TWI640524B - Aminopyran ring derivatives and materials and uses thereof - Google Patents

Abstract

The present invention relates to an aminopyran ring derivative, and compositions and uses thereof, particularly to an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt, and a former Medicine, pharmaceutical composition containing the same, and medicinal use in the preparation of dipeptidyl peptidase IV (DPP-IV) inhibitor,

Wherein the definition of each substituent in the formula (I) is the same as defined in the specification.

Description

Aminopyran ring derivatives and compositions and uses thereof

The present invention relates to an aminopyran ring derivative, and compositions and uses thereof, in particular to an aminopyran ring derivative of the formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof and a A pharmaceutical composition of the derivative or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and its use as a therapeutic agent, in particular as a dipeptidyl peptidase IV (DPP-IV) inhibitor.

Diabetes is a major medical problem worldwide. According to the International Diabetes Federation (IDF), the number of people with diabetes worldwide reached 382 million in 2013, and global medical expenses reached 548 billion US dollars, accounting for 11% of global medical expenditure. The global medical cost associated with diabetes is expected to reach $627.3 billion by 2035. Insulin is a hormone that is needed to convert sucrose, starch, and other foods into energy. Diabetes is usually caused by autologous secretion or inappropriate use of insulin. Diabetes is usually classified into Type I diabetes (or insulin-dependent diabetes mellitus, IDDM) and Type II diabetes (or non-insulin-dependent diabetes mellitus, NIDDM). The most common type of diabetes is type 2 diabetes, and worldwide type II diabetes accounts for about 90% of all diabetes. The incidence of type 2 diabetes is gradually increasing due to modern unhealthy lifestyles such as reduced exercise and high-calorie diets. Great market potential attracts a large number of pharmaceutical companies and research centers to develop new anti-diabetic targets And drugs.

The currently approved drugs for the treatment of type 2 diabetes are mainly insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), α-glucosidase inhibitors, and dextrin-like drugs. , an incretin hormone analog, a dipeptidyl peptidase inhibitor (DPP-IV), and the like. However, long-term use of these hypoglycemic agents does not achieve the expected reduction in glycated hemoglobin (HbA1c), and these hypoglycemic agents have side effects such as hypoglycemia, weight gain and cardiovascular risk. These side effects add to the burden on diabetics. Therefore, there is an urgent need to develop a novel hypoglycemic agent that is highly effective and has few side effects for Type II diabetes.

Dipeptidyl Peptidase IV (DPP-IV, EC 3.4.14.5) is a serine protease that hydrolyzes N-terminally from the N-position of the N-terminus of L-valine and L-alanine-containing peptides. Peptide. Although the function of DPP-IV has not been fully elucidated, it is considered to be a major physiological regulator of certain regulatory polypeptides, neuropeptides, circulating hormones, and chemokines. Although DPP-IV has many receptors as a pleiotropic enzyme, it is best known as incretin, which includes glucagon-like peptide-1 (GLP-1) and glycoprotein-dependent insulin releasing peptide (GIP). ). Incretin is an intestinal hormone that secretes and promotes the intake of nutrients within minutes of ingestion of nutrients. GLP-1 and GIP have the same effect on β cells, which can improve β cell function, including promoting glucose-dependent insulin secretion, inducing β cell proliferation, and enhancing anti-apoptotic effect (Diabetes and Vascular Dis ethyl acetate se Res ethyl acetate rch) 20063:159).

Unlike GIP, GLP-1 is still promoting insulin secretion in Type II diabetes, and therefore, increasing GLP-1 is a promising means of treating Type II diabetes (Pharmacol Rev 60: 470-512, 2008). GLP-1 can significantly reduce blood glucose in patients with type 2 diabetes (Lancet, 2002, 359: 824-830). However, GLP-1, as a receptor for DPP-IV, is rapidly hydrolyzed and deactivated in vivo, so DPP was developed. -IV inhibitors are of great importance for the treatment of diabetes.

At present, DPP-IV inhibitor research has made great progress, and DPP-IV inhibitors including sitagliptin, saxagliptin and alogliptin have been approved for marketing and entered clinical use. The most striking feature of DPP-IV inhibitors is that since incretin is secreted only after the organism has eaten, DPP-IV inhibitors are not easy to increase insulin levels when inappropriate, resulting in a common side effect of many hypoglycemic agents - hypoglycemia. Recent clinical data have shown that inhibition of DPP-IV increases insulin secretion, lowers blood glucose levels, and improves islet beta cell function (Diabetes, 1998, 47: 1253-1258). Common side effects of DPP-IV inhibitors are respiratory infections, sore throat, diarrhea, flu-like symptoms, headache and dizziness. However, overall safety and tolerability are good. No patients have been found to have severe weight gain or potential weight loss and edema. In recent years, long-acting DPP-IV inhibitors have been particularly attractive. Long-acting DPP-IV inhibitors are more convenient to use and have the ideal hypoglycemic effect, which makes them more popular in patients with type 2 diabetes. Phase II clinical data showed that the once-daily DPP-IV inhibitor Omarigliptin developed by Merck significantly reduced blood sugar. Trelagliptin is another once-a-week DPP-IV inhibitor developed by Takeda Pharmaceutical Co., Ltd. The safety and efficacy of this drug has been confirmed in Phase III clinical trials and is currently being submitted in Japan.

The incidence of diabetes (mainly type 2 diabetes) is increasing year by year in the world, becoming the third non-communicable disease that threatens people's health and life after cardiovascular disease and cancer. The treatment of diabetes poses a heavy burden on families and society. Therefore, there is an urgent need to develop more updated and better DPP-IV inhibitor drugs to meet the needs of patients in clinical medicine.

Currently, the literature on DPP-IV inhibitor related research has been reported:

(1) US2007232676 discloses compounds of the following structure as DPP-IV inhibitors, wherein: Ar is selected from phenyl substituted with 1 to 5 substituents selected from halogen, hydroxy, C _1-6 alkyl; And the like, and R ^3a and R ^{3b are} independently selected from hydrogen, C _1-4 alkyl substituted by 1 to 5 fluorine atoms; R ^{2 is} selected from the group consisting of hydrogen, hydroxy, halogen, carboxyl and the like; R ^{8 is} selected A group such as hydrogen, -(CH ₂ ) _p -phenyl, but no methylsulfonyl; the detailed description in this patent is not considered to be part of the present invention.

(2) US20100120863 discloses the use of a compound of the following structure as a dipeptidyl peptidase IV (DPP-IV) inhibitor for the treatment and prevention of type II diabetes, wherein: Ar is selected from the group consisting of hydrogen, alkyl and the like; V is selected from And R ^3a and R ^{3b are} selected from C _1-4 alkyl groups independently selected from hydrogen and substituted by 1 to 5 fluorine atoms; R ^{2 is} selected from the group consisting of hydrogen, hydroxyl, halogen, carboxyl and the like; R ^{8 is} selected A group such as -S(O) ₂ -C _1-6 cycloalkyl, -S(O) ₂ -C _1-6 alkyl; the detailed description in this patent is not considered to be part of the present invention.

(3) WO2011103256 discloses a compound having a structure having a DPP-IV inhibitor action as a prophylactic and/or therapeutic drug for diabetes, wherein: Ar is phenyl optionally substituted by 1 to 5 groups independently selected from the group consisting of halogen, cyano, hydroxy, etc.; And the like, and R ^{2 is} selected from the group consisting of hydrogen, hydroxy, cyano, halogen, alkyl, alkoxy, carbonyl, etc.; R ^3a , R ^{3b are} selected from hydrogen or optionally substituted with from 1 to 5 fluorine atoms. C _1-4 alkyl; R ^{8 is} selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl, -SO ₂ -C _1-6 alkyl; the detailed description in this patent is not considered It is part of the invention.

(4) WO2007126745 discloses a DPP-IV inhibitor compound of the following structure for the treatment of diabetes, wherein: Ar is selected from substituted or unsubstituted phenyl groups, and when substituted, phenyl is substituted by 1-3 selected from halogen, hydroxy, C _1-6 alkyl, etc.; And the like, and R ^{2 is} selected from the group consisting of hydrogen, hydroxy, halogen, alkenyl, alkynyl, aryl, heteroaryl, etc.; R ^3a , R ^{3b are} selected from hydrogen, C _1- substituted by 1 to 5 fluorine atoms ₄ alkyl; R ^{8 is} selected from the group consisting of H, cycloalkyl, phenyl, alkyl, and the like; the detailed description in this patent is not considered to be part of the present invention.

Also, WO2011103256, WO2008060488, WO2007087231, WO2011037793, WO2011028455, WO2009025784, etc. also disclose about DPP-IV inhibitor compounds for the treatment of diabetes.

The object of the present invention is to introduce a novel class of DPP-IV inhibitors, in particular There are compounds represented by the general formula (I), and studies have shown that the compounds of such structures have good dipeptidyl peptidase IV (DPP-IV) inhibitory activity and selectivity, and are useful for treating or alleviating type II diabetes. And the prospect of similar diseases.

The present invention relates to an aminopyran ring derivative of the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof:

Where: V is selected from the following groups:

