CN105646492B

CN105646492B - Substituted xanthine class compound and its preparation method and application containing five yuan of heteroaromatics

Info

Publication number: CN105646492B
Application number: CN201410645621.5A
Authority: CN
Inventors: 黄海洪; 申竹芳; 李刚; 袁保昆; 环奕; 姜茜; 林紫云; 唐武; 刘泉; 刘率男; 李彩娜
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2014-11-14
Filing date: 2014-11-14
Publication date: 2019-04-09
Anticipated expiration: 2034-11-14
Also published as: CN105646492A

Abstract

The invention discloses the substituted xanthine class compounds and its preparation method and application for containing five yuan of heteroaromatics.Specifically, the present invention relates to the compound and its stereoisomer of formula (I), pharmaceutically acceptable salt, as used in the description.The invention further relates to the pharmaceutical compositions comprising the compounds of this invention, the compounds of this invention is preparing the purposes in the drug for treating and/or preventing to over-express the method for related disease or illness with DPP-IV hyperactivity or with DPP-IV, and the method using the compounds of this invention treatment related disease.The compounds of this invention has effective DPP-IV inhibitory activity.

Description

Substituted xanthine compound containing five-membered aromatic heterocycle and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines. Relates to a substituted xanthine compound containing five-membered aromatic heterocycle shown in general formula (I), and pharmaceutically acceptable salt and isomer thereof, preparation of the compound, a pharmaceutical composition containing the compound and application of the compound in preventing and/or treating diabetes, hyperlipoidemia, obesity and metabolic syndrome, in particular to application in inhibiting DPP-IV.

Background

Diabetes Mellitus (DM) is a chronic metabolic disease of multiple etiologies that severely affects patient health and quality of life. By the end of 2013, the number of diabetics is about 3.82 hundred million globally, and is estimated to reach 5.92 hundred million in 2035 years. According to statistics, the number of Diabetes in 2013 is about 0.984 million, which is located at the first of the world, and the number of Diabetes will increase to 1.42 million by 2035 (International Diabetes Federation,2013 Update). Diabetes has become the 3 rd leading killer threatening human health following cardiovascular disease and tumors.

Diabetes mellitus is classified into insulin-dependent diabetes mellitus (IDDM, i.e., type 1 diabetes mellitus) and non-insulin-dependent diabetes mellitus (noninsulin-dependent diabetes mellitus NIDDM, i.e., type2diabetes mellitus), of which type2diabetes mellitus is the most common and accounts for more than 90% of the total number of diabetic patients, and clinically, drugs for treating diabetes mellitus mainly include insulin secretagogues (sulfonylureas, repaglinides), insulin sensitizers (biguanides, thiazolidinediones), α glucosidase inhibitors (acarbose), and the like, but diabetic patients often suffer from reduced sensitivity and reactivity to insulin due to factors such as gene defects, body function deterioration, environment, and the like, so that the drugs are secondarily disabled and have adverse reactions such as hypoglycemia, weight gain, cardiovascular side effects, and the like [ Kahn Med SE, Haffner SM, et al. glycydig. systemic toxicity of diabetes mellitus, formamemin, mor, and monobutyl ] urgent development of new drugs [ 3580J-3577, and thus, a new drug is required.

The research shows that GLP-1 can promote the release of insulin and inhibit the secretion of glucagon when blood sugar rises, can stimulate the expression of an insulin gene, promote the synthesis of the insulin and the proliferation of β cells, and participate in the regulation of the blood sugar homeostasis of an organism through a plurality of ways of acting on neurons which promote satiety of a hypothalamus, inhibiting appetite, reducing food intake and the like.

Dipeptidyl peptidase-IV (DPP-IV) is a novel target for the treatment of type2diabetes, a highly specific serine protease that exists in a dimeric form. DPP-IV is highly expressed in the intestine, and is also expressed in the liver, pancreas, placenta, thymus, spleen, etc., and is present in the circulating blood partially in a soluble form. Specifically recognizing the alanine residue at the 2 nd position of the N-terminus of GLP-1 and cleaving the dipeptide therefrom to inactivate GLP-1. DPP-IV inactivates GLP-1 rapidly and irreversibly, resulting in an extremely short half-life of endogenously produced active GLP-1. Therefore, the DPP-IV inhibitor can prolong the half-life of plasma GLP-1, promote insulin secretion, inhibit inappropriate secretion of glucagon, control blood sugar level and not cause side effects of hypoglycemia and weight gain, and is a research and development hotspot of medicaments for treating type2diabetes due to clear action targets. Currently, the commercially available DPP-IV inhibitors comprise sitagliptin, saxagliptin, vildagliptin, linagliptin and the like.

DPP-IV belongs to the serine peptidase family, and also DPP2, DPP8, DPP9, FAP, POP and the like are commonly belonging to the family. Animal model experimental results show that inhibition of DPP8/9 causes toxic reactions such as anemia, alopecia, thrombocytopenia, and splenomegaly [ Lankas GR, Leiting B, et al. Therefore, the design and development of selective inhibitors against a single DPP-IV target have important significance [ Bhumika DP, Manjunath DG.Recentryproaches to Medicinal Chemistry and therapeutic potential of dipeptidylpeptidase-4(DPP-4) inhibitors, European Journal of Medicinal Chemistry 2014,74:574-605], which is also a difficult and critical point for the development of novel selective DPP-IV inhibitors.

Therefore, there is still a need in the art for new and potent selective DPP-IV inhibitors to meet the needs of clinical therapy.

Disclosure of Invention

The invention aims to provide a compound which has a novel structure and strong activity and has DPP-IV inhibition effect. The inventor finds that the substituted xanthine compound containing the five-membered aromatic heterocycle with the novel structure has DPP-IV inhibitory activity and better selectivity on DPP-IV, and can be used for preventing and treating diabetes. The present invention has been completed based on the above findings.

Summary of The Invention

To this end, the present invention provides, in a first aspect, compounds of formula (I) and stereoisomers thereof, and pharmaceutically acceptable salts thereof,

wherein,

x is independently selected from C, N;

ring B is independently selected from five-membered heteroaryl groups containing 1-4 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur;

r is independently selected from hydrogen and C_1-10Alkyl radical, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-8Cycloalkyl radical, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_6-10aryl-C_1-3Alkyl radical, C_3-7heteroaryl-C_1-3Alkyl, heterocycloalkyl containing from 3 to 9 carbon atoms and from 1 to 3 heteroatoms chosen from nitrogen, oxygen, sulfur, C_6-10Aryl, heteroaryl containing 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, amino, substituted amino;

wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl radical, C_6-10Aryl radical, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryl radicalOxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

wherein said substituted amino is optionally substituted with 1-2 of the following groups: c_1-6An alkyl group.

m is independently selected from 0, 1,2 or 3.

A compound according to any one of the first aspect of the invention which is a compound of formula (IA), a pharmaceutically acceptable salt thereof,

wherein,

wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl radical, C_6-10Aryl radical, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formazanAcyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

wherein said substituted amino is optionally substituted with 1-2 of the following groups: c_1-6An alkyl group;

m is independently selected from 0, 1,2 or 3.

A compound according to any one of the first aspect of the invention which is a compound of formula (I B), a pharmaceutically acceptable salt thereof,

wherein,

wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroAryl groups may be unsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl radical, C_6-10Aryl radical, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

m is independently selected from 0, 1,2 or 3.

A compound according to any one of the first aspect of the invention which is a compound of formula (IAa), a pharmaceutically acceptable salt thereof,

wherein,

y, Z, P and Q are the same or different and are each independently selected from C, N, O, S;

r is independently selected from hydrogen and C_1-10Alkyl radical, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-8Cycloalkyl radical, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_6-10aryl-C_1-3Alkyl radical, C_3-7heteroaryl-C_1-3Alkyl radical, containing 3-9Heterocycloalkyl of carbon atoms and 1-3 hetero atoms chosen from nitrogen, oxygen, sulfur, C_6-10Aryl, heteroaryl containing 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, amino, substituted amino;

m is independently selected from 0, 1,2 or 3.

A compound according to any one of the first aspect of the invention which is a compound of formula (IBa), a pharmaceutically acceptable salt thereof,

wherein,

l is independently selected from C, N;

m is independently selected from 0, 1,2 or 3.

A compound according to any one of the first aspect of the invention which is a compound of formula (IAa-1), a pharmaceutically acceptable salt thereof,

r is independently selected from C_1-10Alkyl radical, C_3-8Cycloalkyl radical, C_6-10Aryl, heteroaryl containing 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur;

wherein said alkyl, cycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl radical, C_6-10Aryl radical, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

A compound according to any one of the first aspect of the invention which is a compound of formula (IAa-2), a pharmaceutically acceptable salt thereof,

wherein said alkyl group,Cycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl radical, C_6-10Aryl radical, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

A compound according to any one of the first aspect of the invention which is a compound of formula (IAa-3), a pharmaceutically acceptable salt thereof,

A compound according to any one of the first aspect of the invention which is a compound of formula (IAa-4), a pharmaceutically acceptable salt thereof,

R₁、R₂independently selected from C_1-10Alkyl radical, C_3-8Cycloalkyl radical, C_6-10Aryl, heteroaryl containing 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur;

wherein said alkyl, cycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl radical, C_6-10Aryl radical, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl radicalFormyl radical, C_4-9A heteroaryloxycarbonyl group;

A compound according to any one of the first aspect of the invention which is a compound of formula (IAa-5), a pharmaceutically acceptable salt thereof,

A compound according to any one of the first aspect of the invention which is a compound of formula (IBa-1), a pharmaceutically acceptable salt thereof,

A compound according to any one of the first aspect of the invention which is a compound of formula (IBa-2), a pharmaceutically acceptable salt thereof,

r is independently selected from C_1-10Alkyl radical, C_3-8Cycloalkyl radical, C_6-10Aryl, containing 1 to 9 carbon atoms and 1 to 4 substituents selected fromHeteroaryl of heteroatoms of nitrogen, oxygen, sulfur;

A compound according to any one of the first aspect of the invention which is a compound of formula (IBa-3), a pharmaceutically acceptable salt thereof,

A compound according to any one of the first aspect of the invention which is a compound of formula (IBa-4), a pharmaceutically acceptable salt thereof,

wherein said alkyl, cycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl radical, C_6-10Aryl radical, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylCarbamoyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

A compound according to any one of the first aspect of the invention which is a compound of formula (IBa-5), a pharmaceutically acceptable salt thereof,

A compound according to any one of the first aspect of the invention which is a compound of formula (IBa-6), a pharmaceutically acceptable salt thereof,

A compound according to any one of the first aspect of the invention which is a compound of formula (IBa-7), a pharmaceutically acceptable salt thereof,

r is independently selected from C_1-10Alkyl, aryl, heteroaryl, and heteroaryl,C_3-8Cycloalkyl radical, C_6-10Aryl, heteroaryl containing 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur;

The compound according to the first aspect of the present invention, which is a pharmaceutically acceptable salt thereof, is characterized in that in the compound,

x is preferably C, N;

ring B is preferably selected from substituted or unsubstituted oxadiazole, substituted or unsubstituted pyrazole, substituted or unsubstituted triazole, substituted or unsubstituted tetrazole, substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted imidazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted isoxazole;

R、R₁、R₂preferably methyl, isopropyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl;

wherein said substituents may be unsubstituted or optionally substituted with 1 to 4 groups selected from: trifluoromethyl, trifluoromethoxy, substituted amino, nitro, fluoro, chloro, bromo, C_1-6Alkyl radical, C_1-6An alkyloxy group.

The pharmaceutically acceptable salts described in the present invention are salts of the compounds of the present invention with an acid selected from the group consisting of: hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid. Preferably hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid or trifluoroacetic acid.

A compound according to any one of the first aspect of the present invention, which is the subject compound of the present invention prepared in the examples (represented by structural formula or described by systematic name) and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

A compound according to any one of the first aspect of the invention, which is a compound selected from:

in a second aspect, the present invention provides a process for the preparation of a compound according to any one of the first aspect of the invention, comprising the steps of:

step one

Reacting the compound represented by formula 1a with (R) -3- (tert-butoxycarbonyl) aminopiperidine in a solvent (e.g., N-dimethylformamide) in the presence of a base (e.g., potassium carbonate) at a temperature of 50 ℃ to 100 ℃ (e.g., 50 ℃ to 70 ℃, 60 ℃ to 80 ℃ or 80 ℃ to 100 ℃) for about 6-24 hours to obtain a compound represented by formula 2 a;

step two (method 1)

Reacting the compound represented by formula 2a with 1, 3-dibromopropane in a solvent (e.g., N-dimethylformamide) in the presence of a base (e.g., potassium carbonate) at a temperature of 10 ℃ to 40 ℃ (e.g., 10 ℃ to 35 ℃, 15 ℃ to 30 ℃,20 ℃ to 30 ℃, or 20 ℃ to 25 ℃) for about 3 to 12 hours to give a compound represented by formula 3 a-1;

step two (method 2)

Reacting the compound represented by formula 2a with 3-bromopropanol in a solvent (e.g., N-dimethylformamide) in the presence of a base (e.g., potassium carbonate) at a temperature of 40 ℃ to 80 ℃ (e.g., 40 ℃ to 55 ℃, 45 ℃ to 60 ℃, 50 ℃ to 65 ℃, or 65 ℃ to 80 ℃) for about 3-12 hours to obtain a compound represented by formula 2 a-1;

reacting a compound represented by formula 2a-1 with a sulfonyl chloride (e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.) in a solvent (e.g., dichloromethane) at a temperature of 0 ℃ to 30 ℃ (e.g., 0 ℃ to 25 ℃,20 ℃ to 30 ℃, or 25 ℃ to 30 ℃) in the presence of a base (e.g., triethylamine) for 1-2h to give a compound represented by formula 3 a-2;

step three:

reacting the compound of formula 3a with an aliphatic heterocyclic amine b in a solvent (e.g., N-dimethylformamide) in the presence of a base (e.g., diisopropylethylamine) at a temperature of 50 ℃ to 100 ℃ (e.g., 50 ℃ to 70 ℃, 60 ℃ to 80 ℃, or 80 ℃ to 100 ℃) for about 6-24 hours to give a compound of formula c;

step four:

stripping the Boc protecting group from the compound of formula c in a 25% trifluoroacetic acid/dichloromethane solution at a temperature of 10 ℃ to 40 ℃ (e.g., 10 ℃ to 35 ℃, 15 ℃ to 30 ℃,20 ℃ to 30 ℃, or 20 ℃ to 25 ℃) to provide the compound of the invention of formula I;

wherein,

ring B, R, X and m are as defined in the first aspect of the invention;

g is independently selected from Cl, Br, I, OMs, OTf, OTs.

