It is plain, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted Naphthenic base, substituted or unsubstituted Heterocyclylalkyl or substituted or unsubstituted heteroaryl；R^AIn, the alkyl, alkoxy, virtue When base, heteroaryl, naphthenic base or Heterocyclylalkyl are substituted, halogen, hydroxyl, amino, C further can be selected from by 1~3_1-4Alkane Base or halogenated C_1-3The substituent group of alkoxy replaces at an arbitrary position；

R₁For H or C_1-6Alkyl；Alternatively, R₁For-C (O) N (R_b)₂、-C(O)R_a、-C(O)OR_a、-S(O)₂N(R_b)₂、-S(O)₂R_a, replace C_1-6Alkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6It is alkynyl, substituted or unsubstituted C_3-8Naphthenic base, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 member Heteroaryl；The C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, 3-8 membered heterocycloalkyl, phenyl or 5-6 unit's heteroaryl It is preferably selected from by 1~3 when substituted: deuterium, halogen, hydroxyl, sulfydryl, amino, cyano, C_1-3Alkyl, C_1-3Alkoxy, C_1-3Alkane Amido, halogenated C_1-3Alkoxy, halogenated C_1-3Alkyl, carboxylic acid, ester group, amide groups ,-NH (CO)-C_1-6Alkyl ,-C (O)-C_1-6Alkane Base ,-S (O)_0-2-C_1-6Alkyl, C_3-8The substituent group of naphthenic base or 3-8 membered heterocycloalkyl replaces at an arbitrary position；

R₂For substituted C_1-6Alkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substitution or Unsubstituted C_3-8Naphthenic base, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl replace or do not take The 5-6 unit's heteroaryl in generation；As the C_1-6Halogen, C preferably are selected from by 1~3 when alkyl is substituted_1-4Alkoxy, C_1-4Alkanamine Base, halogenated C_1-4Alkoxy ,-OH ,-NH₂Replace at an arbitrary position with one of-CN or a variety of substituent groups；As the C_2-6Alkene Base, C_2-6Alkynyl, C_3-8Naphthenic base, 3-8 membered heterocycloalkyl, phenyl or 5-6 unit's heteroaryl are preferably selected from by 1~3 when being substituted Deuterium, halogen, C_1-4Alkyl, C_1-4Alkoxy, halogenated C_1-4Alkyl, halogenated C_1-4Alkoxy, C_1-4Alkylamino radical ,-OH ,-NH₂With in-CN One or more substituent groups replace at an arbitrary position；Or R₂For halogen ,-CN ,-OR_a、-C(O)N(R_b)₂、-C(O)R_a、-C (O)OR_a、-S(O)₂N(R_b)₂、-S(O)₂R_a、-N(R_b)₂Or-NR_bC(O)R_a；

R₁And R₂For independent substitution or R₁And R₂It is interconnected to form 5-10 membered heterocycloalkyl or 5-6 unit's heteroaryl； The 5-10 membered heterocycloalkyl also can further include 1~3 selected from N, O, S (O)_0-2, C (O) hetero atom or group；It is described 5-10 membered heterocycloalkyl or 5-6 unit's heteroaryl are unsubstituted or are further selected from halogen, C by 1~3_1-4Alkyl, C_1-4Alkane Oxygroup, halogenated C_1-4Alkyl, halogenated C_1-4Alkoxy, C_1-4Alkylamino radical ,-OH ,-NH₂It is taken with one of-CN or a variety of substituent groups In generation, is at an arbitrary position；

R₃For H, deuterium, halogen, cyano, amide groups, ester group or C_1-3Alkyl；

R₄For H ,-OH ,-CN, C_1-6Alkyl or C_1-6Alkoxy；

Each R_aWith each R_bIt is each independently selected from hydrogen, alkyl, halogenated alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl Base, hetercycloalkylalkyl, cycloalkyl-alkyl, aryl alkyl or heteroaryl alkyl, alternatively, two R_bThe N being connect jointly with them Atom is formed together the monocyclic heterocycloalkyl of 3-8 member；

M is 1,2 or 3；

N is 0,1 or 2.

The combination of all embodiments and any embodiment as described in Formulas I as described below is all contained in the present invention In the range of structural formula shown in formula I.

In some embodiments, the L is CH₂。

In some embodiments, the U is CH.

In some embodiments, the V is CH.

In some embodiments, 1 n.

In some embodiments, 1 m.

In some embodiments, in the Cy, the 5-10 unit's heteroaryl is 5-6 unit's heteroaryl.

In some embodiments, in the Cy, the 5-10 unit's heteroaryl is thienyl, imidazole radicals, pyrazolyl, oxazole Base, isoxazolyl, thiazolyl, 1,2,3- oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,4- triazole Base, 1,2,3- triazol radical, 1,2,3- thiadiazolyl group, 1,2,5- thiadiazolyl group, tetrazole base, pyridyl group, pyrimidine radicals, pyrazine Base or pyridazinyl；The thienyl, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3- oxadiazoles base, 1, 2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,4- triazol radical, 1,2,3- triazol radical, 1,2,3- thiadiazolyl group, 1,2, 5- thiadiazolyl group, tetrazole base, pyridyl group, pyrimidine radicals, pyrazinyl or pyridazinyl are unsubstituted or are further taken by 1~3 Replace at an arbitrary position for base, the substituent group is as defined above；The substituent group is preferred are as follows: deuterium, halogen, amino, cyanogen Base, C_1-3Alkyl (such as: methyl), C_1-3Alkoxy (such as: methoxyl group, ethyoxyl) and halogenated C_1-3Alkoxy (such as: trifluoro Methoxyl group, difluoro-methoxy) one of or it is a variety of.

In some embodiments, in the Cy, the 5-10 unit's heteroaryl is pyridyl group, pyrimidine radicals or pyrazinyl；Institute Pyridyl group, pyrimidine radicals or pyrazinyl is stated to be unsubstituted or further replaced at an arbitrary position by 1~2 substituent group, it is described to take Dai Ji is as defined above；The substituent group is preferred are as follows: deuterium, halogen, amino, cyano, C_1-3Alkyl (such as: methyl), C_1-3 Alkoxy (such as: methoxyl group, ethyoxyl) and halogenated C_1-3One of alkoxy (such as: trifluoromethoxy, difluoro-methoxy) Or it is a variety of.

In some embodiments, in the Cy, the 5-10 unit's heteroaryl is pyridyl group；The pyridyl group is unsubstituted Or further replaced at an arbitrary position by 1~2 substituent group, the substituent group is as defined above；The substituent group is excellent It is selected as: deuterium, halogen, amino, cyano, C_1-3Alkyl (such as: methyl), C_1-3Alkoxy (such as: methoxyl group, ethyoxyl) and it is halogenated C_1-3One of alkoxy (such as: trifluoromethoxy, difluoro-methoxy) is a variety of.

In some embodiments, the Cy is following any structure: OrWherein, R₅And R₆Separately selected from H, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylthio group, halogenated C_1-6Alkyl, halogenated C_1-6Alkoxy, C_2-6Alkynyl, C_2-6Alkenyl, C_3-6Cycloalkanes Base ,-OH ,-SH ,-CN ,-NO₂、-OC(O)R_a、-OC(O)OR_b、-OC(O)N(R_b)₂、-C(O)OR_b、-C(O)R_a、-C(O)N (R_b)₂、-NR_bC(O)R_a、-N(R_b)₂、-NR_bC(O)R_a、-S(O)_0-2R_aOr-S (O)₂N(R_b)₂；R_aAnd R_bIt is as defined above. The R₅Preferably hydrogen, methyl, methoxyl group, cyano, trifluoromethoxy, ethyoxyl or difluoro-methoxy；The R₆Preferably hydrogen, Deuterium, halogen, amino, cyano, C_1-3Alkyl, C_1-3Alkoxy or halogenated C_1-3Alkoxy.

In some embodiments, the Cy is following any structure:OrWherein, R₅And R₆It is defined as described above.

In some embodiments, the Cy is following any structure:OrIts In, R₅And R₆It is defined as described above.

In some embodiments, in the Cy, the R₅For H.

In some embodiments, in the Cy, the R₅For methoxyl group, difluoro-methoxy or trifluoromethoxy.

In some embodiments, in the Cy, the R₅For trifluoromethoxy.

In some embodiments, in the R, the substituted or unsubstituted aryl is substituted or unsubstituted C_6-10Virtue Base (for example, substituted or unsubstituted phenyl or substituted or unsubstituted naphthalene).

In some embodiments, in the R, the substituted or unsubstituted heteroaryl is preferably substituted or unsubstituted 5-10 unit's heteroaryl is substituted or unsubstituted pyridyl group, substituted or unsubstituted N- pyridine oxide base, substituted or unsubstituted Pyrimidine radicals, substituted or unsubstituted quinolyl or substituted or unsubstituted isoquinolyl, substituted or unsubstituted pyridazinyl, substitution Or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrole radicals, substituted or unsubstituted imidazoles Base, substituted or unsubstituted triazol radical, substituted or unsubstituted tetrazole base；

In some embodiments, in the R, the substituted or unsubstituted naphthenic base is substituted or unsubstituted C_3-8 Naphthenic base.

In some embodiments, in the R, the substituted or unsubstituted naphthenic base is substituted or unsubstituted C_3-8 Monocyclic cycloalkyl.

In some embodiments, in the R, the substituted or unsubstituted Heterocyclylalkyl is substituted or unsubstituted 5- 8 membered heterocycloalkyls.

In some embodiments, in the R, the substituted or unsubstituted Heterocyclylalkyl is substituted or unsubstituted 5- 8 yuan of single Heterocyclylalkyls.

In some embodiments, when the R be replace naphthenic base, substituted Heterocyclylalkyl, substituted aryl or It can be by following 1~3 R when substituted heteroaryl^AGroup replaces at an arbitrary position :-OH ,-SH ,-CN ,-NO₂、-NH₂、-C(O)N (R_b)₂、-OC(O)R_a、-OC(O)OR_b、-OC(O)N(R_b)₂、-C(O)OR_b、-C(O)R_a、-C(O)N(R_b)₂、-N(R_b)₂、-NR_bC (O)R_a、-NR_bC(O)R_a、-NR_bC(O)OR_a、-NR_bC(O)N(R_b)₂、-NR_bC(O)N(R_b)₂、-NR_bS(O)₂R_a、-NR_bS(O)₂N (R_b)₂、-S(O)_0-2R_a、-S(O)₂N(R_b)₂, halogen, alkylthio group, substituted or unsubstituted alkyl, substituted or unsubstituted alcoxyl Base, substituted or unsubstituted aryl, substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl or replace or not Substituted heteroaryl.

In some embodiments, the R^AIn, the halogen is F, Cl, Br, I；More preferable F or Cl.

In some embodiments, the R^AIn, the substituted or unsubstituted alkyl is substituted or unsubstituted C_1-4Alkane Base；More preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl.

In some embodiments, the R^AIn, the substituted or unsubstituted alkoxy is substituted or unsubstituted C_1-4 Alkoxy；More preferably methoxyl group, ethyoxyl.

In some embodiments, the R^AIn, the substituted or unsubstituted aryl is substituted or unsubstituted phenyl.

In some embodiments, the R^AIn, the substituted or unsubstituted heteroaryl is substituted or unsubstituted 5-6 Unit's heteroaryl.

In some embodiments, the R^AIn, the substituted or unsubstituted naphthenic base is substituted or unsubstituted C_3-8 Naphthenic base.

In some embodiments, the R^AIn, the substituted or unsubstituted Heterocyclylalkyl is substituted or unsubstituted 5-8 membered heterocycloalkyl.

In some embodiments, the R^AIn, the alkyl, alkoxy, aryl, heteroaryl, naphthenic base or heterocycle alkane When base is substituted, halogen, hydroxyl, amino, C further can be selected from by 1-3_1-3Alkyl or halogenated C_1-3The substituent group of alkoxy Replace at an arbitrary position.

In some embodiments, the R_aAnd R_bIt is each independently hydrogen, C_1-4Alkyl, halogenated C_1-3Alkyl, C_3-8Cycloalkanes Base, 3-8 membered heterocycloalkyl, phenyl, 5-6 unit's heteroaryl, 3-8 membered heterocycloalkyl C_1-3Alkyl, C_3-8Naphthenic base C_1-3Alkyl, phenyl Alkyl or 5-6 unit's heteroaryl C_1-3Alkyl, alternatively, two R_bThe monocycle of 3-8 member is formed together with the N atom that they connect jointly Heterocyclylalkyl.

In some embodiments, the R_aFor hydrogen, methyl, ethyl, n-propyl or isopropyl.

In some embodiments, the R_bFor hydrogen, methyl, ethyl, n-propyl or isopropyl.

In some embodiments, the R is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl group, substitution Or it unsubstituted N- pyridine oxide base, substituted or unsubstituted quinolyl, substituted or unsubstituted isoquinolyl, substitution or does not take The pyridazinyl in generation, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, takes substituted or unsubstituted pyrimidine radicals Generation or unsubstituted pyrrole radicals；The substituted R can be by following 1~3 R^AGroup replaces at an arbitrary position: C_1-3Alkyl (example Such as: methyl, ethyl, isopropyl), C_1-3Alkoxy (such as: methoxyl group, ethyoxyl), F, Cl, Br ,-OH ,-NH₂With in-CN It is one or more.

In some embodiments, the R is substituted or unsubstituted phenyl, substituted or unsubstituted quinolyl or takes Generation or unsubstituted isoquinolyl；The substituted R can be replaced at an arbitrary position by following 1 F.

In some embodiments, the R is

In some embodiments, the R₁For H.