Ar is a benzene ring substituted with 0 to 5 R ¹ groups, preferably 2,5-difluorophenyl or 2,4,5-trifluorophenyl; R ^{1 is} selected from H, F, Cl, Br, I, hydroxy, cyano, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _m -C _3-15 cycloalkyl , -(CH ₂ ) _m -3 to 15 membered heterocycloalkyl, -(CH ₂ ) _m -C _6-10 aryl, -(CH ₂ ) _m -6 to 10 membered heteroaryl, -(CH _{2 m} -C(=O)-R ⁵ , -(CH ₂ ) _m -NR ⁶ R ⁷ , -(CH ₂ ) _m -C(=O)-NR ⁶ R ⁷ , -(CH ₂ ) _m -OC (=O)-NR ⁶ R ⁷ , -(CH ₂ ) _m -S(=O) _n -R ⁸ , -(CH ₂ ) _m -NR ⁹ -S(=O) _n -R ⁸ , -(CH ₂ ) _m -NR ⁹ -C(=O)-NR ⁶ R ⁷ or -(CH ₂ ) _m -NR ⁹ -C(=O)-R ⁵ , wherein the alkyl group, alkoxy group, alkenyl group, Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy Substituted with a substituent of a C _1-4 alkyl group or a C _1-4 alkoxy group containing from 1 to 5 atoms or groups selected from N, O or S(=O) _n ; R ^{1 is} preferably H or F; R ^2a and R ^2b are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, C _1-8 alkyl, C _1-8 alkoxy, C _{2 -8} olefin , C _2-8 alkynyl, -(CH ₂ ) _m -C _3-15 cycloalkyl, -(CH ₂ ) _m -3 to 15 heterocycloalkyl, -(CH ₂ ) _m -C _6-10 Aryl, -(CH ₂ ) _m -6 to 10 membered heteroaryl, -(CH ₂ ) _m -C(=O)-R ⁵ , -(CH ₂ ) _m -NR ⁶ R ⁷ , -(CH _{2 m} -C(=O)-NR ⁶ R ⁷ , -(CH ₂ ) _m -OC(=O)-NR ⁶ R ⁷ , -(CH ₂ ) _m -S(=O) _n -R ⁸ ,- (CH ₂ ) _m -NR ⁹ -S(=O) _n -R ⁸ , -(CH ₂ ) _m -NR ⁹ -C(=O)-NR ⁶ R ⁷ or -(CH ₂ ) _m -NR ⁹ - C(=O)-R ⁵ , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further further selected from 0 to 3 Substituted by a substituent of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, C _1-4 alkyl or C _1-4 alkoxy, said heterocycloalkyl containing 1 to 5 atoms or groups selected from N, O or S(=O) _n ; preferably R ^2a and R ^2b are each independently selected from H, C _1-6 alkyl, -(CH ₂ ) _m - C _3-6 cycloalkyl or -(CH ₂ ) _m -3 to 8 membered heterocycloalkyl, wherein said alkyl, cycloalkyl or heterocycloalkyl group is further further selected from 0 to 3 selected from F, _{cl, Br, I, -CH 2} F, -CHF 2, -CF 3, hydroxy, C _1-4 alkyl or C _1-4 alkoxy substituents, the Heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O or S (= O) _n is an atom or group; more preferably, R ^2b is selected from H, R ^2a is selected from H, C _1-6 alkyl Or -(CH ₂ ) _m -C _3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is further further 0 to 3 selected from F, hydroxy, C _1-4 alkyl or C _1-4 Substituted by a substituent of an alkoxy group; R ^3a and R ^3b are each independently selected from H, F, Cl, Br, I, hydroxy, cyano or C _1-8 alkyl, wherein said alkyl group is optionally further Substituted to 5 substituents selected from F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, C _1-4 alkyl or C _1-4 alkoxy; R ^3a And R ^3b are each independently preferably from H or C _1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C _1-4 alkoxy; Further preferably, R ^3a and R ^3b are each independently selected from H; and R ^4a and R ^4b are each independently selected from H, F, Cl, Br, I, hydroxy, cyano or C _1-8 alkyl, wherein The alkyl group is optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, C _1-4 alkyl or C _1-4 alkoxy. substituents, and R ^4a and R ^4b different It is H; R ⁴ is selected from H, cyano, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _{2-8 alkynyl, - (CH 2) m -C} 3 _-15 cycloalkyl, -(CH ₂ ) _m -3 to 15 membered heterocycloalkyl, -(CH ₂ ) _m -C _6-10 aryl, -(CH ₂ ) _m -6 to 10 membered heteroaryl , -(CH ₂ ) _m -C(=O)-R ⁵ , -(CH ₂ ) _m -NR ⁶ R ⁷ , -(CH ₂ ) _m -C(=O)-NR ⁶ R ⁷ , -(CH ₂ ) _m -OC(=O)-NR ⁶ R ⁷ , -(CH ₂ ) _m -S(=O) _n -R ⁸ , -(CH ₂ ) _m -NR ⁹ -S(=O) _n -R ⁸ , -(CH ₂ ) _m -NR ⁹ -C(=O)-NR ⁶ R ⁷ or -(CH ₂ ) _m -NR9-C(=O)-R ⁵ , wherein the alkyl group, alkoxy group Or alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , Substituted by a substituent of CF ₃ , hydroxy, C _1-4 alkyl or C _1-4 alkoxy containing 1 to 5 atoms selected from N, O or S(=O) _n Or a group; R ^{4 is} preferably from H or -(CH ₂ ) _m -S(=O) _n -R ⁸ ; further preferably -S(=O) ₂ -CH ₃ ; R ^{5 is} selected from a hydroxyl group, C _1-8 alkyl, C _1-8 alkoxy, C _3-15 cycloalkyl, C _6-10 aryl, 6 to 10 membered heteroaryl, -OC _3-15 cycloalkyl, -OC _{6 -10} aryl or -O- (6 to 10 membered An aryl group), preferably a C _1-8 alkyl group or a C _1-8 alkoxy group, more preferably a C _1-8 alkoxy group; R ^6, R ⁷ and R ⁹ are each independently selected from H, C _{1 -8} alkyl, C _3-15 cycloalkyl, C _6-10 aryl, 6 to 10 membered heteroaryl or 3 to 15 membered heterocycloalkyl; preferably each independently selected from H or C _1-8 Alkyl; R ^{8 is} selected from C _1-8 alkyl, C _3-15 cycloalkyl, C _6-10 aryl, 6 to 10 membered heteroaryl or 3 to 15 membered heterocycloalkyl; preferably C _1-8 alkyl, C _3-15 cycloalkyl or 3-15 heterocycloalkyl, more preferably a C _1-8 alkyl group; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl Or a heteroaryl group optionally further substituted with from 0 to 5 F, the heterocycloalkyl or heteroaryl containing from 1 to 5 atoms or groups selected from N, O or S(=O) _n ; m is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0; n is selected from 0, 1 or 2, preferably 0 or 2, further preferably 2.

Preferred embodiments of the present invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein: R ^{1 is} selected from H or F; R ^2a and R ^2b are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or 3 to 8 membered heterocycloalkyl, wherein said alkyl, cycloalkyl or heterocycloalkyl Optionally further from 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, C _1-4 alkyl or C _1-4 alkoxy Substituted, the heterocycloalkyl group contains 1 to 3 atoms or groups selected from N, O or S(=O) ₂ ; R ^2a and R ^2b are each independently preferably H, C _1-6 alkane Or a C _3-6 cycloalkyl group, wherein the alkyl or cycloalkyl group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy Substituted; R ^3a and R ^3b are each independently selected from H or C _1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C _1-4 alkoxy Substituted; each independently preferably H; R ^{4 is} selected from H or -S(=O) ₂ -R ⁸ , preferably -S(=O) ₂ -R ⁸ ; R ^{8 is} selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl group, 6 10 heteroaryl or 3-8 heterocycloalkyl, preferably C _1-2 alkyl, 4-6 heterocycloalkyl or C _3-6 cycloalkyl, more preferably C _1-2 An alkyl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is optionally further substituted by 0 to 5 F, the heterocycloalkyl group or heteroaryl group having 1 to 5 An atom or group selected from N, O or S(=O) ₂ .

Preferred embodiments of the present invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein: V is selected from the group consisting of: Ar is selected from 2,5-difluorophenyl or 2,4,5-trifluorophenyl; R ^{2a is} selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the alkyl or The cycloalkyl group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy; preferably H, C _1-2 alkyl or a C _3-6 cycloalkyl group, wherein the alkyl or cycloalkyl group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy R ^3a and R ^3b are each independently selected from H or C _1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C _1-4 alkoxy; And each independently is preferably H; R ⁴ is -S(=O) ₂ -R ⁸ , preferably -S(=O) ₂ -CH ₃ ; R ^{8 is} selected from C _1-2 alkyl, 3 to 6 a heterocycloalkyl or C _3-6 cycloalkyl group, wherein the alkyl, heterocycloalkyl or cycloalkyl group is optionally further substituted by 0 to 5 F, the heterocycloalkyl group having 1 to 3 An atom or group selected from N, O or S(=O) ₂ .

Preferred embodiments of the present invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein: R ^{2a is} selected from the group consisting of H and C _{1 a -2} alkyl or -C _3-6 cycloalkyl group, wherein the alkyl or cycloalkyl group is further further selected from 0 to 3 selected from the group consisting of F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy Substituted by a substituent; R ^{2a is} preferably H or C _1-2 alkyl, wherein the alkyl group is optionally further 0 to 3 selected from F, hydroxy, C _1-4 alkyl or C _1- Substituted by a substituent of ₄ alkoxy; R ^{2a is} further preferably H or methyl.

Preferred embodiments of the present invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein: V is selected from the group consisting of Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl; R ^{2a is} selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the alkyl or ring The alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy; preferably H, C _1-2 alkyl or -C _{a 3-6} cycloalkyl group, wherein the alkyl group or cycloalkyl group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy; R ^3a and R ^3b are each independently selected from H or C _1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C _1-4 alkoxy; Each is preferably independently H; R ⁴ is -S(=O) ₂ -R ⁸ , preferably -S(=O) ₂ -CH ₃ ; R ^{8 is} selected from C _1-2 alkyl, 3 to 6 members a heterocycloalkyl or C _3-6 cycloalkyl group, wherein said alkyl group, heterocycloalkyl group or cycloalkyl group is optionally further substituted by 0 to 5 F, said heterocycloalkyl group having 1 to 3 An atom or group selected from N, O or S(=O) ₂ .

Preferred embodiments of the present invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein: V is selected from the group consisting of Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl; R ^{2a is} selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the alkyl or ring The alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy; preferably H, C _1-2 alkyl or -C _{a 3-6} cycloalkyl group, wherein the alkyl group or cycloalkyl group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy; R ^3a and R ^3b are each independently selected from H or C _1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C _1-4 alkoxy; Each is preferably independently H; R ⁴ is -S(=O) ₂ -R ⁸ ; R ^{8 is} selected from C _1-2 alkyl, 4 to 6 membered heterocycloalkyl or C _3-6 cycloalkyl, wherein The alkyl, heterocycloalkyl or cycloalkyl group is optionally further substituted by 0 to 5 F, the heterocycloalkyl group having 1 to 3 atoms selected from N, O or S(=O) ₂ Or a group.

Preferred embodiments of the present invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein: R ^{8 is} selected from the group consisting of methyl and ethyl. base, Cyclopropyl, cyclobutyl or cyclopentyl, preferably methyl, and said groups are optionally further substituted by from 0 to 5 F.

Preferred embodiments of the present invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein: R ^{8 is} selected from the group consisting of methyl and ethyl. base, , cyclopropyl, cyclobutyl or cyclopentyl.

Preferred embodiments of the present invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein: V is selected from the group consisting of Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl; R ^{2a is} selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the alkyl or ring The alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy; preferably H, C _1-2 alkyl or -C _{a 3-6} cycloalkyl group, wherein the alkyl group or cycloalkyl group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy; R ^3a and R ^3b are each independently selected from H or C _1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C _1-4 alkoxy; Each is preferably independently H; R ⁴ is -S(=O) ₂ -R ⁸ ; R ^{8 is} selected from methyl, ethyl, , cyclopropyl, cyclobutyl or cyclopentyl.

Preferred embodiments of the present invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein the aminopyran ring derivative is selected from the group consisting of : Preferred Further preferably

In a preferred embodiment of the invention, the invention is selected from the group consisting of, but not limited to:

Preferred Further preferably

The present invention also relates to a pharmaceutical composition comprising: an effective amount of an aminopyran ring derivative represented by the formula (I) according to any one of the preceding claims, or a stereoisomer thereof, pharmacy An acceptable salt or prodrug, and a pharmaceutically acceptable carrier or excipient.

The invention further relates to the use of a compound of the formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a composition thereof, or a prodrug thereof, for the preparation of a dipeptidyl peptidase-IV inhibitor.

According to the use of the present invention, the dipeptidyl peptidase-IV inhibitor is used for the preparation of a medicament for treating a metabolic disease, wherein the metabolic disease is selected from the group consisting of diabetes, diabetic retinopathy, and diabetes. Neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated fatty acid or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis Hardening or high blood pressure.

According to the use of the invention, the diabetes is Type II diabetes.

The present invention also relates to a method for treating a metabolic disease, which comprises administering an aminopyran ring derivative of the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, or A pharmaceutical composition according to any of the inventions.

The method according to the present invention, wherein the metabolic diseases include diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated fatty acid or glycerol, Hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension.

According to the method of the present invention, the diabetes is Type II diabetes.

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

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. The nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, and the hydrogen isotopes include ruthenium (H), ruthenium (D, also known as heavy hydrogen) , 氚 (T, also known as super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes including ¹⁴ N and ¹⁵ N The fluorine isotope ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Alkyl" means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more It is preferably a linear or branched group of 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, most preferably 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2- Hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl -3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4- Methylhexyl, 5-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-di Methylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl Base, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl and n-decyl. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, and an alkane. Base, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, amino, cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged ring, Spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m - Alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethyl Sulfhydrazyl, optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocycloalkyl group. R ^a and R ^d are each independently selected from the group consisting of aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged, spiro, and cyclylene.

"Alkoxy" means an -O-alkyl group wherein alkyl is as defined above. The alkoxy group may be substituted or unsubstituted, and examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Third butoxy group, second butoxy group, n-pentyloxy group, n-hexyloxy group and the like. When substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, Amino, cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester , -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n is 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocycloalkane. The radicals R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged, spiro or cyclo.

