CN105646492B - Substituted xanthine compound containing five-membered aromatic heterocycle and its preparation method and use - Google Patents

Abstract

The invention discloses a substituted xanthine compound containing a five-membered aromatic heterocycle and a preparation method and application thereof. In particular, the present invention relates to compounds of formula (I) and their stereoisomers, their pharmaceutically acceptable salts, as described in the specification. The present invention also relates to a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for use in a method for the treatment and/or prophylaxis of a disease or disorder associated with DPP-IV hyperactivity or DPP-IV overexpression uses, and methods of using the compounds of the present invention to treat related diseases. The compounds of the present invention have potent DPP-IV inhibitory activity.

Description

Substituted xanthine compound containing five-membered aromatic heterocycle and its preparation method and use

technical field

The invention belongs to the technical field of medicine. It relates to the substituted xanthine compounds containing five-membered aromatic heterocycles represented by the general formula (I), and pharmaceutically acceptable salts and isomers thereof, the preparation of such compounds, the pharmaceutical compositions containing them and the Use of these compounds in the prevention and/or treatment of diabetes, hyperlipidemia, obesity and metabolic syndrome, especially the use in inhibiting DPP-IV.

Background technique

Diabetes Mellitus (DM) is a chronic metabolic disease with multiple etiologies, which seriously affects the health and quality of life of patients. At the end of 2013, there were about 382 million people with diabetes in the world, and it is expected that the number of people with diabetes will reach 592 million by 2035. According to statistics, the number of people with diabetes in China in 2013 was about 98.4 million, ranking first in the world, and the number of people with diabetes will increase to 142 million by 2035 (International Diabetes Federation, 2013 Update). Diabetes has become the third largest killer of human health after cardiovascular disease and tumor.

Diabetes is divided into insulin-dependent diabetes mellitus (IDDM, namely type 1 diabetes) and non-insulin-dependent diabetes mellitus (NIDDM, namely type 2 diabetes), of which type 2 diabetes is the most common, accounting for the majority of diabetic patients. more than 90% of the total. The main drugs for the clinical treatment of diabetes are insulin secretagogues (sulfonylureas, repaglinide), insulin sensitizers (biguanides, thiazolidinediones) and α-glucosidase inhibitors (acarbose). )Wait. However, diabetic patients often have reduced insulin sensitivity and responsiveness due to genetic defects, body function decline, and environmental factors, resulting in secondary drug failure and adverse reactions, such as hypoglycemia, weight gain, and cardiovascular side effects. Kahn SE, Haffner SM, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. [J]. N Engl J Med, 2006, 355: 2477-80], so there is an urgent need to develop new drugs.

Glucagon-like peptide 1 (GLP-1, glucagon-like peptide-1) and glucose-dependent insulinotropic polypeptide (GIP, glucose-dependent insulinotropic polypeptide) are an incretin. Studies have shown that GLP-1 can promote insulin release and inhibit glucagon secretion when blood sugar increases, and can also stimulate insulin gene expression, promote insulin synthesis and β-cell proliferation, and promote satiety by acting on the hypothalamus. Neurons, appetite suppression, food intake and other pathways are involved in the regulation of the body's blood glucose homeostasis.

Dipeptidyl peptidase-IV (DPP-IV), a new target for the treatment of type 2 diabetes, is a highly specific serine protease that exists in the form of dimers. DPP-IV is highly expressed in the intestine, and also expressed in the liver, pancreas, placenta, thymus, spleen, etc., and part of it exists in the circulating blood in a soluble form. It specifically recognizes the alanine residue at position 2 of the N-terminus of GLP-1, and cleaves the dipeptide from there to inactivate GLP-1. The inactivation of GLP-1 by DPP-IV is rapid and irreversible, resulting in an extremely short half-life of endogenously produced active GLP-1. Therefore, DPP-IV inhibitors can prolong the half-life of plasma GLP-1, promote insulin secretion, and inhibit the inappropriate secretion of glucagon, thereby controlling blood sugar levels, without causing the side effects of hypoglycemia and weight gain, because of its effect The target is clear, and it has become a hot spot in the research and development of drugs for the treatment of type 2 diabetes. Currently listed DPP-IV inhibitors include sitagliptin, saxagliptin, vildagliptin and linagliptin.

DPP-IV belongs to the serine peptidase family, and it also belongs to this family together with DPP2, DPP8, DPP9, FAP and POP. The results of animal model experiments show that inhibition of DPP8/9 can cause toxic reactions such as anemia, alopecia, thrombocytopenia and splenomegaly [Lankas GR, Leiting B, et al. Dipeptidyl peptidase IV inhibition for the treatment of type2diabetes:potential importance of selectivity overdipeptidyl peptidases8and9. Diabetes, 2005, 54:2988-2994]. Therefore, the design and development of selective inhibitors against a single target of DPP-IV is of great significance [Bhumika DP, ManJunath DG. Recentapproaches to medicinal chemistry and therapeutic potential of dipeptidylpeptidase-4 (DPP-4) inhibitors. European Journal of Medicinal Chemistry, 2014, 74:574-605], which is also the difficulty and key point in the development of new selective DPP-IV inhibitors.

Therefore, there is still a need in the art for selective DPP-IV inhibitors with novel structures and strong activity to meet the needs of clinical treatment.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a DPP-IV inhibitory compound with novel structure and strong activity. The present inventors found that a new class of substituted xanthine compounds containing five-membered aromatic heterocycles has DPP-IV inhibitory activity and good selectivity to DPP-IV, and can be used for the prevention and treatment of diabetes. The present invention has been completed based on the above findings.

SUMMARY OF THE INVENTION

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

in,

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, C _1-10 alkyl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-8 cycloalkyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkylformyl, C _3-7 cycloalkyloxyformyl, C _6-10 aryl-C _1-3 alkyl, C _3-7 hetero Aryl-C _1-3 alkyl, heterocycloalkyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, C _6-10 aryl, containing 1-9 Heteroaryl, amino, substituted amino with carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur;

Wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted by 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, Substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _{3 -7} Heteroaryl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkane ylformyl, C _3-7 cycloalkyloxyformyl, C _3-7 heterocycloalkyloxy, C _3-7 heterocycloalkylformyl, C _3-7 heterocycloalkyloxyformyl, aryl aryloxy, arylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

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

The compound according to any one of the first aspects of the present invention, the compound is a compound represented by formula (IA), a pharmaceutically acceptable salt thereof,

in,

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, C _1-10 alkyl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-8 cycloalkyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkylformyl, C _3-7 cycloalkyloxyformyl, C _6-10 aryl-C _1-3 alkyl, C _3-7 hetero Aryl-C _1-3 alkyl, heterocycloalkyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, C _6-10 aryl, containing 1-9 Heteroaryl, amino, substituted amino with carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur;

Wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted by 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, Substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _{3 -7} Heteroaryl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkane ylformyl, C _3-7 cycloalkyloxyformyl, C _3-7 heterocycloalkyloxy, C _3-7 heterocycloalkylformyl, C _3-7 heterocycloalkyloxyformyl, aryl aryloxy, arylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

Wherein the substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl;

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

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IB), a pharmaceutically acceptable salt thereof,

in,

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, C _1-10 alkyl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-8 cycloalkyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkylformyl, C _3-7 cycloalkyloxyformyl, C _6-10 aryl-C _1-3 alkyl, C _3-7 hetero Aryl-C _1-3 alkyl, heterocycloalkyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, C _6-10 aryl, containing 1-9 Heteroaryl, amino, substituted amino with carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur;

Wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted by 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, Substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _{3 -7} Heteroaryl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkane ylformyl, C _3-7 cycloalkyloxyformyl, C _3-7 heterocycloalkyloxy, C _3-7 heterocycloalkylformyl, C _3-7 heterocycloalkyloxyformyl, aryl aryloxy, arylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

Wherein the substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl;

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

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IAa), a pharmaceutically acceptable salt thereof,

in,

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

R is independently selected from hydrogen, C _1-10 alkyl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-8 cycloalkyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkylformyl, C _3-7 cycloalkyloxyformyl, C _6-10 aryl-C _1-3 alkyl, C _3-7 hetero Aryl-C _1-3 alkyl, heterocycloalkyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, C _6-10 aryl, containing 1-9 Heteroaryl, amino, substituted amino with carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur;

Wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted by 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, Substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _{3 -7} Heteroaryl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkane ylformyl, C _3-7 cycloalkyloxyformyl, C _3-7 heterocycloalkyloxy, C _3-7 heterocycloalkylformyl, C _3-7 heterocycloalkyloxyformyl, aryl aryloxy, arylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

Wherein the substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl;

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

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IBa), a pharmaceutically acceptable salt thereof,

in,

L is independently selected from C, N;

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

R is independently selected from hydrogen, C _1-10 alkyl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-8 cycloalkyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkylformyl, C _3-7 cycloalkyloxyformyl, C _6-10 aryl-C _1-3 alkyl, C _3-7 hetero Aryl-C _1-3 alkyl, heterocycloalkyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, C _6-10 aryl, containing 1-9 Heteroaryl, amino, substituted amino with carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur;

Wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be unsubstituted or optionally substituted by 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, Substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _{3 -7} Heteroaryl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkane ylformyl, C _3-7 cycloalkyloxyformyl, C _3-7 heterocycloalkyloxy, C _3-7 heterocycloalkylformyl, C _3-7 heterocycloalkyloxyformyl, aryl aryloxy, arylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

Wherein the substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl;

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

The compound according to any one of the first aspects of the present invention, the compound is a compound represented by formula (IAa-1), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IAa-2), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IAa-3), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IAa-4), a pharmaceutically acceptable salt thereof,

R ₁ , R ₂ are independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 selected from nitrogen, oxygen, sulfur Heteroaryl of the heteroatom;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IAa-5), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IBa-1), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IBa-2), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IBa-3), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IBa-4), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IBa-5), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IBa-6), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

According to the compound of any one of the first aspect of the present invention, the compound is a compound represented by formula (IBa-7), a pharmaceutically acceptable salt thereof,

R is independently selected from C _1-10 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, sulfur Heteroaryl;

The alkyl, cycloalkyl, aryl and heteroaryl groups mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of hydroxyl, halogen, cyano, amino, substituted amino, nitro , trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, C _3-7 heteroaryl , C _1-6 alkyloxy, C _1-6 alkyl formyl, C _1-6 alkyloxy formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkyl formyl, C _3-7 cycloalkyloxycarbonyl, _C3-7 heterocycloalkyloxy, _C3-7 heterocycloalkylcarbonyl, _C3-7 heterocycloalkyloxycarbonyl, aryloxy, aryl ylformyl, aryloxyformyl, _C4-9 heteroaryloxy, _C4-9 heteroarylformyl, _C4-9 heteroaryloxyformyl;

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

The compound according to any one of the first aspects of the present invention, its pharmaceutically acceptable salt, is characterized in that, in the compound,

X is preferably C, N;

Ring B is preferably selected from substituted or unsubstituted oxadiazoles, substituted or unsubstituted pyrazoles, substituted or unsubstituted triazoles, substituted or unsubstituted tetrazoles, substituted or unsubstituted thiazoles, substituted or unsubstituted Unsubstituted oxazoles, substituted or unsubstituted imidazoles, substituted or unsubstituted thiadiazoles, substituted or unsubstituted isoxazoles;

R, R ₁ , R ₂ are preferably methyl, isopropyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl;

The substituents mentioned therein may be unsubstituted or optionally substituted with 1-4 groups selected from the group consisting of: trifluoromethyl, trifluoromethoxy, substituted amino, nitro, fluorine, chlorine, bromine, C _{1 -6} alkyl, C _1-6 alkyloxy.

