WO2016155545A1 - Sulfamyl-containing 1,2,5-oxadiazole derivative, preparation method therefor and use thereof in pharmaceuticals - Google Patents

Abstract

Disclosed are a sulfamyl-containing 1,2,5-oxadiazole derivative, a preparation method therefor, and a use thereof in pharmaceuticals. Specifically disclosed are a sulfamyl-containing 1,2,5-oxadiazole derivative of generic formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and use thereof as an IDO (Indoleamine-pyrrole-2,3-dioxygenase) inhibitor, and the sulfamyl-containing 1,2,5-oxadiazole derivative can be applied to treating diseases having IDO-mediated tryptophan metabolic pathway pathological features, including tumors, cancers, Alzheimer's Disease, autoimmune diseases, depression, anxiety disorder, cataract, psychological disorder and AIDS. Wherein various substituents in generic formula (I) have the same meanings as defined in the description.

Description

1,2,5-oxadiazole derivative containing sulfamoyl group, preparation method thereof and application thereof in medicine Technical field

The invention belongs to the field of medicine and relates to a method for synthesizing a 1,2,5-oxadiazole derivative containing a sulfamoyl group and its application in medicine. The present invention discloses its use as an IDO inhibitor for the treatment of diseases having the pathological features of the IDO-mediated tryptophan metabolism pathway, including cancer, Alzheimer's disease, autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS.

Background technique

Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries. The incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3%-5%. It is estimated that by 2020, 4 million people will develop cancer in China and 3 million will die from cancer. The main reasons are: Ageing, urbanization, industrialization and lifestyle changes. In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.

Due to the unrestricted growth and infiltration and metastasis of malignant tumors, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) used in clinical practice cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs. Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy. The host's natural defense mechanisms (such as inhibition of IDO-mediated tumor immune escape mechanisms) or the naturally occurring highly targeted substances to achieve anti-tumor effects.

Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds. The alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket. IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan. Fast enzyme, which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein. IDO is closely related to interferon (IFN), interleukin (IL), tumor necrosis factor and other cytokines, and they can activate IDO under certain conditions. In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels. On the one hand, IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells; On the other hand, IDO catalyzes the main product produced by the metabolism of tryptophan. Canine urea is induced by oxygen free radicals to induce changes in intracellular oxidants and antioxidants to induce T-cell apoptosis, which is an intrinsic immunosuppressive mechanism present in the body. A large number of studies have shown that IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack. Already discovered Most human tumors constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.

1-methyltryptophan is an oral small molecule IDO inhibitor developed by NewLink Genetics for the treatment of metastatic breast cancer and solid tumors and is currently in clinical phase II in the United States. Studies have shown that 1-methyltryptophan can enhance the sensitivity of tumor cells to T-cell immune stimulation in vitro, and can delay the growth of tumor cells and strengthen the anti-tumor effect of chemotherapy drugs in animal models in vivo, and almost All spontaneous tumors work. In addition, Incyte is developing a series of oral IDO small molecule inhibitors, INCB-24360 is also undergoing clinical phase II trials, mainly for the treatment of a variety of cancers including myelodysplastic syndrome.

Inhibitors of the disclosed selective inhibitors of IDO include WO2004094409, WO2006122150, WO2007075598, WO2010005958 and WO2014066834, and the like.

IDO inhibitors have good application prospects in the pharmaceutical industry as a drug, but no good IDO inhibitors have been found as marketable drugs. In order to achieve better tumor treatment effects and better meet market demand, we hope to Developed a new generation of highly efficient and low toxicity selective IDO inhibitors. The present invention will provide a novel structure of selective IDO inhibitors, and it has been found that compounds having such structures exhibit excellent effects and effects, particularly excellent pharmacogen absorption activities.

Summary of the invention

The object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the following structure:

among them:

a mixture selected from the group consisting of a cis isomer, a trans isomer or a cis and trans isomer;

R ^{1 is} selected from the group consisting of an alkyl group, a cycloalkyl group, and an alkoxy group, wherein the alkyl group, the cycloalkyl group, and the alkoxy group are each independently optionally further selected from the group consisting of a hydroxyl group, an alkyl group, an alkoxy group, and a halogenated alkyl group. Substituted by one or more substituents;

R ^{2 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and an alkoxy group, wherein the alkyl group, the cycloalkyl group, and the alkoxy group are each independently optionally further selected from the group consisting of a hydroxyl group, an alkyl group, an alkoxy group, and Substituting one or more substituents in the haloalkyl group;

Or R ¹ and R ² together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further selected from the group consisting of alkyl, halogen, cyano, cycloalkyl , heterocyclyl, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -NHS(O) _m R ⁸ , -S(O) _p R ⁸ , -NHC(O Substituting one or more substituents of R ⁸ , —OR ⁸ , —C(O)R ⁸ , —OC(O)R ⁸ and —C(O)OR ⁸ ;

R ³ and R ⁴ are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cyano group, an amino group, a halogen, an alkenyl group, an alkynyl group, a hydroxyl group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from the group consisting of hydroxyl, halogen, amino, cyano, alkyl, alkoxy, cycloalkyl, hetero Substituting one or more substituents of a cyclic group, an aryl group, and a heteroaryl group;

R ^{5 is} selected from the group consisting of an alkyl group and an amino group, which are optionally further selected from the group consisting of a hydroxyl group, a halogen, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a hetero group. Substituting one or more substituents in the aryl group; the alkyl group is preferably a C _1-4 alkyl group;

R ⁶ and R ⁷ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or hetero group The aryl groups are each independently optionally further substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Optionally optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, amino, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m is 0, 1, 2;

n is 0, 1, 2;

p is 0, 1, 2.

In a preferred embodiment of the invention, the compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are each independently selected from a hydrogen atom, a halogen, an alkyl group, or a halogenated alkyl group, and the halogen is preferably fluorine, chlorine or bromine, the alkyl group It is preferably a C _1-4 alkyl group, and the haloalkyl group is preferably a trifluoromethyl group.

In a preferred embodiment of the invention, the compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

R ¹ is an alkyl group or an alkoxy group, and the alkyl group or alkoxy group is further substituted by one or more hydroxyl groups or alkoxy groups; wherein preferably R ¹ is an alkyl group substituted by a hydroxy group or an alkoxy group;

R ³ to R ⁵ , m, n are as defined in the formula (I).

Preferred compounds of the formula (II) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salt:

among them:

R ¹ is an alkyl group or an alkoxy group, and the alkyl group or alkoxy group is further substituted by one or more hydroxyl groups or alkoxy groups;

R ³ is halogen, alkyl or haloalkyl, more preferably halogen;

R ⁴ is halogen, alkyl or haloalkyl, more preferably halogen;

R ⁵ is an amino group;

m is an integer of 0 to 2, more preferably 0;

n is an integer of 0 to 2, and more preferably 1.

In a preferred embodiment of the invention, the compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

A is a 3- to 8-membered ring, preferably a 3- to 6-membered ring, wherein the ring is selected from a carbocyclic or heterocyclic ring;

R ³ to R ⁵ , m, n are as defined in the formula (I).