"Alkoxyalkyl" means an alkyl group attached to an alkoxy group. The alkoxyalkyl group can be substituted or unsubstituted, non-limiting examples of which include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxy Base, propoxyethyl, 2-propoxymethyl, butoxypropyl, tert-butoxyethyl, pentyloxyethyl, hexyloxyethyl, cyclopropyloxymethyl, ring a propoxyethyl group, a cyclopropoxypropyl group and a cyclohexyloxymethyl group; when substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl , alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, amino, cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, and Cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O )-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^c is independently selected from the group comprising H, a hydroxyl group, an amino group, a carbonyl group, , Alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl sulfonic, trifluoromethane sulfonic acyl, optionally, R ^b and R ^c may form a five or six membered ring group Or a heterocycloalkyl group. R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.

"Alkenyl" means an alkyl group as defined herein, having at least one carbon-carbon double bond, preferably having from 2 to 20 carbon atoms, further preferably from 2 to 12 carbon atoms, more preferably There are 2 to 8 carbon atoms in the main chain, and the alkenyl group may be substituted or unsubstituted. Non-limiting examples include: vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2- Pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl , 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-decenyl, 3-decenyl, 1 -decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, 3-undecyl, 4-dodecenyl and 4,8,12-tetradecenetrienyl and the like. When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, amino, Cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, - (CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of: H, hydroxy, amino, carbonyl, alkyl, alkoxy , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocycloalkyl group. . R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.

"Alkynyl" means an alkyl group as defined herein above containing at least one carbon-carbon triple bond, preferably containing from 2 to 20 carbon atoms, further preferably from 2 to 8 carbon atoms, more preferably An alkynyl group having 2 to 4 carbon atoms in the main chain. An alkynyl group can be substituted or unsubstituted. Non-limiting examples include: ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4 -Pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptyne a group, a 3-octynyl group, a 3-decynyl group, a 4-decynyl group, a 3-undynyl group, a 4-dodecynyl group, etc.; when substituted, the substituent is preferably one or more of the following a group independently selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, amino, cyano, isocyano, Aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C (=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n are 0, 1 or 2), Arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkane Oxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic ring. alkyl. R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.

"Amino" means -NH ₂ and may be substituted or unsubstituted, and when substituted, the substituent is preferably from 1 to 3 or less, independently selected from alkyl, cycloalkyl, haloalkyl, Thiol, hydroxy, thiol, amino, cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged ring, spiro group, cyclylene, hydroxyalkyl, =0, carbonyl , aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m - alkynyl-R ^a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, Amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form five or A six-membered cycloalkyl or heterocycloalkyl group. R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.

"Alkylthio" means -S-alkyl or -S-(unsubstituted cycloalkyl), and non-limiting examples include methylthio, ethylthio, propylthio, butylthio and the like.

"Indenyl" or "carbonyl" refers to a -C(=O)-R ^a group, wherein R ^{a is} as defined above.

"Aldehyde" means -C(=O)-H.

"Halogen" means fluorine, chlorine, bromine, or iodine.

"Hydroxy" means -OH.

"Cyano" means -C≡N.

"Isocyano" means -N≡C.

"Nitro" means -NO ₂ .

"Carboxylic acid" means -C(=O)-OH.

"Carboxylic acid ester" refers to ^{-C (= O) -OR d,} R d is selected from alkyl, cycloalkyl, or heterocycloalkyl.

"Haloalkyl" means a halogen-substituted alkyl group as defined herein above, and non-limiting examples include: monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tri Bromomethyl, 1-fluoroethyl-2-yl, 2-fluoroethyl-2-yl, 1,1-difluoroethyl-2-yl, 1,2-difluoroethyl-2-yl, 1,1,1-fluoroethyl-2-yl, 1-bromoethyl-2-yl, 2-bromoethyl-2-yl and 1,1,1-tribromoethyl-2-yl and the like.

"Thiol group" means -SH.

"thiol" means a hydrocarbon in which one or more hydrogen atoms in the alkyl group are replaced by a thiol group, Non-limiting examples include: methyl mercaptan, ethanethiol, 1,2-dithiol.

"Thioindolyl" or "thiocarbonyl" refers to a -C(=S)-R ^a group, wherein R ^{a is} as defined above.

"Hydroxyalkyl" means that the alkyl group is substituted by one or more hydroxyl groups, preferably by 1, 2 or 3 hydroxyl groups, and the alkyl group is preferably a lower alkyl group. Non-limiting examples include: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl, and the like .

"Cycloalkyl" means a saturated or unsaturated non-aromatic ring group which may be substituted or unsubstituted, and the ring carbon atom includes 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl , cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl, and the like. When substituted, the substituent may be from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, amino , cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n a group of 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of: H, hydroxy, amino, carbonyl, alkyl , alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl group or Heterocycloalkyl. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Heterocycloalkyl" means a substituted or unsubstituted saturated or unsaturated and contains at least 1 to 5 non-aromatic rings selected from N, O or S heteroatoms, and the non-aromatic ring may be a 3 to 10 membered single Rings, 4 to 20 membered spiro, ring or bridged rings, and optionally substituted N, S in the heterocycloalkyl ring can be oxidized to various oxidation states. It is preferably a 3- to 12-membered heterocyclic ring. Non-limiting examples include: oxacyclopropane, oxetanyl, oxearyl, oxetan, oxetan, oxacyclooctyl, aziridine, nitrogen heterocycle Butyl, azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3 dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclopentyl, 1 , 3-dioxacyclohexyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazole Base, 1,4-dioxadienyl, Wait. When substituted, the substituent may be from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, amino , cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n a group of 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, Alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or hetero Cycloalkyl. R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.

"Spiro" refers to a 5 to 20 membered polycyclic group that shares a carbon atom (referred to as a spiro atom) between a substituted or unsubstituted monocyclic ring, which may contain 0 to 5 double bonds, and may contain 0 to Five heteroatoms selected from N, O or S(=O) _n . Preferably, it is from 6 to 14 members, further preferably from 6 to 12 members, more preferably from 6 to 10 members, non-limiting examples of which include: When substituted, the substituent may be from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, amino , cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n a group of 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of: H, hydroxy, amino, carbonyl, alkyl , alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl group or Heterocycloalkyl. R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.

"Paracyclic" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain zero or more double bonds and may be The substituted or unsubstituted, each ring in the cis ring system may contain from 0 to 5 heteroatoms selected from N, S(=O) _n or O. It is preferably 5 to 20 members, further preferably 5 to 14 members, more preferably 5 to 12 members, and still preferably 5 to 10 members. Non-limiting examples include When substituted, the substituent may be from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, amino , cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n a group of 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of: H, hydroxy, amino, carbonyl, alkyl , alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl group or Heterocycloalkyl. R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.

"Bridge ring" refers to any two polycyclic groups of carbon atoms that are not directly bonded, may contain zero or more double bonds, and may be substituted or unsubstituted, and any ring in the ring system may contain 0 to 5 are selected from N, S(=O) _n or O heteroatoms or groups (where n is 1, 1, 2). The ring atom contains 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, and further preferably 5 to 10. Non-limiting examples include And adamantane. When substituted, the substituent may be from 1 to 5 selected from the group consisting of: F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, Amino, cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester , -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n is a group of 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of: H, hydroxy, amino, carbonyl, alkane Alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl group. Or a heterocycloalkyl group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Benzyl" refers to -CH ₂ - phenyl, substituted or unsubstituted of substituted, non-limiting examples include -CH ₂ - phenyl and -CH ₂ - p-methylphenyl and the like.

"Aryl" means a substituted or unsubstituted 6 to 14 membered cyclic aromatic group, including monocyclic aromatic groups and fused ring aromatic groups. It is preferably a 6 to 14 member aromatic ring, further preferably a 6 to 10 member aromatic ring, and non-limiting examples thereof include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group and the like. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising: When substituted, the substituent may be from 1 to 5 selected from the group consisting of: F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, Amino, cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester , -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n is a group of 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl , alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl group or Heterocycloalkyl. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Heteroaryl" means a substituted or unsubstituted 5 to 14 membered aromatic ring and contains 1 to 5 heteroatoms or groups selected from N, O or S(=O) _n , preferably 5 to 10 members. The heteroaromatic ring is further preferably from 5 to 6 members. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl , piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, piperidinyl, benzimidazole, benzopyridine, pyrrolopyridine and the like. The heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include

When substituted, the substituent may be from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, amino , cyano, isocyano, aryl, heteroaryl, heterocycloalkyl, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n a group of 0, 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of: H, hydroxy, amino, carbonyl, alkyl , alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl group or Heterocycloalkyl. R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.

"Arylthio" means an -S-aryl or -S-heteroaryl group as defined herein. Examples of arylthio groups include, but are not limited to, phenylthio, pyridylthio, furylthio, thienylthio, and pyrimidinylthio, and the like.

"Mercaptoalkyl" means a group formed by the substitution of one or more hydrogen atoms in the methane with an alkyl group, examples including, but not limited to, trimethylsulfonyl, triethylsulfonyl, and tert-butyl A fluorenyl group and a tert-butyldiphenyl fluorenyl group and the like.

The term "single bond" refers to a chemical single bond, such as "a single bond between A and B" means that there is a chemical single bond between A and B, namely: A-B.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "alkyl group optionally substituted by F" means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic or organic base, Or the free acid described is passed with a non-toxic inorganic acid or organic Those salts obtained by acid reaction.

"Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

"Excipient" refers to an inert substance that is added to a pharmaceutical composition to further rely on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.

"Prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying a phenolic group in the compound which can be removed by conventional procedures or in vivo to give the parent compound. When the precursor drug of the present invention is administered to a mammalian subject, the precursor drug is cleaved to form free hydroxyl groups, respectively. Examples of prodrugs include, but are not limited to, phenolic hydroxyl groups and phosphoric acid sodium salt derivatives of the compounds of the invention.

Certain of the compounds described herein can exist as tautomers with different hydrogen attachment points with the transfer of one or more double bonds. For example, keto-enol tautomers. Both single tautomers and mixtures thereof are included within the scope of the compounds of the invention. Tautomers within the scope of the compounds of the invention include, but are not limited to:

The compounds described herein may contain one or more asymmetric centers and may thus be racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. presence.

Certain compounds described herein contain double bonds and, unless otherwise indicated, include E and Z geometries.

"Co-crystal" or "eutectic" refers to a crystal in which an active pharmaceutical ingredient (API) and a cocrystal former (CCF) are combined by hydrogen bonding or other non-covalent bonds. The pure state of API and CCF is solid at room temperature and there is a fixed stoichiometric ratio between the components. A eutectic is a multi-component crystal that contains both a two-membered eutectic formed between two neutral solids and a multi-membered eutectic formed by a neutral solid with a salt or solvate.

"X Syndrome" refers to conditions, diseases, and conditions of metabolic syndrome. For a detailed description, see Johannsson J. Clin. Endocrinol. Metab., 1997, 82, 727-734.

"Effective dose" refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of compound that occurs or reduces it to some extent.

"Solvate" means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

"IC ₅₀ " refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

Method for synthesizing the compound of the present invention: For the purpose of the present invention, the compound of the present invention can be prepared by the following scheme: Scheme 1:

The intermediates I-A and I-B are reacted by reductive amination conditions to give intermediates I-C which are obtained by further removal of the amino protecting group to give the compound of formula (I).

The intermediate IA can be prepared by referring to the documents WO2010056708 and US2007232676, the method of which is described as follows:

Wherein Ar, R ¹ and V are as defined above, and P is an amino protecting group such as a third butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz) or a 9-fluorenylmethoxycarbonyl group (Fmoc).

Figure 1 is a ¹ H- ¹ H COSY spectrum of Compound 1.

2 is a ¹ H- ¹ H NOESY spectrum of Compound 1.

Figure 3 is a ¹ H- ¹ H J-analytical spectrum of Compound 1.

4 is a ¹ H- ¹ H COSY spectrum of Compound 2.