1-2 of said substituted amino groups are optionally substituted by the following groups: C _1-6 alkyl.

The pharmaceutically acceptable salts described in the present invention are salts formed by 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. Preferred are hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid or trifluoroacetic acid.

The compound according to any one of the first aspect of the present invention is the target compound of the present invention (represented by the structural formula or described by the systematic name) and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

A compound according to any one of the first aspects of the present invention, which is a compound selected from the group consisting of:

A second aspect of the present invention provides a method for preparing the compound described in any one of the first aspects of the present invention, comprising the steps of:

step one

in the presence of a base such as potassium carbonate, in a solvent such as N,N-dimethyl (R)-3-(tert-butoxycarbonyl)aminopiperidine reacts with (R)-3-(tert-butoxycarbonyl)aminopiperidine for about 6-24 hours to obtain the compound shown in formula 2a;

Step 2 (Method 1)

in the presence of a base (eg potassium carbonate) in a solvent (eg N,N-dimethylformamide), the compound shown in formula 2a is reacted with 1,3-dibromopropane for about 3-12 hours to obtain the compound shown in formula 3a-1;

Step 2 (Method 2)

in the presence of a base (eg potassium carbonate) in a solvent (eg N,N-dimethylformamide), the compound shown in formula 2a is reacted with 3-bromopropanol for about 3-12 hours to obtain the compound shown in formula 2a-1;

in a solvent (eg dichloromethane) in the presence of a base (eg triethylamine) at a temperature of 0°C to 30°C (eg 0°C to 25°C, 20°C to 30°C or 25°C to 30°C) , the compound shown in formula 2a-1 is reacted with sulfonyl chloride (such as methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.) for 1-2h to obtain the compound shown in formula 3a-2;

Step 3:

in the presence of a base (such as diisopropylethylamine) in a solvent (such as N, N-dimethylformamide), the compound shown in formula 3a is reacted with aliphatic heterocyclic amine b for about 6-24 hours to obtain the compound shown in formula c;

Step 4:

in a 25% solution of trifluoroacetic acid/dichloromethane at a temperature of 10°C to 40°C (eg 10°C to 35°C, 15°C to 30°C, 20°C to 30°C, or 20°C to 25°C) The Boc protecting group is removed from the compound shown in formula c to obtain the compound of the present invention shown in formula I;

in,

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

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

A third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the compound of any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, and optionally one or more A pharmaceutically acceptable carrier or excipient.

The fourth aspect of the present invention provides the compound of any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of the third aspect of the present invention, prepared for the treatment and/or prevention of and Use in the medicament of a disease or condition in which DPP-IV activity is too high or is associated with DPP-IV overexpression. In one embodiment, the disease or disorder associated with DPP-IV overactivity or DPP-IV overexpression is a disease or disorder selected from the group consisting of diabetes, hyperlipidemia, obesity, and metabolic syndrome.

The fourth aspect of the present invention also provides the compound of any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of the third aspect of the present invention, when prepared for treatment and/or prevention Use in medicines for diabetes, hyperlipidemia, obesity and metabolic syndrome.

The fourth aspect of the present invention also provides the compound of any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of the third aspect of the present invention, when prepared as a DPP-IV inhibitor Use in medicine.

A fifth aspect of the present invention provides a method of treating and/or preventing a disease or condition associated with overactivity of DPP-IV or overexpression of DPP-IV in a subject in need thereof, the method comprising administering to a subject in need thereof A subject using a therapeutically and/or prophylactically effective amount of a compound of any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the third aspect of the present invention. The method according to any one of the fifth aspects of the present invention, wherein the disease or condition associated with overactivity of DPP-IV or overexpression of DPP-IV is selected from the group consisting of diabetes, hyperlipidemia, obesity and metabolic syndrome.

A fifth aspect of the present invention also provides a method of treating and/or preventing diabetes, hyperlipidemia, obesity and metabolic syndrome in a subject in need thereof, the method comprising administering a treatment to the subject in need thereof and/or a prophylactically effective amount of the compound of any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of the third aspect of the present invention.

The sixth aspect of the present invention provides the compound according to any one of the first aspect of the present invention, which is pharmaceutically acceptable for use in the treatment and/or prevention of diseases or conditions associated with overactivity of DPP-IV or overexpression of DPP-IV. Salt. The compound according to the sixth aspect of the present invention, wherein the disease or condition related to DPP-IV overactivity or DPP-IV overexpression is selected from the group consisting of diabetes, hyperlipidemia, obesity and metabolic syndrome.

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

Features of any aspect of the invention or any one of that aspect are equally applicable to any other aspect or to any of the other aspects, so long as they do not contradict each other, and of course where applicable to each other , if necessary, make appropriate modifications to the corresponding features. In the present invention, for example, when referring to "any one of the first aspect of the present invention", the "any one" refers to any sub-aspect of the first aspect of the present invention, and when referring to other aspects in a similar manner, also have a similar meaning.

Detailed description of the invention:

Various aspects and features of the present invention are further described below.

All documents cited in the present invention, their entire contents are incorporated herein by reference, and if the meaning expressed by these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have ordinary meanings known to those skilled in the art. Even so, the present invention still hopes to make more detailed descriptions and explanations for these terms and phrases. The terms and phrases mentioned are such as If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail. The following are definitions of various terms used in the present invention, and these definitions apply to the terms used throughout the specification of this application unless otherwise indicated in a specific case. Definitions of various groups of the compounds of the present invention are provided below, and unless otherwise defined, they are used uniformly in the specification and claims.

As mentioned in the present invention, "a five-membered heteroaryl group containing 1-4 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur" includes 1 carbon atom and 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered heteroaryl with heteroatoms of nitrogen, oxygen, sulfur, and specific groups such as tetrazolyl, preferably tetrazolyl; containing 2 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, and sulfur five-membered heteroaryl, 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 groups, and specific groups such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, preferably imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl; Five-membered heteroaryl groups containing 4 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, and specific groups such as pyrrolyl, furyl, thienyl, preferably pyrrolyl, furyl, thienyl.

As referred to in the present invention, the terms "halo", "halogen", "halogen atom", "halo" and the like mean fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

As mentioned in the present invention, the term "alkyl" refers to an alkyl group having the specified number of carbon atoms, which may be a straight-chain or branched-chain alkyl group, such as the "C _1-10 alkyl group" mentioned. , refers to alkyl groups with carbon atoms of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, which may include C _1-9 alkyl, C _1-8 alkyl, C _2-10 The groups of the sub-ranges represented by alkyl, C _2-9 alkyl, C _2-8 alkyl, C _3-10 alkyl, C _3-9 alkyl, C _3-8 alkyl, etc., and preferred specific Groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, more preferably methyl ,Isopropyl. For example, "C _1-6 alkyloxy", "C _1-6 alkyl formyl", "C _1-6 alkyloxyformyl" or "C _1-6 alkyl" in "C 1-6 alkyl"" _1-6 alkyl" refers to an alkyl group with 1, 2, 3, 4, 5, and 6 carbon atoms, which may include C _1-5 alkyl, C _1-4 alkyl, and C _2-6 alkyl , C _2-5 alkyl, C _2-4 alkyl, C _3-6 alkyl, C _3-5 alkyl, C _3-4 alkyl, etc. represented by sub-range groups, and preferred specific groups For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and more preferably methyl. For example, "C _1-3 alkyl" in "C _6-10 aryl-C _1-3 alkyl" or "C _3-7 heteroaryl-C _1-3 alkyl" refers to carbon Alkyl groups having 1, 2, and 3 atoms can include groups in sub-ranges represented by C _1-2 alkyl groups, C _2-3 alkyl groups, etc., as well as preferred specific groups such as methyl, ethyl, n- propyl, isopropyl.

As referred to in the present invention, the term "cycloalkyl" refers to a cyclic alkyl group having the specified number of ring carbon atoms, for example, when referring to "C _3-8 cycloalkyl", it refers to the number of carbon atoms being The cycloalkyl groups of 3, 4, 5, 6, 7, and 8 may include groups in the sub-ranges represented by C _3-7 cycloalkyl, C _3-4 cycloalkyl, C _4-6 cycloalkyl, etc., And preferred specific groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, more preferably cyclopropyl, cyclopentyl, cyclohexyl. For example the "C _3-7 cycloalkyloxy", "C _3-7 cycloalkylformyl", "C _3-7 cycloalkyloxycarbonyl" or "C _3-7 cycloalkyl" The "C _3-7 cycloalkyl" in the above refers to a cycloalkyl group with 3, 4, 5, 6, and 7 carbon atoms, which may include C _3-6 cycloalkyl, C _3-5 cycloalkyl, Groups of sub-ranges represented by C _4-5 cycloalkyl and the like, and preferred specific groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, more preferably cyclopropyl, cyclopentyl base, cyclohexyl.

As mentioned in the present invention, "heterocycloalkyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen and sulfur" refers to a cyclic heterocyclic alkyl group having a specified number of ring atoms. Alkyl groups, including monocyclic or fused ring groups, have 4 to 10 ring atoms in the ring, of which 1 to 3 ring atoms are selected from heteroatoms of nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. These rings may also have one or more double bonds, however, these rings do not have a fully conjugated pi electron system. Including alkyl groups containing 3 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as 1,3-oxiranyl, ,3-Epithiopropanyl, 4,5-tetrahydrooxazolyl; alkyl groups containing 4 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as tetrahydrofuranyl , pyrrolidinyl, morpholinyl, thiomorpholinyl; alkyl groups containing 5 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as piperidinyl, homo Piperazinyl; alkyl groups containing 7 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as octahydrobenzoxazolyl; containing 8 carbon atoms and 1 to Alkyl groups containing 2 heteroatoms selected from nitrogen, oxygen and sulfur, preferably specific groups such as octahydroindolyl; alkanes containing 9 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur group, a preferred specific group such as decahydroquinolinyl.

"C _3-7 heterocycloalkyloxy", "C _3-7 heterocycloalkylcarbonyl", "C _3-7 heterocycloalkyloxycarbonyl" or "C _3-7 heterocycloalkyloxycarbonyl" as mentioned in the present invention "C _3-7 heterocycloalkyl" in " _-7 heterocycloalkyl" refers to a heterocycloalkyl group containing 3-7 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen and sulfur" , refers to a cyclic heteroalkyl group with the specified number of ring atoms, including monocyclic or fused ring groups, in the ring, with 4 to 9 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen, oxygen or Heteroatoms of sulfur, the remaining ring atoms are carbon; these rings may also have one or more double bonds, however, these rings do not have a fully conjugated pi-electron system; including those containing 3 carbon atoms and 1 to 2 selected from Alkyl groups of heteroatoms of nitrogen, oxygen, sulfur, preferred specific groups such as 1,3-epoxypropanyl, 1,3-cycloaziranyl, 1,3-epithiopropanyl, 4,5-tetrakis Hydroxazolyl; alkyl groups containing 4 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as tetrahydrofuranyl, pyrrolidinyl, morpholinyl, thiomorpholine Alkyl; alkyl groups containing 5 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as piperidinyl, homopiperazinyl; containing 7 carbon atoms and 1 to 2 An alkyl group of heteroatoms selected from nitrogen, oxygen, sulfur, a preferred specific group such as octahydrobenzoxazolyl.