Preferred compounds of the formula (III) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salt:

among them:

A is a cycloalkyl group, more preferably a cyclopropyl group;

R ³ is halogen, alkyl or haloalkyl, more preferably halogen;

R ⁴ is halogen, alkyl or haloalkyl, more preferably halogen;

R ⁵ is an amino group;

m is an integer from 0 to 2;

n is an integer of 1-2.

The present invention also provides a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or A method of the mixture, or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the formula (IV) is ring-opened under basic conditions to give a compound of the formula (I), wherein the reagent of the basic condition is potassium carbonate or sodium hydroxide;

among them:

R ¹ to R ⁵ , m, n are as defined in the formula (I).

The invention also relates to a compound of the formula (IV) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or its pharmaceutically acceptable salt:

among them:

R ¹ to R ⁵ , m, n are as defined in the formula (I).

In a preferred embodiment of the invention, a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (V) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

R ¹ , R ³ to R ⁵ , m, n are as defined in the formula (I).

In a preferred embodiment of the invention, a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (VI) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

A is a 3- to 8-membered ring wherein the ring is selected from a carbocyclic or heterocyclic ring;

R ³ to R ⁵ , m, n are as defined in the formula (I).

The present invention synthesizes typical compounds of the general formula (I), (II), (III) by a series of reactions including, but not limited to:

Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I), (II) and (III) or a tautomer thereof, a mesogen, an external Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present invention also relates to a process for the preparation of the above composition comprising the compounds of the formulae (I), (II) and (III) or tautomers, meso- and racemic forms thereof The enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, are admixed with a pharmaceutically acceptable carrier, diluent or excipient.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention and/or treatment of a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway. IDO inhibitors can be used for the inhibition of cardiac disorders as well as for the treatment of other pathological features of IDO-mediated tryptophan metabolism pathways, including infections of viruses such as AIDS, such as Lyme disease and streptococcal infections. Infection, neurodegenerative disorders (eg Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, anxiety, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer) , eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, and brain cancer. , skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal swelling Tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.

The present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of a disease preventing the pathological features of the IDO-mediated tryptophan metabolism pathway. These diseases include infections of viruses such as AIDS, cellular infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (such as Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, solid tumors, gliomas, glioblastoma, hepatocellular carcinoma, papillary renal tumors, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

The present invention also relates to a method of treating a disease preventing and/or treating a pathological feature having an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. These diseases include infections of viruses such as AIDS, cellular infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (such as Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, solid tumors, gliomas, glioblastoma, hepatocellular carcinoma, papillary renal tumors, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. The method exhibits outstanding efficacy and less side effects, wherein the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid Renal tumors, head and neck tumors, leukemias, lymphomas, myelomas and non-small cell lung cancers, preferably fallopian tube tumors, peritoneal tumors, stage IV melanoma, myeloma and breast cancer, more preferably breast cancer.

The active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.

It is also possible to use hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Soft gelatin capsules provide oral preparations.

The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols A condensation product of a partial ester such as polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agents such as sucrose, saccharin or aspartame.

The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.

The dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan An oleate, and a condensation product of the partial ester and ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the bloodstream of the patient by a local injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be prepared as an injection.

The compounds of the invention may be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of the formula or the type of pharmaceutically acceptable salt may be Traditional treatment options to verify.

Detailed description of the invention

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 An alkyl group of a carbon atom. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Base, 2, 2 2-Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(O)OR ⁷ , -OC(O)R ⁷ , -NHS(O) _p R ⁷ ,- C(O)R ⁷ , -NHC(O)R ⁷ , -NHC(O)OR ⁷ , -NR ⁸ R ⁹ , -OC(O)NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms. The carbon atoms further preferably contain 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic The ring is more preferably a 5- to 5- or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, -C(O)OR ⁷ , -OC(O)R ⁷ , -NHS(O) _p R ⁷ , -C(O)R ⁷ , -NHC(O)R ⁷ - -NHC(O)OR ⁷ , -NR ⁸ R ⁹ , -OC(O)NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). A hetero atom of _m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably from 3 to 10 ring atoms; more preferably from 3 to 8 ring atoms; more preferably from 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) _m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of the shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A π-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, -C(O)OR ⁷ , -OC(O)R ⁷ , -NHS(O) _p R ⁷ , -C(O)R ⁷ , -NHC(O)R ⁷ - -NHC(O)OR ⁷ , -NR ⁸ R ⁹ , -OC(O)NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, -C(O)OR ⁷ , -OC(O)R ⁷ , -NHS(O) _p R ⁷ , -C(O)R ⁷ , -NHC(O)R ⁷ , -NHC(O) OR ⁷ , -NR ⁸ R ⁹ , -OC(O)NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetra Azolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)OR ⁷ , -OC(O)R ⁷ , -NHS(O) _p R ⁷ , -C(O)R ⁷ , -NHC(O)R ⁷ , -NHC (O)OR ⁷ , -NR ⁸ R ⁹ , -OC(O)NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)OR ⁷ , -OC(O)R ⁷ , -NHS(O) _p R ⁷ , -C(O)R ⁷ , -NHC(O)R ⁷ , -NHC (O)OR ⁷ , -NR ⁸ R ⁹ , -OC(O)NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

The term "hydroxy" refers to an -OH group.

The term "halogen" means fluoro, chloro, bromo or iodo.

The term "amino" means -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo" refers to =0.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.

The term "acyl halide" refers to a compound containing a -C(O)-halogen group.

The term "vinyloxy" refers to CH ₂ =CH-O-.

The term "methylene" refers to -CH ₂ -.

The term "ethylene" refers to -(CH ₂ ) ₂ -.

The term "propylene" refers to -(CH ₂ ) ₃ -.

The term "butylene" refers to -(CH ₂ ) ₄ -.

The term "alkenyl" refers to -CH=CH-.

The term "alkynyl" refers to -C≡C-.

In the present invention, "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" are expressed in different terms. The same meaning means that X can be any one or several of A, B, and C.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by alkyl" "Group" means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

The method for preparing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:

Option One

The compound of the formula (Ia) is oxidized to a compound of the formula (Ib) under acidic conditions; the compound of the formula (Ib) is reacted with a compound of the formula (Ic) under basic conditions to give a compound of the formula (Id); The compound of the formula (Id) is ring-formed under heating and basic conditions, and the base is preferably N,N'-carbonyldiimidazole to give a compound of the formula (Ie); the compound of the formula (Ie) after ring formation is acidic The protecting group on the amino group is removed under the conditions to obtain a compound of the formula (If) or a salt thereof; an alkali solution of the compound of the formula (If) or a salt thereof is reacted with an alcohol solution of chlorosulfonyl isocyanate at a low temperature to obtain a formula (Ig). a compound, the alcohol solution is preferably a t-butanol solution; the compound of the formula (Ig) is deprotected under acidic conditions to give a compound of the formula (IV); the obtained compound of the formula (IV) is obtained under basic conditions. The lower ring is opened to give the compound of the formula (I).

The reagents providing basic conditions include organic bases and inorganic bases including, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, n-butyl Lithium lithium, potassium t-butoxide, tetrabutylammonium bromide, and the inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.

The oxidizing agents used include, but are not limited to, hydrogen peroxide, potassium permanganate, and manganese dioxide.