In some embodiments, the R₁For substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substitution or Unsubstituted isopropyl or substituted or unsubstituted cyclopropyl.The methyl, ethyl, isopropyl or cyclopropyl are unsubstituted, or Person's selectivity is replaced at an arbitrary position by 1-OH.

In some embodiments, R₁For methyl, ethyl, isopropyl or cyclopropyl.The ethyl is unsubstituted, or Selectivity is replaced at an arbitrary position by 1-OH.

In some embodiments, R₁For H, methyl, ethyl, isopropyl or cyclopropyl.The ethyl is unsubstituted, or Person's selectivity is replaced at an arbitrary position by 1-OH.

In some embodiments, the R₂In, the substituted C_1-6Alkyl is the C replaced_1-4Alkyl, the substituent group For F or-OH.

In some embodiments, the R₂In, the substituted C_1-6Alkyl is the C replaced by 1 hydroxyl_1-4Alkyl.

In some embodiments, the R₂In, the substituted C_1-6Alkyl is the methyl replaced, and the substituent group is excellent It is selected as-OH.

In some embodiments, the R₂In, the substituted C_1-6Alkyl is the ethyl replaced, n-propyl, isopropyl Base, normal-butyl, isobutyl group, sec-butyl or tert-butyl；The substituent group is F or-OH.

In some embodiments, the R₂In, the substituted C_1-6Alkyl is trifluoromethyl, difluoromethyl, 2- fluorine Propyl- 2- base, 2,2- bis-fluoro ethyls, 1,1- bis-fluoro ethyls, hydroxymethyl (- CH₂OH), 2- hydroxyl propyl- 2- base (- C (CH₃)₂OH)、 Or 1- hydroxy-2-methyl propyl- 2- base (- C (CH₃)₂CH₂OH)。

In some embodiments, the R₂In, the substituted C_1-6Alkyl is hydroxymethyl (- CH₂OH), 2- hydroxyl Propyl- 2- base (- C (CH₃)₂) or 1- hydroxy-2-methyl propyl- 2- base (- C (CH OH₃)₂CH₂OH)。

In some embodiments, the R₂In, the substituted or unsubstituted C_3-8Naphthenic base is substituted or unsubstituted C_3-6Naphthenic base, such as: cyclopropyl, 1- methylcyclopropyl groups1- hydroxycyclopropylCyclobutyl, cyclopenta, ring Hexyl or 1- fluorine cyclopropyl

In some embodiments, the R₂In, the substituted or unsubstituted C_3-8Naphthenic base is substituted or unsubstituted C_3-6Naphthenic base, such as: cyclopropyl, 1- methylcyclopropyl groups1- hydroxycyclopropylCyclobutyl, cyclopenta or Cyclohexyl.

In some embodiments, the R₂In, the substituted or unsubstituted 3-8 membered heterocycloalkyl is to replace or do not take The 3-6 membered heterocycloalkyl in generation, such as: 3- oxetanylmethoxy, 2- oxetanylmethoxy, 3- azelidinyl, 2- azelidinyl.

In some embodiments, the R₂For halogen, C_2-4Alkenyl, the C replaced by 1 hydroxyl_1-4Alkyl, substitution or not Substituted C_3-6Naphthenic base, substituted or unsubstituted 3-6 membered heterocycloalkyl；The C_3-6Naphthenic base or 3-6 membered heterocycloalkyl are not Replace, or selectivity is by 1 F ,-CH₃Or-OH replaces at an arbitrary position.

In some embodiments, the R₂For fluorine, chlorine, trifluoromethyl, difluoromethyl, 2- fluorine propyl- 2- base, 2,2- difluoro Ethyl, 1,1- bis-fluoro ethyls, hydroxymethyl, 1- methylcyclopropyl groups, 1- hydroxycyclopropyl, 1- fluorine cyclopropyl, cyclobutyl, cyclopropyl Base, 3- oxetanylmethoxy or 2- oxetanylmethoxy.

In some embodiments, the R₂For 1- hydroxy-2-methyl propyl- 2- base, 3- azelidinyl or 2- azacyclo- Butyl.

In some embodiments, the R₂For fluorine, chlorine, propyl- 1- alkene -2- base, hydroxymethyl, 1- methylcyclopropyl groups, 1- Hydroxycyclopropyl, cyclobutyl, cyclopropyl, 3- oxetanylmethoxy, 2- oxetanylmethoxy, 1- hydroxy-2-methyl propyl- 2- base, 3- nitrogen Heterocycle butyl or 2- azelidinyl.

In some embodiments, the R₂For fluorine, chlorine, propyl- 1- alkene -2- base, hydroxymethyl, 1- methylcyclopropyl groups, 1- Hydroxycyclopropyl, cyclobutyl, cyclopropyl, 3- oxetanylmethoxy, 2- oxetanylmethoxy or 1- hydroxy-2-methyl propyl- 2- base.

In some embodiments, the R₃For H, deuterium, fluorine, chlorine, bromine, cyano or methyl.

In some embodiments, the R₃For H.

In some embodiments, the R₄For H.

In some embodiments, five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotopes The definition of certain groups can be as described below in derivative or pharmaceutically acceptable salt, and the group not described can either a program as above It is described:

1) X is NR₁, Y CR₂It is CR with Z₃；

2) X is CR₂, Y NR₁It is CR with Z₃；

5) X is NR₁, Y CR₂It is N with Z；Or

L is CH₂；

U and V are separately selected from N；

Cy isOrR₅For methoxyl group, difluoro-methoxy or trifluoromethoxy；

R is

R₁For substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl or replace Or unsubstituted cyclopropyl.The methyl, ethyl, isopropyl or cyclopropyl are unsubstituted, or selectivity is by 1-OH substitution At an arbitrary position.

R₂For halogen, C_2-4Alkenyl, the C replaced by 1 hydroxyl_1-4Alkyl, substituted or unsubstituted C_3-6Naphthenic base, substitution Or unsubstituted 3-6 membered heterocycloalkyl；The C_3-6Naphthenic base or 3-6 membered heterocycloalkyl are unsubstituted, or selectivity is by 1 F、-CH₃Or-OH replaces at an arbitrary position；

R₃For H；

M is 1；N is 1.

DescribedForOr

In some embodiments, five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope derivative method Biology or pharmaceutically acceptable salt are the compound as shown in formula (II), its isomers, prodrug, stable isotope derivatives Or pharmaceutically acceptable salt:

Wherein, Cy, R, R₁、R₂And R₃It is defined as described above.

Following preferred embodiment includes in the definition of the compound as shown in formula (II):

In some preferred embodiments, Cy isOr

In some preferred embodiments, R is

In some preferred embodiments, R₁For H.

In some preferred embodiments, R₁For methyl or hydroxyethyl.

In some preferred embodiments, R₁For H or methyl.

In some preferred embodiments, R₂For hydroxymethyl, propyl- 1- alkene -2- base, 1- methylcyclopropyl groups, 1- hydroxyl cyclopropyl Base, cyclobutyl, cyclopropyl, 3- oxetanylmethoxy, 2- oxetanylmethoxy, 1- hydroxy-2-methyl propyl- 2- base, 3- azelidinyl, Or 2- azelidinyl.

In some preferred embodiments, R₃For H or D.

In some preferred embodiments, R₃For H.

In some embodiments, five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope derivative method Biology or pharmaceutically acceptable salt are the compound as shown in formula (III), its isomers, prodrug, stable isotope derivatives Or pharmaceutically acceptable salt:

Wherein, Cy, R, R₁、R₂And R₃It is defined as described above.

Following preferred embodiment includes in the definition of the compound as shown in formula (III):

In some preferred embodiments, Cy isOr

In some preferred embodiments, R is

In some preferred embodiments, R₁For H.

In some preferred embodiments, R₁For methyl.

In some preferred embodiments, R₂For substituted F, Cl, hydroxymethyl.

In some preferred embodiments, R₃For H or D.

In some preferred embodiments, R₃For H.

In some embodiments, five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope derivative method Biology or pharmaceutically acceptable salt are the compound as shown in formula (IV), its isomers, prodrug, stable isotope derivatives Or pharmaceutically acceptable salt:

Wherein, Cy, R, R₁、R₂And R₃It is defined as described above.

Following preferred embodiment includes in the definition of the compound as shown in formula (IV):

In some preferred embodiments, Cy isOr

In some preferred embodiments, R is

In some preferred embodiments, R₁For H.

In some preferred embodiments, R₂For cyclopropyl or cyclobutyl.

In some embodiments, five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope derivative method Biology or pharmaceutically acceptable salt are the compound as shown in formula (V) or (VI), its isomers, prodrug, stable isotope derivative method Biology or pharmaceutically acceptable salt:

Wherein, X, Y, Z, Cy, L and R are defined as described above.

Following preferred embodiment includes in the definition of the compound as shown in formula (V) or (VI):

In some preferred embodiments, L CH₂。

In some preferred embodiments, Cy isOr

In some preferred embodiments, R is

1) X is NR₁, Y CR₂It is CR with Z₃；

2) X is CR₂, Y NR₁It is CR with Z₃；

3) X is CR₃, Y CR₂It is NR with Z₁；Or

4) X is CR₃, Y NR₁It is CR with Z₂；

L is CH₂、CH(CH₃)、C(CH₃)₂Or CH₂CH₂；

U and V is separately selected from N or CR₄；

R is naphthenic base, Heterocyclylalkyl, aryl or heteroaryl；The R is unsubstituted or further by 1~3 R^AGroup Replace at an arbitrary position :-CN ,-OR_a、-C(O)N(R_b)₂、-OC(O)R_a、-OC(O)OR_b、-OC(O)N(R_b)₂、-C(O)OR_b、-C (O)R_a、-C(O)N(R_b)₂、-N(R_b)₂、-NR_bC(O)R_a、-NR_bC(O)R_a、-NR_bC(O)OR_a、-NR_bC(O)N(R_b)₂、-NR_bC (O)N(R_b)₂、-NR_bS(O)₂R_a、-NR_bS(O)₂N(R_b)₂、-S(O)_0-2R_a、-S(O)₂N(R_b)₂, it is halogen, substituted or unsubstituted Alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted naphthenic base, substitution do not take The Heterocyclylalkyl in generation or substituted or unsubstituted heteroaryl；R^AIn, the alkyl, alkoxy, aryl, heteroaryl, naphthenic base, Or Heterocyclylalkyl be substituted when, can further by 1~3 be selected from halogen, hydroxyl, amino, C_1-4Alkyl or halogenated C_1-3Alkoxy Substituent group replace at an arbitrary position；

R₁For H or C_1-6Alkyl；

R₂For substituted C_1-6Alkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substitution or Unsubstituted C_3-8Naphthenic base or substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl replace or not Substituted 5-6 unit's heteroaryl；As the C_1-6Alternative is selected from halogen, C by 1~3 when alkyl is substituted_1-4Alkoxy, halogen For C_1-4Alkoxy ,-OH ,-NH₂Replace at an arbitrary position with one of-CN or a variety of substituent groups；As the C_2-6Alkenyl, C_2-6 Alkynyl, C_3-8When naphthenic base, 3-8 membered heterocycloalkyl, phenyl or 5-6 unit's heteroaryl are substituted alternative by 1~3 selected from deuterium, Halogen, C_1-4Alkyl, C_1-4Alkoxy, halogenated C_1-4Alkyl, halogenated C_1-4Alkoxy ,-OH ,-NH₂With one of-CN or a variety of Substituent group replaces at an arbitrary position；

R₄For H ,-OH ,-CN, C_1-6Alkyl or C_1-6Alkoxy；

M is 1,2 or 3；

N is 0,1 or 2.

In some embodiments, five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope derivative method Biology or pharmaceutically acceptable salt are following any structure:

The present invention also provides five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope are derivative The preparation method of object or pharmaceutically acceptable salt is following either method.

Method one: in solvent, in the presence of alkali, compound I-b and compound X-1 is subjected to condensation reaction；

Wherein, Cy, X, Y, Z, L, R, U, V, m and n are 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, N- methylmorpholine or triethylamine；Preferred 1:1~the 5:1 of molar ratio of the alkali and compound I-b；To accelerate reaction speed, The 4-dimethylaminopyridine of catalytic amount, the 4-dimethylaminopyridine and compound I-b can also be added into reaction system The preferred 0.05:1~0.2:1 of molar ratio.Condensing agent in the condensation reaction is preferably 1- (3- dimethylamino-propyl) -3- second Base carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N, N'- diisopropylcarbodiimide (DIC), it is more excellent It is selected as EDCI, the preferred 1:1~3:1 of the molar ratio of the condensing agent and compound I-b；The temperature of the reaction preferably 0~30 ℃；The reaction can be detected by TLC, generally using compound I-b disappear when as reaction terminal, preferably 0.5~ 24 hours；It is described after reaction, can also by post-processing product be further purified, preferably include following steps: will react It after system is quenched with ice water, is diluted with solvent, separates organic phase, organic phase is dry, organic solvent is removed under reduced pressure, residue is with often Means of purification is advised, for example, silica gel column chromatography, Flash column chromatography or prep-HPLC purifying.The silica gel column chromatography, Flash The step of the step of column chromatography or prep-HPLC are purified and condition can be general purification in this field 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 C_1-6Alkyl, more preferably methyl or ethyl；Cy, X, Y and Z's determines It is adopted as described 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.Preferably 20~100 DEG C of the temperature of the deprotection reaction, more preferably 60~100 DEG C, more Preferably 80~100 DEG C.The process of the reaction can be detected by TLC, as anti-when generally being disappeared using compound I-a The terminal answered, preferably 10 minutes~2 hours.It is described after reaction, can also by post-processing product be further purified, preferably Include the following steps: after removing organic solvent is concentrated under reduced pressure, residue is sufficiently acidified, obtained solid is filtered, filter cake is true Compound I-b is obtained after sky is dry.