As mentioned in the present invention, the "C _6-10 aryl-C _1-3 alkyl group" or the "C _6-10 aryl group" in the "C _6-10 aryl group" refers to the number of carbon atoms 6, The aryl groups of 7, 8, 9, and 10 are preferred specific groups such as phenyl, naphthyl, etc., 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 attached to the rest of the compound through an oxygen.

As mentioned in the present invention, "heteroaryl group containing 1-9 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen and sulfur" means having 1 to 4 heteroatoms as ring atoms, The remaining ring atoms are carbon aryl groups, and heteroatoms include oxygen, sulfur and nitrogen. Including aryl groups containing 1 carbon atom and 4 heteroatoms selected from nitrogen, oxygen and sulfur, preferred specific groups such as tetrazolyl; containing 2 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen and sulfur Heteroatom aryl, preferred specific groups such as 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl; containing 3 carbon atoms and 2 aryl groups with heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl; containing 4 carbon atoms and 1-2 aryl groups selected from nitrogen, oxygen, sulfur heteroatoms, preferred specific groups such as pyrrolyl, furanyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl; containing 5 carbon atoms and 1 aryl group selected from nitrogen, oxygen, sulfur heteroatoms, preferred specific groups such as pyridyl, preferably pyridyl; aryl groups containing 6 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur aryl groups, preferred specific groups such as benzotriazolyl; aryl groups containing 7 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as benzimidazolyl, benzopyridine azolyl; aryl groups containing 8 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as indolyl, benzofuranyl, benzothienyl, benzopyridine oxazinyl, benzopyrimidinyl, benzopyridazinyl; aryl containing 9 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, preferred specific groups such as quinolinyl, isoquinolinyl .

As mentioned in the present invention, "C _3-7 heteroaryl" in "C _3-7 heteroaryl-C _1-3 alkyl" or "C _3-7 heteroaryl" refers to a group having 1 to Four heteroatoms are used as ring atoms, the remaining ring atoms are carbon aryl groups, and the heteroatoms include oxygen, sulfur and nitrogen. Includes aryl groups containing 3 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole aryl groups; aryl groups containing 4 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as pyrrolyl, furyl, thienyl, pyridazinyl, pyrimidinyl, pyrazine aryl; containing 5 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, preferred specific groups such as pyridyl; containing 6 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur aryl groups of atoms, preferred specific groups such as benzotriazolyl; aryl groups containing 7 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as benzimidazolyl, Benzopyrazolyl.

"C _4-9 heteroaryloxy", "C _4-9 heteroarylcarbonyl", "C _4-9 heteroaryloxycarbonyl" or "C _4-9 heteroaryl" as mentioned in the present invention "C _4-9 heteroaryl" in "Aryl" refers to an aryl group having 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, and the heteroatoms include oxygen, sulfur and nitrogen. Includes aryl groups containing 4 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as pyrrolyl, furyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl ; Aryl containing 5 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, preferred specific groups such as pyridyl; containing 6 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur aryl groups, preferred specific groups such as benzotriazolyl; aryl groups containing 7 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as benzimidazolyl, benzene Pyrazolyl; Aryl containing 8 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as indolyl, benzofuranyl, benzothienyl, benzene Pyrazinyl, benzopyrimidinyl, benzopyridazinyl; aryl groups containing 9 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, preferred specific groups such as quinolinyl, isoquinoline Linyl.

As referred to in the present invention, the term "effective amount" refers to a dose that can achieve treatment and/or prevention of the disease or condition of the present invention in a subject.

As referred to in the present invention, the term "pharmaceutical composition", which may also refer to a "composition", which can be used to achieve the treatment and/or prevention of the diseases or conditions of the present invention in a subject, especially a mammal .

As referred to in the present invention, the term "subject" may refer to a patient or other animal, particularly a mammal, receiving a compound of formula I of the present invention or a pharmaceutical composition thereof for the treatment and/or prevention of the disease or condition of the present invention , such as humans, dogs, monkeys, cows, horses, etc.

As referred to in the present invention, the term "disease and/or disorder" refers to a physical state of the subject that is associated with the disease and/or disorder of the present invention. For example, the diseases and/or conditions described in the present invention can refer to either a physical state, such as a physical state of high blood sugar, or a disease state, such as a disease state of hyperglycemia, diabetes and the like. No distinction is made herein between a physical state and a disease state, or the two may refer to each other, eg, "hyperglycemia" and "hyperglycemia" are used interchangeably.

As referred to in the present invention, "%" refers to a weight/weight percentage unless otherwise specified, especially in the context of describing solid matter. Of course, when describing liquid substances, the "%" may refer to a weight/volume percentage (in the case of a solid dissolved in a liquid), or a volume/volume percentage (in the case of a liquid dissolved in a liquid).

As referred to in the present invention, the term "pharmaceutically acceptable", for example, when describing a "pharmaceutically acceptable salt", means that the salt is not only physiologically acceptable to the subject, but also refers to the use in pharmacy Synthetic substances of value, such as salts formed as intermediates for chiral resolution, although salts of such intermediates cannot be administered directly to a subject, the salts may be used in obtaining the final product of the invention. kick in.

Still another aspect of the present invention relates to pharmaceutical compositions comprising the compounds of the present invention as active ingredients. The pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.

The compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w, w/o and double emulsion), suspensions, injections (including water injection, powder injection and infusion), eye drops solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.

The compounds of the present invention can be prepared into ordinary preparations, as well as into sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

In order to formulate the compounds of the present invention into tablets, various excipients well known in the art can be widely used, including diluents, binders, wetting agents, disintegrating agents, lubricants, cosolvents. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; Propanol, etc.; the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia mucilage, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polymer Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfonate, etc.; lubricants and cosolvents It can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

The tablets can also be further prepared as coated tablets, such as sugar-coated, film-coated, enteric-coated, or bilayer and multi-layer tablets.

In order to form a dosage unit into a capsule, the active ingredient, the compound of the present invention, can be mixed with a diluent, a cosolvent, and the mixture can be directly placed in a hard capsule or a soft capsule. The compound of the present invention can also be made into granules or pellets with diluents, binders and disintegrating agents, and then placed in hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, solubilizers used to prepare tablets of the compounds of the present invention can also be used to prepare capsules of the compounds of the present invention.

To prepare the compounds of the present invention into injections, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvents and appropriate amount of solubilizers, cosolvents, pH regulators and osmotic pressure regulators commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure adjuster can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, in the preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppant.

In addition, colorants, preservatives, fragrances, flavors, or other additives can also be added to the pharmaceutical preparations, if desired.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicament 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 may vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form. In general, a suitable daily dosage range of the compounds of the invention is 0.001-150 mg/Kg body weight, preferably 0.1-100 mg/Kg body weight, more preferably 1-60 mg/Kg body weight, and most preferably 2-30 mg/Kg body weight. The above doses may be administered in a single dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosing 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 drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

beneficial technical effect

All the compounds in the present invention have novel chemical structures, and most of the substituted xanthine compounds in the present invention have an in vitro DPP-IV inhibitory activity of more than 50%, of which 17 compounds have an in vitro DPP-IV inhibitory activity IC ₅₀ of micromolar In particular, the IC ₅₀ values of 5 compounds reached the level of 10 ^-7 mol/L, and the IC ₅₀ values of 12 compounds reached the level of 10 ^{- 8} mol/L, showing good DPP-IV inhibitory activity; Of the 10 compounds, there is no obvious DPP8/9 inhibitory activity, showing good DPP-IV selectivity, and its high selectivity can reduce the risk of toxic reactions caused by inhibiting DPP8/9, such as thrombocytopenia and splenomegaly, etc. . This study provides a class of selective DPP-IV inhibitors with novel structure and strong activity, which can be used for the prevention and treatment of type 2 diabetes and related diseases.

Detailed ways

The present invention can 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 can be made in the present invention without departing from the spirit and scope of the inventions. The present invention provides general and/or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of operation used for the purposes of the present invention are known in the art, the present invention is described in as much detail as possible.

For all of the following examples, standard procedures and purification methods known to those skilled in the art can be used. All temperatures are expressed in °C (degrees Celsius) unless otherwise stated. The structures of the compounds were determined by nuclear magnetic resonance spectroscopy (NMR) and/or mass spectrometry (MS). m.p. are melting points given in °C, temperature uncorrected.

Preparation Examples Section

The structures of the compounds were determined by hydrogen nuclear magnetic resonance spectroscopy ( ¹ H NMR) or mass spectrometry (MS). H NMR spectral shifts (δ) are given in parts per million (ppm). The nuclear magnetic resonance spectrum was measured with Mercury-300 or Mercury-400 nuclear magnetic resonance apparatus, deuterated chloroform (CDCl ₃ ) or deuterated dimethyl sulfoxide (DMSO-d6) as solvent, tetramethylsilane (TMS) or 3- (Trimethylsilyl) sodium deuterated propionate (TSM) was used as the internal standard.

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

Electronic balance adopts Japanese Yanaco LY-300 electronic balance.

The polarimeter was measured with a Perkin-Elmer241MC polarimeter under a sodium lamp (20°C).

Column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel as a carrier.

Anhydrous solvents were all worked up by standard methods. All other reagents were of commercially available analytical grade.

in,

DMF is N,N-dimethylformamide, that is, N,N-dimethylformamide.

DIPEA is N,N-diisomromylethylamine, namely N,N-diisopropylethylamine.

TFA is trifluoroacetic acid, namely trifluoroacetic acid.

CDI is N,N-Carbonyldiimidazole, namely N,N-carbonyldiimidazole.

HOBt is N-Hydroxybenzotriazole, namely N-hydroxybenzotriazole.

EDCI is 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride, namely

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

MsCl is Methanesulfonyl chloride, namely methanesulfonyl chloride.

Boc is -Butyloxy carbonyl, that is, tert-butoxycarbonyl.

OMs are Methanesulfonate, ie methanesulfonyl ester group.

OTf is Trifluoromethanesulfonate, that is, trifluoromethanesulfonate group.

OTs are p-toluenesulfonate, the p-toluenesulfonyl ester group.

Preparation example

Scheme 1 Synthetic route of intermediate 3a-1

The first step 8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1H - Preparation of purine-2,6-dione 2a

8-Bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione 1a (2.08 g, 7.00 mmol), (R)- 3-(tert-butoxycarbonyl)aminopiperidine (1.75g, 8.75mmol) and potassium carbonate (1.94g, 14.00mmol) were placed in a 50mL single-neck flask, DMF (15mL) was added, and the reaction was carried out at 75°C under argon protection 7h, TLC detected that the reaction was complete, DMF was evaporated to obtain a tan solid, 50 mL of water was added to make slurry, filtered, and dried under infrared light to obtain 2a, 2.60 g of a tan solid with a yield of 89.7%. ¹ H NMR (400MHz, CDCl ₃ )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).