In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.

The fourth aspect of the present invention provides a compound according to the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the present invention for use in the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with hyperphosphatemia of DPP-IV or with overexpression of DPP-IV. In one embodiment, the disease or condition associated with DPP-IV hyperactivity or DPP-IV overexpression is a disease or condition selected from: diabetes, hyperlipidemia, obesity, and metabolic syndrome.

The fourth aspect of the present invention also provides a use of a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspect of the present invention for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes, hyperlipidemia, obesity, and metabolic syndrome.

The fourth aspect of the present invention also provides a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspect of the present invention for use in the manufacture of a medicament for use as a DPP-IV inhibitor.

In a fifth aspect, the present invention provides a method for the treatment and/or prevention of a disease or condition associated with DPP-IV hyperactivity or DPP-IV overexpression in a subject in need thereof, which method comprises administering to the subject in need thereof a therapeutically and/or prophylactically effective amount of a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspect of the present invention. The method according to the fifth aspect of the present invention, wherein the disease or disorder associated with DPP-IV hyperactivity or DPP-IV overexpression is selected from diabetes, hyperlipidemia, obesity and metabolic syndrome.

The fifth aspect of the present invention also provides a method for the treatment and/or prophylaxis of diabetes, hyperlipidemia, obesity and metabolic syndrome in a subject in need thereof, which comprises administering to the subject in need thereof a therapeutically and/or prophylactically effective amount of a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspect of the present invention.

In a sixth aspect, the present invention provides a compound according to any one of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a disease or condition associated with DPP-IV hyperactivity or DPP-IV overexpression. A compound according to a sixth aspect of the present invention, wherein said disease or condition associated with DPP-IV hyperactivity or DPP-IV overexpression is selected from: diabetes, hyperlipidemia, obesity, and metabolic syndrome.

The sixth aspect of the present invention also provides a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of diabetes, hyperlipidemia, obesity and metabolic syndrome.

Any aspect of the invention or any one of the aspects having features is equally applicable to any other aspect or any one of the other aspects as long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. In the present invention, for example, reference to "any of the first aspects of the invention" means any sub-aspect of the first aspects of the invention, and in other respects similarly referred to, has similar meaning.

Detailed description of the invention:

various aspects and features of the disclosure are described further below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure. The following are definitions of various terms used herein, which apply to the terms used throughout the specification of the present application unless otherwise specified in specific instances. Definitions for various groups of the compounds of the present invention are provided below and, unless otherwise defined, are used uniformly throughout the specification and claims.

As referred to herein, "a five-membered heteroaryl group containing 1 to 4 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur" includes a five-membered heteroaryl group containing 1 carbon atom and 4 heteroatoms selected from nitrogen, oxygen, sulfur, and a specific group such as a tetrazolyl group, preferably a tetrazolyl group; a five-membered heteroaryl group containing 2 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur, and specific groups such as 1,2, 3-triazolyl, 1,2, 4-triazolyl, oxadiazolyl, thiadiazolyl, preferably 1,2, 3-triazolyl, 1,2, 4-triazolyl, oxadiazolyl, thiadiazolyl; five-membered heteroaryl containing 3 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, and specific groups such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, preferably imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl; five-membered heteroaryl containing 4 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, and specific groups such as pyrrolyl, furanyl, thienyl, preferably pyrrolyl, furanyl, thienyl.

As referred to herein, the terms "halo", "halogen atom", "halo" and the like denote fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine.

As referred to herein, the term "alkyl" refers to an alkyl group having the indicated number of carbon atoms, which may be straight or branched, such as the indicated "C_1-10The "alkyl group" means an alkyl group having 1,2,3, 4,5, 6, 7, 8, 9 or 10 carbon atoms and may include C_1-9Alkyl radical, C_1-8Alkyl radical, C_2-10Alkyl radical, C_2-9Alkyl radical, C_2-8Alkyl radical, C_3-10Alkyl radical, C_3-9Alkyl radical、C_3-8Alkyl group, etc., and preferable specific groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, and further preferable are methyl group and isopropyl group. For example said "C_1-6Alkyloxy group and C_1-6Alkyl formyl group and C_1-6Alkyl oxygen formyl radical "or" C_1-6C in alkyl_1-6Alkyl "refers to an alkyl group having 1,2,3, 4,5, 6 carbon atoms, and may include C_1-5Alkyl radical, C_1-4Alkyl radical, C_2-6Alkyl radical, C_2-5Alkyl radical, C_2-4Alkyl radical, C_3-6Alkyl radical, C_3-5Alkyl radical, C_3-4Alkyl, etc., and preferable specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and methyl is more preferable. For example said "C_6-10aryl-C_1-3Alkyl "or" C_3-7heteroaryl-C_1-3C in alkyl_1-3Alkyl "refers to an alkyl group having 1,2,3 carbon atoms, and may include C_1-2Alkyl radical, C_2-3Alkyl, etc., and preferred specific groups are methyl, ethyl, n-propyl, isopropyl.

As referred to herein, the term "cycloalkyl" refers to a cyclic alkyl group having the indicated number of ring carbon atoms, e.g., as referred to as "C_3-8When "cycloalkyl" is used, it means a cycloalkyl group having 3, 4,5, 6, 7, 8 carbon atoms and may include C_3-7Cycloalkyl radical, C_3-4Cycloalkyl radical, C_4-6Cycloalkyl groups and the like, and preferred specific groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and further preferred are cyclopropyl, cyclopentyl, cyclohexyl. For example said "C_3-7Cycloalkyloxy group "," C_3-7Cycloalkylcarboxoyl "," C_3-7Cycloalkanoyloxyformyl "or" C_3-7"C in cycloalkyl_3-7Cycloalkyl means a group having 3, 4,5, 6 carbon atoms,7 cycloalkyl group, which may include C_3-6Cycloalkyl radical, C_3-5Cycloalkyl radical, C_4-5Cycloalkyl group and the like, and preferred specific groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and further preferred are cyclopropyl, cyclopentyl, cyclohexyl.

As referred to herein, "heterocycloalkyl group containing 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur" means a cyclic heteroalkyl group having the indicated number of ring atoms, including monocyclic or fused ring groups, having 4 to 10 ring atoms in the ring, wherein 1 to 3 ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. These rings may also have one or more double bonds, but these rings do not have a completely conjugated pi-electron system. Alkyl groups containing 3 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups are 1, 3-glycidylalkyl, 1, 3-cycloaziridinyl, 1, 3-cyclothiodipropyl, 4, 5-tetrahydrooxazolyl; alkyl containing 4 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are tetrahydrofuranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl; alkyl containing 5 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are piperidinyl, homopiperazinyl; alkyl having 7 carbon atoms and 1 to 2 hetero atoms selected from nitrogen, oxygen, sulfur, preferred embodiments are octahydrobenzoxazolyl; alkyl containing 8 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, with particular groups preferred such as octahydroindolyl; alkyl groups containing 9 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, with particular groups preferred such as decahydroquinolinyl.

"C" as referred to in the invention_3-7Heterocycloalkyloxy group (C)_3-7Heterocycloalkylcarbonyl group "," C_3-7Heterocycloalkyloxycarbonyl radical "or" C_3-7C in heterocycloalkyl_3-7Heterocycloalkyl, meaning a heterocycloalkyl group containing from 3 to 7 carbon atoms and from 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur, meaning a cyclic heteroalkyl group having the indicated number of ring atoms, includingIncluding monocyclic or fused ring groups having 4 to 9 ring atoms in the ring, wherein 1 to 3 ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon; these rings may also have one or more double bonds, but these rings do not have a completely conjugated pi-electron system; alkyl groups containing 3 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups are 1, 3-glycidylalkyl, 1, 3-cycloaziridinyl, 1, 3-cyclothiodipropyl, 4, 5-tetrahydrooxazolyl; alkyl containing 4 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are tetrahydrofuranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl; alkyl containing 5 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are piperidinyl, homopiperazinyl; alkyl groups containing 7 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, with particular preference given to octahydrobenzoxazolyl groups.

"C" as referred to in the invention_6-10aryl-C_1-3Alkyl "or" C_6-10"C in" aryl_6-10The "aryl group" means an aryl group having 6, 7, 8, 9 or 10 carbon atoms, and specific preferred groups include phenyl, naphthyl and the like, and phenyl is more preferred.

As referred to herein, the term "aryl" is defined herein, alone or in combination, as a monocyclic or bicyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like. Similarly, the term "aryloxy-" refers to an aryl group that is attached to the rest of the compound through an oxygen.

As referred to herein, "heteroaryl group containing 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur" means an aryl group having 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, the heteroatoms including oxygen, sulfur and nitrogen. Including aryl groups containing 1 carbon atom and 4 heteroatoms selected from nitrogen, oxygen, sulfur, with particular groups such as tetrazolyl being preferred; aryl containing 2 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as 1,2, 3-triazolyl, 1,2, 4-triazolyl, oxadiazolyl, thiadiazolyl; aryl containing 3 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl; aryl containing 4 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, with preferred embodiments such as pyrrolyl, furyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl; aryl containing 5 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, preferred embodiments are e.g. pyridyl, preferably pyridyl; aryl containing 6 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are groups such as benzotriazolyl; aryl containing 7 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are benzimidazolyl, benzpyrazolyl; aryl containing 8 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, with preferred embodiments such as indolyl, benzofuranyl, benzothienyl, benzopyrazinyl, benzopyrimidinyl, and benzopyrazinyl; aryl containing 9 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, with particular preference given to quinolinyl, isoquinolinyl.

"C" as referred to in the invention_3-7heteroaryl-C_1-3Alkyl "or" C_3-7"C in" heteroaryl group_3-7Heteroaryl "refers to an aryl group having 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, the heteroatoms including oxygen, sulfur and nitrogen. Aryl groups comprising 3 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl; aryl containing 4 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, with preferred embodiments such as pyrrolyl, furyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl; aryl containing 5 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, with particular preference being given to pyridyl; aryl containing 6 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are groups such as benzotriazolyl; containing 7 carbon atoms and 2 hetero atoms selected from nitrogen, oxygen, sulfurAryl, preferred embodiments are benzimidazolyl, benzpyrazolyl.

"C" as referred to in the invention_4-9Heteroaryloxy group and C_4-9Heteroaryl formyl "," C_4-9Heteroaryloxycarbonyl "or" C_4-9"C in" heteroaryl group_4-9Heteroaryl "refers to an aryl group having 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, the heteroatoms including oxygen, sulfur and nitrogen. Aryl groups comprising 4 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, with particular groups being preferred such as pyrrolyl, furyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl; aryl containing 5 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, with particular preference being given to pyridyl; aryl containing 6 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are groups such as benzotriazolyl; aryl containing 7 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are benzimidazolyl, benzpyrazolyl; aryl containing 8 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, with preferred embodiments such as indolyl, benzofuranyl, benzothienyl, benzopyrazinyl, benzopyrimidinyl, and benzopyrazinyl; aryl containing 9 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, with particular preference given to quinolinyl, isoquinolinyl.

As referred to herein, the term "effective amount" refers to a dose that achieves treatment and/or prevention of a disease or disorder described herein in a subject.

As referred to herein, the term "pharmaceutical composition" may also refer to a "composition" which may be used to effect treatment and/or prevention of a disease or disorder described herein in a subject, particularly a mammal.

As referred to herein, the term "subject" may refer to a patient or other animal, particularly a mammal, e.g., a human, dog, monkey, cow, horse, etc., that receives a compound of formula I of the invention or a pharmaceutical composition thereof for the treatment and/or prevention of a disease or condition described herein.

