CN107033097A - Oxadiazole analog derivative, its preparation method and its in application pharmaceutically - Google Patents

Abstract

This invention She is Ji oxadiazole analog derivative, its preparation method and its in application pharmaceutically.Especially, pharmaceutical composition the present invention relates to the oxadiazole analog derivative shown in logical formula (I), its preparation method and containing the derivative, and its purposes in the medicine for preparing the disease of prevention and/or treatment with the IDO tryptophan metabolic pathway pathological characteristicses mediated, described disease includes cancer, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS.Each substituent in its formula of (I) is identical with the definition in specification.

Description

Oxadiazole analog derivative, its preparation method and its in application pharmaceutically

Technical field

The invention belongs to field of medicaments, She Ji oxadiazole analog derivative, its preparation method and its answering on medical research With Gong Kai oxadiazole analog derivatives of the present invention are as IDO inhibitor, for treating the tryptophan metabolism way mediated with IDO The disease of footpath pathological characteristicses, described disease includes cancer, Alzheimer disease, autoimmune disease, depression, anxiety Disease, cataract, mental handicape and AIDS.

Background technology

Tumor biotherapy is the new treatment that treatment and prevention of tumour is carried out using modern biotechnology and its Related product, Yin Qian Entirely, effectively, the low feature of adverse reaction, the 4th kind of pattern (Clin as the oncotherapy after operation, radiotherapy, chemotherapy Cancer Res,1997；3:2623-2629), its natural immunology defense by transferring host, such as suppress the swollen of IDO mediations Knurl Immune escaping mechanism, or give naturally-produced targeting very strong material to obtain antineoplastic effect.

IDO (Indoleamine-pyrrole-2,3-dioxygenase, IDO) is a kind of iron content Ferroheme monomeric protein, is made up of 403 amino acid residues, includes the α-helixstructure domain of two foldings, big structure domain is included Catalytic pocket, substrate can occur hydrophobic wait with IDO in catalytic pocket and act on (Int J Biochem Cell Biol.2007； 39(12):2167-72).In mammal, the irrelevant enzyme containing ferroheme for having two kinds of gene codes can be catalyzed color The oxidative degradation of propylhomoserin：IDO and tryptophan 2,3- dioxygenases (TDO).Every kind of enzymatic identical reaction：On kynurenin road Promote the oxidation Decomposition of the 2,3- double bonds of indole ring in first rate-limiting step tryptophan catabolism in footpath.TDO expression master It is limited to liver, it appears that be used as a homeostasis or " house keeper " gene, it is impossible to induced or reconciled by the signal of immune system (Nat Rev Immunol.2004；4(10):762-74).IDO is to be catalyzed the enzyme that tryptophan transfer turns to formylkynurenine, extensively It is general to be distributed in people and other tissues of mammal (rabbit, mouse) in addition to liver, it is that tryptophan can be uniquely catalyzed beyond liver The rate-limiting enzyme of catabolism, and tryptophan is cell maintenance activation and the necessary amino acid of propagation, is also to constitute protein not Important component (the Adv Exp Med Biol.2003 that can lack；527:455-63、Biochim Biophys Acta.2001； 1527(3):167-75).IDO and interferon (interferon, IFN), interleukins (interleukin, IL), tumour are bad The cytokine profiles such as necrosis factor are in close relations, and they can activate IDO (J Psychiatry under certain condition Neurosci.2004；29(1):11–17、Med Hypotheses.2003；61(5-6):519-25).And the cell of T- cells There is the very sensitive point of adjustment of a tryptophan level in cycle, on the one hand, IDO makes local tryptophan depletion, causes T- Cells arrest is in the G1 interim phases, so as to inhibit the propagation of T cell；On the other hand, IDO is catalyzed the main of tryptophan metabolism generation Product cynruin is caused Cellular Oxidation agent and antioxidant to change and is induced T- Apoptosis by Mediated by Free Radicals, and this is to deposit It is the intrinsic immunosuppression mechanism of body.Current numerous studies show IDO higher expression in leukaemia, make part T cell propagation is suppressed, suppresses the cell-mediated immune responses of T-, the transduction of T- cell activation signals is obstructed, so that mediate tumor The attack of cell evasion immune system.It has been found that most of mankind's tumor groups express IDO (J Exp Med.2002 with becoming second nature； 196(4):459-68、Nat Med.2003；9(10):1269-74、Trends Mol Med.2004；10(1):15-8).Cause This, IDO is the target of the cancer immunotherapy of a tool potentiality.

Disclosed selective depression IDO inhibitor patent application include WO2004094409, WO2006122150, WO2007075598、WO200409387、WO2008147283、WO2013174947、WO2008075991、WO2004093871、 WO2005051321, WO2006056304, WO2010005958 and WO2014066834 etc..

IDO inhibitor has a good application prospect as medicine in pharmaceuticals industry, but not yet finds at present well IDO inhibitor, in order to reach the purpose of more preferable oncotherapy effect, can better meet the market demand as marketed drug, Inventor wishes to develop the selective IDO inhibitor of the high-efficiency low-toxicity of a new generation.The present invention will provide a kind of new structure Selective IDO inhibitor, and find that the compound with this class formation shows excellent effect and effect, it is particularly excellent Medicine generation absorb activity.

The content of the invention

It is an object of the invention to provide the compound shown in a kind of logical formula (I) or its dynamic isomer, mesomer, outer Raceme, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt,

Wherein：

Mixture selected from cis-isomer, transisomer and cis-trans-isomer；

Ring A is selected from cycloalkyl, heterocyclic radical, aryl and heteroaryl；

Ring B is aryl or heteroaryl；

R¹It is identical or different, and it is each independently selected from hydrogen atom, alkyl, cyano group, amino, halogen, alkenyl, alkynyl, hydroxyl Base, nitro, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein described alkyl, alkene Base, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally further independently of one another One or many be selected from hydroxyl, halogen, amino, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl Individual substituent is replaced；

R²It is identical or different, and it is each independently selected from hydrogen atom, alkyl, hydroxyl, amino, alkoxy, hydroxyalkyl, halo Alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR³、-C(O)R³、-C(O)OR³、-S(O)_mR³、-C(O)NR³R⁴、-OC (O)NR³R⁴、-NR³R⁴、-NR³C(O)R⁴、-NR³S(O)_mR⁴With-NR³S(O)_mNHR⁴, wherein described alkyl, alkoxy, hydroxyl alkane Base, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, amino, nitre independently of one another Base, cyano group, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR⁵、-C(O)R⁵、-C(O)OR⁵、-S (O)_mR⁵、-NR⁵R⁶、-C(O)NR⁵R⁶、-NR⁵C(O)R⁶With-NR⁵S(O)_mR⁶One or more of substituent replaced；

R³And R⁴It is identical or different, and be each independently selected from hydrogen atom, alkyl, hydroxyl, amino, alkoxy, hydroxyalkyl, Haloalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR⁵、-C(O)R⁵、-C(O)OR⁵、-S(O)_mR⁵、-NR⁵R⁶、-C(O) NR⁵R⁶、-NR⁵C(O)R⁶With-NR⁵S(O)_mR⁶, wherein described alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocycle Base, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, hydroxyl, amino, nitro, cyano group, alkane independently of one another Epoxide, hydroxyalkyl, cycloalkyl, heterocyclic radical ,-C (O) OR⁷, one or more of aryl and heteroaryl substituent replaced；

R⁵And R⁶It is identical or different, and it is each independently selected from hydrogen atom, alkyl, hydroxyl, amino, carboxylic acid ester groups, alcoxyl Base, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein described alkyl, amino, alkoxy, hydroxyl alkane Base, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, hydroxyl, ammonia independently of one another One or more of base, carboxylic acid ester groups, nitro, cyano group, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl Substituent is replaced；

R⁷Selected from hydrogen atom, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl；

M is 0,1 or 2；

N is 0,1,2,3,4 or 5；And

X is 0,1,2,3,4 or 5.

In yet other embodiments, lead to the compound shown in formula (I) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, its middle ring B are virtue Base, preferably phenyl.

In yet other embodiments, lead to the compound shown in formula (I) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, wherein R¹It is former for hydrogen Son or halogen.

In yet other embodiments, lead to the compound shown in formula (I) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, wherein R²Selected from hydrogen Atom, alkyl, hydroxyl, amino ,-C (O) R³、-S(O)_mR³、-C(O)NR³R⁴、-OC(O)NR³R⁴、-NR³R⁴、-NR³C(O)R⁴、- NR³S(O)_mR⁴With-NR³S(O)_mNHR⁴；It is preferred that-NR³S(O)_mNHR⁴；R³、R⁴With m as defined in logical formula (I).

In yet other embodiments, lead to the compound shown in formula (I) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, wherein n are 1 or 2.

In yet other embodiments, lead to the compound shown in formula (I) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, wherein x are 1.

In yet other embodiments, lead to the compound shown in formula (I) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, it is logical formula (II) Shown compound：

Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula, or its officinal salt,

Wherein：

Mixture selected from cis-isomer, transisomer and cis-trans-isomer；

G is selected from C, O, N, S (O)_mAnd S；

R²It is identical or different, and it is each independently selected from hydrogen atom, alkyl, hydroxyl, amino, alkoxy, hydroxyalkyl, halo Alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR³、-C(O)R³、-C(O)OR³、-S(O)_mR³、-C(O)NR³R⁴、-OC (O)NR³R⁴、-NR³R⁴、-NR³C(O)R⁴、-NR³S(O)_mNHR⁴With-NR³S(O)_mR⁴, wherein described alkyl, alkoxy, hydroxyl alkane Base, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, amino, nitre independently of one another Base, cyano group, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR⁵、-C(O)R⁵、-C(O)OR⁵、-S (O)_mR⁵、-NR⁵R⁶、-C(O)NR⁵R⁶、-NR⁵C(O)R⁶With-NR⁵S(O)_mR⁶One or more of substituent replaced；

X is 0 or 1；

Y is 0,1,2 or 3；

Z is 0,1,2 or 3；And

Ring B, R¹、R³~R⁶, m and n be as defined in logical formula (I).

In yet other embodiments, lead to the compound shown in formula (I) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt, its middle ring A are selected from ring Hexyl, indenyl, pyrazolyl, cyclopenta, tetrahydrofuran base, pyranose, cyclobutyl, piperidyl, oxetanylmethoxy, azetidine Base and pyrrolidinyl.

The typical compound of logical formula (I) includes but is not limited to：

Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula, or its officinal salt.

The present invention also provides a kind of intermediate for preparing compound shown in logical formula (I), and the intermediate is shown in logical formula (III) Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, Or its officinal salt,

Wherein：

Ring B is selected from aryl and heteroaryl；

R¹It is identical or different, and it is each independently selected from hydrogen atom, alkyl, cyano group, amino, halogen, alkenyl, alkynyl, hydroxyl Base, nitro, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein described alkyl, alkene Base, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from independently of one another One or more of hydroxyl, halogen, amino, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl replace Base is replaced；

N is 0,1,2,3,4 or 5.

The present invention also provides a kind of intermediate for preparing compound shown in logical formula (I), and the intermediate is logical formula (V) shownization Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or Its officinal salt,

Wherein：

Ring A, ring B, R¹、R², x and n be as defined in logical formula (I).

The typical compound of logical formula (V) includes but is not limited to：

Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula, or its officinal salt.

The present invention also provides one kind and prepares compound shown in logical formula (I) or its dynamic isomer, mesomer, racemic Body, enantiomter, diastereoisomer or its form of mixtures or the method for its officinal salt, this method include：

Logical formula (III) compound is reacted under room temperature alkalescence condition with logical formula (IV), obtains logical formula (I) compound；

Wherein：

Ring A, ring B, R¹、R², x and n be as defined in logical formula (I).

The present invention also provides one kind and prepares compound shown in logical formula (I) or its dynamic isomer, mesomer, racemic Body, enantiomter, diastereoisomer or its form of mixtures or the method for its officinal salt, this method include：

Logical formula (V) compound open loop under room temperature alkalescence condition, obtains logical formula (I) compound；

Wherein：

Ring A, ring B, R¹、R², x and n be as defined in logical formula (I).

The present invention also provides one kind and prepares compound shown in logical formula (I) or its dynamic isomer, mesomer, racemic Body, enantiomter, diastereoisomer or its form of mixtures or the method for its officinal salt, this method include：

The open loop under room temperature alkalescence condition of formula (II-B) compound, obtains logical formula (II) compound；

Wherein：

Ring B, G, R¹、R², y, z, x and n be as defined in logical formula (II).

Another aspect of the present invention is related to a kind of pharmaceutical composition, and it contains shown in the logical formula (I) for the treatment of effective dose Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its mixture shape Formula or pharmaceutically useful salt, and one or more pharmaceutically acceptable carriers, diluent or excipient.The invention further relates to A kind of method for preparing above-mentioned composition, it include by the compound shown in logical formula (I) or its dynamic isomer, mesomer, Racemic modification, enantiomter, diastereoisomer or its form of mixtures or its pharmaceutically useful salt with it is pharmaceutically acceptable Carrier, diluent or excipient mix.