The second step 8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1 Preparation of -(3-bromopropyl)-1H-purine-2,6-dione 3a-1

Potassium carbonate (1.72 g, 12.50 mmol) was added to 8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidinyl-1-]-7-(2-butynyl)-3,7- Dihydro-3-methyl-1H-purine-2,6-dione 2a (2.60 g, 6.30 mmol) and 1,3-dibromopropane (1.15 mL, 14.00 mmol) in DMF (20 mL) at room temperature After stirring for 12h, TLC detected that the reaction of the raw materials was complete. DMF was evaporated to obtain an off-white solid. 80 mL of water was added to make a slurry, filtered, and dried under infrared light to obtain 3a-1. ¹ H NMR (400 MHz, CDCl ₃ ) 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 of intermediate 3a-2

The first step 8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1 Preparation of -(3-hydroxypropyl)-1H-purine-2,6-dione 2a-1

Potassium carbonate (0.10 g, 0.72 mmol) was added to 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) solution, 70 ℃ reaction After stirring for 4h, TLC detected that the reaction of the raw materials was complete, and DMF was evaporated to obtain an off-white solid, which was added with 10 mL of water, stirred, filtered, and dried under infrared light to obtain 2a-1, an off-white solid 0.15g, the yield was 88.8%.

The second step 8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1 Preparation of -(3-Mesylate propyl)-1H-purine-2,6-dione 3a-2

2a-1 (0.15g, 0.32mmol) was dissolved in 3mL of anhydrous dichloromethane, then triethylamine (0.07mL) was added and stirred for 5min, and then added dropwise into MsCl (0.03mL) under ice bath conditions, dropwise After the addition was completed, the reaction was carried out at room temperature for 3 h, and the reaction of the raw materials was detected by TLC. The reaction solution was washed successively with 10% citric acid, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3a-2, 0.16 g of an off-white solid with a yield of 91.4%. ¹ H NMR (400 MHz, CDCl ₃ ) 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 of intermediate 1b

The first step (Z)-N-hydroxybenzamidine 4a preparation

A 50% hydroxylamine aqueous solution (1.18 mL, 20.00 mmol) was added to a solution of benzonitrile (2.00 mL, 19.60 mmol) in ethanol (25 mL), heated under reflux for 10 h, after the reaction was complete, the solvent was evaporated, and then 20 mL of toluene was added, Concentrated to obtain off-white solid 4a, which was directly carried out to the next step.

Preparation of the second step 3-phenyl-5-trichloromethyl-1,2,4-oxadiazole 5a

Trichloroacetic anhydride (4.30 mL, 23.50 mmol) was added dropwise into the toluene (20 mL) solution of 4a, heated under reflux for 10 h, after TLC detected the reaction was complete, the solvent was evaporated, 80 mL of ethyl acetate was added, followed by water, saturated carbonic acid It was washed with sodium hydrogen solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated by column chromatography on silica gel (300-400 mesh) using petroleum ether-dichloromethane (V:V=100:1) mixed solution as eluent. The intermediate 5a was obtained as 4.39 g of colorless oil, and the two-step yield was 84.6%. ¹ H NMR (400MHz, CDCl3): δ 8.13 (m, 2H), 7.53 (m, 3H).

Preparation of the third step 1-(3-phenyl-1,2,4-oxadiazol-5-yl)piperazine 1b

5a (4.39 g, 16.66 mmol) was dissolved in DMF (15 mL), slowly dropped into anhydrous piperazine in DMF solution (20 mL), stirred at room temperature for 6 h, concentrated under reduced pressure, and 150 mL of deionized water was added to the residue, Extracted with ethyl acetate (3×100 mL), dried, filtered, and the obtained crude product was separated by column chromatography on silica gel (300-400 mesh) using dichloromethane-methanol (V:V=100:1) mixture as eluent. Intermediate 1b was obtained, white foamy solid 2.35g, yield 61.2%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.99 (m, 2H), 7.44 (m, 3H), 3.73 (m, 4H), 3.04 (m, 4H), 2.16 (brs, 1H).

Scheme 4 Synthetic route of intermediate 2b

The first step (Z)-N-hydroxy-4-pyridinecarboxamidine 6a preparation

Using 4-cyanopyridine (1.00 g, 9.61 mmol) as a raw material, the same operation procedure as the first step in preparation 1b was adopted to obtain intermediate 6a, white solid 1.30 g, yield 98.5%.

Preparation of the second step 3-(4-pyridyl)-5-trichloromethyl-1,2,4-oxadiazole 7a

Using (Z)-N-hydroxy-4-pyridinecarboxamidine 6a (1.30 g, 9.48 mmol) as raw material, the similar operation procedure of the second step in preparation 1b was adopted to obtain intermediate 7a, brown solid 1.30 g, yield 52.0 %.

Preparation of the third step 1-[3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)piperazine 2b

Using 7a (0.90 g, 3.38 mmol) as the raw material, the similar operation procedure of the third step in the preparation 1b was adopted to obtain the intermediate 2b, 0.45 g of yellow solid, and the yield was 57.5%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.72 (m, 2H), 7.84 (m, 2H), 3.68 (m, 4H), 2.99 (m, 4H), 1.69 (brs, 1H).

Scheme 5 Synthetic route of intermediate 3b

Preparation of the first step (Z)-N-hydroxyacetamidine 8a

Using acetonitrile (1.00 mL, 19.24 mmol) as the raw material, following the same operation procedure as the first step in preparation 1b, intermediate 8a was obtained, white solid 1.01 g, yield 76.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.66 (brs, 1H), 5.34 (brs, 2H), 1.62 (s, 3H).

Preparation of the second step 3-methyl-5-trichloromethyl-1,2,4-oxadiazole 9a

Trichloroacetic anhydride (1.36 mL, 7.43 mmol) was added dropwise into a solution of 8a (0.50 g, 6.75 mmol) in toluene (15 mL), heated to reflux for 10 h, the solvent was evaporated, 40 mL of ethyl acetate was added, followed by water, saturated Wash with sodium bicarbonate solution and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain light brown oily substance 9a, which is directly used in the next reaction.

Preparation of the third step 1-(3-methyl-1,2,4-oxadiazol-5-yl)piperazine 3b

Using 9a as the raw material, the similar operation steps of the third step in the preparation 1b were adopted to obtain the intermediate 3b, 0.38 g of a brown oily substance, and the two-step yield was 33.5%.

Scheme 6 Synthetic route of intermediate 4b

The first step (Z)-N-hydroxyisobutyramidine 10a preparation

Using isobutyronitrile (1.30 mL, 14.47 mmol) as a raw material, the same operation procedure as the first step in preparation 1b was adopted to obtain intermediate 10a, white solid 1.15 g, yield 78.3%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.86 (brs, 1H), 4.52 (brs, 2H), 2.43 (m, 1H), 1.16 (s, 3H), 1.14 (s, 3H).

Preparation of the second step 3-isopropyl-5-trichloromethyl-1,2,4-oxadiazole 11a

Trichloroacetic anhydride (1.5 mL, 8.22 mmol) was added dropwise into a solution of 10a (0.80 g, 7.83 mmol) in toluene (15 mL), heated to reflux for 12 h, the solvent was evaporated, 40 mL of ethyl acetate was added, followed by water, saturated Wash with sodium bicarbonate solution and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain light brown oily substance 11a, which is directly used in the next reaction.

Preparation of the third step 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperazine 4b

Using 11a as the raw material, the similar operation procedure of the third step in the preparation 1b was adopted to obtain the intermediate 4b, 0.42 g of a brown-yellow oil, and the two-step yield was 27.3%.

Scheme 7 Synthetic route of intermediate 5b

Preparation of the first step (Z)-N-hydroxy-1-cyclopropylformamidine 12a

Using cyclopropylcarbonitrile (1.10 mL, 14.91 mmol) as the starting material, the similar operation procedure of the first step in the preparation 1b was adopted to obtain the intermediate 12a, 1.45 g of a colorless oil with a yield of 97.1%.

Preparation of the second step 3-cyclopropyl-5-trichloromethyl-1,2,4-oxadiazole 13a

Using 12a (0.60 g, 5.99 mmol) as the raw material, the similar operation procedure of the second step in the preparation 1b was adopted to obtain the intermediate 13a, 1.04 g of colorless oil, the yield was 76.5%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.14 (m, 1H), 1.15 (m, 4H).

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

Using 13a (1.02 g, 4.46 mmol) as the starting material, the similar operation procedure of the third step in the preparation 1b was adopted to obtain the intermediate 5b, 0.33 g of a brownish yellow oil, the yield was 38.1%. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.56 (m, 4H), 2.94 (m, 4H), 2.17 (brs, 1H), 1.87 (m, 1H), 0.94 (m, 4H).

Scheme 8 Synthetic route of intermediate 6b

The first step (Z)-N-hydroxy-1-cyclopentylcarboxamidine 14a preparation

Using cyclopentylcarbonitrile (1.10 mL, 10.51 mmol) as the raw material, the same operation procedure as the first step in preparation 1b was used to obtain intermediate 14a, colorless oil 0.70 g, yield 52.8%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.83 (brs, 1H), 4.54 (brs, 2H), 2.58 (m, 1H), 1.88 (m, 2H), 1.64 (m, 6H).

Preparation of the second step 3-cyclopentyl-5-trichloromethyl-1,2,4-oxadiazole 15a

Using 14a (0.65 g, 5.07 mmol) as raw material, the similar operation procedure of the second step in preparation 1b was adopted to obtain intermediate 15a, colorless oily substance 1.16 g, yield 89.6%.

Preparation of the third step 1-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)piperazine 6b

Using 15a (1.16 g, 4.57 mmol) as the starting material, the similar operation procedure of the third step in the preparation 1b was adopted to obtain the intermediate 6b, 0.40 g of a brownish yellow oil, the yield was 39.4%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.57 (m, 4H), 2.94 (m, 4H), 2.17 (brs, 1H), 1.98-1.62 (m, 9H).

Scheme 9 Synthetic route of intermediate 7b

Preparation of the first step (Z)-N-hydroxy-1-(4-methyl)phenylformamidine 16a

Using p-toluonitrile (1.00 g, 8.54 mmol) as a raw material, and adopting a similar operation procedure of the first step in preparation 1b, intermediate 16a was obtained, white solid 1.26 g, yield 98.6%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.52 (m, 2H), 7.20 (m, 2H), 4.88 (brs, 2H), 2.38 (s, 3H).

Preparation of the second step 3-(4-methyl)phenyl-5-trichloromethyl-1,2,4-oxadiazole 17a

Using 16a (0.60 g, 4.00 mmol) as the starting material, the similar operation procedure of the second step in the preparation 1b was adopted to obtain the intermediate 17a, 1.00 g of a colorless oil, and the yield was 90.1%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.01 (m, 2H), 7.31 (m, 2H), 2.44 (s, 3H).

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

Using 17a (1.00 g, 3.60 mmol) as the raw material, the similar operation procedure of the third step in the preparation 1b was adopted to obtain the intermediate 7b as a light yellow solid, 0.33 g, and the yield was 37.5%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.87 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 3.67 (m, 4H), 2.98 (m, 4H), 2.39(s, 3H), 1.93(brs, 1H).

Scheme 10 Synthetic route of intermediate 8b

Preparation of the first step (Z)-N-hydroxy-1-(4-trifluoromethyl)phenylformamidine 18a

Using p-trifluoromethylbenzonitrile (1.00 g, 5.84 mmol) as the raw material, the same operation procedure as the first step in preparation 1b was adopted to obtain intermediate 18a, 1.26 g of white solid, and the yield was 99.0%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.76 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 4.92 (brs, 2H).