As referred to herein, the term "disease and/or disorder" refers to a physical condition of the subject that is associated with the disease and/or disorder of the present invention. For example, the disease and/or condition of the present invention may refer to a physical condition, such as a physical condition exhibiting elevated blood glucose levels, or a disease condition, such as a disease condition characterized by hyperglycemia, diabetes, and the like. The body state and the disease state are not distinguished herein or may be referred to one another, e.g., "hyperglycemia" may be used interchangeably with "hyperglycemia".

As referred to herein, "%" refers to weight/weight percentages, particularly where solid matter is described, unless otherwise specified. Of course, in describing liquid materials, the "%" may refer to weight/volume percentages (for the case of solids dissolved in liquids) or may refer to volume/volume percentages (for the case of liquids dissolved in liquids).

As referred to herein, the term "pharmaceutically acceptable" when describing a "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but may also refer to a synthetic substance of pharmaceutical value, e.g., a salt formed as an intermediate in order to effect chiral resolution, which salt may play a role in obtaining the final product of the invention, although such intermediate salt may not be directly administered to the subject.

In a further aspect, the invention relates to pharmaceutical compositions comprising as active ingredient a compound of the invention. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.

The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.

For tableting the compound of the present invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and cosolvent may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

To encapsulate the administration unit, the active ingredient of the compound of the present invention may be mixed with a diluent and a cosolvent, and the mixture may be directly placed in a hard capsule or soft capsule. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare the compound tablets of the present invention can also be used to prepare capsules of the compounds of the present invention.

In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field are added, wherein the solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl- β -cyclodextrin and the like, the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like, the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate and the like, and the mannitol, glucose and the like can also be added as a propping agent for preparing freeze-dried powder injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.

For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/Kg body weight, preferably from 0.1 to 100mg/Kg body weight, more preferably from 1 to 60mg/Kg body weight, and most preferably from 2 to 30mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.

Advantageous technical effects

All the compounds in the invention have novel chemical structures, and the in vitro DPP-IV inhibitory activity of most of the substituted xanthine compounds in the invention reaches more than 50%, wherein the in vitro DPP-IV inhibitory activity IC of 17 compounds₅₀To micromolar levels, especially IC of 5 compounds₅₀Value of up to 10^-7At mol/L level, IC of 12 Compounds₅₀Value of up to 10^- ⁸The mol/L level shows good DPP-IV inhibitory activity; in addition, 10 tested compounds have no obvious DPP8/9 inhibitory activity, show better DPP-IV selectivity, and the high selectivity of the compounds can reduce the risk of toxic reaction caused by DPP8/9 inhibition, such as thrombocytopenia, splenomegaly and the like. The research content provides a selective DPP-IV inhibitor with novel structure and strong activity, which can be used for preventing and treating type2diabetes and related diseases.

Detailed Description

The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.

For all of the following examples, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structure of the compounds is determined by nuclear magnetic resonance spectroscopy (NMR) and/or Mass Spectrometry (MS). m.p. is the melting point given in ° c, the temperature is uncorrected.

Preparation examples section

The structure of the compound is shown by nuclear magnetic resonance hydrogen spectrum (¹H NMR) or Mass Spectrometry (MS). The nuclear magnetic resonance hydrogen spectral shift (δ) is given in parts per million (ppm). NMR spectra were measured using a Mercury-300 or Mercury-400 NMR spectrometer, deuterated chloroform (CDCl)₃) Or deuterated dimethyl sulfoxide (DMSO-d6) as a solvent, and Tetramethylsilane (TMS) or 3- (trimethylsilyl) deuterated sodium propionate (TSM) as an internal standard.

The melting point was measured using a Yanaco model M.P-500D melting point tester, Japan, and the temperature was not corrected.

The electronic balance used was an electronic balance model Yanaco LY-300, Japan.

Polarimeters were measured using a Perkin-Elmer model 241MC polarimeter under a sodium lamp (20 ℃).

The column chromatography is generally carried out by using 200-300 mesh or 300-400 mesh silica gel as a carrier.

The anhydrous solvents were all processed by standard methods. Other reagents were all commercially available analytical grade.

Wherein,

DMF is N, N-dimethylformamide, i.e., N-dimethylformamide.

DIPEA is N, N-diisomyricylethylamine, i.e., N-diisopropylethylamine.

TFA is trifluoroacetic acid, i.e., trifluoroacetic acid.

CDI is N, N-carboxyldiimidazole, i.e., N-Carbonyldiimidazole.

HOBt is N-Hydroxybenzotriazole, namely N-Hydroxybenzotriazole.

EDCI is 1-Ethyl-3- (3-dimethyllaprophyl) carbodiimide hydrochloride, i.e.

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.

MsCl is Methanesulfonyl chloride, i.e.methanesulfonyl chloride.

Boc is-Butyloxy carbonyl, i.e.t-butyloxycarbonyl.

OMs are Methanesulfonates, i.e.methylsulfonyl esters.

OTf is triflate.

OTs are p-tolumenesulfonate, i.e., p-toluenesulfonyl ester groups.

Preparation example

Scheme 1 synthetic route for intermediate 3a-1

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione 2a

Placing 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione 1a (2.08g,7.00mmol), (R) -3- (tert-butoxycarbonyl) aminopiperidine (1.75g,8.75mmol) and potassium carbonate (1.94g,14.00mmol) in a 50mL single-neck bottle, adding DMF (15mL), reacting at 75 ℃ under the protection of argon gas for 7H, detecting the reaction by TLC, evaporating DMF to obtain a tan solid, adding 50mL of water, pulping, filtering, and drying under an infrared lamp to obtain 2a, tan2.60g of a colored solid, yield 89.7%.¹H NMR(400MHz,CDCl₃)δ:7.84(brs,1H),5.60(brs,1H),4.85(m,2H),3.86(m,1H),3.54(m,1H),3.53(s,3H),3.36(m,2H),3.28(m,1H),1.89(m,2H),1.82(s,3H),1.73(m,2H),1.45(s,9H).

Second step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- (3-bromopropyl) -1H-purine-2, 6-dione 3a-1

Potassium carbonate (1.72g,12.50mmol) was added to 8- [ (3R) -3- (tert-butoxycarbonyl) aminopiperidinyl-1-]-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione 2a (2.60g,6.30mmol) and 1, 3-dibromopropane (1.15mL,14.00mmol) in DMF (20mL) were stirred at room temperature for 12H, TLC checked for completion of the reaction of the starting materials, DMF was evaporated off to give an off-white solid, 80mL of water was added and slurried, filtered, and dried under infrared lamp to give 3a-1 as an off-white solid, 3.03g, 89.9% yield.¹H NMR(400MHz,CDCl₃)δ:5.61(brs,1H),4.88(m,2H),4.14(t,J＝7.2Hz,2H),3.86(m,1H),3.53(s,3H),3.50(m,1H),3.44(t,J＝7.2Hz,2H),3.35(m,2H),3.26(m,1H),2.25(m,2H),1.86(m,2H),1.82(s,3H),1.60(m,2H),1.45(s,9H).

Scheme 2 synthetic route for intermediate 3a-2

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- (3-hydroxypropyl) -1H-purine-2, 6-dione 2a-1

Potassium carbonate (0.10g,0.72mmol) was added to a solution of 8- [ (3R) -3- (tert-butoxycarbonyl) aminopiperidinyl-1- ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione 2a (0.15g,0.36mmol) and 3-bromopropanol (0.07mL,0.72mmol) in DMF (2mL) and the reaction was stirred at 70 ℃ for 4H, TLC checked for completion of the starting material reaction and DMF was evaporated to give an off-white solid, 10mL of water was added and stirred, filtered and dried under an infrared lamp to give 2a-1 as an off-white solid 0.15g, 88.8% yield.

Second step preparation of 8- [ (3R) -3- (tert-butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- (3-methanesulfonate-propylyl) -1H-purine-2, 6-dione 3a-2

Dissolving 2a-1(0.15g,0.32mmol) in 3mL of anhydrous dichloromethane, adding triethylamine (0.07mL) and stirring for 5min, then adding MsCl (0.03mL) dropwise under ice bath conditions, reacting at room temperature for 3h after the dropwise addition is finished, and detecting the completion of the raw material reaction by TLC. The reaction solution was washed with 10% citric acid, then with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 3a-2 as an off-white solid (0.16g, 91.4% yield).¹H NMR(400MHz,CDCl₃)δ:5.60(brs,1H),4.86(m,2H),4.29(t,J＝6.8Hz,2H),4.15(t,J＝6.8Hz,2H),3.85(m,1H),3.54(m,1H),3.52(s,3H),3.36(m,2H),3.27(m,1H),3.06(s,3H),2.15(m,2H),1.86(m,2H),1.82(s,3H),1.72(m,2H),1.45(s,9H).

Scheme 3 synthetic route for intermediate 1b

First step preparation of (Z) -N-hydroxybenzamidine 4a

Adding 50% hydroxylamine aqueous solution (1.18mL,20.00mmol) into an ethanol (25mL) solution of benzonitrile (2.00mL,19.60mmol), heating and refluxing for 10h, after the reaction is completed, evaporating the solvent, adding 20mL of toluene, concentrating to obtain an off-white solid 4a, and directly carrying out the next reaction.

Second step preparation of 3-phenyl-5-trichloromethyl-1, 2, 4-oxadiazole 5a

Trichloroacetic anhydride (4.30mL,23.50mmol) was added dropwise to a 4a toluene (20mL) solution, heated under reflux for 10h, after completion of the TLC detection reaction, the solvent was evaporated, 80mL of ethyl acetate was added, water, a saturated sodium bicarbonate solution and a saturated common salt were sequentially added, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Subjecting the crude product to silica gel (300-400 mesh) column chromatographySeparating, and using a petroleum ether-dichloromethane (V: V ═ 100:1) mixed solution as an eluent. Intermediate 5a was obtained as a colorless oil 4.39g, 84.6% yield over two steps.¹H NMR(400MHz,CDCl3):δ8.13(m,2H),7.53(m,3H).

The third step is the preparation of 1- (3-phenyl-1, 2, 4-oxadiazole-5-yl) piperazine 1b

5a (4.39g,16.66mmol) was dissolved in DMF (15mL), slowly added dropwise to a solution of anhydrous piperazine in DMF (20mL), stirred at room temperature for 6h, concentrated under reduced pressure, 150mL of deionized water was added to the residue, extracted with ethyl acetate (3X100mL), dried, filtered, and the resulting crude product was chromatographed on silica gel (300-400 mesh) column using dichloromethane-methanol (V: V ═ 100:1) mixture as eluent. Intermediate 1b was obtained as a white foamy solid, 2.35g, yield 61.2%.¹H NMR(400MHz,CDCl₃):δ7.99(m,2H),7.44(m,3H),3.73(m,4H),3.04(m,4H),2.16(brs,1H).

Scheme 4 synthetic route for intermediate 2b

First step preparation of (Z) -N-hydroxy-4-pyridinecarboxamidine 6a

Starting from 4-cyanopyridine (1.00g, 9.61mmol), similar procedure as in the first step of preparation 1b gave intermediate 6a as a white solid in 1.30g with a yield of 98.5%.

Second step preparation of 3- (4-pyridyl) -5-trichloromethyl-1, 2, 4-oxadiazole 7a

Starting from (Z) -N-hydroxy-4-pyridinecarboxamidine 6a (1.30g, 9.48mmol), the second analogous operating procedure of preparation 1b gave intermediate 7a as a tan solid in a yield of 1.30g, 52.0%.

Third step preparation of 1- [3- (4-pyridyl) -1,2, 4-oxadiazol-5-yl) piperazine 2b

Starting from 7a (0.90g,3.38mmol), the third step of preparation 1b is carried out analogouslyProcedure gave intermediate 2b as a yellow solid, 0.45g, yield 57.5%.¹H NMR(400MHz,CDCl₃):δ8.72(m,2H),7.84(m,2H),3.68(m,4H),2.99(m,4H),1.69(brs,1H).

Scheme 5 synthetic route to intermediate 3b

First step preparation of (Z) -N-Hydroxyacetamidine 8a

Starting from acetonitrile (1.00mL, 19.24mmol), similar procedure as the first step in preparation 1b gave intermediate 8a as a white solid in 1.01g, 76.8% yield.¹H NMR(400MHz,DMSO-d₆):δ8.66(brs,1H),5.34(brs,2H),1.62(s,3H).

Second step preparation of 3-methyl-5-trichloromethyl-1, 2, 4-oxadiazole 9a

Trichloroacetic anhydride (1.36mL,7.43mmol) was added dropwise to a toluene (15mL) solution of 8a (0.50g,6.75mmol), heated under reflux for 10h, the solvent was evaporated, 40mL of ethyl acetate was added, water, a saturated sodium bicarbonate solution and a saturated common salt water were sequentially added, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a light brown oil 9a, which was used directly in the next reaction.

The third step is the preparation of 1- (3-methyl-1, 2, 4-oxadiazole-5-yl) piperazine 3b

Starting from 9a, a similar procedure to that of the third step of preparation 1b was used to give intermediate 3b as a tan oil in 0.38g yield in two steps of 33.5%.

Scheme 6 synthetic route for intermediate 4b

First step preparation of (Z) -N-hydroxyisobutyramidine 10a

Using isobutyronitrile (1.30mL, 14.47mmol) as the starting material, similar procedure as the first step in preparation 1b gave intermediate 10a as a white solid in 1.15g, 78.3% yield.¹H NMR(400MHz,CDCl₃):δ8.86(brs,1H),4.52(brs,2H),2.43(m,1H),1.16(s,3H),1.14(s,3H).