Solvents used include, but are not limited to, N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane or water.

among them:

R ¹ to R ⁴ , m, and n are as defined in the formula (I).

The preparation method of the compound of the formula (II) of the present invention or a salt thereof comprises the following steps:

Option II

The compound of the formula (Ia) is oxidized to a compound of the formula (Ib) under acidic conditions; the compound of the formula (Ib) is reacted with a compound of the formula (IIc) under basic conditions to give a compound of the formula (IId); The compound of the formula (IId) is ring-formed under heating and basic conditions, and the base under this condition is preferably N,N'-carbonyldiimidazole to give a compound of the formula (IIe); the compound of the formula (IIe) after ring formation is acidic The protective group on the amino group is removed to obtain a compound of the formula (IIf) or a salt thereof; an alkali solution of the compound of the formula (IIf) or a salt thereof is reacted with an alcohol solution of chlorosulfonyl isocyanate at a low temperature to obtain a formula (IIg). a compound, the alcohol solution is preferably a t-butanol solution; the compound of the formula (IIg) is deprotected under acidic conditions to give a compound of the formula (V); and the obtained compound of the formula (V) is obtained under basic conditions. The lower ring is opened to give the compound of the formula (II).

The alkaline conditions include organic bases and inorganic bases including, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, n-butyl. Lithium, potassium t-butoxide, tetrabutylammonium bromide, including, but not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.

The oxidizing agents used include, but are not limited to, hydrogen peroxide, potassium permanganate, and manganese dioxide.

Solvents used include, but are not limited to, N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane or water.

among them:

R ¹ , R ³ , R ⁴ , m, n are as defined in the general formula (I).

The preparation method of the compound of the formula (III) of the present invention or a salt thereof comprises the following steps:

third solution

Under acidic conditions, the compound of the formula (Ia) is oxidized to a compound of the formula (Ib); the compound of the formula (Ib) is reacted with a compound of the formula (IIIc) under basic conditions to give a compound of the formula (IIId); The compound of the formula (IIId) is ring-formed under heating and basic conditions, and the base under this condition is preferably N,N'-carbonyldiimidazole to give a compound of the formula (IIIe); the compound of the formula (IIIe) after ring formation is acidic The protective group on the amino group is removed to obtain a compound of the formula (IIIf) or a salt thereof; an alkali solution of the compound of the formula (IIIf) or a salt thereof is reacted with an alcohol solution of chlorosulfonyl isocyanate at a low temperature to obtain a formula (IIIg) a compound, the alcohol solution is preferably a t-butanol solution; the compound of the formula (IIIg) is deprotected under acidic conditions to give a compound of the formula (VI); and the obtained compound of the formula (VI) is obtained under basic conditions. The lower ring is opened to give the compound of the formula (III).

The alkaline conditions include organic bases and inorganic bases including, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, n-butyl. Lithium, potassium t-butoxide, tetrabutylammonium bromide, including, but not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.

The oxidizing agents used include, but are not limited to, hydrogen peroxide, potassium permanganate, and manganese dioxide.

Solvents used include, but are not limited to, N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane or water.

among them:

A is a 3- to 8-membered ring wherein the ring is selected from a carbocyclic or heterocyclic ring;

R ³ , R ⁴ , m, n are as defined in the general formula (I).

detailed description

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four. Methylsilane (TMS), chemical shifts are given in units of 10 ^-6 (ppm).

The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for separation and purification of thin layer chromatography is 0.4mm. ~0.5mm silica gel plate.

Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.

In the examples, unless otherwise specified, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.

In the examples, the solution in the reaction means an aqueous solution unless otherwise specified.

In the examples, the temperature of the reaction was room temperature unless otherwise specified.

Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

The system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.

Example 1

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-(((1-(sulfamoylamino)cyclopropyl)methyl)amino)-1,2,5-oxadi Oxazole-3-carboxamidine 1

first step

4-(3-Bromo-4-fluorophenyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5 (4H )-ketone 1b

3-(4-Amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazole-5 (4H - ketone 1a (264 mg, 2.23 mmol, prepared by the method disclosed in the patent application "WO2010005958") was added to 5 mL of trifluoroacetic acid, and 3 mL of hydrogen peroxide (30%) was added, and the reaction was carried out at 45 ° C for 16 hours. After completion of the reaction, the reaction was quenched with EtOAc EtOAc EtOAc (EtOAc m. The title product 1b (210 mg, yellow oil) was obtained.

MS m/z (LC-MS): 342.9 [M-1]

Second step

(1-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxymethylindolyl)-1,2,5-oxadiazol-3-yl)amino)methyl Cyclopropyl)carbamic acid tert-butyl ester 1d

1b (210 mg, 0.56 mmol) was dissolved in 15 mL of tetrahydrofuran, and (1-(aminomethyl)cyclopropyl)carbamic acid tert-butyl ester 1c (210 mg, 1.13 mmol) was prepared using the method disclosed in the patent application "WO2013052394". Then, 1.5 mL of 2N sodium hydroxide solution was added and reacted at room temperature for 30 minutes. After the reaction was completed, 1N aqueous HCl was added, and the mixture was evaporated to EtOAc. The product was directly subjected to the next reaction without purification.

MS m/z (LC-MS): 485.2 [M+1]

third step

(1-((4-(4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-) 1,2,5-oxadiazol-3-yl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester 1e

The crude product 1d (260 mg, 0.535 mmol) was dissolved in 20 mL of THF, and N,N'-carbonyldiimidazole (95 mg, 0.586 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals. The crude title product 1e (330 mg, yellow solid).

MS m/z (LC-MS): 455.3 [M+1-56]

the fourth step

3-(4-((1-aminocyclopropyl)methyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)- 1,2,4-oxadiazole-5(4H)-one trifluoroacetate 1f

The crude product 1e (330 mg, 0.645 mmol) was dissolved in dichloromethane (30 mL), and 2 mL of trifluoroacetic acid was added and allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

the fifth step

N-(1-(((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -1,2,5-oxadiazol-3-yl)amino)methyl)cyclopropyl)sulfamoylcarbamic acid tert-butyl ester 1 g

Chlorosulfonyl isocyanate (0.793 g, 5.6 mmol, prepared by the well-known method "Organic Syntheses, 1966, 46, 23-7") was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, and tert-butanol was added ( 0.43 g, 5.8 mmol), and the reaction liquid was reacted at 0 ° C for 1 hour to obtain a reaction liquid A. The crude product 1f (400 mg, 1.0 mmol) was dissolved in 20 mL of dichloromethane, and 0.75 mL of triethylamine was added to obtain a reaction liquid B. The reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted at 0 ° C for 1 hour. After the reaction is completed, the reaction mixture is quenched with saturated sodium hydrogen carbonate solution, and the organic layer is washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue was purified to give titled product (1 g, m.