Method two: in solvent, under trimethyl aluminium effect, it is anti-that compound I-a and compound X-1 is subjected to amine transesterification It answers；

Wherein, Pg is carboxy protective group, preferably C_1-6Alkyl, more preferably methyl or ethyl；Cy,X,Y,U,V,m, N, Z, L and R are as defined above.

In the method as shown in reaction equation 3, the condition and step of the condensation reaction can be handed over for the amine ester of this field routine The condition and step of reaction are changed, following reaction condition specifically preferred according to the invention: the solvent is preferably toluene, the solvent Dosage preferably 5~20mL/mmol compound I-a；Preferred 2:1~the 3:1 of molar ratio of trimethyl aluminium and compound X-1.Compound Preferred 1:1~the 3:1 of the molar ratio of X-1 and compound I-a；Preferred room temperature~the solvent refluxing of the temperature of the reaction；Described More preferable 90~110 DEG C of the temperature of reaction；The reaction can be detected by TLC, generally to make when compound I-a disappearance For the terminal of reaction, preferably 1~24 hour；It is described also product to be further purified by post-processing after reaction, it is described Purification process includes silica gel column chromatography, Flash column chromatography or prep-HPLC purifying.The silica gel column chromatography, Flash column layer The step of the step of analysis or prep-HPLC are purified and condition can be general purification in this field and condition.

Compound I-a can be synthesized by method shown in reaction equation 4~6:

Wherein, Pg is carboxy protective group, preferably C_1-6Alkyl, more preferably methyl or ethyl；X is iodine, bromine or chlorine； Cy、R₁And R₂It is as defined above.

Wherein, Pg is carboxy protective group, preferably C_1-6Alkyl, more preferably methyl, ethyl or tert-butyl；R₂For Cl Or Br；Cy is as defined above.

Wherein, Pg is carboxy protective group, preferably C_1-6Alkyl, more preferably methyl or ethyl；Cy and R₂Definition such as It is upper described.

In above-mentioned reaction equation 1~7, when there is the amino group, hydroxyl group or carboxylic group that are not involved in reaction, the ammonia Base group, hydroxyl group or carboxylic group are preferably protected by protecting group, and any side reaction is avoided.If there is above-mentioned Amido protecting group or hydroxy-protective group then need to obtain compound shown in formula I after subsequent deprotection steps.Appoint What suitable amido protecting group, such as: tertbutyloxycarbonyl (Boc) group may be incorporated for protection amino group.If used For Boc as protecting group, subsequent deprotection reaction can be in standard conditions, for example, p-methyl benzenesulfonic acid/methanol system, dichloromethane Alkane/trifluoroacetic acid system, the ether solution of hydrogen chloride of saturation or Trimethylsilyl trifluoromethanesulfonate/2,6- lutidines/bis- It is carried out in chloromethanes system；Any suitable hydroxy-protective group, such as: t-Butyldimethylsilyl may be incorporated for protecting Hydroxyl group, subsequent deprotection reaction can be in standard conditions, for example, sodium hydroxide/methanol/water system；It is any suitable Carboxy protective group, such as: it is formed carboxylate group (for example, carboxylate methyl ester, carboxylic acid, ethyl ester), may be incorporated for protection carboxyl base Group, subsequent deprotection reaction can in standard conditions, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide tetrahydrofuran, It is deprotected in water and/or methanol solvate.

The pharmaceutically acceptable salt of five yuan of heteroaromatic ring 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 five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope derivatives With 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 five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope are derivative The application of object or pharmaceutically acceptable salt or described pharmaceutical composition in preparation indoleamine 2,3-dioxygenase inhibitor. The indole amine 2,3-dioxygenase inhibitor (IDO1 inhibitor), which refers to, can inhibit IDO1 activity or expression (including IDO1 Abnormal movement or overexpression), and reverse IDO1- mediate immunosuppressive compound.The IDO1 inhibitor can press down IDO1 processed.

The present invention also provides five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope are derivative The application of object or pharmaceutically acceptable salt or described pharmaceutical composition in preparation stimulation T cell hyperproliferation agent.

Described in heretofore described any embodiment five yuan of heteroaromatic ring derivatives as shown in formula (I) and/ Or the related disease that pharmaceutically acceptable salt or described pharmaceutical composition are mediated in preparation treatment, alleviation and/or prevention by IDO1 Application in the drug of disease, the application include giving the individual (such as: patient) to treat the desired amount of of the present inventionization Close object or pharmaceutical composition.The related disease that the IDO1 is mediated refers to any disease, and situation or disorder can be pressed down with IDO1 Preparation for treating, alleviation and/or prevention.Disease caused by the special immunosupress mediated as IDO1, the disease Disease includes but is not limited to: virus infection 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 present invention also provides five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope are derivative Object or pharmaceutically acceptable salt or described pharmaceutical composition in preparation treatment, alleviation and/or are prevented by indoleamine 2, and 3- is bis- to be added Application in the drug for the related disease that oxygenase mediates.Five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, solvation Object, hydrate, stable isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition can also with it is a kind of or more The therapeutic agent and/or treatment method for treating cancer of the other types of kind are combined for treating, alleviating and/or prevent by indoles Amine 2, the related disease that 3- dioxygenase mediates.The related disease that 2, the 3- dioxygenase mediates refers to by the bis- oxygenations of 2,3- Enzyme mediate immunosupress caused by disease, the disease can include: virus infection or it is other infection (such as: skin sense Dye, alimentary infection, urogenital infections, systemic infection etc.), cancer or autoimmune disease (such as: class wind Wet arthritis, lupus erythematosus, psoriasis etc.).

The therapeutic agent for treating cancer of other types can be made into five yuan of heteroaromatic ring derivatives (I) The therapeutic dosage forms of single 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), PD-L2, LAG3, TIM1, TIM3、TIM4、CD73、Galectin9、CEACAM-1、BTLA、CD69、Galectin-1、TIGIT、CD113、GPR56、 One of VISTA, 2B4, CD48, GARP, PD1H and LAIR1 or a variety of；2) the active protein agonist of T cell: B7- is stimulated 1、B7-2、CD28、ICOS、ICOS-L、GITR、GITRL、CD70、DR3、CD28H、GITR、OX40、OX40L、4-1BB (CD137), one of CD27 and CD40 or a variety of.3) receptor antagonist on NK cell is acted on: KIR (such as: Iirilumab)；4) inhibit or be lost the receptor antagonist of macrophage or monocyte: CSF-1R.

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 type B virus (HBV), Hepatitis C Virus (HCV), mankind's cream Head tumor virus (HPV), cytomegalovirus (CMV), epstein-Barr virus (EBV), poliovirus, varicella-band Infection caused by the virus such as shape herpesviral, Coxsackie virus or human immunodeficiency virus (HIV).

The cancer may include solid tumor or liquid tumors.

In some embodiments, the solid tumor may include but be not limited to eye, bone, lung, stomach, pancreas, mammary gland, preceding Column gland, brain (including glioblastoma and medulloblastoma), ovary (including those from epithelial cell generate stroma cell, Reproduction cell and interstitial cell), bladder, testis, spinal cord, kidney (including gland cancer, the nephroblastoma), mouth, lip, throat, oral cavity (including squamous cell carcinoma), nasal cavity, small intestine, colon, rectum, parathyroid gland, gall-bladder, bile duct, uterine neck, the heart, hypopharyngeal gland, branch gas Pipe, liver, ureter, vagina, anus, larynx gland, thyroid gland (including thyroid cancer and cephaloma), esophagus, nasopharynx adenohypophysis, saliva Gland, adrenal gland, incidence intraepithelial neoplasia (including Bowen disease and paget's disease), sarcoma (including leiomyosarcoma, cross Line muscle tumor, embryonal-cell lipoma, fibrosarcoma, osteosarcoma), skin (including melanoma, Kaposi's sarcoma, basocellular Cancer and squamous cell carcinoma) etc. relevant tumour.

In some embodiments, the liquid tumors may include but be not limited to lymphoid tissue (including acute lymphoblastic be thin Born of the same parents' leukaemia, lymthoma, myeloma, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin lymphoma and lymphatic Lymthoma, T cell and B cell chronic lymphocytic leukemia), chronic lymphocytic leukemia, marrow series leukemia and AIDS The relevant tumour such as relevant leukaemia.

In some embodiments, the autoimmune disease may include but be not limited to: rheumatoid arthritis, complete Body lupus erythematosus, mixed connective tissue disease (MCTD), system chorionitis (including: CREST syndrome), dermatomyositis, tubercle Property vasculitis, nephrosis (include: empsyxis nephrotic syndrome, acute glomerulonephritis, primary membranoproliferative glomerulonephtitis Deng), endocrine related disease (including: type-1 diabetes mellitus, sexual gland insufficiency, pernicious anaemia, hyperthyroidism etc.), liver Disease (includes: primary biliary cirrhosis, autoimmune cholangitis, oneself immunity hepatitis, primary sclerotic cholangitis Deng) and due to one of autoimmune response (such as: AIDS, malaria etc.) caused by infection or a variety of.

The present invention also provides a kind of with five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable same position The method of tryptophan degradation in plain derivative or pharmaceutically acceptable salt or described pharmaceutical composition inhibition system comprising Following steps: a effective amount of as formula (I) compound represented inhibits color ammonia in the mammalian body by giving mammalian therapeutic The degradation of acid；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 1~8 carbon atom, More preferable 1~6,1~5,1~4,1~3 or 1~2 carbon atom, the representative example of alkyl includes but is not limited to: methyl, second Base, n-propyl, isopropyl, normal-butyl, sec-butyl, tert-butyl, isobutyl group, amyl, hexyl, heptyl, 4,4- dimethyl amyl group, 2, 2,4- tri-methyl-amyls 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." monocyclic cycloalkyl " preferably 3-10 unit monocycle alkyl, more preferable 3-8 unit monocycle alkyl, more preferable 3-6 member Monocycle alkyl, such as: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclodecyl, cyclo-dodecyl, ring Hexenyl." polycyclic naphthene base " includes " fused cycloalkyl " and " spiro cycloalkyl group ", and " fused cycloalkyl " includes to be fused to aryl, ring Monocyclic cycloalkyl ring on alkyl or heteroaryl, condensed-bicyclic naphthenic base includes but is not limited to: benzocyclobutene, 2,3- dihydro- 1-H- indenes, 2,3- cyclopenta pyridine, 5,6- dihydro -4H- cyclopenta [B] thiophene, decahydronaphthalene etc.." spiro cycloalkyl group " refers to two Naphthenic base shares the bicyclic radicals that a carbon atom is formed, and spiro cycloalkyl group includes but is not limited to: spiral shell [2.4] heptyl, spiral shell [4.5] last of the ten Heavenly stems Alkane etc..Monocyclic cycloalkyl or bicyclic cycloalkyl can be connected on parent molecule by carbon atom chain arbitrary on ring.

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." monocyclic heterocycloalkyl " preferred 3-10 Unit monocycle Heterocyclylalkyl, more preferable 5-8 unit monocycle Heterocyclylalkyl.Such as: '-aziridino, tetrahydrofuran -2- base, morpholine -4- base, Thiomorpholine -4- base, thiomorpholine-S-oxide -4- base, piperidin-1-yl, N- Alkylpiperidine -4- base, pyrrolidin-1-yl, N- Alkyl pyrrolidine -2- base, piperazine -1- base, 4- alkyl piperazine -1- base etc.." polycyclic Heterocyclylalkyl " includes " annelated heterocycles alkyl " " spiro heterocyclic radical "." annelated heterocycles alkyl " includes the monocyclic heterocycles alkane for being fused to phenyl, Heterocyclylalkyl, naphthenic base or heteroaryl Basic ring, annelated heterocycles alkyl includes but is not limited to: 2,3- dihydro benzo furyls, 1,3- dihydroisobenzofuran base, dihydro Yin Diindyl base, 2,3- dihydrobenzo [b] thienyl, dihydrobenzo piperazine are muttered base and 1,2,3,4- tetrahydric quinoline group etc.." spiro heterocyclic radical " is Refer to that two Heterocyclylalkyls or a naphthenic base and a Heterocyclylalkyl share the bicyclic radicals that a carbon atom is formed.Monocyclic heterocycles Alkyl and polycyclic Heterocyclylalkyl can be linked on parent molecule by annular atom arbitrary on ring.Above-mentioned annular atom refers in particular to form The carbon atom and/or nitrogen-atoms of ring skeleton.

Term " cycloalkyl-alkyl ", which refers to, to be connected between naphthenic base and mother nucleus structure by alkyl." naphthenic base alkane as a result, Base " includes the definition of abovementioned alkyl and naphthenic base.

Term " hetercycloalkylalkyl ", which refers to, to be connected between Heterocyclylalkyl and mother nucleus structure by alkyl." heterocycle alkane as a result, Base alkyl " includes the definition of abovementioned alkyl and Heterocyclylalkyl.

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 that cyclic annular or acyclic alkyl groups are connected with each other by sulphur atom and parent molecule, includes alkane Base sulfydryl, naphthenic base sulfydryl and Heterocyclylalkyl sulfydryl." alkylthio group " includes abovementioned alkyl, Heterocyclylalkyl and naphthenic base as a result, Definition.

Term " alkenyl " refers to the straight chain containing at least one carbon-carbon double bond, branch or cyclic annular non-aromatic alkyl.It wherein can be with There are 1-3 carbon-carbon double bonds, preferably there is 1 carbon-carbon double bond.Term " C_2-4Alkenyl " refers to the alkenyl with 2-4 carbon atom, Term " C_2-6Alkenyl " refers to the alkenyl with 2-6 carbon atom, including vinyl, acrylic, cyclobutenyl, 2- methyl butene base And cyclohexenyl group.