Preparation of the second step 3-(4-trifluoromethyl)phenyl-5-trichloromethyl-1,2,4-oxadiazole 19a

Using 18a (0.60 g, 2.94 mmol) as the starting material, the similar operation procedure of the second step in the preparation 1b was adopted to obtain the intermediate 19a, 0.92 g of a colorless oil, the yield was 93.9%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.26 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H).

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

Using 19a (0.92 g, 2.76 mmol) as the raw material, the similar operation procedure of the third step in the preparation 1b was adopted to obtain the intermediate 8b as a light yellow solid, 0.30 g, and the yield was 36.4%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.11 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 3.70 (m, 4H), 3.01 (m, 4H), 2.00(brs,1H).

Scheme 11 Synthetic route of intermediate 9b

Preparation of the first step (Z)-N-hydroxy-1-(4-fluoro)phenylformamidine 20a

Using p-fluorobenzonitrile (1.00 g, 8.26 mmol) as a raw material, and adopting a similar operation procedure of the first step in preparation 1b, intermediate 20a was obtained, white solid 1.24 g, yield 97.7%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.41 (brs, 1H), 7.61 (m, 2H), 7.08 (m, 2H), 4.90 (brs, 2H).

Preparation of the second step 3-(4-fluoro)phenyl-5-trichloromethyl-1,2,4-oxadiazole 21a

Using 20a (0.60 g, 3.89 mmol) as the raw material, the similar operation procedure of the second step in the preparation 1b was adopted to obtain the intermediate 21a, 1.04 g of a colorless oil with a yield of 95.0%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 (m, 2H), 7.21 (m, 2H).

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

Using 21a (0.69 g, 2.43 mmol) as the raw material, the similar operation procedure of the third step in the preparation 1b was adopted to obtain the intermediate 9b, 0.35 g of a light yellow solid, and the yield was 58.1%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.98 (m, 2H), 7.10 (m, 2H), 3.66 (m, 4H), 2.98 (m, 4H), 1.77 (brs, 1H).

Scheme 12 Synthetic route of intermediate 10b

Preparation of the first step (Z)-N-hydroxy-1-(4-methoxy)phenylformamidine 22a

Using p-methoxybenzonitrile (1.00 g, 7.51 mmol) as a raw material, the same operation procedure as the first step in preparation 1b was adopted to obtain intermediate 22a, white solid 1.22 g, yield 97.8%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.56 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 4.84 (brs, 2H), 3.83 (s, 3H).

Preparation of the second step 3-(4-methoxy)phenyl-5-trichloromethyl-1,2,4-oxadiazole 23a

Using 22a (0.60 g, 3.61 mmol) as the raw material, the similar operation procedure of the second step in preparation 1b was adopted to obtain intermediate 23a, white solid 0.76 g, yield 71.5%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.05 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 3.88 (s, 3H).

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

Using 23a (0.74 g, 2.50 mmol) as the raw material, the similar operation procedure of the third step in the preparation 1b was adopted to obtain the intermediate 10b, 0.37 g of a light yellow solid, and the yield was 56.8%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.91 (m, 2H), 6.93 (m, 2H), 3.84 (s, 3H), 3.65 (m, 4H), 2.97 (m, 4H), 1.89 (brs , 1H).

Scheme 13 Synthetic route of intermediate 11b

The first step of the preparation of 3-phenyl-5-chloro-1,2,4-thiadiazole 24a

Benzamidine hydrochloride (0.50 g, 3.19 mmol) and perchloromethanethiol were dissolved in 10 mL of dichloromethane, and under ice bath conditions, 1 mL of aqueous sodium hydroxide (0.64 g, 15.96 mmol) was added dropwise into the above In the reaction solution, stirred for 1 hour, then moved to room temperature for 2 hours, and TLC detected that the reaction of the raw materials was complete. 10 ml of deionized water was added, extracted with dichloromethane (3×15 mL), dried and concentrated to obtain crude product 24a as a pale yellow oil, which was directly carried out to the next step.

Preparation of the second step [4-(3-phenyl-1,2,4-thiadiazol-5-yl)]piperazine-1-carboxylate tert-butyl ester 25a

24a and N-Boc-piperazine (0.60 g, 3.19 mmol) were dissolved in 4 mL of DMF, then triethylamine (1.8 mL, 12.77 mmol) was added and stirred at room temperature overnight. The reaction solvent was evaporated, then 20 mL of deionized water was added, extracted with ethyl acetate (3×20 mL), washed once with saturated sodium chloride, dried, and the obtained crude product was separated by silica gel (300-400 mesh) column chromatography, petroleum ether-ethyl acetate ( V:V=10:1) mixed solution is the eluent. Intermediate 25a was obtained as a pale yellow solid, 0.62 g, with a two-step yield of 55.6%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (m, 2H), 7.42 (m, 3H), 3.60 (m, 8H), 1.49 (s, 9H).

Preparation of the third step 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine 11b

25a (0.61 g, 1.76 mmol) was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. TLC detected the complete reaction of the raw materials, 15 mL of ether and 15 mL of deionized water were added to the reaction solution, the organic layer was discarded, the pH of the aqueous layer was adjusted to alkaline with potassium carbonate powder, and then extracted with dichloromethane (4×20 mL), anhydrous sodium sulfate It was dried and concentrated to obtain 11b as an off-white solid, 0.34 g, with a yield of 79.2%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (m, 2H), 7.42 (m, 3H), 3.60 (m, 4H), 3.03 (m, 4H), 2.08 (brs, 1H).

Scheme 14 Synthetic route for intermediate 12b

Preparation of the first step [4-(benzoylthiocarbamoyl)]piperazine-1-carboxylate tert-butyl ester 26a

Under ice bath conditions, a solution of benzoyl isothiocyanate (0.38 mL, 2.68 mmol) in anhydrous dichloromethane (5 mL) was added dropwise into a solution of N-Boc-piperazine (0.50 g, 2.68 mmol) in anhydrous In dichloromethane, after the dropwise addition was completed, the reaction was carried out at room temperature for 2 h. TLC detected that the reaction of the raw materials was complete, and the solvent was evaporated. The obtained solid was washed with ether-n-hexane = 1:2, filtered and dried to obtain Intermediate 26a, an off-white solid 0.85 g with a yield of 90.6%.

Preparation of the second step 3-phenyl-5-(4-tert-butoxycarbonyl-1-piperazinyl)-4H-1,2,4-triazole 27a

26a (0.30 g, 0.86 mmol) and hydrazine hydrate (0.17 mL, 4.29 mmol) were dissolved in 8 ml of chloroform, and the reaction was refluxed for 4 h. TLC detected the complete reaction of the raw materials, evaporated the solvent, added 15 mL of deionized water, extracted with ethyl acetate (3×15 mL), dried over anhydrous sodium sulfate, concentrated, and the obtained crude product was separated by silica gel (300-400 mesh) column chromatography, petroleum ether-acetic acid A mixture of ethyl esters (V:V=2:1) was the eluent. The intermediate 27a was obtained as an off-white solid 0.15 g with a yield of 53.3%. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.81 (brs, 1H), 7.89 (m, 2H), 7.41 (m, 3H), 3.52 (m, 4H), 3.45 (m, 4H), 1.48 (s ,9H).

Preparation of the third step 1-(3-phenyl-4H-1,2,4-triazol-5-yl)piperazine 12b

27a (0.46 g, 1.40 mmol) was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. TLC detected the complete reaction of the raw materials, 15 mL of ether and 15 mL of deionized water were added to the reaction solution, the organic layer was discarded, the pH of the aqueous layer was adjusted to alkaline with potassium carbonate powder, and then extracted with dichloromethane (4×30 mL), anhydrous sodium sulfate It was dried and concentrated to obtain 12b as an off-white solid, 0.26 g, with a yield of 81.3%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.91 (m, 2H), 7.39 (m, 3H), 5.14 (brs, 1H), 3.42 (m, 4H), 2.96 (m, 4H).

Scheme 15 Synthetic route of intermediate 13b

The first step [4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)]piperazine-1-carboxylate tert-butyl ester 28a preparation

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

Preparation of the second step 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine 13b

28a (3.1 g, 9.06 mmol) was dissolved in dichloromethane (33 mL), TFA (11 mL) was added dropwise under an ice-water bath, stirred for 1.5 h, water (90 mL) was added, the aqueous phase was separated, and dichloromethane (20 mL×2 )wash. The pH of the aqueous phase was adjusted to 8-9 with potassium carbonate, and the system was milky white and cloudy. Extract with ethyl acetate (40 mL×3), combine the organic phases, wash with brine (15 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain Intermediate 13b, an off-white solid 2.16 g, yield 98.6%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.76 (d, J=8.0 Hz, 2H), 7.45 (t, J=8.0 Hz, 2H), 7.26 (t, J=7.6 Hz, 1H), 5.77 (s,1H),2.72(brs,4H),2.70(brs,4H),2.50(s,3H).

Scheme 16 Synthetic route of intermediate 14b

Preparation of the first step 4-(tert-butoxycarbonyl)piperazine-1-thiocarboxamide 29a

26a (0.33 g, 0.93 mmol) was dissolved in 1.5 mL of hydrazine hydrate and stirred at room temperature for 4 h. TLC detected that the reaction of the raw materials was complete, 15 mL of dichloromethane was added to the reaction solution, washed with 10% citric acid (2×15 mL), saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the obtained solid was washed with a small amount of ether to obtain an intermediate 29a, off-white solid 0.19g, yield 81.1%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.82 (brs, 2H), 3.84 (m, 4H), 3.55 (m, 4H), 1.47 (s, 9H).

Preparation of the second step [4-(4-phenylthiazol-2-yl)]piperazine-1-carboxylate tert-butyl ester 30a

α-Bromoacetophenone (0.19 g, 0.94 mmol) was added dropwise into a solution of 29a (0.22 g, 0.89 mmol) and sodium bicarbonate (0.15 g, 1.79 mmol) in ethanol (3 mL), and then refluxed for 4 h. TLC detected that the reaction of the raw materials was complete, the reaction solution was concentrated, and the obtained crude product was separated by column chromatography on silica gel (300-400 mesh) using petroleum ether-dichloromethane (V:V=1:1) mixed solution as the eluent. The intermediate 30a was obtained in the form of 0.25 g of pale yellow oil, and the yield was 80.0%. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.83(m, 2H), 7.39(m, 2H), 7.30(m, 1H), 6.78(s, 1H), 3.59(m, 8H), 1.49(s ,9H).