Second step preparation of 3-isopropyl-5-trichloromethyl-1, 2, 4-oxadiazole 11a

Trichloroacetic anhydride (1.5mL,8.22mmol) was added dropwise to a 10a (0.80g, 7.83mmol) solution in toluene (15mL), heated under reflux for 12h, the solvent was evaporated, 40mL of ethyl acetate was added, water, a saturated sodium bicarbonate solution and a saturated common salt water were sequentially added, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a light brown oil 11a, which was used directly in the next reaction.

The third step is the preparation of 1- (3-isopropyl-1, 2, 4-oxadiazole-5-yl) piperazine 4b

Starting from 11a, a similar procedure to that of the third step of preparation 1b was used to give intermediate 4b as a tan oil in 0.42g yield of 27.3% over the two steps.

Scheme 7 synthetic route to intermediate 5b

First step preparation of (Z) -N-hydroxy-1-cyclopropylcarboxamidine 12a

Using cyclopropylcarbonitrile (1.10mL, 14.91mmol) as a starting material, analogous to the procedure described for the first step of preparation 1b, gives intermediate 12a as a colorless oil in 1.45g, 97.1% yield.

Second step preparation of 3-cyclopropyl-5-trichloromethyl-1, 2, 4-oxadiazole 13a

Using 12a (0.60g, 5.99mmol) as the starting material, the second similar procedure in preparation 1b gave intermediate 13a as a colorless oil in 1.04g, 76 yield.5％。¹H NMR(400MHz,CDCl₃):δ2.14(m,1H),1.15(m,4H).

The third step is 1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-yl) piperazine 5b preparation

Starting from 13a (1.02 g; 4.46mmol), a similar procedure to that of the third step of preparation 1b was used, giving intermediate 5b as a tan oil, 0.33g, in 38.1% yield.¹H NMR(300MHz,CDCl₃):δ3.56(m,4H),2.94(m,4H),2.17(brs,1H),1.87(m,1H),0.94(m,4H).

Scheme 8 synthetic route to intermediate 6b

First step preparation of (Z) -N-hydroxy-1-cyclopentylmethylamidine 14a

Starting from cyclopentylcarbonitrile (1.10mL, 10.51mmol), similar procedure as in the first step of preparation 1b gave intermediate 14a as a colorless oil in 0.70g, 52.8% yield.¹H NMR(400MHz,CDCl₃):δ7.83(brs,1H),4.54(brs,2H),2.58(m,1H),1.88(m,2H),1.64(m,6H).

Second step preparation of 3-cyclopentyl-5-trichloromethyl-1, 2, 4-oxadiazole 15a

Starting from 14a (0.65g, 5.07mmol), the second analogous procedure in preparation 1b gave intermediate 15a as a colourless oil in 1.16g, 89.6% yield.

The third step is 1- (3-cyclopentyl-1, 2, 4-oxadiazole-5-yl) piperazine 6b preparation

Starting from 15a (1.16 g; 4.57mmol), a similar procedure to that of the third step of preparation 1b was carried out, giving intermediate 6b as a tan oil, 0.40g, in 39.4% yield.¹H NMR(400MHz,CDCl₃):δ3.57(m,4H),2.94(m,4H),2.17(brs,1H),1.98-1.62(m,9H).

Route 9 synthetic route to intermediate 7b

First step preparation of (Z) -N-hydroxy-1- (4-methyl) phenylcarboxamidine 16a

Using p-methylbenzonitrile (1.00g, 8.54mmol) as the starting material, similar procedure as the first step in preparation 1b gave intermediate 16a as a white solid in 1.26g with a yield of 98.6%.¹H NMR(400MHz,CDCl₃):δ7.52(m,2H),7.20(m,2H),4.88(brs,2H),2.38(s,3H).

Second step preparation of 3- (4-methyl) phenyl-5-trichloromethyl-1, 2, 4-oxadiazole 17a

Starting from 16a (0.60g, 4.00mmol), the second analogous procedure used in preparation 1b gave intermediate 17a as a colourless oil in 1.00g, 90.1% yield.¹H NMR(400MHz,CDCl₃):δ8.01(m,2H),7.31(m,2H),2.44(s,3H).

Third step preparation of 1- [3- (4-methyl) phenyl-1, 2, 4-oxadiazol-5-yl ] piperazine 7b

Starting from 17a (1.00g, 3.60mmol), the third analogous procedure used in preparation 1b gave intermediate 7b as a pale yellow solid, 0.33g, 37.5% yield.¹H NMR(400MHz,CDCl₃):δ7.87(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),3.67(m,4H),2.98(m,4H),2.39(s,3H),1.93(brs,1H).

Route 10 synthetic route to intermediate 8b

First step preparation of (Z) -N-hydroxy-1- (4-trifluoromethyl) phenylformamidine 18a

Starting from p-trifluoromethylbenzonitrile (1.00g, 5.84mmol), as described in the first step of preparation 1bSimilar procedure gave intermediate 18a as a white solid in 1.26g with a yield of 99.0%.¹H NMR(400MHz,CDCl₃):δ7.76(d,J＝8.4Hz,2H),7.67(d,J＝8.4Hz,2H),4.92(brs,2H).

Second step preparation of 3- (4-trifluoromethyl) phenyl-5-trichloromethyl-1, 2, 4-oxadiazole 19a

Starting from 18a (0.60g, 2.94mmol), the second analogous procedure of preparation 1b gave intermediate 19a as a colourless oil in 0.92g, 93.9% yield.¹H NMR(400MHz,CDCl₃):δ8.26(d,J＝8.4Hz,2H),7.78(d,J＝8.4Hz,2H).

Third step preparation of 1- [3- (4-trifluoromethyl) phenyl-1, 2, 4-oxadiazol-5-yl ] piperazine 8b

Starting from 19a (0.92g, 2.76mmol), analogous to the third step in preparation 1b, intermediate 8b is obtained in the form of a pale yellow solid, 0.30g, yield 36.4%.¹H NMR(400MHz,CDCl₃):δ8.11(d,J＝8.4Hz,2H),7.69(d,J＝8.4Hz,2H),3.70(m,4H),3.01(m,4H),2.00(brs,1H).

Route 11 synthetic route to intermediate 9b

First step preparation of (Z) -N-hydroxy-1- (4-fluoro) phenylcarboxamidine 20a

Starting from p-fluorobenzonitrile (1.00g, 8.26mmol), similar procedure to that used in the first step of preparation 1b gave intermediate 20a as a white solid in 1.24g, 97.7% yield.¹H NMR(400MHz,CDCl₃):δ8.41(brs,1H),7.61(m,2H),7.08(m,2H),4.90(brs,2H).

Second step preparation of 3- (4-fluoro) phenyl-5-trichloromethyl-1, 2, 4-oxadiazole 21a

Starting from 20a (0.60g, 3.89mmol), a similar procedure as in the second step of preparation 1b was used to give intermediate 21a,1.04g of colorless oil, yield 95.0%.¹H NMR(400MHz,CDCl₃):δ8.13(m,2H),7.21(m,2H).

Third step preparation of 1- [3- (4-fluoro) phenyl-1, 2, 4-oxadiazol-5-yl ] piperazine 9b

Using 21a (0.69g,2.43mmol) as the starting material, the procedure analogous to the third step in preparation 1b gave intermediate 9b as a pale yellow solid, 0.35g, 58.1% yield.¹H NMR(400MHz,CDCl₃):δ7.98(m,2H),7.10(m,2H),3.66(m,4H),2.98(m,4H),1.77(brs,1H).

Route 12 synthetic route to intermediate 10b

First step preparation of (Z) -N-hydroxy-1- (4-methoxy) phenylformamidine 22a

Starting from p-methoxybenzonitrile (1.00g, 7.51mmol), the first analogous procedure used in preparation 1b gave intermediate 22a as a white solid in 1.22g, 97.8% yield.¹H NMR(400MHz,CDCl₃):δ7.56(d,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,2H),4.84(brs,2H),3.83(s,3H).

Second step preparation of 3- (4-methoxy) phenyl-5-trichloromethyl-1, 2, 4-oxadiazole 23a

Starting from 22a (0.60g, 3.61mmol), the second analogous procedure used in preparation 1b gave intermediate 23a as a white solid in 0.76g with a yield of 71.5%.¹H NMR(400MHz,CDCl₃):δ8.05(d,J＝8.8Hz,2H),7.00(d,J＝8.8Hz,2H),3.88(s,3H).

Third step preparation of 1- [3- (4-methoxy) phenyl-1, 2, 4-oxadiazol-5-yl ] piperazine 10b

Starting from 23a (0.74g, 2.50mmol), analogous to the third step in preparation 1b, intermediate 10b is obtained in the form of a pale yellow solid, 0.37g, with a yield of 56.8%.¹H NMR(400MHz,CDCl₃):δ7.91(m,2H),6.93(m,2H),3.84(s,3H),3.65(m,4H),2.97(m,4H),1.89(brs,1H).

Route 13 synthetic route to intermediate 11b

First step preparation of 3-phenyl-5-chloro-1, 2, 4-thiadiazole 24a

Benzamidine hydrochloride (0.50g, 3.19mmol) and perchloromethylmercaptan were dissolved in 10mL of dichloromethane, and 1mL of an aqueous solution of sodium hydroxide (0.64g, 15.96mmol) was added dropwise to the reaction solution under ice-bath conditions, stirred for 1h, and then moved to room temperature for 2h, and TLC checked for completion of the starting material reaction. 10ml of deionized water was added, extracted with dichloromethane (3X15mL), dried and concentrated to give crude 24a as a pale yellow oil which was directly subjected to the next reaction.

Second step preparation of [4- (3-phenyl-1, 2, 4-thiadiazol-5-yl) ] piperazine-1-carboxylic acid tert-butyl ester 25a

24a and N-Boc-piperazine (0.60g, 3.19mmol) were dissolved in 4mL DMF, followed by addition of triethylamine (1.8mL,12.77mmol) and stirring at room temperature overnight. The reaction solvent was evaporated, then 20mL of deionized water was added, extracted with ethyl acetate (3 × 20mL), washed once with saturated sodium chloride, dried, and the crude product was separated by column chromatography on silica gel (300-400 mesh) using petroleum ether-ethyl acetate (V: V ═ 10:1) as eluent. Intermediate 25a was obtained in the form of a pale yellow solid (0.62 g), two-step yield 55.6%.¹HNMR(400MHz,CDCl₃):δ8.19(m,2H),7.42(m,3H),3.60(m,8H),1.49(s,9H).

The third step is the preparation of 1- (3-phenyl-1, 2, 4-thiadiazole-5-yl) piperazine 11b

25a (0.61g, 1.76mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. TLC detects that the raw material is completely reacted, 15mL of diethyl ether and 15mL of deionized water are added into the reaction solution, the organic layer is discarded, and the pH value of the water layer is adjusted to be alkaline by potassium carbonate powderThen extracted with dichloromethane (4 × 20mL), dried over anhydrous sodium sulfate and concentrated to give 11b as an off-white solid 0.34g, yield 79.2%.¹H NMR(400MHz,CDCl₃):δ8.19(m,2H),7.42(m,3H),3.60(m,4H),3.03(m,4H),2.08(brs,1H).

Route 14 synthetic route to intermediate 12b

First step preparation of [4- (benzoylthiocarbamoyl) ] piperazine-1-carboxylic acid tert-butyl ester 26a

A solution of benzoyl isothiocyanate (0.38mL,2.68mmol) in dry dichloromethane (5mL) was added dropwise to N-Boc-piperazine (0.50g, 2.68mmol) in dry dichloromethane under ice-bath conditions, and after completion of the addition, the reaction was carried out at room temperature for 2 h. TLC detected the starting material reacted completely, the solvent was evaporated, the resulting solid was washed with ether-n-hexane 1:2, filtered and dried to give intermediate 26a as an off-white solid 0.85g, yield 90.6%.

The second step is the preparation of 3-phenyl-5- (4-tert-butyloxycarbonyl-1-piperazinyl) -4H-1,2, 4-triazole 27a

26a (0.30g, 0.86mmol) and hydrazine hydrate (0.17mL,4.29mmol) were dissolved in 8mL chloroform and reacted at reflux for 4 h. TLC detects the material reaction is complete, the solvent is evaporated, 15mL deionized water is added, ethyl acetate extraction (3x15mL) is carried out, anhydrous sodium sulfate is dried and concentrated, the obtained crude product is separated by silica gel (300-400 meshes) column chromatography, and petroleum ether-ethyl acetate (V: V ═ 2:1) mixed solution is used as eluent. Intermediate 27a was obtained as an off-white solid, 0.15g, yield 53.3%.¹H NMR(400MHz,CDCl₃):δ8.81(brs,1H),7.89(m,2H),7.41(m,3H),3.52(m,4H),3.45(m,4H),1.48(s,9H).

