TWI659031B - Pyrroloimidazole ring derivatives and their application in medicine - Google Patents

Abstract

The present invention relates to a pyrroloimidazole ring derivative and its use in medicine, in particular, a pyrrolomidazole ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof , prodrugs, pharmaceutical compositions containing the derivatives, and pharmaceutical uses in the preparation of dipeptidyl peptidase IV (DPP-IV) inhibitors,

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

Description

Pyrroloimidazole ring derivatives and their application in medicine

The present invention relates to a pyrroloimidazole ring derivative and its use in medicine, in particular to a pyrrolomidazole ring derivative of the formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof and the same 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 beta cells, which can improve beta cell function, including promoting glucose-dependent insulin secretion, inducing beta cell proliferation, and enhancing anti-apoptotic effects (Diabetes and Vascular Disease Research 2006 3: 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, including sitar DPP-IV inhibitors such as statin, saxagliptin and alogliptin have been approved for marketing and are in 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 the side effects of many hypoglycemic agents. 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 by 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 main object of the present invention is to provide a novel class of DPP-IV inhibitors, in particular, compounds having the formula (I), which have been shown to have good dipeptidyl peptidase IV (DPP). -IV) inhibitory activity and/or selectivity, with Prospects for treating or ameliorating type 2 diabetes and similar diseases.

The present invention relates to a pyrroloimidazole 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 the group consisting of H, cyano, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _m -C _3-15 cycloalkyl, -(CH ₂ ) _m -3 to 15 membered heterocyclic group, -(CH ₂ ) _m -C _6-10 aryl, -(CH ₂ ) _m -5 to 10 membered heteroaryl, -(CH ₂ ) _m -C ( =O)-R ⁶ , -(CH ₂ ) _m -NR ⁷ R ⁸ , -(CH ₂ ) _m -C(=O)-NR ⁷ R ⁸ , -(CH ₂ ) _m -OC(=O)- NR ⁷ R ⁸ , -(CH ₂ ) _m -S(=O) _n -R ⁹ , -(CH ₂ ) _m -NR ¹⁰ -S(=O) _n -R ⁹ , -(CH ₂ ) _m -NR ¹⁰ -C(=O)-NR ⁷ R ⁸ or -(CH ₂ ) _m -NR ¹⁰ -C(=O)-R ⁶ , wherein the CH ₂ , alkyl, alkenyl, alkynyl, cycloalkyl Or a heterocyclic group, an aryl group or a heteroaryl group, optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, cyano, C _1- Substituted by a substituent of a _4- alkyl or C _1-4 alkoxy group containing from 1 to 5 atoms or groups selected from N, O or S(=O) _n ; ^{2 is} selected from the group consisting of 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 heterocyclic group, -(CH ₂ ) _m -C _6-10 aryl, -(CH ₂ ) _m -5 to 10 member heteroaryl, -(CH ₂ ) _m -C(=O)-R ⁶ , -(CH ₂ ) _m -OC(=O)-R ⁶ , -(CH ₂ ) _m -NR ⁷ R ⁸ , -(CH ₂ ) _m -C(=O) -NR ⁷ R ⁸ , -(CH ₂ ) _m -OC(=O)-NR ⁷ R ⁸ , -(CH ₂ ) _m -S(=O) _n -R ⁹ , -(CH ₂ ) _m -NR ¹⁰ -S(=O) _n -R ⁹ , -(CH ₂ ) _m -NR ¹⁰ -C(=O)-NR ⁷ R ⁸ , -(CH ₂ ) _m -NR ¹⁰ -C(=O)-R ⁶ Or -(CH ₂ ) _m -P(=O) _n R ¹¹ R ¹² , preferably H, F, Cl, Br, I, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy , C _2-4 alkenyl, C _2-4 alkynyl, -(CH ₂ ) _m -3 membered cycloalkyl, -(CH ₂ ) _m -4 membered cycloalkyl, -(CH ₂ ) _m -5 Cycloalkyl, -(CH ₂ ) _m -6 membered cycloalkyl, -(CH ₂ ) _m -7 membered cycloalkyl, -(CH ₂ ) _m -8 membered cycloalkyl, -(CH ₂ ) _m -9 membered cycloalkyl, -(CH ₂ ) _m -10 membered cycloalkyl, -(CH ₂ ) _m -3 membered heterocyclic group, -(CH ₂ ) _m -4 membered heterocyclic group, -(CH _{2 M-} 5 membered heterocyclic group, -(CH ₂ ) _m -6 membered heterocyclic group, -(CH ₂ ) _m -7 membered heterocyclic group, -(CH ₂ ) _m -9 membered heterocyclic group, -( CH ₂ ) _m -10 membered heterocyclic group, -(CH ₂ ) _m -phenyl, -(CH ₂ ) _m -5 membered heteroaryl, -(CH ₂ ) _{m -} 6 membered heteroaryl, -(CH _{2) m} -7-membered heteroaryl, - (CH _{2) m} -8-membered heteroaryl, - (CH _{2) m} -9-membered heteroaryl, - (CH _{2) m} -10 membered _{Aryl, - (CH 2) m -C} (= O) -R 6, - (CH 2) m -OC (= O) -R 6, - (CH 2) m -C (= O) -NR 7 R ⁸ or -(CH ₂ ) _m -S(=O) _n -R ⁹ , wherein the CH ₂ , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or The heteroaryl group is optionally further substituted with 0 to 3 C _1-8 alkyl groups selected from F, Cl, Br, I, hydroxy, cyano, =0, substituted with 0 to 3 F, and 0 to 3 F Substituted C _3-10 cycloalkyl, substituted by 0 to 3 F substituted 3 to 10 membered heterocyclic or C _1-4 alkoxy, said heterocyclic or heteroaryl containing 1 Up to 5 atoms or groups selected from N, O or S(=O) _n are preferably CH ₂ , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl or heterocyclic groups. Or an aryl or heteroaryl group optionally further consisting of 0 to 3 C _1-4 alkyl groups selected from F, Cl, Br, I, hydroxy, hydroxy, cyano, substituted with 0 to 3 F, and 0 to Substituted by three F-substituted C _3-8 cycloalkyl groups, substituted by 0 to 3 F substituted 3 to 6 membered heterocyclic groups or C _1-3 alkoxy groups, said heterocyclic group or heteroaryl group group containing 1 to 5 heteroatoms selected from N, O or S (= O) _n is an atom or group; optionally, R ¹ and R ² atom to which they are attached, a Form R ^{3 is} selected from H, F, Cl, Br or I, preferably H or F, further preferably H; R ⁴ and R ⁵ are each independently selected from H, F, Cl, Br, I or C _{1- An} alkyl group, which is optionally further substituted with from 0 to 5 substituents selected from F, Cl or a hydroxyl group; preferably, R ⁴ and R ⁵ are each independently selected from the group consisting of H, F, Cl, Br, I or -CF ₃ ; further preferably R ⁴ and R ⁵ are each independently selected from H, -CF ₃ or F; with the proviso that when R ⁴ and R ^{5 are} simultaneously selected from H, R ² cannot be -CF ₃ R ⁶ are each independently selected from H, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _3-15 cycloalkyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -OC _3-15 cycloalkyl, -OC _6-10 aryl or -O- (5 to 10 membered heteroaryl); R ⁷ , R ⁸ and R ¹⁰ are each independently selected from H, C _1-8 alkane a C _3-15 cycloalkyl group, a C _6-10 aryl group, a 5 to 10 membered heteroaryl group or a 3 to 15 membered heterocyclic group; preferably R ⁷ and R ⁸ are each independently selected from H, C _{1 -4} alkyl or C _3-10 cycloalkyl, further preferably R ⁷ and R ⁸ are each independently selected from H, C _1-2 alkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 member 6-membered heterocyclic group or a heterocyclic group; optionally, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, a 3- to 10-membered heterocyclic group, preferably a 3- to 6-membered heterocyclic group, further preferably a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group. The heterocyclic group contains 1 to 5 atoms or groups selected from N, O or S(=O) _n , wherein the heterocyclic group is optionally further further 0 to 3 F, Cl, Br, I, hydroxy, C _C1-8 alkyl, = O or an amino group substituted with a substituent, preferably a heterocyclyl group is further substituted with = O or 0-3 F, Cl, hydroxy, C _1-4 alkyl group substituted; R ⁹ each Independently selected from C _1-8 alkyl, C _3-15 cycloalkyl, C _6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered heterocyclic; preferably C _1-8 alkane a group, a C _3-10 cycloalkyl group or a 3 to 10 membered heterocyclic group, further preferably a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a 3-membered heterocyclic group, a 4-membered heterocyclic group, 5 a heterocyclic group or a 6 membered heterocyclic group; R ¹¹ and R ¹² are each independently selected from a hydroxy group, a C _1-8 alkyl group or a C _1-8 alkoxy group; and optionally, R ¹¹ and R ¹² are attached thereto. The phosphorus atoms together form a 5 to 10 membered heterocyclic group containing 1 to 5 atoms or groups selected from N, O, P or S(=O) _n , wherein the heterocyclic group is optionally further 0 to 3 F, Cl, Br, I Substituted with a substituent of a hydroxyl group, =O or an amino group; m is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0; and r is selected from 0, 1 or 2, preferably 0 or 1, Further preferably, 1; n is selected from 0, 1, or 2, preferably 1 or 2, and further preferably 2.

Preferred embodiments of the present invention include a pyrroloimidazole 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 the group consisting of H and cyanide. , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -(CH ₂ ) _m -C _3-10 cycloalkyl, -(CH ₂ ) _m -3 to 10 member Ring group, -(CH ₂ ) _m -5 to 10 membered heteroaryl, -(CH ₂ ) _m -C(=O)-R ⁶ , -(CH ₂ ) _m -C(=O)-NR ⁷ R ⁸ or -(CH ₂ ) _m -S(=O) _n -R ⁹ , preferably R ^{1 is} selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, - (CH ₂ ) _m -3 membered cycloalkyl, -(CH ₂ ) _m -4 membered cycloalkyl, -(CH ₂ ) _m -5 membered cycloalkyl, -(CH ₂ ) _{m -} 6 membered cycloalkyl , -(CH ₂ ) _m -7 membered cycloalkyl, -(CH ₂ ) _m -8 membered cycloalkyl, -(CH ₂ ) _m -3 membered heterocyclic group, -(CH ₂ ) _m -4 Cyclo, -(CH ₂ ) _m -5 membered heterocyclic group, -(CH ₂ ) _m -6 membered heterocyclic group, -(CH ₂ ) _m -7 membered heterocyclic group, -(CH ₂ ) _m -8 Heterocyclyl, -(CH ₂ ) _m -5 membered heteroaryl, -(CH ₂ ) _m -6 membered heteroaryl, -(CH ₂ ) _m -6 membered heteroaryl, -(CH ₂ ) _m -8 membered heteroaryl, -(CH ₂ ) _m - 9 membered heteroaryl, -(CH ₂ ) _m -10 membered heteroaryl or -(CH ₂ ) _m -S(=O) _n -R ⁹ , among them Said CH _2, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is further optionally substituted with 0 to 3 substituents selected from F, Cl, Br, I, -CH 2 F, -CHF 2 Substituted with a substituent of -CF ₃ , hydroxy, cyano, C _1-2 alkyl or C _1-2 alkoxy, said heterocyclic or heteroaryl containing from 1 to 5 selected from N, O or An atom or group of S(=O) _n , preferably a heterocyclic group containing 1 to 3 atoms or groups selected from N, O or S(=O) _n ; R ^{2 is} selected from H, F, Cl , Br, I, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, -(CH ₂ ) _m -C _3-10 Cycloalkyl, -(CH ₂ ) _m -3 to 10 membered heterocyclic, -(CH ₂ ) _m -phenyl, -(CH ₂ ) _m -5 to 10 membered heteroaryl, -(CH ₂ ) _m -C(=O)-R ⁶ , -(CH ₂ ) _m -OC(=O)-R ⁶ , -(CH ₂ ) _m -C(=O)-NR ⁷ R ⁸ or -(CH ₂ ) _m -S(=O) _n -R ⁹ , preferably R ^{2 is} selected from the group consisting of H, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkynyl, -(CH ₂ ) _m -3 Cycloalkyl, -(CH ₂ ) _m -4 membered cycloalkyl, -(CH ₂ ) _m -5 membered cycloalkyl, -(CH ₂ ) _m -6 membered cycloalkyl, -(CH ₂ ) _m -7 membered cycloalkyl, -(CH ₂ ) _m- 8 membered cycloalkyl, -(CH ₂ ) _m -3 membered heterocyclic group, -(CH ₂ ) _m -4 membered heterocyclic group , -(CH ₂ ) _m -5 membered heterocyclic group, -(CH ₂ ) _m -6 membered heterocyclic group, -(CH ₂ ) _m -7 membered heterocyclic group, -(CH ₂ ) _m -8 Cyclic group, -(CH ₂ ) _m -5 membered heteroaryl, -(CH ₂ ) _m -6 membered heteroaryl, -(CH ₂ ) _m -6 membered heteroaryl, -(CH ₂ ) _m -8 Heteroaryl, -(CH ₂ ) _m - 9 membered heteroaryl, -(CH ₂ ) _m -10 membered heteroaryl, -(CH ₂ ) _m -C(=O)-R ⁶ , -(CH ₂ ) _m -OC(=O)-R ⁶ , -(CH ₂ ) _m -C(=O)-NR ⁷ R ⁸ or -(CH ₂ ) _m -S(=O) _n -R ⁹ , wherein Said CH ₂ , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy a substituent of a hydroxyl group, a cyano group, a =0, a C _1-4 alkyl group substituted by 0 to 3 F, a C _3-8 cycloalkyl group substituted by 0 to 3 F or a C _1-3 alkoxy group Substituted, the heterocyclic or heteroaryl group contains 1 to 5 atoms or groups selected from N, O or S(=O) _n , preferably the heterocyclic or heteroaryl group contains 1 to 3 atoms or groups selected from N, O or S(=O) _n ; optionally, R ¹ and R ² together with the atoms to which they are attached R ^{3 is} selected from H or F; R ⁴ and R ⁵ are each independently selected from H, F or -CF ₃ ; preferably R ^{4 is} selected from H or F, and R ^{5 is} selected from H or -CF ₃ ; When R ⁴ and R ^{5 are} simultaneously selected from H, R ^{2 may} not be -CF ₃ ; R ^{6 is} each independently selected from H, hydroxy, C _1-4 alkyl or C _1-6 alkoxy; preferably H , hydroxy, C _1-4 alkyl or C _1-4 alkoxy; R ⁷ and R ⁸ are each independently selected from H, C _1-4 alkyl or C _3-10 cycloalkyl, preferably R ⁷ And R ⁸ are each independently selected from H, C _1-2 alkyl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic or 6-membered heterocyclic; as appropriate, R ⁷ and R ⁸ are The nitrogen atoms to which they are bonded together form a 3- to 6-membered heterocyclic group, preferably a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group, and the heterocyclic group contains 1 Up to 3 atoms or groups selected from N, O or S(=O) _n wherein the heterocyclic group is optionally further 0 to 3 F, Cl, hydroxy, C _1-4 alkyl, amino, =0 or a -CF ₃ substituents; R ⁹ is independently selected from C _1-8 alkyl, C _3-10 cycloalkyl or 3-10 heterocyclyl group, preferably a C _1-6 alkyl group, C _3-6 cycloalkyl, heterocyclyl 3, 4 heterocyclyl, 5 or 6-membered heterocyclic group heteroaryl m is selected from 0, 1 or 2; r is selected from 0, 1 or 2, preferably 0 or 1, further preferably 1; n is selected from 0, 1 or 2, preferably n is selected from 1 or 2.

Preferred embodiments of the present invention include a pyrroloimidazole 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 the group consisting of H and C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -(CH ₂ ) _m -C _3-8 cycloalkyl, -(CH ₂ ) _m -3 to 8 membered heterocyclic group, -(CH ₂ ) _m -5 to 10 membered heteroaryl, -(CH ₂ ) _m -C(=O)-R ⁶ or -(CH ₂ ) _m -S(=O) _n -R ⁹ , wherein Said CH ₂ , alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl or heterocyclic group optionally further from 0 to 3 selected from the group consisting of F, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxyl Substituted with a substituent of a cyano group, a C _1-2 alkyl group or a C _1-2 alkoxy group containing from 1 to 3 selected from N, O or S(=O) _n Atom or group; R ^{2 is} selected from H, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkynyl, -(CH ₂ ) _m -C _3-8 naphthenic , -(CH ₂ ) _m -3 to 8 membered heterocyclic group, -(CH ₂ ) _m -5 to 10 membered heteroaryl, -(CH ₂ ) _m -C(=O)-R ⁶ , -( CH ₂ ) _m -OC(=O)-R ⁶ , -(CH ₂ ) _m -C(=O)-NR ⁷ R ⁸ or -(CH ₂ ) _m -S(=O) _n -R ⁹ , wherein the CH _2, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heteroaryl Or heterocyclyl optionally further substituted by 0 to 3 substituents selected from F, hydroxy, cyano, = O, substituted with 0-3 F C _1-3 alkyl, substituted with 0-3 F C _3- Substituted by a substituent of an ₈ -cycloalkyl or C _1-3 alkoxy group containing from 1 to 4 atoms or groups selected from N, O or S(=O) _n ; Depending on the case, R ¹ and R ² together with the atoms to which they are attached R ^{3 is} selected from H or F, preferably H; R ⁴ and R ⁵ are each independently selected from H, F or -CF ₃ ; preferably R ^{4 is} selected from H or F, and R ^{5 is} selected from H or -CF. _3; more preferably R ⁴ is selected from H, R ⁵ is selected from H or -CF _3, then R ⁵ is selected from H Jia; with the proviso that when R ⁴ and when R ⁵ is selected from H, R ² is not - CF ₃ ; R ⁶ are each independently selected from H, hydroxy, C _1-4 alkyl or C _1-4 alkoxy, preferably hydroxy or C _1-2 alkoxy; R ⁷ and R ⁸ are each independently selected From H, C _1-3 alkyl or C _3-10 cycloalkyl, preferably H, C _1-3 alkyl or C _3-6 cycloalkyl; optionally, R ⁷ and R ⁸ are attached thereto The nitrogen atom together form a 3- to 6-membered heterocyclic group, preferably a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group, and the heterocyclic group contains 1 to 3 An atom or group selected from N, O or S(=O) _n wherein the heterocyclic group is optionally further substituted by 0 to 3 F, Cl, hydroxy, methyl, ethyl, =0 or -CF ₃ Substituted; R ^{9 is} each independently selected from C _1-6 alkyl, C _3-7 cycloalkyl or 3 to 6 membered heterocyclic, preferably C _1-4 alkyl, C _3-6 naphthenic a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group; m is selected from 0 or 1 Preferably, it is 0; r is selected from 0 or 1, further preferably 1; n is selected from 1 or 2, preferably 2.

Preferred embodiments of the present invention include a pyrroloimidazole 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 the group consisting of H and A Base, ethyl, -CHF ₂ , -CF ₃ , isopropyl, tert-butyl, 2-hydroxyethyl, 2-hydroxypropyl, vinyl, propenyl, n-butenyl, 2-butenyl , ethynyl, propynyl, n-butynyl, 2-butynyl, cyclopropyl, cyclobutyl, cyclopentyl, methylsulfonyl, ethylsulfonyl, cyclopropylsulfonyl, , , R ^{2 is} selected from the group consisting of H, cyano, methyl, ethyl, 1-hydroxyethyl, 1-fluoroethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, cyclopropyl , cyclobutyl, methylsulfonyl, methylsulfinyl, ethylsulfonyl, cyclopropylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, -CH ₂ F , -CHF ₂ , -CH ₂ OH, -CH ₂ OCOCH ₃ , Depending on the case, R ¹ and R ² together with the atoms to which they are attached , , R ^{3 is} selected from H or F; R ^{4 is} selected from H or F; R ^{5 is} selected from H or -CF ₃ ; R ¹⁴ and R ¹⁵ are each independently selected from H, C _1-4 alkyl or 1 to 5 F Substituted C _1-4 alkyl; q is selected from 0, 1, 2, 3 or 4.