MS m/z (LC-MS): 607.1 [M+18]

Step 6

N-{1-[({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) ]-1,2,5-oxadiazol-3-yl}amino)methyl]cyclopropyl}aminosulfonamide 1h

1 g (120 mg, 0.198 mmol) was dissolved in 20 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

MS m/z (LC-MS): 490.0 [M+1]

Seventh step

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-(((1-(sulfamoylamino)cyclopropyl)methyl)amino)-1,2,5-oxadi Oxazole-3-carboxamidine 1

The crude product 1 h (160 mg, 0.27 mmol) was dissolved in 20 mL of methanol, and potassium carbonate (230 mg, 1.67 mmol) was added and reacted at 50 ° C for 1 hour. After the reaction is completed, the reaction is neutralized by adding a saturated ammonium chloride solution, and the liquid is separated. The aqueous phase was extracted with EtOAc (EtOAc) EtOAc (EtOAc m. Solid), yield 7.5%.

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

^{1 H NMR (400MHz, DMSO-} d 6) δ11.54 (s, 1H), 8.89 (s, 1H), 7.11-7.25 (m, 3H), 6.78-6.79 (m, 1H), 6.68 (s, 2H ), 6.23 (t, 1H), 3.44 (d, 2H), 0.94 (s, 2H), 0.68 (s, 2H).

Example 2

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-(((1-((sulfamoylamino)methyl)cyclopropyl)methyl)amino)-1,2, 5-oxadiazole-3-carboindole 2

first step

((1-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxymethylindolyl-1,2,5-oxadiazol-3-yl)amino)methyl Cyclopropyl)methyl)carbamic acid tert-butyl ester 2b

1b (360 mg, 0.968 mmol) was dissolved in 30 mL of tetrahydrofuran, and ((1-(aminomethyl)cyclopropyl)methyl)carbamic acid tert-butyl ester 2a (387 mg, 1.935 mmol) was used, as disclosed in patent application "WO2009054468" The method was prepared by adding 2.9 mL of 2N sodium hydroxide solution and reacting at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to adjust the pH of the mixture to pH <7, and the mixture was extracted with EtOAc (EtOAc). Solid), the product was directly subjected to the next reaction without purification.

Second step

((1-((4-(4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)) -1,2,5-oxadiazol-3-yl)amino)methyl)cyclopropyl)methyl)carbamic acid tert-butyl ester 2c

The crude product 2b (650 mg, 1.3 mmol) was dissolved in 30 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (222 mg, 1.37 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals. The crude title product 2c (715 mg, brown brown solid).

third step

3-(4-((1-(Aminomethyl)cyclopropyl)methyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluoro) Phenyl)-1,2,4-oxadiazol-5(4H)-one 2d

The crude 2c (715 mg, 1.36 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added and allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

MS m/z (LC-MS): 427.0 [M+1]

the fourth step

N-((1-(((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-) -1,2,5-oxadiazol-3-yl)amino)methyl)cyclopropyl)methyl)sulfamoylcarbamic acid tert-butyl ester 2e

The chlorosulfonyl isocyanate (509 mg, 3.59 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, tert-butanol (267 mg, 3.59 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction liquid A. . The crude product 2d (1.021 g, 2.4 mmol) was dissolved in 20 mL of dichloromethane, and 1 mL of triethylamine was added to obtain a reaction liquid B. The reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted at 0 ° C for 1 hour. After the reaction is completed, the reaction mixture is quenched with saturated sodium hydrogen carbonate solution, and the organic layer is washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue was purified with EtOAcjjjjjjj

MS m/z (LC-MS): 621.0 [M+18]

the fifth step

N-({1-[({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- 1,1,2,5-oxadiazol-3-yl}amino)methyl]cyclopropyl}methyl)aminosulfonamide 2f

2e (282 mg, 0.466 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

MS m/z (LC-MS): 504.0 [M+1]

Step 6

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-(((1-((sulfamoylamino)methyl)cyclopropyl)methyl)amino)-1,2, 5-oxadiazole-3-carboindole 2

The crude product 2f (386 mg, 0.765 mmol) was dissolved in methanol (10 mL), and potassium carbonate (528 mg, 3.86 mmol) was added and reacted at 50 ° C for 1 hour. After the completion of the reaction, the mixture was neutralized with a saturated aqueous solution of ammonium chloride, and the mixture was separated. The residue obtained was purified to afford title product 2 (180 mg, white solid)

MS m/z (ESI): 478.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ11.47 (s, 1H), 8.89 (s, 1H), 7.19 (t, 1H), 7.10-7.12 (m, 1H), 6.78-6.79 (m, 1H ), 6.77 (t, 1H), 6.49 (s, 2H), 6.14 (t, 1H), 3.23 (d, 2H), 2.86 (d, 2H), 0.48 (s, 4H).

Example 3

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-1,2,5- Oxadiazole-3-carboindole 3

first step

(1-(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxymethylindolyl)-1,2,5-oxadiazol-3-yl)amino) Ethyl)cyclopropyl)carbamic acid tert-butyl ester 3b

1b (210 mg, 0.564 mmol) was dissolved in 20 mL of tetrahydrofuran, and tert-butyl ester (1-(2-aminoethyl)cyclopropyl)carbamic acid 3a (240 mg, 1.19 mmol) was added, using the method disclosed in the patent application "WO2013020993" Prepared), 1.5 mL of 2N sodium hydroxide solution was added and reacted at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to adjust the pH of the reaction solution to <7, and extracted three times with ethyl acetate. The residue was dried over anhydrous sodium

MS m/z (LC-MS): 497.1 [M-1]

Second step

(1-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -1,2,5-oxadiazol-3-yl)amino)ethyl)cyclopropyl)carbamic acid tert-butyl ester 3c

The crude product 3b (370 mg, 0.74 mmol) was dissolved in 15 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (126 mg, 0.78 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals. The crude title product 3c (350 mg, yellow solid).

MS m/z (LC-MS): 523.0 [M-1]

third step

3-(4-((2-(1-Aminocyclopropyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) )-1,2,4-oxadiazole-5(4H)-one 3d

The crude product 3c (350 mg, 0.666 mmol) was dissolved in 5 mL dichloromethane. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

the fourth step

N-(1-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3) -yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)cyclopropyl)sulfamoylcarbamic acid tert-butyl ester 3e

The chlorosulfonyl isocyanate (145 mg, 1.024 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, tert-butanol (76 mg, 1.025 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction solution A. . The crude product 3d (500 mg, 1.17 mmol) was dissolved in 20 mL of dichloromethane, and 1 mL of triethylamine was added to obtain a reaction liquid B. The reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted at 0 ° C for 1 hour. After the reaction is completed, the reaction mixture is quenched with saturated sodium hydrogen carbonate solution, and the organic layer is washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified with EtOAc EtOAc (EtOAc)

MS m/z (LC-MS): 602.0 [M-1]

the fifth step

N-{1-[2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]cyclopropyl}aminosulfonamide 3f

3e (180 mg, 0.298 mmol) was dissolved in 40 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

Step 6

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-1,2,5- Oxadiazole-3-carboindole 3

The crude product 3f (223 mg, 0.44 mmol) was dissolved in 15 mL of methanol, and potassium carbonate (380 mg, 2.75 mmol) was added and reacted at 50 ° C for 1 hour. After the completion of the reaction, the mixture was neutralized with a saturated aqueous solution of ammonium chloride, and the mixture was separated. The residue obtained was purified to afford titled product (yield: EtOAc, EtOAc:

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

^{1 H NMR (400MHz, DMSO-} d 6) δ11.45 (s, 1H), 8.89 (s, 1H), 7.19 (t, 1H), 7.07-7.10 (m, 2H), 6.77-6.78 (m, 1H ), 6.60 (s, 2H), 6.13 (t, 1H), 3.38-3.43 (m, 2H), 1.82 (t, 2H), 0.88 (t, 2H), 0.46 (t, 2H).