The third step is the preparation of 1- (3-phenyl-4H-1, 2, 4-triazole-5-yl) piperazine 12b

27a (0.46g, 1.40mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the mixture was cooled to room temperatureStirring for 2 h. TLC detected the starting material was completely reacted, 15mL of diethyl ether and 15mL of deionized water were added to the reaction solution, the organic layer was discarded, the aqueous layer was adjusted to alkaline with potassium carbonate powder and then extracted with dichloromethane (4x30mL), dried over anhydrous sodium sulfate and concentrated to give 12b as an off-white solid 0.26g with 81.3% yield.¹H NMR(400MHz,CDCl₃):δ7.91(m,2H),7.39(m,3H),5.14(brs,1H),3.42(m,4H),2.96(m,4H).

Route 15 synthetic route to intermediate 13b

Preparation of [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) ] piperazine-1-carboxylic acid tert-butyl ester 28a in a first step

Methyl 3-oxodithiobutyrate (0.95g, 6.40mmol) and N-Boc-piperazine (1.43g, 7.68mmol) were dissolved in absolute ethanol (30mL), heated at reflux for 3h, and phenylhydrazine (0.75mL, 7.68mmol), acetic acid (5 drops) and 4A molecular sieves (1.28g) were added and heated at reflux for 12 h. The ethanol was evaporated under reduced pressure, dissolved in dichloromethane (90mL), and the mixture was washed with 1N hydrochloric acid (6mL), water (10mL) and saturated NaHCO in that order₃The solution (10mL) was washed with saturated brine (10mL) and dried over anhydrous sodium sulfate. Filtering, concentrating under reduced pressure, and separating the crude product by silica gel (300-400 mesh) column chromatography, wherein petroleum ether-ethyl acetate (V: V ═ 9:1) mixed solution is used as eluent. Intermediate 28a was obtained in 80.7% yield as a white solid, 1.77 g.

Second step preparation of 1- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine 13b

28a (3.1g, 9.06mmol) was dissolved in dichloromethane (33mL), TFA (11mL) was added dropwise in an ice water bath, stirred for 1.5h, water (90mL) was added, the aqueous phase was separated and washed with dichloromethane (20 mL. times.2). The pH of the water phase is adjusted to 8-9 by potassium carbonate, and the system is milky turbid. Extraction with ethyl acetate (40 mL. times.3) combined the organic phases, washed with brine (15mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 13b as an off-white solid, 2.16g, 98.6% yield.¹H NMR(400MHz,DMSO-d₆)δ:7.76(d,J＝8.0Hz,2H),7.45(t,J＝8.0Hz,2H),7.26(t,J＝7.6Hz,1H),5.77(s,1H),2.72(brs,4H),2.70(brs,4H),2.50(s,3H).

Route 16 synthetic route to intermediate 14b

First step preparation of 4- (tert-Butoxycarbonyl) piperazine-1-carbothioamide 29a

26a (0.33g, 0.93mmol) was dissolved in 1.5mL hydrazine hydrate and stirred at room temperature for 4 h. TLC detected the starting material was completely reacted and 15mL dichloromethane was added to the reaction mixture, which was washed sequentially with 10% citric acid (2 × 15mL), saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated and the resulting solid was washed with a small amount of ether to give intermediate 29a as an off-white solid, 0.19g, 81.1% yield.¹HNMR(400MHz,CDCl₃):δ5.82(brs,2H),3.84(m,4H),3.55(m,4H),1.47(s,9H).

Second step preparation of [4- (4-phenylthiazol-2-yl) ] piperazine-1-carboxylic acid tert-butyl ester 30a

α -bromoacetophenone (0.19g,0.94mmol) is added dropwise into a solution of 29a (0.22g,0.89mmol) and sodium bicarbonate (0.15g,1.79mmol) in ethanol (3mL), then the reflux reaction is carried out for 4h, the TLC detection shows that the raw materials are reacted completely, the reaction solution is concentrated, the obtained crude product is separated by silica gel (300-400 meshes) column chromatography, a petroleum ether-dichloromethane (V: V ═ 1:1) mixed solution is used as an eluent, and the intermediate 30a, 0.25g of light yellow oily matter and the yield is 80.0 percent.¹H NMR(400MHz,CDCl₃):δ7.83(m,2H),7.39(m,2H),7.30(m,1H),6.78(s,1H),3.59(m,8H),1.49(s,9H).

Third step preparation of 1- (4-phenylthiazol-2-yl) piperazine 14b

Dissolving 30a (0.38g, 1.10mmol) in dichloromethane (3mL), adding TFA (1mL) dropwise in an ice-water bath, stirring for 2h, adding water (10mL) and diethyl ether (10mL), separating to obtain an aqueous phase, adjusting the pH of the aqueous phase to 8-9 with potassium carbonate, and enabling the system to be milky turbid. With dichloromethane (3)X15mL), the organic phases are combined, washed with brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate 14b as an off-white solid, 0.24g, yield 87.4%.¹H NMR(400MHz,CDCl₃):δ7.82(m,2H),7.37(m,2H),7.28(m,1H),6.80(s,1H),3.64(m,4H),3.11(m,4H).

Scheme 17 synthetic route to intermediate 15b

First step preparation of N-tert-Butoxycarbonyl-4-phenylcarbamoylpiperidine 31a

N-tert-Butoxycarbonylpiperidine-4-carboxylic acid (1.00g,4.37mmol), HOBt (0.59g,4.37mmol), triethylamine (0.68mL,4.81mmol) and aniline (0.44g, 4.37mmol) were placed in a 50mL single-neck flask, 10mL acetonitrile was added followed by EDCI (0.843g,4.4mmol) and stirred at room temperature for 5 h. Dichloromethane (50mL) and saturated sodium bicarbonate solution (10mL) were added, the dichloromethane layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was subjected to silica gel (300-400 mesh) column chromatography with petroleum ether-ethyl acetate (V: V ═ 7:3) as an eluent. Intermediate 31a was obtained in the form of an off-white solid (0.83 g, yield 62.5%).

Second step preparation of 4- (1-phenyl-1H-tetrazol-5-yl) piperidine dihydrochloride 15b

31a (400mg,1.316mmol) was dissolved in 10mL of anhydrous tetrahydrofuran, triphenylphosphine (800mg,2.63mmol) and trimethylsilylazidomethane (0.35mL,2.63mmol) were added, DIAD (0.52mL,2.63mmol) was added dropwise under ice bath, stirred at room temperature for 6 days, heated under reflux for 1h, after cooling, 7N ethyl hydrogen chloride acetate solution was added to the system, and stirred at room temperature for 1 h. Ethyl acetate was added, the supernatant discarded, and the reaction mixture was repeated 2 times, followed by filtration, and the filter cake was washed with ethyl acetate and dried to give intermediate 15b as a white solid (300 mg) with a yield of 86.0%.¹H NMR(400MHz,DMSO-d₆)δ:9.29(brs,1H),9.16(brs,1H),8.35(brs,1H),7.68(s,5H),3.29(m,3H),2.96(m,2H),2.02(m,4H).

Route 18 synthetic route to intermediate 16b

The first step is the preparation of N-tert-butyloxycarbonyl-4- (4-phenyl-1H-1, 2, 3-triazol-1-yl) piperidine 32a

N-tert-Butoxycarbonyl-4-azidopiperidine (0.23g,1.0mmol), diisopropylethylamine (0.65g,5mmol), cuprous iodide (0.057g, 0.03mmol) were placed in a 25mL single-neck flask, 10mL of methanol was added followed by phenylacetylene (0.107g,1.05mmol) and stirred at room temperature for 2 h. Concentrated under reduced pressure, ethyl acetate (50mL) and water (10mL) were added, and the ethyl acetate layer was separated, washed with 10% citric acid, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. Intermediate 32a was obtained as a pale yellow solid, 0.285g, yield 80.3%.¹H NMR(400MHz,CDCl₃):δ7.82(m,2H),7.77(s,1H),7.43(m,2H),7.34(m,1H),4.66(m,1H),4.30(m,2H),2.96(m,2H),2.24(m,2H),2.01(m,2H),1.49(s,9H).

The second step is 4- (4-phenyl-1H-1, 2, 3-triazole-1-yl) piperidine 16b preparation

Dissolve 32a (0.28g, 0.84mmol) in dichloromethane (2mL), add TFA (0.7mL) dropwise in an ice-water bath, and stir at room temperature for 2 h. TLC detection raw material reaction is complete, 20mL deionized water and 20mL ether are added, organic layer is discarded, aqueous layer is separated, and pH is adjusted to 8-9 with saturated sodium bicarbonate solution. Extraction with dichloromethane (20 mL. times.5), combining the organic phases, washing with brine (10mL), drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure. Intermediate 16b was obtained as an off-white solid, 170mg, yield 89.0%.¹H NMR(400MHz,CDCl₃):δ7.83(m,2H),7.78(s,1H),7.43(m,2H),7.32(m,1H),4.62(m,1H),3.28(m,2H),2.82(m,2H),2.24(m,2H),1.99(m,2H),1.57(brs,1H).

Route 19 synthetic route to intermediate 17b

First step preparation of [4- (4-phenylthiazol-2-yl) ] piperidine-1-carboxylic acid tert-butyl ester 33a

α -bromoacetophenone (0.26g,1.29mmol) was added dropwise into a solution of 1-tert-butoxycarbonylpiperidine-4-carbothioamide (0.30g,1.23mmol) and sodium bicarbonate (0.21g,2.46mmol) in ethanol (5mL), followed by reflux reaction for 3 h.TLC to detect completion of the reaction of the starting materials, the reaction solution was concentrated, the obtained crude product was chromatographed on a silica gel (300-400 mesh) column, and a dichloromethane-ethyl acetate (V: V ═ 40:1) mixture was used as an eluent to obtain intermediate 33a, 0.40g of light pink oil, and the yield was 93.2%.¹HNMR(400MHz,CDCl₃):δ7.90(m,2H),7.42(m,2H),7.38(s,1H),7.34(m,1H),4.21(m,2H),3.33(m,1H),2.93(m,2H),2.17(m,2H),1.77(m,2H),1.48(s,9H).

Second step preparation of 4- (4-phenylthiazol-2-yl) piperidine 17b

Dissolve 33a (0.39g, 1.15mmol) in dichloromethane (3mL), add TFA (1mL) dropwise in an ice-water bath, stir for 2h, add water (15mL) and diethyl ether (10mL), separate the aqueous phase, and adjust the pH of the aqueous phase to 8-9 with potassium carbonate. Extraction with dichloromethane (3X15mL) combined the organic phases, washed with brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate 17b as an off-white solid 0.24g, 85.7% yield.¹H NMR(400MHz,CDCl₃):δ7.88(m,2H),7.41(m,2H),7.35(s,1H),7.30(m,1H),3.20(m,3H),2.80(m,2H),2.17(m,2H),1.73-1.84(m,3H).

Route 20 synthetic route to intermediate 18b

First step preparation of benzyl 4- [ (2-oxo-2-phenylethyl) carbamoyl ] piperidine-1-carboxylate 34a

Reacting N-benzyloxycarbonyl-4-piperidinecarboxylic acid (2.0)0g,7.60mmol) is dissolved in anhydrous dichloromethane, CDI (1.42g,8.74mmol) is added under ice bath condition, stirring is carried out for 4h at room temperature under the protection of argon, α -aminoacetophenone hydrochloride (1.37g,7.98mmol) and DIPEA (1.39mL,7.98mmol) are sequentially added, reaction is carried out for 15h at room temperature, the raw materials are completely reacted through TLC detection, reaction liquid is concentrated, the obtained crude product is separated through silica gel (300 meshes and 400 meshes) column chromatography, dichloromethane-ethyl acetate (V: V ═ 40:1) mixed liquid is used as eluent, intermediate 34a is obtained, 1.50g of light pink oily matter is obtained, and the yield is 51.9%.¹H NMR(400MHz,CDCl₃):δ7.97(m,2H),7.63(m,1H),7.51(m,2H),7.34(m,5H),6.60(brs,1H),5.14(s,2H),4.76(d,J＝4.0Hz,2H),4.24(m,2H),2.88(m,2H),2.42(m,1H),1.88(m,2H),1.73(m,2H).

Second step preparation of [4- (5-phenyloxazol-2-yl) ] piperidine-1-carboxylic acid benzyl ester 35a

34a (0.80g,2.10mmol) was dissolved in 5mL pyridine, followed by addition of phosphorus oxychloride (1mL, 10.5mmol) and stirring at room temperature for 2 h. TLC detects the raw material reaction is complete, the reaction liquid is slowly poured into 20mL of ice sodium bicarbonate saturated solution, extraction is carried out by ethyl acetate (20mL multiplied by 3), organic phases are combined, drying and concentration are carried out, the obtained crude product is separated by silica gel (300-400 meshes) column chromatography, and petroleum ether-ethyl acetate (V: V ═ 1:1) mixed liquid is used as eluent. Intermediate 35a was obtained as a pale yellow oil, 0.66g, yield 86.8%.¹H NMR(400MHz,CDCl₃):δ7.60(m,2H),7.37(m,8H),7.24(s,1H),5.15(s,2H),4.20(m,2H),3.07(m,2H),2.11(m,2H),1.05(m,3H).