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 " C_2-6Alkynyl " refers to the alkynyl with 2-6 carbon atom, including Acetenyl, propinyl, butynyl and 3- methylbutynyl.

Term " aryl " refers to any stable 6-10 unit monocycle or bicyclic aromatic groups, 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 virtue by the hetero atom displacement selected from N, O or S Fragrant cyclic group, wherein the N atom can be further oxidized.The heteroaryl can be 5-7 unit monocycle structure or 7-12 membered bicyclic Structure, preferably 5-10 unit's heteroaryl, more preferable 5-6 member hetero-aromatic ring.In the present invention, hetero atom number preferably 1,2 or 3, including But it is not limited to: pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, (2H) -one of pyridazine -3 base, furyl, thienyl, thiazolyl, pyrrole Cough up base, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,3- oxadiazoles Base, 1,2,3- thiadiazolyl group, 1,2,5- thiadiazolyl group, triazol radical (1,2,4- triazol radical, 1,2,3- triazol radical), four nitrogen Oxazolyl, indazolyl, iso indazolyl, indyl, isoindolyl, benzofuranyl, benzothienyl, benzo [d] [1,3] dioxy penta Ring group, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolyl etc..

Term " aryl alkyl ", which refers to, to be connected between aryl and mother nucleus structure by alkyl." aryl alkyl " includes as a result, The definition of abovementioned alkyl and aryl.

Term " heteroaryl alkyl ", which refers to, to be connected between Heterocyclylalkyl and mother nucleus structure by alkyl." heteroaryl alkane as a result, Base " includes the definition of abovementioned alkyl and heteroaryl.

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 " cyano " refers to-CN.

Term " amino " refers to-NH₂.Term " alkylamino " refers to that at least one hydrogen atom is replaced alkyl on amino, Including but not limited to :-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂。

Term " amide groups " refers to-C (O) N (R ')₂, wherein each R ' independently is hydrogen or C_1-6Alkyl.

Term " ester group " refers to-C (O) OR ', wherein each R ' independently is hydrogen or C_1-6Alkyl.

SymbolIndicate the position that substituent group is connected with parent molecule.

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." isomers " of the present invention is preferably " stereoisomer ".

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 (CD₃OD), deuterated dimethyl sulfoxide (DMSO-d₆), tetramethylsilane conduct Internal standard (TMS).

Low resolution mass spectrometry (MS) is measured by Agilent 1200HPLC/6120 mass spectrograph, and ion source is the source ESI, is used XBridge C18,4.6 × 50mm, 3.5 μm, acid system: solvent A: the aqueous solution of 0.01% trifluoroacetic acid (TFA)；Solvent B: The acetonitrile solution of 0.01% trifluoroacetic acid；Percentage is the percentage by volume that solute accounts for solution.Alkaline process: solvent A: the carbonic acid of 10mM The aqueous solution of hydrogen ammonium；Solvent B: 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/Cheetah^TM) 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 (alkaline process): solvent A: the aqueous solution of the ammonium hydrogen carbonate of 10mM, solvent B: acetonitrile, gradient 1: mobile phase A: 80~25% (v/v%), gradient 2: Mobile phase B: 15~65% (v/v%)；Elution requirement (acid system): solvent A: 0.05% trifluoroacetic acid Aqueous solution, Mobile phase B: acetonitrile；Gradient: Mobile phase B: 90~30% (v/v%).

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 1a/1b

1:-78 DEG C of step, under nitrogen protection, to Isosorbide-5-Nitrae-dioxo spiro [4.5] decane -8- ketone (6.0g, 38.4mmol), N- Bis- (front threes are added dropwise in methyl tertiary butyl ether(MTBE) (95mL) solution of phenyl bis- (trifluoromethanesulfonimides) (16.5g, 46.1mmol) Base silicon substrate) Sodamide tetrahydrofuran solution (2.0M, 23mL), finish, by reaction system stir 1 hour.Then by reaction solution It is warmed to room temperature, is stirred overnight.It is extracted with saturated aqueous ammonium chloride quenching reaction, and with ethyl acetate (100mL × 3), it is organic Phase is dry with anhydrous sodium sulfate, filtering, is concentrated, and residue chromatographs (petrol ether/ethyl acetate=10/1) with Flash column and purifies To compound 1.1, (10.8g, yield: 97%) being yellow oil.

Step 2: by compound 1.1 (8.0g, 27.8mmol), double pinacol borates (9.17g, 36.1mmol), acetic acid Potassium (8.18g, 83.3mmol), sodium bromide (1.14g, 11.1mmol) and Pd (dppf) Cl₂The Isosorbide-5-Nitrae-two of (1.0g, 1.4mmol) Six ring of oxygen (100mL) mixture return stirring is stayed overnight.Then reaction system is cooled to room temperature, solvent, residue is removed under reduced pressure Obtaining compound 1.2 with Flash column chromatographic purifying (petrol ether/ethyl acetate=8/1), (4.7g, yield: 55%) being yellow oil Shape object.

Step 3: under nitrogen protection, by compound 1.2 (3.22g, 12.1mmol), the chloro- 6- fluorine quinoline of 4- (2.1g, 13.8mol), potassium carbonate (3.85g, 27.3mmol) and Pd (PPh₃)₄Water/Isosorbide-5-Nitrae-the dioxane of (0.22g, 0.19mmol) (50mL, 4:1) mixture return stirring is stayed overnight, and then reaction solution is concentrated, and is extracted with ethyl acetate (60mL × 3), organic Phase is dry with anhydrous sodium sulfate, filtering, is concentrated, and residue chromatographs (petrol ether/ethyl acetate=3/1) with Flash column and purifies To compound 1.3, (2.0g, yield: 58%) being light yellow solid.

Step 4: into isopropanol (30mL) solution of compound 1.3 (2.0g, 7.02mmol) be added Pd/C (200mg, 10%) it, by the reaction system under nitrogen atmosphere (hydrogen balloon), is stirred overnight at 55 DEG C.Then by reaction system diatomite It is filtered to remove Pd/C, filtrate decompression is concentrated to get compound 1.4, and (1.9g, yield: 90%) being yellow oil.m/z:[M+H]⁺ 288.0。

Step 5: acetone (20mL) mixture of compound 1.4 (2.0g, 6.97mmol) and hydrochloric acid (6.0M, 5mL) is existed It is stirred 48 hours at 45 DEG C.Then reaction system is concentrated under reduced pressure, residue with sodium hydrate aqueous solution (6M) adjust pH value=8~ 9, mixture is extracted with ethyl acetate (30mL × 3), and organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated, and residue is used Flash column chromatography (petrol ether/ethyl acetate=4/1~2/1) purifying obtains compound 1.5, and (750mg, yield: 44%) being Huang Color solid.

Step 6: under condition of ice bath, to compound 1.5 (750mg, 3.09mmol) and to Methyl benzenesulfonyl methyl isocyanide (TosMIC) potassium tert-butoxide is added in the glycol dimethyl ether (20mL) of (784mg, 4.02mmol) and ethyl alcohol (2mL) mixed solution (943mg, 7.73mmol).Reaction system is stirred overnight at room temperature, and with aqueous ammonium chloride solution quenching reaction, then uses ethyl acetate (30mL × 3) extraction, isolates organic phase.Organic phase saturated common salt water washing, filtering, filtrate decompression concentration.Residue is used Flash column chromatography (petrol ether/ethyl acetate=3/1) purifying obtains compound 1.6a, and (263mg, polarity is smaller, single solid structure Type) and 1.6b (300mg, polarity is larger, single spatial configuration), it is colorless oil.

Step 7: under nitrogen protection, thunder is added into methanol (12mL) solution of compound 1.6a (300mg, 1.18mmol) Reaction system hydrogen is replaced 3 times, is then stirred 7 hours at 45 DEG C by Buddhist nun's nickel (weight in wet base 0.5g).TLC (petroleum ether/acetic acid Ethyl ester=3/1) monitoring reaction raw materials disappear after, system is filtered with diatomite, filtrate decompression is concentrated to get compound 1a (280mg, yield: 92%) being light yellow oil.m/z:[M+H]⁺259.0。

Embodiment 2: the synthesis of compound 2

Step 1: under condition of ice bath, to 3- (6- chloro- 2- (trifluoromethoxy) pyridin-3-yl) -3- propionic acid methyl ester Be added portionwise in the tetrahydrofuran (10mL) of (2.2g, 7.39mmol) and the mixed solution of methanol (10mL) sodium borohydride (84mg, 2.22mmol), reaction system stirs 30 minutes at 0 DEG C, then uses water (10mL) quenching reaction, ethyl acetate (50mL x 2) Extraction merges organic phase saturated common salt water washing, and anhydrous sodium sulfate is dry, filter, being concentrated to get compound 2.1, (2.2g is produced Rate: 99%) being off-white powder.m/z:[M+H]⁺300.0。

Step 2: compound 2.1 (2.2g, 7.34mmol) is dissolved in toluene (50mL), and p-methyl benzenesulfonic acid monohydrate is added (1.4g, 7.34mmol) reacts 150 DEG C and flows back 10 hours, and most of toluene is removed by being concentrated under reduced pressure, and ethyl acetate is added (200mL) uses saturated sodium bicarbonate solution (50mLx2) and saturated common salt water washing respectively, and anhydrous sodium sulfate is dry, filters, is dense Contract crude product silica gel column chromatography (petrol ether/ethyl acetate=4/1) purifying obtain compound 2.2 (400mg, yield: It 19%) is faint yellow solid.¹H NMR(400MHz,CDCl₃): δ 7.90 (d, J=8.4Hz, 1H), 7.73 (d, J=16.4Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 6.52 (d, J=16.4Hz, 1H), 3.84 (s, 3H).

Step 3: by compound 2.2 (200mg, 0.71mmol) and to Methyl benzenesulfonyl methyl isocyanide (208mg, It 1.07mmol) is dissolved in anhydrous tetrahydro furan (15mL), potassium tert-butoxide (239mg, 2.13mmol) is added portionwise under condition of ice bath, Obtained mixture stirs 3 hours at 0 DEG C, adds water quenching reaction, ethyl acetate (20mLx2) extraction, and merging organic phase is used full And brine It, anhydrous sodium sulfate drying, filtering, concentration prepare plate (petrol ether/ethyl acetate=10/1~1/1) with silica gel Purifying obtains compound 2.3, and (138mg, yield: 61%) being off-white powder.m/z:[M+H]⁺321.0。

Step 4: compound 2.3 (138mg, 0.43mmol) is dissolved in methanol (5mL), addition ammonium formate (109mg, 1.73mmol) it is heated to reflux 16 hours, then incites somebody to action under a hydrogen atmosphere (1 atmospheric pressure) with 10% palladium carbon (20mg), reaction system Reaction solution is filtered with diatomite, and filter cake is sufficiently washed with ethyl acetate, and filtrate is concentrated to get compound 2.4 (64mg, crude product) and is Off-white powder.

Step 5: compound 2.4 (64mg, crude product) is dissolved in tetrahydrofuran (5mL), and N- chloro dicarboximide is added (27mg, 0.20mmol), reaction system stir 6 hours at 80 DEG C, are then quenched with water reaction, ethyl acetate aqueous phase extracted, Merge organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, is concentrated, and residue chromatographs (petroleum with Flash column Ether/ethyl acetate=10/1~3/1) purifying obtain compound 2.5 (40mg, yield: 57%) be white solid.m/z:[M+H]⁺ 321.0。

Step 6: the ethyl alcohol (3mL) of compound 2.5 (40mg, 0.13mmol) and sodium hydrate aqueous solution (4M, 3mL) is molten Liquid return stirring 1 hour.Then it is concentrated under reduced pressure after reaction system being cooled to room temperature and removes solvent.Residue is adjusted with hydrochloric acid (1M) PH to 4~5, filtering, filter cake are dried in vacuo to obtain the chloro- 4- of 5- (2- (trifluoromethoxy) pyridin-3-yl) -1H- pyrroles's -3- carboxylic acid (compound 2,30mg, crude product) is white solid.m/z:[M+H]⁺327.0。

Embodiment 3: the synthesis of compound 3

Step 1: by bromacetone (2.0g, 14.7mmol), cyan-acetic ester (1.66g, 14.7mmol), sodium ethoxide (1g, It 14.7mmol) is dissolved in anhydrous tetrahydro furan (40mL) with diisopropylethylamine (1.89g, 14.7mmol), reaction solution is in room It is stirred overnight under temperature.Then it after reaction solution being diluted with ethyl acetate, is washed with saturated sodium bicarbonate aqueous solution.It separates organic Phase, organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated.Residue chromatographs (30% ethyl acetate/petroleum ether) with Flash column Purifying obtains compound 3.1, and (1.5g, yield: 60%) being yellow oil.