Preferred embodiments of the present invention include a pyrroloimidazole 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 the group consisting of H and methyl. , ethyl, -CHF ₂ , -CF ₃ , isopropyl, tert-butyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-butynyl, cyclopropyl, methylsulfonyl, B Sulfosyl, cyclopropylsulfonyl, , , , , , , , or ; preferably H, methyl, ethyl, methylsulfonyl or R ^{2 is} selected from the group consisting of H, cyano, methyl, ethyl, 1-hydroxyethyl, 1-fluoroethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, cyclopropyl , cyclobutyl, methylsulfonyl, methylsulfinyl, ethylsulfonyl, cyclopropylsulfonyl, isopropylsulfonyl, -CH ₂ F, -CHF ₂ , -CH ₂ OH, -CH ₂ OCOCH ₃ , , , or Preferred is cyano, methyl, ethoxy, cyclopropyl, methylsulfonyl, methylsulfinyl, cyclopropylsulfonyl, , , , , , Depending on the case, R ¹ and R ² together with the atoms to which they are attached , , , or Preferred or R ³ is H; R ⁴ is H, and R ^{5 is} selected from H or -CF ₃ , and preferably R ⁵ is H.

In a preferred embodiment of the invention, the compounds include, but are not limited to:

The present invention relates to an intermediate for synthesizing a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof as shown in the following formula (II) or Its stereoisomers:

among them: Is a single bond or a double bond, preferably a double bond; R ^{1 is} selected from the group consisting of H, methyl, ethyl, -CH ₂ F, -CHF ₂ , -CF ₃ , isopropyl, tert-butyl, cyclopropyl , 2-butynyl, methylsulfonyl, , , , R ^{2 is} selected from the group consisting of H, -CH ₂ F, -CHF ₂ , -CHFCH ₃ , -CH ₂ OH, -CH(OH)CH ₃ , methoxy, ethoxy, cyano, cyclopropyl, isopropyl , tert-butyl, -CH ₂ OCOCH ₃ , -C(=O)-R ⁶ , -S(=O) _n -R ⁹ , -C(=O)-NR ⁷ R ⁸ , , , , Depending on the case, R ¹ and R ² together with the atoms to which they are attached Q is selected from H or an amino protecting group; R ^{6 is} selected from H, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _3-15 cycloalkyl, C _6-10 aryl, 5 to 10 a heteroaryl group, -OC _3-15 cycloalkyl, -OC _6-10 aryl or -O- (5 to 10 membered heteroaryl); R ⁷ and R ⁸ are each independently selected from H, C _{1- 8-} alkyl, C _3-15 cycloalkyl, C _6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered heterocyclic; optionally, R ⁷ and R ⁸ and the nitrogen atom to which they are attached Forming together a 3 to 10 membered heterocyclic group containing 1 to 5 atoms or groups selected from N, O or S(=O) _n wherein the heterocyclic group is optionally further 0 to 3 Substituted with a substituent of F, Cl, Br, I, hydroxy, C _1-8 alkyl, =0 or amino; R ^{9 is} selected from C _1-8 alkyl, C _3-15 cycloalkyl, C _6-10 aryl a 5- to 10-membered heteroaryl group or a 3- to 15-membered heterocyclic group; provided that the formula (II) is not n is selected from 0, 1 or 2; r is selected from 0, 1 or 2; q is selected from 0, 1, 2, 3 or 4; R ¹⁴ and R ¹⁵ are each independently selected from C _1-4 alkyl, C _{3- 6} cycloalkyl or C _1-4 alkyl substituted by 1 to 5 F.

In a preferred embodiment of the present invention, the pyrrolimidazole ring derivative represented by the formula (I) represented by the formula (II) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof is synthesized. An intermediate or a stereoisomer thereof, wherein: Is a double bond; R ^{1 is} selected from the group consisting of H, methyl, ethyl, -CF ₃ , isopropyl, -CH ₂ F, -CHF ₂ , methylsulfonyl, or ; R ^{2 is} selected from -CH ₂ F, -CHF ₂ , -CHFCH ₃ , -CH ₂ OH, -CH(OH)CH ₃ , methoxy, ethoxy, cyano, cyclopropyl, isopropyl, Third butyl, -CH ₂ OCOCH ₃ , -C(=O)-R ⁶ , -S(=O) _n -R ⁹ , -C(=O)-NR ⁷ R ⁸ , , , , , Depending on the case, R ¹ and R ² together with the atoms to which they are attached or ;Q is selected from H, a third butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl or benzyloxycarbonyl; R ^{6 is} selected from H, hydroxy, C _1-6 alkyl, C _1-6 alkoxy Or a C _3-10 cycloalkyl group; R ⁷ and R ⁸ are each independently selected from H, C _1-6 alkyl or C _3-10 cycloalkyl; optionally, R ⁷ and R ⁸ are attached to the nitrogen to which they are attached The atoms together form a 3 to 10 membered heterocyclic group containing 1 to 5 atoms or groups selected from N, O or S(=O) _n , wherein the heterocyclic group is optionally further 0 to 3 Substituted with a substituent of F, Cl, hydroxy, C _1-4 alkyl, =0 or amino; R ^{9 is} selected from C _1-6 alkyl or C _3-10 cycloalkyl; provided that formula (II) Not for n is selected from 0, 1, or 2.

In a preferred embodiment of the present invention, the pyrrolimidazole ring derivative represented by the formula (I) represented by the formula (II) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof is synthesized. An intermediate or a stereoisomer thereof, selected from the group consisting of:

Q is selected from the group consisting of H, a third butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl group or a benzyloxycarbonyl group.

The present invention also relates to a synthesis of a pyrrolomidazole ring derivative represented by the general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof as represented by the following formula (II-B) Or its stereoisomer:

Wherein: R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined above; P is an amino protecting group.

In a preferred embodiment of the present invention, the pyrroloimidazole ring derivative represented by the formula (I) represented by the formula (II-B) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof An intermediate or a stereoisomer thereof, wherein: R ^{1 is} selected from the group consisting of H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -(CH ₂ ) _m -C _3-8 Cycloalkyl, -(CH ₂ ) _m -3 to 8 membered heterocyclic, -(CH ₂ ) _m -5 to 10 membered heteroaryl, -(CH ₂ ) _m -C(=O)-R ⁶ or -(CH ₂ ) _m -S(=O) _n -R ⁹ , wherein the CH ₂ , alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl or heterocyclic group is optionally further 0 to 3 Substituted by a substituent selected from the group consisting of F, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, cyano, C _1-2 alkyl or C _1-2 alkoxy, said heterocyclic group or hetero The aryl group contains 1 to 3 atoms or groups selected from N, O or S(=O) _n ; R ^{2 is} selected from H, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkynyl, -(CH ₂ ) _m -C _3-8 cycloalkyl, -(CH ₂ ) _m -3 to 8 membered heterocyclic group, -(CH ₂ ) _m -5 to 10 membered heteroaryl , -(CH ₂ ) _m -C(=O)-R ⁶ , -(CH ₂ ) _m -C(=O)-NR ⁷ R ⁸ , -(CH ₂ ) _m -OC(=O)-R ⁶ or _{- (CH 2) m -S (} = O) n -R 9, wherein the CH _2, alkyl , Alkoxy, alkynyl, cycloalkyl, heteroaryl or heterocyclyl group is optionally further substituted 0-3 selected from F, hydroxy, cyano, = O, substituted with 0-3 F, C _{1- a 3-} alkyl group substituted with 0 to 3 F-substituted C _3-8 cycloalkyl groups or a C _1-3 alkoxy group having 1 to 4 selected from N An atom or group of O or S(=O) _n ; optionally, R ¹ and R ² together with the atom to which they are attached R ³ is selected from H; R ⁴ and R ⁵ are each independently selected from H, F, or -CF _3; with the proviso that when R ⁴ and R ⁵ are selected from H, R ² is not -CF _3; R ⁶ is selected from From H, hydroxy, C _1-4 alkyl or C _1-4 alkoxy; R ⁷ and R ⁸ are each independently selected from H, C _1-3 alkyl or C _3-10 cycloalkyl; optionally, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a 3 to 6 membered heterocyclic group containing 1 to 3 atoms or groups selected from N, O or S(=O) _n , wherein The heterocyclic group is optionally further substituted with 0 to 3 substituents of F, Cl, hydroxy, methyl, ethyl, =0 or -CF ₃ ; R ^{9 is} selected from C _1-6 alkyl, C _3-7 ring An alkyl group or a 3 to 6 membered heterocyclic group; m is selected from 0 or 1; r is selected from 0 or 1; and n is selected from 0, 1 or 2, preferably 1 or 2.

The invention further relates to a process for the preparation of a pyrrolomidazole ring derivative intermediate of the formula (II), the process comprising:

Compound (II-A1) of the general formula (II-A2), to give the compound of formula (II-A3); the formula (II-A3) oxidation reaction of general formula (II-A4); formula (the II- A4) with R ¹ -X ¹ occurs alkylation or acylation reaction to give a compound of formula (II-A5); the formula (II-A5) hydrolysis reaction to give a compound of formula (II-A6); formula (II -A6 ) a condensation reaction of the compound to give a compound of the formula (II); as the case may be,

The general formula ( II-A4 ) is hydrolyzed to obtain a compound of the formula ( II-A7 ); the compound of the formula ( II-A7 ) is subjected to a condensation reaction to obtain a compound of the formula ( II-A8 ); the formula ( II-A8 ) and R Alkylation or deuteration of ¹ -X ¹ gives a compound of formula ( II ); as the case may be,

The aminolysis reaction of the formula ( II-A5 ) gives the compound of the formula ( II ); as the case may be,

The aminolysis reaction of the formula ( II-A4 ) gives a compound of the formula ( II-A8 ); wherein: R ^{2a is} selected from H or C _1-8 alkyl; R ^{2b is} selected from C _1-8 alkoxy, - SC _1-8 alkyl or -NR ⁷ R ⁸ ; R ^{1 is} selected from H, methyl, ethyl, -CH ₂ F, -CHF ₂ , -CF ₃ , isopropyl, tert-butyl, cyclopropyl , 2-butynyl, methylsulfonyl, , , , R ^{2 is} selected from -C(=O)-NR ⁷ R ⁸ ; R ⁷ and R ⁸ are each independently selected from H, C _1-8 alkyl, C _3-15 cycloalkyl, C _6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered heterocyclic group; optionally, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclic group containing 1 to 5 An atom or group selected from N, O or S(=O) _n wherein the heterocyclic group is optionally further substituted by 0 to 3 F, Cl, Br, I, hydroxy, C _1-8 alkyl, =0 Or a substituent of an amino group; Q is an amino protecting group; n is selected from 0, 1 or 2; and X ¹ is a leaving group, preferably a halogen.

In a preferred embodiment of the present invention, there is provided a process for preparing a pyrrolomidazole ring derivative intermediate of the formula (II), wherein: R ^{1 is} selected from the group consisting of H, methyl, ethyl, -CH ₂ F, - CHF ₂ , -CF ₃ , isopropyl, tert-butyl, cyclopropyl, 2-butynyl, methylsulfonyl or R ^{2 is} selected from -C(=O)-NR ⁷ R ⁸ ; R ⁷ and R ⁸ are each independently selected from H, methyl, ethyl, isopropyl or tert-butyl; optionally, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a five-membered heterocyclic or six-membered heterocyclic group; Q is a third butoxycarbonyl group; and X ^{1 is} selected from I, Cl, Br or F.

The present invention relates to a process for the preparation of a pyrrolomidazole ring derivative intermediate of the formula (II), which comprises: Compound ( II-A1 ) and carbon disulfide or The reaction gives the compound ( II-B2 ), the compound ( II-B2 ) is alkylated to obtain the compound ( II-B3 ), and the compound ( II-B3 ) is oxidized to obtain the compound ( II-B4 ), the compound ( II-B4 ). Oxidation reaction gives compound ( II-B5 ), and compound ( II-B5 ) undergoes alkylation or oximation to give compound ( II ); wherein: R ¹ , R ⁹ , n are as defined above; R ^{2 is} selected From -S(=O) _n -R ⁹ ; Q is an amino protecting group; L ¹ is a leaving group.

In a preferred embodiment of the present invention, a process for preparing a pyrrolomidazole ring derivative intermediate of the formula (II), wherein: R ^{1 is} selected from H, C _1-4 alkyl or 1 to 3 F Substituted C _1-4 alkyl; R ^{2 is} selected from -S(=O) _n -R ⁹ ; Q is selected from the group consisting of a third butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group or a 9-fluorenylmethoxycarbonyl group; R ^{9 is} selected from C _1-4 alkyl or -C _3-10 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further substituted with 0 to 3 F; n is selected from 0, 1 or 2, Preferably, L ^{1 is} selected from the group consisting of F, Cl, Br, I or imidazolyl.

The present invention relates to an intermediate for synthesizing a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof as shown in the following formula (III) or Its stereoisomers:

Wherein: R ^{3 is} selected from H, F, Cl, Br or I; and P is an amino protecting group.

The present invention relates to a process for the preparation of a synthetic pyrrolomidazole ring derivative intermediate of the formula (III), which comprises:

The compound of the formula ( IA-9 ) is reacted with a secondary amine compound NHR ²⁰ R ²¹ to give a compound of the formula ( IA-10 ); a compound of the formula ( IA-10 ) and S-(trifluoromethyl)dibenzothiophene The trifluoromethylsulfonate is reacted to give the formula (III); wherein: R ^{3 is} selected from H, F, Cl, Br or I; P is an amino protecting group; and R ²⁰ and R ²¹ are each independently selected from H or C _{1 -8} alkyl; as the case, R ²⁰ and R ²¹ form a 5- to 8-membered heterocycloalkyl group with a bonded nitrogen atom, and the heterocycloalkyl group contains 1 to 3 selected from N, O or -S (=O) ) _n hetero atom or group; n-is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, a method for synthesizing a pyrrolomidazole ring derivative intermediate represented by the formula (III), wherein: R ^{3 is} selected from H or F; and P is selected from the group consisting of a third butoxycarbonyl group, Benzyloxycarbonyl, benzyl or 9-fluorenylmethoxycarbonyl; R ²⁰ and R ²¹ form a morpholine ring with the attached nitrogen atom.

The present invention relates to a process for the preparation of a pyrroloimidazole ring derivative of the formula (I), which comprises:

Reductive amination of a compound of the formula ( IA ) with a compound of the formula ( II-C ) to give a compound of the formula ( II-B ); a compound of the formula ( II-B ) is deprotected to give a compound of the formula ( I); wherein: R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined above; P is an amino protecting group.

The present invention relates to a process for the preparation of a pyrroloimidazole ring derivative of the formula (I), which comprises:

Reductive amination of a compound of the formula ( IA ) with a compound of the formula ( II-A9 ) to give a compound of the formula ( II-B' ); alkylation of the formula ( II-B' ) with R ¹ -X ¹ Or a deuteration reaction to obtain a compound of the formula ( II-B ); the compound of the formula ( II-B ) is deprotected to give a compound of the formula (I); wherein: R ¹ , R ² , R ³ , R ⁴ and The definition of R ^{5 is} as defined above; X ^{1 is} selected from a leaving group, preferably a halogen; and P is an amino protecting group.

In a preferred embodiment of the present invention, there is provided a method of producing a pyrrolomidazole ring derivative of the formula (I), wherein: R ^{1 is} selected from the group consisting of H, C _1-8 alkyl, and substituted by 0 to 3 F C _1-8 alkyl or -S(=O) _n -R ⁹ ; R ^{2 is} selected from H, cyano, C _1-8 alkyl, -C _3-15 cycloalkyl, 3 to 15 membered heterocyclic ring , -C _6-10 aryl, 5 to 10 membered heteroaryl, -C(=O)-R ⁶ , -C(=O)-NR ⁷ R ⁸ or -S(=O) _n -R ⁹ Wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from 0 to 3 C _1-2 alkyl groups selected from F, Cl or substituted by 0 to 3 F Substituted by a substituent, the heterocyclic or heteroaryl group contains 1 to 5 atoms or groups selected from N, O or S(=O) _n ; R ^{3 is} selected from H or F; and R ^{4 is} selected from H R ^{5 is} selected from H or -CF ₃ ; R ^{6 is} selected from H, hydroxy, C _1-8 alkyl or C _1-8 alkoxy; R ⁷ and R ⁸ are each independently selected from H or C _1-8 Alkyl; R ^{9 is} selected from C _1-8 alkyl or C _3-15 cycloalkyl; n is selected from 0, 1 or 2, preferably 2; P is selected from the group consisting of a third butoxycarbonyl group, a benzyloxycarbonyl group, Benzyl or 9-fluorenylmethoxycarbonyl.

The present invention relates to a process for the preparation of a pyrroloimidazole ring derivative of the formula (I), which comprises:

The compound of the formula ( II-D ) is hydrolyzed to obtain a compound of the formula ( II-E ); the condensation of the formula ( II-E ) is carried out to obtain a compound of the formula ( II-F ); and the formula ( II-F ) is removed. Amino protecting group provides a compound of formula (I); as the case, formula ( II-F ) is obtained by aminolysis of formula ( II-D ):

Wherein: R ² is -C(=O)-NR ⁷ R ⁸ ; R ¹ , R ⁷ , R ^{8 are} as defined above; R ^{3 is} selected from H or F; R ⁴ is H; and R ^{5 is} selected from H Or -CF ₃ ; R ¹³ is a C _1-8 alkoxy group; P is an amino protecting group.

The present invention also relates to a pharmaceutical composition comprising: an effective amount of a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer thereof, pharmaceutically An acceptable salt or prodrug, or further comprising one or more additional therapeutic agents; and a pharmaceutically acceptable carrier or excipient.

The present invention also relates to a method for treating a metabolic disease, which comprises administering to a subject an effective amount of the pyrroloimidazole ring derivative represented by the above formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or A prodrug or a pharmaceutical composition, wherein the metabolic diseases include diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or glycerol content High, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension. In a specific embodiment of the invention, the diabetes is Type II diabetes.

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, wherein The dipeptidyl peptidase-IV inhibitor is for use in the preparation of a medicament for treating a metabolic disease, wherein the metabolic disease is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, Hyperglycemia, hyperinsulinemia, elevated fatty acid or glycerol levels, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension. In a specific embodiment of the 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 referred to in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the related groups and compounds of 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 chain 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-methyl Hexyl, 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-dimethyl Hexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl 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, heterocyclic, bridged, snail Cyclo, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -(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 -ene -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, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonate Base, optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.

"Alkoxy" means an -O-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Tributoxy, second butoxy, n-pentyloxy, n-hexyloxy 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, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -(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 , cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"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, heterocyclyl, bridged, spiro, cyclo Base, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -(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 is R ^c is independently selected from the group comprising H, a hydroxyl group, an amino group, a carbonyl group, an alkoxy , Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl sulfonic, trifluoromethane sulfonic acyl, optionally, R ^b and R ^c may form a five or six membered ring or a heteroaryl group Ring base. 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Alkenyl" means an alkyl group as defined herein above containing 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-pentyl Alkenyl, 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, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -( 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, ring Alkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Alkynyl" means an alkyl group, as defined herein above, comprising at least one carbon-carbon triple bond, preferably having 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-heptynyl , 3-octynyl, 3-decynyl, 4-nonynyl, 3-undynyl and 4-dodecynyl, etc.; when substituted, the substituent is preferably one or more of the following groups 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, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -(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), aryl Thio, 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 And a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and optionally, R ^b and R ^c may form a five- or six-membered cycloalkyl group or a heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo 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, Mercaptan, hydroxy, thiol, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, Aldehyde, carboxylic acid, formate, -(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 -alkyne a group -R ^a (wherein m, n is 0, 1 or 2), an arylthio group, a thiocarbonyl group, a decyl group 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, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as the case, R ^b and R ^c can form five or six members Cycloalkyl or heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo 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.

"Carboxylate" refers to a ^{-C (= O) -OR d,} R d is selected from alkyl, cycloalkyl, or heterocyclyl group.

"Haloalkyl" means a halogen-substituted alkyl group as defined herein above, and non-limiting examples include monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromo. Methyl, 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 monocyclic cyclic hydrocarbon 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, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, (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 a group such as 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, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Heterocyclyl" means substituted or unsubstituted saturated or unsaturated and contains at least 1 to 5 non-aromatic rings selected from N, O, P or S heteroatoms, and the non-aromatic ring may be 3 to 10 members. Monocyclic, 4 to 20 membered spiro, ac or bridged, optionally substituted N, S in the heterocyclyl ring can be oxidized to various oxidation states. It is preferably a 3- to 12-membered heterocyclic ring. Non-limiting examples include oxiranyl, oxetanyl, oxearyl, oxetan, oxacyclooctyl, aziridine, azetidinyl, azacyclocycle Pentyl, azacyclohexyl, azacyclopropenyl, 1,3 dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclohexyl, 1,3-dithiocyclohexyl , azacycloheptenyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxadienyl, or 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, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, (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 a group such as 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, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo 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: , , , , with . 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, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, (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 a group such as 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, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Paracyclic" refers to a polycyclic group in which each ring of the system shares a pyridyl pair of carbon atoms with other rings in the reaction system, wherein one or more of the rings may contain zero or more double bonds, and It may be substituted or unsubstituted, and each ring in the ring reaction system may contain 0 to 5 hetero atoms 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, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, (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 a group such as 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, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo 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 reaction system may Containing 0 to 5 heteroatoms or groups selected from N, S(=O) _n or O (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, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, (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 a group such as 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, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic 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, -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, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising: , , , with . 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, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, (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 a group such as 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, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic 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, Acridinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, decyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include , , , , , , with . 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, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, (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 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, alkane Oxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic 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 heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo 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.