Third step preparation of 4- (5-Phenyloxazol-2-yl) piperidine 18b

35a (0.70g, 1.93mmol) was dissolved in dichloromethane (10mL), and trimethyliodosilane (0.66mL,4.64mmol) was added dropwise under ice-water bath and stirred at room temperature for 4 h. TLC detects that the raw material completely reacts, 1mL of methanol is added, stirring is carried out for 10min, then 2N hydrochloric acid (15mL) and ether (10mL) are added, water phase is obtained through separation, and the pH value of the water phase is adjusted to 8-9 by potassium carbonate. Extraction with dichloromethane (3X15mL) combined the organic phases, washed with brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate 18b as an off-white solid 0.43g, 96.4% yield.¹H NMR(400MHz,CDCl₃):δ7.61(m,2H),7.40(m,2H),7.30(m,1H),7.22(s,1H),3.19(m,2H),3.00(m,1H),2.77(m,2H),2.10(m,2H),1.96(brs,1H),1.84(m,2H).

Route 21 synthetic route to intermediate 19b

First step preparation of benzyl [4- (4-phenylimidazol-2-yl) ] piperidine-1-carboxylate 36a

34a (0.73g,1.92mmol) was dissolved in 5mL glacial acetic acid, followed by addition of ammonium acetate (2.07g, 26.86mmol) and refluxing reaction for 5 h. TLC detects the material reaction is complete, 20mL deionized water is added, dichloromethane extraction (20mL multiplied by 3) is carried out, organic phases are combined, drying and concentration are carried out, the obtained crude product is separated by silica gel (300-400 meshes) column chromatography, and petroleum ether-ethyl acetate (V: V ═ 1:1) mixed liquid is used as eluent. Intermediate 36a was obtained as a pale yellow oil, 0.66g, 83.7% yield.¹H NMR(400MHz,CDCl₃):δ7.67(m,2H),7.38(m,7H),7.23(m,2H),5.13(s,2H),4.28(m,2H),3.04(m,1H),2.93(m,2H),2.05(m,2H),1.73(m,2H).

Second step preparation of 4- (4-phenylimidazol-2-yl) piperidine 19b

36a (0.63g, 1.73mmol) was dissolved in dichloromethane (10mL), and trimethyliodosilane (0.60mL,4.15mmol) was added dropwise under ice-water bath and stirred at room temperature for 4 h. TLC detects that the raw material completely reacts, 1mL of methanol is added, stirring is carried out for 10min, then 2N hydrochloric acid (15mL) and ether (10mL) are added, water phase is obtained through separation, and the pH value of the water phase is adjusted to 8-9 by potassium carbonate. Extraction with dichloromethane (3X15mL) combined the organic phases, washed with brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate 19b as an off-white solid 0.44g, 99.3% yield.¹H NMR(400MHz,CDCl₃):δ7.68(m,2H),7.35(m,2H),7.21(m,2H),3.18(m,2H),2.94(m,1H),2.72(m,2H),2.02(m,2H),1.76(m,2H).

Route 22 synthetic route to intermediate 20b

First step preparation of [4- (5-phenylthiazol-3-yl) ] piperidine-1-carboxylic acid tert-butyl ester 37a

Tert-butyl 4- (hydroxyimino) methylpiperidine-1-carboxylate (2.13g,9.33mmol), phenylacetylene (2.56mL,23.32mmol) and potassium chloride (0.70g,9.33mmol) were dissolved in 20mL of water, and oxone complex salt (8.57g,13.95mmol) was added under ice-bath conditions, followed by stirring at room temperature overnight. TLC detects the reaction completion of the raw material, and the raw material is extracted by dichloromethane (30mL multiplied by 3), the organic phases are combined, dried, concentrated and the reaction solution is concentrated, and the obtained crude product is separated by silica gel (300 and 400 meshes) column chromatography, and dichloromethane-ethyl acetate (V: V ═ 40:1) mixed solution is used as eluent. Intermediate 37a was obtained in 37.9% yield as a colorless oil 1.16 g.¹H NMR(400MHz,CDCl₃):δ7.76(m,2H),7.46(m,3H),6.38(s,1H),4.18(m,2H),2.94(m,3H),1.98(m,2H),1.72(m,2H),1.48(s,9H).

Second step preparation of 4- (5-phenylthiazol-3-yl) piperidine 20b

Dissolve 37a (1.10g, 3.55mmol) in dichloromethane (10mL), add TFA (3mL) dropwise in an ice water bath, stir for 2h, add water (20mL) and diethyl ether (20mL), separate the aqueous phase, and adjust the pH of the aqueous phase to 8-9 with potassium carbonate. Extraction with dichloromethane (3X 30mL) combined the organic phases, washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate 20b as an off-white solid 0.65g, 85.0% yield.¹H NMR(400MHz,CDCl₃):δ7.82(m,2H),7.50(m,3H),6.98(s,1H),3.83(brs,1H),3.05(m,2H),2.86(m,1H),2.66(m,2H),1.87(m,2H),1.59(m,2H).

Route 23 synthetic route to intermediate 21b

First step preparation of benzyl [4- (3-phenyl-1, 2, 4-oxadiazol-5-yl) ] piperidine-1-carboxylate 38a

Dissolving N-Cbz-4-piperidinecarboxylic acid (1.50g,5.70mmol) and 0.03mL of DMF in 5mL of anhydrous dichloromethane, dropwise adding 0.45mL of oxalyl chloride, reacting at room temperature for 3h, detecting the reaction completion of raw materials by TLC, concentrating, evaporating to remove the solvent, dissolving the residue in 4mL of toluene, dropwise adding 4a (0.29g,1.9mmol) of toluene solution under ice bath conditions, refluxing for 4h, concentrating the reaction solution, separating the obtained crude product by silica gel (300-400 mesh) column chromatography, and using petroleum ether-ethyl acetate (V: V ═ 9:1) mixed solution as an eluent. Intermediate 38a was obtained as a pale yellow oil, 0.89g, 77.4% yield.

Second step preparation of 4- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperidine 21b

38a (0.89g, 2.45mmol) was dissolved in dichloromethane (6mL), and trimethyliodosilane (0.84mL,5.88mmol) was added dropwise under ice-water bath and stirred at room temperature for 4 h. TLC detects that the raw material completely reacts, 1mL of methanol is added, stirring is carried out for 10min, then 2N hydrochloric acid (15mL) and ether (10mL) are added, water phase is obtained through separation, and the pH value of the water phase is adjusted to 8-9 by potassium carbonate. Extraction with dichloromethane (3X15mL) combined the organic phases, washed with brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford intermediate 21b as a pale yellow solid, 0.49g, 87.2% yield.¹H NMR(400MHz,CDCl₃):δ8.08(m,2H),7.49(m,3H),3.23(m,2H),3.15(m,1H),2.82(m,2H),2.54(brs,1H),2.15(m,2H),1.92(m,2H).

Examples

Example 1

The compound 18- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

The method comprises the following steps:

the second method comprises the following steps:

first step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 1c

The method comprises the following steps:

8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidinyl-1- ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- (3-bromopropyl) -1H-purine-2, 6-dione 3a-1(0.42g,0.77mmol) and 1- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperazine 1b (0.18g,0.78mmol) were dissolved in 3mL of anhydrous DMF and then DIPEA (0.40mL,2.32mmol) was added and reacted at 75 ℃ for 8H under argon protection. TLC detection raw material reaction is complete, the solvent is evaporated, 20mL deionized water is added, ethyl acetate extraction (3X20mL) is carried out, organic phases are combined, washing is carried out once with saturated salt water, drying is carried out by anhydrous sodium sulfate, filtration and concentration are carried out. The crude product is separated by silica gel (300-400 meshes) column chromatography, and petroleum ether-ethyl acetate (V: 2:3) mixed liquid is used as eluent. Intermediate 1c was obtained as a light brown solid, 0.35g, yield 65.7%.

The second method comprises the following steps:

8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidinyl-1- ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- (3-methanesulfonylcarbonylpropyl) -1H-purine-2, 6-dione 3a-2(0.15g,0.28mmol) and 1- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperazine 1b (0.067g,0.29mmol) were dissolved in 2mL of anhydrous DMF and then reacted with DIPEA (0.15mL,0.84mmol) under argon at 75 ℃ for 8H. TLC detection raw material reaction is complete, the solvent is evaporated, 20mL deionized water is added, ethyl acetate extraction (3X20mL) is carried out, organic phases are combined, washing is carried out once with saturated salt water, drying is carried out by anhydrous sodium sulfate, filtration and concentration are carried out. The crude product is separated by silica gel (300-400 meshes) column chromatography, and petroleum ether-ethyl acetate (V: 2:3) mixed liquid is used as eluent. Intermediate 1c was obtained as a light brown solid 0.080g, yield 41.7%.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 1

Dissolve 1c (0.34g,0.50mmol) in 3mL of dichloromethane, then add 1mL of TFA and stir at room temperature for 2 h. TLC detects that the raw material is completely reacted, 30mL of deionized water and 20mL of diethyl ether are added, an organic layer is discarded, an aqueous layer is separated, and the pH of the aqueous layer is adjusted to 8-9 by potassium carbonate powder. Extraction with dichloromethane (30 mL. times.5) combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1 as an off-white solid 0.27g, yield 90.1%. m.p.83-85 ℃,(c1.08,CHCl₃)。¹H NMR(400MHz,CDCl₃)δ:7.98(m,2H),7.43(m,3H),4.87(m,2H),4.08(t,J＝7.2Hz,2H),3.65(m,4H),3.62(m,1H),3.54(m,1H),3.51(s,3H),3.09(m,2H),2.90(m,1H),2.53(m,6H),1.70-1.99(m,10H),1.37(m,1H).HR-MS(ESI):C₃₀H₃₉N₁₀O₃calculated value 587.32011, found [ M + H]⁺587.31818.

Example 2

The compound 28- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (pyridin-4-yl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (pyridin-4-yl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 2c

Starting from 3a-1(0.20g,0.37mmol) and 1- [3- (4-pyridyl) -1,2, 4-oxadiazol-5-yl) piperazine 2b (0.09g,0.39mmol), using a procedure similar to the first step in example 1, intermediate 2c was obtained as a white solid, 0.14g, 54.7% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (pyridin-4-yl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 2

Using 2c (0.13g,0.19mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 1 to give compound 2 as a white solid in a yield of 0.10g and 90.5%.¹H NMR(400MHz,CDCl₃)δ:8.71(m,2H),7.84(m,2H),4.87(m,2H),4.08(t,J＝7.2Hz,2H),3.67(m,4H),3.62(m,1H),3.55(m,1H),3.51(s,3H),3.09(m,2H),2.91(m,1H),2.54(m,6H),1.70-2.00(m,10H),1.39(m,1H).HR-MS(ESI):C₂₉H₃₈N₁₁O₃Calculated value 588.31536, found [ M + H]⁺588.31335.

Example 3

The compound 38- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-methyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-methyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 3c

Starting from 3a-1(0.11g,0.21mmol) and 1- (3-methyl-1, 2, 4-oxadiazol-5-yl) piperazine 3b (0.045g,0.27mmol), the first analogous procedure used in example 1 gave intermediate 3c as a colorless oil, 0.060g, 46.9% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-methyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 3

Using 3c (0.11g,0.17mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 1 to give compound 3 as an off-white solid in a yield of 0.060g, 65.2%. m.p.75-77 deg.C,(c1.05,CHCl₃)。¹H NMR(400MHz,CDCl₃)δ:4.85(m,2H),4.06(t,J＝7.2Hz,2H),3.62(m,1H),3.55(m,5H),3.50(s,3H),3.07(m,2H),2.88(m,1H),2.48(m,6H),2.20(s,3H),1.98(m,1H),1.81-1.89(m,9H),1.35(m,1H).HR-MS(ESI):C₂₅H₃₇N₁₀O₃calculated value 525.30446, found [ M + H]⁺525.30420.

Example 4

The compound 48- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-isopropyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-isopropyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 4c

Starting from 3a-1(0.15g,0.28mmol) and 1- (3-isopropyl-1, 2, 4-oxadiazol-5-yl) piperazine 4b (0.056g,0.29mmol), using a procedure similar to the first step in example 1, intermediate 4c was obtained as an off-white solid in a yield of 0.11g and 57.7%.

Second step preparation of 8- [ (3R) -3-aminopiperidinyl-1- ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-isopropyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 4

Using 4c (0.090g,0.14mmol) as a starting material, the procedure was similar to the second step of example 1 to give compound 4 as a colorless oil, 0.070g, 92.1% yield.¹H NMR(400MHz,CDCl₃)δ:4.85(m,2H),4.06(t,J＝7.2Hz,2H),3.63(m,1H),3.44-3.56(m,8H),3.04(m,2H),2.90(m,2H),2.48(m,6H),1.98(m,1H),1.86(m,3H),1.82(s,3H),1.72(m,1H),1.63(brs,2H),1.35(m,1H),1.27(d,J＝6.8Hz,6H).HR-MS(ESI):C₂₇H₄₁N₁₀O₃Calculated value 553.33576, found [ M + H]⁺553.33466.

Example 5

The compound 58- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 5c

Starting from 3a-1(0.16g,0.30mmol) and 1- (3-isopropyl-1, 2, 4-oxadiazol-5-yl) piperazine 5b (0.060g,0.30mmol), the procedure was analogous to the first step in example 1 to give intermediate 5c as a pale yellow solid, 0.14g, 72.2% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 5

Using 5c (0.14g,0.21mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 1 to give compound 5 as an off-white solid in a yield of 0.11g and 92.1%.¹H NMR(400MHz,CDCl3):δ4.87(m,2H),4.05(t,J＝7.6Hz,2H),3.62(m,1H),3.51(m,8H),3.06(m,2H),2.87(m,1H),2.47(m,6H),1.98(m,1H),1.77(m,10H),1.35(m,1H),0.91(m,4H).HR-MS(ESI):C₂₇H₃₉N₁₀O₃Calculated value 551.32011, found [ M + H]⁺551.31921.