Figure 5 is a ¹ H- ¹ H NOESY spectrum of Compound 2.

Figure 6 is a ¹ H- ¹ H J-analytical spectrum of Compound 2.

Figure 7 is a ¹ H- ¹ H COSY spectrum of Compound 3.

Figure 8 is a ¹ H- ¹ H NOESY spectrum of Compound 3.

Figure 9 is a ¹ H- ¹ H J-analytical spectrum of Compound 3.

Figure 10 is a ¹ H- ¹ H COSY spectrum of Compound 6.

Figure 11 is a ¹ H- ¹ H NOESY spectrum of Compound 6.

Figure 12 is a ¹ H- ¹ H J-analytical spectrum of Compound 6.

Figure 13 is a graph showing the effect of a single oral administration on DPP4 activity in ob/ob mice.

Figure 14 is a graph showing the results of the experiment of compound 3 on monkey plasma DPP-IV enzymatic screening.

The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).

The NMR shift (δ) is output in units of 10 ^-6 (ppm).

The NMR was measured by a (Bruker ADVANCE III 400) nuclear magnetic apparatus, and the solvent was deuterated dimethyl hydrazine (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), internal standard. For tetramethylnonane (TMS), 1H NMR information is listed in the following format: chemical shift (multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), Number of protons).

For the determination of MS (Agilent 6120B (ESI)).

The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorba x SB-C18 100 x 4.6 mm).

The thin layer chromatography gelatin plate uses Yantai Huanghai HSGF254 or Qingdao GF254 gelatin plate. The specification of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Pipe column chromatography generally uses Yantai Huanghai Tanji 200~300 mesh silicone as carrier.

Unless otherwise specified, triethylamine, methyl tert-butyl ether, hydrazine hydrate, tetrabutyl Ammonium bromide, dichlorohydrazine, imidazole, sodium hydride, triphenylphosphine, trifluoroacetic acid purchased from Chengdu Kelon Chemical Reagent Factory; di-tert-butyl dicarbonate, N, N'-dicarbonyldiimidazole , N,N-dimethylformamide dimethyl acetal, N,O-dimethylhydroxylamine hydrochloride, cis-4-hydroxy-D-valine hydrochloride purchased from Ester ( Chengdu) Pharmaceutical Technology Co., Ltd.; barium carbonate, lithium borohydride, tert-butyldimethylchlorodecane, N-hydroxybutylimine, sodium bis(trimethyldecyl)amide, diphenylmethylene glycine Ethyl ester, trans-L-hydroxyproline purchased from Anike Chemical; Des Martin purchased from Shanghai Titan Technology Co., Ltd.; methyl trifluoromethanesulfonate, 2,5-difluorobromobenzene, S- (Trifluoromethyl)dibenzothiophene trifluoromethanesulfonate purchased from Shanghai Demer Pharmaceutical Technology Co., Ltd.; 2-iodopropane purchased from Shanghai Bi De Pharmaceutical Technology Co., Ltd.; isopropylmagnesium chloride / lithium chloride tetrahydrofuran The solution was purchased from Belling Technology Co., Ltd.; propargyl benzene sulfonate, tetrabutylammonium fluoride, sodium tris(ethyloxy)borohydride, tetrabutylammonium hexafluorophosphate purchased from Ada Reagents; cyclopentadienyl bis(triphenylphosphine) ruthenium chloride (II) purchased from ACROS orgainics; borane dimethyl sulfide purchased from Suiyuan Chemical Technology (Shanghai) Co., Ltd.; tetrahydrofuran-3-sulfonate Purine-based chlorine was purchased from Nanjing Kangmanlin Chemical Industry Co., Ltd.; sodium perborate was purchased from Tianjin Guangfu Fine Chemical Research Institute; [(R,R)-N-(2-amino-1,2-diphenylethyl)pentafluorobenzene Sulfonamide] Chlorinated (p-hydrocarbon) 钌 (II) was purchased from Strem chemical; methyl iodide and methyl sulfonium chloride were purchased from Sinopharm Pharmaceutical Co., Ltd.

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

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 2 L.

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

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The optimum reaction temperature at room temperature is 20 ° C to 30 ° C.

Intermediate 1 : tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-carbonyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3- Carbamate ( intermediate 1 )

Tert-butyl

((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

First step: 2-amino-4-acetylpentanoic acid ethyl ester (1B)

Ethyl 2-aminopent-4-ynoate

Diphenylmethylene glycine ethyl ester 1A (50 g, 0.187 mol) was dissolved in methyl tert-butyl ether (300 mL) at room temperature to give propargyl besylate (44 g, 0.224 mol), four Ammonium bromide (6.1 g, 0.019 mol) was added to the reaction mixture, the temperature was raised to 50 ° C, and cesium carbonate (121.8 g, 0.374 mol) was added thereto, and the reaction was carried out at 50 ° C overnight. The reaction solution was filtered, and the filter cake was washed with methyl t-butyl ether (40 mL × 2), and the organic phase was combined, concentrated to a half volume by rotary evaporation, and a hydrochloric acid solution (3 mol/L, 100 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was allowed to stand for stratification, and the aqueous phase was extracted with methyl tert-butyl ether (70 mL × 2), and the aqueous phase was collected to obtain 1B .

Second step: 2-((t-butoxycarbonyl)amino)-4-acetylpentanoic acid ( 1C )

2-((tert-butoxycarbonyl)amino)pent-4-ynoic acid

Sodium hydroxide (33.7 g, 0.842 mol) was dissolved in water (100 mL), and added dropwise to a reaction mixture of 1B (26.4 g, 0.187 mol), and stirred at room temperature for 2 hours. Dibutyl butyl carbonate (45 g, 0.206 mol) was dissolved in methyl tert-butyl ether (125 mL), added dropwise to the reaction mixture, and stirred at room temperature for 4 hours. The mixture was allowed to stand for stratification, the aqueous phase was washed with methyl tert-butyl ether (80 mL × 2), and the aqueous phase was adjusted to pH 3 with 3 mol/L hydrochloric acid solution, using methyl t-butyl ether (100 mL × 2) The combined organic phases with saturated aqueous sodium chloride solution (30mL × 2), dried the organic phase is dried over anhydrous magnesium sulfate, filtered, rotary evaporation, to give a yellow oily liquid 1C (33g, 83% yield).

MS m/z (ESI): 212.0 [M-1].

Third step: tert-butyl (1-(methoxy(methyl)amino)-1-carbonylpentyl-4-yn-2-yl)carbamate (1D)

Tert-butyl(1-(methoxy(methyl)amino)-1-oxopent-4-yn-2-yl)carbamate

1C (33 g, 0.155 mol) was dissolved in N,N-dimethylformamide (200 mL), the temperature was controlled to be less than 10 ° C, and N,N'-carbonyldiimidazole (32.58 g, 0.201 mol) was added to the reaction. In a solution, the reaction was carried out at 0 ° C for 1 hour. N,O-dimethylhydroxylamine hydrochloride (19.6 g, 0.186 mol) was added to the reaction mixture, and stirred at room temperature overnight. Water (150 mL) was added dropwise, and the mixture was stirred for 1 hour, and extracted with ethyl acetate (100 mL×2). The organic phase was combined and washed with saturated sodium hydrogen carbonate solution (60 mL×3) and saturated sodium chloride solution (60 mL×3) The organic phase was dried over anhydrous magnesium sulfate. Filtered, and the filtrate was concentrated and isolated by column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1), to give a white solid 1D (35g, 88.2% yield).

MS m/z (ESI): 156.9 [M-99].

Fourth step: tert-butyl (1-(2,5-difluorophenyl)-1-carbonylpentyl-4-yn-2-yl)carbamate (1E)

Tert-butyl(1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl)carbamate

2,5-difluorobromobenzene (15.05g, 78mmol) was dissolved in dry toluene (50mL) under nitrogen, and the ice salt bath was cooled to below -10 °C. Isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution was added dropwise. (66 mL, 1.3 mol/L), kept stirring at about -10 ° C for 1 hour. 1D (10 g, 39 mmol) was dissolved in dry tetrahydrofuran (100 mL), and added dropwise to the reaction mixture, maintaining the temperature at -10 ° C, and the reaction was carried out at room temperature for 4 hours. The temperature was lowered to about -10 ° C, saturated ammonium chloride solution (40 mL) was added dropwise, stirred for 10 minutes, and the pH was adjusted to 5-6 with a 3 mol/L hydrochloric acid solution, and the layer was allowed to stand, and the aqueous phase was methylated. The third butyl ether (50 mL×2) was extracted, and the organic phase was combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. /ethyl acetate (v/v) = 50:1 - 8:1) to give a pale yellow solid 1E (10.1 g, yield 83.5%).

MS m/z (ESI): 210.1 [M-99].

The fifth step: the third butyl ((1R, 2S)-1-(2,5-difluorophenyl)-1-hydroxypentyl-4-yn-2-yl)carbamate (1F)

Tert-butyl((1R,2S)-1-(2,5-difluorophenyl)-1-hydroxypent-4-yn-2-yl)carbamate

1E (16.07 g, 52 mmol) was dissolved in tetrahydrofuran (100 mL), and triethylenediamine (17.39 g, 155 mmol) and [(R,R)-N-(2-amino-1,2-diphenylethyl) were added. Pentafluorobenzenesulfonamide] Chlorinated (for dill hydrocarbon) ruthenium (II) (ie RuCl(p-cymene)(R,R)-FSDPEN) (0.37 g, 0.52 mmol), formic acid (14.27 g) , 310 mmol), added, and reacted at 40 ° C overnight. The tetrahydrofuran and formic acid in the reaction mixture were evaporated off, and water (60 mL), hydrochloric acid (3 mol/L, 10 mL) was added, and extracted with methyl t-butyl ether (90 mL×3), and the organic phase was combined, and saturated sodium hydrogen carbonate solution (35 mL × 2), the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography ( petroleum ether / ethyl acetate (v / v) = 60: 1-10:1) Glue 1F (15.37 g, yield 95%).

MS m/z (ESI): 334.2 [M+23].

Step 6: Tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate (1G )

Tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate

1F (15.37 g, 49.4 mmol) was dissolved in N,N-dimethylformamide (75 mL) under heating, and tetrabutylammonium hexafluorophosphate (2.49 g, 6.42 mmol), N-hydroxybutanedifluoride was added. Imine (2.84 g, 24.75 mmol), triphenylphosphine (0.86 g, 3.26 mmol), sodium hydrogencarbonate (2.16 g, 25.69 mmol), three times with nitrogen, vacuum for 15 min, and added cyclopentadienyl bis ( Triphenylphosphine) ruthenium (II) chloride (i.e., CpRuCl(PPh ₃ ) ₂ ) (1.79 g, 2.47 mmol) was replaced with nitrogen three times and vacuumed for 15 minutes, and the reaction was heated to 85 ° C overnight under nitrogen. Water (300 mL) and methyl tert-butyl ether (200 mL) were added to the reaction mixture, and the mixture was filtered over silica gel, and the filtrate was allowed to stand for separation. The aqueous phase was extracted with methyl t-butyl ether (90 mL × 2), and the organic phase was combined. Washed with saturated sodium bicarbonate solution (60 mL × 2), dried over anhydrous sodium sulfate, and concentrated by filtration, eluting with column chromatography ( petroleum ether / ethyl acetate (v / v) = 80:1-30: 1) A pale yellow powder solid 1G (8.9 g, yield 57.9%) was obtained.

MS m/z (ESI): 256.2 [M - 55].