"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 depend 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, granulation. Agents, lubricants, binders and disintegrants.

"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 an amino group, a hydroxyl group in the compound, which can be removed by conventional procedures or in vivo to give the parent compound. When the prodrug of the present invention is administered In a mammalian individual, the prodrug is cleaved to form a free amino or hydroxyl group, respectively.

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.

This article The ring may contain one or more double bonds to form an aromatic ring.

This article Indicates that a ring atom is substituted with one or more R substituents.

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

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

"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. "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 compound of the formula (IA ) is subjected to reductive amination with a compound of the formula ( II-C ) to give a compound of the formula ( II-B ); the compound of the formula ( II-B ) is deprotected to give a compound of the formula ( I); wherein: R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined above; P is an amino protecting group.

Reductive amination of a compound of the formula ( IA ) with a compound of the formula ( II-A9 ) to give a compound of the formula ( II-B' ); alkylation of the formula ( II-B' ) with R ¹ -X ¹ Or a deuteration reaction to obtain a compound of the formula ( II-B ); the compound of the formula ( II-B ) is deprotected to give a compound of the formula (I); wherein: R ¹ , R ² , R ³ , R ⁴ and The definition of R ^{5 is} as defined above; X ^{1 is} selected from a leaving group, preferably a halogen; and P is an amino protecting group.

third solution:

The compound of the formula ( II-D ) is hydrolyzed to obtain a compound of the formula ( II-E ); the condensation of the formula ( II-E ) is carried out to obtain a compound of the formula ( II-F ); and the formula ( II-F ) is removed. Amino protecting group provides a compound of formula (I); formula (II-F) is obtained by aminolysis of formula (II-D):

Wherein: R ² is -C(=O)-NR ⁷ R ⁸ ; R ¹ , R ⁷ , R ^{8 are} as defined above; R ^{3 is} selected from H or F; R ⁴ is H; and R ^{5 is} selected from H Or -CF ₃ ; R ¹³ is a C _1-8 alkoxy group; P is an amino protecting group.

When both R ⁴ and R ⁵ are H, the intermediate IA is prepared by reference to the documents WO2010056708 and US2007232676, the method of which is described as follows:

Wherein R ¹ , R ² and R ³ 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) ).

When R ⁴ is H and R ^{5 is} not H, the intermediate IA can be prepared as follows:

The compound of the formula ( IA-9 ) is reacted with the secondary amine compound NHR ²⁰ R ²¹ to give a compound of the formula ( IA-10 ); the formula ( IA-10 ) and S-(trifluoromethyl)dibenzothiophene III The fluoromethylsulfonate is reacted to give the formula (III); wherein: R ^{3 is} selected from H, F, Cl, Br or I; P is an amino protecting group such as a third butoxycarbonyl group (Boc), a benzyloxy group. a carbonyl group (Cbz) or a 9-fluorenylmethoxycarbonyl group (Fmoc); each of R ²⁰ and R ^{21 is} independently selected from H or a C _1-8 alkyl group; and, as the case may be, R ²⁰ and R ²¹ form a 5 with a bonded nitrogen atom. To an 8-membered heterocycloalkyl group, the heterocycloalkyl group contains 1 to 3 hetero atoms or groups selected from N, O or -S(=O) _n ; n is selected from 0, 1 or 2.

The compound of the present invention The compound of the formula (II) can be produced as follows:

(1) When R ² is -C(=O)-NR ⁷ R ⁸ :

Compound (II-A1) of the general formula (II-A2), to give the compound of formula (II-A3); the formula (II-A3) oxidation reaction of general formula (II-A4); formula (the II- A4) with R ¹ -X1 occurred alkylation or acylation reaction to give a compound of formula (II-A5); the formula (II-A5) hydrolysis reaction to give a compound of formula (II-A6); formula (the II- A6 ) the compound is subjected to a condensation reaction to obtain a compound of the formula (II), or the formula ( II-A5 ) is subjected to an aminolysis reaction to obtain a compound of the formula (II); or:

The general formula ( II-A4 ) is hydrolyzed to obtain a compound of the formula ( II-A7 ); the compound of the formula ( II-A7 ) is subjected to a condensation reaction to obtain a compound of the formula ( II-A8 ); the formula ( II-A8 ) and R Alkylation or deuteration of ¹ -X ¹ to give a compound of the formula (II), or a solution of the formula ( II-A4 ) to give a compound of the formula ( II-A8 ); wherein: R ^{2a is} selected from H Or C _1-8 alkyl; R ^{2b is} selected from C _1-8 alkoxy, -SC _1-8 alkyl or -NR ⁷ R ⁸ ; R ^{1 is} selected from H, ethyl, -CH ₂ F, -CHF ₂ , -CF ₃ , isopropyl, tert-butyl, cyclopropyl, 2-butynyl, methylsulfonyl, , , , , , R ⁷ and R ⁸ are each independently selected from H, C _1-8 alkyl, C _3-15 cycloalkyl, C _6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered heterocyclic; Depending on the case, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclic group containing from 1 to 5 atoms selected from N, O or S(=O) _n or a group wherein the heterocyclic group is optionally further substituted with 0 to 3 substituents of F, Cl, Br, I, hydroxy, C _1-8 alkyl, =0 or amino; Q is an amino protecting group; X ¹ is The leaving group is preferably a halogen.

(2) When R ² is -(CH ₂ ) _m -S(=O) _n -R ⁹ and m=0:

Compound ( II-B1 ) with carbon disulfide or The reaction gives the compound ( II-B2 ); the compound ( II-B2 ) undergoes alkylation to give the compound ( II-B3 ); the compound ( II-B3 ) undergoes oxidation to give the compound ( II-B4 ); the compound ( II-B4) Oxidation reaction gives compound ( II-B5 ); compound ( II-B5 ) undergoes alkylation or oximation to give compound (II); wherein: R ¹ , R ⁹ , n are as defined above; R ^{2 is} selected From -S(=O) _n -R ⁹ ; Q is an amino protecting group; L ¹ is a leaving group.

The embodiments of the present invention and the beneficial effects thereof are described in detail below by way of specific examples, which are intended to provide a better understanding of the nature and characteristics of the present invention.

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. It is tetramethyl decane (TMS). 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, methyl tert-butyl ether, tetrabutylammonium bromide, sodium hydride, triphenylphosphine, trifluoroacetic acid were purchased from Chengdu Kelon Chemical Reagent Factory; dibutyl phthalate, B Ethyl acetimidate hydrochloride, trimethyl orthoformate, N, N'-dicarbonyldiimidazole, N,O-dimethylhydroxylamine hydrochloride purchased from Ester (Chengdu) Pharmaceutical Technology Co., Ltd.;铯, N-hydroxybutanediimide, NN-diisopropylethylamine, diphenylmethylene glycine ethyl ester purchased from Anike Chemical; ethyl cyanoformate, 2,5-difluorobromide Benzene, m-chloroperoxybenzoic acid was purchased from Shanghai Demer Pharmaceutical Technology Co., Ltd.; isopropylmagnesium chloride / lithium chloride tetrahydrofuran solution was purchased from Belling Technology Co., Ltd.; propargyl benzene sulfonate, tris(ethoxy) Sodium borohydride and tetrabutylammonium hexafluorophosphate were purchased from Adamas Reagent; cyclopentadienyl bis(triphenylphosphine) ruthenium chloride (II) was purchased from ACROS orgainics; borane dimethyl sulfide was purchased from Suiyuan Chemical Technology (Shanghai) Co., Ltd.; benzenesulfonic acid and sodium perborate purchased from Tianjin Guangfu Fine Chemical Research Institute; [(R,R)-N-(2-amino-1,2-diphenylethyl) Fluorobenzenesulfonamide] Chlorinated (dilose hydrocarbon) 钌 (II) was purchased from Strem chemical; methyl iodide was purchased from Sinopharm Pharmaceutical Co., Ltd.; 1,1'-thiocarbonyldiimidazole was purchased in Shanghai. Pharmaceutical Technology Co., Ltd.; hexafluoroisopropanol Nanjing Kangmanlin Chemical Industry Co., Ltd.

The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume. 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 room temperature is 20 ° C ~ 30 ° C. Meaning of abbreviated group: Et: ethyl; Ac: ethyl hydrazide; Me: methyl; Boc: third butoxycarbonyl; TBTU: O-benzotriazole-N, N, N', N'- Tetramethylurea tetrafluoroboric acid; SO ₃ H: sulfonic acid group.

Intermediate 1: tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate ( intermediate) 1 )

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

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

Ethyl 2-aminopent-4-ynoate

Dibenzylidene 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) Tetrabutylammonium bromide (6.1 g, 0.019 mol) was added to the reaction liquid, and the temperature was raised to 50 ° C, and cesium carbonate (121.8 g, 0.374 mol) was added thereto, and the mixture was reacted 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, and spin-dried to give a yellow oily liquid 1C (33g, 83% yield).

MS m/z (ESI): 212.0 [MH ⁺ ].

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+H ⁺ ].

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+H ⁺ ].

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 (时), ruthenium (II) (ie RuCl(p-cymene)(R,R)-FSDPEN) (0.37g, 0.52mmol), added dropwise toluene (14.27g) , 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+Na ⁺ ].

The sixth step: the third 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)carbam Ate

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+H ⁺ ].

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+H ⁺ ].

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

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

1H (11.53 g, 35.03 mmol) was dissolved in dichloromethane (130 mL), cooled to 0 ° C, and Dess-Martin oxidant (29.72 g, 70.06 mmol) was added portionwise to the reaction mixture, and naturally. The reaction was carried out for 4 hours at room temperature. 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 Intermediate 1 (10.85 g, yield 94.7%).

MS m/z (ESI): 272.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.29-7.13 (m, 4H), 4.77-4.75 (d, 1H), 4.12 (d, 2H), 4.08-4.02 (m, 1H), 2.75-2.70 (m, 2H), 1.23 (s, 9H).

Intermediate 2 : tert-butyl 3,4-diaminopyrrolidinyl-1-carboxylate hydrochloride ( Intermediate 2 )

Tert-butyl 3,4-diaminopyrrolidine-1-carboxylate

First step: tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate ( 2B )

Tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

N-tert-butoxycarbonyl-pyrroline ( 2A ) (100 g, 0.59 mol) was dissolved in dichloromethane (600 mL), and m-chloroperoxybenzoic acid (198.70 g, 0.88 mol) was added portionwise at room temperature Stir for 17 hours. The reaction solution was slowly added to a 17% sodium thiosulfate solution (46.64 g, 0.29 mol), stirred well, filtered over celite, and the filtrate was separated and the aqueous phase was extracted with dichloromethane (400 mL×3) The combined organic phases were washed with saturated potassium carbonate solution (500mL × 1), saturated sodium chloride solution (1000mL × 1), dried organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a yellow oil 2B , used directly in the next step.

MS m/z (ESI): 208.1 [M+Na ⁺ ].

Second step: tert-butyl 3-azido-4-hydroxypyrrolidinyl-1-carboxylate ( 2C )

Tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate

2B (109.32 g, 0.59 mol) was dissolved in a mixed solvent of dioxane (800 mL) and water (260 mL), sodium azide (115.24 g, 1.77 mol) was added, and the mixture was heated to 105 ° C to reflux for 60 hours. The reaction solution was cooled to room temperature, and a saturated sodium chloride solution (3000 mL) was added, and the aqueous phase was extracted with dichloromethane (2000 mL × 4). Oil 2C was used directly in the next step.

MS m/z (ESI): 2521. [M+Na ⁺ ].

The third step: tert-butyl 3-azido-4-((methylsulfonyl)oxy)pyrrolidinyl-1-carboxylate ( 2D )

Tert-butyl 3-azido-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

2C (134.72 g, 0.59 mol) was dissolved in dichloromethane (3400 mL) under a nitrogen atmosphere, cooled to 0 ° C, and then triethylamine (89.70 g, 0.88 mol) and methylsulfonium chloride (87.99 g, 0.76) were sequentially added. Mol), after the addition, naturally rose to room temperature for 17 hours. The reaction was washed with saturated sodium chloride solution (1500mL × 3) washing the organic phase with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a yellow oil 2D, was used directly in the next step.

MS m/z (ESI): 207.1 [M+H ⁺ ].

Fourth step: tert-butyl 3,4-diazidopyrrolidinyl-1-carboxylate ( 2E )

Tert-butyl 3,4-diazidopyrrolidine-1-carboxylate

2D (181.02 g, 0.59 mol) was dissolved in N'N-dimethylformamide (3370 mL), sodium azide (115.23 g, 1.77 mol) was added, and the mixture was heated to 90 ° C and stirred for 60 hours. Water (12L) was added to the reaction mixture, extracted with methyl tert-butyl ether (2000mL × 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a brown oil 2E, direct Used in the next step.

MS m/z (ESI): 276 [M+Na ⁺ ].

Step 5: Tert-butyl 3,4-diaminopyrrolidinyl-1-carboxylate hydrochloride ( Intermediate 2 )

Tert-butyl 3,4-diaminopyrrolidine-1-carboxylate hydrochloride

2E (130 g, 0.51 mol) was dissolved in toluene (2340 mL), triphenylphosphine (404.32 g, 1.54 mol) was added, and the mixture was heated to 115 ° C for 1 hour, cooled to room temperature, and tetrahydrofuran (468 mL) and water (65 mL) were added. ), reflux for 17 hours. Water (600 mL) was added to the reaction mixture, and the mixture was cooled with ice-cooled, and the mixture was adjusted to pH 5 with dilute hydrochloric acid (1 mol/L), ethyl acetate (500 mL×3), and the aqueous phase was concentrated under reduced pressure to give a white powder. Intermediate 2 (85.0 g, yield 69.6%).

MS m/z (ESI): 146.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 5.71 (brs, 4H), 3.54 (d, 4H), 3.22-3.20 (s, 2H), 1.40 (s, 9H).

Intermediate 3 : tert-butyl 3,4-diaminopyrrolidinyl-1-carboxylate ( intermediate 3 )

Tert-butyl 3,4-diaminopyrrolidine-1-carboxylate

2E (50g, 0.19mol) was dissolved in methanol (500ml) at room temperature, replaced three times in a nitrogen atmosphere, palladium carbon (5g, 10%) was added, three times of hydrogen was replaced, and the temperature was raised to 40 ° C in a hydrogen atmosphere. hour. Diatomaceous earth filtration, the filtrate was concentrated under reduced pressure to give an orange oil Intermediate 3 (32.32g, yield 81.3%).

MS m/z (ESI): 146.1 [M+H ⁺ ].

Intermediate 4 : tert-butyl 4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate (intermediate 4)

Tert-butyl 4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

First step: tert-butyl 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 4A )

Tert-butyl 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

The compound intermediate 3 (11 g, 54.7 mmol) was dissolved in hexafluoroisopropanol (54.7 mL), and trimethyl orthoformate (5.8 g, 54.7 mmol) was added with stirring, and the mixture was stirred at 34 ° C for 64 hours. The reaction mixture was concentrated, purified by silica gel column chromatography separation (dichloromethane / methanol (v / v) = 10: 1, adding a small amount of ammonia), to give a brown oil 4A (11g, 95.6% yield).

MS m/z (ESI): 21.21. [M+H ⁺ ].

Second step: tert-butyl 4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate (intermediate 4)

Tert-butyl 4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

The grass chloroform (2.85 g, 22.5 mmoL) was dissolved in dry dichloromethane (15 mL), cooled to -78 ° C with dry ice acetone bath, and dried dimethyl hydrazide (3.284 g, 42 mmoL) was added dropwise with stirring. , continue to stir for 30 minutes. 4A (2.11g, 10mmoL) of dichloromethane (5mL) solution was added dropwise to the reaction solution, stirring was continued for 20 minutes, triethylamine (10.1g, 100mmoL) was added dropwise at -78 °C, and naturally stirred to room temperature. Reaction for 2 hours. Saturated ammonium chloride solution (50 mL), saturated sodium chloride solution (50 mL) and dichloromethane (50 mL) were successively added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (50 mL×3). It was washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane/methanol (v/v) = 30:1, with a small amount of aqueous ammonia). Intermediate 4 in brown solid (700 mg, yield 33.4%).

MS m/z (ESI): 210.3 [M+H ⁺ ].

Intermediate 5 : 5-t-butyl 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate ( Intermediate 5 )

5-tert-butyl 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

First step: 2-ethoxy-2-iminoethyl acetate hydrochloride ( 5B )

Ethyl 2-ethoxy-2-iminoacetate hydrochloride

Ethyl cyanoacetate ( 5A ) (9.9 g, 0.1 mol) was dissolved in dry diethyl ether (50 mL), and dry anhydrous ethanol (5.52 g, 0.12 mol) was added until saturated (by weight of the reaction system 5g) and stirring was continued for 2 hours, the precipitated white solid was filtered, the filter cake was washed, dried over anhydrous ether (20mL × 3) in vacuo to give a white solid 5B (14g, 77% yield).

Second step: 5-t-butyl 2-ethyl 3a, 4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate ( 5C )

5-tert-butyl 2-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

Intermediate 2 (980 mg, 4.126 mmol) was dissolved in hexafluoroisopropanol (10 mL), and 5B (886 mg, 4.538 mmol) was added with stirring, and stirred at 50 ° C for 16 hours. The reaction solution was concentrated to dryness, and brine (50 mL) was added, and the pH was adjusted to 2 to 3 with dilute hydrochloric acid, and ethyl acetate (50 mL×2). The aqueous phase was collected, and the pH was adjusted to 7~8 with saturated sodium hydrogen carbonate solution, extracted with ethyl acetate (50 mL×4), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. Methyl chloride/methanol (v/v) = 20:1) gave a white solid 5C (700mg, yield 60%).

MS m/z (ESI): 284.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.64 (S, 2H), 4.37-4.33 (q, 2H), 3.72-3.69 (d, 2H), 3.55-3.50 (dd, 2H), 1.44 (s, 9H), 1.40-1.37 (t, 3H).

Third step: 5-t-butyl 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate ( intermediate 5 )

(2R,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate

The grass chloroform (652.5 mg, 5.14 mmoL) was dissolved in dry dichloromethane (15 mL), cooled to -78 ° C with a dry ice acetone bath, and dried dimethyl hydrazine (803.96 mg, 10.29mmoL) was added dropwise with stirring. ), stirring for 30 minutes. A 5C (970 mg, 3.43 mmol) of dichloromethane (5 mL) solution was added dropwise to the mixture and stirring was continued for 20 min. Diisopropylethylamine (2.216 g, 17.15 mmol) was added dropwise at -78 ° C, and naturally allowed to react to room temperature for 2 hours. A saturated ammonium chloride solution (50 mL), a saturated sodium chloride solution (50 mL), and dichloromethane (50 mL) were added to the mixture, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (50 mL×3). Washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography ( petroleum ether / ethyl acetate = 1:1) to give white solid intermediate 5 (520 mg, yield Rate 54%).

MS m/z (ESI): 282.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.54 (s, 2H), 4.47 (s, 2H), 4.46-4.41 (q, 2H) , 1.51 (s, 9H), 1.44-1.41 (t, 3H).

Intermediate 6 : tert-butyl 2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate ( Intermediate 6 )

Tert-butyl 2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

First step: tert-butyl 2-thiohexahydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 6A )

Tert-butyl 2-thioxohexahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 3 (3 g, 15 mmol) was dissolved in dichloromethane (30 mL) at room temperature, then cooled to 0 ° C, and 1,1'-thiocarbonyldiimidazole (2.67 g, 15 mmol) was slowly added dropwise. A solution of methyl chloride (30 mL) was kept at 0 ° C for 2 hours. Dichloromethane (300 mL) was added to the mixture, and the mixture was evaporated. Was added diethyl ether (100 mL), dried by suction filtration to give a white solid 6A (2.24g, yield 61.5%).

MS m / z (ESI): 244.2 [M + H +].