The invention further relates to lead to formula (I) shown in compound or its dynamic isomer, mesomer, racemic modification, It is prepared by enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or the pharmaceutical composition comprising it Have for prevention and/or Prevention in the medicine of disease of the pathological characteristicses of the tryptophan metabolic pathway of IDO mediations Purposes.IDO inhibitor can be used for the suppression of cardiac disorder and treat other tryptophan metabolic pathways that there is IDO to mediate The disease of pathological characteristicses, the infection of these diseases virus such as including AIDS, such as AIDS, Lyme disease and streptococcus sense Cell infection, myelodysplastic syndrome, Neurodegenerative conditions (such as Alzheimer disease, Huntington disease and the handkerchiefs such as dye The gloomy disease of gold), autoimmune disease, depression, anxiety disorder, mental handicape, cancer (including T cell leukaemia and colon cancer), Disease of eye (such as cataract and age-related yellow), wherein described cancer can be selected from breast cancer, cervical carcinoma, knot Intestinal cancer, lung cancer, stomach cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, wing Guang cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phases melanoma, solid tumor, glioma, neuroglia are female Cytoma, hepatocellular carcinoma, mastoid process kidney knurl, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.

The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, mapping shown in formula (I) Isomers, diastereoisomer or its form of mixtures, or its officinal salt, or the pharmaceutical composition comprising it, it is used for pre- Anti- and/or Prevention has the disease of the pathological characteristicses of the tryptophan metabolic pathway of IDO mediations.These diseases are included such as The infection of the virus such as AIDS, the cell infection such as AIDS, Lyme disease and streptococcal infection, myelodysplastic syndrome, Neurodegenerative conditions (such as Alzheimer disease, Huntington disease and Parkinson's), autoimmune disease, depression, Jiao Consider disease, mental handicape, cancer (including T cell leukaemia and colon cancer), disease of eye (such as cataract and age-related Yellow), wherein described cancer can be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, stomach cancer, the carcinoma of the rectum, cancer of pancreas, brain Cancer, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tube cneoplasms, ovarioncus, peritonaeum Tumour, IV phases melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process kidney knurl, incidence Tumour, leukaemia, lymthoma, myeloma and non-small cell lung cancer.

There is the disease of the tryptophan metabolic pathway of IDO mediations the invention further relates to a kind of Prevention and/or Prevention The method of the disease of feature of science, it includes compound shown in the logical formula (I) of patient therapeuticallv's effective dose or its is mutual Tautomeric, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its is pharmaceutically acceptable Salt, or the pharmaceutical composition comprising it.The disease including AIDS etc. virus infection, such as AIDS, Lyme disease and The cell infections such as streptococcal infection, myelodysplastic syndrome, Neurodegenerative conditions (such as Alzheimer disease, the prosperous court of a feudal ruler Disease and Parkinson's), autoimmune disease, depression, anxiety disorder, mental handicape, cancer (including T cell leukaemia and Colon cancer), disease of eye (such as cataract and age-related yellow), wherein described cancer can selected from breast cancer, Cervical carcinoma, colon cancer, lung cancer, stomach cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, Oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phases melanoma, solid tumor, glioma, Spongioblastoma, hepatocellular carcinoma, mastoid process kidney knurl, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell Lung cancer.

Another aspect of the present invention is related to a kind of method for the treatment of cancer, and this method is included to patient therapeuticallv's effective dose Logical formula (I) of the invention described in compound or its dynamic isomer, mesomer, racemic modification, enantiomter, non-right Reflect isomers or its form of mixtures, or its officinal salt.This method shows prominent curative effect and less side effect, wherein Described cancer can be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, stomach cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, mouth Chamber cancer, prostate cancer, osteocarcinoma, kidney, oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phases are black Melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process kidney knurl, head and neck neoplasm, white blood Disease, lymthoma, myeloma and non-small cell lung cancer, preferably fallopian tube cneoplasms, peritoneal tumor, IV phases melanoma, myeloma And breast cancer, more preferably breast cancer.

Pharmaceutical composition containing active component can apply to oral form, such as tablet, dragee, lozenge, water Or oil suspension, dispersible powder or particle, emulsion, hard or soft capsule, or syrup or elixir.Can be any according to this area Know that the method for preparing Pharmaceutical composition prepares Orally administered composition, such composition can containing it is one or more selected from it is following into Point：Sweetener, flavouring, colouring agent and preservative, to provide pleasing and tasty pharmaceutical formulation.Tablet contain active component and The suitable nontoxic pharmaceutically useful excipient for preparing tablet for mixing.These excipient can be inert excipient, granulation Agent and disintegrant, adhesive and lubricant.These tablets can not be coated or can be by covering the taste of medicine or in intestines and stomach Middle delay disintegration and absorption, thus the known technology of offer slow releasing function is coated in a long time.For example, water can be used Dissolubility taste masked material or extension time material.

Also wherein active component and inert solid diluent or wherein active component and water-solubility carrier or oily solvent be can use The Perle of mixing provides oral formulations.

Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Such excipient is Suspending agent, dispersant or wetting agent.Aqueous suspension can also contain one or more preservatives, one or more colouring agents, one Plant or a variety of flavourings and one or more sweeteners.

Oil suspension can be formulated by making active component be suspended in vegetable oil or mineral oil.Oil suspension can contain Thickener, such as beeswax, hard paraffin or cetanol.Above-mentioned sweetener and flavouring can be added, to provide tasty preparation.Can These compositions are preserved by adding antioxidant.

The dispersible powder and particle being suspended also by adding water to make suitable for preparing water provide active component and are used for The dispersant or wetting agent of mixing, suspending agent or one or more preservatives.Suitable dispersant or wetting agent and suspending agent can Illustrate above-mentioned example.Also other excipient such as sweetener, flavouring and colouring agent can be added.By adding antioxidant example As ascorbic acid preserves these compositions.

The pharmaceutical composition of the present invention can also be the form of oil in water emulsion.Oil phase can be vegetable oil or mineral oil or Its mixture.Suitable emulsifying agent can be the condensation product of naturally-produced phosphatide, partial ester and the partial ester and oxirane. Emulsion can also contain sweetener, flavouring, preservative and antioxidant.Such preparation can also contain moderator, preservative, coloring Agent and antioxidant.

Pharmaceutical composition can be sterile injectable aqueous form.The acceptable solvent or solvent that can be used have water, Ringer's solution and isotonic sodium chlorrde solution.Aseptic injection preparation can be the aseptic injection water bag that wherein active component is dissolved in oil phase Oil microemulsion.Parenteral solution or micro emulsion can be injected in the blood flow of patient by local a large amount of injections.Or, preferably by can keep this The mode of invention compound constant circulating concentration gives solution and micro emulsion.To keep this constant density, continuous vein can be used Interior drug delivery systems.The example of this device is DeltecCADD-PLUS.TM.5400 type Iv pumps.

Pharmaceutical composition can be aseptic injection water or the form of oil suspension for intramuscular and subcutaneous administration.Can be by Know technology, the suspension is prepared with the suitable dispersant of those described above or wetting agent and suspending agent.Aseptic injection preparation can also It is the aseptic injectable solution or suspension prepared in the acceptable non-toxic diluent of parenteral or solvent.In addition, it is convenient to Solvent or suspension media are used as with sterile fixed oil.For this purpose, can be used any including synthetic glycerine list or diester Mediation fixing oil.In addition, aliphatic acid can also prepare injection.

The compounds of this invention can be given by the suppository form for rectally.Can be by by medicine and at normal temperatures For solid but be liquid in the rectum, thus the suitable nonirritant excipient mixing of medicine can be dissolved and discharged in the rectum To prepare these pharmaceutical compositions.

As it is well known to the skilled in the art, the dosage of medicine depends on many factors, including it is but and non-limiting In following factor：The activity of particular compound used, the age of patient, the body weight of patient, the health status of patient, the row of patient Quilt, the diet of patient, administration time, administering mode, speed, the combination of medicine of excretion etc.；In addition, optimal therapeutic modality is such as The species of the pattern for the treatment of, the consumption per day of general formula compound (I) or pharmaceutically useful salt can be tested according to traditional therapeutic scheme Card.

Detailed description of the invention

Unless stated to the contrary, the term used in the specification and in the claims has following implications.

Term " alkyl " refers to saturated aliphatic hydrocarbons group, and it is the straight or branched group for including 1 to 20 carbon atom, excellent Select the alkyl containing 1 to 12 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting examples include methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- diformazans Base propyl group, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls third Base, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethyl butyrates Base, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methyl oneself Base, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl Amyl group, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethyl oneself Base, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- Ethylhexyl, 4- ethylhexyls, 2- methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethyls Hexyl, 2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and Its various branched chain isomer etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example includes first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- Dimethyl propyl, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- ethyl -2- first Base propyl group, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- diformazans Base butyl, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be with It is substitution or non-substituted, when substituted, substituent can be substituted on any workable tie point, the substitution Base is preferably one or more following groups, its independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, Halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkanes Sulfenyl, heterocycle alkylthio group, oxo base, carboxyl or carboxylic acid ester groups.

Term " alkylidene " refers to that a hydrogen atom of alkyl is further substituted, for example：" methylene " refers to-CH₂-, it is " sub- Ethyl " refers to-(CH₂)₂-, " propylidene " refer to-(CH₂)₃-, " butylidene " refer to-(CH₂)₄- etc..

Term " alkenyl " refers to the alkane as defined above by being at least made up of two carbon atoms and at least one carbon-to-carbon double bond Base, such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl.Alkenyl can be substitution or non-substituted, When substituted, substituent is preferably one or more following groups, its independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkanes oxygen Base, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.

Term " alkynyl ", which refers to the alkynes that do not include containing C ≡ C in molecule, turns into alkynes, and row are such as：Acetylene, propine, 1- butine, 2- Butine, 3- methyl isophthalic acids-butine or valerylene etc..Alkynyl can be substitution or non-substituted, and when substituted, substituent is preferred For one or more following groups, its independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, Sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, Heterocycle alkylthio group.

Term " cycloalkyl " refers to saturation or part is unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprise 3 to 12 carbon atoms, more preferably comprising 3 to 6 carbon atoms.Monocyclic cycloalkyl it is non-limiting Example includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl Trialkenyl, cyclooctyl etc.；Polycyclic naphthene base includes the cycloalkyl of loop coil, condensed ring and bridged ring.

Term " spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (title spiro-atom) is shared between 5 to 20 yuan monocyclic, It can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more Preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into by single spiro cycloalkyl group, double spirocyclanes according to the number of shared spiro-atom between ring and ring Base or many spiro cycloalkyl groups, are preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 Member/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting examples of spiro cycloalkyl group include：

Term " cycloalkyl " refers to each ring in 5 to 20 yuan, system and shared a pair adjoined of other rings in system The full carbon polycyclic moiety of carbon atom, wherein one or more rings can contain one or more double bonds, but neither one ring has The pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into according to the number of composition ring double Ring, three rings, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl. The non-limiting examples of cycloalkyl include：

Term " bridge ring alkyl " refers to 5 to 20 yuan, and the full carbon that any two ring shares two carbon atoms being not directly connected is more Cyclic group, it can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to the number of composition ring, it is excellent Elect bicyclic, three rings or Fourth Ring as, more elect bicyclic or three rings as.The non-limiting examples of bridge ring alkyl include：

The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure Ring together is cycloalkyl, and non-limiting examples include indenyl, tetralyl, benzocyclohepta alkyl etc..Cycloalkyl can be appointed Selection generation or non-substituted, when substituted, substituent is preferably one or more following groups, and it is independently selected from alkane Base, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, Aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl or carboxylic acid ester groups.

Term " heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 rings Atom, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), but do not wrap - O-O- ,-O-S- or-S-S- loop section are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 It is hetero atom；3 to 8 annular atoms are most preferably comprised, wherein 1~3 is hetero atom；5 to 6 annular atoms are most preferably comprised, its In 1~2 or 1~3 be hetero atom.The non-limiting examples of monocyclic heterocycles base include pyrrolidinyl, imidazolidinyl, tetrahydrofuran Base, tetrahydro-thienyl, glyoxalidine base, dihydrofuran base, pyrazoline base, pyrrolin base, piperidyl, piperazinyl, morpholine Base, thio-morpholinyl, homopiperazine base, pyranose, azetidinyl etc., preferably 1,2,5- oxadiazolyls, pyranose, piperidines Base, azetidinyl, pyrrolidinyl or morpholinyl.Multiring heterocyclic includes the heterocyclic radical of loop coil, condensed ring and bridged ring.