Example 4

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((3-hydroxy-2-(sulfamoylamino)propyl)amino)-1,2,5-oxadiazole -3-甲脒4

first step

4-(((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxymethylindolyl)-1,2,5-oxadiazol-3-yl)amino)methyl) -2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester 4b

1b (505 mg, 1.54 mmol) was dissolved in 30 mL of tetrahydrofuran, and 4-(aminomethyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester 4a (630 mg, 2.73 mmol) was used. Apply for "WO2013020993" Prepared by the disclosed method), 4 mL of 2N sodium hydroxide solution was added, and the reaction was carried out for 30 minutes at room temperature. After completion of the reaction, a saturated ammonium chloride solution was added to adjust the pH of the solution to 9 and ethyl acetate. Solid), the product was directly subjected to the next reaction without purification.

MS m/z (LC-MS): 529.1 [M-1]

Second step

4-(((4-(4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1 , 2,5-oxadiazol-3-yl)amino)methyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester 4c

The crude product 4b (667 mg, 1.26 mmol) was dissolved in 20 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (225 mg, 1.38 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals. The crude title product 4c (710 mg, EtOAc) elute.

MS m/z (LC-MS): 555.1 [M-1]

third step

(1-((4-(4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1 , 2,5-oxadiazol-3-yl)amino)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester 4d

The crude product 4c (710 mg, 1.28 mmol) was dissolved in 20 mL of methanol, and p-toluenesulfonic acid monohydrate (124 mg, 0.65 mmol) was added and allowed to react at room temperature for 12 hours. After the reaction was completed, the reaction mixture was combined with EtOAc EtOAc (EtOAc m. The residue was purified by EtOAc EtOAc (EtOAc)

MS m/z (LC-MS): 513.0 [M-1]

the fourth step

3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1, 2,5-oxadiazol-3-yl)amino)-2-((tert-butoxycarbonyl)amino)propyl acetate 4e

4d (310 mg, 0.60 mmol) was dissolved in 30 mL of dichloromethane, 0.18 mL of triethylamine was added, and the mixture was cooled to 0 ° C, and acetyl chloride (0.066 mL, 0.92 mmol) was added dropwise and reacted at 0 ° C for 1 hour. After the reaction was completed, a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was evaporated. EtOAcjjjjjjjj The product was directly subjected to the next step without purification.

MS m/z (LC-MS): 556.0 [M-1]

the fifth step

2-amino-3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -1,2,5-oxadiazol-3-yl)amino)propyl acetate trifluoroacetate 4f

The crude product 4e (300 mg, 0.538 mmol) was dissolved in dichloromethane (5 mL), and then, 3mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was evaporated.

Step 6

3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1, 2,5-oxadiazol-3-yl)amino)-2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)propyl acetate 4g

Chlorosulfonyl isocyanate (120 mg, 0.848 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, tert-butanol (63 mg, 0.849 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction liquid A. The crude product 4f (510 mg, 1.11 mmol) was dissolved in 10 mL of dichloromethane, and 1 mL of triethylamine was added to obtain a reaction liquid B. The reaction liquid A was added to the reaction liquid B at room temperature, and reacted at room temperature for 1 hour. After the reaction is completed, the reaction mixture is quenched by the addition of a saturated sodium hydrogencarbonate solution, and the organic phase is washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure The resulting residue was purified to give the titled product 4 g (238 mg,yel.

MS m/z (LC-MS): 653.0 [M+18]

Seventh step

3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1, 2,5-oxadiazol-3-yl)amino)-2-(sulfamoylamino)propyl acetate 4h

4 g (238 mg, 0.37 mmol) was dissolved in 5 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

Eighth step

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((3-hydroxy-2-(sulfamoylamino)propyl)amino)-1,2,5-oxadiazole -3-甲脒4

The crude product was dissolved in 20 mL of methanol, and then potassium carbonate (600 mg, 4.35 mmol) was added and reacted at 50 ° C for 1.5 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjj

MS m/z (ESI): 468.1 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ11.47 (s, 1H), 8.87 (s, 1H), 7.12-7.19 (m, 2H), 6.77-6.78 (m, 2H), 6.61 (d, 1H ), 6.56 (s, 1H), 6.20-6.22 (m, 1H), 4.82 (t, 1H), 4.02-4.04 (m, 1H), 3.44 - 3.57 (m, 3H), 3.24 - 3.26 (m, 1H) ).

Example 5

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((3-methoxy-2-(sulfamoylamino)propyl)amino)-1,2,5-acean Diazole-3-carboxamidine 5

first step

(1-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxymethylindolyl)-1,2,5-oxadiazol-3-yl)amino)-3- Methoxypropan-2-yl)carbamic acid tert-butyl ester 5b

1b (756 mg, 2.03 mmol) was dissolved in 50 mL of tetrahydrofuran, and (1-amino-3-methoxypropan-2-yl)carbamic acid tert-butyl ester 5a (800 mg, 3.92 mmol) was used as disclosed in patent application "WO2012002577" The method was prepared by adding 6 mL of 2N sodium hydroxide solution and reacting at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was stirred to EtOAc EtOAc (EtOAc m. Solid), the product was directly subjected to the next reaction without purification.

MS m/z (LC-MS): 475.1 [M+1-28]

Second step

(1-((4-(4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1 , 2,5-oxadiazol-3-yl)amino)-3-methoxypropan-2-alkyl)-tert-butyl carbamate 5c

The crude product 5b (1 g, 1.99 mmol) was dissolved in 30 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (322 mg, 1.99 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals. The crude title product 5c (1 g, yellow solid).

third step

3-(4-((2-Amino-3-methoxypropyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) -1,2,4-oxadiazole-5(4H)-one 5d

The crude product 5c (1 g, 1.89 mmol) was dissolved in 10 mL of dichloromethane, and then 10 mL of trifluoroacetic acid was added and reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjj

MS m/z (LC-MS): 429.1 [M+1]

the fourth step

N-(1-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -1,2,5-oxadiazol-3-yl)amino)-3-methoxypropan-2-yl)sulfamoylcarbamic acid tert-butyl ester 5e

The chlorosulfonyl isocyanate (400 mg, 2.83 mmol) was dissolved in 30 mL of dichloromethane, cooled to 0 ° C, tert-butanol (210 mg, 2.83 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction liquid A. The crude product 5d (1.55 g, 3.6 mmol) was dissolved in 20 mL of dichloromethane, cooled to 0 ° C, and 2.5 mL of triethylamine was added to obtain a reaction liquid B. The reaction liquid A was added dropwise to the reaction liquid B at room temperature, and reacted at room temperature for 1 hour. After the reaction is completed, the reaction mixture is quenched with a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue obtained was purified to afford titled product 5e (1.3 g, m.