Second step: tert-butyl 2-(methylthio)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-formate ( 6B )

Tert-butyl 2-(methylthio)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)- Carboxylate

6A (2.21 g, 9.10 mmol) was dissolved in ethanol (150 mL) at room temperature, and the mixture was warmed to 35 ° C, and methyl iodide (1.93 g, 13.7 mmol) was quickly added and reacted for 2 hours. The reaction mixture was concentrated to give EtOAc (EtOAc:EtOAc:EtOAc. dichloromethane (300mL × 3). the combined organic phases were washed with saturated aqueous sodium chloride (100mL × 1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 6B (3.40g, yield 97.1%) .

MS m/z (ESI): 258.3 [M+H ⁺ ].

The third step: tert-butyl 2-(methylthio)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 6C )

Tert-butyl 2-(methylthio)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

The grass chloroform (1.24 g, 9.80 mmol) was dissolved in dichloromethane (10 mL) at room temperature under a nitrogen atmosphere. The mixture was cooled to -78 ° C, and dimethyl hydrazide dissolved in dichloromethane (20 mL) was slowly added dropwise. (1.53 g, 19.6 mmol), and the reaction was maintained at -78 ° C for 30 minutes. A 6B (1.26 g, 4.90 mmol) solution of dichloromethane (20 mL) was slowly added dropwise and the mixture was stirred at -78 ° C for 15 min. Triethylamine (4.95 g, 49.0 mmol) was added to the reaction liquid, and the mixture was allowed to react to room temperature for 3 hours. Dichloromethane (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), and the organic layer was washed with saturated aqueous brine (50 mL×1) and dried over anhydrous sodium sulfate. Separation and purification (dichloromethane/methanol (v/v) = 20:1, a small amount of aqueous ammonia) to afford brown solid 6C (0.67 g, yield 53.6%).

MS m/z (ESI): 256.3 [M+H ⁺ ].

Fourth step: tert-butyl 2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( intermediate 6 )

Tert-butyl 2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

6C (0.57 g, 2.23 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and m-chloroperoxybenzoic acid (0.771 g, 4.46 mmol) was added, and the mixture was allowed to react at room temperature for 12 hours. The reaction mixture was diluted with saturated sodium thiosulfate (10 mL), and the mixture was evaporated. pH was adjusted to 7, liquid separation, the organic phase was washed with saturated saline solution (50mL × 1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 6 (0.389g, 60.8% yield) as a yellow solid intermediate.

MS m/z (ESI): 288.2 [M+H ⁺ ].

Intermediate 7: 2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( Intermediate 7 )

2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

First step: tert-butyl 2-methyl-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 7A )

Tert-butyl 2-methyl-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 2 (2 g, 8.4 mmol) was dissolved in ethanol (100 mL) and ethyl acetonitrile hydrochloride (1.56 g, 12.6 mmol), and refluxed at 80 ° C for 1 hour. The reaction mixture was dried with EtOAc (EtOAc)EtOAc. The aqueous layer was separated, and the mixture was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The filtrate was concentrated to give 7A (2.3 g).

MS m/z (ESI): 226.3 [M+H ⁺ ].

Second step: tert-butyl 2-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 7B )

Tert-butyl 2-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

The grass chloroform (0.749 g, 5.9 mmol) was dissolved in dichloromethane (10 mL) at room temperature under nitrogen, cooled to -78 ° C, and dimethyl ether dissolved in dichloromethane (10 mL) was slowly added dropwise. Azolla (0.914 g, 11.7 mmol) was stirred and kept at -78 ° C for 30 minutes. 7A (1g, 3.9mmol) of dichloromethane (10mL) was added dropwise, and stirred at -78 °C for 15 minutes, N,N-diisopropylethylamine (2.5 g, 9.5 mmol) was added dropwise. The reaction was naturally raised to room temperature for 3 hours. Dichloromethane (300 mL) was added to the reaction mixture, and the mixture was diluted with EtOAc (EtOAc) (EtOAc) Concentration by pressure gave a white solid 7B (1.0 g).

MS m/z (ESI): 224.2 [M+H ⁺ ].

The third step: 2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( intermediate 7 )

2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

7B (1 g, 4.46 mmol) and benzenesulfonic acid 1.5 H ₂ O (1.23 g, 6.7 mmol) were dissolved in dichloromethane (20 mL). The reaction solution was concentrated under reduced pressure to give Intermediate 7 (l.

MS m/z (ESI): 124.2 [M+H ⁺ ].

Intermediate 8: tert-butyl 2-cyano-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate (Intermediate 8)

Tert-butyl 2-cyano-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

First step: 5-t-butyl 2-ethyl 1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate ( 8A )

5-tert-butyl 2-ethyl 1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

Intermediate 5 (5.4 g, 19.2 mmol) was dissolved in N,N-dimethylformamide (110 mL), potassium carbonate (3.3 g, 23.9 mmol) was added, and iodine methane (3.4 g, 23.9) MmoL), the reaction was carried out for 2 hours at room temperature, and a saturated ammonium chloride solution (300 mL) and a saturated sodium chloride solution (200 mL) were added to the mixture, and extracted with ethyl acetate (200 mL×3). Wash with sodium chloride solution (200 mL x 3). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid 8A (5.3g, 94% yield).

Second step: tert-butyl 2-carbamimidyl-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 8B )

Tert-butyl 2-carbamoyl-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

8A (2.3 g, 7.8 mmol) was dissolved in an ammonia-methanol solution (40 mL, 7 mol/L, 280 mmol), and the mixture was warmed to 85 ° C and the mixture was stirred for 20 hours. The reaction was cooled to room temperature, filtered, the filter cake was washed combined filtrate was concentrated and the cake was washed with ethyl acetate (10mL × 3), to give a white solid 8B (1.914g, 93% yield).

Third step: tert-butyl 2-cyano-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate (intermediate 8)

Tert-butyl 2-cyano-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

8B (1.576 g, 5.925 mmol) was dissolved in N,N-dimethylformamide (45 mL), phosphorus pentachloride (1.482 g, 7.109 mmol) was added, and the mixture was heated to 50 ° C for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL), saturated sodium chloride solution (150 mL) was added and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). (50 mL × 3), a saturated sodium hydrogencarbonate solution (50 mL × 2), and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give white solid intermediate 8 (1.25 g, yield 85%).

Intermediate 9 : 3-bromopropyl acetate ( Intermediate 9 )

3-bromopropyl acetate

3-Bromopropanol was dissolved in dichloromethane (150 mL) at room temperature, and then triethylamine (14.5 g, 14.4 mmol), acetic anhydride (14.7 g, 14.4 mmol) was added, and the reaction was carried out at room temperature. 12 hours. Saturated sodium bicarbonate solution (100 mL) was added dropwise to the reaction mixture until no bubble production, liquid separation, and the organic phase was adjusted to pH 7 with 0.5 mol/L dilute hydrochloric acid solution (20 mL), and the organic phase was separated again, and the organic phase was saturated. saline solution (100mL × 1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to give 9 (11.4g, yield 87%) as a yellow liquid intermediate.

MS m/z (ESI): 183.1 [M+H ⁺ ].

Example 1

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-d]imidazole-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 1 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H -pyran-3-amine

First step: 2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 1a )

2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

Intermediate 6 (0.18 g, 0.627 mmol) and benzenesulfonic acid 1.5 H ₂ O (0.139 g, 0.75 mmol) were dissolved in dichloromethane (10 mL). The reaction solution was concentrated under reduced pressure to give 1a (0.216 g).

MS m/z (ESI): 188.1 [M+H ⁺ ].

Second step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 1b )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-yl)carbamate

1a (0.215 g, 0.62 mmol) was dissolved in N,N-dimethylacetamide (4 mL) at room temperature. Intermediate 1 (0.225 g, 0.69 mmol) was added and stirred at room temperature 1 hour. The temperature was lowered to 0 ° C, and sodium tris(ethyloxy)borohydride (0.171 g, 0.806 mmol) was added to the reaction mixture, and the mixture was allowed to react to room temperature for 16 hours. The reaction solution was cooled to 0 ° C, and then water (20 mL), aqueous ammonia (2 mL) was added to the mixture to adjust to pH 8 and extracted with dichloromethane (50 mL×3). The organic phase was combined and washed with a saturated aqueous solution of brine (50 mL×1). dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography separation (dichloromethane / methanol (v / v) = 30: 1), to give a yellow solid 1b (0.179g, yield 56.1%).

MS m/z (ESI): 499.3 [M+H ⁺ ].

The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-d]imidazole-5 ( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 1 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H -pyran-3-amine

1b (0.05 g, 0.10 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 ° C, trifluoroacetic acid (1. 5 mL), and the mixture was reacted at 0 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc) The organic phases were combined and washed with brine brine (50 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. .

MS m/z (ESI): 399.3 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.12-6.97 (m, 3H), 4.23-4.20 (d, 1H), 4.23-4.13 ( m, 1H), 3.35-3.30 (t, 1H), 3.10 (s, 3H), 3.05-2.99 (m, 2H), 2.89-2.83 (m, 2H), 2.39-2.36 (m, 1H), 2.27- 2.23 (m, 1H), 1.94 (m, 1H), 1.48-1.39 (q, 2H).

Example 2

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 2 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-methyl-2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 2a )

Tert-butyl 1-methyl-2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 6 (0.70 g, 2.4 mmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0 ° C, then potassium carbonate (0.405 g, 2.9 mmol) Methylene chloride (179 μL, 2.9 mmol) was quickly added in a minute, and the reaction was carried out at 0 ° C for 2 hours. Water (80 mL) was added to the reaction mixture, and the mixture was extracted with methyl tributyl ether (100 mL × 2), and the organic phase was combined, washed with saturated aqueous sodium chloride (100 mL × 1), dried over anhydrous sodium sulfate Concentration gave a yellow solid 2a (0.609 g, yield 84.3%).

MS m/z (ESI): 302.3 [M+H ⁺ ].

Second step: 1-methyl-2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium sulfonate ( 2b )

1-methyl-2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

2a (0.18 g, 0.60 mmol) and benzenesulfonic acid 1.5 H ₂ O (0.166 g, 0.90 mmol) were dissolved in dichloromethane (10 mL). The reaction solution was concentrated under reduced pressure to give 2b (0.372 g).

MS m/z (ESI): 2021. [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 2c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

2b (0.198 g, 0.66 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and Intermediate 1 (0.237 g, 0.72 mmol) was added and stirred at room temperature for 1 hour. . The temperature was lowered to 0 ° C, and sodium tris(ethyloxy)borohydride (0.182 g, 0.86 mmol) was added to the reaction mixture, and the mixture was allowed to react to room temperature for 16 hours. The reaction solution was cooled to 0 ° C, and then water (20 mL), aqueous ammonia (2 mL) was added to the mixture to adjust to pH 8 and extracted with dichloromethane (50 mL×3). The organic phase was combined and washed with a saturated aqueous solution of brine (50 mL×1). dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography separation (dichloromethane / methanol (v / v) = 60: 1) to give a yellow solid was purified 2c (0.039g, yield 11.2%).

MS m/z (ESI): 513.3 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 2 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

2c (0.038 g, 0.074 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 ° C, trifluoroacetic acid (1. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc)EtOAc. The organic phases were combined and washed with brine brine (50 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. .

MS m/z (ESI): 413.3 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.24-7.07 (m, 3H), 4.35-4.33 (d, 1H), 4.28-4.24 (m, 1H), 4.02-4.01 (m, 2H), 3.93 (s, 3H), 3.88-3.87 (m, 2H), 3.44-3.39 (t, 1H), 3.27 (s, 3H), 3.14-2.99 (m, 2H), 2.49-2.45 (m, 1H), 1.59-1.50 (q, 1H).

Example 3

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl) Tetrahydro-2H-pyran-3-amine ( Compound 3 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran- 3-amine

First step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylpyrrolo[3,4-d]imidazole-5 ( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 3a )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro- 2H-pyran-3-yl)carbamate

A mixture of Intermediate 7 (0.55g, 4.49mmol) was dissolved in N, N- dimethylacetamide (10 mL) was added Intermediate 1 (1.6g, 5.0mmol), stirred at room temperature for the addition was completed 1 hour. The temperature was lowered to 0 ° C, and sodium tris(ethyloxy)borohydride (1.38 g, 6.5 mmol) was added to the reaction mixture, and the mixture was allowed to react to room temperature for 16 hours. The temperature was lowered to 0 ° C, and water (50 mL) and aqueous ammonia (2 mL) were successively added to adjust the pH to 8 and extracted with dichloromethane (100 mL×3). The organic phase was combined and washed with a saturated aqueous solution of brine (100 mL×1). Drying, filtration, and concentrating the filtrate under reduced pressure, rotary drying, purification by column chromatography (dichloromethane/methanol (v/v) = 10:1, a small amount of aqueous ammonia) to give a brown solid 3a (0.68 g, yield 31.3) %).

MS m/z (ESI): 435.1 [M+H ⁺ ].

Second step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methylpyrrolo[3,4-d]imidazole-5 (1H,4H,6H )-yl)tetrahydro-2H-pyran-3-amine ( compound 3 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran- 3-amine

3a (0.10 g, 0.23 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 ° C, trifluoroacetic acid (1.5 mL), and then reacted at 0 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc) The organic phases were combined and washed with brine brine (50 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. .

MS m/z (ESI): 335.3 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.15-6.99 (m, 3H), 4.27 - 4.25 (d, 1H), 4.17 - 4.14 (m, 1H), 3.76 (s, 4H), 3.32-3.29 (t, 1H), 3.03-2.92 (m, 2H), 2.40-2.37 (m, 1H), 2.26 (s, 3H), 1.49-1.40 (q, 1H).

Example 4

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(methylsulfonyl)pyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 4 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

First step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(methylsulfonyl)pyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 4a )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

3a (0.30g, 0.69mmol) was dissolved in dichloromethane (10mL) at room temperature, cooled to 0 ° C, added triethylamine (0.085g, 0.84mmol), reacted for 30 minutes, slowly added methane sulfonate Chlorofluorene (0.96 g, 0.84 mmol) was added and the mixture was allowed to react to room temperature for 12 hours. The reaction solution was cooled to 0 ° C, water (30 mL) was added, and the mixture was extracted with methylene chloride (30 mL × 3). The organic phase was combined, washed with saturated aqueous sodium chloride (30 mL × 1), dried over anhydrous sodium sulfate Concentration by pressure and purification by column chromatography (dichloromethane/methanol (v/v) = 40:1) afforded brown solid 4a (0.30 g, yield 84.9%).

MS m / z (ESI): 512.3 [M + H +].

The second step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(methylsulfonyl)pyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 4 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

4a (0.27 g, 0.52 mmol) was dissolved in dichloromethane (4 mL), cooled to 0 ° C, trifluoroacetic acid (2 mL), and the mixture was reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced vacuoluent, and then filtered and evaporated. The organic phases were combined and washed with brine brine (50 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated. .

MS m/z (ESI): 413.3 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.12-6.97 (m, 3H), δ4.21-4.18 (d, 1H), δ4 .15-4.12(m,1H),δ3.96-3.95(m,2H),δ3.76-3.72(m,2H),δ3.36(s,3H),δ3.30-3.27(t,1H ), δ3.03-2.95(m,1H), δ2.86-2.80(m,1H), δ2.52(s,3H), δ2.36-2.33(m,1H),δ1.45-1.36( q, 1H).

Example 5

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(methylsulfonyl)pyrrolo[3,4-d]imidazole-5 (1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-amine ( compound 5 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H -pyran-3-amine

First step: 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 5a )

1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

Intermediate 4 (0.21 g, 0.76 mmol) and benzenesulfonic acid 1.5 H ₂ O (0.210 g, 1.13 mmol) were dissolved in methanol (10 mL) at room temperature and reacted at 68 ° C for 12 hours. The reaction solution was concentrated under reduced pressure to give crude product 5a ,

MS m/z (ESI): 110.2 [M+H ⁺ ].

Second step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-pyrrolo[3,4-d]imidazole-5 (1H,4H,6H )-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 5b )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H- Pyran-3-yl)carbamate

5a (0.083 g, 0.76 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and Intermediate 1 (0.224 g, The temperature was lowered to 0 ° C, and sodium tris(ethyloxy)borohydride (0.209 g, 0.99 mmol) was added to the reaction mixture, and the mixture was allowed to react to room temperature for 16 hours. The reaction mixture was cooled to 0 ° C, and then water and aqueous ammonia was added to adjust to pH 8 and extracted with dichloromethane (30 mL × 3). The organic phase was combined, washed with a saturated aqueous solution of brine (50 mL×1), dried over anhydrous magnesium sulfate, filtered The filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 30:1) to afford white solid 5b (0.179 g, yield 56.1%).

MS m/z (ESI): 421.3 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(methylsulfonyl)pyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 5c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-yl)carbamate

5b (0.179g, 0.43mmol) was dissolved in tetrahydrofuran (10mL) at room temperature, cooled to 0 ° C, added triethylamine (0.087g, 0.86mmol), reacted for 30 minutes, slowly added metformin chloride (0.063 g, 0.55 mmol), and reacted at 0 ° C for 2 hours. The reaction solution was cooled to 0 ° C, water (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3), and the organic phase was combined, washed with a saturated aqueous sodium chloride solution (30 mL × 1), dried over anhydrous sodium sulfate Concentration by pressure gave a yellow solid 5c (0.179 g, yield: 84.0%).

MS m/z (ESI): 499.3 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-(methylsulfonyl)pyrrolo[3,4-d]imidazole-5 ( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 5 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H -pyran-3-amine

5c (0.179 g, 0.36 mmol) was dissolved in dichloromethane (12 mL), cooled to 0 ° C, trifluoroacetic acid (6 mL), and the mixture was reacted at 0 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc) The organic phases were combined and washed with brine brine (50 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated. .

MS m/z (ESI): 399.3 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.03 (s, 1H), δ 7.21 - 7.04 (m, 3H), δ 4.29 -4.26(d,1H),δ4.25-4.21(m,1H),δ4.11-4.09(t,2H),δ3.89-3.87(t,2H),δ3.49-3.48(s,3H ), δ3.42-3.37 (m, 1H), δ3.13-3.06 (m, 1H), δ2.93-2.87 (m, 1H), δ2.46-2.42 (m, 1H), δ1.54- 1.45 (q, 1H).

Example 6

Ethyl 5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6- Tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( Compound 6 )

Ethyl 5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4- d]imidazole-2-carboxylate

First step: ethyl 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-benzenesulfonate ( 6a )

Ethyl 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate benzenesulfonate

Intermediate 5 (281 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), benzene sulfonic acid. The reaction solution was concentrated rotary drying, and dried in vacuo to give a brown oil 6a (366mg), the next step directly.

MS m/z (ESI): 1821. [M+H ⁺ ].

Second step: ethyl 5-((3R,5S,6S)-5-((t-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( 6b )

Ethyl 5-((3R,5S,6S)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

6a (366 mg, 1.0 mmoL) and Intermediate 1 (327 mg, 1.0 mmol) were dissolved in N,N-dimethylacetamide (5 mL) and stirred at room temperature for 1 hour. Sodium triethoxyhydride borohydride (0.284 g, 1.3 mmoL) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The pH of the reaction mixture was adjusted to 7-8 with a saturated sodium hydrogen carbonate solution (50 mL), and extracted with ethyl acetate (20 mL×5). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated The preparation plate was separated and purified (dichloromethane/ethanol = 20:1) to afford white solid 6b (150 mg, yield 30%).

MS m/z (ESI): 493.2 [M+H ⁺ ].

The third step: ethyl 5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4, 5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( Compound 6 )

Ethyl 5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4- d]imidazole-2-carboxylate

6b (110 mg, 0.223 mmol) was dissolved in dichloromethane (0.5 mL), and the mixture was stirred and stirred, and then trifluoroacetic acid (0.5 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness. EtOAc (EtOAc) The aqueous phase was adjusted to pH 7-8 with sodium bicarbonate, extracted with a mixed solvent of dichloromethane/methanol (v/v = 20:1) (10 mL×4), and the organic phases were combined, dried over anhydrous sodium sulfate Drying, purification by thin layer chromatography (dichloromethane/ethanol (v/v) = 20:1) gave Compound 6 (45 mg, yield 51.3%).

MS m/z (ESI): 393.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.14-7.10 (m, 1H), 7.07-6.99 (m, 2H), 4.72-4.28 (q, 2H), 4.26-4.23 (d, 1H), 4.21-4.15 (dd, 1H), 3.83 (s, 4H), 3.34-3.20 (t, 1H), 3.04-2.99 (m, 1H), 2.90 -2.83 (m, 1H), 2.39-2.36 (d, 1H), 1.47-1.39 (q, 1H), 1.31-1.27 (t, 3H).