Preparation of the third step 1-(4-phenylthiazol-2-yl)piperazine 14b

30a (0.38 g, 1.10 mmol) was dissolved in dichloromethane (3 mL), TFA (1 mL) was added dropwise in an ice-water bath, stirred for 2 h, water (10 mL) and ether (10 mL) were added, and the aqueous phase was separated, and the aqueous phase was washed with carbonic acid The pH was adjusted to 8-9 with potassium, and the system was milky white and turbid. Extract with dichloromethane (3×15 mL), combine the organic phases, wash with brine (15 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain Intermediate 14b as an off-white solid, 0.24 g, yield 87.4%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82 (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 of intermediate 15b

Preparation of the first step N-tert-butoxycarbonyl-4-phenylcarbamoylpiperidine 31a

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

Preparation of the second step 4-(1-phenyl-1H-tetrazol-5-yl)piperidine dihydrochloride 15b

31a (400 mg, 1.316 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, triphenylphosphine (800 mg, 2.63 mmol) and trimethylsilyl azide (0.35 mL, 2.63 mmol) were added, and DIAD ( 0.52 mL, 2.63 mmol) was stirred at room temperature for 6 days, heated to reflux for 1 hour, and after cooling, 7N hydrogen chloride ethyl acetate solution was added to the system, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, the supernatant was discarded, repeated twice, filtered, the filter cake was washed with ethyl acetate, and dried to obtain Intermediate 15b, 300 mg of white solid, yield 86.0%. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Scheme 18 Synthetic route of intermediate 16b

Preparation of the first step N-tert-butoxycarbonyl-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 In a 25 mL single-necked bottle, 10 mL of methanol was added, followed by phenylacetylene (0.107 g, 1.05 mmol), and the mixture was stirred at room temperature for 2 h. Concentrate under reduced pressure, add ethyl acetate (50 mL) and water (10 mL), separate the ethyl acetate layer, wash with 10% citric acid, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate the solvent. The intermediate 32a was obtained as a pale yellow solid, 0.285 g, with a yield of 80.3%. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.82 (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).

Preparation of the second step 4-(4-phenyl-1H-1,2,3-triazol-1-yl)piperidine 16b

32a (0.28 g, 0.84 mmol) was dissolved in dichloromethane (2 mL), TFA (0.7 mL) was added dropwise in an ice-water bath, and the mixture was stirred at room temperature for 2 h. TLC detected that the reaction of the raw materials was complete, 20 mL of deionized water and 20 mL of ether were added, the organic layer was discarded, the aqueous layer was separated, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. Extract with dichloromethane (20 mL×5), combine the organic phases, wash with brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The intermediate 16b was obtained as an off-white solid 170 mg with a yield of 89.0%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.83 (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).

Scheme 19 Synthetic route of intermediate 17b

The first step [4-(4-phenylthiazol-2-yl)]piperidine-1-carboxylate tert-butyl ester 33a preparation

α-Bromoacetophenone (0.26g, 1.29mmol) was added dropwise into 1-tert-butoxycarbonylpiperidine-4-thiocarboxamide (0.30g, 1.23mmol) and sodium bicarbonate (0.21g, 2.46mmol) ) in ethanol (5 mL) solution, and then refluxed for 3 h. TLC detected that the reaction of the raw materials was complete, the reaction solution was concentrated, and the obtained crude product was separated by column chromatography on silica gel (300-400 mesh), and a mixture of dichloromethane-ethyl acetate (V:V=40:1) was used as the eluent. Intermediate 33a was obtained, pale pink oily substance 0.40 g, yield 93.2%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.90 (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).

Preparation of the second step 4-(4-phenylthiazol-2-yl)piperidine 17b

33a (0.39 g, 1.15 mmol) was dissolved in dichloromethane (3 mL), TFA (1 mL) was added dropwise under an ice-water bath, stirred for 2 h, water (15 mL) and ether (10 mL) were added, and the aqueous phase was separated, and the aqueous phase was washed with carbonic acid Potassium adjusts pH to 8-9. Extract with dichloromethane (3×15 mL), combine the organic phases, wash with brine (15 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain intermediate 17b as an off-white solid 0.24 g, yield 85.7%. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.88 (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).

Scheme 20 Synthetic route of intermediate 18b

Preparation of the first step 4-[(2-oxo-2-phenylethyl)carbamoyl]piperidine-1-carboxylic acid benzyl ester 34a

N-benzyloxycarbonyl-4-piperidinecarboxylic acid (2.00 g, 7.60 mmol) was dissolved in anhydrous dichloromethane, CDI (1.42 g, 8.74 mmol) was added under ice bath conditions, and stirred at room temperature for 4 h under argon protection , and then α-aminoacetophenone hydrochloride (1.37 g, 7.98 mmol) and DIPEA (1.39 mL, 7.98 mmol) were added successively, and the reaction was carried out at room temperature for 15 h. TLC detected that the reaction of the raw materials was complete, the reaction solution was concentrated, and the obtained crude product was separated by column chromatography on silica gel (300-400 mesh), and a mixture of dichloromethane-ethyl acetate (V:V=40:1) was used as the eluent. Intermediate 34a was obtained, 1.50 g of pale pink oily substance, and the yield was 51.9%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.97 (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) .

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

34a (0.80 g, 2.10 mmol) was dissolved in 5 mL of pyridine, then phosphorus oxychloride (1 mL, 10.5 mmol) was added, and the mixture was stirred at room temperature for 2 h. TLC detected that the reaction of the raw materials was complete. The reaction solution was slowly poured into 20 mL of ice-saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried, and concentrated. The obtained crude product was filtered through silica gel (300-400 mesh). ) column chromatography using petroleum ether-ethyl acetate (V:V=1:1) mixture as eluent. The intermediate 35a was obtained in the form of 0.66 g of a pale yellow oil, with a yield of 86.8%. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.60 (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).

Preparation of the third step 4-(5-phenyloxazol-2-yl)piperidine 18b

35a (0.70 g, 1.93 mmol) was dissolved in dichloromethane (10 mL), trimethylsilyl iodide (0.66 mL, 4.64 mmol) was added dropwise under an ice-water bath, and the mixture was stirred at room temperature for 4 h. TLC detected that the reaction of the raw materials was complete, 1 mL of methanol was added, stirred for 10 min, then 2N hydrochloric acid (15 mL) and diethyl ether (10 mL) were added to separate the aqueous phase, and the pH of the aqueous phase was adjusted to 8-9 with potassium carbonate. Extracted with dichloromethane (3×15 mL), combined the organic phases, washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 18b as an off-white solid 0.43 g, yield 96.4%. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.61 (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).

Scheme 21 Synthetic route of intermediate 19b

Preparation of the first step [4-(4-phenylimidazol-2-yl)]piperidine-1-carboxylic acid benzyl ester 36a

34a (0.73 g, 1.92 mmol) was dissolved in 5 mL of glacial acetic acid, then ammonium acetate (2.07 g, 26.86 mmol) was added, and the reaction was refluxed for 5 h. TLC detected the complete reaction of the raw materials, added 20 ml of deionized water, extracted with dichloromethane (20 mL×3), combined the organic phases, dried and concentrated, the obtained crude product was separated by silica gel (300-400 mesh) column chromatography, petroleum ether-ethyl acetate The ester (V:V=1:1) mixture was the eluent. The intermediate 36a was obtained in the form of 0.66 g of a pale yellow oil, with a yield of 83.7%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.67 (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).

Preparation of the second step 4-(4-phenylimidazol-2-yl)piperidine 19b

36a (0.63 g, 1.73 mmol) was dissolved in dichloromethane (10 mL), trimethylsilyl iodide (0.60 mL, 4.15 mmol) was added dropwise under an ice-water bath, and the mixture was stirred at room temperature for 4 h. TLC detected that the reaction of the raw materials was complete, 1 mL of methanol was added, stirred for 10 min, then 2N hydrochloric acid (15 mL) and diethyl ether (10 mL) were added to separate the aqueous phase, and the pH of the aqueous phase was adjusted to 8-9 with potassium carbonate. Extract with dichloromethane (3×15 mL), combine the organic phases, wash with brine (15 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain Intermediate 19b as an off-white solid, 0.44 g, yield 99.3%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.68 (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).

Scheme 22 Synthetic route of intermediate 20b

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

Dissolve tert-butyl 4-(oximino)methylpiperidine-1-carboxylate (2.13 g, 9.33 mmol), phenylacetylene (2.56 mL, 23.32 mmol) and potassium chloride (0.70 g, 9.33 mmol) in 20 mL of water , potassium hydrogen persulfate complex salt (8.57 g, 13.95 mmol) was added under ice bath conditions, and then stirred at room temperature overnight. TLC detected that the reaction of the raw materials was complete, extracted with dichloromethane (30 mL×3), combined the organic phases, dried, concentrated, and concentrated the reaction solution. The obtained crude product was separated by silica gel (300-400 mesh) column chromatography, dichloromethane-ethyl acetate (V:V=40:1) mixed solution is the eluent. The intermediate 37a was obtained as a colorless oily substance 1.16 g with a yield of 37.9%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.76 (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).

Preparation of the second step 4-(5-phenylthiazol-3-yl)piperidine 20b

37a (1.10 g, 3.55 mmol) was dissolved in dichloromethane (10 mL), TFA (3 mL) was added dropwise under an ice-water bath, stirred for 2 h, water (20 mL) and ether (20 mL) were added, and the aqueous phase was separated, and the aqueous phase was washed with carbonic acid Potassium adjusts pH to 8-9. Extract with dichloromethane (3×30 mL), combine the organic phases, wash with brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain Intermediate 20b as an off-white solid 0.65 g, yield 85.0%. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.82 (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).

Scheme 23 Synthetic route of intermediate 21b

The first step [4-(3-phenyl-1,2,4-oxadiazol-5-yl)]piperidine-1-carboxylic acid benzyl ester 38a preparation

N-Cbz-4-piperidinecarboxylic acid (1.50 g, 5.70 mmol) and 0.03 mL of DMF were dissolved in 5 mL of anhydrous dichloromethane, and then added dropwise into 0.45 mL of oxalyl chloride, reacted at room temperature for 3 h, and TLC detected that the reaction of the raw materials was complete, The solvent was evaporated by concentration, the residue was dissolved in 4 mL of toluene, the toluene solution of 4a (0.29 g, 1.9 mmol) was added dropwise under ice bath conditions, the reaction was refluxed for 4 h, the reaction solution was concentrated, and the obtained crude product was filtered through silica gel (300-400 mesh) Separation by column chromatography, using petroleum ether-ethyl acetate (V:V=9:1) mixture as eluent. Intermediate 38a was obtained as pale yellow oil 0.89g, yield 77.4%.

Preparation of the second step 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine 21b

38a (0.89 g, 2.45 mmol) was dissolved in dichloromethane (6 mL), trimethylsilyl iodide (0.84 mL, 5.88 mmol) was added dropwise under an ice-water bath, and the mixture was stirred at room temperature for 4 h. TLC detected that the reaction of the raw materials was complete, 1 mL of methanol was added, stirred for 10 min, then 2N hydrochloric acid (15 mL) and diethyl ether (10 mL) were added to separate the aqueous phase, and the pH of the aqueous phase was adjusted to 8-9 with potassium carbonate. Extract with dichloromethane (3×15 mL), combine the organic phases, wash with brine (15 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain intermediate 21b, pale yellow solid 0.49 g, yield 87.2%. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.08 (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).

Example

Example 1

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

method one:

Method Two:

The first step 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 preparation

method one:

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 (0.42 g, 0.77 mmol) with 1-(3-phenyl-1,2,4-oxadiazol-5-yl) Piperazine 1b (0.18 g, 0.78 mmol) was dissolved in 3 mL of anhydrous DMF, then DIPEA (0.40 mL, 2.32 mmol) was added, and the reaction was carried out at 75° C. for 8 h under argon protection. TLC detected the complete reaction of the raw materials, evaporated the solvent, added 20 mL of deionized water, extracted with ethyl acetate (3×20 mL), combined the organic phases, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was separated by column chromatography on silica gel (300-400 mesh) using petroleum ether-ethyl acetate (V:V=2:3) mixture as eluent. Intermediate 1c was obtained as a light brown solid, 0.35 g, with a yield of 65.7%.