Example 6

The compound 68- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-cyclopentyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-cyclopentyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 6c

Starting from 3a-1(0.20g,0.37mmol) and 1- (3-cyclopentyl-1, 2, 4-oxadiazol-5-yl) piperazine 6b (0.085g,0.38mmol), using a procedure similar to the first step in example 1, intermediate 6c was obtained as an off-white solid in a yield of 0.14g, 57.5%.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-cyclopentyl-1, 2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 6

Using 6c (0.13g,0.19mmol) as a starting material, by the similar procedure as in the second step in example 1, Compound 6 was obtained as a pale yellow transparent oil in a yield of 0.095g and 85.6%.¹H NMR(400MHz,CDCl3):δ4.87(m,2H),4.06(t,J＝7.2Hz,2H),3.62(m,1H),3.55(m,4H),3.45-3.53(m,4H),3.11(m,2H),2.97(m,2H),2.48(m,6H),1.61-2.03(m,18H),1.44(m,1H).HR-MS(ESI):C₂₉H₄₃N₁₀O₃Calculated value 579.35141, found [ M + H]⁺579.34967.

Example 7

The compound 78- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-methylphenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-methylphenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 7c

Starting from 3a-1(0.11g,0.20mmol) and 1- [3- (4-methyl) phenyl-1, 2, 4-oxadiazol-5-yl ] piperazine 7b (0.051g,0.21mmol), the first similar procedure used in example 1 gave intermediate 7c as a pale brown solid in 0.10g, 69.4% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-methylphenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 7

Using 7c (0.15g,0.21mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 1 to give compound 7 as an off-white solid in an amount of 0.11g with a yield of 85.9%.¹H NMR(400MHz,CDCl₃)δ:7.86(m,2H),7.23(m,2H),4.89(m,2H),4.08(t,J＝7.2Hz,2H),3.64(m,4H),3.60(m,1H),3.51(s,3H),3.47(m,1H),3.19(m,2H),3.02(m,1H),2.53(m,6H),2.39(s,3H),2.00(m,1H),1.88(m,3H),1.83(s,3H),1.74(m,1H),1.52(m,1H).HR-MS(ESI):C₃₁H₄₁N₁₀O₃Calculated value 601.33576, found [ M + H]⁺601.33380.

Example 8

The compound 88- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-trifluoromethylphenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-trifluoromethylphenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 8c

Starting from 3a-1(0.11g,0.20mmol) and 1- [3- (4-trifluoromethyl) phenyl-1, 2, 4-oxadiazol-5-yl ] piperazine 8b (0.062g,0.21mmol), the first analogous procedure used in example 1 gave intermediate 8c as a pale brown solid in a yield of 61.3% at 0.095 g.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-trifluoromethylphenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 8

Using 8c (0.090g,0.12mmol) as a starting material, the second similar procedure as in example 1 was conducted to give compound 8 as an off-white solid in an amount of 0.055g with a yield of 69.6%.¹H NMR(400MHz,CDCl₃)δ:8.11(d,J＝8.2Hz,2H),7.68(d,J＝8.2Hz,2H),4.98(m,2H),4.08(m,2H),3.68(m,5H),3.56(m,1H),3.51(s,3H),3.36(m,3H),2.54(m,6H),1.94(m,5H),1.84(s,3H),1.75(m,1H).HR-MS(ESI):C₃₁H₃₈N₁₀O₃F₃Calculated value 655.30750, found [ M + H]⁺655.30487.

Example 9

The compound 98- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-fluorophenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-fluorophenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 9c

Starting from 3a-1(0.16g,0.29mmol) and 1- [3- (4-fluoro) phenyl-1, 2, 4-oxadiazol-5-yl ] piperazine 9b (0.075g,0.30mmol), the first similar procedure used in example 1 gave intermediate 9c as an off-white solid in a yield of 0.13g and 61.9%.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-fluorophenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 9

Using 9c (0.12g,0.18mmol) as a starting material, by a procedure similar to the second step in example 1, Compound 9 was obtained in the form of an off-white solid (0.095 g, yield 91.8%).¹H NMR(400MHz,CDCl₃)δ:7.97(m,2H),7.11(m,2H),4.87(m,2H),4.01(m,2H),3.70(m,5H),3.50(m,4H),3.11(m,2H),2.93(m,1H),2.53(m,6H),1.70-1.99(m,8H),1.37(m,1H).HR-MS(ESI):C₃₀H₃₈N₁₀O₃F calculated 605.31069, found [ M + H]⁺605.30817.

Example 10

The compound 108- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-methoxyphenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-methoxyphenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 10c

Starting from 3a-1(0.16g,0.29mmol) and 1- [3- (4-methoxy) phenyl-1, 2, 4-oxadiazol-5-yl ] piperazine 10b (0.078g,0.30mmol), the first analogous procedure to example 1 was followed to give intermediate 10c as a pale yellow solid, 0.12g, 55.1% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3- (4-methoxyphenyl) -1,2, 4-oxadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 10

Using 10c (0.11g,0.16mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 1 to give compound 10 as a white solid in an amount of 0.085g with a yield of 89.5%.¹H NMR(400MHz,CDCl₃)δ:7.90(d,J＝7.6Hz,2H),6.92(d,J＝7.6Hz,2H),4.86(m,2H),4.07(t,J＝7.2Hz,2H),3.84(s,3H),3.63(m,5H),3.50(s,3H),3.46(m,1H),3.06(m,2H),2.87(m,1H),2.50(m,6H),1.98(m,1H),1.87(m,2H),1.82(s,3H),1.69(m,2H),1.35(m,1H).HR-MS(ESI):C₃₁H₄₁N₁₀O₄Calculated value 617.33068, found [ M + H]⁺617.32843.

Example 11

The compound 118- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-phenyl-1, 2, 4-thiadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-phenyl-1, 2, 4-thiadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 11c

Starting from 3a-1(0.15g,0.28mmol) and 1- (3-phenyl-1, 2, 4-thiadiazol-5-yl) piperazine 11b (0.072g,0.29mmol), the first analogous procedure used in example 1 gave intermediate 11c as an off-white solid, 0.16g, 83.7% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-phenyl-1, 2, 4-thiadiazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 11

Using 11c (0.15g,0.21mmol) as a starting material, by a procedure similar to the second step in example 1, Compound 11 was obtained in the form of an off-white solid (0.12 g), yield 90.2%.¹H NMR(400MHz,CDCl₃)δ:8.17(m,2H),7.41(m,3H),4.89(m,2H),4.09(t,J＝7.2Hz,2H),3.56(m,9H),3.15(m,2H),2.99(m,1H),2.56(m,6H),1.99(m,1H),1.89(m,3H),1.83(s,3H),1.72(m,1H),1.52(m,1H).HR-MS(ESI):C₃₀H₃₉N₁₀O₂S calculated value 603029727, found [ M + H]⁺603.29468.

Example 12

Compound 128- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (5-phenyl-4H-1, 2, 4-triazol-3-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (5-phenyl-4H-1, 2, 4-triazol-3-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 12c

Starting from 3a-1(0.20g,0.37mmol) and 1- (3-phenyl-4H-1, 2, 4-triazol-5-yl) piperazine 12b (0.090g,0.39mmol), the first analogous procedure of example 1 was followed to give intermediate 12c as an off-white solid, 0.25g, 98.0% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (5-phenyl-4H-1, 2, 4-triazol-3-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 12

Using 12c (0.24g,0.35mmol) as a starting material, the second similar procedure as in example 1 was followed to obtainCompound 12, off-white solid 0.17g, yield 83.0%.¹H NMR(400MHz,CDCl₃)δ:7.92(m,2H),7.38(m,3H),4.91(m,2H),4.15(m,2H),3.49(m,1H),3.46(s,3H),3.28(m,3H),3.17(m,4H),3.00(m,1H),2.51(m,6H),1.99(m,4H),1.80(s,3H),1.67(m,2H).HR-MS(ESI):C₃₀H₄₀N₁₁O₂Calculated value 586.33610, found [ M + H]⁺586.33362.

Example 13

The compound 138- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-methyl-1-phenyl-1-H-pyrazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-methyl-1-phenyl-1-H-pyrazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 13c

Starting from 3a-1(0.080g,0.15mmol) and 1- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine 13b (0.038g,0.16mmol), the first similar procedure used in example 1 gave intermediate 13c as an off-white solid in 0.075g, 72.1% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-methyl-1-phenyl-1-H-pyrazol-5-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 13

Using 13c (0.16g,0.23mmol) as a starting material, by a procedure similar to the second step in example 1, Compound 13 was obtained in the form of an off-white solid (0.11 g), yield 82.7%. m.p.119-121 ℃,(c1.08,CHCl₃)。¹H NMR(400MHz,CDCl₃)δ:7.74(m,2H),7.38(m,2H),7.22(m，1H),5.64(s,1H),4.93(m,2H),4.04(t,J＝7.2Hz,2H),3.59(m,1H),3.48(s,3H),3.35(m,4H),2.83(m,4H),2.49(m,6H),2.26(s,3H),1.68-2.00(m,9H).HR-MS(ESI):C₃₂H₄₃N₁₀O₂calculated value 599.35650, found [ M + H]⁺599.35406.

Example 14

The compound 148- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenylthiazol-2-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenylthiazol-2-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 14c

Starting from 3a-1(0.16g,0.39mmol) and 1- (4-phenylthiazol-2-yl) piperazine 14b (0.074g,0.30mmol), the first similar procedure used in example 1 gave intermediate 14c as a white solid, 0.15g, 71.8% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenylthiazol-2-yl) piperazin-1-yl ] propyl } -1H-purine-2, 6-dione 14

Using 14c (0.14g,0.20mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 1 to give compound 14 as an off-white solid in a yield of 0.10g, 83.3%.¹H NMR(400MHz,CDCl₃)δ:7.82(m,2H),7.36(m,2H),7.28(m,1H),6.75(s,1H),4.90(m,2H),4.09(t,J＝7.2Hz,2H),3.60(m,1H),3.43-3.51(m,8H),3.19(m,2H),3.01(m,1H),2.55(m,6H),1.83-1.99(m,8H),1.73(m,2H),1.53(m,1H).HR-MS(ESI):C₃₁H₄₁N₉O₂S calculated value 602.30017, found [ M + H]⁺602.30202.

Example 15

Compound 158- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (1-phenyl-1H-tetrazol-5-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (1-phenyl-1H-tetrazol-5-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 15c

3a-1(0.16g,0.30mmol) and 4- (1-phenyl-1H-tetrazol-5-yl) piperidine dihydrochloride 15b (0.10g,0.30mmol) were dissolved in 3mL DMF, and 0.26mL triethylamine was added, and the mixture was reacted at 75 ℃ for 12H under argon protection. The reaction solution was concentrated, and the crude product was separated by silica gel (300-.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (1-phenyl-1H-tetrazol-5-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 15

Using 15c (0.13g,0.19mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 1 to give compound 15 as a yellowish solid in an amount of 0.060g with a yield of 53.4%.¹H NMR(400MHz,CDCl₃)δ:7.59(m,3H),7.39(m,2H),4.87(m,2H),4.04(m,2H),3.64(m,1H),3.48(s,3H),3.44(m,1H),3.00-3.28(m,5H),2.83(m,1H),2.50(m,2H),2.02(m,4H),1.61-1.85(m,12H),1.30(m,1H).HR-MS(ESI):C₃₀H₄₀N₁₁O₂Calculated value 586.33610, found [ M + H]⁺586.33356.

Example 16

Compound 168- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenyl-1H-1, 2, 3-triazol-1-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenyl-1H-1, 2, 3-triazol-1-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 16c

By using 3a-1(0.15g,0.27mmol) and 4- (4-phenyl-1H-1, 2, 3-triazol-1-yl) piperidine 16b (0.065g,0.28mmol) as raw materials and using the similar operation steps of the first step in example 1, intermediate 16c is obtained as an off-white solid, 0.16g, with a yield of 83.8%.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenyl-1H-1, 2, 3-triazol-1-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 16

Using 16c (0.16g,0.23mmol) as a starting material, by a procedure similar to the second step in example 1, Compound 16 was obtained as a white solid in a yield of 76.6%.¹H NMR(400MHz,CDCl₃)δ:7.82(m,2H),7.75(s,1H),7.43(m,2H),7.33(m,1H),4.86(m,2H),4.49(m,1H),4.11(t,J＝7.2Hz,2H),3.59(m,1H),3.53(s,3H),3.48(m,1H),3.06(m,4H),2.86(m,1H),2.53(m,2H),2.14(m,4H),1.90(m,5H),1.81(s,3H),1.69(m,1H),1.65(brs,2H),1.31(m,1H).HR-MS(ESI):C₃₁H₄₁N₁₀O₂Calculated value 585.34085, found [ M + H]⁺585.33856.