Example 7

Ethyl 5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4 ,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( Compound 7 )

Ethy 5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxylate

First step: ethyl 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate besylate ( 7a )

Ethyl 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate benzenesulfonate

The 8A (220mg, 0.746mmoL) was dissolved in dichloromethane (5mL) was added benzenesulfonic acid _{1.5 H 2 O (207.2g, 1.12mmoL} ) was stirred at, 40 ℃ 16 hours. The reaction solution was concentrated rotary drying, and dried in vacuo to give a brown oil 7a (283mg), used directly in the next reaction.

MS m/z (ESI): 196.1 [M+H ⁺ ].

Second step: ethyl 5-((3R,5S,6S)-5-((t-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( 7b )

Ethy 5-((3R,5S,6S)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4, 5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

7a (283 mg, 0.746 mmoL) and Intermediate 1 (327 mg, 1.0 mmol) were dissolved in N,N-dimethylacetamide (5 mL) and stirred at room temperature for 1 hour. Sodium tris(acetoxy)borohydride (0.284 g, 1.3 mmoL) was added under ice-cooling and stirred at room temperature for 4 hr. Saturated sodium bicarbonate solution (50 mL) was added to the reaction mixture to adjust the pH to 7-8, and extracted with ethyl acetate (20 mL × 5). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, spin dried, thin The layer chromatography preparative plate was purified (dichloromethane/methanol (v/v) = 20:1) to afford white solid 7b (44 mg, yield 11.65%).

MS m/z (ESI): 507.1 [M+H ⁺ ].

The third step: ethyl 5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl -1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( Compound 7 )

Ethyl 5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[ 3,4-d]imidazole-2-carboxylate

7b (44 mg, 0.087 mmol) was added to dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was dried (MgSO.sub.2) The aqueous phase was extracted with a sodium carbonate solution to adjust the pH to 7-8, a mixture solvent of dichloromethane/ethanol (V/V=20:1) (10 mL×4), and the combined extracts were dried over anhydrous sodium sulfate and filtered. spin drying, purified by preparative plate thin layer chromatography (methylene chloride / ethanol (v / v) = 20: 1), to give a pale yellow solid compound 7 (16mg, yield 45.7%).

MS m/z (ESI): 407.3 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.14-7.09 (m, 1H), 7.08-6.96 (m, 2H), 4.30-4.24 (q, 2H), 4.22-4.20 (d, 1H), 4.18-4.14 (dd, 1H), 3.9 (t, 2H), 3.85 (s, 3H), 3.77 (t, 2H), 3.34-3.29 (t , 1H), 3.04-2.96 (m, 1H), 2.89-2.82 (td, 1H), 2.39-2.35 (m, 1H), 1.47-1.38 (dd, 1H), 1.32-1.28 (t, 3H).

Example 8

5-((3R,5S,6S)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 8 )

5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxamide

First step: tert-butyl ((2R,3S,5R)-5-(2-carbamoyl-1-methylpyrrolo[3,4-d]imidazole-5(1H,4H,6H) -yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 8a )

Tert-butyl((2R,3S,5R)-5-(2-carbamoyl-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5- Difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

7b (0.186 g, 0.367 mmoL) was dissolved in a methanol solution of ammonia (5 mL, 35 mmoL), and heated to 80 ° C in a stainless steel sealed tube and stirred for 16 hours. The reaction solution was cooled to room temperature, and a saturated aqueous solution of sodium chloride (50 mL) was added, and the mixture was combined with methylene chloride (20 mL × 3). , evaporated to dryness, purified by silica gel column chromatography separation (dichloromethane / methanol (v / v) = 40: 1), to give a yellow solid 8a (87mg, yield 49.6%).

MS m/z (ESI): 478.2 [M+H ⁺ ].

Second step: 5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 8 )

5-((3R,5S,6S)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxamide

8a (0.087g, 0.182mmoL) was added to dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness. EtOAc (EtOAc) (EtOAc (EtOAc) The combined extracts were dried over anhydrous sodium sulfate, filtered, rotary drying, purified by preparative plate thin layer chromatography (methylene chloride / ethanol (v / v) = 20: 1), to give a pale yellow solid compound 8 (22mg, yield 32 %).

MS m/z (ESI): 378.2 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.15-7.11 (m, 1H), 7.09-6.99 (m, 2H), 4.26-4.23 (d, 2H), 4.19-4.15 (ddd, 1H), 3.90-3.89 (t, 2H), 3.86 (s, 3H), 3.77-3.76 (t, 2H), 3.35-3.30 (t, 1H), 3.04 -2.99 (m, 1H), 2.95-2.89 (m, 1H), 2.40-2.37 (m, 1H), 1.49-1.40 (dd, 1H).

Example 9

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-ethoxy-1-methylpyrrolo[3,4-d]imidazole-5(1H,4H ,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 9 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-ethoxy-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro- 2H-pyran-3-amine

First step: tert-butyl 2-ethoxy-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-formate ( 9a )

Tert-butyl 2-ethoxy-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 2 (2 g, 8.4 mmol) was dissolved in hexafluoroisopropanol (100 mL), tetraethoxymethane (1.78 g, 9.25 mmol) was added and stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced pressure to give a yellow solid 9a (yield: 9.

MS m/z (ESI): 256.2 [M+H ⁺ ].

Second step: tert-butyl 2-ethoxy-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 9b )

Tert-butyl 2-ethoxy-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

In a nitrogen atmosphere, grass chloroform (1.49 g, 11.75 mol) was dissolved in dichloromethane (30 mL), cooled to -78 ° C, dimethyl hydrazine (1.84 g, 23.50 mol) was added dropwise, and stirred at -70 ° C After 30 minutes, a solution of 9a (2.00 g, 7.83 mol) in dichloromethane (10 mL) was added dropwise, and the mixture was stirred at -70 ° C for 30 minutes, and N'N-diisopropylethylamine (5.06 g, 39.17) was added dropwise. Mol), naturally stirred to room temperature and stirred for 4 hours. Dichloromethane (100 mL) and saturated ammonium chloride solution (200 mL) were added to the reaction mixture, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (100 mL×3), and the organic phase was combined, and then citric acid solution (0.1 mol/ L, 100 mL), washed with a saturated sodium chloride solution (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, the residue was separated (petroleum ether / ethyl acetate (v / v) = 5: 1) by column chromatography to give a yellow powder 9b (0.90g , yield 45%).

MS m/z (ESI): 254.1 [M+H ⁺ ].

Third step: tert-butyl 2-ethoxy-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate ( 9c )

Tert-butyl 2-ethoxy-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

9b (400 mg, 1.58 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (436 g, 3.16 mmol) was added, and the mixture was cooled to 0 ° C, and iodomethane (672 mg, 4.73 mmol) was added dropwise. The reaction was stirred up to room temperature for 60 hours. Water (40 mL) was added to the mixture and the mixture was evaporated. The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered, evaporated, evaporated, jjjjjjjjjjjj One step reaction.

MS m/z (ESI): 268.2 [M+H ⁺ ].

Step 4: 2-Ethoxy-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 9d )

2-ethoxy-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesμLfonate

9c (400 mg, 1.50 mmol) was dissolved in dichloromethane (20 mL), benzenesulfonic acid (415.70 mg, 2.24 mmol) was added, and the reaction was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to give a brown oil 9D, it was used directly in the next reaction.

MS m/z (ESI): 168.2 [M+H ⁺ ].

Step 5 : Tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-ethoxy-1-methylpyrrolo[3,4- d] imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 9e )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-ethoxy-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)- Yl)tetrahydro-2H-pyran-3-yl)carbamate

Intermediate 1 (451 mg, 1.38 mmol) was dissolved in N,N-dimethylacetamide (5 mL), and 9d (450 mg, 1.38 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The temperature was lowered to 0 ° C, and sodium tris(ethyloxy) borohydride (440 mg, 2.07 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 17 hours. The reaction solution was cooled to room temperature, and water (20 mL) and aqueous ammonia (2 mL) were sequentially added and stirred for 20 minutes. After adding water (50 mL), dichloromethane (30 mL×6), EtOAc (EtOAc) v/v) = 1:50) gave a red wine solid 9e (104 mg, yield 15.7%).

MS m/z (ESI): 479.2 [M+H ⁺ ].

Step 6: (2R, 3S, 5R)-2-(2,5-Difluorophenyl)-5-(2-ethoxy-1-methylpyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 9 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-ethoxy-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro- 2H-pyran-3-amine

9e (104 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced vacuoluent, and water (10mL) The aqueous phase was adjusted to pH 8 with a saturated aqueous solution of potassium carbonate, and extracted with dichloromethane (10 mL×6). The methylene chloride extract was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound (methanol / methylene chloride (v/v) = 1 : 10) was obtained.

MS m/z (ESI): 379.2 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ7.11-6.99 (m, 3H), 4.22-4.15 (m, 3H), 4.15-4.11 (m, 1H), 3.81-3.80 (t, 2H), 3.71-3.69 (t, 2H), 3.30-3.27 (m, 4H), 2.98-2.94 (m, 1H), 2.92-2.80 (m, 1H) , 2.37-2.33 (t, 1H), 1.42-1.39 (q, 1H), 1.32-1.28 (t, 3H).

Example 10

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 10 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxamide

First step: 5-t-butyl 2-ethyl 1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate ( 10a )

5-tert-butyl 2-ethyl 1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

Intermediate 5 (600 mg, 2.13 mmoL) was added to N,N-dimethylformamide (8 mL), and the mixture was stirred and dissolved. Potassium carbonate (590 mg, 4.26 mmol) was added, and ethyl iodide (1000 mg) was added dropwise with stirring at 0 °C. , 6.4 mmoL), and the reaction was stirred at room temperature for 6 hours. Water (20 mL) and methyl tertiary butyl ether (20 mL) were added to the reaction mixture, and the layers were allowed to stand. The aqueous phase was extracted with methyl-tert-butyl ether (20 mL×1), and the organic phase was combined, washed with water (20 mL×1), brine (20 mL×2), dried over anhydrous sodium sulfate Oil 10a (500 mg, yield 75.8%).

The second step: ethyl 1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate besylate ( 10b )

Ethyl 1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate benzenesulfonate

10a (500mg, 1.62mmoL), benzenesulfonic acid. 1.5 molecule hydrate (450mg, 2.42mmoL) was dissolved in dichloromethane (7mL), heated to 30 ° C for 2 hours, and then warmed to 40 ° C to continue the reaction overnight . The reaction was continued for 3 hours with the addition of benzenesulfonic acid .1.5 molecular hydrate (150 mg, 0.8 mmoL). At the end of the reaction, the reaction solution is concentrated After spin drying, the obtained solid was washed with ethyl acetate (5 mL × 3) to yield yellow solid 10b (600 mg).

Third step: ethyl 5-((3R,5S,6R)-5-((t-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( 10c )

Ethyl 5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4 ,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

10b (600 mg, 1.78 mmoL) and Intermediate 1 (580 mg, 1.78 mmol) were dissolved in N,N-dimethylacetamide (5 mL) and stirred at room temperature for 0.5 hour. Sodium tri(acetoxy)borohydride (890 mg, 4.19 mmol) was added under ice-cooling and stirred at room temperature for 2 hr. Intermediate 1 (400 mg, 1.22 mmol) and tris(ethyloxy) borohydride (275 mg, 1.29 mmol) were added and stirring was continued for 2 hours. The reaction solution was poured into a saturated sodium hydrogen carbonate solution (200 mL) and filtered. The filter cake was washed with water (20 mL×2), methylene chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and dried. = 50: 1) gave a yellow solid 10c (540 mg, yield 64%).

MS m/z (ESI): 521.2 [M+H ⁺ ];

The fourth step: the third butyl ((2R, 3S, 5R)-5-(2-aminomethylmethyl-1-ethylpyrrolo[3,4-d]imidazole-5 (1H, 4H, 6H) -yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 10d )

Tert-butyl((2R,3S,5R)-5-(2-carbamoyl-1-ethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5- Difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

10c (485 mg, 0.93 mmol) was dissolved in an ammonia methanol solution (10 mL, 7 mol/L), and the mixture was heated to 85 ° C, and the mixture was stirred for 16 hours. The reaction was cooled to room temperature, concentrated and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100: 1 ~ 50: 1), to give a white solid 10d (287mg, yield 62%).

MS m/z (ESI): 492.2 [M+H ⁺ ];

Step 5: 5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 10 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxamide

10d (262mg, 0.533mmoL) was added to dichloromethane (2mL), trifluoroacetic acid (1mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was vortexed, dissolved with dichloromethane (100 mL), and then filtered and evaporated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, purified by preparative plate thin layer chromatography (methylene chloride / ethanol (v / v) = 10: 1, adding a small amount of ammonia), to give a white solid compound 10 (138mg , yield 66%).

MS m/z (ESI): 392.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23 - 7.08 (m, 3H), 4.48 - 4.43 (q, 2H), 4.29 - 4.27 (d,1H), 4.26-4.23 (m,1H), 4.02-4.01(t,2H),3.84-3.83(t,2H),3.43-3.37(t,1H),3.13-3.05(m,1H) , 2.93 - 2.87 (m, 1H), 2.48-2.44 (m, 1H), 1.54-1.45 (q, 1H), 1.40-1.37 (t, 3H).

Example 11

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydro Pyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 11 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d ]imidazole-2-carboxamid e

First step: ethyl 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate-2-benzenesulfonate ( 11a )

Ethyl 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate benzenesulfonate

Intermediate 5 (800 mg, 2.84 mmoL), benzenesulfonic acid. 1.5 molecular hydrate (790 mg, 4.26 mmol) was dissolved in dichloromethane (8 mL), and the mixture was stirred at 30 ° C for 2 hours, and then heated to 40 ° C. overnight. The reaction was continued for 3 hours with the addition of benzenesulfonic acid 1.5 H ₂ O (160 mg, 0.85 mmol). The reaction completed, the reaction mixture was concentrated spin drying, washed with ethyl acetate (5mL × 3), and concentrated to give a yellow solid 11a (960mg), used directly in the next reaction.

Second step: ethyl 5-((3R,5S,6R)-5-((t-butyloxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran -3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( 11b )

Ethyl 5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophen Yl)tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

11a (960 mg, 2.84 mmol) and Intermediate 1 (1020 mg, 3.12 mmol) were dissolved in N,N-dimethylacetamide (5 mL). Sodium tris(acetoxy)borohydride (1410 mg, 6.67 mmol) was added under ice-cooling and stirred at room temperature for 5 hr. 10 drops of aqueous ammonia was added to the ice bath, and water (5 mL) was slowly added dropwise and filtered. The filter cake was washed with water (10 mL), EtOAc (EtOAc) :1~10:1) gave a pale yellow solid 11b (700mg, yield 50%).

The third step: tert-butyl ((2R,3S,5R)-5-(2-aminomercaptopyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2 -(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 11c )

Tert-butyl((2R,3S,5R)-5-(2-carbamoylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro- 2H-pyran-3-yl)carbamate

11b (700 mg, 1.42 mmol) was dissolved in an ammonia-methanol solution (10 mL, 7 mol/L, 70 mmol), and the mixture was warmed to 90° C. The reaction was cooled to room temperature, concentrated and the residue triturated with ether (15mL) was filtered to give a yellow solid 11c (540mg, 82% yield).

Fourth step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5, 6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 11 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d Imidazole-2-carboxamide

11c (540 mg, 1.167 mmoL) was added to dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added and the mixture was warmed to room temperature for 2 hours. The reaction solution was spin-dried, dissolved in dichloromethane (100 mL), and saturated sodium bicarbonate solution (50 mL) was added to adjust the pH 7-8, and the liquid phase was separated with dichloromethane/methanol ((v/v)= A 20:1) mixed solution (50 mL x 5) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, the residue was purified by silica gel column chromatography (methylene chloride / methanol (v / v) = 60: 1, adding a small amount of ammonia), to give compound 11 as a white solid (159 mg, yield 38%).

MS m/z (ESI): 364.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23 - 7.05 (m, 3H), 4.30 - 4.27 (d, 1H), 4.26 - 4.23 (m,1H), 4.92(s,4H),3.43-3.38(t,1H),3.13-3.06(m,1H),2.93-2.87(m,1H),2.48-2.44(m,1H),1.54 -1.46 (q, 1H).

Example 12

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 12 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4,6-dihydropyrrolo[3,4-d Imidazole-5(1H)-formate ( 12a )

Tert-butyl 1-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

The intermediate 8 (500 mg, 2.016 mmol) was dissolved in ethanol (5 mL), and hydroxylamine hydrochloride (158.9 mg, 2.218 mmol) and potassium carbonate (695.5 mg, 5.04 mmol) were added at room temperature, and the mixture was heated to 80 ° C for 1 hour. The reaction mixture was dried with EtOAc (EtOAc)EtOAc. Ethyl acetate (50 mL) and a saturated sodium chloride solution (100 mL) were added to the reaction mixture, and the mixture was separated, and the aqueous phase was filtered, and the filtrate was extracted with ethyl acetate (50 mL×3), and the organic phase was combined with 0.5 mol/L. The citric acid solution (50 mL×1) was washed, the pH was adjusted to 5, dried over anhydrous sodium sulfate, filtered, and dried, and the residue was purified by column chromatography ( petroleum ether/ethyl acetate (v/v) = 2:1~1:1) gave a yellow solid 12a (273mg, yield 44%).

MS m/z (ESI): 306.2 [M+H ⁺ ].

Second step: 5-methyl-3-(1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1,2,4-oxa Diazole dibenzene sulfonate ( 12b )

5-methyl-3-(1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1,2,4-oxadiazole dibenzenesulfonate

12a (273 mg, 0.895 mmoL), benzenesulfonic acid 1.5 H ₂ O (331.2 mg, 1.790 mmoL) was dissolved in dichloromethane (10 mL), and the mixture was warmed to 40 ° C overnight. The reaction mixture was concentrated to dryness to give a yellow solid 12b ( 554 g).

MS m/z (FSI): 206.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(5-methyl-1,2, 4-oxadiazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 12c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrrolo[ 3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

12b (556 mg, 0.895 mmoL) and Intermediate 1 (322.1 mg, 0.984 mmol) were dissolved in N,N-dimethylacetamide (5 mL) and stirred at room temperature for 0.5 hour. Sodium tri(acetoxy)borohydride (512.2 mg, 2.417 mmol) was added under ice-cooling, and stirred at 0 ° C for 0.5 hour, and then stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (100 mL) and stirred for 0.5 hr. The filter cake was washed with water (10 mL×2), methylene chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and dried. = 50: 1) gave a yellow solid 12c (236 mg, yield 51%).

MS m/z (ESI): 517.2 [M+H ⁺ ];

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(5-methyl-1,2,4-oxadiazole) 3-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 12 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

12c (210 mg, 0.407 mmol) was added to dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 0 ° C for 0.5 hour and then allowed to react to room temperature for 2 hours. The reaction solution was spin-dried, and saturated sodium bicarbonate solution (50 mL) was added to adjust pH 7-8, and the aqueous phase was extracted with dichloromethane (30mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, the residue was purified by silica gel column chromatography separation (dichloromethane / methanol (v / v) = 50: 1) to give a white solid compound 12 (138mg, Yield 82%).

MS m/z (ESI): 417.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23 - 7.06 (m, 3H), 4.31-4.25 (d, 1H), 4.26-4.24 (m, 1H), 4.04 (m, 2H), 3.98 (s, 3H), 3.91 (m, 2H), 3.44 - 3.39 (t, 1H), 3.14 - 3.08 (m, 1H), 2.95 - 2.89 (m , 1H), 2.66 (s, 3H), 2.49-2.44 (m, 1H), 1.56-1.47 (q, 1H).

Example 13

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazol-2-carbonitrile (Compound 13)

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carbonitrile

First step: 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-carboxanidiphenyl sulfonate ( 13a )

1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonit Rile dibenzenesulfonate

Intermediate 8 (500 mg, 2.016 mmol), benzenesulfonic acid 1.5 H ₂ O (559 mg, 3.024 mmol) was dissolved in dichloromethane (20 mL), and the mixture was warmed to 40 ° C for 6 hours. Add benzenesulfonic acid 1.5 H ₂ O (200 mg, 1.082 mmol), and react at 40 ° C overnight. The reaction mixture was concentrated to dryness to give a white solid 13a (935mg).

MS m/z (ESI): 249.1 [M+H ⁺ ].