MS m/z (LC-MS): 625.0 [M+18]

the fifth step

N-[1-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl] -1,2,5-oxadiazol-3-yl}amino)-3-methoxypropan-2-yl]aminosulfonamide 5f

5e (410 mg, 0.67 mmol) was dissolved in 10 mL of dichloromethane, and 8 mL of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjj

Step 6

N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((3-methoxy-2-(sulfamoylamino)propyl)amino)-1,2,5-acean Diazole-3-carboxamidine 5

The crude product 5f (574 mg, 1.129 mmol) was dissolved in 10 mL of tetrahydrofuran, and 3 mL of 2N sodium hydroxide solution was added and reacted at room temperature for 15 minutes. After the completion of the reaction, the mixture was neutralized with a saturated aqueous solution of ammonium chloride, and the mixture was separated. The residue obtained was purified to afford title product 5 (150 mg, white solid).

MS m/z (ESI): 484.1 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ11.45 (s, 1H), 8.88 (s, 1H), 7.12-7.19 (m, 2H), 6.74-6.78 (m, 2H), 6.59 (s, 2H ), 6.20-6.2 (m, 1H), 3.61-3.63 (m, 1H), 3.43-3.46 (m, 2H), 3.25-3.36 (m, 2H), 3.28 (s, 3H).

Example 6

N-(3-chlorophenyl)-N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-1,2,5-oxadiazole- 3-甲脒6

first step

4-amino-N-(3-chlorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboindole 6b

3-Chloroaniline (4.7 g, 36.8 mmol) was dissolved in 100 mL of ethanol, and pre-formed 50 mL of 4-amino-N-hydroxy 1,2,5-oxadiazole-3-carbimidoyl chloride 6a (5 g, 30.8 mmol, an ethanol suspension prepared by a known method "Journal of the American Chemical Society, 2015, 137 (33), 10532-10535"), triethylamine (5.1 mL, 36.7 mmol) was added dropwise, and stirred. Reaction for 12 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

Second step

3-(4-Amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one 6c

6b (5 g, 19 mmol) was dissolved in 100 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (3.2 g, 19 mmol) was added, and the mixture was reacted at 70 ° C for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, ethyl acetate and 1N hydrochloric acid was added, and the organic layer was washed with a saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium The filtrate was concentrated under reduced pressure. EtOAc EtOAc m.

third step

4-(3-Chlorophenyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 6d

The crude 6c (800 mg, 2.86 mmol) was dissolved in 15 mL of trifluoroacetic acid, and 7 mL of hydrogen peroxide (30%) was added and reacted at 50 ° C for 12 hours. After the reaction was completed, ethyl acetate was added, and then a saturated sodium sulfite solution was added, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate. Chromatography of the residue obtained from EtOAc (EtOAc)

the fourth step

(1-(2-(4-(4-(3-Chlorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2 ,5-oxadiazol-3-yl)amino)ethyl)cyclopropyl)carbamic acid tert-butyl ester 6e

6d (320 mg, 1.03 mmol) and 3a (227 mg, 1.135 mmol) were dissolved in 20 mL of tetrahydrofuran, 1.1 mL of 1N sodium hydroxide solution was added, and the reaction was stirred for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to adjust the pH of the reaction mixture, and ethyl acetate was added, and the mixture was separated. The crude title product 6e (540 mg, pale yellow solid) was obtained.

the fifth step

3-(4-((2-(1-Aminocyclopropyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1, 2,4-oxadiazole-5(4H)-one 6f

The crude 6e (540 mg, 1.17 mmol) was dissolved in 15 mL of dichloromethane and then stirred and stirred for 1 hour with 10 mL of trifluoroacetic acid. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

Step 6

N-(1-(2-((4-(4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-) 1,2,5-oxadiazol-3-yl)amino)ethyl)cyclopropyl)sulfamoylcarbamic acid tert-butyl ester 6g

The chlorosulfonyl isocyanate (215 mg, 1.52 mmol) was dissolved in 15 mL of dichloromethane, cooled to 0 ° C, tert-butanol (113 mg, 1.52 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction liquid A. . The crude 6f (900 mg, 2.48 mmol) was dissolved in 30 mL of dichloromethane, and 1 mL of triethylamine was added to obtain a reaction liquid B. The reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted for 1 hour. After the reaction is completed, the reaction is quenched by the addition of a saturated sodium hydrogen carbonate solution, and the organic phase is washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The resulting residue was purified to afford the title product 6 g (270 mg, white solid).

Seventh step

N-{1-[2-({4-[4-(3-Chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]- 1,2,5-oxadiazol-3-yl}amino)ethyl]cyclopropyl}aminosulfonamide 6h

6 g (270 mg, 0.498 mmol) was dissolved in 10 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

Eighth step

N-(3-chlorophenyl)-N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-1,2,5-oxadiazole- 3-甲脒6

The crude product 6h (264 mg, 0.597 mmol) was dissolved in 30 mL of tetrahydrofuran, and 1.2 mL of a 2.5 M sodium hydroxide solution was added, and the reaction was stirred for 15 minutes. After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added, and the mixture was separated. The resulting residue was purified with EtOAcqqqqqq

MS m/z (ESI): 414.3 [M+1]

¹ H NMR (400 MHz, CD ₃ OD) δ 7.17 (t, 1H), 6.97-6.99 (m, 1H), 6.86 (t, 1H), 6.74 - 6.76 (m, 1H), 3.56 (t, 2H) , 1.93 (t, 2H), 1.00-1.03 (m, 2H), 0.59-0.62 (m, 2H).

Example 7

N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-1 , 2,5-oxadiazole-3-carboindole 7

The title material 7 (170 mg, white solid) was obtained from the title compound (yield: EtOAc).

MS m/z (ESI): 468.3 [M+1]

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.14-7.20 (m, 2H), 7.10-7.12 (m, 1H), 3.56 (t, 2H), 1.94 (t, 2H), 1.00-1.03 (m, 2H), 0.60-0.63 (m, 2H).

Example 8

N-(4-Fluoro-3-methylphenyl)-N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-1,2,5 -oxadiazole-3-carboindole 8

Using the synthetic route of Example 6, the first starting material was replaced by 6a and 4-fluoro-3-methylaniline to give the title product 8 (150 mg, white solid).

MS m/z (ESI): 414.3 [M+1]

¹ H NMR (400 MHz, CD ₃ OD) δ 6.87 (t, 1H), 6.78-6.81 (m, 1H), 6.68-6.72 (m, 1H), 3.53 (d, 2H), 2.20 (d, 3H) , 1.91 (t, 2H), 0.99-1.02 (m, 2H), 0.58-0.61 (m, 2H).

Example 9

N-(3-bromophenyl)-N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-1,2,5-oxadiazole- 3-甲脒9

Using the synthetic route of Example 6, the first starting material was replaced with 6a and 3-bromoaniline to give the title product 9 (50 mg, white solid).

MS m/z (ESI): 462.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD) δ 7.11 - 7.12 (m, 2H), 7.01 - 7.02 (m, 1H), 6.78-6.80 (m, 1H), 3.55 (t, 2H), 1.93 (t, 2H), 1.00-1.03 (m, 2H), 0.59-0.62 (m, 2H).

Example 10

N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-N-(m-methylphenyl)-1,2,5-oxadiazole-3 -甲脒10

Using the synthetic route of Example 6, the first starting material was replaced with 6a and m-toluidine to give the title product 10 (250 mg, white solid).