Step 2: compound 3.1 (1.2g, 7.09mmol) is dissolved in methyl tertiary butyl ether(MTBE) (3mL) and methylene chloride (2mL) In the mixed solvent, at 5 DEG C, above-mentioned solution is slowly dropped in the acetic acid solution of hydrobromic acid (33%, 12mL), what is obtained is mixed Object is closed to stir at this temperature 15 minutes.8.1 fully reacting of TLC (petrol ether/ethyl acetate=4/1) detection compound.It will be anti- Liquid is answered to be extracted with dichloromethane, separation organic phase, concentration.It is pure that residue Flash column chromatographs (30% ethyl acetate/petroleum ether) Change obtains compound 3.2, and (900mg, yield: 56%) being yellow solid.m/z:[M+H]⁺233.0。

Step 3: by compound 3.2 (200mg, 0.86mmol), (2- methoxypyridine -3- base) boric acid (263mg, 1.72mmol), potassium carbonate (356mg, 2.58mmol), the Isosorbide-5-Nitrae dioxane of tetra-triphenylphosphine palladium (92.4mg, 0.08mmol) The suspension of (3mL) and water (1mL) is microwave reaction 1 hour under the conditions of 120 DEG C.Then reaction solution is filtered, filtrate acetic acid Ethyl ester extraction, separation organic phase, concentration.Residue Flash column chromatographs (30% ethyl acetate/petroleum ether) purifying and obtains chemical combination (200mg, yield: 81%) being yellow solid to object 3.3.m/z:[M+H]⁺261.0。

Step 4: by the ethyl alcohol (3mL) of compound 3.3 (200mg, 0.77mmol) and sodium hydrate aqueous solution (4M, 3mL) Solution stirs 6 hours at 100 DEG C.Then pH=3~4 are adjusted with hydrochloric acid (2M), mixture is extracted with ethyl acetate, and separates organic Phase, organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated.Residue chromatographs (60% ethyl acetate/petroleum ether) with Flash column Purifying obtains 4- (2- methoxypyridine -3- base) -5- methyl-1 H- pyrroles -3- carboxylic acid, and (yield: 30%) compound 3,53mg is Yellow oil.m/z:[M+H]⁺233.2。

Embodiment 4: the synthesis of compound 11

Step 1: under nitrogen protection, to the four of 6- chloro- 3- (trifluoromethoxy) pyridine -2- formic acid (108mg, 0.45mmol) N is added in the mixed solution of hydrogen furans (3mL) and acetonitrile (12mL), N'- carbonyl dimidazoles (146mg, 0.90mmol) will react System is stirred at room temperature 0.5 hour.Then malonic acid monomethyl ester sylvite (141mg, 0.90mmol) is added into reaction solution, three Ethamine (137mg, 1.35mmol) and magnesium chloride (190mg, 2.03mmol), obtained mixture are stirred at room temperature 2 hours.Instead It answers liquid to be concentrated to dryness, then with hydrochloric acid (1M) quenching reaction and adjusts PH=7~8.It is extracted, is closed with ethyl acetate (100mL × 3) And organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, is concentrated.Residue Flash column chromatographic purifying (stone Oily ether/ethyl acetate=4/1~1/1) obtaining compound 11.1, (60mg, yield: 45%) being light yellow oil.

Step 2: under condition of ice bath, under nitrogen protection, to the tetrahydrofuran of compound 11.1 (60mg, 0.20mmol) It is added portionwise in (5mL) solution sodium hydrogen (60%, 12mg, 0.30mmol), reaction system stirs 0.5 hour at 0 DEG C.Then will The bromo- 1- cyclopropyl ethyl ketone (50mg, 0.30mmol) of 2- is added in reaction solution, is then heated to reflux reaction solution 2 hours.Then will Reaction solution pours into quenching reaction in saturated aqueous ammonium chloride, and obtained mixture is extracted with ethyl acetate (50mL × 3).Merge Organic phase and with saturated common salt water washing.Separation organic phase and it is dry with anhydrous sodium sulfate, filter, be concentrated to get compound 11.2 (76mg, yield: 100%) being yellow oil.

Step 3: under nitrogen protection, compound 11.2 (76mg, 0.20mmol) and ammonium acetate (46mg, 0.60mmol) being added Enter reflux 6 hours in ethyl alcohol (3mL), then reaction solution is concentrated, ethyl acetate is added in residue, then uses saturated salt solution Washing.Organic phase is separated, dried, filtered, be concentrated with anhydrous sodium sulfate, residue chromatographs (petroleum ether/acetic acid second with Flash column Ester=10/1) purifying obtain compound 11.3 (37mg, yield: 51%) be yellow oil.

Step 4: by compound 11.3 (37mg, 0.10mmol), ammonium formate (25mg, 040mmol) and palladium charcoal (20mg, 10%) it is added in methanol (3mL), reaction system is replaced 3 times with hydrogen, is then flowed back 1 hour under a hydrogen atmosphere, then will be anti- It answers system to be down to room temperature, and is filtered with diatomite, filtrate concentration.Ethyl acetate is added into residue, uses water and saturation respectively Brine It, organic phase anhydrous sodium sulfate is dry, filters, is concentrated to get compound 11.4 (33.5mg, yield: 100%) For yellow oil.

Step 5: by the methanol of compound 11.4 (33.5mg, 0.10mmol) and sodium hydrate aqueous solution (4M, 3mL) (3mL) solution return stirring 2 hours.Then water (40mL) is added into reaction system after reaction system being cooled to room temperature, subtracts Pressure concentration removes organic solvent.Residue adjusts pH to 3~4 that water is extracted with ethyl acetate after stirring 30 minutes with hydrochloric acid (1M) Phase, organic phase are dried, filtered with anhydrous sodium sulfate, are concentrated to get 5- cyclopropyl -2- (3- (trifluoromethoxy) pyridine -2- base) - (compound 11,33mg, yield: 100%) being yellow oil to 1H- pyrroles -3- carboxylic acid.m/z:[M+H]⁺313.2。

Embodiment 5: the synthesis of compound 12

The synthesis of the bromo- 1- of 2- (1- methylcyclopropyl groups) ethyl ketone: 1- methylcyclopropylmethyl ketone (1.0g, 10.2mmol) is molten In methanol (10mL), reaction system is cooled to 0 DEG C.Bromine (1.6g, 10.2mmol) is slowly added dropwise.Reaction solution is in 0 DEG C of item It is stirred 2 hours under part.Water (10mL) quenching reaction is added.It is extracted with dichloromethane, merges organic phase and is washed with saturated common salt It washs, anhydrous sodium sulfate is dry, filtering, is concentrated, and residue chromatographs (petrol ether/ethyl acetate=100/1~10/1) with Flash column (compound 12,790mg, yield: 44%) being light yellow oil to the isolated bromo- 1- of 2- (1- methylcyclopropyl groups) ethyl ketone.

Using the synthetic method of compound 11.3,6- chloro- 3- (trifluoromethoxy) pyridine -2- formic acid in step 1 is replaced It is changed to 3- (trifluoromethoxy) pyridine -2- formic acid, the bromo- 1- cyclopropyl ethyl ketone of 2- in step 2 replaces with 2- bromo- 1- (1- methyl Cyclopropyl) ethyl ketone obtains compound 12.3, using the synthetic method of 11 step 5 of compound, 5- is obtained with the reaction of compound 12.3 (1- methylcyclopropyl groups) -2- (3- (trifluoromethoxy) pyridine -2- base) -1H- pyrroles -3- carboxylic acid (compound 12) is that white is solid Body.

Embodiment 6: the synthesis of compound 13

Using the synthetic method of compound 12, the bromo- 1- of 2- (1- methylcyclopropyl groups) ethyl ketone in step 2 is replaced with into 2- Bromo- 1- cyclobutyl ethyl ketone obtains 5- cyclobutyl -2- (3- (trifluoromethoxy) pyridine -2- base) -1H- pyrroles's -3- carboxylic acid (compound It 13) is white solid.

Embodiment 7: the synthesis of compound 14

Step 1: compound 11.4 (155mg, 0.48mmol) being dissolved in acetone (4mL), potassium carbonate is separately added into (133mg, 0.96mmol) and iodomethane (82mg), reaction solution are heated to 60 DEG C and stir 12 hours.Add water quenching reaction and uses second Acetoacetic ester extraction, merges organic phase, then uses saturated common salt water washing, and organic phase is dry with anhydrous sodium sulfate, filters, concentration, Residue with Flash column chromatographic purifying (petrol ether/ethyl acetate=4/1) obtains compound 14.1, and (yield: 28%) 45mg is Brown oil.

Step 2: by compound 14.1 (45mg, 0.13mmol) be added ethyl alcohol (2mL) and sodium hydrate aqueous solution (4M, In mixed solution 2mL), reaction system return stirring 1 hour.Reaction solution is concentrated after removing solvent and adjusts pH with hydrochloric acid (6M) =3~4.Ethyl acetate aqueous phase extracted merges organic phase, and anhydrous sodium sulfate is dry, filters, is concentrated to get 5- cyclopropyl -1- first (compound 14,30mg, yield: 71%) being brown to base -2- (3- (trifluoromethoxy) pyridine -2- base) -1H- pyrroles -3- carboxylic acid Grease.m/z:[M+H]⁺313.2。

Embodiment 8: the synthesis of compound 15

The synthesis of the bromo- 3- hydroxy-3-methyl butyl- 2- ketone of 1-: by 3- hydroxy-3-methyl butyl- 2- ketone (1.0g, 9.8mmol) It is dissolved in ether (20mL), the diethyl ether solution (5mL, 1.25g, 7.8mmol) of bromine is then slowly added dropwise at room temperature, finishes, Reaction solution is stirred at room temperature 10 minutes, and solution colour becomes light yellow from kermesinus.Reaction solution is concentrated to get the bromo- 3- hydroxyl -3- of 1- Methyl butyl- 2- ketone (1.8g) is yellow oil.¹H NMR(400MHz,CDCl₃):δ4.71(s,2H),1.25(s,6H)。

Using the synthetic method of compound 11, the bromo- 1- cyclopropyl ethyl ketone of 2- in step 2 is replaced with into the bromo- 3- hydroxyl-of 1- 3- methyl butyl- 2- ketone obtain 5- (2- hydroxypropyl -2- base) -2- (3- (trifluoromethoxy) pyridine -2- base) -1H- pyrroles -3- carboxylic acid and 5- (propyl- 1- alkene -2- base) -2- (3- (trifluoromethoxy) pyridine -2- base) -1H- pyrroles's -3- carboxylic acid mixture (1/2, chemical combination Object 15,2- hydroxypropyl -2- base partially removes under final step alkaline condition) for white solid.m/z:[M+H]⁺313.2, 331.2。

Embodiment 9: the synthesis of compound 16

The synthesis of the bromo- 1- of 2- (oxa- ring butyl- 3- yl) ethyl ketone: the synthetic method of the bromo- 1- of 2- (1- methylcyclopropyl groups) ethyl ketone, It is reacted to obtain the bromo- 1- of 2- (oxa- ring butyl- 3- yl) ethyl ketone with 1- (oxa- ring butyl- 3- yl) ethyl ketone.¹H NMR(400MHz, CDCl₃):δ4.87-4.76(m,4H),3.97-3.87(m,1H),2.18(s,3H)。

Using the synthetic method of compound 11, the bromo- 1- cyclopropyl ethyl ketone of 2- in step 2 is replaced with into the bromo- 1- (oxa- of 2- Ring butyl- 3- yl) ethyl ketone obtains 5- (oxa- ring butyl- 3- yl) -2- (3- (trifluoromethoxy) pyridine -2- base) -1H- pyrroles's -3- carboxylic Sour (compound 16) is white solid.m/z:[M+H]⁺329.0。

Embodiment 10: the synthesis of compound 17

Using the synthetic method of compound 14, the iodomethane in step 1 is replaced with into 2- iodopropane and obtains 5- cyclopropyl -1- Isopropyl -2- (3- (trifluoromethoxy) pyridine -2- base) -1H- pyrroles -3- carboxylic acid (compound 17) is white solid.m/z:[M+ H]⁺355.2。

Embodiment 11: the synthesis of compound 18

Using the synthetic method of compound 11, the bromo- 1- cyclopropyl ethyl ketone of 2- in step 2 is replaced with into 4- hydroxyl -3,3- Dimethyl-butyl- 2- ketone obtains 5- (1- hydroxy-2-methyl propyl- 2- yl) -2- (3- (trifluoromethoxy) pyridine -2- base) -1H- pyrrole Coughing up -3- carboxylic acid (compound 18) is white solid.m/z:[M+H]⁺359.2。

Embodiment 12: the synthesis of compound 19

The synthesis of 1-Cbz-3- (2- acetyl bromide) azetidine:

Step 1&2: under condition of ice bath, to 1-Cbz- azetidine -3- formic acid (1.0g, 4.5mmol) and oxalyl chloride (1.62g, 12.8mmol's) is added dropwise 2 drop n,N-Dimethylformamide in methylene chloride (20mL) solution, finishes, reaction system It is warmed to room temperature after being stirred 15 minutes at 0 DEG C and continues stirring 2 hours.Reaction solution is directly concentrated under reduced pressure, residue is dissolved in anhydrous In tetrahydrofuran (20mL), trimethyl silicane diazomethane (hexane solution of 5.4mL, 2.5M) is added dropwise under condition of ice bath, reaction System is stirred overnight at room temperature.Then reaction solution is concentrated under reduced pressure, ethyl acetate dissolution is added in residue.Organic phase unsaturated carbonate Hydrogen sodium water solution and saturated common salt water washing, separate organic phase and, filtering dry with anhydrous sodium sulfate, filtrate decompression are concentrated to get 1-Cbz-3- (2- diazonium ethanoyl) azetidine (1.3g, crude product) is yellow oil.m/z:[M+H]⁺260.0。

Step 3: under condition of ice bath, to the ether (20mL) of 1-Cbz-3- (2- diazonium ethanoyl) azetidine (1.3g) Hydrobromic acid (0.6mL, 48% aqueous solution) is added dropwise in solution, is stirred 1 hour at 0 DEG C of reaction system.It will with saturated sodium bicarbonate Reaction solution pH is adjusted to 8.Ethyl acetate aqueous phase extracted.Organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filters, filter Liquid is concentrated under reduced pressure, and residue obtains 1-Cbz-3- by Flash column chromatography (petrol ether/ethyl acetate=8/1~2/1) purifying (980mg, yield: 73%) being colorless oil to (2- acetyl bromide) azetidine.m/z:[M+H]⁺312.0。

Step 1: under nitrogen protection, compound 11.1 (500mg, 1.70mmol) being added in acetone (20mL), will be reacted System is cooled to 0 DEG C.By potassium carbonate (705mg, 5.1mmol) and 1-Cbz-3- (2- acetyl bromide) azetidine (575mg, It 1.87mmol) is added sequentially in above-mentioned reaction solution, stirs 1 hour under room temperature.Add water quenching reaction, ethyl acetate extraction Three times.Merge organic phase, then uses saturated common salt water washing.Separate organic phase, be concentrated to get compound 19.1 (980mg, slightly Product) it is yellow oil.m/z:[M+H]⁺529.0。

Step 2: under nitrogen protection, compound 19.1 (980mg) and ammonium acetate (525mg, 6.8mmol) being added to ethyl alcohol Return stirring 4 hours, then reaction solution is concentrated in (20mL), and ethyl acetate, organic phase saturation food are added into residue Salt water washing.Separate organic phase, concentration.Residue chromatographs (petrol ether/ethyl acetate=8/1~2/1) with Flash column and purifies To compound 19.2, (345mg, yield: 40%) being yellow oil.m/z:[M+H]⁺510.2。

Step 3: ethyl alcohol (2.5mL) and sodium hydrate aqueous solution is added in compound 19.2 (115mg, 0.23mmol) In the mixed solution of (2.5mL, 4M), reaction solution is heated to reflux stirring 1 hour.After being cooled to room temperature, two are added into reaction solution Dimethyl dicarbonate butyl ester (100mg, 0.46mmol).Reaction system continues after being stirred at room temperature 1 hour, and reaction solution concentration removes second Alcohol simultaneously adjusts pH=3~4 with hydrochloric acid (2M).Water phase is extracted with ethyl acetate three times, merges organic phase, and anhydrous sodium sulfate is dry, It filters, be concentrated to get 5- (1- (tertbutyloxycarbonyl) azetidin -3- base) -2- (6- chloro- 3- (trifluoromethoxy) pyridine -2- Base) -1H- pyrroles -3- carboxylic acid (compound 19,120mg) be yellow oil.