Step 7: Tert-Butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamate (1H)

Tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamate

1 G (8.9 g, 28.6 mmol) was dissolved in dry methyl tert-butyl ether (90 mL), dry toluene (9 mL) was added, the temperature was dropped to -10 ° C, and borane dimethyl sulfide tetrahydrofuran solution was added dropwise ( 2 mol/L, 35.9 mL), and reacted at 0 ° C for 3.5 hours. Water (4 mL) was slowly added, and a sodium hydroxide solution (1 mol/L, 89 mL) was added dropwise, and the mixture was stirred for 15 minutes, and sodium perborate (13.2 g, 85.8 mmol) was added portionwise, and stirred at room temperature overnight. The layers were separated, and the aqueous layer was extracted with EtOAc (EtOAc) (EtOAc (EtOAc) Toluene (50 mL) was added, and the mixture was heated to 90 ° C to dissolve. N-hexane (200 mL) was added dropwise to the reaction mixture to precipitate a white solid, which was filtered, washed with n-hexane (30 mL × 2), and the solvent was evaporated to give a white solid powder. 1H (7.9 g, yield 84%).

MS m/z (ESI): 274.1 [M - 55].

Step 8: Tert-Butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate (1I)

Tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate

1H (11.53g, 35.03mmol) was dissolved in dichloromethane (130mL), cooled to 0 ° C, and Dess Martin oxidant (29.72g, 70.06mmol) was added to the reaction mixture in portions and naturally raised to room temperature. hour. The mixture was cooled to 0 ° C, and a saturated sodium hydrogen carbonate solution (60 mL) was added dropwise to the reaction mixture, and the mixture was stirred for 20 minutes, filtered, and the filtrate was allowed to stand for separation, and the aqueous phase was extracted with methyl t-butyl ether (60 mL × 3). The organic phase was combined, washed with saturated sodium bicarbonate (30 mL×2), dried over anhydrous sodium sulfate. -4:1) gave white crystalline powder 1I (10.85 g, yield 94.7%).

MS m/z (ESI): 272.0 [M-55]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.29-7.13 (m, 4H), 4.77-4.75 (d, 1H), 4.22-4.02 (m, 3H), 2.75-2.70 (m, 2H), 1.23 (s, 9H).

Ninth step: tert-butyl N-[(2R,3S)2-(2,5-difluorophenyl)-5-morpholine-3,4-dihydro-2H-pyran-3-yl] Carbamate (1J)

tert-butylN-[(2R,3S)-2-(2,5-difluorophenyl)-5-morpholino-3,4-dihydro-2H-pyran-3-yl]carbamate

1I (2.5 g, 7.64 mmol) was added to 40 mL of a toluene solution, morpholine (1.30 g, 15.30 mmol) was added, and the reaction was heated to reflux, and water was separated with a water separator for 6 hours. The reaction liquid was cooled to room temperature, and a solid was precipitated, which was filtered, and washed with toluene to give a white solid 1J (2.1 g, yield 70%).

^{1 H NMR (400MHz, DMSO- d} 6): δ 7.27-7.12 (m, 3H), 6.89 (d, 1H), 6.10 (s, 1H), 4.55 (d, 1H), 3.99-3.83 (m, 1H ), 3.61 (t, 4H), 2.64 (qd, 4H), 2.41-2.20 (m, 2H), 1.27-1.10 (m, 9H).

Step 10: Tert-Butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-carbonyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3- Carbamate (intermediate 1)

Tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

Add 1 J (2.3 g, 5.80 mmol) to 30 mL of N,N-dimethylformamide solution, then add 4-dimethylaminopyridine (0.070 g, 0.58 mmol) in anhydrous, oxygen-free, nitrogen-protected conditions Next, S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate (2.33 g, 5.80 mmol) was added, and the mixture was reacted at 0 ° C for 2 hours. To the above reaction solution, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×3). Petroleum ether / ethyl acetate (v / v) = 10:1), obtained as a yellow solid. The solid was added to a 7 mL tetrahydrofuran solution, and hydrochloric acid (3 mL, 1 mol/L) was added, and the mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 7 with a 2 mol/L sodium hydroxide solution, and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate Column chromatography and purification (petroleum ether: ethyl acetate (v/v) = 8:1) gave pale yellow solid intermediate 1 (0.41 g, yield 18%).

MS m/z (ESI): 394.0 [M-1]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.27 (dd, 4H), 5.20 (q, 1H), 5.07 (d, 1H), 4.13 (dd, 1H), 2.96 (dd, 1H), 2.83 (dd, 1H), 1.26-1.15 (m, 9H).

Intermediate 2: tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate (Intermediate 2)

Tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate

First step: tert-butyl (3Z)-3-(dimethylaminomethylene)-4-oxo-pyrrole-1-carboxylate (2B)

Tert -butyl(3Z)-3-(dimethylaminomethylene)-4-oxo-pyrrolidine-1-carboxylate

1-1,3-Butoxycarbonyl-3-pyrrolidone 2A (100 g, 0.54 mol) was dissolved in N,N-dimethylacetamide (600 mL), and N,N -dimethylformamide was added . The aldehyde (83.6 g, 0.70 mmol) was heated to 105 ° C and stirred for 40 minutes. The reaction was quenched with water (500 mL), ethyl acetate (500 mL×2), and the mixture was washed with water (500 mL×2). The organic phase was dried over anhydrous sodium sulfate. The ester (v/v) = 4:1 to 1:1) gave 2B (50 g, yield 47%) as a pale yellow liquid.

Second step: tert-butyl 6a-hydroxy-1,3a,4,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxylate (2C)

Tert-butyl 6a-hydroxy-1,3a,4,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxylate

2B (50 g, 0.21 mol) was dissolved in methanol (200 mL), hydrazine hydrate (7.8 g, 0.16 mmol) was added, and the mixture was reacted at room temperature for 4 hours, and the organic solvent was evaporated to the next step.

Third step: tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate (intermediate 2)

Tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate

2C (47.5 g, 0.21 mol) obtained in the above reaction was dissolved in a mixed solvent of dichloromethane (300 mL) and methanol (180 mL), and p-toluenesulfonic acid (5.64 g, 0.029 mmol) was added at 0 ° C overnight. . The reaction solution was spin-dry the solvent, separation and purification of silica gel column chromatography (dichloromethane) to give a pale yellow solid of Intermediate 2 (20g, 44% yield).

^{1 H NMR (400MHz, MeOD)} : δ 7.44 (d, 1H), 4.53-4.33 (m, 4H), 1.54 (s, 9H).

Intermediate 3: tert-butyl ((2R,3S)-2-(2,3,5-trifluorophenyl)-5-carbonyl-6-(trifluoromethyl)tetrahydro-2H-pyran- 3-yl)carbamate (intermediate 3)

Tert-butyl((2R,3S)-2-(2,3,5-trifluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

First step: tert-butyl (1-carbonyl-1-(2,4,5-trifluorophenyl)pentyl-4-yn-2-yl)carbamate (3A)

Tert-butyl(1-oxo-1-(2,4,5-trifluorophenyl)pent-4-yn-2-yl)carbamate

2,3,5-trifluorobromobenzene (42.2g, 200mmol) was dissolved in dry toluene (130mL) under nitrogen, and the ice salt bath was cooled to below -10 °C. Isopropylmagnesium chloride/lithium chloride was added dropwise. A tetrahydrofuran solution (100 mL, 2.2 mol/L) was stirred at about -10 ° C for 1 hour. 1D (25.6 g, 100 mmol) was dissolved in dry tetrahydrofuran (250 mL), and added dropwise to the reaction mixture, maintaining the temperature at -10 ° C, and the reaction was carried out at room temperature for 4 hours. The temperature was lowered to about -10 ° C, saturated ammonium chloride solution (100 mL) was added dropwise, stirred for 10 minutes, and the pH was adjusted to 5-6 with a 3 mol/L hydrochloric acid solution, and the layer was allowed to stand. The aqueous phase was methylated. The third butyl ether (150 mL×2) was extracted, and the organic phase was combined, washed with a saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography /ethyl acetate (v/v) = 50:1 - 8:1) afforded white solid 3A (27 g, yield 82.6%).

Second step: tert-butyl ((1R,2S)-1-hydroxy-1-(2,4,5-trifluorophenyl)pentyl-4-yn-2-yl)carbamate (3B )

Tert-butyl((1R,2S)-1-hydroxy-1-(2,4,5-trifluorophenyl)pent-4-yn-2-yl)carbamate

3A (27 g, 82.6 mmol) was dissolved in tetrahydrofuran (200 mL), and triethylenediamine (27.8 g, 248 mmol) and [(R,R)-N-(2-amino-1,2-diphenylethyl) were added. Pentafluorobenzenesulfonamide] Chlorinated (p-hydrocarbyl) ruthenium (II) (ie RuCl(p-cymene)(R,R)-FSDPEN) (0.57 g, 0.8 mmol), formic acid (22.8 g) , 496 mmol), added, and reacted at 40 ° C overnight. The tetrahydrofuran and formic acid in the reaction liquid were removed by rotary evaporation, and water (120 mL), hydrochloric acid (3 mol/L, 20 mL) was added, and extracted with methyl t-butyl ether (180 mL × 3), and the organic phase was combined, and saturated sodium hydrogen carbonate solution (70mL × 2), the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography ( petroleum ether / ethyl acetate (v / v) = 60:1-10:1) to give a white solid 3B (23.6 g, yield 87.4%).

Third step: tert-butyl ((2R,3S)-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate (3C)

Tert-butyl((2R,3S)-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate

3B (23.6 g, 71.7 mmol) was dissolved in N,N-dimethylformamide (250 mL) under heating, and tetrabutylhexafluorophosphoric acid (3.6 g, 9.3 mmol), N-hydroxybutanediamine was added. Imine (4.1 g, 35.8 mmol), triphenylphosphine (1.24 g, 4.73 mmol), sodium hydrogencarbonate (3.13 g, 37.3 mmol), three times with nitrogen, vacuuming for 15 minutes, adding cyclopentadienyl bis ( Triphenylphosphine) ruthenium (II) chloride (i.e., CpRuCl(PPh ₃ ) ₂ ) (2.6 g, 3.58 mmol) was replaced with nitrogen three times and vacuumed for 15 minutes, and the reaction was heated to 85 ° C overnight under nitrogen. Water (500 mL) and methyl tert-butyl ether (300 mL) were added to the reaction mixture, and the mixture was filtered over silica gel. The filtrate was partitioned and the aqueous phase was extracted with methyl butyl ether (150 mL × 2). Washed with saturated sodium bicarbonate solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (v/v) (v/v) = 80:1-30: 1) A white powder solid 3C (9.0 g, yield 38.1%) was obtained.

Fourth step: tert-butyl ((2R,3S)-5-hydroxy-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 3D)

Tert-butyl((2R,3S)-5-hydroxy-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

3C (9.0 g, 27.4 mmol) was dissolved in dry methyl tributyl ether (60 mL), dry toluene (9 mL) was added, the temperature was dropped to -10 ° C, and borane dimethyl sulfide tetrahydrofuran solution was added dropwise ( 2 mol/L, 34.2 mL), and reacted at 0 ° C for 3.5 hours. Water (4 mL) was slowly added, and a sodium hydroxide solution (1 mol/L, 90 mL) was added dropwise, and the mixture was stirred for 15 minutes, and sodium perborate (12.6 g, 82.2 mmol) was added portionwise and stirred at room temperature overnight. The layers were separated, and the aqueous layer was extracted with EtOAc (EtOAc) (EtOAc (EtOAc) Toluene (50 mL) was added, and the mixture was heated to 90 ° C to dissolve. N-hexane (200 mL) was added dropwise to the reaction mixture to precipitate a white solid, which was filtered, washed with n-hexane (30 mL×2) and concentrated to give a white solid powder 3D ( 8.6 g, yield 90.5%).

Fifth step: tert-butyl ((2R,3S)-5-carbonyl-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 3E)

Tert-butyl((2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

3D (8.6g, 24.8mmol) was dissolved in dichloromethane (100mL), cooled to 0 ° C, dimethyl phthalate (21.1g, 49.6mmol) was added to the reaction mixture in portions, naturally rise to the room The temperature was reacted for 4 hours. The mixture was cooled to 0 ° C, and a saturated sodium hydrogen carbonate solution (50 mL) was added dropwise to the reaction mixture, stirred for 20 minutes, filtered, and the filtrate was allowed to stand for separation, and the aqueous phase was extracted with methyl t-butyl ether (50 mL × 3). The organic phase was combined, washed with aq. EtOAc (EtOAc) 1~4:1), white crystalline powder 3E (6.8 g, yield 80%) was obtained.