Term " spiro heterocyclic radical " refers to the multiring heterocyclic that an atom (title spiro-atom) is shared between 5 to 20 yuan monocyclic Group, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom For carbon.It can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 Member, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiro heterocyclic radical by the number according to spiro-atom is shared between ring and ring, double Spiro heterocyclic radical or many spiro heterocyclic radicals, are preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 Member/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting examples of spiro heterocyclic radical include：

Term " condensed hetero ring base " refers to each ring in 5 to 20 yuan, system and shared a pair adjoined of other rings in system The polycyclic heterocyclic group of atom, one or more rings can contain one or more double bonds, but neither one ring is with completely common The pi-electron system of yoke, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe miscellaneous original of (wherein m is integer 0 to 2) Son, remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to composition ring number can be divided into it is bicyclic, Three rings, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero rings Base.The non-limiting examples of condensed hetero ring base include：

Term " bridge heterocyclic radical " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocycle of two atoms being not directly connected Group, it can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, one of them or Multiple annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is carbon.Preferably 6 To 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge heterocyclic radical can be divided into according to the number of composition ring, Preferably bicyclic, three rings or Fourth Ring, more elect bicyclic or three rings as.The non-limiting examples of bridge heterocyclic radical include：

The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure The ring risen is heterocyclic radical, and its non-limiting examples includes：

Deng.

Heterocyclic radical can be it is optionally substituted or non-substituted, when substituted, substituent be preferably it is one or more with Lower group, its independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, carboxyl or carboxylic acid ester groups.

Term " aryl ", which refers to, has 6 to 14 yuan of full carbon of the pi-electron system being conjugated monocyclic or fused polycycle (is namely shared The ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, such as phenyl and naphthyl.More preferably phenyl.The aryl rings can be with Condense on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is aryl rings, its is unrestricted Property example includes：

Aryl can be substitution or non-substituted, and when substituted, substituent is preferably one or more following groups, It is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid Ester group.

Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom is selected From oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan, containing 1 to 3 hetero atom；More preferably 5 yuan or 6 yuan, containing 1 to 2 miscellaneous original Son；It is preferred that such as imidazole radicals, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridine radicals, phonetic Piperidinyl, thiadiazoles, pyrazinyl etc., preferably imidazole radicals, thiazolyl, pyrazolyl or pyrimidine radicals, thiazolyl；More select pyrazolyl or Thiazolyl.The heteroaryl ring can be condensed on aryl, heterocyclic radical or cycloalkyl ring, wherein being linked together with precursor structure Ring be heteroaryl ring, its non-limiting examples includes：

Heteroaryl can be it is optionally substituted or non-substituted, when substituted, substituent be preferably it is one or more with Lower group, its independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl Or carboxylic acid ester groups.

Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted cycloalkyl), wherein alkyl, cycloalkyl definition such as It is upper described.The non-limiting examples of alkoxy include：Methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, ring fourth oxygen Base, cyclopentyloxy, cyclohexyloxy.Alkoxy can be optionally substituted or non-substituted, and when substituted, substituent is preferably One or more following groups, it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercapto It is base, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, miscellaneous Cycloalkylthio, carboxyl or carboxylic acid ester groups.

Term " haloalkyl " refers to the alkyl replaced by one or more halogens, wherein alkyl as defined above.

Term " halogenated alkoxy " refers to the alkoxy replaced by one or more halogens, wherein alkoxy as defined above.

Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, wherein alkyl as defined above.

Term " hydroxyl " refers to-OH groups.

Term " halogen " refers to fluorine, chlorine, bromine or iodine.

Term " amino " refers to-NH₂。

Term " cyano group " refers to-CN.

Term " nitro " refers to-NO₂。

Term " oxo base " refers to=O.

Term " carbonyl " refers to C=O.

Term " carboxyl " refers to-C (O) OH.

Term " isocyanate group " refers to-NCO.

Term " oximido " refers to=N-OH.

Term " sulfydryl " refers to-SH.

Term " alkenyl " refers to the alkyl of few one or several hydrogen atoms in olefin hydrocarbon molecules.

Term " alkynyl " refers to the hydrocarbon containing triple carbon-carbon bonds in molecule.

Term " carboxylic acid ester groups " refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), and wherein alkyl, cycloalkyl is as above determined Justice.

Term " carboxylic acid halides " refers to the compound of the group containing-C (O)-halogen.

" optional " or " optionally " mean event described later or environment can with but need not occur, the explanation includes The occasion that the event or environment occur or do not occurred.For example, " optionally by alkyl-substituted heterocyclic group " means that alkyl can be with But necessarily exist, the explanation includes heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.

" substituted " refers to one or more of group hydrogen atom, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent of respective number.Self-evident, substituent is only in their possible chemical position, this Art personnel can determine that (by experiment or theoretical) may or impossible take in the case where not paying excessive make great efforts Generation.For example, amino or hydroxyl with free hydrogen are probably unstable when being combined with the carbon atom with unsaturated (such as olefinic) key Fixed.

" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or Pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine The purpose of compositions is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.

" officinal salt " refers to the salt of the compounds of this invention, and this kind of salt has security and had when being used in mammal body Effect property, and with due bioactivity.

" X is selected from A, B or C ", " X is selected from A, B and C ", " X is A, B or C ", " X is the difference use such as A, B and C " in the present invention Language expresses identical meaning, that is, it can be any one or a few in A, B, C to represent X.

The synthetic method of the compounds of this invention

In order to complete the purpose of the present invention, the present invention is adopted the following technical scheme that：

Scheme one

Compound or its dynamic isomer, mesomer, racemic modification, enantiomter shown in the logical formula (I) of the present invention, Diastereoisomer or its form of mixtures, or its pharmaceutically useful salt preparation method, comprise the following steps：

Under heating acid condition, formula (A) compound, which is oxidized, obtains logical formula (III) compound；Obtained formula (III) compound obtains logical formula (I) compound under room temperature alkalescence condition with the reaction of logical formula (VI)；Or obtained formula (III) compound obtains logical formula (V) compound under room temperature alkalescence condition with the reaction of logical formula (VI)；Obtained logical formula (V) chemical combination Open loop obtains logical formula (I) compound to thing in the basic conditions.

There is provided the reagent of alkalescence condition includes organic base and inorganic base, and described organic bases include but is not limited to three second Amine, DIPEA, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, it is described Inorganic base includes but is not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.The reagent for providing alkalescence condition is excellent Elect sodium hydroxide as.

Oxidant used includes but is not limited to：Selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide, preferably 30% Hydrogen peroxide solution.

The reagent for providing acid condition includes but is not limited to trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, excellent Select trifluoroacetic acid.

Wherein：

Ring A, ring B, R¹、R², x and n define as described in logical formula (I).

Scheme two

Compound or its dynamic isomer, mesomer, racemic modification, enantiomerism shown in the logical formula (II) of the present invention Body, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt preparation method, comprise the following steps：

Under heating acid condition, formula (A) compound, which is oxidized, obtains logical formula (III) compound；Obtained formula (III) compound obtains formula (II-B) compound under room temperature alkalescence condition with formula (II-A) reaction；Obtained formula (II-B) open loop obtains logical formula (II) compound to compound in the basic conditions.

There is provided the reagent of alkalescence condition includes organic base and inorganic base, and described organic bases include but is not limited to three second Amine, DIPEA, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, it is described Inorganic base includes but is not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.The reagent for providing alkalescence condition is excellent Elect sodium hydroxide as.

Oxidant used includes but is not limited to：Selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide, preferably 30% Hydrogen peroxide solution.

The reagent for providing acid condition includes but is not limited to trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, excellent Select trifluoroacetic acid.

Wherein：

Ring B, G, R¹、R², y, z, x and n lead to formula (II) described in define.

Embodiment

The present invention is further described with reference to embodiments, but these embodiments not limit the scope of the present invention.

Embodiment

The structure of compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).NMR displacements (δ) are with 10-⁶ (ppm) unit is provided.NMR measure is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated dimethyl sulfoxide (DMSO-d₆), deuterochloroform (CDCl₃), deuterated methanol (CD₃), OD inside it is designated as tetramethylsilane (TMS).

MS measure is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer:Thermo, model：Finnigan LCQ advantage MAX)。

HPLC measure uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire C18150 × 4.6mm chromatograms Post) and Waters 2695-2996 high pressure liquid chromatographs (Gimini C18150 × 4.6mm chromatographic columns).

Chiral HPLC is determined using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.)；

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and thin-layered chromatography (TLC) makes The specification that silica gel plate is used is 0.15mm~0.2mm, the specification that thin-layer chromatography isolates and purifies product use be 0.4mm~ 0.5mm。

Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.

Chiral preparatory column chromatography uses Prep Star SD-1 (Varian Instruments Inc.) or SFC- multigram(Berger Instruments Inc.)

Kinases average inhibition and IC₅₀The measure of value is with NovoStar ELIASAs (German BMG companies).

The known initiation material of the present invention can be used or synthesized according to methods known in the art, or can purchase certainly ABCR GmbH＆Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemical science and technology (Accela ChemBio Inc), up to companies such as auspicious chemicals.

Without specified otherwise in embodiment, reaction can be carried out under argon atmospher or blanket of nitrogen.

Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.

Pressure hydration reaction uses Parr 3916EKX types hydrogenation instrument and clear indigo plant QL-500 types hydrogen generator or HC2-SS Type hydrogenates instrument.

Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.

Microwave reaction uses the type microwave reactors of CEM Discover-S 908860.

Without specified otherwise in embodiment, solution refers to the aqueous solution.

Without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C~30 DEG C.

The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), the system of solvent used in reaction Have：A：Dichloromethane and methanol system, B：N-hexane and ethyl acetate system, C：Petroleum ether and ethyl acetate system, D：Acetone, The volume ratio of solvent is adjusted according to the polarity difference of compound.

The system of eluant, eluent and the solvent system of thin-layered chromatography for the column chromatography that purifying compound is used include：A：Two Chloromethanes and methanol system, B：N-hexane and ethyl acetate system, C：Dichloromethane and acetone system, the volume ratio of solvent according to The polarity of compound is different and is adjusted, and can also add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent is adjusted Section.

Embodiment 1,2

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1s, 3s) -3- (sulphamoylamino) cyclobutane) is thio) -1, 2,5- oxadiazole -3- carbonamidines 1

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1r, 3r) -3- (sulphamoylamino) cyclobutane) is thio) -1, 2,5- oxadiazole -3- carbonamidines 2

The first step

3- ((tertbutyloxycarbonyl) amino) cyclobutylmethyl sulphonic acid ester 1b

By (3- hydroxycyclobutanes) t-butyl carbamate 1a (1.2g, 6.94mmol, using patent application Method disclosed in " WO2013107405 " is prepared) it is dissolved in 5mL dichloromethane, 0 DEG C is cooled to, methylsufonyl chloride is added dropwise to (953mg, 8.32mmol), is warmed to room temperature stirring reaction 30 minutes.Reaction solution is poured into 30mL frozen water, extracted with dichloromethane (30mL), organic phase uses saturated sodium bicarbonate solution (30mL), saturated nacl aqueous solution (30mL) washing, anhydrous sodium sulfate successively Dry, filtering, filtrate decompression is concentrated to give crude title product 1b (1.84g), the not purified directly progress next step of product is anti- Should.

Second step

S- (3- ((tertbutyloxycarbonyl) amino) cyclobutyl) thioacetic acid 1c

Crude product 1b (1.84g, 6.93mmol) is dissolved in 30mL DMFs, thioacetic acid potassium is added (1.58g, 13.9mmol), is warming up to 70 DEG C of stirring reactions 12 hours.Reaction solution is cooled to room temperature, pours into 50mL water, uses second Acetoacetic ester extracts (50mL × 2), merges organic phase, is washed with saturated nacl aqueous solution (50mL × 2), anhydrous sodium sulfate drying, Filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 1c (1.4g), yield：82.3%.

3rd step

(3- sulfydryls cyclobutane) t-butyl carbamate 1d

1c (1.3g, 2.3mmol) is dissolved in 20mL methanol, be cooled to after 0 DEG C add potassium carbonate (1.09g, 7.9mmol), stirring reaction 20 minutes.50mL dichloromethane is added into reaction solution, (50mL is washed with saturated nacl aqueous solution × 2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title product 1d (1.07g), product is not purified Directly carry out next step reaction.