Method Two:

8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidinyl-1-]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-( 3-Methanesulfonyl propyl)-1H-purine-2,6-dione 3a-2 (0.15 g, 0.28 mmol) with 1-(3-phenyl-1,2,4-oxadiazole- 5-yl)piperazine 1b (0.067 g, 0.29 mmol) was dissolved in 2 mL of anhydrous DMF, then DIPEA (0.15 mL, 0.84 mmol) was added, and the reaction was carried out at 75° C. for 8 h under argon protection. TLC detected the complete reaction of the raw materials, evaporated the solvent, added 20 mL of deionized water, extracted with ethyl acetate (3×20 mL), combined the organic phases, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was separated by column chromatography on silica gel (300-400 mesh) using petroleum ether-ethyl acetate (V:V=2:3) mixture as eluent. Intermediate 1c was obtained as a light brown solid, 0.080 g, with a yield of 41.7%.

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

1c (0.34 g, 0.50 mmol) was dissolved in 3 mL of dichloromethane, then 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 h. TLC detected that the reaction of the raw materials was complete, 30 mL of deionized water and 20 mL of ether were added, the organic layer was discarded, the aqueous layer was separated, and the pH of the aqueous layer was adjusted to 8-9 with potassium carbonate powder. Extract with dichloromethane (30 mL×5), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 1 as an off-white solid, 0.27 g, yield 90.1%. mp83-85℃, (c1.08, _CHCl3 ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.98 (m, 2H), 7.43 (m, 3H), 4.87 (m, 2H), 4.08 (t, J=7.2 Hz, 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): Calculated for C ₃₀ H ₃₉ N ₁₀ O ₃ 587.32011, found [M+H] ⁺ 587.31818.

Example 2

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

The first step 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 - Preparation of diketone 2c

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

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

Using 2c (0.13 g, 0.19 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 2, white solid 0.10 g, yield 90.5%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.71 (m, 2H), 7.84 (m, 2H), 4.87 (m, 2H), 4.08 (t, J=7.2 Hz, 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): Calculated for C ₂₉ H ₃₈ N ₁₁ O ₃ 588.31536, found [M+H] ⁺ 588.31335.

Example 3

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

The first step 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 preparation

Using 3a-1 (0.11 g, 0.21 mmol) and 1-(3-methyl-1,2,4-oxadiazol-5-yl)piperazine 3b (0.045 g, 0.27 mmol) as raw materials, the following examples were used. Similar to the first step in 1, the intermediate 3c was obtained as a colorless oily substance, 0.060 g, and the yield was 46.9%.

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

Using 3c (0.11 g, 0.17 mmol) as a raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 3, an off-white solid 0.060 g, a yield of 65.2%. mp75-77℃, (c1.05, _CHCI3 ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 4.85 (m, 2H), 4.06 (t, J=7.2 Hz, 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): Calculated for C ₂₅ H ₃₇ N ₁₀ O ₃ 525.30446, found [M+H] ⁺ 525.30420.

Example 4

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

The first step 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 preparation

Using 3a-1 (0.15g, 0.28mmol) and 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperazine 4b (0.056g, 0.29mmol) as raw materials, the Similar to the first step in Example 1, the intermediate 4c was obtained as an off-white solid 0.11 g with a yield of 57.7%.

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

Using 4c (0.090 g, 0.14 mmol) as a raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 4, a colorless oily substance 0.070 g, a yield of 92.1%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 4.85 (m, 2H), 4.06 (t, J=7.2 Hz, 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): Calculated for C ₂₇ H ₄₁ N ₁₀ O ₃ 553.33576, found [M+H] ⁺ 553.33466.

Example 5

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

The first step 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 preparation

Using 3a-1 (0.16g, 0.30mmol) and 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperazine 5b (0.060g, 0.30mmol) as raw materials, the The first step in Example 1 was similar to the operation steps to obtain intermediate 5c, 0.14 g of light yellow solid, and the yield was 72.2%.

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

Using 5c (0.14 g, 0.21 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 5, 0.11 g of an off-white solid, and the yield was 92.1%. ¹ H 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): C ₂₇ H ₃₉ N ₁₀ O ₃ calcd 551.32011, found [M+H] ⁺ 551.31921.

Example 6

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

The first step 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 preparation

Using 3a-1 (0.20 g, 0.37 mmol) and 1-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)piperazine 6b (0.085 g, 0.38 mmol) as raw materials, the Similar to the first step in Example 1, the intermediate 6c was obtained as an off-white solid, 0.14 g, and the yield was 57.5%.

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

Using 6c (0.13 g, 0.19 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 6, 0.095 g of light yellow transparent oil, and the yield was 85.6%. ¹ H 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): C ₂₉ H Calcd for ₄₃ N ₁₀ O ₃ 579.35141, found [M+H] ⁺ 579.34967.

Example 7

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

The first step 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, Preparation of 6-diketone 7c

3a-1 (0.11 g, 0.20 mmol) and 1-[3-(4-methyl)phenyl-1,2,4-oxadiazol-5-yl]piperazine 7b (0.051 g, 0.21 mmol) As the raw material, a similar operation procedure of the first step in Example 1 was adopted to obtain the intermediate 7c, 0.10 g of a light brown solid, and the yield was 69.4%.

The second step 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 preparation

Using 7c (0.15 g, 0.21 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 7, 0.11 g of an off-white solid, and the yield was 85.9%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.86 (m, 2H), 7.23 (m, 2H), 4.89 (m, 2H), 4.08 (t, J=7.2 Hz, 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): C ₃₁ H ₄₁ N ₁₀ O ₃ Calculated value 601.33576, measured value [M+H] ⁺ 601.33380.

Example 8

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

The first step 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- Preparation of 2,6-diketone 8c

3a-1 (0.11 g, 0.20 mmol) and 1-[3-(4-trifluoromethyl)phenyl-1,2,4-oxadiazol-5-yl]piperazine 8b (0.062 g, 0.21 mmol) was used as the raw material, and a similar operation procedure of the first step in Example 1 was adopted to obtain the intermediate 8c as a light brown solid, 0.095 g, and the yield was 61.3%.

The second step 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 Preparation

Using 8c (0.090 g, 0.12 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 8, 0.055 g of an off-white solid, and the yield was 69.6%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.11 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.2 Hz, 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): calcd for _{C31H38N10O3F3 655.30750} , found [ _M +H] ⁺ _655.30487 .

Example 9

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

The first step 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 - Preparation of diketone 9c

Using 3a-1 (0.16 g, 0.29 mmol) and 1-[3-(4-fluoro)phenyl-1,2,4-oxadiazol-5-yl]piperazine 9b (0.075 g, 0.30 mmol) as For the raw materials, a similar operation procedure of the first step in Example 1 was used to obtain intermediate 9c, 0.13 g of an off-white solid, and a yield of 61.9%.

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

Using 9c (0.12 g, 0.18 mmol) as a raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 9, an off-white solid 0.095 g, a yield of 91.8%. ¹ H NMR (400 MHz, CDCl ₃ ) 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): C ₃₀ H Calculated for ₃₈ N ₁₀ O ₃ F 605.31069, found [M+H] ⁺ 605.30817.

Example 10

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

The first step 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 Preparation of ,6-diketone 10c

3a-1 (0.16 g, 0.29 mmol) and 1-[3-(4-methoxy)phenyl-1,2,4-oxadiazol-5-yl]piperazine 10b (0.078 g, 0.30 mmol) ) was used as the raw material, and a similar operation procedure of the first step in Example 1 was adopted to obtain the intermediate 10c, 0.12 g of a light yellow solid, and the yield was 55.1%.

The second step 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 preparation

Using 10c (0.11 g, 0.16 mmol) as a raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 10, white solid 0.085 g, yield 89.5%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.90 (d, J=7.6 Hz, 2H), 6.92 (d, J=7.6 Hz, 2H), 4.86 (m, 2H), 4.07 (t, J=7.2 Hz) ,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): C ₃₁ H ₄₁ N ₁₀ O ₄ calculated 617.33068, found [M+H] ⁺ 617.32843.

Example 11

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

The first step 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 preparation

Using 3a-1 (0.15g, 0.28mmol) and 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine 11b (0.072g, 0.29mmol) as raw materials, the following examples were used. Similar to the first step in 1, the intermediate 11c was obtained as a khaki solid 0.16 g with a yield of 83.7%.

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

Using 11c (0.15 g, 0.21 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 11, 0.12 g of an off-white solid, and the yield was 90.2%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.17 (m, 2H), 7.41 (m, 3H), 4.89 (m, 2H), 4.09 (t, J=7.2 Hz, 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): Calculated for C ₃₀ H ₃₉ N ₁₀ O ₂ S 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

The first step 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 Preparation of 12c

Using 3a-1 (0.20 g, 0.37 mmol) and 1-(3-phenyl-4H-1,2,4-triazol-5-yl)piperazine 12b (0.090 g, 0.39 mmol) as starting materials, using Similar to the first step in Example 1, the intermediate 12c was obtained as an off-white solid 0.25 g with a yield of 98.0%.

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

Using 12c (0.24 g, 0.35 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 12, 0.17 g of an off-white solid, and the yield was 83.0%. ¹ H NMR (400 MHz, CDCl ₃ ) 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): Calculated for C ₃₀ H ₄₀ N ₁₁ O ₂ 586.33610, found [M+H] ⁺ 586.33362.

Example 13

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

The first step 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 Preparation of 13c

Using 3a-1 (0.080g, 0.15mmol) and 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine 13b (0.038g, 0.16mmol) as raw materials, using Example Similar to the first step in 1, the intermediate 13c was obtained as an off-white solid, 0.075 g, and the yield was 72.1%.

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

Using 13c (0.16 g, 0.23 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 13, 0.11 g of an off-white solid, and the yield was 82.7%. mp119-121℃, (c1.08, _CHCl3 ). ¹ H NMR (400 MHz, CDCl ₃ ) 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): Calculated for C ₃₂ H ₄₃ N ₁₀ O ₂ 599.35650, found [M+H] ⁺ 599.35406.

Example 14

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

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

Using 3a-1 (0.16g, 0.39mmol) and 1-(4-phenylthiazol-2-yl)piperazine 14b (0.074g, 0.30mmol) as raw materials, a similar operation procedure of the first step in Example 1 was adopted, Intermediate 14c was obtained as a white solid, 0.15 g, with a yield of 71.8%.

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

Using 14c (0.14 g, 0.20 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 14, an off-white solid 0.10 g, and the yield was 83.3%. ¹ H NMR (400 MHz, CDCl ₃ ) 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): Calculated for C ₃₁ H ₄₁ N ₉ O ₂ S 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

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

3a-1 (0.16 g, 0.30 mmol) and 4-(1-phenyl-1H-tetrazol-5-yl)piperidine dihydrochloride 15b (0.10 g, 0.30 mmol) were dissolved in 3 mL DMF, 0.26mL of triethylamine was added, and the reaction was carried out at 75°C for 12h under the protection of argon. The reaction solution was concentrated, and the obtained crude product was separated by column chromatography on silica gel (300-400 mesh) using petroleum ether-ethyl acetate (V:V=2:3) mixed solution as eluent to obtain Intermediate 15c, 0.14 g of a khaki solid , the yield is 68.6%.