MS m/z (ESI): 290.1 [M-55];

Step 6: Tert-butyl ((2R,3S)-5-morpholin-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran-3-yl Carbamate (3F)

Tert-butyl((2R,3S)-5-morpholino-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate

3E (6.8 g, 19.7 mmol) was added to a 70 mL toluene solution, morpholine (6.8 g, 78.8 mmol) was added, and the reaction was heated to reflux at 138 ° C, and water was separated by a water separator for 6 hours. The reaction solution was cooled to room temperature, and a solid was precipitated, which was filtered, and washed with toluene to afford white solid 3F (6.7 g, yield 82%).

MS m/z (ESI): 415.1 [M+1];

Step 7: Tert-Butyl ((2R,3S)-5-carbonyl-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran- 3-yl)carbamate (intermediate 3)

Tert-butyl((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

Add 3F (6.7 g, 16.2 mmol) to N,N-dimethylformamide (70 mL) and add 4-dimethylaminopyridine (0.19 g, 1.62 mmol) in anhydrous anhydrous Next, S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate (6.5 g, 16.2 mmol) was added, and the mixture was reacted at 0 ° C for 2 hours. Water (200 mL) was added to the mixture, and the mixture was evaporated. Purification (petroleum ether/ethyl acetate (v/v) = 10:1),yield of yellow solid was added to 70mL of tetrahydrofuran, hydrochloric acid (30mL, 1mol/L) was added, and the reaction was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 7 with a 2 mol/L sodium hydroxide solution, and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate Column chromatography and purification (petroleum ether: ethyl acetate (v/v) = 8:1) afforded pale yellow solid intermediate 3 (3.0 g, yield 44%).

^{1 H NMR (400MHz, DMSO- d} 6): δ 7.61-7.49 (m, 2H), 7.31 (d, 1H), 5.21-5.17 (m, 1H), 5.05 (d, 1H), 4.17-4.09 (m , 1H), 2.99 (dd, 1H), 2.85 (dd, 1H), 1.22 (s, 9H).

Example 1:

(2R,3S,5R,6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazole -5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 1)

(2R,3S,5R,6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)- 6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-(cyclopropylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate (1a)

Tert-butyl2-(cyclopropylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate

Processing of anhydrous oxygen-free nitrogen atmosphere, Intermediate 2 (604mg, 2.87mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 deg.] C, was added sodium hydride (180mg, 60wt%, 4.5mmol) , stirred for 30 minutes, was added dropwise Cyclopropylsulfonium chloride (1.27 g, 9.0 mmol) was naturally warmed to room temperature for 1 hour. The reaction mixture was quenched with water (20 mL), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Potassium tert-butoxide (36 mg, 0.32 mmol) was added and the reaction was maintained at this temperature for 28 hours. After the reaction was completed, aqueous citric acid (1 mL, 15%) was evaporated. The residue was separated and purified by column chromatography over silica gel (petroleum ether / ethyl acetate (v / v) = 2: 1), to give a white solid 1a (660mg, 73% yield).

Second step: 2-(cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (1b)

2-(cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

1a (645 mg, 2.06 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (8 mL) was added and the mixture was reacted at room temperature for 2 hr. The reaction mixture by rotary evaporation, add ammonia (1 mL) the reaction was quenched, purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10: 1) to give a pale yellow solid 1b (400mg, yield 91%).

¹ H NMR (400 MHz, MeOH): δ 7.85 (s, 1H), 4.01-3.94 (m, 4H), 3.36 (s, 3H).

The third step: the third butyl ((2R, 3S, 5R, 6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazole-5 (2H, 4H, 6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (1c)

Tert-butyl((2R,3S,5R,6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5 -difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

The third butyl intermediate 1 (305 mg, 0.77 mmol) and 2-(cyclopropylsulfonate)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole 1b (197 mg , 0.93 mmol) was added to 5 mL of toluene, and the mixture was reacted at 140 ° C oil bath temperature until the solvent was evaporated to dryness. The residue was cooled to room temperature under nitrogen atmosphere, redissolved in 1,2-dichloroethane (10 mL), and then sodium tris(ethyloxy) borohydride (650 mg, 3.08 mmol) and acetic acid (92.5). Mg, 1.54 mmol), and reacted at room temperature for 3 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc. Separation and purification by hydrazine column chromatography (petrole ether / ethyl acetate (v/v) = 4:1) gave white foamy solid 1c (190 mg, yield 42%).

Step 4: (2R, 3S, 5R, 6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-yl) -2-(2,5-Difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 1)

(2R,3S,5R,6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)- 6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

1c (190 mg, 0.32 mmol) was dissolved in dichloromethane (4.5 mL) and trifluoroacetic acid (1.5 mL). The reaction mixture was quenched with saturated aqueous sodium hydrogen sulfate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated. Purification silica gel column chromatography (methylene chloride / methanol (v / v) = 50: 1), to give a white powdery solid compound 1 (126mg, 80% yield).

MS m / z (ESI): 493.1 [M + 1]; 1 H NMR (400MHz, DMSO- d 6) δ 7.98 (m, 1H), 7.27 (m, 3H), 4.81-4.68 (qd, 1H), 4.50 (d, 1H), 3.94 (dd, 2H), 3.78 (dd, 2H), 3.46 (m, 1H), 3.11-3.04 (m, 1H), 3.03-2.94 (ddd, 1H), 2.37-2.26 ( m, 1H), 1.83 (m, 1H), 1.28-1.21 (m, 4H).

The ¹ H- ¹ H COSY, ¹ H- ¹ H NOESY and ¹ H- ¹ H J - analytical spectra of Compound 1 are shown in Figures 1-3, and the data are shown in Table 1, demonstrating that the configuration of Compound 1 is as shown in the following formula. :

Table 1 ¹ H NMR, ¹ H- ¹ H COSY and ¹ H- ¹ H NOESY number of compound 1

* Read out according to 1H-1H J - analytical spectrum

** NH ₂ protons exchanged with water peaks

Example 2

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)pyrrolo[3,4-c]pyrazole-5 (2H ,4H,6H)-yl)-6-(trifluoroethyl)tetrahydro-2H-pyran-3-amine (Compound 2)

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)- 6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-(ethylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate (2a)

Tert-butyl 2-(ethylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate

Anhydrous anoxic treatment, nitrogen-protected, intermediate 2 (627 mg, 3.0 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 ° C, sodium hydride (180 mg, 60 wt%, 4.5 mmol) was added, stirred for 30 minutes, added dropwise Ethylsulfonium chloride (1.16 g, 9.0 mmol) was naturally warmed to room temperature for 1 hour. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. At ° C, potassium t-butoxide (35 mg, 0.31 mmol) was added and the reaction was maintained at this temperature for 24 hours. After completion of the reaction, aq. EtOAc EtOAc (EtOAc) Purification by column chromatography over silica gel residue (petroleum ether / ethyl acetate (v / v) = 5: 1), to give a white solid 2a (730mg, 81% yield).

Second step: 2-(ethylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (2b)

2-(ethylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

2a (710 mg, 2.36 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (8 mL) was added and the mixture was reacted at room temperature for 2 hours. The reaction mixture by rotary evaporation, add ammonia (1 mL) the reaction was quenched, purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10: 1) to give a pale yellow solid 2b (460mg, yield 97%).

Third step: tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)pyrrolo[3,4 -c]pyrazole-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (2c)

Tert-butyl((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H) -yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

Add intermediate 1 (350 mg, 0.89 mmol) and 2-(ethylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole 2b (244 mg, 1.21 mmol) Into toluene (5 mL), the round bottom flask was reacted at 140 ° C oil bath temperature until the solvent was evaporated to dryness. The residue was cooled to room temperature under nitrogen and redissolved in 1,2-dichloroethane (10 mL). Sodium tri(acetoxy)borohydride (854 mg, 4.04 mmol) and acetic acid (0.115 mL, 2.02 mmol) were sequentially added, and the mixture was reacted at room temperature for 3 hours. The reaction mixture was diluted with EtOAc EtOAc. Separation and purification by hydrazine column chromatography (petroleum ether / ethyl acetate (v/v) = 5:1) gave white foamy solid 2c (220 mg, yield 38%).

Step 4: (2R,3S,5R,6S)-2-(2,5-Difluorophenyl)-5-(2-(ethylsulfonyl)pyrrolo[3,4-c]pyrazole -5(2H,4H,6H)-yl)-6-(trifluoroethyl)tetrahydro-2H-pyran-3-amine (Compound 2)

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)- 6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

2c (220 mg, 0.38 mmol) was dissolved in dichloromethane (4.5 mL) and trifluoroacetic acid (1.5 mL). After the reaction was completed, EtOAc EtOAc m. Separation and purification by hydrazine column chromatography (dichloromethane/methanol (v/v) = 50:1) gave white powdery solid compound 2 (60 mg, yield 33%).

MS m/z (ESI): 481.1 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 7.98 (m, 1H), 7.33-7.22 (m, 3H), 4.88-4.71 (qd, 1H) ), 4.51 (d, 1H), 3.95 (dd, 2H), 3.78 (dd, 2H), 3.64 (q, 2H), 3.49-3.43 (m, 1H), 3.05-2.97 (ddd, 1H), 2.35- 2.29 (m, 1H), 1.82 (m, 1H), 1.12 (t, 3H).

The ¹ H- ¹ H COSY, ¹ H- ¹ H NOESY and ¹ H- ¹ H J - analytical spectra of Compound 2 are shown in Figure 4-6, and the data are shown in Table 2, demonstrating the configuration of Compound 2 as shown in the following formula. :

* Read out according to 1H-1H J - analytical spectrum

** NH ₂ protons exchanged with water peaks

Example 3:

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-pyrrolo[3,4]pyrazole-5 (2H, 4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (compound 3)

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)- 6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-methylsulfonate-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate (3a)

Tert -butyl 2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate

Intermediate 2 (3.5 g, 16.7 mmol) was dissolved in tetrahydrofuran (35 mL), sodium hydride (1.0 g, 25.4 mmol, 60%) was added at 0 ° C, and reacted for 30 minutes, and methyl sulfonium chloride (2.9 g) was added. , 25.4 mmol) was reacted for 1 hour. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) (v/v) = 1:1) gave white solid 3a (2.1 g, yield 44%).

Step 2: 2-Methylsulfonyl-5,6-dihydro-4-H-pyrrolo[3,4-c]pyrazole (3b)

2-methylsulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole

3a (2.1 g, 7.3 mmol) was dissolved in dichloromethane (25 mL), trifluoroacetic acid (5 mL) was added at 0 ° C, and the mixture was reacted at 0 ° C for 2 hours. The reaction mixture by rotary evaporation, add ammonia (2mL) The reaction was quenched and purified using silica gel column chromatography (methylene chloride / methanol (v / v) = 50: 1), to give a white solid 3b (1.1g, yield 80.5%).

¹ H NMR (400 MHz, MeOH): δ 7.85 (s, 1H), 4.01-3.94 (m, 4H), 3.36 (s, 3H).

The third step: the third butyl ((2R, 3S, 5R, 6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-pyrrolo[3, 4-c]pyrazole-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (3c)

Tert-butyl((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H) -yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

Intermediate 1 (490 mg, 1.24 mmol) and 3 b (254 mg, 1.36 mmol) were added to 10 mL of toluene, and the round bottom flask was reacted at 140 ° C oil bath temperature until the solvent was evaporated to dryness. The residue was cooled to room temperature under nitrogen atmosphere, redissolved in 1,2-dichloroethane (15 mL) and sodium tris(ethyloxy) borohydride (1.05 mg, 4. 149 mg, 2.48 mmol), and reacted at room temperature for 3 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Separation and purification by gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) gave white oily liquid 3c (455 mg, yield 60%) and white solid 3d (45 mg, yield 5.9%) ).