Embodiment 13: the synthesis of compound 20

Step 1: under condition of ice bath, to 3- (6- chloro- 3- (trifluoromethoxy) pyridine -2- base) -3- methyl pyruvate Dess- is slowly added in methylene chloride (30mL) solution of (500mg, 1.68mmol) and pyridine (398mg, 5.04mmol) Martin oxidant (1.07g, 2.53mmol), finishes, and reaction system is stirred at room temperature 3 hours, is then added into reaction system Saturated aqueous sodium thiosulfate (8mL) and saturated sodium bicarbonate aqueous solution (8mL), room temperature continue stirring 1 hour.By reactant (30mL × 3) are extracted with ethyl acetate in system.Organic phase is washed with saturated sodium-chloride, and anhydrous sodium sulfate is dry, filters, filtrate decompression Concentration.Residue with flash column chromatograph (petrol ether/ethyl acetate=6/1~2/1) purifying obtain compound 20.1 (270mg, Yield: 48%) being yellow oil.m/z:[M+H]⁺312.0。

Step 2: by compound 20.1 (220mg, 0.71mmol), ammonium acetate (546mg, 7.10mmol) and cyclopropyl formaldehyde Lower 150 DEG C of acetic acid (3mL) the solution microwave condition of (149mg, 2.12mmol) are stirred 15 minutes；It is concentrated under reduced pressure, residue second Acetoacetic ester extracts (30mL × 3).Organic phase is washed with saturated sodium-chloride, and anhydrous sodium sulfate is dry, filters, filtrate decompression concentration. Residue obtains compound 20.2 (98mg, 31%) with flash column chromatography (petrol ether/ethyl acetate=8/1~1/1) purifying White solid.m/z:[M+H]⁺362.0。

Step 3: by compound 20.2 (98mg, 0.27mmol), palladium carbon (20mg, 10%) and ammonium formate (68mg, Methanol (20mL) mixture 1.08mmol) replaces 3 times with hydrogen, then reaction system return stirring 1 hour under a hydrogen atmosphere. Reaction system is cooled to room temperature, with diatomite filter remove palladium carbon, then by filtrate be concentrated to get compound 20.3 (110mg, slightly Product) it is white solid.m/z:[M+H]⁺328.0。

Step 4: by the ethyl alcohol (2mL) of compound 20.3 (110mg, 0.27mmol) and sodium hydrate aqueous solution (2mL, 4M) Solution stirs 1 hour at 90 DEG C.It is concentrated under reduced pressure and removes organic solvent, water phase adjusts pH to 4~5 with hydrochloric acid (1M), there is solid analysis Out, be filtered under diminished pressure to obtain 2- cyclopropyl -5- (3- (trifluoromethoxy) pyridine -2- base) -1H- imidazoles -4- carboxylic acid (compound 20, 20mg, two step yields: 54%) being yellow solid.m/z:[M+H]⁺314.0。

Embodiment 14: the synthesis of compound 21

Using the synthetic method of compound 20, the cyclopropyl formaldehyde in step 2 is replaced with into ring fourth formaldehyde and obtains 2- cyclobutyl- 5- (3- (trifluoromethoxy) pyridine -2- base) -1H- imidazoles -4- carboxylic acid (compound 21) is white solid.m/z:[M+H]⁺ 328.0。

Embodiment 15: the synthesis of compound 22

Using the synthetic method of compound 12,3- (trifluoromethoxy) pyridine -2- formic acid in step 1 is replaced with into benzene first Acid, the bromo- 1- of 2- (1- methylcyclopropyl groups) ethyl ketone in step 2 replace with the bromo- 1- cyclopropyl ethyl ketone of 2- and obtain 5- cyclopropyl -2- benzene Base -1H- pyrroles -3- carboxylic acid (compound 22) is white solid.m/z:[M+H]⁺228.2。

Embodiment 16: the synthesis of compound 23

Step 1: under condition of ice bath, to 2- (6- chloro- 3- (trifluoromethoxy) pyridine -2- base) -5- methyl-1 H- pyrroles -3- The bromo- 1- cyclopropyl ethyl ketone of 2- in step 2 (using the synthetic method of compound 11.3, is replaced with bromacetone) by carboxylate methyl ester Sodium hydrogen (67.2mg, 1.68mmol, 60%) is added in n,N-Dimethylformamide (5mL) solution of (280mg, 0.84mmol), Reaction system stirs 30 minutes at 0 DEG C, states addition (2- bromine oxethyl) (tert-butyl) dimethyl in reaction system then up Silane (402mg, 1.68mmol).Reaction system continues to be stirred at room temperature overnight, and water quenching reaction is added and uses ethyl acetate Extraction merges organic phase saturated common salt water washing, separates organic phase, is concentrated under reduced pressure.Residue chromatographs (petroleum with flash column Ether/ethyl acetate=10/1~2/1) purifying obtain compound 23.1 (450mg, crude product) be light yellow oil.

Step 2&3: using the synthetic method of compound 11,1- (2- ethoxy) -5- first is obtained with the reaction of compound 23.1 Base -2- (3- (trifluoromethoxy) pyridine -2- base) -1H- pyrroles -3- carboxylic acid (compound 23).m/z:[M+H]⁺331.2。

Embodiment 17: the synthesis of compound 1-1

To compound 11 (33mg, 0.10mmol), compound 1a (30mg, 0.11mmol), 1- (3- dimethylamino-propyl)- N, N- are slowly added in n,N-Dimethylformamide (5mL) solution of 3- ethyl-carbodiimide hydrochloride (40mg, 0.21mmol) Diisopropylethylamine (41mg, 0.32mmol) and 4-dimethylaminopyridine (1.3mg, 0.01mmol), reaction system is at 45 DEG C Then stirring 2 hours is quenched (10mL) reaction with ice water, and separates organic phase, organic phase after being diluted with ethyl acetate (30mL) It is washed with saturated salt solution (25mL), anhydrous sodium sulfate dries, filters, with prep-HPLC (alkaline process, stream after filtrate decompression concentration Dynamic phase B:15~65% (v/v%)) purifying obtain compound 1-1 (UPLC retention time: 7.125 minutes, 3.9mg, yield: It 7%) is white solid.m/z:[M+H]⁺553.2,¹H NMR(400MHz,CD₃OD): δ 8.75 (d, J=4.4Hz, 1H), 8.55- 8.56(m,1H),8.05-8.09(m,1H),7.80-7.86(m,2H),7.54-7.61(m,2H),7.43-7.46(m,1H), 6.25(s,1H),3.34-3.50(m,3H),2.08-2.09(m,1H),1.77-1.92(m,9H),0.89-0.93(m,2H), 0.68-0.72(m,2H)。

Embodiment 18: the synthesis of compound 1-2

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 12 and obtains compound 1-2 (UPLC reservation Time: 7.279 minutes).m/z:[M+H]⁺567.2,¹H NMR(400MHz,CD₃OD): δ 8.76-8.77 (d, J=4.8Hz, 1H),8.57-8.59(m,1H),8.07-8.11(m,1H),7.83-7.91(m,2H),7.58-7.63(m,2H),7.46-7.50 (m, 1H), 6.39 (s, 1H), 3.51-3.52 (d, J=4.8Hz, 2H), 3.37-3.38 (m, 1H), 2.07-2.17 (m, 1H), 1.71-1.92(m,8H),1.47(s,3H),0.92-0.96(m,2H),0.73-0.76(m,2H)。

Embodiment 19: the synthesis of compound 1-3

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 13 and obtains compound 1-3 (UPLC reservation Time: 7.361 minutes).m/z:[M+H]⁺567.2,¹H NMR(400MHz,CD₃OD): δ 8.76-8.77 (d, J=4.4Hz, 1H), 8.58-8.59 (d, J=4.4Hz, 1H), 8.07-8.11 (m, 1H), 7.83-7.90 (m, 2H), 7.56-7.61 (m, 2H), 7.46-7.49(m,1H),6.46(s,1H),3.50-3.57(m,3H),3.33-3.39(m,1H),2.03-2.39(m,6H), 1.79-1.91(m,9H)。

Embodiment 20: the synthesis of compound 1-4

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 14 and obtains compound 1-4 (UPLC reservation Time: 7.321 minutes).m/z:[M+H]⁺567.2,¹H NMR(400MHz,CD₃OD): δ 8.73-8.72 (d, J=4.0Hz, 1H), 8.63-8.62 (d, J=4.0Hz, 1H), 8.08-8.04 (m, 1H), 7.87-7.82 (m, 2H), 7.60-7.51 (m, 3H), 6.29(s,1H),3.48(s,3H),3.42-3.39(m,2H),3.35(m,1H),2.05(m,1H),1.84-1.73(m,8H), 1.29(s,1H),1.00-0.88(m,2H),0.66(s,2H)。

Embodiment 21: the synthesis of compound 1-5 and 1-6

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 15 and obtains the mixed of compound 1-5 and 1-6 Object is closed, through prep-HPLC (alkaline process, Mobile phase B: 20%~40% (5min)；40%~70% (15min) (v/v%)) separation Obtain compound 1-5 (appearance time: 16~17 minutes, UPLC retention time: 6.291 minutes) and 1-6 (appearance time: 20~ 21 minutes, UPLC retention time: 7.207 minutes), it is single spatial configuration.1-5:m/z:[M+H]⁺571.2,¹H NMR (400MHz,CD₃OD):δ8.79-8.74(m,1H),8.09-8.06(m,1H),7.86-7.85(m,3H),7.61-7.52(m, 3H),6.50(s,1H),3.29-3.27(m,3H),2.17-1.75(m,9H),1.59(s,6H)；1-6:m/z:[M+H]⁺ 553.2,¹H NMR(400MHz,CD₃OD):δ8.75-8.74(m,1H),8.59-8.58(m,1H),8.08-8.05(m,1H), 7.89-7.83(m,2H),7.59-7.48(m,3H),6.69(s,1H),5.40(s,1H),4.96(s,1H),3.50-3.48(m, 2H),3.36(s,1H),2.21(s,4H),1.85-1.77(m,8H)。

Embodiment 22: the synthesis of compound 1-7

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 16 and obtains compound 1-7 (UPLC reservation Time: 6.047 minutes).m/z:[M+H]⁺569.2,¹H NMR(400MHz,CD₃OD): δ 8.75 (d, J=4.8Hz, 1H), 8.58 (d, J=4.4Hz, 1H), 8.11-8.03 (m, 1H), 7.94-7.78 (m, 2H), 7.65-7.45 (m, 3H), 6.65 (s, 1H), 5.04-4.99 (m, 4H), 4.37 (q, J=8.0Hz, 1H), 3.56-3.45 (m, 3H), 2.06-2.00 (m, 1H), 1.93-1.74 (m,8H)。

Embodiment 23: the synthesis of compound 1-8

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 17 and obtains compound 1-8 (UPLC reservation Time: 7.604 minutes).m/z:[M+H]⁺595.2,¹H NMR(400MHz,CD₃OD): δ 8.73-8.72 (d, J=4.0Hz, 1H), 8.59-8.58 (d, J=4.0Hz, 1H), 8.08-8.04 (m, 1H), 7.87-7.82 (m, 2H), 7.60-7.50 (m, 3H), 6.32 (s, 1H), 4.38-4.31 (m, 1H), 3.37-3.35 (d, J=8.0Hz, 2H), 3.33-3.32 (m, 1H), 2.03-2.02 (m,1H),1.98-1.91(m,1H),1.79-1.72(m,8H),1.48-1.46(m,3H),1.43-1.41(m,3H),1.00- 0.95(m,2H),0.79-0.73(m,2H)。

Embodiment 24: the synthesis of compound 1-9

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 18 and obtains compound 1-9 (UPLC reservation Time: 6.583 minutes).m/z:[M+H]⁺585.2,¹H NMR(400MHz,CD₃OD):δ8.98-8.97(m,1H),8.60- 8.59(m,1H),8.25-8.15(m,2H),7.92-7.91(m,3H),7.51(m,1H),6.53(s,1H),3.59-3.13(m, 5H),2.25-1.75(m,9H),1.33(s,6H)。