Second step: tert-butyl ((2R,3S,5R)-5-(2-cyano-1-methylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl )-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 13b )

Tert-butyl((2R,3S,5R)-5-(2-cyano-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5- Difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

13a (935mg, 2.016mmoL) and Intermediate 1 (725.6mg, 2.218mmoL) were dissolved in N,N-dimethylacetamide (10mL), and tris(ethyloxy)borane was added to the ice salt bath. Sodium (1189 mg, 5.610 mmol) was stirred at room temperature for 3 hours. The reaction mixture was poured into a cold saturated aqueous solution of sodium hydrogen carbonate (150 mL), filtered, and the filtered cake was washed with water (50mL×2), dissolved in dichloromethane (100mL), dried over anhydrous sodium sulfate It was isolated and purified silica gel column chromatography (methylene chloride / methanol (v / v) = 60: 1) to give a yellow solid 13b (670mg, 72% yield).

MS m/z (ESI): 460.1 [M+H ⁺ ].

The third step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonitrile ( Compound 13 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-c Arbonitrile

13b (300 mg, 0.654 mmol) was added to dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added and the mixture was allowed to react to room temperature for 2 hours. The reaction solution was spin-dried, and a saturated sodium hydrogen carbonate aqueous solution (50 mL) was added to adjust pH 7-8, and the aqueous phase was extracted with dichloromethane (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and dried with EtOAc EtOAc EtOAc EtOAc (EtOAc Preparation of compound 13 as a white solid (72 mg, yield 30%).

MS m/z (ESI): 360.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23-7.08 (m, 3H), 4.31-4.28 (d, 1H), 4.26-4.22 (m,1H),4.01-4.00(t,2H),3.86-3.85(t,2H),3.83(s,3H),3.43-3.37(t,1H),3.12-3.07(m,1H),2.96 - 2.90 (m, 1H), 2.47-2.43 (m, 1H), 1.55-1.41 (q, 1H).

Example 14

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3 , 4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 14 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-methyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formic acid Ester ( 14a )

Tert-butyl 1-methyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 8 (1030 mg, 4.153 mmol) was dissolved in N,N-dimethylformamide (20 mL), sodium azide (810 mg, 12.459 mmol) and ammonium acetate (960 mg, 12.459 The reaction was carried out at 120 ° C overnight. The pH was adjusted to 1 to 2 by adding a 1 mol/L hydrochloric acid solution, water (200 mL) was added, and the filtrate was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, and drying to give a yellow solid 14a (1000mg, 83% yield).

MS m/z (ESI): 29.21. [M+H ⁺ ].

Second step: tert-butyl 1-methyl-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 ( 1H)-formate ( 14b-2 )

Tert-butyl 1-methyl-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Third butyl 1-methyl-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-A Acid ester ( 14b-1 )

Tert-butyl 1-methyl-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

14a (1000mg, 3.436mmoL) was dissolved in N,N-dimethylformamide (25mL), sodium hydride (165mg, 4.124mmoL) was added under ice bath, stirred for 0.5 hour in ice bath, then iodine (586mg) , 4.124mmoL), naturally warmed up overnight. The reaction solution was slowly added to crushed ice (50 g), sodium chloride was added to saturate the solution, and ethyl acetate (50 mL × 4) was extracted. The organic phase was combined, washed with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated to dryness. = 2: 1 to 1:1) gave white solid 14b-1 (682 mg, yield 55%) and white solid 14b-2 (230 mg, yield 18%).

MS m/z (ESI): 306.1 [M+H ⁺ ].

The third step: 1-methyl-2-(1-methyl-1H-tetrazolyl-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole diphenyl Sulfonate ( 14c )

1-methyl-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole dibenzenesulfonate

14b-1 (682 mg, 2.236 mmoL), benzenesulfonic acid 1.5 H ₂ O (827.3 mg, 4.472 mmoL) was dissolved in dichloromethane (25 mL), and the mixture was warmed to 40 ° C overnight. The reaction solution was concentrated to dryness and dried in vacuo to give 14c (1165 mg).

MS m/z (ESI): 206.1 [M+H ⁺ ].

Fourth step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazole) -5-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 14d )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

14c (1165mg, 2.236mmoL) and intermediate 1 (804.4mg, 2.459mmoL) were dissolved in N,N-dimethylacetamide (10mL), stirred at room temperature for 0.5 hours, and added to the ice bath. Sodium hydride) sodium borohydride (1279 mg, 6.037 mmol) was stirred at 0 ° C for 0.5 hour and then allowed to warm to room temperature and stirred for 2 hours. Intermediate 1 (400 mg, 1.223 mmoL) and sodium tris(acetoxy)borohydride (400 mg, 1.887 mmol) were added and allowed to react at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (100 mL), and stirred for 0.5 hr, filtered, filtered, washed with water (20 mL × 3) The residue was purified with EtOAc EtOAc EtOAc EtOAc (EtOAc (MeOH) 14d (480mg, yield 42%).

MS m/z (ESI): 517.1 [M+H ⁺ ].

Step 5: (2R, 3S, 5R)-2-(2,5-Difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazol-5-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 14 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

14d (440mg, 0.853mmoL) was added to dichloromethane (5mL), trifluoroacetic acid (2mL) was added under ice-cooling, and the mixture was allowed to react to room temperature for 2 hours. The reaction solution was spin-dried, and a saturated sodium bicarbonate solution (100 mL) was added to adjust pH 7-8, and the aqueous phase was extracted with dichloromethane (30mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, the residue was purified by silica gel column chromatography separation (dichloromethane / methanol (v / v) = 30: 1, adding a small amount of ammonia), to give a yellow solid compound 14 (134 mg, yield 38%).

MS m/z (ESI): 417.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23 - 7.06 (m, 3H), 4.38 (s, 3H), 4.32-4.26 (m) , 2H), 4.07-4.05 (t, 2H), 4.03 (s, 3H), 3.95-3.94 (t, 2H), 3.46-3.41 (t, 1H), 3.17-3.09 (m, 1H), 2.96-2.90 (m, 1H), 2.51-2.47 (m, 1H), 1.58-1.49 (q, 1H).

Example 15

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3 , 4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 15 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: 1-methyl-2-(2-methyl-2H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium Acid salt ( 15a )

1-methyl-2-(2-methyl-2H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole dibenzenesulfonate

14b-2 (200 mg, 0.656 mmoL), benzenesulfonic acid 1.5 H ₂ O (242.6 mg, 1.311 mmol) was dissolved in dichloromethane (10 mL), and the mixture was warmed to 40 ° C overnight. The reaction mixture was concentrated to dryness and dried in vacuo to afford white crystals 15a (342mg).

MS m/z (ESI): 206.1 [M+H ⁺ ].

Second step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(2-methyl-2H-tetrazole) -5-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 15b )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

15a (342mg, 0.656mmoL) and intermediate 1 (236mg, 0.722mmoL) were dissolved in N,N-dimethylacetamide (5mL), stirred at room temperature for 0.5 hours, and added to the ice bath. Sodium oxy) borohydride (375.3 mg, 1.671 mmol) was stirred at room temperature for 2 hours. Concentrated aqueous ammonia (10 mL) and saturated sodium chloride solution (30 mL) were added to the reaction mixture under ice-cooling, and the mixture was stirred for 0.5 hr, filtered, and the filtrate was extracted with dichloromethane (30 mL×3). Dissolve, dry with anhydrous sodium sulfate, filter, spin dry, and purify the residue by column chromatography (dichloromethane / methanol (v / v) = 30:1~20:1, add a small amount of aqueous ammonia) to obtain yellow Solid yellow solid 15b (200 mg, yield 59%).

MS m/z (ESI): 517.2 [M+H ⁺ ].

The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(2-methyl-2H-tetrazol-5-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 15 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

15b (180 mg, 0.349 mmol) was added to dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added and the mixture was warmed to room temperature for 2 hours. The reaction solution was spin-dried, dissolved with water (50 mL), and adjusted to pH 7-8 with sodium hydrogen carbonate, and extracted with dichloromethane (30mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, the residue was purified by thin layer chromatography separation (dichloromethane / methanol (v / v) = 30: 1) to give a yellow solid compound 15 (66mg, Yield 46%).

MS m/z (ESI): 417.2 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23 - 7.06 (m, 3H), 4.48 (s, 3H), 4.36 - 4.34 (d) , 1H), 4.31-4.27 (m, 1H), 4.07-4.05 (t, 2H), 4.01 (s, 3H), 3.95-3.94 (t, 2H), 3.47-3.42 (t, 1H), 3.17-3.13 (m, 1H), 3.05-2.99 (m, 1H), 2.53-2.49 (m, 1H), 1.61-1.52 (q, 1H).

Example 16

Methyl 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4 ,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( Compound 16 )

Methyl 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[ 3,4-d]imidazole-2-carboxylate

First step: 5-t-butyl 2-methyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate ( 16a )

5-tert-butyl 2-methyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

The grass chloroform (652.5 mg, 5.14 mmoL) was dissolved in dry dichloromethane (15 mL), cooled to -78 ° C with a dry ice acetone bath, and dried dimethyl hydrazine (803.96 mg, 10.29mmoL) was added dropwise with stirring. ), stirring for 30 minutes. A 5C (970 mg, 3.43 mmol) solution of dichloromethane (5 mL) was added dropwise to the mixture and stirring was continued for 20 min. Diisopropylethylamine (2.216 g, 17.15 mmol) was added dropwise at -78 ° C, and naturally allowed to react to room temperature for 2 hours. A saturated ammonium chloride solution (50 mL), a saturated sodium chloride solution (50 mL), and dichloromethane (50 mL) were added to the mixture, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (50 mL×3). Washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane/methanol (v/v) = 50:1). , a white solid 16a (520 mg, yield 54%) was obtained.

MS m/z (ESI): 2821. [M+H ⁺ ].

Second step: 5-t-butyl 2-methyl 1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate ( 16b )

5-tert-butyl 2-methyl 1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

16a (1000mg, 3.56mmoL) was dissolved in N,N-dimethylformamide (20mL), potassium carbonate (589.3mg, 4.27mmoL) was added, and methyl iodide (606.4mg, 4.27mmoL) was added dropwise in an ice bath. Stir at 0 ° C for 18 hours. A saturated ammonium chloride solution (40 mL) and a saturated sodium chloride solution (40 mL) were added to the mixture, and the mixture was combined with ethyl acetate (40 mL×4), and the organic phase was combined and washed with a saturated sodium chloride solution (50 mL×2). Drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) ).

MS m/z (ESI): 296.1 [M+H ⁺ ].

The third step: methyl 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate besylate (16c)

Methyl 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate benzenesulfonate

16b (620 mg, 2.206 mmol) and benzenesulfonic acid 1.5 H ₂ O (613 mg, 3.310 mmol) were dissolved in methanol (5 mL), and the mixture was heated to 40 ° C for 6 hours. The reaction mixture was concentrated under rotary drying, and dried in vacuo to give a yellow oil 16c (748mg), used directly in the next reaction.

The fourth step: methyl 5-((3R,5S,6R)-5-((t-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( 16d )

Methyl 5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4 ,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

16c (748mg, 2.206mmoL) and intermediate 1 (792mg, 2.421mmoL) were dissolved in N,N-dimethylacetamide (10mL), stirred at room temperature for 0.5 hours, and added to the ice bath. Sodium oxy) borohydride (624.8 mg, 2.860 mmol) was reacted overnight at room temperature. Add saturated sodium bicarbonate solution (50 mL) to the reaction solution to adjust the pH value of 7-8, extract with dichloromethane (30 mL × 4), and combine the organic phase, wash with saturated sodium chloride solution (30mL × 1), with anhydrous over sodium sulfate, filtered, rotary drying, the residue was purified by silica gel column chromatography separation (dichloromethane / methanol (v / v) = 50: 1) to give a yellow solid 16d (236mg, 22% yield).

MS m/z (ESI): 493.1 [M+H ⁺ ].

Step 5: Methyl 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl -1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( Compound 16 )

Methyl 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[ 3,4-d]imidazole-2-carboxylate

16d (235mg, 0.477mmoL) was added to dichloromethane (1mL), trifluoroacetic acid (1mL) was added under ice bath, and the mixture was allowed to react to room temperature overnight. The reaction solution was spin-dried, and a sodium hydrogencarbonate solution (20 mL) was added thereto to adjust pH 7-8, and extracted with a mixed solution of dichloromethane and methanol (v/v) = 30:1 (20 mL × 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and dried with EtOAc EtOAc EtOAc EtOAc EtOAc Separation and purification by chromatography (dichloromethane/methanol (v/v) = 30:1, a small amount of aqueous ammonia) to afford compound 16 (30 mg, yield 16%).

MS m/z (ESI): 393.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.24-7.07 (m, 3H), 4.33-4.31 (d, 1H), 4.28-4.24 (m,1H), 4.02-4.01(t,2H),3.96(s,3H),3.90(s,3H),3.88-3.87(t,2H),3.44-3.39(t,1H),3.14-3.07 (m, 1H), 3.01-2.94 (m, 1H), 2.49-2.45 (m, 1H), 1.58-1.49 (q, 1H).

Example 17

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1,2-dimethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H) -yl)tetrahydro-2H-pyran-3-amine (Compound 17)

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1,2-dimethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H- Pyran-3-amine

First step: tert-butyl 1,2-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 17a )

Tert-butyl 1,2-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

7B (446.52 mg, 2.0 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, cooled to -20 ° C, and sodium hexamethyldidecylamine (1.1 mL, 2 mol/L, 2.2 mmol) was added dropwise. Stirring was continued for 30 minutes in the reaction mixture. Methanol (567.7 mg, 4.0 mmol) was added dropwise to the reaction solution while maintaining -20 ° C, and the reaction was carried out at -20 ° C for 1 hour. The reaction was naturally raised to room temperature and the reaction was continued for 2 hours. After completion of the reaction, saturated sodium hydrogencarbonate (20 mL) was added dropwise to the reaction mixture, which was extracted with methyl t-butyl ether (25 mL×4), and the organic phase was combined, and then saturated ammonium chloride solution (40 mL×3), a saturated saline solution (30mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, to give a khaki solid 17a (400mg, yield 84%).

MS m/z (ESI): 238.2 [M+H ⁺ ].

Second step: 1,2-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium benzene sulfonate ( 17b )

1,2-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

17a (450 mg, 1.9 mmol) was dissolved in dichloromethane (20 mL), hexanes succinic acid 1.5 H ₂ O (526.8 mg, 2.85 mmol) was added and allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give 17b (yield: 570 mg, yield: 100%).

MS m/z (ESI): 138.2 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1,2-dimethylpyrrolo[3,4-d]imidazole -5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 17c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1,2-dimethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) Tetrahydro-2H-pyran-3-yl)carbamate

17b (561.3 mg, 1.9 mmol) was dissolved in N,N-dimethylacetamide (10 mL) at room temperature, and intermediate 1 (683.7 mg, 2.1 mmol) was added, and the reaction was carried out at room temperature for 1 hour. . The temperature was lowered to 0 ° C or lower, and sodium tris(ethyloxy)borohydride (885.9 mg, 4.18 mmol) was added to the reaction mixture, and the mixture was reacted at room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and water (60 mL) and aqueous ammonia (5 mL) were successively added to the reaction liquid, and extracted with dichloromethane (60 mL×4), and the organic phase was combined, and then water (40 mL×2) and saturated aqueous salt solution (40mL × 1) washing, drying with anhydrous magnesium sulfate, filtration, concentration of the filtrate, separation and purification by column chromatography (dichloromethane / methanol (v / v) = 100:1 ~ 70:1, adding a small amount of ammonia), Earthy solid 17c (370 mg, yield 39%).

MS m/z (ESI): 449.2 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1,2-dimethylpyrrolo[3,4-d]imidazole-5 (1H, 4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 17 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1,2-dimethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H- Pyran-3-amine

17c (350 mg, 0.78 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C, trifluoroacetic acid (5 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dichloromethane (30 mL), and then evaporated. The organic phases were combined and washed with brine brine (30 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated. .

MS m/z (ESI): 349.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23-7.08 (m, 3H), 4.30-4.28 (d, 1H), 4.26-4.22 (m,1H),3.93-3.91(t,2H),δ3.81-3.80(t,2H),3.55(s,3H),3.42-3.37(t,1H),3.09-3.03(m,1H) , 2.94 - 2.88 (m, 1H), 2.47 - 2.43 (m, 1H), 2.35 (s, 3H), 1.54-1.45 (q, 1H).

Example 18

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-methylpyrrolo[3,4-d]imidazole-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 18 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro- 2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate (18a)

Tert-butyl 1-ethyl-2-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

7B (446.54mg, 2.0mmol) was dissolved in tetrahydrofuran (10mL) at room temperature, cooled to -20 ° C, sodium hexamethyldidecylamino (1.1mL, 2mol / L, 2.2mmol) was added dropwise In the reaction mixture, stirring was continued for 30 minutes. While maintaining -20 ° C, ethyl iodide (623.88 mg, 4.0 mmol) was added dropwise to the reaction liquid, and the reaction was carried out at -20 ° C for 1 hour. The reaction was continued to room temperature for 4 hours. After completion of the reaction, saturated sodium hydrogencarbonate (25 mL) was added dropwise to the reaction mixture, which was extracted with methyl t-butyl ether (30 mL × 4), and the organic phase was combined with saturated ammonium chloride solution (30 mL×2). The mixture was washed with saturated aqueous sodium chloride (30 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (v/v) (v/v) = 100:1~70: 1) A pale yellow viscous liquid 18a (500 mg, yield 99%) was obtained.

MS m/z (ESI): 2521. [M+H ⁺ ].

Second step: 1-ethyl-2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 18b )

1-ethyl-2-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

18a (500mg, 1.99mmol) was dissolved in a mixed solvent of dichloromethane (20mL) and methanol (10mL), benzenesulfonic acid 1.5 H ₂ O (555.60mg, 3.0mmol) was added and reacted at room temperature. 16 hours. The reaction solution was concentrated under reduced pressure to give 18b (yield: 650 mg, yield: 100%).

MS m/z (ESI): 1521. [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-methylpyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 18c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)- Yl)tetrahydro-2H-pyran-3-yl)carbamate

18b (615.7 mg, 1.99 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and Intermediate 1 (654.2 mg, 2.0 mmol) was added and stirred at room temperature for 1 hour. . After dropping to 0 ° C, sodium tris(acetoxy)borohydride (932.5 mg, 4.4 mmol) was added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The reaction solution was cooled to 0 ° C, and water (30 mL) and aqueous ammonia (5 mL) were successively added to the reaction liquid, and extracted with dichloromethane (40 mL×4), and the organic phase was combined, and then water (30 mL×2) and saturated aqueous salt solution (30 mL × 1) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 100:1 to 30:1) to give brown solid 18c ( 462.5 mg, yield 50%).

MS m/z (ESI): 463.2 [M+H ⁺ ].

Fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-methylpyrrolo[3,4-d]imidazole-5 ( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 18 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro- 2H-pyran-3-amine

18c (462.5 mg, 1.0 mmol) was dissolved in dichloromethane (16 mL), cooled to 0 ° C, and trifluoroacetic acid (8 mL) was added dropwise. The reaction mixture was concentrated under reduced pressure and dichloromethane (30 mL), and then evaporated. The organic phases were combined and washed with brine brine (30 mL×1). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure, and then purified by chromatography (dichloromethane/methanol (v/v) = 10:1) to give brown viscous liquid compound 18 (140 mg, yield 38%) ).

MS m/z (ESI): 363.2 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23 - 7.07 (m, 3H), 4.30 - 4.27 (d, 1H), 4.26 - 4.22 (m,1H), 3.97-3.91 (m, 4H), 3.81-3.80 (t, 2H), 3.42-3.37 (t, 1H), 3.09-3.04 (m, 1H), 2.93-2.86 (m, 1H) , 2.47-2.43 (m, 1H), 2.37 (s, 3H), 1.53-1.44 (q, 1H), 1.37-1.33 (t, 3H).

Example 19

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,4- d] imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( compound 19 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-methyl-1-(2,2,2-trifluoroethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Formate ( 19a )

Tert-butyl 2-methyl-1-(2,2,2-trifluoroethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

7B (446.54 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature, then cooled to -20 ° C, then potassium carbonate (557.04 mg, 2.4 mmol), 1,1-Trifluoro-2-((trifluoromethyl)sulfonyl)ethane (331.2 mg, 2.4 mmol) was added to the reaction mixture, and the mixture was stirred to room temperature and stirred for 16 hr. After completion of the reaction, water (50 mL) was added dropwise to the reaction mixture, which was extracted with methyl t-butyl ether (30 mL × 4), and the organic phase was combined with water (30 mL×2) and brine (30 mL×1) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol (v/v) = 100:1 to 70:1) to give a pale yellow thick. Liquid 19a (580 mg, yield 94%).