Fourth step: (2R, 3S, 5R, 6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-pyrrolo[3,4]pyrazole- 5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (compound 3)

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)- 6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

3c (410 mg, 0.72 mmol) was dissolved in 6 mL of dichloromethane and 2 mL of trifluoroacetic acid and stirred at room temperature for one hour. After the reaction was completed, the mixture was evaporated. Separation and purification by hydrazine column chromatography (dichloromethane/methanol (v/v) = 30:1) gave white powdery solid compound 3 (250 mg, yield 75%).

MS m/z (ESI): 467.1 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 7.96 (m, 1H), 7.35-7.04 (m, 3H), 4.86-4.63 (qd, 1H), 4.50 (d, 1H), 3.95 (dd, 2H), 3.78 (dd, 2H), 3.49 (s, 3H), 3.45 (m, 1H), 3.00 (ddd, 1H), 2.33 (m, 1H) ), 1.82 (m, 1H), 1.48 (br, 2H).

The ¹ H- ¹ H COSY, ¹ H- ¹ H NOESY and ¹ H- ¹ H J - analytical spectra of Compound 3 are shown in Figures 7-9, and the data are shown in Table 3, demonstrating that the compound 3 configuration is as shown in the following formula. :

Table 3 ¹ H NMR, ¹ H- ¹ H COSY and ¹ H- ¹ H NOESY data for compound 3 (DMSO- d ₆ , 400 MHz)

* Read out according to 1H-1H J - analytical spectrum

** NH ₂ protons exchanged with water peaks

Example 4:

(2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-yl)-6-(III Fluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine (Compound 4)

(2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)-2-(2 ,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl ((2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H )-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (4a)

Tert-butyl((2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)- 2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

Intermediate 3 (3 g, 7.26 mmol) and 3b (1.76 g, 9.44 mmol) were added to 100 mL of toluene, and the round bottom flask was reacted at 140 ° C oil bath temperature until the solvent was evaporated to dryness. The residue was cooled to room temperature under a nitrogen atmosphere, and the residue was redissolved in 1,2-dichloroethane (30 mL), followed by sodium tris(ethyloxy) borohydride (4.62 g, 21.8 mmol) and Acetic acid (0.87 g, 14.5 mmol) was reacted at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous sodium hydrogen sulfate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and evaporated. Separation and purification by hydrazine column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) gave white oily liquid 4a (1.3 g, yield 30.6%).

Step 2: (2R, 3S, 5R, 6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-yl)- 6-(Trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine (Compound 4)

(2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)-2-(2 ,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine

4a (1.3 g, 2.44 mmol) was dissolved in dichloromethane (7.8 mL) and trifluoroacetic acid (2.6 mL). After the reaction was completed, aq. EtOAc EtOAc. Separation and purification by hydrazine column chromatography (dichloromethane/methanol (v/v) = 30:1) gave white powdery solid compound 4 (700 mg, yield: 65%).

MS m/z (ESI): 485.0 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 7.97 (s, 1H), 7.58-7.53 (m, 2H), 4.78-4.74 (m, 1H), 4.47 (d, 1H), 3.98-3.91 (m, 2H), 3.81-3.73 (m, 2H), 3.49 (s, 3H), 3.46-3.43 (m, 1H), 2.99 (m, 1H) , 2.33 (m, 1H), 1.82 (q, 1H), 1.50 (s, 2H).

Example 5

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4 -c]pyrazole-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 5)

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5 (2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

First step: (R)-t-butyl 2-((tetrahydrofuran-3-yl)sulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5-formate (5a)

(R)-tert-butyl 2-((tetrahydrofuran-3-yl)sulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate

Anhydrous anaerobic treatment, nitrogen protection, intermediate 2 (1000 mg, 4.78 mmol) was dissolved in N,N-dimethylformamide (15 mL), cooled to -15 ° C, bis (trimethyl sulfonium) amino group was added Sodium (4.78 mL, 2 mol/L, 9.56 mmol) was stirred for 30 minutes, and S-tetrahydrofuran-3-sulfonium chloride (1.39 g, 8.13 mmol) was added dropwise to the reaction mixture, and the reaction was kept at this temperature for 16 hours. After the reaction was completed, the mixture was warmed to EtOAc (20 mL), EtOAc (EtOAc) , cooled to -10 ° C to 0 ° C. Potassium tert-butoxide (85 mg, 0.76 mmol) was added and the reaction was maintained at this temperature for 24 hours. After completion of the reaction, aq. EtOAc EtOAc (EtOAc) Purification by column chromatography over silica gel residue (petroleum ether / ethyl acetate (v / v) = 5: 1), to give a white solid 5a (810mg, 62.3% yield).

The second step: (R)-2-((tetrahydrofuran-3-yl)sulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (5b)

(R)-2-((tetrahydrofuran-3-yl)sulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

5a (400 mg, 1.17 mmol) was dissolved in a solution of hydrochloric acid in ethyl acetate (5 mL, 4 mol/L) and allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was allowed to stand, and the liquid was removed, and ethyl acetate was added and stirred for 1 minute, and the mixture was allowed to stand to remove the liquid. The residual solid column was purified by chromatography (dichloromethane/methanol (v/v) = 20:1, with a little aqueous ammonia) to afford a pale yellow solid 5b (210 mg, yield 74%).

Third step: tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)) Mercapto)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamic acid Ester (5c)

Tert-butyl((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c ]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

Intermediate 1 (271 mg, 0.686 mmol) and 5b (200 mg, 0.823 mmol) were added to toluene (5 mL), and the round bottom flask was reacted at a temperature of 140 ° C oil bath until the solvent was evaporated to dryness. The residue was cooled to room temperature under nitrogen atmosphere, dissolved in 1,2-dichloroethane (10 mL), and then sodium tris(ethyloxy) borohydride (580 mg, 2.744 mmol) and acetic acid (103 mg, 2.50 mmol), reacted at room temperature for 3 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc. Separation and purification by hydrazine column chromatography (petrole ether / ethyl acetate (v/v) = 5:1) afforded white foamy solid 5c (255 mg, yield 61%).

Step 4: (2R,3S,5R,6S)-2-(2,5-Difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo [3,4-c]pyrazole-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 5)

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5 (2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

5c (255 mg, 0.41 mmol) was dissolved in 6 mL of dichloromethane and 2 mL of trifluoroacetic acid and stirred at room temperature for 1 hour. After the reaction was completed, EtOAc EtOAc m. Separation and purification by hydrazine column chromatography (dichloromethane/methanol (v/v) = 50:1) gave white powdery solid compound 5 (175 mg, yield 82%).

MS m/z (ESI): 523.1 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 8.05 (s, 1H), 7.32-7.22 (m, 3H), 4.82-4.72 (m, 1H) ), 4.49 (m, 2H), 4.09 (ddd, 1H), 4.00-3.80 (m, 4H), 3.80-3.72 (m, 2H), 3.64 (dd, 1H), 3.49-3.42 (m, 1H), 3.00 (ddt, 1H), 2.36-2.28 (m, 1H), 2.23 (dt, 2H), 1.81 (dd, 1H).

Example 6

(2R,3S,5R,6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-yl)-2-( 2,5-Difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 6)

(2R,3S,5R,6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)- 6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-(cyclopentylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-formate (6a)

Tert-butyl 2-(cyclopentylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate

Anhydrous anaerobic treatment, nitrogen protection, intermediate 2 (1000 mg, 4.78 mmol) was dissolved in N,N-dimethylformamide (15 mL), cooled to -15 ° C, bis (trimethyl sulfonium) amino group was added Sodium (4.78 mL, 2 mol/L, 9.56 mmol) was stirred for 30 minutes, and S-cyclopentylsulfonyl group (1.37 g, 8.13 mmol) was added dropwise, and the reaction was maintained at -15 ° C for 16 hours. After the reaction was completed, the mixture was heated to EtOAc (EtOAc) (EtOAc) Re-dissolved in tetrahydrofuran (20 mL), cooled to -10 ° C to 0 ° C, and added potassium butoxide (85 mg, 0.76 mmol), and allowed to react at this temperature for 24 hours. After completion of the reaction, aq. EtOAc EtOAc (EtOAc) Purification by column chromatography over silica gel residue (petroleum ether / ethyl acetate (v / v) = 5: 1), to give a white solid 6a (800mg, 62% yield).

Second step: 2-(cyclopentylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (6b)

2-(cyclopentylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

6a (430 mg, 1.26 mmol) was dissolved in a solution of hydrochloric acid in ethyl acetate (8 mL, 4 mol/L) and allowed to react at room temperature for 1 hour. After the reaction was completed, it was allowed to stand to remove the liquid. Ethyl acetate was added and stirred for 1 minute, and allowed to stand to remove the liquid. Column chromatography and purification (dichloromethane/methanol (v/v) = 20:1, with a little aqueous ammonia) afforded pale yellow solid 6b (290mg, yield 95%).

The third step: the third butyl ((2R, 3S, 5R, 6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazole-5 (2H, 4H ,6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (6c)

Tert-butyl((2R,3S,5R,6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5 -difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

Intermediate 1 (327 mg, 0.828 mmol) and 6b (280 mg, 1.16 mmol) were added to toluene (8 mL), and the bottom-bottomed flask was reacted at 140 ° C oil bath temperature until solvent evaporated. The residue was cooled to room temperature under nitrogen atmosphere, dissolved in 1,2-dichloroethane (10 mL), and then sodium tris(ethyloxy) borohydride (700 mg, 3.31 mmol) and acetic acid (0.1 ml). , 1.82 mmol), and reacted at room temperature for 3 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc. Separation and purification by hydrazine column chromatography (petrole ether / ethyl acetate (v/v) = 5:1) gave white foamy solid 6c (210 mg, yield 41%).

Step 4: (2R, 3S, 5R, 6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-yl) -2-(2,5-Difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 6)

(2R,3S,5R,6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4 H,6H)-yl)-2-(2,5-difluorophenyl)-6-(trif1uoromethyl)tetrahydro-2H-pyran-3-amine

6c (210 mg, 0.34 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL). After the reaction was completed, EtOAc EtOAc m. Separation and purification by hydrazine column chromatography (dichloromethane/methanol (v/v) = 50:1) gave white powdery solid compound 6 (105 mg, yield 60%).

MS m/z (ESI): 521.1 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 8.00 (m, 1H), 7.34 - 7.19 (m, 3H), 4.81-4.70 (qd, 1H) ), 4.50 (d, 1H), 4.09 (m, 1H), 4.00-3.89 (m, 2H), 3.84 - 3.73 (m, 2H), 3.50-3.40 (m, 1H), 3.00 (td, 1H), 2.37-2.27 (m, 1H), 1.96-1.85 (m, 4H), 1.85-1.75 (m, 1H), 1.63-1.56 (m, 4H).

The ¹ H- ¹ H COSY, ¹ H- ¹ H NOESY and ¹ H- ¹ H J - analytical spectra of Compound 6 are shown in Figures 10-12, and the data are shown in Table 4, demonstrating the configuration of Compound 6 as shown in the following formula. :

* Read out according to 1H-1H J - analytical spectrum

** NH ₂ protons exchanged with water peaks

Example 7

(2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5 (2H ,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 7)

(2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)- 6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

First step: (2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole -5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 7)

(2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)- 6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

3d (400 mg, 0.7 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL). After the reaction was completed, the mixture was evaporated and evaporated. Separation and purification by hydrazine column chromatography (dichloromethane/methanol (v/v) = 30:1) gave white powder solid compound 7 (200 mg, yield 61%).