MS m/z (ESI): 396.3 [M+1]

¹ H NMR (400 MHz, CD ₃ OD) δ 7.08 (t, 1H), 6.84 (d, 1H), 6.64 (s, 1H), 6.63 (d, 1H), 3.52 (t, 2H), 2.27 (s) , 3H), 1.90 (t, 2H), 0.98-1.01 (m, 2H), 0.57-0.60 (m, 2H).

Example 11

N-(3-chloro-4-fluorophenyl)-N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-1,2,5- Oxadiazole-3-carboquinone 11

Using the synthetic route of Example 6, the first step of the material was replaced by 6a and 3-chloro-4-fluoroaniline to give the title product 11 (30 mg, brown solid).

MS m/z (ESI): 434.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD) δ 7.08 (t, 1H), 6.98-6.99 (m, 1H), 6.80-6.82 (m, 1H), 3.55 (t, 2H), 1.93 (t, 2H) , 1.01 (s, 2H), 0.61 (s, 2H).

Example 12

N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)amino)-N-(3-(trifluoromethyl)phenyl)-1,2,5 -oxadiazole-3-carboquinone 12

The title material 12 (105 mg, white solid) was obtained from the title compound.

MS m/z (ESI): 450.3 [M+1]

¹ H NMR (400 MHz, CD ₃ OD) δ 7.38 (t, 1H), 7.25 (d, 1H), 7.10 (s, 1H), 7.05 (d, 1H), 3.57 (t, 2H), 1.94 (t) , 2H), 1.00-1.03 (m, 2H), 0.59-0.62 (m, 2H).

Biological evaluation

The invention is further described below in conjunction with the test examples, but these examples are not intended to limit the scope of the invention.

Test Example 1:

1. Determination of the inhibitory activity of the compound of the present invention against human IDO1 protease

The human IDO1 protease activity in vitro was tested by the following method.

This method is used to determine the inhibitory effect of the compounds of the invention on the activity of human IDO1 protease.

First, experimental materials and instruments

1. Microplate reader (Synergy HT, BIOTEK)

2. Tryptophan (T0254-5G, Sigma-Aldrich)

3. Catalase is derived from bovine liver (C1345-1G, Sigma-Aldrich)

4, methylene blue (M9140-25G, Sigma-Aldrich)

5. L-ascorbate (A7631-25G, Sigma-Aldrich)

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

7. Trichloroacetic acid (T9159-100G, Aigma-Aldrich)

8, IDO1 gene (SC126221, Origene)

9, rosseta (CW0811A, Beijing Kangwei Century Biotechnology Co., Ltd.)

10. Vortex mixer (6776, Corning)

11, mini plate centrifuge (mini-p25, ABSON life science equipment)

Second, the experimental steps

Homemade IDO1 protease

The IDO1 gene was transferred into the PET30a plasmid by gene cloning technology and then transferred into competent E. coli rosseta; in liquid LB (Luria-Bertani) medium [according to the Guide to Molecular Cloning (J. Sambrook DW La Selva) was prepared by enlarging culture in each liter of medium, collecting the cells, sonicating, and eluting the column to elute the purified IDO1 protease.

Compound test experiment:

100 ul of enzyme (IDO1) was diluted 30 times with 3 mM of KPB to a concentration of 26 ng/ul of enzyme solution per well in a 96-well reaction plate (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as the reaction plate). Add 24 ul of enzyme solution. Add 24 ul of KPB buffer to blank wells [KPB buffer preparation (50 mM): Weigh KH ₂ PO ₄ 6.805 g into an 1000 ml beaker with an analytical balance, add deionized water to 900 ml with a measuring cylinder, and adjust the pH with 1 M KOH to 6.5, introduce it into a 1L measuring cylinder and replenish it to 1L. Store at 4 ° C]. Add 1 ul of compound or DMSO to the reaction wells to the corresponding wells. Prepare solution A: Take 250 ul of 500 mM L-ascorbate plus 1437 ul of KPB and mix at a maximum speed of 3 seconds for the vortex mixer. Solution B: 125 ul of 10 mM color ammonia acid plus 100 ul of 100000 units/ml of catalase, add 5 ul of 10 mM methylene blue, and finally add 1437 ul of KPB, and mix at a maximum speed of 3 seconds for the vortex mixer. Take 1500 ul of A solution and 1500 ul of B solution and mix for 3 seconds at the maximum speed on the votex. This mixture was then added to the reaction plate at 24 ul per well. The reaction plate was placed in a plate centrifuge for 15 seconds at the highest speed, and the reaction liquid was collected at the bottom. The shaker was mixed for 30 seconds, and incubated at 37 ° C for 1 h in a constant temperature incubator. In the reaction plate, 10 ul of 30% (w/v) trichloroacetic acid was added to each well, and incubated at 65 ° C for 15 minutes in an incubator. The plate was centrifuged at 4700 RPM on a centrifuge at room temperature for 5 minutes. 40 ul of supernatant was transferred from the reaction plate using a lance to a corresponding 96-well test plate (corning, #3599). Add 40 ul of 2% (w/v) 4-(dimethylamino)benzaldehyde/glacial acetic acid solution to each well and mix for 1 minute at maximum speed on the shaker. After incubation for 2 minutes at room temperature, the absorbance at 480 nm was read on Synergy HT (BIOTEK).

The protease inhibitory activity of the compound of the present invention against human IDO1 was measured by the above test, and the IC ₅₀ values measured are shown in Table 1.

Table 1 Inhibition of human IDO1 protease activity by the compounds of the present invention IC ₅₀

Example number	IC 50 (nM)
2	78
3	18

4	57
5	68
6	28
7	98
8	15
9	9
11	77
12	70

Conclusion: The compounds of the present invention have a significant inhibitory effect on the activity of human IDO1 protease.

Test Example 2: Determination of IDO protease inhibitory activity in Hela cells by the compound of the present invention

The IDO protease activity in Hela cells was tested by the following method.

This method was used to determine the inhibitory effect of the compounds of the invention on IDO protease activity in HeLa cells. (Note: HeLa cell line expresses indoleamine 2,3-dioxygenase (IDO) under the induction of interferon gamma (INF-γ))

First, experimental materials and instruments

1. Microplate reader (Synergy HT, BIOTEK)

2. Tryptophan (T0254-5G, Sigma-Aldrich)

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

4. Trichloroacetic acid (T9159-100G, Aigma-Aldrich)

5. HeLa cell line (CCL-2, ATCC)

Second, the experimental steps

A HeLa cell suspension was prepared from fresh cell culture medium, and added to a 100-well culture system 96-well cell culture plate at 10,000 cells/well, and cultured at 5% carbon dioxide at 37 ° C for 24 hours. The supernatant was removed, and 90 ul of serum-free DMEM high glucose medium was added to each well; then 10 ul of each compound formulated in INF-γ and tryptophan-containing medium was added to each well (the final concentration was: 100000, 10000, 1000). , 100, 10, 1 nM), 48 hours 5% carbon dioxide 37 ° C culture out of the 96-well cell culture plate supernatant 80ul to 96-well round bottom plate, add 16ul 30% (w / v) trichloroacetic acid per well, in the incubation Incubate at 65 ° C for 25 minutes in the chamber. The plate was centrifuged at 4700 RPM on a centrifuge for 5 minutes. Transfer 50 ul of supernatant from the reaction plate to a 96-well flat-bottom transparent plate with a lance, then add 50 ul of 2% (w/v) 4-(dimethylamino)benzaldehyde/glacial acetic acid solution to each well. Mix on for 1 minute. After incubation for 2 minutes at room temperature, the absorbance at 480 nm was read on a Synergy HT Reader.