MS m/z (ESI): 306.1 [M+H ⁺ ].

Second step: 2-methyl-1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 19b )

2-methyl-1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

A mixture of 19a (580mg, 1.9mmol) was dissolved in dichloromethane (5mL) was added benzenesulfonic acid _{1.5 H 2 O (527.8mg, 2.85mmol} ), the reaction at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give 19b (yield: 690mg).

MS m/z (ESI): 206.1 [M+H ⁺ ].

The third step: the third butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(2,2,2-trifluoroethyl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 19c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

19b (690.4mg, 1.9mmol) was dissolved in N,N-dimethylacetamide (6mL), and then added to intermediate 1 (621.5mg, 1.9mmol), and stirred at room temperature for 1 hour. . After dropping to 0 ° C, sodium tris(ethyloxy)borohydride (926.2 mg, 4.37 mmol) was added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The reaction liquid was cooled to 0 ° C, and water (12 mL) and aqueous ammonia (4 mL) were successively added to the reaction liquid to precipitate a solid yellow solid. Filtration, the filter cake was washed with water (10 mL×2), petroleum ether (10 mL×2), and dried. The filter cake was dissolved in dichloromethane (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Chromatograph separation and purification (dichloromethane/methanol (v/v) = 100:1 to 20:1, with a small amount of aqueous ammonia) afforded a solid yellow solid 19c (360 mg, yield 36%).

MS m/z (ESI): 517.2 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(2,2,2-trifluoroethyl)pyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 19 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)tetrahydro-2H-pyran-3-amine

19c (300 mg, 0.58 mmol) was dissolved in dichloromethane (12 mL), cooled to 0 ° C, and trifluoroacetic acid (6 mL) was added dropwise to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dichloromethane (30 mL), and then evaporated. The organic phases were combined and washed with brine brine (30 mL×1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated. .

MS m/z (ESI): 417.1 [M+H ⁺ ]; 1H NMR (400 MHz, CD ₃ OD): δ 7.23 - 7.08 (m, 3H), 4.81-4.77 (q, 2H), 4.29 - 4.27 ( d, 1H), 4.25-4.21 (m, 1H), 3.96-3.96 (m, 2H), 3.84-3.82 (m, 2H), 3.42-3.36 (t, 1H), 3.10-3.03 (m, 1H), 2.92-2.86 (m, 1H), 2.48-2.44 (m, 1H), 2.42 (s, 3H), 1.53-1.44 (q, 1H).

Example 20

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,1-dimethyl-1, 4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 20 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,1-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazole-2-carboxamide

First step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylaminomethylmethyl)pyrrolo [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 20a )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylcarbamoyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

7b (200 mg, 0.39 mmol) was mixed with a methylamine/methanol solution (15 mL, 2 mol/L), sealed, and the mixture was warmed to 85 ° C for 16 hours. The reaction was cooled to room temperature and concentrated to dryness to give a pale yellow solid 20a (190mg, 99%), was used directly in the next reaction.

MS m/z (ESI): 4921. [M+H ⁺ ].

Second step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,1-dimethyl 1,-,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 20 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,1-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazole-2-carboxamide

20a (190mg, 0.387mmol) was dissolved in dichloromethane (6mL) at room temperature, cooled to 0 ° C, trifluoroacetic acid (3mL) was added dropwise to the reaction solution, added, stirred at room temperature 2 hour. The reaction solution was concentrated under reduced pressure and dichloromethane (30 mL), and then evaporated and evaporated. The organic phases were combined and washed with brine brine (30 mL×1). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated.

MS m/z (ESI): 392.2 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23 - 7.08 (m, 3H), 4.31-4.29 (d, 1H), 4.28-4.23 (m,1H),3.99-3.98(t,2H),3.95(s,3H),3.85-3.84(t,2H),3.43-3.38(t,1H),3.12-3.05(m,1H),2.96 - 2.92 (m, 1H), 2.88 (s, 3H), 2.48-2.44 (m, 1H), 1.55-1.47 (q, 1H).

Example 21

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid ( Compound 21 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxylic acid

First step: 5-((3R,5S,6R)-5-((t-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid ( 21a )

5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4, 5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid

7b (202.6mg, 0.4mmol) was dissolved in methanol (10mL), cooled to 0 ° C, a mixture of lithium hydroxide hydrate (21.8mg, 0.52mmol) and water (10mL) was added to the reaction solution, added It was allowed to react to room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and dissolved with dichloromethane (30 mL). 3 mol/L hydrochloric acid (15mL) was added dropwise to the reaction mixture to adjust the pH to 4~5, and the liquid phase was separated with dichloromethane (30mL×5) extraction. The organic phases were combined and washed with brine brine (30 mL×1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid 21a (120mg, yield 62%).

MS m/z (ESI): 479.1 [M+H ⁺ ].

Second step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid ( Compound 21 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxylic acid

21a (80 mg, 0.16 mmol) was dissolved in dichloromethane (8 mL), cooled to 0 ° C, trifluoroacetic acid (3 mL) was added dropwise to the reaction mixture, and stirring was continued for 2 hours. The reaction mixture was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol = 10: 1) to give white solid compound 21 (22mg, 22% yield).

_{^{1 H NMR (400MHz, CD 3}} OD): δ7.28-7.16 (m, 3H), 4.51-4.49 (d, 1H), 4.30-4.26 (m, 1H), 3.98-3.94 (m, 2H), 3.94 (s, 3H), 3.88-3.81 (m, 2H), 3.49-3.43 (t, 1H), 3.35-3.30 (m, 1H), 3.18-3.10 (m, 1H), 2.56-2.51 (m, 1H) , 1.70-1.62 (q, 1H).

Example 22

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,N,1-trimethyl- 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 22 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,N,1-trimethyl-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidaz Ole-2-carboxamide

First step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(dimethylaminomethylmethyl)-1-methylpyrrole [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 22a )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(dimethylcarbamoyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H )-yl)tetrahydro-2H-pyran-3-yl)carbamate

21a (150 mg, 0.31 mmol) was dissolved in dichloromethane (10 mL), followed by 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluoro Phosphate (143.4 mg, 0.37 mmol) and triethylamine (47.6 mg, 0.47 mmol) were stirred at room temperature for 30 min. The temperature was lowered to 0 ° C, and a solution of dimethylamine tetrahydrofuran (0.17 mL, 0.34 mmol, 2 mol/L) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Dichloromethane (30 mL) was added dropwise to the reaction mixture, which was washed with saturated aqueous brine (30 mL×1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid was purified by thin layer chromatography (dichloromethane / methanol (v / v) = 10: 1) to afford a pale gray solid 22a (90mg, yield The rate is 56.6%).

MS m/z (ESI): 506.3 [M+H ⁺ ].

Second step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,N,1- Trimethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 22 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,N,1-trimethyl-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

22a (90 mg, 0.17 mmol) was dissolved in dichloromethane (8 mL), cooled to 0 ° C, trifluoroacetic acid (4mL) was added dropwise, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure and dichloromethane (30 mL), and then evaporated and evaporated. The organic phases were combined and washed with brine brine (30 mL×1). The organic layer was dried over anhydrous sodium sulfate (MgSO4) .

MS m/z (ESI): 406.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.24 - 7.12 (m, 3H), 4.39 - 4.37 (d, 1H), 4.31-4.25 (m, 1H), 4.01-4.00 (t, 2H), 3.89-3.88 (m, 2H), 3.74 (s, 3H), 3.46-3.41 (t, 1H), 3.24 (s, 3H), 3.16-3.13 (t, 1H), 3.10 (s, 3H), 2.53-2.46 (m, 1H), 2.37-2.33 (m, 1H), 1.62-1.53 (q, 1H).

Example 23

2-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-2,3,7,8-tetrahydro -1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyrazine-5(6H)-one (Compound 23)

2-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-2,3,7,8-tetrahydro-1H-pyrrolo[3 ',4':4,5]imidazo[1,2-a]pyrazin-5(6H)-one

First step: 5-t-butyl 2-ethyl 1-(2-(((benzyloxy)carbonyl))amino)ethyl)-4,6-dihydropyrrolo[3,4-d]imidazole- 2,5(1H)-dicarboxylate ( 23a )

5-tert-butyl 2-ethyl 1-(2-(((benzyloxy)carbonyl)amino)ethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

Intermediate 5 (600 mg, 2.13 mmoL) was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (494.0 mg, 3.58 mmol) was added, and reacted for 10 minutes at room temperature, then benzyl (2) was added. -Bromoethyl)carbamic acid tert-butyl ester (660.8 mg, 2.56 mmol) was reacted at room temperature for 16 hours. The reaction solution was poured into water (40 mL), extracted with methyl-tert-butyl ether (60 mL×3), and the organic phase was combined and washed with water (40 mL×2) and saturated sodium chloride solution (40 mL×1) , dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 100: 1 ~ 40: 1), to give a pale yellow liquid 23a (980mg).

MS m/z (ESI): 459.2 [M+H ⁺ ].

Second step: tert-butyl 5-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyrazine- 2(3H)-formate ( 23b )

Tert-butyl 5-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyrazine-2(3H)-carboxylate

23a (917 mg, 2.00 mmol) was dissolved in ethanol (30 mL), palladium carbon (180 mg, wt = 10%) was added, and the reaction system was evacuated, replaced with hydrogen three times, and heated to 60 ° C for 16 hours. The pad diatomaceous earth was suction filtered, filtered, and the filter cake was washed with methanol (15 mL×3). The filtrate was concentrated and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 100: 1 ~ 25: 1), to give a white solid 23b (510mg, 92% yield).

MS m/z (ESI): 279.1 [M+H ⁺ ].

Third step: 2,3,7,8-tetrahydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyrazine-5(6H)-ketobenzenesulfonic acid Salt ( 23c )

2,3,7,8-tetrahydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyrazin-5(6H)-one benzenesulfonate

23b (500 mg, 1.80 mmol) and benzenesulfonic acid 1.5 H ₂ O (500 mg, 2.70 mmol) were dissolved in dichloromethane (20 mL), and the mixture was warmed to 40 ° C for 16 hours. The reaction mixture was concentrated to give an off-white solid 23c (610mg), used directly in the next reaction.

Fourth step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-oxo-5,6,7,8-tetrahydro-1H -pyrrolo[3',4':4,5]imidazo[1,2-a]pyrazine-2(3H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 23d )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[3',4':4 ,5]imidazo[1,2-a]pyrazin-2(3H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

23c (605.5mg, 1.80mmoL) and intermediate 1 (588.8mg, 1.80mmoL) were dissolved in N,N-dimethylacetamide (8mL), stirred at room temperature for 1 hour, below 0 °C, added three (Ethyloxy) sodium borohydride (915.6 mg, 4.32 mmol) was reacted at room temperature for 3 hours. After cooling to 0 ° C or less, water (25 mL) and ammonia water (5 mL) were added to the reaction liquid. After filtration, the filter cake was washed with water (10 mL×2) and petroleum ether (10 mL×2) and dried. The filter cake was dissolved in a mixed solution (150 mL) of dichloromethane/methanol (v/v) = 20:1. Dried over anhydrous sodium sulfate, filtered, and concentrated to give an off-white solid 23d (380mg, 43% yield).

MS m/z (ESI): 490.2 [M+H ⁺ ].

Step 5: 2-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-2,3,7, 8-tetrahydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyrazine-5(6H)-one (Compound 23)

2-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-2,3,7,8-tetrahydro-1H-pyrrolo[3 ',4':4,5]imidazo[1,2-a]pyrazin-5(6H)-one

23d (350mg, 0.715mmoL) was added to dichloromethane (12mL), trifluoroacetic acid (6mL) was added dropwise in an ice bath, and the mixture was reacted at room temperature for 2 hours. The reaction solution was spin-dried at a temperature lower than 30 ° C, dichloromethane (50 mL) was added, the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution (25 mL), and the mixture was separated, and the aqueous phase was mixed with dichloromethane/isopropanol. (30 mL × 8, v/v = 3:1) extraction. The combined organic layers were dried with anhydrous sodium s Purification by preparative separation gave Compound 23 (40 mg, yield 10%) as white solid.

MS m/z (ESI): 390.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23-7.08 (m, 3H), 4.30-4.23 (m, 4H), 4.01-4.00 (t, 2H), 3.89-3.88 (t, 2H), 3.72-3.69 (m, 2H), 3.44 - 3.39 (t, 1H), 3.13 - 3.07 (m, 1H), 2.93 - 2.88 (m, 1H) , 2.48-2.44 (m, 1H), 1.55-1.47 (q, 1H).

Example 24

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydro Pyrrolo[3,4-d]imidazole-2-carbonitrile ( Compound 24 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-p Yran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonitrile

First step: tert-butyl 2-carbamoyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 24a )

Tert-butyl 2-carbamoyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 5 (5.00 g, 17.79 mmol) was dissolved in ammonia-methanol (50 mL). Methyl tert-butyl ether (20mL) was stirred, filtered, and the filter cake was washed with methyl tert-butyl ether (20mL × 3), to give a white solid 24a (3.5g, 78% yield).

MS m/z (ESI): 253.1 [M+H ⁺ ].

Second step: tert-butyl 2-cyano-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 24b )

Tert-butyl 2-cyano-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

24a (2.10g, 8.33mmol) was dissolved in N,N-dimethylformamide (53mL), and N-(triethylammoniumsulfonyl)carbamate (9.93g, 41.67mmol) was added at room temperature. Stir for 17 hours. Water (500 mL) was added to the reaction mixture, and extracted with ethyl acetate (200 mL×2), and the organic phase was combined with saturated sodium chloride solution (500 mL×1), saturated sodium hydrogen carbonate solution (500 mL×1), saturated The sodium solution (500 mL × 1) was washed, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (dichloromethane / methanol (v / v) = 50: 1), to give the crude product 24b as a white solid (2.1g).

MS m / z (ESI): 235.1 [M + H +]; 1 H NMR (400MHz, DMSO- d 6): 4.37-4.36 (d, 4H), 1.45 (s, 9H).

The third step: 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonitrile besylate ( 24c )

1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonitrile benzenesulfonate

24b (500 mg, 2.14 mmol) was dissolved in dichloromethane (25 mL), benzenesulfonic acid 1.5 H ₂ O (594 mg, 3.21 mmol) was added, and the reaction was carried out at 40 ° C for 17 hours. The solution was concentrated under reduced pressure to give the crude product 24c as a brown solid, cast directly in the next reaction.

MS m/z (ESI): 135.1 [M+H ⁺ ].

Fourth step: tert-butyl ((2R,3S,5R)-5-(2-cyanopyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2-( 2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 24d )

Tert-butyl((2R,3S,5R)-5-(2-cyanopyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro- 2H-pyran-3-yl)carbamate

Intermediate 1 (839 mg, 2.57 mmol) was dissolved in N,N-dimethylacetamide (15 mL), and then added to 24c (625 mg, 2.14 mmol). After the ice bath was cooled to 0 ° C, sodium tris(ethyloxy) borohydride (903 mg, 4.28 mmol) was added, and the mixture was stirred from 0 ° C to room temperature and stirred for 4 hours. The reaction was completed, and the mixture was cooled with ice-cooled. Water (20 mL), EtOAc (2 mL), EtOAc (EtOAc) , filtered and the filtrate was concentrated under reduced pressure, the residue was separated by column chromatography (dichloromethane / methanol (v / v) = 50: 1), to give a brown solid 24d (689mg, 72% yield).

MS m/z (ESI): 446.2 [M+H ⁺ ].

Step 5: 5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5, 6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonitrile ( Compound 24 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d Imididazole-2-carbonitrile

24d (650 mg, 1.46 mmol) was dissolved in dichloromethane (10 mL). EtOAc (EtOAc m. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjj purification by column chromatography (dichloromethane / methanol (v / v) = 60: 1 ~ 15: 1, adding a small amount of ammonia) to give a yellow solid compound 24 (63mg, 12% yield).

MS m/z (ESI): 346.2 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): 8.32 (s, 1H), 7.17-7.03 (m, 3H), 4.41-4.39 (d, 1H) ), 4.22-4.19 (m, 1H), 3.91-3.84 (t, 4H), 3.40-3.34 (m, 1H), 3.12-3.03 (m, 1H), 2.46-2.43 (dd, 1H), 1.94-1.88 (m, 1H), 1.62-1.56 (t, 1H).

Example 25

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonitrile ( Compound 25 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carbonitrile

First step: tert-butyl 2-cyano-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 25a )

Tert-butyl 2-cyano-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

24b (600mg, 2.56mmol) was dissolved in N,N-dimethylformamide (30mL), potassium carbonate (709mg, 5.12mmol) was added, the temperature was lowered to 0 ° C, and ethyl iodide (1200mg, 7.69mmol) was added dropwise. The reaction was naturally stirred up to room temperature for 5 hours. Water (80 mL) was added to the mixture and the mixture was evaporated, evaporated, evaporated, evaporated The residue was separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 5: 1), to give crude product 25a as a brown oil (800mg).

MS m/z (ESI): 235.1 [M+H ⁺ ].

The second step: 1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonitrile besylate ( 25b )

1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonitrile benzenesulfonate

25a (672.59 mg, 2.56 mmol) was dissolved in dichloromethane (30 mL), benzenesulfonic acid 1.5 H ₂ O (730 mg, 3.94 mmol) was added and reacted at 40 ° C for 17 hours. The solution was concentrated under reduced pressure to give the crude product as a brown solid 25b.

MS m/z (ESI): 135.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-5-(2-cyano-1-ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl )-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 25c )

Tert-butyl((2R,3S,5R)-5-(2-cyano-1-ethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5- Difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

Intermediate 1 (1005 mg, 3.07 mmol) was dissolved in N,N-dimethylacetamide (10 mL), 25b (820.50 mg, 2.56 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and cooled to an ice bath. After 0 ° C, sodium tris(ethyloxy)borohydride (1080 mg, 5.12 mmol) was added, and the mixture was stirred from 0 ° C to room temperature and stirred for 2 hr. The ice bath was cooled, water (25 mL) and aqueous ammonia (2.5 mL) were added to the reaction mixture, stirred for 20 minutes, filtered, and the filter cake was washed with water (50 mL×6), and the filter cake was separated by column chromatography (dichloromethane/methanol) (v/v) = 50: 1) gave a brown solid 25c (1.05 mg, yield 87%).

MS m/z (ESI): 474 [M+H ⁺ ].

Fourth step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carbonitrile ( Compound 25 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carbonitrile

25c (1.00 g, 2.11 mmol) was dissolved in methylene chloride (15 mL). EtOAc (EtOAc,EtOAc. The solution was concentrated under reduced pressure. Water (20 mL), EtOAc (EtOAc) The solution was concentrated under reduced pressure, the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 60: 1 ~ 15: 1, adding a small amount of ammonia) to give a yellow solid compound 25 (332mg, 42% yield) .

MS m/z (ESI): 374.2 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): 7.24-7.11 (m, 3H), 4.57 (s, 1H), 4.32-4.21 (m, 4H) ), 4.27-4.06 (t, 2H), 3.88-3.86 (t, 2H), 3.45-3.40 (t, 1H), 3.16-3.09 (m, 1H), 2.96-2.90 (m, 1H), 2.48-2.44 (m, 1H), 1.51-1.47 (t, 3H).

Example 26

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-((S)-tetrahydrofuran-3-yl)pyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 26 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-((S)-tetrahydrofuran-3-yl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: (S)-tetrahydrofuran-3-ylmethylsulfonate ( 26b )

(S)-tetrahydrofuran-3-yl methanesulfonate

26a (7.05 g, 80.0 mmol) was dissolved in dichloromethane (80 mL), cooled to 0 ° C, triethylamine (10.5 g, 104.0 mmol) was added and stirred for 10 min. Methylsulfonium chloride (10.94 g, 96.0 mmol) was added dropwise to the reaction mixture, and the reaction was stirred at room temperature for 4 hours. The reaction solution was filtered, and the filter cake was washed with dichloromethane (30 mL×3), and the organic phase was washed successively with water (30mL×2) and saturated aqueous salt solution (30mL×2). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid 26b (10.2g).

The second step: (S)-t-butyl 2-methyl-1-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Acid ester ( 26c )

(S)-tert-butyl 2-methyl-1-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

7B (223.2 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL), EtOAc (EtOAc) 26b (216.1 mg, 1.2 mmol) was added to the reaction liquid, and the reaction was stirred at room temperature for 1 hour, and the temperature was raised to 80 ° C to continue the reaction for 16 hours. The reaction solution was cooled to room temperature, poured into ice water (30 mL), EtOAc (30 mL, 1), and the organic phase was combined and washed with water (30 mL×3) and brine (30 mL×1). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a brown liquid 26c (300mg).