4th step

4- (the bromo- 4- fluorophenyls of 3-) -3- (4- nitro -1,2,5- oxadiazole -3- bases) -1,2,4- oxadiazoles -5 (4H) -one 1f

By 3- (4- amino -1,2,5- oxadiazole -3- bases) -4- (the bromo- 4- fluorophenyls of 3-) -1,2,4- oxadiazoles -5 (4H) - Ketone 1e

(13.0g, 41.1mmol are prepared using method disclosed in patent application " WO2014066834 ") adds In 150mL trifluoroacetic acids, 90mL hydrogen peroxide solutions (30%) are added, are reacted 48 hours in 45 DEG C.After reaction terminates, cooling, plus Enter 300mL saturated sodium thiosulfates solution and 150mL ethyl acetate, stirring reaction 20 minutes, with potassium iodide starch paper detection without mistake Oxide.Divide liquid, aqueous phase is extracted with ethyl acetate (100mL × 2), merge organic phase, with anhydrous sodium sulfate drying, filter, filter Liquid is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1f (4.5g), produce Rate 30%.

5th step

(3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Evil Diazole -3- bases) thio) cyclobutane) t-butyl carbamate 1g

1f (1.76g, 4.74mmol) is dissolved in 20mL tetrahydrofurans, crude product 1d (1.07g, 5.26mmol) and carbon is added Sour potassium (1.45g, 1.05mmol), stirring reaction 1 hour.Reaction solution is poured into 50mL water, be extracted with ethyl acetate (30mL × 2), merge organic phase, washed with saturated nacl aqueous solution (30mL × 2), anhydrous sodium sulfate drying, filtered, filtrate decompression concentration Gained residue n-hexane and ethyl acetate (V:V=1:1) mixed solvent mashing obtains crude title product 1g (2g), produces Product are not purified directly to carry out next step reaction.

6th step

3- (4- ((3- amino cyclobutane) is thio) -1,2,5- oxadiazole -3- bases) -4- (the bromo- 4- fluorophenyls of 3-) -1,2,4- (4H) -one of oxadiazole -5 1h

Crude product 1g (1g, 1.89mmol) is dissolved in 10mL dichloromethane, 4mL trifluoroacetic acids are added, stirring reaction 1 is small When.Reaction solution is concentrated under reduced pressure, and obtains crude title product 1h (700mg), and product is not purified directly to carry out next step reaction.

7th step

N- (3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Oxadiazole -3- bases) thio) cyclobutane base) sulphamoylamino t-butyl formate 1j

Crude product 1h (700mg, 1.64mmol) is dissolved in 50mL dichloromethane, triethylamine is added after being cooled to 0 DEG C (469mg, 4.92mmol), stirring reaction added after 10 minutes chlorosulfonyl t-butyl carbamate 1i (526mg, 2.45mmol, It is prepared using method disclosed in patent application " US2015133674 "), it is warmed to room temperature stirring reaction 1 hour.By reaction solution Pour into 30mL water.Extracted with dichloromethane (30mL × 2), merge organic phase, successively with saturated sodium bicarbonate solution (30mL), Saturated nacl aqueous solution (30mL) is washed, anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to give crude title product 1j (900mg), product is not purified directly to carry out next step reaction.

8th step

N- [3- ({ 4- [4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases] -1,2,5- Oxadiazole -3- bases } sulfenyl) cyclobutane] sulfamide 1k

Crude product 1j (900mg, 1.48mmol) is dissolved in 10mL dichloromethane, 4mL trifluoroacetic acids, stirring reaction 1 is added Hour.Reaction solution obtains crude title product 1k (700mg) after being concentrated under reduced pressure, the not purified directly progress next step of product is anti- Should.

9th step

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1s, 3s) -3- (sulphamoylamino) cyclobutane) is thio) -1, 2,5- oxadiazole -3- carbonamidines 1

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1r, 3r) -3- (sulphamoylamino) cyclobutane) is thio) -1, 2,5- oxadiazole -3- carbonamidines 2

Crude product 1k (400mg, 0.79mmol) is dissolved in 10mL tetrahydrofurans, 2.5M sodium hydroxide solutions are added 0.63mL, stirring reaction 1 hour.Reaction solution is poured into 30mL water, is extracted with ethyl acetate (30mL × 2), merges organic phase, Washed (40mL × 2), anhydrous sodium sulfate drying, filtered with saturated ammonium chloride solution, high performance liquid chromatography is used in filtrate decompression concentration Method purifying gained residue, obtains title product 1 (40mg) and title product 2 (100mg), yield：36.9%.

Embodiment 1:

MS m/z(ESI):481.2[M+1]

¹HNMR(400MHz,DMSO-d₆)δ11.71(s,1H),8.96(s,1H),7.15-7.20(m,1H),7.05-7.07 (m,2H),6.68-6.70(m,1H),6.56(s,2H),3.79-3.83(m,1H),3.70-3.76(m,1H),2.85-2.87 (m,2H),2.06-2.11(m,2H).

Embodiment 2：

MS m/z(ESI):481.2[M+1]

¹HNMR(400MHz,DMSO-d₆)δ11.72(s,1H),8.97(s,1H),7.15-7.20(m,1H),7.06-7.10 (m,2H),6.71-6.73(m,1H),6.56(s,2H),3.99-4.06(m,2H),2.58-2.64(m,2H),2.32-2.36 (m,2H).

Embodiment 3,4

4- (((1r, 3r) -3- amino cyclobutane) is thio)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -1,2,5- Evil bis- Azoles -3- carbonamidines 3

4- (((1s, 3s) -3- amino cyclobutane) is thio)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -1,2,5- Evil bis- Azoles -3- carbonamidines 4

Crude product 1h (200mg, 0.47mmol) is dissolved in 10mL tetrahydrofurans, 2.5M sodium hydroxide solutions are added 0.38mL, stirring reaction 1 hour.Reaction solution is poured into 30mL water, is extracted with ethyl acetate (30mL × 2), merges organic phase, Washed (30mL × 2), anhydrous sodium sulfate drying, filtered with saturated ammonium chloride solution, high performance liquid chromatography is used in filtrate decompression concentration Method purifying gained residue, obtains title product 3 (30mg) and title product 4 (30mg), yield：32.1%.

Embodiment 3：

MS m/z(ESI):402.2[M+1]

¹HNMR(400MHz,DMSO-d₆)δ8.96(s,1H),7.15-7.20(m,1H),7.04-7.06(m,1H),6.67- 6.70(m,1H),3.65-3.69(m,1H),3.26-3.28(m,1H),2.73-2.75(m,2H),1.73-1.80(m,2H).

Embodiment 4：

MS m/z(ESI):402.1[M+1]

¹HNMR(400MHz,DMSO-d₆)δ8.98(s,1H),7.16-7.21(m,1H),7.05-7.08(m,1H),6.69- 6.73(m,1H),4.00-4.04(m,1H),3.59-3.63(m,1H),2.20-2.28(m,4H).

Embodiment 5,6

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1s, 3s) -3- (sulfonyloxy methyl amido) cyclobutane) is thio) -1, 2,5- oxadiazole -3- carbonamidines 5

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1r, 3r) -3- (sulfonyloxy methyl amido) cyclobutane) is thio) -1, 2,5- oxadiazole -3- carbonamidines 6

The first step

N- (3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Oxadiazole -3- bases) thio) cyclobutane) methylsulfonamides 5a

Crude product 1h (200mg, 0.47mmol) is dissolved in 30mL dichloromethane, 0 DEG C is cooled to, add triethylamine (95mg, 0.94mmol), then methylsufonyl chloride (64mg, 0.56mmol) is added dropwise to, is warmed to room temperature stirring reaction 1 hour.Reaction solution is fallen Enter in 30mL water, extracted with dichloromethane (30mL), organic phase uses saturated sodium bicarbonate solution (30mL), saturated sodium-chloride successively Solution (30mL) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, is obtained crude title product 5a (200mg), is produced Product are not purified directly to carry out next step reaction.

Second step

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1s, 3s) -3- (sulfonyloxy methyl amido) cyclobutane) is thio) -1, 2,5- oxadiazole -3- carbonamidines 5

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1r, 3r) -3- (sulfonyloxy methyl amido) cyclobutane) is thio) -1, 2,5- oxadiazole -3- carbonamidines 6

Crude product 2a (200mg, 0.4mmol) is dissolved in 10mL tetrahydrofurans, 2.5M sodium hydroxide solution 0.32mL are added, Stirring reaction 1 hour.Reaction solution is poured into 30mL water, is extracted with ethyl acetate (30mL × 2), merges organic phase, uses saturation Ammonium chloride solution washs (30mL × 2), anhydrous sodium sulfate drying, filtering, pure with high performance liquid chromatography after filtrate decompression concentration Change gained residue, obtain title product 5 (30mg) and title product 6 (30mg), yield：31.7%.

Embodiment 5：

MS m/z(ESI):480.1[M+1]

¹HNMR(400MHz,DMSO-d₆)δ8.98(s,1H),7.15-7.20(m,1H),7.07-7.09(m,1H),6.73- 6.75(m,1H),4.02-4.08(s,2H),2.87(s,3H),2.58-2.61(m,2H),2.36-2.40(m,2H).

Embodiment 6：

MS m/z(ESI):480.1[M+1]

¹HNMR(400MHz,DMSO-d₆)δ11.72(s,1H),8.97(s,1H),7.56-7.58(m,1H),7.16-7.20 (m,1H),7.06-7.08(m,1H),6.70-6.72(m,1H),3.79-3.84(m,2H),2.85-2.91(m,5H),2.03- 2.11(m,2H).

Embodiment 7

N- (3- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) is thio) rings Butane) acetamide 7

The first step

N- (3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Oxadiazole -3- bases) thio) cyclobutane) acetamide 7a

Crude product 1h (200mg, 0.47mmol) is dissolved in 20mL dichloromethane, 0 DEG C is cooled to, add triethylamine (71mg, 0.71mmol), then acetic anhydride (48mg, 0.47mmol) is added dropwise to, is warmed to room temperature stirring reaction, LC-MS detection reactions terminate.Will Reaction solution is poured into 30mL water, is extracted with dichloromethane (30mL), and organic phase uses saturated sodium bicarbonate solution (30mL) successively, is satisfied With sodium chloride solution (30mL) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title product 7a (200mg), product is not purified directly to carry out next step reaction.

Second step

N- (3- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) is thio) rings Butane) acetamide 7

Crude product 7a (200mg, 0.45mmol) is dissolved in 10mL tetrahydrofurans, 2.5M sodium hydroxide solutions are added 0.45mL, stirring reaction 1 hour.Reaction solution is poured into 50mL saturated ammonium chloride solutions, be extracted with ethyl acetate (50mL × 2), merge organic phase, washed with saturated nacl aqueous solution (50mL × 2), anhydrous sodium sulfate drying, filtered, filtrate decompression concentration, With thin-layered chromatography with solvent system A purify gained residue, obtain title product 7 (30mg), yield：15.9%.

MS m/z(ESI):444.2[M+1]

Embodiment 8

4- ((1- acetyl group azetidine -3- bases) is thio)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -1,2,5- Evil Diazole -3- carbonamidines 8

The first step

3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Evil Diazole -3- bases) thio) azetidine -1- t-butyl formates 8b

1f (1g, 2.7mmol) is dissolved in 30mL tetrahydrofurans, 3- mercapto nitrogen heterocyclic butane t-butyl formates 8a is added (1.02g, 5.4mmol are prepared using method disclosed in patent application " WO201084767 ") and potassium carbonate (745mg, 5.4mmol), stirring reaction 12 hours.Reaction solution is poured into 50mL water, is extracted with ethyl acetate (30mL × 2), is merged organic Phase, is washed (30mL × 2), anhydrous sodium sulfate drying with saturated nacl aqueous solution, filtering, filtrate decompression concentration, uses silicagel column color Spectrometry purifies gained residue with eluant, eluent system B, is beaten with ether, obtains title product 8b (850mg), yield：61.6%.

Second step

3- (4- (azetidine -3- bases are thio) -1,2,5- oxadiazole -3- bases) -4- (the bromo- 4- fluorophenyls of 3-) -1,2, (4H) -one of 4- oxadiazoles -5 8c

8b (750mg, 1.46mmol) is dissolved in 10mL dichloromethane, 2mL trifluoroacetic acids, stirring reaction 1 hour is added. Reaction solution is concentrated under reduced pressure, and obtains crude title product 8c (604mg), and product is not purified directly to carry out next step reaction.

3rd step

3- (4- ((1- acetyl group azetidine -3- bases) is thio) -1,2,5- oxadiazole -3- bases) -4- (bromo- 4- fluorine of 3- Phenyl) (4H) -one of -1,2,4- oxadiazoles -5 8d

Crude product 8c (100mg, 0.24mmol) is dissolved in 100mL dichloromethane, 0 DEG C is cooled to, triethylamine is added (48mg, 0.48mmol), then acetic anhydride (29mg, 0.29mmol) is added dropwise to, it is warmed to room temperature stirring reaction 12 hours.By reaction solution Pour into saturated sodium bicarbonate solution, extracted with dichloromethane (30mL), organic phase washs (30mL) with saturated ammonium chloride solution, Anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title product 8d (80mg), product is not purified directly to be entered Row next step is reacted.