Embodiment 25: the synthesis of compound 1-10

Step 1: under hydrogen atmosphere, compound 1-10-1 (with the synthetic method of compound 1-1, compound 11 being replaced Obtained for compound 19) (73mg, 0.1mmol), methanol is added in palladium carbon (10mg, 10%) and ammonium formate (26mg, 0.42mmol) Reflux 1 hour in (15mL).It is cooled to room temperature, filtering removes palladium carbon, and it is white that filtrate, which is concentrated to get compound 1-10-2 (70mg), Color solid.m/z:[M+H]⁺668.2。

Step 2: compound 1-10-2 (70mg, crude product) and trifluoroacetic acid (0.5mL) are dissolved in methylene chloride (5mL), It is stirred 1 hour under room temperature.Decompression is lower to remove organic solvent, with saturated sodium bicarbonate aqueous solution tune pH to 7~8, ethyl acetate extraction Water intaking phase.Merge organic phase and, filtering dry with anhydrous sodium sulfate, filtrate decompression concentration.Residue with prep-HPLC (alkaline process, Mobile phase B: 80~25% (v/v%)) purifying obtain compound 1-10 (UPLC retention time: 4.304 minutes, 10.1mg, produce Rate: 17%) being off-white powder.m/z:[M+H]⁺568.2；¹HNMR(400MHz,CD₃OD): δ 8.76-8.78 (d, J= 4.8Hz, 1H), 8.60-8.62 (d, J=4.8Hz, 1H), 8.07-8.11 (m, 1H), 7.85-7.92 (m, 2H), 7.49-7.61 (m, 3H), 6.62 (s, 1H), 3.91-4.13 (m, 5H), 3.51-3.53 (d, J=8.0Hz, 2H), 3.36-3.43 (m, 1H), 2.10-2.18(m,1H),1.75-1.95(m,8H)。

Embodiment 26: the synthesis of compound 1-11

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 22 and obtains compound 1-11 (UPLC reservation Time: 7.197 minutes).m/z:[M+H]⁺468.2,¹H NMR(400MHz,CD₃OD): δ 8.76-8.77 (d, J=4.8Hz, 1H),8.07-8.09(m,1H),7.87-7.90(m,1H),7.53-7.61(m,4H),7.29-7.39(m,3H),6.12(s, 1H), 3.45-3.47 (d, J=8.0Hz, 2H), 3.36-3.40 (m, 1H), 2.00-2.09 (m, 1H), 1.74-1.93 (m, 9H), 0.85-0.91(m,2H),0.65-0.71(m,2H)。

Embodiment 27: the synthesis of compound 1-12 and 1-13

Step 1: (with the synthetic method of compound 1-1, compound 11 being replaced with into compound 23 to compound 1-12-1 and is obtained Add into tetrahydrofuran, water and acetic acid (1/1/1.2,3.2mL) mixed solution of compound 1-12-1) (45mg, 0.078mmol) Enter to take ammonium ceric nitrate (174mg, 0.31mmol), reaction system is stirred at room temperature 2 hours, is then diluted with ethyl acetate, with saturation Sodium bicarbonate aqueous solution adjusts pH >=7, separates organic phase and is concentrated under reduced pressure to give the mixture of compound 1-12-2 and 1-12-3 (38mg) is pale yellow oily liquid.

Step 2: step 1 gained mixture (35mg) is dissolved in methanol (1mL), addition sodium borohydride (5mg, It 0.12mmol) is added, 20 molecules are stirred at room temperature in obtained mixture, and hydrochloric acid (2M) is added to adjust PH ≈ 5, then plus unsaturated carbonate Hydrogen sodium solution adjusts PH >=7, and water phase is extracted with dichloromethane, and merges organic phase, and with anhydrous sodium sulfate drying, filtering, filtrate subtracts Pressure concentration, residue with prep-HPLC (acid system) purify obtain compound 1-12 (UPLC retention time: 5.525 minutes, 35mg, Two step yields: 72%) being off-white powder.[M+H]⁺587.0,¹H NMR(400MHz,D₂O):δ8.83-8.82(m,1H), 8.51-8.50(m,1H),8.15-8.10(m,2H),7.90-7.82(m,3H),7.57-7.53(m,1H),6.51(s,1H), 4.59(s,2H),4.18-4.14(m,1H),4.00-3.90(m,1H),3.47-3.24(m,5H),1.92(s,1H),1.70- 1.61(m,8H)。

Step 3: compound 1-12 (10mg, 0.017mmol) being dissolved in pyridine (1.0mL), paratoluensulfonyl chloride is added (10mg, 0.051mmol), reaction system stir 6 hours at 80 DEG C, and reaction system is concentrated and removes solvent, and residue is used Prep-HPLC (acid system) purifying obtains compound 1-13, and (UPLC retention time: 4.186 minutes, 4.6mg, yield: 47%) being class White solid.[M+H]⁺569.1,¹HNMR(400MHz,D₂O):δ8.79-8.78(m,1H),8.75-8.74(m,2H),8.50- 8.46(m,2H),8.12-8.10(m,1H),8.08-8.07(m,1H),8.04-8.00(m,2H),7.98-7.76(m,3H), 7.56-7.52(m,1H),6.84(s,1H),5.91(s,1H),4.18-4.10(m,1H),3.60-3.48(m,1H),3.41- 3.22(m,1H),1.95-1.90(m,1H),1.69-1.56(m,9H)。

Embodiment 28: the synthesis of compound 2-1

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 2 and obtains compound 2-1 (when UPLC retains Between: 7.027 minutes).m/z:[M+H]⁺547.2,¹H NMR(400MHz,CD₃OD): δ 8.75-8.76 (d, J=4.4Hz, 1H), 8.22-8.23(m,1H),8.07-8.11(m,1H),7.85-7.91(m,2H),7.54-7.63(m,2H),7.36-7.39(m, 1H), 7.33 (s, 1H), 3.44 (d, J=7.8Hz, 2H), 3.33-3.34 (m, 1H), 2.04-2.13 (m, 1H), 1.75-1.90 (m,8H)。

Embodiment 29: the synthesis of compound 2-2

Using the synthetic method of compound 1-1, compound 11 is replaced with into compound 3 and obtains compound 2-A.

Step 1: being dissolved in tetrahydrofuran (2mL), acetic acid (3mL) and water (2mL) to compound 2-A (80mg, 0.17mmol) Mixed solution in be added ammonium ceric nitrate (371mg, 0.68mmol), reaction system is stirred at room temperature 3 hours, with the sodium carbonate of saturation Aqueous solution quenching reaction simultaneously adjusts pH >=8, and water phase is extracted with ethyl acetate, merge organic phase and, filtering dry with anhydrous sodium sulfate, Being concentrated to give compound 2-B, (80mg, yield: 97%) being off-white powder.

Step 2: into methanol (3mL) solution of compound 2-B (80mg, 0.16mmol) be added sodium borohydride (12mg, 0.32mmol), reaction system is stirred at room temperature 20 minutes, then with hydrochloric acid (2M) quenching reaction and adjusts pH=6, then use carbon Sour hydrogen sodium solid adjusts pH=8, and water phase is extracted with ethyl acetate, and merges organic phase and, filtering dry with anhydrous sodium sulfate, dense Contracting, residue is purified with prep-HPLC (alkaline process, Mobile phase B: 15~65% (v/v%)) obtains compound 2-2 (UPLC reservation Time: 4.525 minutes, 10mg, yield: 13%) being white solid.m/z:[M+H]⁺489.2,¹H NMR(400MHz,CD₃OD): δ8.78-8.79(m,1H),8.11-8.07(m,2H),7.90-7.87(m,1H),7.67-7.53(m,3H),7.31(s,1H), 7.03-7.00(m,1H),4.38(s,2H),3.86(s,3H),3.42-3.40(m,2H),1.84(m,1H),1.82-1.74(m, 1H),1.38-1.34(m,8H)。

Embodiment 30: the synthesis of compound 3-2

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 20 and obtains compound 3-1 (UPLC reservation Time: 6.346 minutes).m/z:[M+H]⁺554.2,¹H NMR(400MHz,CD₃OD): δ 8.76-8.77 (d, J=4.8Hz, 1H), 8.62-8.63 (d, J=4.8Hz, 1H), 8.07-8.11 (m, 1H), 7.88-7.91 (m, 2H), 7.56-7.63 (m, 3H), 3.37-3.61(m,3H),2.05-2.12(m,2H),1.76-1.96(m,8H),1.05-1.07(m,4H)。

Embodiment 31: the synthesis of compound 3-2

With the synthetic method of compound 1-1, compound 11 is replaced with into compound 21 and obtains compound 3-2 (UPLC reservation Time: 6.715 minutes).m/z:[M+H]⁺568.2,¹H NMR(400MHz,CD₃OD): δ 8.76-8.77 (d, J=4.8Hz, 1H),8.64(s,1H),8.07-8.11(m,1H),7.88-7.92(m,2H),7.57-7.61(m,3H),3.69-3.73(m, 1H),3.52-3.63(m,2H),3.36-3.44(m,1H),2.40-2.47(m,4H),2.07-2.19(m,2H),1.75-2.04 (m,9H)。

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 use 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.

Five yuan of heteroaromatic ring derivative active testings of the present invention are as a result, IC₅₀Value is as shown in the table:

Embodiment 2: cytochrome pathways inhibiting effect test

Compound is assessed using LC-MS/MS method to the inhibiting effect of CYP3A4 hypotype.This method will test compound It is mixed with the solution of people's hepatomicrosome containing CYP model substrates, is incubated for jointly under conditions of NADPH is added, passes through measurement The amount of the metabolin of model substrates calculates compound to the inhibition IC of CYP3A4 in reaction solution₅₀.Specific experimental method is as follows:

Untested compound is formulated as the storage liquid of 10mM concentration with DMSO, is then diluted to 4mM with acetonitrile solution.Together When prepared for CYP hypotype and refer to mortifier solution accordingly, such as with reference to mortifier be Ketoconazole, the two is single respectively (+12 μ L acetonitrile of 8 μ L mortifier DMSO storing liquid) solely is prepared, the sample prepared under above-mentioned condition is 400X concentration.It then will be upper Solution is stated with DMSO: the mixed liquor (v/v:40:60) of acetonitrile carries out 3 times of gradient dilutions and is formulated as final test solution, each Test compound sets 7 concentration points, and final concentration of 10uM is tested in starting.Respectively with preheating kaliumphosphate buffer (0.1M, pH7.4) By NADPH, CYP catalator substrate and people's hepatomicrosome solution are diluted to suitable concentration.Wherein people's hepatomicrosome solution is purchased In BD Gentest (20mg/mL, Corning, article No. #452161).

People's hepatomicrosome solution (0.2mg/mL) of 400 μ L is added in each hole of test compound into 96 orifice plates, later The aforementioned test compound final test sample prepared by gradient dilution of 2 μ L is added；Each hole is corresponded to for reference mortifier, People's hepatomicrosome solution (0.2mg/mL) of 200 μ L and the final test sample of 1 μ L is added.The correspondence model bottom that will be prepared The every hole of object dispenses in 15 μ L to one pieces of 96 orifice plates, and particle liquid solution takes the test compound of 30 μ L/with reference to mortifier-people after mixing Hepatomicrosome mixed liquor is simultaneously transferred in 96 orifice plates added with substrate, is mixed and is preheated 5 minutes at 37 DEG C, 15 μ L are added later The 8mM NADPH solution preheated at 37 DEG C starts to react.Each test is equipped with multiple holes and compares, while adding equipped with no test substances The blank control entered.It will be incubated at 37 DEG C containing 96 orifice plates that total volume is 60 μ L reaction solutions, after incubation, to each 120 μ L cold acetonitrile solution containging interior traget is added in hole and terminates reaction, 96 orifice plates are then vibrated 5 points in microplate oscillator Clock (600rpm/min), is put into centrifuge 6000rpm, and 4 degree, from 20 minutes.40 μ L supernatants are taken to be transferred to from each hole later In another 96 orifice plate, then 80 μ L ultrapure waters are added into each hole, are put into oscillator and mix 5 minutes (600rpm/min), centrifuge 6000rpm, 4 degree, from 20 minutes.Then LC-MS/MS detection is carried out.Add by comparing under each test concentrations and without test substances The amount of model substrates metabolin in the case of entering determines inhibiting rate, in 5.0 software of GraphPad Prism, dense to test The logarithm of degree is abscissa, and inhibiting rate is that ordinate carries out nonlinear regression (Sigmoidal (non-linear) dose- Response model) analysis, obtain the IC of test compound₅₀Value.As a result it see the table below:

It infuses, the Ref.A (positive control) in biological test embodiment is public in Chinese patent application 201710644418.X The compound 14-1b opened, chemical name: 5- methyl-N- (((1r, 4r or 1s, 4s) -4- (2- picoline -4- base) cyclohexyl) Methyl) -2- (pyridin-3-yl) -1H- pyrrole-3-carboxamide.