Example 17

The compound 178- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenylthiazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenylthiazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 17c

Using 3a-1(0.16g,0.29mmol) and 4- (4-phenylthiazol-2-yl) piperidine 17b (0.074g,0.30mmol) as starting materials, the procedure similar to the first step in example 1 was followed to give intermediate 17c as an off-white solid in 0.16g at a yield of 76.6%.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenylthiazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 17

Using 17c (0.15g,0.22mmol) as a starting material, by a procedure similar to the second step in example 1, Compound 17 was obtained as an off-white solid in a yield of 0.11g and 86.4%.¹H NMR(400MHz,CDCl₃)δ:7.87(m,2H),7.40(m,2H),7.31(m,2H),4.85(m,2H),4.07(t,J＝7.2Hz,2H),3.61(m,1H),3.54(m,1H),3.51(s,3H),3.05(m,5H),2.84(m,1H),2.52(m,2H),2.15(m,4H),1.69-2.16(m,12H),1.32(m,1H).HR-MS(ESI):C₃₂H₄₁N₈O₂S calculated value 601.30677, found [ M + H]⁺601.30469.

Example 18

The compound 188- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (5-phenyloxazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (5-phenyloxazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 18c

Starting from 3a-1(0.14g,0.26mmol) and 4- (5-phenyloxazol-2-yl) piperidine 18b (0.062g,0.27mmol), using the procedure similar to the first step in example 1, intermediate 18c was obtained as a white solid in 0.14g and 79.1% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (5-phenyloxazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 18

Using 18c (0.13g,0.19mmol) as a starting material, by a procedure similar to the second step in example 1, Compound 18 was obtained as a white solid in a yield of 86.9%.¹H NMR(400MHz,CDCl₃)δ:7.59(m,2H),7.39(m,2H),7.29(m,1H),7.20(s,1H),4.85(m,2H),4.06(t,J＝6.8Hz,2H),3.61(m,1H),3.54(m,1H),3.50(s,3H),3.04(m,4H),2.86(m,2H),2.52(m,2H),1.69-2.16(m,14H),1.34(m,1H).HR-MS(ESI):C₃₂H₄₁N₈O₃Calculated value 585.32961, found [ M + H]⁺585.32739.

Example 19

The compound 198- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenyl-1H-imidazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenyl-1H-imidazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 19c

Starting from 3a-1(0.18g,0.34mmol) and 4- (4-phenylimidazol-2-yl) piperidine 19b (0.080g,0.36mmol), the first similar procedure used in example 1 gave intermediate 19c as a white solid, 0.17g, 74.2% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenyl-1H-imidazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 19

Using 19c (0.17g,0.25mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 1 to give compound 19 as a white solid in a yield of 0.13g and 89.6%.¹H NMR(400MHz,CDCl₃)δ:7.67(m,2H),7.33(m,2H),7.19(m,2H),4.83(m,2H),4.06(t,J＝7.2Hz,2H),3.60(m,1H),3.52(m,1H),3.50(s,3H),3.03(m,4H),2.83(m,2H),2.48(m,2H),1.65-2.06(m,14H),1.32(m,1H).HR-MS(ESI):C₃₂H₄₂N₉O₂Calculated value 584.36560, found [ M + H]⁺584.34393.

Example 20

The compound 208- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (5-phenylisoxazol-3-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (4-phenyl-1H-imidazol-2-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 20c

Starting from 3a-1(0.18g,0.34mmol) and 4- (4-phenylimidazol-2-yl) piperidine 20b (0.078g,0.35mmol), the first similar procedure described in example 1 gave intermediate 20c as a pale brown solid in 0.18g, 80.8% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (5-phenylisoxazol-3-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 20

Using 20c (0.18g,0.26mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 1 to give compound 20 as an yellowish solid in an amount of 0.13g with a yield of 87.6%.¹H NMR(400MHz,CDCl₃)δ:7.75(m,2H),7.44(m,3H),6.39(s,1H),4.85(m,2H),4.08(m,2H),3.61(m,1H),3.52(s,3H),3.51(m,1H),3.04(m,4H),2.82(m,2H),2.52(m,2H),2.09(m,2H),1.65-1.96(m,14),1.30(m,1H).HR-MS(ESI):C₃₂H₄₁N₈O₃Calculated value 585.32961, found [ M + H]⁺585.32764.

Example 21

The compound 218- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione

First step preparation of 8- [ (3R) -3- (tert-Butoxycarbonyl) aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 21c

Starting from 3a-1(0.18g,0.34mmol) and 4- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperidine 21b (0.081g,0.35mmol), the first analogous procedure used in example 1 gave intermediate 21c as a tan solid in 0.18g, 78.3% yield.

Second step preparation of 8- [ (3R) -3-aminopiperidin-1-yl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- {3- [4- (3-phenyl-1, 2, 4-oxadiazol-5-yl) piperidin-1-yl ] propyl } -1H-purine-2, 6-dione 21

Using 21c (0.18g,0.26mmol) as a starting material, the same procedures as in the second step of example 1 were carried out to give compound 21 as a pale brown solid in an amount of 0.12g with a yield of 81.0%.¹H NMR(400MHz,CDCl₃)δ:8.06(m,2H),7.48(m,3H),4.86(m,2H),4.07(t,J＝7.2Hz,2H),3.62(m,1H),3.49(s,3H),3.47(m,1H),3.05(m,5H),2.87(m,1H),2.55(m,2H),2.15(m,4H),1.69-2.08(m,12H),1.36(m,1H).HR-MS(ESI):C₃₁H₄₀N₉O₃Calculated value 586.32486, found [ M + H]⁺586.32300.

Test examples section

Test example 1 in vitro screening method for DPP-IV inhibitor

Reagent:

1. reaction substrate: Gly-Pro-m-nitroanilide hydrochloride (Sigma, G0513) using ddH₂Dissolving O to obtain 0.026M stock solution, and storing at-20 deg.C in dark.

DPP-IV enzyme: recombinant human DPP-IV protein (Sigma, D4943) is preserved at-20 ℃.

3. A sample to be tested: DMSO is dissolved in 10^-2M, storing at 4 ℃.

4. Positive control drug: linagliptin was dissolved in DMSO to 10^-2M, storing at 4 ℃.

5.2×Hepes buffer：1.6g NaCl，0.074g KCl，0.027g Na₂HPO₄·2H₂O, 0.2g of glucose, 1g of Hepes in 90ml of ddH₂Adjusting pH to 7.05 with NaOH, diluting to 100ml, filtering at 0.22 μm, and storing at 4 deg.C.

Tis-HCl buffer: 6.06g Tris in 1L distilled water, adjusted to pH 8.0 with HCl.

Detection method

ddH for samples and positive drug Linagliptin₂Diluting O to 10%^-4M, DPP-IV, was prepared at a concentration of 2mU/ml using Tis/HClbuffer (pH 8.0). The substrate Gly-Pro-m-nitroanalide working solution was diluted with Hepesbuffer (pH 7.05) to a concentration of 0.26 mM. The experiment is provided with a negative control group, a positive control group and a sample group. The total volume of the reaction was 100. mu.l, in which ddH was added to the negative control group₂O10 mul, DPP-IV enzyme working solution 50 mul and substrate working solution 40 mul; adding Linagliptin solution 10 mul, DPP-IV enzyme working solution 50 mul and substrate working solution 40 mul into a positive control group; the sample set was loaded with 10. mu.l of sample solution, 50. mu.l of DPP-IV working solution and 40. mu.l of substrate working solution. The inhibition of DPP-IV by the samples was evaluated by monitoring the change in absorbance of the reaction at 405nm at 37 ℃ for 60 min.

The inhibition rate of the sample on DPP-IV is calculated as follows:

inhibition ratio (%) - (Δ OD)_60-0Negative control group-. DELTA.OD_60-0Sample set)/Δ OD_60-0Negative control group X100%

The positive control Linagliptin is generally considered to be at 10^-5The inhibition rate of M is 90-100%, the reaction of the experiment is reliable, and the inhibition rate of the sample is more than 40%, so that the reaction is effective.

Compound IC₅₀The calculation of (2):

1. for the primary screening (concentration of test compound 10)^-5M) active compounds (i.e. inhibitory activity greater than 50%), with different concentration gradients set i.e. 10^-8，10^-7，10^-6And 10^-5M DPP-IV inhibition experiments are carried out.

2. Drawing a concentration-reaction curve by using the reaction concentration and the inhibition rate of the compound, statistically processing the curve to obtain a fitting formula, wherein Y is the inhibition rate, X is the concentration of the compound, and when Y is 50 percent, namely the activity of 50 percent of the inhibition rate is reached, the corresponding concentration of the compound is the half effective Inhibition Concentration (IC) of the compound₅₀) The test results are shown in Table 1.

TABLE 1 results of enzyme level Activity assay of Compounds of examples of the invention

*: test concentration of 10^-5M；

And (4) conclusion:

the in vitro DPP-IV inhibitory activity of the tested 17 compounds reaches more than 50 percent, wherein 12 compounds IC₅₀Up to 10^-8mol/L level.

Test example 2 DPP-IV inhibitor selectivity evaluation method (DPP8/9 inhibitory Activity in vitro evaluation method)

1. Reaction substrate: the method is the same as the DPP-IV inhibitor in vitro screening method.

DPP8/9 enzyme: the recombinant human DPP8/9 protein is purified and freeze-dried and then stored at-20 ℃.

3. Sample preparation: the method is the same as the DPP-IV inhibitor in vitro screening method.

4. Positive control drug: the compound (S) -4- (2-amino- (R) -3-methylpentanoyl) isoindoline hydrochloride was dissolved in DMSO to give a solution of 10^-2M, storing at 4 ℃.

5.2 × Hepes buffer: the method is the same as the DPP-IV inhibitor in vitro screening method.

Tis/HCl buffer: the method is the same as the DPP-IV inhibitor in vitro screening method.

Evaluation method

Samples and Positive drugs ddH₂Diluting O to 10%^-4M, DPP8 enzyme was formulated at 60ng/ml using Tis/HClbuffer (pH 8.0) and 40ng/ml DPP9 enzyme. The substrate Gly-Pro-m-nitroanilide working solution was diluted with Hepes buffer (pH 7.05) at a concentration of 0.52 mM. The experiment is provided with a negative control group, a positive control group and a sample group. The total volume of the reaction was 100. mu.l, in which ddH was added to the negative control group₂O10μl, 50 ul of DPP8/9 enzyme working solution and 40 ul of substrate working solution; adding 10 mul of positive control solution, 50 mul of DPP8/9 enzyme working solution and 40 mul of substrate working solution into a positive control group; the sample set was loaded with 10. mu.l of sample solution, 50. mu.l of DPP8/9 enzyme working solution and 40. mu.l of substrate working solution. The selectivity of the DPP-IV inhibitor, i.e. DPP8/9 inhibition, was evaluated by monitoring the change in absorbance of the reaction at 405nm at 37 ℃ for 60 min.

The selectivity of the DPP-IV inhibitor (DPP8/9 inhibitory activity) is calculated as follows:

The test results are shown in Table 2

TABLE 2 results of the determination of the inhibition of DPP8/9 activity by the compounds of the examples of the present invention

*: test concentration of 10^-5M；

The inhibition rate of the positive medicament UAMC00132 under the same concentration is 96.7 percent.

The inhibition rate of the positive medicament Linagliptin under the same concentration is 17.9 percent

And (4) conclusion:

the tested 10 compounds with DPP-IV inhibitory activity have no obvious inhibitory activity on DPP8/9, which indicates that the 10 compounds have high selectivity on DPP-IV.

Claims

1. A compound represented by the general formula (IAa-1), a pharmaceutically acceptable salt thereof,

r is selected from cyclopropyl, cyclopentyl, phenyl and pyridyl;

wherein said cyclopropyl, cyclopentyl, phenyl and pyridyl may be unsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, aminoNitro, trifluoromethyl, trifluoromethoxy, C_1-6An alkyl group.

2. A compound represented by the general formula (IAa-2), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

wherein said phenyl group may be unsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6An alkyl group.

3. A compound represented by the general formula (IAa-3), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

4. A compound represented by the general formula (IAa-4), a pharmaceutically acceptable salt thereof,

R₁selected from methyl, ethyl, n-propyl, isopropyl;

R₂is selected from phenyl;

5. A compound represented by the general formula (IAa-5), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

6. A compound represented by the general formula (IBa-1), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

7. A compound represented by the general formula (IBa-2), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

8. A compound represented by the general formula (IBa-3), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

9. A compound represented by the general formula (IBa-4), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

10. A compound represented by the general formula (IBa-5), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

11. A compound represented by the general formula (IBa-6), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

wherein said phenyl group mayUnsubstituted or optionally substituted with 1 to 4 groups selected from: hydroxy, halogen, cyano, amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6An alkyl group.

12. A compound represented by the general formula (IBa-7), a pharmaceutically acceptable salt thereof,

r is selected from phenyl;

13. The following compounds, pharmaceutically acceptable salts thereof:

14. a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.

15. Use of a compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with DPP-IV hyperactivity or DPP-IV overexpression.

16. Use according to claim 15, wherein the disease or condition associated with DPP-IV hyperactivity or DPP-IV overexpression is a disease or condition selected from the group consisting of: diabetes, hyperlipidemia, obesity, and metabolic syndrome.