4th step

4- ((1- acetyl group azetidine -3- bases) is thio)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -1,2,5- Evil Diazole -3- carbonamidines 8

Crude product 8d (80mg, 0.18mmol) is dissolved in 10mL tetrahydrofurans, 2.5M sodium hydroxide solution 0.14mL are added, Stirring reaction 12 hours.Reaction solution is poured into 30mL saturated ammonium chloride solutions, is extracted with ethyl acetate (30mL × 2), is merged Organic phase, is washed (30mL × 2), anhydrous sodium sulfate drying with saturated nacl aqueous solution, filtering, filtrate decompression concentration, uses silica gel Column chromatography purifies gained residue with eluant, eluent system A, obtains title product 8 (10mg), yield：13.3%.

MS m/z(ESI):430.2[M+1]

¹H NMR(400MHz,DMSO-d₆)δ11.80(s,1H),8.98(s,1H),7.11-7.20(m,2H),6.75- 6.78(m,1H),4.64-4.66(m,1H),4.30-4.38(m,2H),4.06-4.09(m,1H),3.77-3.80(m,1H), 1.77(s,3H).

Embodiment 9

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- amino-sulfonyl azetidine -3- bases) is thio) -1,2, 5- oxadiazole -3- carbonamidines 9

The first step

(3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Evil Diazole -3- bases) thio) azetidine -1- bases) sulfonylcarbamic acid tert-butyl ester 9a

Crude product 8c (400mg, 0.97mmol) is dissolved in 30mL dichloromethane, triethylamine is added after being cooled to 0 DEG C (294mg, 2.91mmol), then 1i (415mg, 1.93mmol) is added dropwise to, it is warmed to room temperature stirring reaction 1 hour.Reaction solution is fallen Enter in 50mL saturated sodium bicarbonate solutions, extracted with dichloromethane (30mL × 2), merge organic phase, use saturated nacl aqueous solution (30mL × 2) are washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain crude title product 9a (400mg), product It is not purified directly to carry out next step reaction.

Second step

3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Evil Diazole -3- bases) thio) azetidine -1- sulfonamide 9b

Crude product 9a (400mg, 0.67mmol) is dissolved in 10mL dichloromethane, 2mL trifluoroacetic acids, stirring reaction 1 is added Hour.Reaction solution is concentrated under reduced pressure, crude title product 9b (400mg) is obtained, the not purified directly progress next step of product is anti- Should.

3rd step

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- amino-sulfonyl azetidine -3- bases) is thio) -1,2, 5- oxadiazole -3- carbonamidines 9

Crude product 9b (400mg, 0.81mmol) is dissolved in 20mL tetrahydrofurans, 2.5M sodium hydroxide solutions are added 0.65mL, stirring reaction 12 hours.Reaction solution is poured into 100mL saturated ammonium chloride solutions, be extracted with ethyl acetate (50mL × 2), merge organic phase, washed with saturated nacl aqueous solution (50mL × 2), anhydrous sodium sulfate drying, filtered, filtrate decompression concentration, With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 9 (200mg), yield：52.9%.

MS m/z(ESI):467.1[M+1]

¹HNMR(400MHz,DMSO-d₆)δ11.81(s,1H),8.98(s,1H),7.11-7.20(m,4H),6.74-6.77 (m,1H),4.33-4.37(m,1H),4.19-4.24(m,2H),3.72-3.76(m,2H).

Embodiment 10

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- (mesyl) azetidine -3- bases) is thio) -1,2, 5- oxadiazole -3- carbonamidines 10

The first step

4- (the bromo- 4- fluorophenyls of 3-) -3- (4- ((1- (mesyl) azetidine -3- bases) is thio) -1,2,5- Evil bis- Azoles -3- bases) (4H) -one of -1,2,4- oxadiazoles -5 10a

Crude product 8c (100mg, 0.24mmol) is dissolved in 10mL dichloromethane, triethylamine is added after being cooled to 0 DEG C (48mg, 0.48mmol), then it is added dropwise to mesyl chloride (33mg, 0.29mmol), stirring reaction 1 hour.Reaction solution is poured into In 30mL saturated sodium bicarbonate solutions, extracted with dichloromethane (30mL), organic phase saturated ammonium chloride solution (30mL), saturation Sodium chloride solution (30mL) is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 10a (100mg), product is not purified directly to carry out next step reaction.

Second step

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- (mesyl) azetidine -3- bases) is thio) -1,2, 5- oxadiazole -3- carbonamidines 10

Crude product 10a (100mg, 0.2mmol) is dissolved in 10mL tetrahydrofurans, 2.5M sodium hydroxide solutions are added 0.16mL, stirring reaction 1 hour.Reaction solution is poured into 30mL saturated ammonium chloride solutions, be extracted with ethyl acetate (30mL × 2), merge organic phase, washed with saturated nacl aqueous solution (30mL × 2), anhydrous sodium sulfate drying, filtered, filtrate decompression concentration, With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 10 (40mg), yield：42%.

MS m/z(ESI):466.2[M+1]

¹H NMR(400MHz,DMSO-d₆)δ11.81(s,1H),8.98(s,1H),7.13-7.18(m,2H),6.75- 6.77(m,1H),4.39-4.42(m,3H),3.91-3.92(m,2H),3.08(s,3H).

Embodiment 11

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- sulfamoyls piperidin-4-yl) is thio) -1,2,5- oxadiazoles - 3- carbonamidines 11

The first step

4- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Evil Diazole -3- bases) thio) piperidines -1- t-butyl formates 11b

1f (1.54g, 4.2mmol) is dissolved in 20mL tetrahydrofurans, 4- sulfhydryl piperidine -1- t-butyl formates 11a is added (1.8g, 8.3mmol are prepared using method disclosed in patent application " WO200730366 ") and potassium carbonate (1.15g, 8.3mmol), stirring reaction 1 hour.Reaction solution is poured into 50mL water, is extracted with ethyl acetate (30mL × 2), is merged organic Phase, is washed (30mL × 2), anhydrous sodium sulfate drying with saturated nacl aqueous solution, filtering, filtrate decompression concentration, gained residue It is beaten with ether, obtains crude title product 11b (2.1g), product is not purified directly carries out next step reaction.

Second step

4- (the bromo- 4- fluorophenyls of 3-) -3- (4- (piperidin-4-yl sulfenyl) -1,2,5- oxadiazole -3- bases) -1,2,4- Evil bis- (4H) -one of azoles -5 11c

Crude product 11b (542mg, 0.1mmol) is dissolved in 15mL dichloromethane, 5mL trifluoroacetic acids, stirring reaction 1 is added Hour.Reaction solution is concentrated under reduced pressure, and obtains crude title product 11c (450mg), and the not purified directly progress next step of product is anti- Should.

3rd step

(4- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Evil Diazole -3- bases) thio) piperidin-1-yl) sulfonylcarbamic acid tert-butyl ester 11d

Crude product 11c (450mg, 0.1mmol) is dissolved in 10mL dichloromethane, triethylamine is added after being cooled to 0 DEG C (202mg, 0.2mmol), then it is added dropwise to 1i (323.5mg, 0.15mmol), stirring reaction 1 hour.Reaction solution is poured into water. Extracted with dichloromethane (30mL × 2), merge organic phase, with water (30mL), saturated nacl aqueous solution (30mL × 2) washing, nothing Aqueous sodium persulfate is dried, filtering, filtrate decompression concentration, obtains crude title product 11d (600mg), product is not purified directly to be entered Row next step is reacted.

4th step

4- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2,5- Evil Diazole -3- bases) thio) piperidines -1- sulfonamide 11e

Crude product 11d (600mg, 0.97mmol) is dissolved in 15mL dichloromethane, 5mL trifluoroacetic acids, stirring reaction is added 30 minutes.Reaction solution is concentrated under reduced pressure, gained residue is dissolved in dichloromethane, saturated sodium carbonate solution is added dropwise under condition of ice bath It is 7 to pH, is extracted with dichloromethane (30mL × 2), merging organic phase, being washed with saturated nacl aqueous solution, anhydrous sodium sulfate is done It is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 11e (200mg), yield：39.8%.

5th step

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- sulfamoyls piperidin-4-yl) is thio) -1,2,5- oxadiazoles - 3- carbonamidines 11

11e (200mg, 0.38mmol) is dissolved in 10mL tetrahydrofurans, 2.5M sodium hydroxide solution 0.5mL is added, stirs Reaction is mixed, TLC detection reactions terminate.Aqueous phase is separated, it is neutrality that 1M hydrochloric acid, which is added dropwise, to PH, and (30mL × 2) are extracted with dichloromethane, Merge organic phase, washed with saturated nacl aqueous solution (30mL × 2), anhydrous sodium sulfate drying, filtered, used after filtrate decompression concentration Silica gel column chromatography purifies gained residue with eluant, eluent system A, obtains title product 11 (110mg), yield：58%.

MS m/z(ESI):495.2[M+1]

¹H NMR(400MHz,DMSO-d₆)δ11.74(s,1H),9.01(s,1H),7.16-7.21(t,1H),7.05- 7.08(dd,1H),6.83(s,2H),6.70-6.71(m,1H),3.78-3.69(m,1H),3.36-3.43(m,2H),2.79- 2.84(t,2H),2.18-2.21(m,2H),1.75-1.79(m,2H).

Embodiment 12

(R)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- aminosulfonyl phenylpiperidines -3- bases) is thio) -1,2,5- Oxadiazole -3- carbonamidines 12

The first step

(R) -3- sulfhydryl piperidines -1- t-butyl formates 12b

By (R) -3- (Acetylsulfanyl) piperidines -3- t-butyl formates 12a (1.7g, 6.56mmol, using patent application Method disclosed in " WO2012138678 " is prepared) be dissolved in 20mL methanol, be cooled to after 0 DEG C add potassium carbonate (1.36g, 9.84mmol), stirring reaction 10 minutes.5mL saturated ammonium chloride solutions are added into reaction solution reaction is quenched, extracted with dichloromethane (50mL) is taken, organic phase is washed with saturated nacl aqueous solution, silicagel column is used in anhydrous sodium sulfate drying, filtering, filtrate decompression concentration Chromatography purifies gained residue with eluant, eluent system B, obtains title product 12b (1.4g), yield：98%.

Second step

(S) -3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) piperidines -1- t-butyl formates 12c

By 12b (1.4g, 6.215mmol), 1f (1.68g, 4.52mmol) is dissolved in 20mL tetrahydrofurans, adds potassium carbonate (1.78g, 12.9mmol), stirring reaction 12 hours.Filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B Purifying gained residue, obtains title product 12c (800mg), yield：32.6%.

3rd step

(S) -4- (the bromo- 4- fluorophenyls of 3-) -3- (4- (piperidines -3- bases sulfenyl) -1,2,5- oxadiazole -3- bases) -1,2,4- (4H) -one of oxadiazole -5 12d

12c (800mg, 1.48mmol) is dissolved in 5mL Isosorbide-5-Nitraes-dioxane, 4M hydrochloric acid 10mL, stirring reaction 24 is added Hour.50mL ethyl acetate is added into reaction solution, it is neutrality that saturated sodium carbonate solution, which is added dropwise, to pH, separates organic phase, decompression Concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 12d (500mg), yield： 76.7%.

4th step

(R)-(3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) piperidin-1-yl) sulfonylcarbamic acid tert-butyl ester 12e

Crude product 12d (490mg, 1.11mmol) is dissolved in 10mL dichloromethane, addition triethylamine (224mg, 2.22mmol), then 1i (238mg, 1.11mmol) is added dropwise to, stirring reaction, TLC detection reactions terminate.Reaction solution is poured into water In, extracted with dichloromethane (30mL × 2), merge organic phase, successively with water (30mL), saturated nacl aqueous solution (30mL × 2) Washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained remnants Thing, obtains title product 12e (420mg), yield：60.9%.

5th step

(R) -3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) piperidines -1- sulfonamide 12f

12e (420mg, 0.676mmol) is dissolved in 5mL 4M hydrochloric acid/Isosorbide-5-Nitrae-dioxane solution, stirring reaction 12 is small When.Reaction solution obtains crude title product 12f (400mg, brown solid) after being concentrated under reduced pressure, under the not purified direct progress of product Single step reaction.

6th step

(R)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- aminosulfonyl phenylpiperidines -3- bases) is thio) -1,2,5- Oxadiazole -3- carbonamidines 12

Crude product 12f (400mg, 0.768mmol) is dissolved in 5mL tetrahydrofurans, 2M sodium hydroxide solution 5mL is added, stirs Mix reaction 2 hours.2mL water is added into reaction solution, is extracted with ethyl acetate (10mL × 2), merges organic phase, after being concentrated under reduced pressure With high performance liquid chromatography purify gained residue, obtain title product 12 (200mg), yield：52.6%.