Claims

1. a kind of five yuan of heteroaromatic ring derivatives (I), its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable Salt；

Wherein, A ring is pyrrole ring or imidazole ring, also, X, Y, Z are selected from following combination:

1) X is NR₁, Y CR₂It is CR with Z₃；

2) X is CR₂, Y NR₁It is CR with Z₃；

3) X is CR₃, Y CR₂It is NR with Z₁；

4) X is CR₃, Y NR₁It is CR with Z₂；

5) X is NR₁, Y CR₂It is N with Z；Or

6) X is N, Y CR₂It is NR with Z₁；

L is CH₂、CH(CH₃)、C(CH₃)₂Or CH₂CH₂；

U and V is separately selected from N or CR₄；

Cy is phenyl ring or 5-10 member hetero-aromatic ring, and the Cy is unsubstituted or is further selected from halogen, C by 1~4_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylthio group, halogenated C_1-6Alkyl, halogenated C_1-6Alkoxy, C_2-6Alkynyl, C_2-6Alkenyl, C_3-6Naphthenic base ,-OH ,- SH、-CN、-NO₂、-OC(O)R_a、-OC(O)OR_b、-OC(O)N(R_b)₂、-C(O)OR_b、-C(O)R_a、-C(O)N(R_b)₂、-NR_bC (O)R_a、-N(R_b)₂、-NR_bC(O)R_a、-S(O)_0-2R_aWith-S (O)₂N(R_b)₂One of or a variety of substituent groups be substituted in any position It sets；

R is naphthenic base, Heterocyclylalkyl, aryl or heteroaryl；The R is unsubstituted or further by 1~3 R^AGroup replaces At an arbitrary position :-CN ,-OR_a、-C(O)N(R_b)₂、-OC(O)R_a、-OC(O)OR_b、-OC(O)N(R_b)₂、-C(O)OR_b、-C(O) R_a、-C(O)N(R_b)₂、-N(R_b)₂、-NR_bC(O)R_a、-NR_bC(O)R_a、-NR_bC(O)OR_a、-NR_bC(O)N(R_b)₂、-NR_bC(O)N (R_b)₂、-NR_bS(O)₂R_a、-NR_bS(O)₂N(R_b)₂、-S(O)_0-2R_a、-S(O)₂N(R_b)₂, halogen, substituted or unsubstituted alkyl, It is substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted naphthenic base, substituted or unsubstituted miscellaneous Naphthenic base or substituted or unsubstituted heteroaryl；R^AIn, the alkyl, alkoxy, aryl, heteroaryl, naphthenic base or heterocycle When alkyl is substituted, halogen, hydroxyl, amino, C further can be selected from by 1~3_1-4Alkyl or halogenated C_1-3The substitution of alkoxy Base replaces at an arbitrary position；

R₁For H ,-C (O) N (R_b)₂、-C(O)R_a、-C(O)OR_a、-S(O)₂N(R_b)₂、-S(O)₂R_a, substituted or unsubstituted C_1-6Alkane Base, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_3-8Naphthenic base, substitution or Unsubstituted phenyl or substituted or unsubstituted 5-6 unit's heteroaryl；The C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkanes Base, 3-8 membered heterocycloalkyl, phenyl or 5-6 unit's heteroaryl are preferably selected from by 1~3 when being substituted: deuterium, halogen, hydroxyl, mercapto Base, amino, cyano, C_1-3Alkyl, C_1-3Alkoxy, C_1-3Alkylamino radical, halogenated C_1-3Alkoxy, halogenated C_1-3Alkyl, carboxylic acid, ester group, Amide groups ,-NH (CO)-C_1-6Alkyl ,-C (O)-C_1-6Alkyl ,-S (O)_0-2-C_1-6Alkyl, C_3-8Naphthenic base or 3-8 circle heterocyclic ring alkane The substituent group of base replaces at an arbitrary position；

R₂For halogen ,-CN ,-OR_a、-C(O)N(R_b)₂、-C(O)R_a、-C(O)OR_a、-S(O)₂N(R_b)₂、-S(O)₂R_a、-N(R_b)₂、- NR_bC(O)R_a, replace C_1-6Alkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substitution do not take The C in generation_3-8Naphthenic base or substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5-6 unit's heteroaryl；As the C_1-6Alternative is selected from halogen, C by 1~3 when alkyl is substituted_1-4Alkoxy, halogenated C_1-4 Alkoxy, C_1-4Alkylamino radical ,-OH ,-NH₂Replace at an arbitrary position with one of-CN or a variety of substituent groups；As the C_2-6Alkene Base, C_2-6Alkynyl, C_3-8Alternative is by 1~3 when naphthenic base, 3-8 membered heterocycloalkyl, phenyl or 5-6 unit's heteroaryl are substituted Selected from deuterium, halogen, C_1-4Alkyl, C_1-4Alkoxy, halogenated C_1-4Alkyl, halogenated C_1-4Alkoxy, C_1-4Alkylamino radical ,-OH ,-NH₂With- One of CN or a variety of substituent groups replace at an arbitrary position；

R₁And R₂For independent substituent group or R₁And R₂It is interconnected to form 5-10 membered heterocycloalkyl or 5-6 unit's heteroaryl；It is described 5-10 membered heterocycloalkyl also can further include 1~3 selected from N, O, S (O)_0-2, C (O) hetero atom or group；The 5-10 Membered heterocycloalkyl or 5-6 unit's heteroaryl are unsubstituted or are further selected from halogen, C by 1~3_1-4Alkyl, C_1-4Alcoxyl Base, halogenated C_1-4Alkyl, halogenated C_1-4Alkoxy, C_1-4Alkylamino radical ,-OH ,-NH₂Replace with one of-CN or a variety of substituent groups At an arbitrary position；

R₄For H ,-OH ,-CN, C_1-6Alkyl or C_1-6Alkoxy；

Each R_aWith each R_bBe each independently selected from hydrogen, alkyl, halogenated alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, Hetercycloalkylalkyl, cycloalkyl-alkyl, aryl alkyl or heteroaryl alkyl, alternatively, two R_bIt is former with the N that they connect jointly Son is formed together the monocyclic heterocycloalkyl of 3-8 member；

M is 1,2 or 3；

N is 0,1 or 2.

2. five yuan of heteroaromatic ring derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt, it is characterised in that: Cy is phenyl, thienyl, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiophene Oxazolyl, 1,2,3- oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,4- triazol radical, 1,2,3- triazole Base, 1,2,3- thiadiazolyl group, 1,2,5- thiadiazolyl group, tetrazole base, pyridyl group, pyrimidine radicals, pyrazinyl or pyridazinyl；It is described Cy is unsubstituted or is further selected from deuterium, halogen, amino, cyano, C by 1~3_1-3Alkyl, C_1-3Alkoxy and halogenated C_1-3 One of alkoxy or a variety of substituent groups replace at an arbitrary position；

And/or R is phenyl, pyridyl group, N- pyridine oxide base, quinolyl, isoquinolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrrole Oxazolyl or pyrrole radicals；The R is unsubstituted or further by 1~3 R^AGroup replaces at an arbitrary position；The R^AIt is selected from C_1-3Alkyl, C_1-3Alkoxy, F, Cl, Br ,-OH ,-NH₂Or-CN；

And/or R₁For H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl or Substituted or unsubstituted cyclopropyl.The methyl, ethyl, isopropyl or cyclopropyl are unsubstituted, or selectivity is by 1-OH Replace at an arbitrary position；

And/or R₂For fluorine, chlorine, propyl- 1- alkene -2- base, trifluoromethyl, difluoromethyl, 2- fluorine propyl- 2- base, 2,2- bis-fluoro ethyls, 1, 1- bis-fluoro ethyls, hydroxymethyl, 1- methylcyclopropyl groups, 1- hydroxycyclopropyl, 1- fluorine cyclopropyl, cyclobutyl, cyclopropyl, 3- oxa- Cyclobutyl, 2- oxetanylmethoxy, 1- hydroxy-2-methyl propyl- 2- base, 3- azelidinyl or 2- azelidinyl；

And/or R₃For H, deuterium, fluorine, chlorine, bromine, cyano or methyl；

And/or R₄For H；

And/or m 1；

And/or n 1.

3. five yuan of heteroaromatic ring derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt, it is characterised in that: Cy is

Wherein, R₅And R₆Separately it is selected from H, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylthio group, halogenated C_1-6Alkyl, halogen For C_1-6Alkoxy, C_2-6Alkynyl, C_2-6Alkenyl, C_3-6Naphthenic base ,-OH ,-SH ,-CN ,-NO₂、-OC(O)R_a、-OC(O)OR_b、-OC (O)N(R_b)₂、-C(O)OR_b、-C(O)R_a、-C(O)N(R_b)₂、-NR_bC(O)R_a、-N(R_b)₂、-NR_bC(O)R_a、-S(O)_0-2R_a、 Or-S (O)₂N(R_b)₂；R_aAnd R_bDefinition it is as described in claim 1.

4. five yuan of heteroaromatic ring derivatives (I) as claimed in claim 3, its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt, it is characterised in that: R₅For hydrogen, methyl, methoxyl group, cyano, trifluoromethoxy, ethyoxyl or difluoro Methoxyl group；

And/or R₆For hydrogen, deuterium, halogen, amino, cyano, C_1-3Alkyl, C_1-3Alkoxy or halogenated C_1-3Alkoxy.

5. five yuan of heteroaromatic ring derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt, wherein it is logical formula (II), compound, its isomers, prodrug, stabilization shown in (III) or (IV) Isotope derivatives or pharmaceutically acceptable salt:

Logical formula (II) compound represented, its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable salt:

Wherein, Cy, R, R₁、R₂And R₃Definition it is as described in claim 1；

Logical formula (III) compound represented, its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable salt:

Wherein, Cy, R, R₁、R₂And R₃Definition it is as described in claim 1；

Logical formula (IV) compound represented, its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable salt:

Wherein, Cy, R, R₁And R₂Definition it is as described in claim 1.

6. five yuan of heteroaromatic ring derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt, wherein it is logical formula (II), compound, its isomers, prodrug, stabilization shown in (III) or (IV) Isotope derivatives or pharmaceutically acceptable salt:

Wherein, Cy isR isR₁For hydrogen, methyl or hydroxyethyl；R₂ For hydroxymethyl, propyl- 1- alkene -2- base, 1- methylcyclopropyl groups, 1- hydroxycyclopropyl, cyclobutyl, cyclopropyl, 3- oxetanylmethoxy, 2- oxetanylmethoxy, 1- hydroxy-2-methyl propyl- 2- base, 3- azelidinyl or 2- azelidinyl；R₃For H；

Wherein, Cy isR isR₁For hydrogen or methyl；R₂For F, Cl, hydroxymethyl；R₃ For H；

Wherein, Cy isR isR₁For hydrogen or methyl；R₂For cyclopropyl or cyclobutyl.

7. five yuan of heteroaromatic ring derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt, it is characterised in that: its general structure is following any:

Wherein, X, Y, Z, Cy, L and R are defined as described above.

8. five yuan of heteroaromatic ring derivatives (I) as described in claim 1, its isomers, prodrug, stable isotope derivatives or Pharmaceutically acceptable salt, it is characterised in that: if formula (I) compound represented is following any structure:

9. one kind compound as shown in formula (I), its isomers, prodrug, stable as described at least one of claim 1~8 The preparation method of isotope derivatives or pharmaceutically acceptable salt, wherein the preparation method of the compound as shown in formula (I) Are as follows:

In solvent, in the presence of alkali, compound I-b and compound X-1 is subjected to condensation reaction；

Wherein, the definition of Cy, X, Y, Z, L, R, U, V, m and n are as described in any one of claim 1~8.

10. a kind of pharmaceutical composition comprising the active component of therapeutically effective amount and pharmaceutically acceptable auxiliary material；The work Property component includes five yuan of heteroaromatic ring derivatives (I) as described in any one of claims 1 to 8, its isomers, prodrug, stable Isotope derivatives or pharmaceutically acceptable salt.

11. pharmaceutical composition as claimed in claim 10, it is characterised in that: in described pharmaceutical composition, the active component It further include other therapeutic agents of 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.

12. five yuan of heteroaromatic ring derivatives (I), its isomers, prodrugs, stable isotopes as described in any one of claim 1~8 Derivative or pharmaceutically acceptable salt, or such as claim 10 or 11 described pharmaceutical compositions are preparing indoleamine 2, and 3- is bis- to be added Application in oxygenase inhibitor.

13. five yuan of heteroaromatic ring derivatives (I), its isomers, prodrugs, stable isotopes as described in any one of claim 1~8 Derivative or pharmaceutically acceptable salt, or as claim 10 or 11 described pharmaceutical compositions are preparing stimulation T cell proliferation Application in drug.

14. five yuan of heteroaromatic ring derivatives (I), its isomers, prodrugs, stable isotopes as described in any one of claim 1~8 Derivative or pharmaceutically acceptable salt, or such as claim 10 or 11 described pharmaceutical compositions in preparation treatment, alleviate and/or Application in the drug for the related disease that prevention is mediated by indole amine 2,3-dioxygenase.

15. application as claimed in claim 14, it is characterised in that: five yuan of heteroaromatic ring 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.

16. application as claimed in claim 14, it is characterised in that: the related disease packet that 2, the 3- dioxygenase mediates It includes: virus infection, cancer or autoimmune disease.

17. application as claimed in claim 16, it is characterised in that: the cancer includes but is not limited to osteocarcinoma, liver cancer, esophagus Cancer, carcinoma of mouth, gastric cancer, the carcinoma of the rectum, colon cancer, cancer of pancreas, breast cancer, prostate cancer, lung cancer, the cancer of the brain, oophoroma, bladder cancer, One of cervix cancer, carcinoma of testis, kidney, head and neck cancer, lymph cancer, leukaemia and cutaneum carcinoma are a variety of；Described itself exempts from Epidemic disease disease is rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, system chorionitis, dermatomyositis, knot Section property vasculitis, nephrosis, endocrine related disease, hepatopathy, psoriasis and due to caused by infection in autoimmune response one Kind is a variety of；The virus infection is by influenza, hepatitis type B virus, Hepatitis C Virus, human papilloma virus, big and small Cellular virus, epstein-Barr virus, poliovirus, varicella virus, Coxsackie virus and the mankind exempt from One of epidemic disease defective virus or a variety of caused infection.