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

Using 15c (0.13 g, 0.19 mmol) as a raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 15, a khaki solid 0.060 g, a yield of 53.4%. ¹ H NMR (400 MHz, CDCl ₃ ) 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): calcd for C ₃₀ H ₄₀ N ₁₁ O ₂ 586.33610, 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

The first step 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 Preparation of 16c

Using 3a-1 (0.15 g, 0.27 mmol) and 4-(4-phenyl-1H-1,2,3-triazol-1-yl)piperidine 16b (0.065 g, 0.28 mmol) as starting materials, using Similar to the first step in Example 1, intermediate 16c was obtained as an off-white solid, 0.16 g, with a yield of 83.8%.

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

Using 16c (0.16 g, 0.23 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 16, white solid 0.10 g, yield 76.6%. ¹ H NMR (400 MHz, CDCl ₃ ) 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): _calcd for _{C31H41N10O2 585.34085} , found [M+H] ⁺ _585.33856 .

Example 17

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

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

Using 3a-1 (0.16 g, 0.29 mmol) and 4-(4-phenylthiazol-2-yl) piperidine 17b (0.074 g, 0.30 mmol) as raw materials, a similar operation procedure of the first step in Example 1 was adopted, The intermediate 17c was obtained as an off-white solid 0.16 g with a yield of 76.6%.

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

Using 17c (0.15 g, 0.22 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 17, 0.11 g of an off-white solid, and the yield was 86.4%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.87 (m, 2H), 7.40 (m, 2H), 7.31 (m, 2H), 4.85 (m, 2H), 4.07 (t, J=7.2 Hz, 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): calcd for C ₃₂ H ₄₁ N ₈ O ₂ S 601.30677, found [M+H] ⁺ 601.30469.

Example 18

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

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

Using 3a-1 (0.14g, 0.26mmol) and 4-(5-phenyloxazol-2-yl)piperidine 18b (0.062g, 0.27mmol) as raw materials, a similar operation procedure of the first step in Example 1 was adopted , to obtain intermediate 18c, white solid 0.14g, yield 79.1%.

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

Using 18c (0.13 g, 0.19 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 18, white solid 0.10 g, yield 86.9%. ¹ H NMR (400 MHz, CDCl ₃ ) 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): calcd for C ₃₂ H ₄₁ N ₈ O ₃ 585.32961, found [M+H] ⁺ 585.32739.

Example 19

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

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

Using 3a-1 (0.18 g, 0.34 mmol) and 4-(4-phenylimidazol-2-yl) piperidine 19b (0.080 g, 0.36 mmol) as raw materials, a similar operation procedure of the first step in Example 1 was adopted, Intermediate 19c was obtained as a white solid, 0.17 g, with a yield of 74.2%.

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

Using 19c (0.17 g, 0.25 mmol) as a raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 19, white solid 0.13 g, yield 89.6%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.67 (m, 2H), 7.33 (m, 2H), 7.19 (m, 2H), 4.83 (m, 2H), 4.06 (t, J=7.2 Hz, 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): Calculated for C ₃₂ H ₄₂ N ₉ O ₂ 584.36560, found [M+H] ⁺ 584.34393.

Example 20

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

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

Using 3a-1 (0.18 g, 0.34 mmol) and 4-(4-phenylimidazol-2-yl) piperidine 20b (0.078 g, 0.35 mmol) as raw materials, a similar operation procedure of the first step in Example 1 was adopted, Intermediate 20c was obtained as a light brown solid, 0.18 g, with a yield of 80.8%.

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

Using 20c (0.18 g, 0.26 mmol) as a raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 20, a khaki solid 0.13 g, a yield of 87.6%. ¹ H NMR (400 MHz, CDCl ₃ ) 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): Calculated for C ₃₂ H ₄₁ N ₈ O ₃ 585.32961, found [M+H] ⁺ 585.32764.

Example 21

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

The first step 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 preparation

Using 3a-1 (0.18g, 0.34mmol) and 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine 21b (0.081g, 0.35mmol) as raw materials, using Example Similar to the first step in 1, the intermediate 21c was obtained as a brownish-yellow solid 0.18 g with a yield of 78.3%.

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

Using 21c (0.18 g, 0.26 mmol) as the raw material, the similar operation procedure of the second step in Example 1 was adopted to obtain compound 21, light brown solid 0.12 g, yield 81.0%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.06 (m, 2H), 7.48 (m, 3H), 4.86 (m, 2H), 4.07 (t, J=7.2 Hz, 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): Calculated for C ₃₁ H ₄₀ N ₉ O ₃ 586.32486, found [M+H] ⁺ 586.32300.

Test example part

Test Example 1. In vitro screening method of DPP-IV inhibitors

Reagents:

1. Reaction substrate: Gly-Pro-m-nitroanilide hydrochloride (Sigma, G0513), dissolved in ddH ₂ O to a 0.026M stock solution, and stored at -20°C in the dark.

2. DPP-IV enzyme: recombinant human DPP-IV protein (Sigma, D4943), stored at -20°C.

3. Sample to be tested: dissolve in DMSO to 10 ^-2 M and store at 4°C.

4. Positive control drug: Linagliptin was dissolved in DMSO to 10 ^-2 M and stored at 4°C.

5.2×Hepes buffer: 1.6g NaCl, 0.074g KCl, 0.027g Na ₂ HPO ₄ 2H ₂ O, 0.2g Glucose, 1g Hepes were dissolved in 90ml ddH ₂ O, adjusted to pH 7.05 with NaOH, and the volume was adjusted to 100ml, Filtered at 0.22 μm and stored at 4°C.

6. Tis-HCl buffer: 6.06g Tris to 1L distilled water, adjust the pH to 8.0 with HCl.

Detection method

The sample and the positive drug Linagliptin were diluted with ddH ₂ O into a solution with a concentration of 10 ^-4 M, and DPP-IV was prepared with Tis/HClbuffer (pH=8.0) with a concentration of 2 mU/ml. The substrate Gly-Pro-m-nitroanilide working solution was diluted with Hepesbuffer (pH=7.05) to a concentration of 0.26 mM. The experiment set up a negative control group, a positive control group and a sample group. The total reaction volume was 100 μl, of which 10 μl of ddH ₂ O, 50 μl of DPP-IV enzyme working solution and 40 μl of substrate working solution were added to the negative control group; 10 μl of Linagliptin solution, 50 μl of DPP-IV enzyme working solution and 40 μl of substrate working solution were added to the positive control group. ; Add 10 μl of sample solution, 50 μl of DPP-IV working solution and 40 μl of substrate working solution to the sample group. The inhibitory effect of samples on DPP-IV was evaluated by monitoring the change of absorbance at 405 nm within 60 min at 37°C.

The calculation method of the inhibition rate of the sample to DPP-IV is as follows:

Inhibition rate (%)=( _{ΔOD 60-0} negative control group-ΔOD _60-0 sample group)/ _{ΔOD 60-0} negative control group×100%

It is generally considered that the inhibition rate of the positive control Linagliptin at 10 ^-5 M is 90-100%, which can be considered as a reliable reaction in this experiment, and the inhibition rate of the sample is more than 40%, which is considered effective.

Calculation of compound _IC50 :

1. For the primary screening (the concentration of the test compound is 10 ^-5 M), the active compounds (ie, the inhibitory activity is greater than 50%), set different concentration gradients, namely 10 ^-8 , 10 ^-7 , 10 ^-6 and 10 ^{- 5} M for DPP-IV inhibition experiments.

2. Draw the concentration-response curve of the reaction concentration and inhibition rate of the compound, and the fitting formula obtained by statistical processing, Y is the inhibition rate, X is the compound concentration, when Y is 50%, that is, when the activity reaches 50% inhibition rate, it corresponds to The concentration of the compound is the half effective inhibitory concentration (IC ₅₀ ) of the compound, and the test results are shown in Table 1.

Table 1 Enzyme level activity assay results of the compounds of the examples of the present invention

*: The tested concentration is 10 ^-5 M;

in conclusion:

The DPP-IV inhibitory activity of the 17 tested compounds in vitro reached more than 50%, of which 12 compounds had IC ₅₀ levels of 10 ^-8 mol/L.

Test Example 2. Method for evaluating the selectivity of DPP-IV inhibitors (in vitro evaluation method for DPP8/9 inhibitory activity)

1. Reaction substrate: the same as the in vitro screening method of DPP-IV inhibitors.

2. DPP8/9 enzyme: recombinant human DPP8/9 protein, purified and lyophilized, and stored at -20°C.

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

4. Positive control drug: Compound (S)-4-(2-amino-(R)-3-methylvaleryl)isoindoline hydrochloride was dissolved in DMSO to 10 ^-2 M, and stored at 4°C.

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

6. Tis/HCl buffer: the same as the in vitro screening method for DPP-IV inhibitors.

Evaluation method

The sample and the positive drug were diluted with ddH ₂ O to a concentration of 10 ^-4 M. The DPP8 enzyme was prepared with Tis/HClbuffer (pH=8.0) at a concentration of 60 ng/ml, and the DPP9 enzyme was prepared at a concentration of 40 ng/ml. The substrate Gly-Pro-m-nitroanilide working solution was diluted with Hepes buffer (pH=7.05) to a concentration of 0.52 mM. The experiment set up a negative control group, a positive control group and a sample group. The total reaction volume was 100 μl, of which 10 μl of ddH ₂ O, 50 μl of DPP8/9 enzyme working solution and 40 μl of substrate working solution were added to the negative control group; 10 μl of positive control drug solution, 50 μl of DPP8/9 enzyme working solution and 40 μl of substrate working solution were added to the positive control group. 40 μl of solution; 10 μl of sample solution, 50 μl of DPP8/9 enzyme working solution and 40 μl of substrate working solution were added to the sample group. The selectivity of DPP-IV inhibitors, ie, DPP8/9 inhibition, was evaluated by monitoring the change in absorbance at 405 nm within 60 min at 37°C.

The selectivity of DPP-IV inhibitors (DPP8/9 inhibition) was calculated as follows:

Inhibition rate (%)=( _{ΔOD 60-0} negative control group-ΔOD _60-0 sample group)/ _{ΔOD 60-0} negative control group×100%

The test results are shown in Table 2

Table 2 The measurement results of the compounds of the examples of the present invention inhibiting the activity of DPP8/9

*: The tested concentration is 10 ^-5 M;

The inhibition rate of the positive drug UAMC00132 at the same concentration was 96.7%.

The inhibition rate of the positive drug Linagliptin at the same concentration was 17.9%

in conclusion:

The 10 tested compounds with DPP-IV inhibitory activity have no obvious inhibitory activity on DPP8/9, indicating that these 10 compounds have high selectivity for DPP-IV.

Claims (16)

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;

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.

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;

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.

5. A compound represented by the general formula (IAa-5), 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.

6. A compound represented by the general formula (IBa-1), 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.

7. A compound represented by the general formula (IBa-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.

8. A compound represented by the general formula (IBa-3), 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.

9. A compound represented by the general formula (IBa-4), 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.

10. A compound represented by the general formula (IBa-5), 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.

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;

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.

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.