MS m/z(ESI):495.0[M+1]

₁H NMR(400MHz,DMSO-d₆):δ11.80(s,1H),9.00(s,1H),7.18(t,1H),7.11-7.09(m, 1H),6.86(s,2H),6.73-6.69(m,1H),3.96(m,1H),3.52-3.49(m,1H),3.11-3.01(m,2H), 2.01(m,1H),1.86(m,1H),1.70(m,2H),1.24(m,1H).

Embodiment 13

(S)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- sulfamoyl piperidines -3- bases) is thio) -1,2,5- Evil Diazole -3- carbonamidines 13

The first step

(R) -3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) piperidines -1- t-butyl formates 13b

1f (171.2mg, 0.46mmol) is dissolved in 10mL tetrahydrofurans, (S) -3- sulfhydryl piperidine -1- carboxylic acid uncles are added Butyl ester 13a (200mg, 0.92mmol, using known method " Bioorganic and Medicinal Chemistry Letters, 2009,19 (10), 2742-2746 " is prepared) and potassium carbonate (95.22mg, 0.69mmol), stirring reaction 1 is small When.Reaction solution is poured into water, is extracted with ethyl acetate (30mL × 2), merges organic phase, is washed with saturated nacl aqueous solution, Anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title product 13b (360mg), and product is not purified directly Carry out next step reaction.

Second step

(R) -4- (the bromo- 4- fluorophenyls of 3-) -3- (4- (piperidines -3- bases are thio) -1,2,5- oxadiazole -3- bases) -1,2,4- (4H) -one of oxadiazole -5 13c

Crude product 13b (360mg, 0.7mmol) is dissolved in 15mL dichloromethane, 5mL trifluoroacetic acids, stirring reaction 30 is added Minute.Reaction solution is concentrated under reduced pressure, and obtains crude title product 13c (350mg), and the not purified directly progress next step of product is anti- Should.

3rd step

(S)-(3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) piperidin-1-yl) sulfonylcarbamic acid tert-butyl ester 13d

Crude product 13c (350mg, 0.79mmol) is dissolved in 5mL dichloromethane, addition triethylamine (160mg, 1.58mmol), it is cooled to after 0 DEG C and is added dropwise to 1i (256mg, 1.2mmol), stirring reaction 1 hour.Reaction solution is poured into water. Extracted with dichloromethane (30mL × 2), merge organic phase, washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtered, Filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 13d (300mg), yield：61%.

4th step

(S) -3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) piperidines -1- sulfonamide 13e

13d (300mg, 0.48mmol) is dissolved in 15mL dichloromethane, 5mL trifluoroacetic acids are added, stirring reaction 1 is small When.Reaction solution is concentrated under reduced pressure, and gained residue dichloromethane dissolves, and it is alkalescence that saturated sodium bicarbonate solution, which is added dropwise, to pH, is used Dichloromethane extracts (30mL × 2), merges organic phase, is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filters, filter Liquid is concentrated under reduced pressure, and obtains crude title product 13e (150mg), and product is not purified directly to carry out next step reaction.

5th step

(S)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- sulfamoyl piperidines -3- bases) is thio) -1,2,5- Evil Diazole -3- carbonamidines 13

Crude product 13e (100mg, 0.19mmol) is dissolved in 5mL tetrahydrofurans, 2.5M sodium hydroxide solutions are added 0.23mL, stirring reaction 30 minutes.Aqueous phase is separated, it is 7 that 1M hydrochloric acid, which is added dropwise, to pH, is extracted with ethyl acetate (10mL × 2), merges Organic phase, is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, uses high performance liquid chromatography Purifying gained residue, obtains title product 13 (50mg), yield：52.7%.

MS m/z(ESI):495.1[M+1]

¹H NMR(400MHz,DMSO-d₆)δ11.78(s,1H),8.99(s,1H),7.15-7.19(t,1H),7.08- 7.10(dd,1H),6.85(s,2H),6.67-6.82(m,1H),3.48-3.50(m,1H),3.00-3.10(m,2H),1.97- 2.00(t,2H),1.67-1.82(m,2H),1.17-1.33(m,2H).

Embodiment 14

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1s, 4s) -4- (sulphamoylamino) cyclohexyl) is thio) -1, 2,5- oxadiazole -3- carbonamidines 14

The first step

((1s, 4s) -4- sulfydryls cyclohexyl) t-butyl carbamate 14b

By S- ((1s, 4s) -4- ((tertbutyloxycarbonyl) amino) cyclohexyl), (800mg, 2.93mmol are adopted thioacetic acid 14a With known method " Journal of Medicinal Chemistry, 1993,36 (19), 2788-2800 " are prepared) it is molten In 20mL methanol, potassium carbonate (605.7mg, 4.39mmol), stirring reaction 20 minutes are added.20mL is added into reaction solution to satisfy And ammonium chloride solution, it is extracted with ethyl acetate (15mL × 2), merges organic phase, (20mL), nothing are washed with saturated nacl aqueous solution Aqueous sodium persulfate is dried, filtering, filtrate decompression concentration, obtains crude title product 14b (800mg), product is not purified directly to be entered Row next step is reacted.

Second step

((1r, 4r)-(4- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- Base) -1,2,5- oxadiazole -3- bases) thio) hexamethylene) t-butyl carbamate 14c

Crude product 14b (600mg, 2.59mmol) is dissolved in 20mL tetrahydrofurans, add 1f (200mg, 0.54mmol) and Potassium carbonate (149.04mg, 1.08mmol), stirring reaction 16 hours.Reaction solution is concentrated under reduced pressure, with silica gel column chromatography to wash De- agent system B purifying gained residue, obtains title product 14c (260mg), yield：86.7%.

3rd step

3- (4- (((1r, 4r) -4- aminocyclohexyls alkyl) is thio) -1,2,5- oxadiazole -3- bases) -4- (bromo- 4- fluorobenzene of 3- Base) (4H) -one of -1,2,4- oxadiazoles -5 14d

14c (300.5mg, 0.54mmol) is dissolved in 5mL dichloromethane, 1mL trifluoroacetic acids are added, stirring reaction 2 is small When.Reaction solution is concentrated under reduced pressure, and obtains crude title product 14d (280mg), and product is not purified directly to carry out next step reaction.

4th step

N- ((1r, 4r) -4- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- Base) -1,2,5- oxadiazole -3- bases) thio) hexamethylene) sulphamoylamino t-butyl formate 14e

Crude product 14d (126.4mg, 0.54mmol) is dissolved in 20mL dichloromethane, triethylamine is added after being cooled to 0 DEG C (0.224mL, 1.62mmol) and 1i (0.54mL, 0.54mmol), is warmed to room temperature stirring reaction 16 hours.Added into reaction solution 1mL methanol, is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 14e (280mg), yield：81.6%.

5th step

N- [4- ({ 4- [4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases] -1,2,5- Oxadiazole -3- bases } sulfenyl) cyclohexyl] sulfamide 14f

14e (300mg, 0.47mmol) is dissolved in 9mL dichloromethane, 2mL trifluoroacetic acids, stirring reaction 3 hours is added. Reaction solution obtains crude title product 14f (260mg) after being concentrated under reduced pressure, product is not purified directly to carry out next step reaction.

6th step

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- (((1s, 4s) -4- (sulphamoylamino) cyclohexyl) is thio) -1, 2,5- oxadiazole -3- carbonamidines 14

Crude product 14f (200mg, 0.37mmol) is dissolved in 10mL tetrahydrofurans, 2.5M sodium hydroxide solutions are added 0.59mL, stirring reaction 1 hour.20mL saturated ammonium chloride solutions are added into reaction solution, be extracted with ethyl acetate (15mL × 3), merge organic phase, washed with saturated nacl aqueous solution (20mL), anhydrous sodium sulfate drying, filtered, filtrate decompression concentration is used Silica gel column chromatography purifies gained residue with eluant, eluent system A, obtains title product 14 (100mg), yield：53.1%.

MS m/z(ESI):509.1[M+1]

¹H NMR(400MHz,DMSO-d₆)δ11.71(s,1H),9.00(s,1H),7.16-7.21(m,1H),7.02- 7.04(m,1H),6.70-6.71(m,1H),6.61-6.62(m,1H),6.49-6.50(m,2H),3.84-3.86(m,1H), 3.25-3.27(m,1H),1.89-1.91(m,4H),1.76-1.79(m,2H),1.61-1.64(m,2H)

Embodiment 15

(R)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- sulfamoyls pyrrolidin-3-yl) is thio) -1,2,5- Oxadiazole -3- carbonamidines

The first step

(R) -3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) pyrrolidines -1- t-butyl formates 15b

1f (280mg, 0.72mmol) is dissolved in 10mL tetrahydrofurans, (R) -3- mercapto pyrrolidine -1- carboxylic acid uncles are added Butyl ester 15a (306mg, 1.5mmol, using known method " Bioorganic and Medicinal Chemistry Letters, 2009,19 (1), 170-174 " is prepared) and potassium carbonate (207mg, 1.5mmol), stirring reaction 16 hours.Instead Answer liquid to be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 15b (300mg), yield：81.5%.

Second step

(R) -4- (the bromo- 4- fluorophenyls of 3-) -3- (4- (pyrrolidin-3-yl is thio) -1,2,5- oxadiazole -3- bases) -1,2, (4H) -one of 4- oxadiazoles -5 15c

15b (300mg, 0.587mmol) is dissolved in 6mL dichloromethane, 1.5mL trifluoroacetic acids are added, stirring reaction 2 is small When.Reaction solution is concentrated under reduced pressure, crude title product 15c (241.4mg) is obtained, the not purified directly progress next step of product is anti- Should.

3rd step

(R)-(3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) pyrrolidin-1-yl) sulfonylcarbamic acid tert-butyl ester 15d

Crude product 15c (241.4mg, 0.587mmol) is dissolved in 20mL dichloromethane, triethylamine is added after being cooled to 0 DEG C (0.162mL, 1.174mmol) and 1i (126.6mg, 0.587mmol), stirring reaction 30 minutes.1mL first is added into reaction solution Alcohol, after being concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 15d (300mg), yield：86.6%.

4th step

(R) -3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) pyrrolidines -1- sulfonamide 15e

15d (300mg, 0.494mmol) is dissolved in 6mL dichloromethane, 1.5mL trifluoroacetic acids are added, stirring reaction 2 is small When.Reaction solution is concentrated under reduced pressure, and obtains crude title product 15e (260mg), and product is not purified directly to carry out next step reaction.

5th step

(R)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- sulfamoyls pyrrolidin-3-yl) is thio) -1,2,5- Oxadiazole -3- carbonamidines 15

Crude product 15e (250.5mg, 0.494mmol) is dissolved in 10mL tetrahydrofurans, 2.5M sodium hydroxide solutions are added 1mL, stirring reaction 1 hour.20mL saturated ammonium chloride solutions are added into reaction solution, are extracted with ethyl acetate (15mL × 3), are closed And organic phase, washed (20mL), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, silicagel column is used in filtrate decompression concentration Chromatography purifies gained residue with eluant, eluent system A, obtains title product 15 (150mg), yield：63.1%.

MS m/z(ESI):481.1[M+1]

¹H NMR(400MHz,DMSO-d₆)δ11.77(s,1H),8.98(s,1H),7.16-7.18(m,1H),7.10- 7.12(m,1H),6.92-6.94(m,2H),6.72-6.74(m,1H),4.19-4.20(m,1H),3.68-3.70(m,1H), 3.16-3.27(m,4H),1.94-1.98(m,1H).

Embodiment 16

(S)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- sulfamoyls pyrrolidin-3-yl) is thio) -1,2,5- Oxadiazole -3- carbonamidines

The first step

(S) -3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) pyrrolidines -1- t-butyl formates 16b

1f (829.5mg, 2.21mmol) is dissolved in 10mL tetrahydrofurans, (S) -3- mercapto pyrrolidine -1- carboxylic acids are added Tert-butyl ester 16a (0.9g, 4.43mmol, using known method " Bioorganic and Medicinal Chemistry Letters, 2009,19 (1), 170-174 " is prepared) and potassium carbonate (611.3mg, 4.43mmol), stirring reaction 1 hour. Reaction solution is poured into water, is extracted with ethyl acetate (15mL × 3), merges organic phase, is washed with saturated nacl aqueous solution (20mL), anhydrous sodium sulfate drying, filtering obtains crude title product 16b (1.5g), product is without pure after filtrate decompression concentration Change and directly carry out next step reaction.

Second step

(S) -4- (the bromo- 4- fluorophenyls of 3-) -3- (4- (pyrrolidin-3-yl is thio) -1,2,5- oxadiazole -3- bases) -1,2, (4H) -one of 4- oxadiazoles -5 16c

Crude product 16b (1.5g, 2.84mmol) is dissolved in 20mL dichloromethane, 5mL trifluoroacetic acids, stirring reaction 1 is added Hour.Reaction solution obtains crude title product 16c (1g) after being concentrated under reduced pressure, product is not purified directly to carry out next step reaction.