MS m / z (ESI): 467.0 [M + 1]; 1H NMR (400MHz, DMSO- d 6): δ 7.94 (s, 1H), 7.39-7.06 (m, 3H), 4.52-4.41 (m, 2H ), 4.07 (s, 2H), 4.01 (s, 2H), 3.49 (m, 4H), 3.28 (d, 1H), 2.48 (d, 1H), 1.75 (ddd, 1H), 1.38 (s, 2H) .

Biological test

Rat pharmacokinetic evaluation

Male SD rats (purchased from Vital River Laboratory Animal Technology Co. LTD, license number: 11400700005540) 200-240 g, fasted overnight. On the day of the experiment, 3 SD rats were intragastrically administered with 5 mg. Kg-1, 0.20 mL of blood was collected from the jugular vein before and 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after administration, and placed in EDTA tubes. After the blood samples were collected, acetonitrile containing an internal standard ( verapamil, 5.00 ng/mL and glibenclamide, 50.0 ng/mL) was added, and vigorously vortexed and centrifuged at 13,000 rpm for 10 min. The supernatant was taken for LC-MS/MS detection. The pharmacokinetic parameters were calculated using the non-compartmental model in Pharsight Phoenix 6.3. The experimental results are shown in Table 5.

Conclusion: The compounds of the present invention have higher maximum concentrations and exposures, longer half-lives, and smaller clearance rates in rats compared to the positive control (Omarigliptin).

2, oral glucose tolerance test

The hypoglycemic effect of the compounds of the present invention in mice was evaluated using an oral glucose tolerance test (OGTT). The animals used were C57 mice, eight weeks old, male, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the animal production certificate number: SCXK (Beijing) 2012-0001. Grouped according to the basic blood glucose values after fasting, 10 in each group. The test compound was formulated into a suspension of 1 mg/mL. The drug was administered by intragastric administration at a dose of 10 mg/kg. The blank control group was given a blank reagent. 50% after 60 minutes of administration A glucose aqueous solution (5 g/kg) was used to measure the blood glucose level of each mouse at 0 min, 15 min, 30 min, 45 min, 60 min, and 120 min, and the area under the drug-time curve (AUC) was calculated. The experimental results are shown in Table 6.

Conclusion: The compound of the present invention has a significant hypoglycemic effect, and the blood glucose can be significantly reduced after a single oral administration of the mouse.

3. Effect of single oral administration on DPP-IV enzyme activity in ob/ob mice

The test compound was formulated into a solution of 0.3 mg/mL, 1.0 mg/mL or 3.0 mg/mL with 0.5% CMC-Na. The ob/ob mice from the Shanghai Institute of Medicine were fasted for 16 hours in advance, and could not help but be watered. The next day, they were evenly divided into 5 groups according to their body weight. The test group was given different doses of the compound, and the control group was given a blank solvent at a volume of 10 mL/kg. Blood was then collected from the eyelids at 0h, 2h, 4h, 10h, 24h, 34h, 48h, 58h and 72h. After anti-coagulation of EDTA-2Na, 40 μl of plasma was taken, and 10 μl of AFC (0.2 mM) was added. After reacting for 15 min at room temperature, the DPP4 enzyme activity in plasma was measured by a microplate reader. The experimental results are shown in Table 7 and Figure 13.

Conclusion: After a single oral administration of ob/ob mice, Compound 3 has a more pronounced effect on inhibiting DPP-IV enzyme activity than the positive control Omarigliptin. At the same dose of compound 3 and the positive control Omarigliptin, the 80% inhibition rate of DPPIV enzyme activity was more than 3 times that of Omarigliptin; and the inhibition effect of DPP-IV enzyme activity was observed at the dose of compound 3 only for the positive control Omarigliptin 1/10. Still more obvious, with the potential for longer-lasting.

4. Rat plasma DPP-IV enzymatic screening experiment

The experimental animals were SD rats, 8 weeks old, male, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the animal production certificate number: SCXK (Beijing) 2012-0001. Rats after fasting were grouped by weight. The rats were given blood by eyelids, and the test compound was orally administered to the EDTA-2Na anticoagulation test group at a dose of 3.0 mg/kg; the control group was orally administered with a blank reagent. Blood was taken at different time points after administration. The blood sample was centrifuged at 2500 rpm for 15 min, and the plasma was taken out and stored at -20 °C. For enzyme activity test, 40 μl of plasma was taken from each sample, and 10 μl of H-Ala-Pro-AFC substrate (0.2 mM) was added. After 15 min of reaction, the value was measured with a microplate reader (excitation wavelength Excitation=405 nM; emission wavelength Emission=535 nM). ), using Origin 7.5 for statistical analysis, calculating the inhibition rate of test compound on plasma DPP-IV enzyme activity The duration of 70% is shown in Table 8.

Conclusion: The compound of the present invention can significantly inhibit the plasma DPPIV enzyme activity in rats, especially the inhibition rate of compound D on plasma DPP-IV enzyme activity. 70% lasted significantly longer than the control compound.

5, canine plasma DPP-IV enzyme screening experiment

The experimental animals were provided by the male beagle dog, Chengdu Dashuo Biotechnology Co., Ltd. The fasted Beagle dogs are grouped by weight. The test group was orally administered with a test compound at a dose of 10.0 mg/kg. Blood was taken at different time points after administration, and EDTA-2Na was anticoagulated. The blood sample was centrifuged at 2500 rpm for 15 min, and the plasma was taken out and stored at -20 °C. For enzyme activity test, 40 μl of plasma was taken from each sample, and 10 μl of H-Ala-Pro-AFC substrate (0.2 mM) was added. After 15 min of reaction, the value was measured with a microplate reader (excitation wavelength Excitation=405 nM; emission wavelength Emission=535 nM). ), using Origin 7.5 for statistical analysis, calculating the inhibition rate of test compound on plasma DPP-IV enzyme activity 80% of the duration, the results are shown in Table 9 below:

Conclusion: The compounds of the present invention inhibit the activity of DPPIV enzyme in dogs plasma significantly longer than the control compounds, and have a better long-term potential.

6. Monkey plasma DPP-IV enzymatic screening experiment

The experimental animals were rhesus monkeys of about 5 kg in healthy males, provided by Sichuan Plymei Biotechnology Co., Ltd. The fasting rhesus monkeys are grouped by weight. The test group was orally administered with a test compound at a dose of 10.0 mg/kg. Blood was taken at different time points after administration, and EDTA-2Na was anticoagulated. The blood sample was centrifuged at 2500 rpm for 15 min, and the plasma was taken out and stored at -20 °C. For enzyme activity test, 40 μl of plasma was taken from each sample, and 10 μl of H-Ala-Pro-AFC substrate (0.2 mM) was added. After 15 min of reaction, the value was measured with a microplate reader (excitation wavelength Excitation=405 nM; emission wavelength Emission=535 nM). ), using Origin 7.5 for statistical analysis, calculating the inhibition rate of test compound on plasma DPP-IV enzyme activity 80% of the duration. At the same time, the concentration of the compound in the plasma was measured by LC-MS/MS. The results are shown in Figure 14 and Table 10 below:

Conclusion: The once-oral administration of the compound of the present invention can inhibit the activity of DPPIV enzyme in monkey plasma for more than 11 days, and has a very good long-term potential.

Claims (14)

An aminopyran ring derivative represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: Where: V is selected from the following groups: Ar is a benzene ring substituted with 0 to 5 R ¹ groups; R ^{1 is} selected from H, F, Cl, Br, I or a hydroxyl group; R ^{2a is} selected from H, C _1-6 alkyl, C _3-6 naphthenic Or a 3- to 8-membered heterocycloalkyl group, wherein the alkyl, cycloalkyl or heterocycloalkyl group is further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF _2, -CF _3, hydroxy, C _1-4 alkyl or C _1-4 alkoxy substituents, a heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O or S (= O) An atom or group of ₂ ; R ^3a and R ^3b are each independently selected from H or C _1-2 alkyl, wherein said alkyl group is optionally further 0 to 3 selected from F, hydroxy or C _1-4 alkoxy Substituted by a substituent; R ^{4 is} selected from H or -S(=O) ₂ -R ⁸ ; R ^{8 is} selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, a 6 to 10 membered heteroaryl or a 3 to 8 membered heterocycloalkyl group, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted with 0 to 5 F, The heterocycloalkyl group contains 1 to 5 atoms or groups selected from N, O or S(=O) ₂ . An aminopyran ring derivative, a stereoisomer or a pharmaceutically acceptable salt thereof, of the formula (I) according to the first aspect of the patent application, wherein: Ar is selected from the group consisting of 2,5-difluorophenyl Or 2,4,5-trifluorophenyl; R ^{2a is} selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally further from 0 to 3 Substituted with a substituent selected from F, hydroxy, C _1-4 alkyl or C _1-4 alkoxy; R ^3a and R ^3b are each independently selected from H or C _1-2 alkyl, wherein said alkyl is Further selected by 0 to 3 substituents selected from F, hydroxy or C _1-4 alkoxy; R ⁴ is -S(=O) ₂ -R ⁸ ; R ^{8 is} selected from C _1-2 alkyl a 3 to 6 membered heterocycloalkyl or C _3-6 cycloalkyl group, wherein said alkyl group, heterocycloalkyl group or cycloalkyl group is optionally further substituted with 0 to 5 F, said heterocycloalkyl group Containing 1 to 3 atoms or groups selected from N, O or S(=O) ₂ . An aminopyran ring derivative of the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, according to the scope of claim 2, wherein: V is selected from the group consisting of . An aminopyran ring derivative, a stereoisomer or a pharmaceutically acceptable salt thereof, of the formula (I) according to the third aspect of the patent application, wherein: R ⁴ is -S(=O) ₂ - R ⁸ ; R ^{8 is} selected from C _1-2 alkyl, 4 to 6 membered heterocycloalkyl or C _3-6 cycloalkyl, wherein the alkyl, heterocycloalkyl or cycloalkyl group is optionally further Substituted to 5 F, the heterocycloalkyl group contains 1 to 3 atoms or groups selected from N, O or S(=O) ₂ . An aminopyran ring derivative, a stereoisomer or a pharmaceutically acceptable salt thereof, according to the formula (I) of claim 4, wherein R ^{8 is} selected from the group consisting of methyl, ethyl, , cyclopropyl, cyclobutyl or cyclopentyl. The aminopyran ring derivative represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of the items 1 to 5, wherein the aminopyridyl The anthracene derivative is selected from: An aminopyran ring derivative, a stereoisomer or a pharmaceutically acceptable salt thereof, according to the formula (I) of claim 6 wherein the aminopyran ring derivative is selected from the group consisting of: An aminopyran ring derivative, a stereoisomer or a pharmaceutically acceptable salt thereof, according to the formula (I) of claim 7, wherein the aminopyran ring derivative is selected from the group consisting of: An aminopyran ring derivative, a stereoisomer or a pharmaceutically acceptable salt thereof, of the formula (I) according to the first aspect of the invention, wherein the aminopyran ring derivative is selected from the group consisting of: An aminopyran ring derivative, a stereoisomer or a pharmaceutically acceptable salt thereof, according to the formula (I) of claim 9 wherein the aminopyran ring derivative is selected from the group consisting of: A pharmaceutical composition comprising: an effective amount of an aminopyran ring derivative represented by the formula (I) according to any one of claims 1 to 10 of the patent application, A construct or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient. An aminopyran ring derivative represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, or the application patent item 11 Use of the composition in the preparation of a dipeptidyl peptidase-IV inhibitor. The use according to the application of claim 12, wherein the dipeptidyl peptidase-IV inhibitor is used for the preparation of a medicament for treating a metabolic disease, wherein the metabolic diseases include: diabetes, diabetic retinopathy , diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated fatty acid or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications , atherosclerosis or high blood pressure. According to the application of claim 13, wherein the diabetes is type II diabetes.