The IDO protease inhibitory activity of the compound of the present invention against HeLa cells was measured by the above test, and the IC ₅₀ values measured are shown in Table 2.

Table 2 compounds of this invention inhibit the protease activity IC ₅₀ within the pair of Hela cells IDO

Example number	IC 50 (nM)
1	73

3	3
4	16
5	73
6	7
7	twenty four
8	6
9	5
10	59
11	14
12	15

Conclusion: The compounds of the present invention have a significant inhibitory effect on IDO protease activity in Hela cells.

Pharmacokinetic evaluation

Test Example 3, Pharmacokinetic Testing of Compounds of Examples 3, 6 and 8 of the Invention

1. Summary

SD rats were used as test animals, and the concentration of the drug in plasma at different times after intravenous administration of the compounds of Examples 3, 6 and 8 was measured by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2, the test plan

2.1 test drugs

Examples 3, 6 and 8 compounds

2.2 Test animals

Twelve healthy adult SD rats, male and female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3 drug preparation

An appropriate amount of the drug was weighed, dissolved in 0.3 ml of dimethylacetamide, and then 10% 2-hydroxypropyl-β-cyclodextrin was added to a final volume, and a 2.0 mg/ml suspension was prepared by ultrasonication.

2.4 administration

Twelve SD rats, male and female, were divided into 3 groups on average. After fasting overnight, they were intragastrically administered with a dose of 10 ml/kg.

3, operation

In the gavage administration group, 0.1 ml of blood was collected from the eyelids before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 h after administration, and placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 10 minutes. Store at 20 ° C and eat 2 h after dosing.

The content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method.

4, pharmacokinetic parameters results

Table 3 Pharmacokinetic parameters of the compounds of Examples 3, 6 and 8 of the present invention

Conclusion: The compound of the present invention has good absorption of the drug and has obvious pharmacological absorption effect.

Claims (16)

1. a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a compound thereof Medicinal salt:

   

   among them:

   

   a mixture selected from the group consisting of a cis isomer, a trans isomer or a cis and trans isomer;

   R ^{1 is} selected from the group consisting of an alkyl group, a cycloalkyl group, and an alkoxy group, wherein the alkyl group, the cycloalkyl group, and the alkoxy group are each independently optionally further selected from the group consisting of a hydroxyl group, an alkyl group, an alkoxy group, and a halogenated alkyl group. Substituted by one or more substituents;

   R ^{2 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and an alkoxy group, wherein the alkyl group, the cycloalkyl group, and the alkoxy group are each independently optionally further selected from the group consisting of a hydroxyl group, an alkyl group, an alkoxy group, and Substituting one or more substituents in the haloalkyl group;

   Or R ¹ and R ² together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further selected from the group consisting of alkyl, halogen, cyano, cycloalkyl , heterocyclyl, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -NHS(O) _m R ⁸ , -S(O) _p R ⁸ , -NHC(O Substituting one or more substituents of R ⁸ , —OR ⁸ , —C(O)R ⁸ , —OC(O)R ⁸ and —C(O)OR ⁸ ;

   R ³ and R ⁴ are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cyano group, an amino group, a halogen, an alkenyl group, an alkynyl group, a hydroxyl group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from the group consisting of hydroxyl, halogen, amino, cyano, alkyl, alkoxy, cycloalkyl, hetero Substituting one or more substituents of a cyclic group, an aryl group, and a heteroaryl group;

   R ^{5 is} selected from the group consisting of an alkyl group and an amino group, which are optionally further selected from the group consisting of a hydroxyl group, a halogen, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a hetero group. Substituting one or more substituents in the aryl group; the alkyl group is preferably a C _1-4 alkyl group;

   R ⁶ and R ⁷ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or hetero group The aryl groups are each independently optionally further substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

   R ^{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Optionally optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, amino, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

   m is 0, 1, 2;

   n is 0, 1, 2;

   p is 0, 1, 2.
2. A compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof a form, or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are each independently selected from a hydrogen atom, a halogen, an alkyl group, or a halogenated alkyl group, and the halogen is preferably fluorine, chlorine or bromine, and the alkyl group is preferably C. _{A 1-4} alkyl group, preferably a haloalkyl group.
3. The compound of the formula (I) according to claim 1 or 2, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a conformation, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

   

   among them:

   R ¹ is an alkyl group or an alkoxy group, and the alkyl group or alkoxy group is further substituted by one or more hydroxyl groups or alkoxy groups; preferably, R ¹ is an alkyl group substituted by a hydroxy group or an alkoxy group;

   

   R ³ to R ⁵ , m, n are as defined in claim 1.
4. The compound of the formula (I) according to claim 3 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein m is 0 and/or n is 1.
5. The compound of the formula (I) according to claim 1 or 2, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a conformation, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

   

   among them:

   A is a 3- to 8-membered ring wherein the ring is selected from a carbocyclic or heterocyclic ring;

   

   R ³ to R ⁵ , m, n are as defined in claim 1.
6. The compound of the formula (I) according to claim 5 or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein A is a cycloalkyl group, preferably a cyclopropyl group.
7. The compound of the formula (I) according to claim 6, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1 and/or n is 1 or 2.
8. The compound of the formula (I) according to any one of claims 1 to 7, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

   
9. A compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a method of the mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

   

   The compound of the formula (IV) is ring-opened under basic conditions to give a compound of the formula (I);

   among them:

   

   R ¹ to R ⁵ , m, n are as defined in claim 1.
10. a compound of the formula (IV) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a compound thereof Medicinal salt:

    

    among them:

    R ¹ to R ⁵ , m, n are as defined in claim 1.
11. The compound of the formula (IV) according to claim 10 or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (V) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof:

    

    Wherein: R ¹ , R ³ to R ⁵ , m, n are as defined in claim 10.
12. The compound of the formula (IV) according to claim 10 or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (VI) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof:

    

    among them:

    A is a 3- to 8-membered ring wherein the ring is selected from a carbocyclic or heterocyclic ring;

    R ³ to R ⁵ , m, n are as defined in claim 10.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to any one of claims 1 to 8, or a tautomer, a mesogen thereof, a racemate thereof An enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
14. The compound of the formula (I) according to any one of claims 1 to 8, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof , or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a composition according to claim 13 for the preparation of a disease for preventing and/or treating a pathological feature having an IDO-mediated tryptophan metabolism pathway Use in medicine.
15. The use according to claim 14, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, Alzheimer's disease, autoimmune disease, depression , anxiety, cataracts, psychological disorders and AIDS.
16. The use according to claim 15, wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, and kidney. Cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck cancer, Leukemia, lymphoma, myeloma and non-small cell lung cancer.