3rd step

(S)-(3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) pyrrolidin-1-yl) sulfonylcarbamic acid tert-butyl ester 16d

Crude product 16c (300mg, 0.7mmol) is dissolved in 10mL dichloromethane, triethylamine (0.2mL, 1.4mmol) is added, It is cooled to after 0 DEG C and is added dropwise to 1i (226.7mg, 1.05mmol), stirring reaction 30 minutes.Reaction solution is poured into water.Use dichloro Methane extracts (30mL × 2), merges organic phase, is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filters, and filtrate subtracts Pressure concentration, obtains crude title product 16d (350mg), and product is not purified directly to carry out next step reaction.

4th step

(S) -3- ((4- (4- (the bromo- 4- fluorophenyls of 3-) -5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) -1,2, 5- oxadiazole -3- bases) thio) pyrrolidines -1- sulfonamide 16e

Crude product 16d (350mg, 0.58mmol) is dissolved in 15mL dichloromethane, 5mL trifluoroacetic acids, stirring reaction 1 is added Hour.Reaction solution is concentrated under reduced pressure, and obtains crude title product 16e (230mg), and the not purified directly progress next step of product is anti- Should.

5th step

(S)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- sulfamoyls pyrrolidin-3-yl) is thio) -1,2,5- Oxadiazole -3- carbonamidines 16

Crude product 16e (230mg, 0.44mmol) is dissolved in 5mL tetrahydrofurans, 1M sodium hydroxide solution 0.08mL are added, Stirring reaction 30 minutes.Aqueous phase is separated, it is neutrality that 1M hydrochloric acid, which is added dropwise, to pH, is extracted with ethyl acetate (10mL × 2), merges organic Phase, is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, with thin-layered chromatography to elute after filtrate decompression concentration Agent system A purifying gained residues, obtain title product 16 (25mg), yield：63.1%.

MS m/z(ESI):481.1[M+1]

¹H NMR(400MHz,DMSO-d₆)δ11.77(s,1H),8.98(s,1H),7.16-7.20(t,1H),7.09- 7.12(dd,1H),6.92(s,2H),6.72-6.74(m,1H),4.19-4.22(m,1H),3.68-3.72(m,1H),3.23- 3.27(m,2H),3.16-3.19(t,1H),2.44-2.48(m,1H),1.92-1.99(m,1H).

Embodiment 17

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- ((2- hydroxyethyls) sulfonyl) azetidine -3- bases) It is thio) -1,2,5- oxadiazole -3- carbonamidines

The first step

2- ((3- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) is thio) nitrogen Azetidine -1- bases) sulfonyl) ethyl acetate 17b

Crude product 8c (250mg, 0.6mmol) is dissolved in 20mL dichloromethane, triethylamine is added after being cooled to 0 DEG C (831.7mg, 6mmol), then it is added dropwise to 2- (chlorosulfonyl) ethyl acetate 17a (225.3mg, 1.21mmol, using patent application Method disclosed in " US20090269305 " is prepared), stirring reaction 0.5 hour.10mL methanol, decompression are added in reaction solution Concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 17b (140mg), yield： 41.3%.

Second step

N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -4- ((1- ((2- hydroxyethyls) sulfonyl) azetidine -3- bases) It is thio) -1,2,5- oxadiazole -3- carbonamidines 17

17b (140mg, 0.25mmol) is dissolved in 5mL tetrahydrofurans, sodium borohydride (23.6mg, 0.62mmol) is added With methanol (16.02mg, 0.5mmol), 65 DEG C of stirring reactions are warming up to 1 hour.Reaction solution is cooled to room temperature, adds 20mL water, Extracted with ethyl acetate (15mL × 2), merge organic phase, washed with saturated nacl aqueous solution (20mL), anhydrous sodium sulfate drying, Filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 17 (55mg), yield：44.3%.

MS m/z(ESI):496.1[M+1]

¹H NMR(400MHz,DMSO-d₆)δ11.83(s,1H),8.99(s,1H),7.13-7.21(m,2H),6.75- 6.79(m,1H),5.15-5.18(m,1H),4.41-4.46(m,3H),3.91-3.93(m,2H),3.75-3.80(m,2H), 3.37-3.39(m,2H).

Biological assessment

The explanation present invention is further described below in conjunction with test case, but these embodiments are not meant as the limitation present invention's Scope.

The measure of test case 1, the compounds of this invention to people source IDO1 protease inhibiting activities

External people source IDO1 proteinase activities are tested by following method.

This method is used for determining inhibitory action of the compound in the present invention to people source IDO1 proteinase activities.

First, experiment material and instrument

1st, ELIASA (Synergy HT, BIOTEK)

2nd, tryptophan (T0254-5G, Sigma-Aldrich)

3rd, catalase derives from cattle liver (C1345-1G, Sigma-Aldrich)

4th, methylenum careuleum (M9140-25G, Sigma-Aldrich)

5th, L-AA sodium (A7631-25G, Sigma-Aldrich)

6th, 4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)

7th, trichloroacetic acid (T9159-100G, Sigma-Aldrich)

8th, people source IDO1 genes (SC126221, Origene)

2nd, experimental procedure

The self-control of IDO1 protease：

People source IDO1 genes are transferred in PET30a plasmids by gene clone technology, the large intestine of competence is then transferred to Bacillus Rosetta (DE3) competent cell (KT1003, Shenzhen HYK Gene Technology Co., Ltd.)；In liquid LB (Luria- Bertani) culture medium [according to《Molecular Cloning:A Laboratory guide》(J. Pehanorm Brooker D.W. Russells work) prepares every liter of culture Base] middle amplification culture, thalline is collected, ultrasonication, by hanging column, affords the IDO1 protease of purifying.

Compound test experiments：

24 μ l 100 times of enzyme (IDO1) is diluted to 2400 μ l with 50mM KPB, concentration is 2.6ng/ μ l enzyme solutions, 24 μ l enzyme solutions are added per hole in 96 hole reaction plates (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as reaction plate).Blank well adds Enter the 24 μ l KPB [preparations (50mM) of KPB buffer solutions：KH is weighed with assay balance₂PO₄6.805g is put into 1000ml beaker, Deionized water is added to 900ml with graduated cylinder, is adjusted PH to 6.5 with 1M KOH, is poured into 1L graduated cylinder, moisturizing to 1L is Can.4 DEG C of storages].1 μ l compound or DMSO are added into corresponding reacting hole in reaction plate.Prepare A liquid：Take 200 μ l 500mML- sodium ascorbates add 1050 μ l KPB, and turbine-type mixer maximal rate is mixed 3 seconds.B liquid：100 μ l 10mM color ammonia The catalase of acid plus 100 μ l 100000unit/ml, plus 5 μ l 10mM methylenum careuleum, finally plus 1050 μ l KPB, turbine Blender maximal rate is mixed 3 seconds.1200 μ l A liquid and 1200 μ l B liquid are taken, maximal rate is mixed 3 seconds on turbine-type mixer. Then this mixed liquor is added in reaction plate with every μ l of hole 24.Reaction plate is put into board-like centrifuge maximum speed to centrifuge 15 seconds, Reaction liquid is all converged to bottom, oscillator is mixed 30 seconds, in constant-temperature incubation case, 37 DEG C, be incubated 1h.In reaction plate, 10 μ l 30% (W/V) trichloroacetic acids are added per hole per hole, 65 DEG C are incubated 15 minutes in incubator.By reaction plate in centrifuge Upper 4700RPM centrifugations, room temperature, 5 minutes.40 μ l supernatants are shifted to 96 hole test boards of correspondence from reaction plate with the volley of rifle fire In (Corning, #3599).40 μ l 2% (W/V) 4- (dimethylamino) benzaldehyde/glacial acetic acid solution is added per hole, is being shaken Maximal rate on device is swung, is mixed 1 minute.After incubation at room temperature 2 minutes, read on Synergy HT (BIOTEK) at 480nm Light absorption value.

Compound is measured to experiment of the people source IDO1 protease inhibiting activities more than in the present invention, is measured IC₅₀Value is shown in Table 1.

Compound suppresses IC to people source IDO1 proteinase activities in the present invention of table 1₅₀

Embodiment is numbered	IC50(nM)
		1	18
2	19
		3	43
4	134
		5	16
6	16
		7	69
8	15
		9	21
10	12
		11	26
12	22
		13	29
14	16
		15	12
16	14

Conclusion：The compounds of this invention has obvious inhibitory action to people source IDO1 proteinase activities.

The measure of test case 2, the compounds of this invention to people source TDO protease inhibiting activities

External people source TDO proteinase activities are tested by following method.

This method is used for determining inhibitory action of the compound in the present invention to people source TDO proteinase activities.

First, experiment material and instrument

1st, ELIASA (Synergy HT, BIOTEK)

2nd, tryptophan (T0254-5G, Sigma-Aldrich)

3rd, catalase derives from cattle liver (C1345-1G, Sigma-Aldrich)

4th, methylenum careuleum (M9140-25G, Sigma-Aldrich)

5th, L-AA sodium (A7631-25G, Sigma-Aldrich)

6th, 4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)

7th, trichloroacetic acid (T9159-100G, Sigma-Aldrich)

8th, people source TDO (U32989.1, Suzhou Jin Weizhi bio tech ltd)

9th, Rosseta (CW0811A, Beijing CoWin Bioscience Co., Ltd.)

10th, turbine-type mixer (6776, Corning)

11st, mini board-like centrifuge (Mini-P25, ABSON life science equipment)

2nd, experimental procedure

The self-control of TDO protease

By the plasmid of the source containing people built TDO genes, the Escherichia coli Rosseta of competence is transferred to；In liquid LB (Luria-Bertani) culture medium [according to《Molecular Cloning:A Laboratory guide》(J. Pehanorm Brooker D.W. Russells work) is prepared every Rise culture medium] middle amplification culture, thalline is collected, ultrasonication, by hanging column, affords the TDO1 protease of purifying.

Compound test experiments：

24 μ l 100 times of enzyme (TDO) is diluted to 2400 μ l with 50mM KPB, concentration is 2.6ng/ μ l enzyme solutions, 96 hole reaction plates (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as reaction plate) add 24 μ l enzyme solutions per hole.Blank well Add the 24 μ l KPB buffer solutions [preparations (50mM) of KPB buffer solutions：KH is weighed with assay balance₂PO₄6.805g it is put into 1000ml Beaker, add deionized water to 900ml with graduated cylinder, adjust PH to 6.5 with 1M KOH, be conducted into 1L graduated cylinder, moisturizing To 1L.4 DEG C of storages].1 μ l compound or DMSO are added into corresponding reacting hole in reaction plate.Prepare A liquid：Take 200 μ l 500mM L-AA sodium adds 1050 μ l KPB, and turbine-type mixer maximal rate is mixed 3 seconds.B liquid：100 μ l 10mM colors The acid of ammonia adds 100 μ l 100000unit/ml catalase, plus 5 μ l 10mM methylenum careuleum, finally plus 1050 μ l KPB, Turbine-type mixer maximal rate is mixed 3 seconds.1200 μ l A liquid and 1200 μ lB liquid are taken, maximal rate mixes 3 on turbine-type mixer Second.Then this mixed liquor is added in reaction plate with every μ l of hole 24.Reaction plate is put into board-like centrifuge maximum speed centrifugation 15 Second, reaction liquid is all converged to bottom, oscillator is mixed 30 seconds, in constant-temperature incubation case, 37 DEG C, be incubated 1h.In reaction plate In, 10 μ l30% (W/V) trichloroacetic acids are added per hole, 65 DEG C are incubated 15 minutes in incubator.By reaction plate on centrifuge 4700RPM is centrifuged, room temperature, 5 minutes.40 μ l supernatants are shifted to 96 hole test boards of correspondence from reaction plate with the volley of rifle fire In (Corning, #3599).40 μ l 2% (W/V) 4- (dimethylamino) benzaldehyde/glacial acetic acid solution is added per hole, is being shaken Maximal rate on device is swung, is mixed 1 minute.After incubation at room temperature 2 minutes, read on Synergy HT Reader at 480nm Light absorption value.

Compound is measured to experiment of the people source TDO protease inhibiting activities more than in the present invention, the IC measured₅₀ Value is shown in Table 2.

Compound suppresses IC to people source TDO proteinase activities in the present invention of table 2₅₀

Conclusion：The compounds of this invention inhibitory action weaker to people source TDO proteinase activities, shows that the compounds of this invention is Selective IDO inhibitor.

The measure of test case 3, the compounds of this invention IDO protease inhibiting activities intracellular to HeLa

The intracellular IDO proteinase activities of HeLa are tested by following method.

This method is used for determining the inhibitory action of the compound IDO proteinase activities intracellular to HeLa in the present invention. (note：HeLa cell lines express indole amine 2,3-dioxygenase (IDO) under interferon gamma (INF- γ) induction)

First, experiment material and instrument

1st, ELIASA (Synergy HT, BIOTEK)

2nd, tryptophan (T0254-5G, Sigma-Aldrich)

3rd, 4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)

4th, trichloroacetic acid (T9159-100G, Sigma-Aldrich)

5th, HeLa cell lines (CCL-2, ATCC)

6th, INF- interferons (R＆D Systems, 285-IF-100)

2nd, experimental procedure

HeLa cell suspensions are produced with Fresh cell culture medium, 100 μ l cultivating systems are added with 10000 cells/wells In 96 porocyte culture plates, 5% 37 DEG C of carbon dioxide is cultivated 24 hours.Supernatant is removed, 90 μ l serum-frees DMEM are first added per hole High glucose medium；Then 10 μ l are separately added into per hole and prepare compound (its end in the culture medium of γ containing INF- and tryptophan Concentration is：10000,1000,100,10,1,0.1nM) 96 porocyte culture plates are taken out in, 48 hours 5% carbon dioxide, 37 DEG C of cultures The middle μ l of supernatant 80 add 16 μ l 30% (W/V) trichloroacetic acids per hole into 96 hole round bottom plates, per hole, are incubated for 65 DEG C in incubator Educate 25 minutes.By reaction plate, 4700RPM is centrifuged on centrifuge, 5 minutes.Shifted with the volley of rifle fire from reaction plate 50 μ l supernatants to In 96 hole flat bottom clear plates, 50 μ l 2% (W/V) 4- (dimethylamino) benzaldehyde/glacial acetic acid solution is then added per hole, Mix 1 minute on the oscillator.After incubation at room temperature 2 minutes, the extinction at 480nm is read on Synergy HT Reader Value.

Experiment of the compound IDO protease inhibiting activities intracellular to HeLa more than is measured in the present invention, is surveyed The IC obtained₅₀Value is shown in Table 3.

Compound IDO proteinase activities intracellular to HeLa suppress IC in the present invention of table 3₅₀

Embodiment is numbered	IC50(nM)
		1	5
2	5
		3	29
4	39
		5	11
6	10
		7	11
8	5
		9	8
10	5
		11	21
12	40
		13	16
14	32
		15	8
16	11

Conclusion：The compounds of this invention IDO proteinase activities intracellular to HeLa have obvious inhibitory action.

Pharmacokinetic Evaluation

The pharmacokinetics test of test case 4, the compound of the embodiment of the present invention 1 and 2

1st, make a summary

Using SD rats as animal subject, determine SD rat oral gavages using LC/MS/MS methods and give Examples 1 and 2 compound Drug concentration not in the same time in blood plasma afterwards.Pharmacokinetics behavior of the compounds of this invention in SD rat bodies is studied, is evaluated Its characteristics of pharmacokinetics.

2nd, testing program

2.1 test drug

Examples 1 and 2 compound

2.2 experimental animal

SD rats 8, male and female half and half, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai.

2.3 medicines are prepared

Appropriate amount of sample is weighed, 0.15ml dimethyl acetamides is added, adds 10%2- hydroxypropyl-b- cyclodextrin to whole body 0.2mg/ml suspensions are made in product, ultrasound.

2.4 administration

SD rats 8, male and female half and half are divided into 2 groups, 4/group；Gastric infusion, administered volume are distinguished after the night of fasting one 10ml/kg。

3rd, operate

SD rats 8, male and female half and half；Gastric infusion group 0.5,1.0,2.0,4.0,6.0,8.0 before being administered and after administration, 11.0,24.0h are taken a blood sample 0.2ml by eye socket, are placed in heparinised tubes, 3500rpm centrifugation 10min separated plasmas, in -20 DEG C of guarantors Deposit, 2h is fed after administration.

The testing compound content after different compound gastric infusions in rat plasma is determined with LC/MS/MS methods.

4th, pharmacokinetic parameter result

The pharmacokinetic parameter of the compound of the embodiment of the present invention 1 and 2 is as follows：

Conclusion：In the medicine generation of the compounds of this invention, absorbs good, with obvious medicine for assimilation effect.

The pharmacokinetics test of test case 5, the compound of the embodiment of the present invention 1 and 2

1st, make a summary

Using Beagle dogs as animal subject, determine Beagle dog gavages using LC/MS/MS methods and give Examples 1 and 2 Drug concentration after compound not in the same time in blood plasma.Study pharmacokinetics row of the compounds of this invention in Beagle dog bodies To evaluate its characteristics of pharmacokinetics.

2nd, testing program

2.1 test drug

Examples 1 and 2 compound

2.2 experimental animal

Beagle dogs 6, male, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai.

2.3 medicines are prepared

Appropriate amount of drug is weighed, adding 3% dimethyl acetamide makes after dissolving, adds 10%2- hydroxypropyl-b- cyclodextrin extremely Homogeneous solution is made in final volume, ultrasound.

2.4 administration

Beagle dogs 6, male, are divided into 2 groups, 3/group；Gastric infusion, administered volume are distinguished after the night of fasting one 5ml/kg。

3rd, operate

Beagle dogs 6, male；Gastric infusion is distinguished after the night of fasting one.Gastric infusion group is in before administration and after administration 0.5,1.0,2.0,4.0,6.0,8.0,12.0,24.0h, by jugular vein blood collection 1.0ml, is placed in heparinised tubes, 3500rpm Centrifuge 10min separated plasmas, -20 DEG C of preservations.3h is fed after administration.

The testing compound content after different compound gastric infusions in Beagle dog plasmas is determined with LC/MS/MS methods.

4th, pharmacokinetic parameter result

The pharmacokinetic parameter of the compound of the embodiment of the present invention 1 and 2 is as follows：

Conclusion：In the medicine generation of the compounds of this invention, absorbs good, with obvious medicine for assimilation effect.

Claims (16)

1. the compound shown in a kind of logical formula (I)：

Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or Its pharmaceutically useful salt,

Wherein：

Mixture selected from cis-isomer, transisomer and cis-trans-isomer；

Ring A is selected from cycloalkyl, heterocyclic radical, aryl and heteroaryl；

Ring B is aryl or heteroaryl；

R¹It is identical or different, and it is each independently selected from hydrogen atom, alkyl, cyano group, amino, halogen, alkenyl, alkynyl, hydroxyl, nitre Base, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein described alkyl, alkenyl, alkynes Base, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl be optionally selected from independently of one another hydroxyl, One or more of halogen, amino, cyano group, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl substituent is taken Generation；

R²It is identical or different, and it is each independently selected from hydrogen atom, alkyl, hydroxyl, amino, alkoxy, hydroxyalkyl, haloalkoxy Base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR³、-C(O)R³、-C(O)OR³、-S(O)_mR³、-C(O)NR³R⁴、-OC(O) NR³R⁴、-NR³R⁴、-NR³C(O)R⁴、-NR³S(O)_mR⁴With-NR³S(O)_mNHR⁴, wherein described alkyl, alkoxy, hydroxyalkyl, Haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, amino, nitro, cyanogen independently of one another Base, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR⁵、-C(O)R⁵、-C(O)OR⁵、-S(O)_mR⁵、-NR⁵R⁶、-C(O)NR⁵R⁶、-NR⁵C(O)R⁶With-NR⁵S(O)_mR⁶One or more of substituent replaced；

R³And R⁴It is identical or different, and it is each independently selected from hydrogen atom, alkyl, hydroxyl, amino, alkoxy, hydroxyalkyl, halo Alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR⁵、-C(O)R⁵、-C(O)OR⁵、-S(O)_mR⁵、-NR⁵R⁶、-C(O) NR⁵R⁶、-NR⁵C(O)R⁶With-NR⁵S(O)_mR⁶, wherein described alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocycle Base, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, hydroxyl, amino, nitro, cyano group, alkane independently of one another Epoxide, hydroxyalkyl, cycloalkyl, heterocyclic radical ,-C (O) OR⁷, one or more of aryl and heteroaryl substituent replaced；

R⁵And R⁶It is identical or different, and it is each independently selected from hydrogen atom, alkyl, hydroxyl, amino, carboxylic acid ester groups, alkoxy, hydroxyl Alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein described alkyl, amino, alkoxy, hydroxyalkyl, halogen Substituted alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, hydroxyl, amino, carboxylic acid independently of one another One or more of ester group, nitro, cyano group, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl substituent institute Substitution；

R⁷Selected from hydrogen atom, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl；

M is 0,1 or 2；

N is 0,1,2,3,4 or 5；And

X is 0,1,2,3,4 or 5.

2. the compound shown in logical formula (I) according to claim 1, its middle ring B is aryl, preferably phenyl.

3. the compound shown in logical formula (I) according to claim 1 or 2, wherein R¹For hydrogen atom or halogen.

4. the compound according to logical formula (I) according to any one of claims 1 to 3, wherein R²Selected from hydrogen atom, alkyl, Hydroxyl, amino ,-C (O) R³、-S(O)_mR³、-C(O)NR³R⁴、-OC(O)NR³R⁴、-NR³R⁴、-NR³C(O)R⁴、-NR³S(O)_mR⁴With- NR³S(O)_mNHR⁴；It is preferred that-NR³S(O)_mNHR⁴；R³、R⁴It is as defined in claim 1 with m.

5. the compound according to logical formula (I) according to any one of claims 1 to 4, wherein n is 1 or 2.

6. the compound according to logical formula (I) according to any one of claims 1 to 5, wherein x is 1.

7. the compound according to logical formula (I) according to any one of claims 1 to 6, it is the change shown in logical formula (II) Compound：

Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or Its officinal salt,

Wherein：

Mixture selected from cis-isomer, transisomer and cis-trans-isomer；

G is selected from C, O, N, S (O)_mAnd S；

R²It is identical or different, and it is each independently selected from hydrogen atom, alkyl, hydroxyl, amino, alkoxy, hydroxyalkyl, haloalkoxy Base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR³、-C(O)R³、-C(O)OR³、-S(O)_mR³、-C(O)NR³R⁴、-OC(O) NR³R⁴、-NR³R⁴、-NR³C(O)R⁴、-NR³S(O)_mNHR⁴With-NR³S(O)_mR⁴, wherein described alkyl, alkoxy, hydroxyalkyl, Haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, amino, nitro, cyanogen independently of one another Base, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR⁵、-C(O)R⁵、-C(O)OR⁵、-S(O)_mR⁵、-NR⁵R⁶、-C(O)NR⁵R⁶、-NR⁵C(O)R⁶With-NR⁵S(O)_mR⁶One or more of substituent replaced；

X is 0 or 1；

Y is 0,1,2 or 3；

Z is 0,1,2 or 3；And

Ring B, R¹、R³~R⁶, m and n it is as defined in claim 1.

8. the compound according to logical formula (I) according to any one of claims 1 to 6, its middle ring A is selected from cyclohexyl, indenes Base, pyrazolyl, cyclopenta, tetrahydrofuran base, pyranose, cyclobutyl, piperidyl, oxetanylmethoxy, azetidinyl and pyrrole Cough up alkyl.

9. the compound shown in logical formula (I) according to any one of in claim 1~8, it is selected from：

10. the compound shown in a kind of logical formula (V)：

Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or Its officinal salt,

Wherein：

Ring A, ring B, R¹、R², x and n it is as defined in claim 1.

11. the compound shown in logical formula (V) according to claim 10, it is selected from：

12. a kind of method for preparing the compound shown in logical formula (I) according to claim 1, this method includes：

Logical formula (V) compound open loop under room temperature alkalescence condition, obtains logical formula (I) compound；

Wherein：

Ring A, ring B, R¹、R², x and n it is as defined in claim 1.

13. a kind of method for preparing the compound shown in logical formula (II) according to claim 7, this method includes：

The open loop under room temperature alkalescence condition of formula (II-B) compound, obtains logical formula (II) compound；

Wherein：

Ring B, G, R¹、R², y, z, x and n it is as defined in claim 7.

14. a kind of pharmaceutical composition, its contain therapeutically effective amount according to logical formula (I) according to any one of claims 1 to 9 Shown compound, and one or more pharmaceutically acceptable carriers, diluent or excipient.

15. compound according to logical formula (I) according to any one of claims 1 to 9 or according to claim 14 Pharmaceutical composition be used to preventing and/or treating the pathological characteristicses with the IDO tryptophan metabolic pathways mediated preparing Purposes in the medicine of disease.

16. purposes according to claim 15, wherein the tryptophan metabolic pathway pathological characteristicses mediated with IDO Disease be selected from cancer, myelodysplastic syndrome, Alzheimer disease, autoimmune disease, depression, anxiety disorder, Cataract, mental handicape and AIDS, wherein described cancer be preferably selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, stomach cancer, The carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tubal Tumour, ovarioncus, peritoneal tumor, IV phases melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, Mastoid process kidney knurl, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.