MS m/z (ESI): 29422 [M+H ⁺ ].

The third step: (S)-2-methyl-1-(tetrahydrofuran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzoate ( 26d )

(S)-2-methyl-1-(tetrahydrofuran-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

26c (586.7 mg, 2.0 mmol) was dissolved in dichloromethane (10 mL), benzenesulfonic acid 1.5 H ₂ O (555.6 mg, 3.0 mmol) was added, and the mixture was reacted at room temperature for 48 hours. The solution was concentrated under reduced pressure to give the crude product 26d as a brown solid (710mg), administered directly in the next reaction.

MS m/z (ESI): 194.2 [M+H ⁺ ].

Fourth step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-((S)-tetrahydrofuran-3-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 26e )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-((S)-tetrahydrofuran-3-yl)pyrrolo[3,4-d] Imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

26d (702.6 mg, 2.0 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and Intermediate 1 (719.7 mg, 2.2 mmol) was added and stirred at room temperature for 1 hour. The temperature was lowered to below 0 ° C, sodium tris(ethyloxy)borohydride (923.5 mg, 4.4 mmol) was added to the reaction solution, and the reaction was carried out for 4 hours at room temperature, and the reaction solution was cooled to 0 ° C in an ice bath. Water (25 mL) and aqueous ammonia (5 mL) were added successively to precipitate a smectite solid, filtered, and the filter cake was washed with water (10 mL×2), petroleum ether (10 mL×2), and the filter cake was dissolved in dichloromethane (150 mL). dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and column chromatographed (dichloromethane / methanol (v / v) = 100: 1 ~ 30: 1), to give a light red solid 26e (400mg, yield 40%).

MS m/z (ESI): 505.2 [M+H ⁺ ].

Step 5: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-methyl-1-((S)-tetrahydrofuran-3-yl)pyrrolo[3 ,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 26 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-((S)-tetrahydrofuran-3-yl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

26e (230 mg, 0.45 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (4 mL) was added dropwise at 0 ° C. The solution was concentrated under reduced pressure. dichloromethane (40 mL) was evaporated and evaporated. The mixture was washed with brine (30 mL×3), dried over anhydrous sodium sulfate Compound ( 26 mg, yield 37%) was obtained as white solid.

MS m/z (ESI): 405.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.21-7.09 (m, 3H), 4.97-4.92 (m, 1H), 4.31-4.29 (d, 1H), 4.26-4.23 (m, 1H), 4.12-4.07 (m, 2H), 4.01-4.00 (t, 2H), 3.91-3.90 (d, 2H), 3.81-3.77 (m, 3H) , 3.42-3.37 (t, 1H), 3.10-3.03 (m, 1H), 2.97-2.91 (m, 1H), 2.60-2.51 (m, 1H), 2.42 (s, 3H), 2.00-1.92 (m, 1H), 1.54-1.45 (q, 1H).

Example 27

(2R,3S,5R)-5-(2-cyclopropylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl Tetrahydro-2H-pyran-3-amine ( Compound 27 )

(2R,3S,5R)-5-(2-cyclopropylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-amine

First step: tert-butyl 2-cyclopropyl-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 27a )

Tert-butyl 2-cyclopropyl-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 2 (5 g, 21.06 mmol) was dissolved in ethanol (250 mL) EtOAc. Cyclopropadienyl hydrochloride (3.3 g, 27.37 mmol) was added to the reaction mixture, and the reaction was refluxed overnight. The reaction mixture was filtered, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Methylene chloride/methanol (v/v) = 30:1 to 10:1) gave pale yellow solid 27a (3.53 g, yield 63%).

MS m/z (ESI): 252.2 [M+H ⁺ ].

Second step: tert-butyl 2-cyclopropyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 27b )

Tert-butyl 2-cyclopropyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

The grass chloroform (2.53g, 20.0mmoL) was dissolved in dry dichloromethane (30mL) under a nitrogen atmosphere at a temperature below -70 ° C for 10 minutes, and dry dimethyl sulfoxide (3.12 g, 39.9) was added dropwise. The solution was mixed with mmoL) and dichloromethane (10 mL) and stirring was continued for 30 minutes. A solution of 27a (3.35 g, 13.3 mmol) in dichloromethane (30 mL) was added dropwise at -70 °C, and stirring was continued for 30 minutes. Diisopropylethylamine (8.61 g, 66.6 mmol) was added dropwise at -70 ° C, and the reaction was continued for 2 hours. The reaction solution was heated to 0 ° C, and a saturated ammonium chloride solution (45 mL) and water (200 mL) were added to the mixture, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (100 mL×3). Washed with saturated ammonium chloride solution (80 mL × 3), saturated sodium chloride solution (80 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography ( petroleum ether / ethyl acetate (v / v) = 10:1 to 1:1) gave a yellow solid 27b (0.8 g, yield 24%).

MS m/z (ESI): 250.2 [M+H ⁺ ].

The third step: 2-cyclopropyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 27c )

2-cyclopropyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

27b (249.3 mg, 1.0 mmoL) was dissolved in dichloromethane (6 mL), benzenesulfonic acid 1.5 H ₂ O (277.8 mg, 1.5 mmoL) was added, and the reaction was stirred at room temperature for 48 hours. The reaction completed, the reaction mixture was concentrated spin-dried to give a yellow solid 27c (310mg), used directly in the next reaction.

MS m/z (ESI): 150.2 [M+H ⁺ ].

Fourth step: tert-butyl ((2R,3S,5R)-5-(2-cyclopropylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2- (2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 27d )

Tert-butyl((2R,3S,5R)-5-(2-cyclopropylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro- 2H-pyran-3-yl)carbamate

A mixture of 27c (307.37mg, 1.0mmol) was dissolved in N, N- dimethylacetamide (5mL) was added Intermediate 1 (327.13mg, 1.0mmol), the addition was completed stirring at rt for 1 h . Sodium (Ethyloxy)borohydride (487.46 mg, 2.3 mmol) was added to the reaction mixture at 0 ° C or lower, and the mixture was reacted at room temperature for 3 hours. The mixture was cooled to 0 ° C, and then water (20 mL) and brine (5 mL) was added, and the mixture was extracted with methylene chloride (300 mL × 4). the filtrate was concentrated under reduced pressure and spin-dried, separated and purified by column chromatography (dichloromethane / methanol (v / v) = 100: 1, adding a small amount of ammonia), to give a khaki solid 27d (230mg, 49% yield).

MS m / z (ESI): 461.2 [M + H +].

Step 5: (2R, 3S, 5R)-5-(2-cyclopropylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5- Difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 27 )

(2R,3S,5R)-5-(2-cyclopropylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-amine

27d (220mg, 0.47mmoL) was added to dichloromethane (8mL), below 0 ° C, trifluoroacetic acid (5mL) was added dropwise, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was dried with EtOAc EtOAc (EtOAc)EtOAc. The combined organic phases were washed with brine (25 mL×1), dried over anhydrous sodium sulfate. The compound 27 (80 mg, yield 46%) was obtained as pale yellow solid.

MS m/z (ESI): 361.2 [M+H+]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.21 - 7.08 (m, 3H), 4.30 - 4.27 (d, 1H), 4.24 - 4.20 ( m, 1H), 3.83 (s, 4H), 3.41-3.36 (t, 1H), 3.08-3.03 (m, 1H), 2.94-2.88 (m, 1H), 2.46-2.41 (m, 1H), 1.97- 1.91 (m, 1H), 1.53-1.44 (q, 1H), 0.97-0.83 (q, 5H).

Example 28

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 28 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 28a )

Tert-butyl 1-ethyl-2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 6 (0.500 g, 1.74 mmol) was dissolved in N,N-dimethylformamide (5 mL), cooled to 0 ° C, then added potassium carbonate (0.480 g, 3.48 mmol), reaction 10 After a minute, ethyl iodide (0.539, 3.48 mmol) was quickly added, and the reaction was carried out at 0 ° C for 2 hours. The reaction mixture was diluted with water (10 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. Distillation gave a yellow solid 28a (0.328 g, yield 60%).

MS m/z (ESI): 316.1 [M+H ⁺ ].

The second step: 1-ethyl-2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 28b )

1-ethyl-2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

28a (0.221 g, 0.70 mmol) and benzenesulfonic acid 1.5 H ₂ O (0.194 g, 1.05 mmol) were dissolved in dichloromethane (10 mL). The reaction solution was concentrated under reduced pressure to give 28b (0.261 g).

MS m/z (ESI): 216.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methylsulfonyl)pyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 28c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

28b (0.261 g, 0.67 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and Intermediate 1 (0.241 g, 0.74 mmol). Sodium (Ethyloxy)borohydride (0.284 g, 1.34 mmol) was added to the reaction mixture at 0 ° C or less. After the addition, the mixture was allowed to react to room temperature for 16 hours. The reaction mixture was cooled to 0 ° C, and water (20 mL) and aqueous ammonia (2 mL) were added to the mixture to adjust to pH 8 and extracted with dichloromethane (50 mL×3), and the organic phase was combined and washed with a saturated aqueous salt solution (50 mL×1). dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness and column chromatography (dichloromethane / methanol (v / v) = 50: 1) was purified to give a white solid 28c (0.28g, 79% yield).

MS m/z (ESI): 527.1 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methylsulfonyl)pyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 28 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

28c (0.16g, 0.30mmol) was dissolved in dichloromethane (5mL), cooled to 0 ° C, added trifluoroacetic acid (2.5mL), added, and reacted at 0 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc)EtOAc. The organic phases were combined and washed with brine brine (50 mL×1). The organic layer was dried over anhydrous magnesium sulfate (MgSO4) .

MS m/z (ESI): 427.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.13 - 6.98 (m, 3H), 4.34 - 4.27 (q, 2H), 4.21-4.19 (d,1H), 4.18-4.14(m,1H), 3.96-3.95(t,2H), 3.78-3.77(t,2H),3.34-3.29(m,1H),3.20(s,3H),3.05 - 2.97 (m, 1H), 2.86-2.80 (m, 1H), 2.38-2.35 (m, 1H), 1.46-1.40 (q, 1H), 1.37-1.33 (t, 3H).

Example 29

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-1-(2,2,2-trifluoroethyl)pyrrole [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 29 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-1-(2,2,2-trifluoroethyl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-(methyl fluorene)-1-(2,2,2-trifluoroethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H)-formate ( 29a )

Tert-butyl 2-(methylsulfonyl)-1-(2,2,2-trifluoroethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 6 (0.450 g, 1.56 mmol) was dissolved in N,N-dimethylformamide (5 mL), cooled to 0 ° C, then potassium carbonate (0.260 g, 1.88 mmol) After a minute, trifluoroethyl trifluoromethanesulfonate (0.436 g, 1.88 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was added dropwise with water (50 mL), and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Ether/ethyl acetate (v/v) = 3:1) gave yellow liquid 29a (0.230 g, yield 39%).

MS m/z (ESI): 370.1 [M+H ⁺ ].

Second step: 2-(methylsulfonyl)-1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzene Sulfonate ( 29b )

2-(methylsulfonyl)-1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

29a (0.230 g, 0.62 mmol) and benzenesulfonic acid 1.5 H ₂ O (0.173 g, 0.93 mmol) were dissolved in dichloromethane (10 mL). The reaction solution was concentrated under reduced pressure to give 29b (0.281 g).

MS m/z (ESI): 270.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-1-(2,2, 2-Trifluoroethyl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 29c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-1-(2,2,2-trifluoroethyl)pyrrolo[3,4-d] Imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

29b (0.281 g, 0.62 mmol) was dissolved in N,N-dimethylacetamide (4 mL), and Intermediate 1 (0.243 g, 0.74 mmol) was added and stirred at room temperature for 60 min. . Sodium tris(ethenyloxy)borohydride (0.288 g, 1.36 mmol) was added to the reaction mixture at 0 ° C, and the mixture was allowed to react to room temperature for 3 hours. The reaction mixture was cooled to 0 ° C, and water (20 mL) and aqueous ammonia (2 mL) were added to the mixture to adjust to pH 8 and extracted with dichloromethane (50 mL×3), and the organic phase was combined and washed with a saturated aqueous salt solution (50 mL×1). dried over anhydrous magnesium sulfate, filtered, rotary drying, silica gel column chromatography (methylene chloride / methanol (v / v) = 60: 1) was purified as a white solid 29c (0.210g, 58% yield).

MS m/z (ESI): 581.1 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-1-(2,2,2-trifluoroethyl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 29 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-1-(2, 2,2-trifluoroethyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

29c (0.198 g, 0.34 mmol) was dissolved in dichloromethane (4 mL), cooled to 0 ° C, trifluoroacetic acid (2 mL) was added, and the mixture was reacted at 0 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuo.EtOAc m. The organic phases were combined and washed with brine brine (50 mL×1). The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

MS m/z (ESI): 481.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.13 - 6.96 (m, 3H), 5.22 - 5.15 (q, 2H), 4.20 - 4.18 (d,1H), 4.17-4.12(m,1H), 3.96-3.95(d,2H),3.82-3.80(t,2H),3.33-3.28(t,1H),3.03-2.98(m,1H) , 2.84-2.78 (m, 1H), 2.37-2.33 (m, 1H), 1.45-1.36 (q, 1H), 1.19 (s, 3H).

Example 30

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)-1-methylpyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 30 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-(ethylthio)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-formate ( 30a )

Tert-butyl 2-(ethylthio)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

6A (2.0 g, 8.26 mmol) was dissolved in ethanol (50 mL) at room temperature, warmed to 50 ° C, and ethyl iodide (3.86 g, 24.8 mmol) was quickly added and reacted for 16 hours. The reaction mixture was vortexed to give a yellow oil. To the oil was added dichloromethane (150 mL), water (300 mL), and the aqueous phase was adjusted to pH 9 with saturated sodium carbonate solution (50 mL). methane (300mL × 3). the combined organic phases were washed with saturated aqueous sodium chloride (100mL × 1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 30a (2.0g, 94% yield).

MS m/z (ESI): 272.2 [M+H ⁺ ].

Second step: tert-butyl 2-(ethylthio)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 30b )

Tert-butyl 2-(ethylthio)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

The grasshopper chlorine (1.27 g, 9.90 mmol) was dissolved in dichloromethane (10 mL) at room temperature under a nitrogen atmosphere, and the mixture was cooled to -78 ° C, and dimethyl hydrazine (1.56 g, 20.0 mmol) was gradually added dropwise. A solution of dichloromethane (20 mL) was added and maintained at -78 ° C for 30 minutes. A solution of 30a (2.0 g, 6.60 mmol) in dichloromethane (20 mL) was slowly added dropwise and the mixture was reacted at -78 ° C for 15 min. N,N-Diisopropylethylamine (4.3 g, 33.2 mmol) was added dropwise, and the mixture was allowed to react to room temperature for 3 hours. Dichloromethane (50 mL) and water (20 mL) were added to the reaction mixture, and the organic phase was separated, and the organic phase was washed with saturated aqueous sodium chloride (50 mL×1), dried over anhydrous sodium sulfate, filtered, and evaporated. Chromatography (dichloromethane / methanol = 150:1) afforded a yellow solid 30b (1.25 g, yield 71%).

MS m/z (ESI): 270.1 [M+H ⁺ ].

Third step: tert-butyl 2-(ethylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate ( 30c )

Tert-butyl 2-(ethylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

30b (1.25g, 4.6mmol) was dissolved in dichloromethane (60 mL) at room temperature, m-chloroperoxybenzoic acid (2.4 g, 14 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with a saturated sodium thiosulfate solution (30 mL), and then the mixture was evaporated to dichloromethane (100 mL), water (30 mL), and the organic phase was separated, and a 15% sodium hydroxide solution was added dropwise to the organic phase ( 10 mL) The pH was adjusted to 7, and the organic phase was separated. The organic phase was washed with saturated aqueous brine (50 mL×1), dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. /v) = 100: 1) gave a yellow solid 30c (1.0 g, yield 72%).

MS m/z (ESI): 3021. [M+H ⁺ ].

Fourth step: tert-butyl 2-(ethylsulfonyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 30d) )

Tert-butyl 2-(ethylsulfonyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

30c (0.50g, 1.66mmol) was dissolved in N,N-dimethylformamide (10mL) at room temperature, cooled to 0 ° C, potassium carbonate (0.276 g, 2.0 mmol) was added, and the reaction was carried out for 10 minutes. Methyl iodide (0.282 g, 2.0 mmol) was added, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was poured into water (200 mL), and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Petroleum ether / ethyl acetate (v / v) = 3:1) gave a yellow solid 30d (0.45 g, yield 87%).

MS m/z (ESI): 316.1 [M+H ⁺ ].

Step 5: 2-(Ethylsulfonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 30e )

2-(ethylsulfonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

30 d (0.428 g, 1.36 mmol) and benzenesulfonic acid 1.5 H ₂ O (0.377 g, 2.0 mmol) were dissolved in dichloromethane (10 mL). The reaction mixture was concentrated under reduced pressure to give a white solid 30e (0.507 g).

MS m/z (ESI): 216.1 [M+H ⁺ ].

Step 6: Tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)-1-methylpyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 30f )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H )-yl)tetrahydro-2H-pyran-3-yl)carbamate

30e (0.507 g, 1.4 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and Intermediate 1 (0.488 g, 1.52 mmol) was added and stirred at room temperature for 60 min. . Sodium tris(ethyloxy)borohydride (0.591 g, 2.8 mmol) was added to the reaction mixture at 0 ° C, and the mixture was stirred and allowed to react to room temperature for 3 hours. The reaction mixture was cooled to 0 ° C, and water (20 mL) and aqueous ammonia (2 mL) were added to the mixture to adjust to pH 8 and extracted with dichloromethane (50 mL×3), and the organic phase was combined and washed with a saturated aqueous salt solution (50 mL×1). dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried silica gel column chromatography (methylene chloride / methanol (v / v) = 50: 1) was purified as a yellow solid 30f (0.380g, 51% yield).

MS m/z (ESI): 527.2 [M+H ⁺ ].

Step 7: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(ethylsulfonyl)-1-methylpyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 30 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) tetrahydro-2H-pyran-3-amine

30f (0.38g, 0.72mmol) was dissolved in dichloromethane (6mL), cooled to 0 ° C, added trifluoroacetic acid (3mL), added, and then reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced vacuoluent. The organic phases were combined and washed with brine brine (50 mL×1). The organic layer was dried over anhydrous magnesium sulfate (MgSO4)

MS m/z (ESI): 427.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23 - 7.06 (m, 3H), 4.31-4.29 (d, 1H), 4.27-4.23 (m, 1H), 4.02-4.01 (t, 2H), 3.93 (s, 3H), 3.88-3.87 (t, 2H), 3.43-3.40 (m, 1H), 3.40-3.34 (q, 2H), 3.14 -3.07 (m, 1H), 2.98-2.92 (m, 1H), 2.47-2.44 (m, 1H), 1.56-1.47 (q, 1H), 1.30-1.26 (t, 3H).

Example 31

7-((3R,5S,6R)-5-amine-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-2,3,4,6,7, 8-hexahydropyrrolo[3',4':4,5]imidazo[2,1-b][1,3]thiazine 1,1-dioxide ( compound 31 )

7-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-2,3,4,6,7,8-hexahydropyrrolo[3 ',4':4,5]imidazo[2,1-b][1,3]thiazine 1,1-dioxide

First step: tert-butyl 2-((3-acetoxypropyl)thio)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5 (1H) -formate ( 31a )

Tert-butyl 2-((3-acetoxypropyl)thio)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

6A (6.0 g, 24.8 mmol) was dissolved in ethanol (100 mL) at room temperature, warmed to 90 ° C, and Intermediate 9 (7.5 g, 41.4 mmol) was added and reacted for 5 hours. The reaction mixture was evaporated to dryness crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssssssss to 9, (300mL × 3) and extracted with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride (100mL × 1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid 31a (7.6g, Yield 89%).

MS m/z (ESI): 344.2 [M+H ⁺ ].

Second step: tert-butyl 2-((3-acetoxypropyl)thio)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate ( 31b )

Tert-butyl 2-((3-acetoxypropyl)thio)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carb-oxylate

The grasshopper chlorine (4.2 g, 33.2 mmol) was dissolved in dichloromethane (50 mL) at room temperature under a nitrogen atmosphere, and the temperature was lowered to -78 ° C, and dimethyl hydrazine dissolved in dichloromethane (50 mL) was gradually added dropwise. (5.2 g, 66.6 mmol), and the reaction was maintained at -78 ° C for 30 minutes. A solution of 31a (7.6 g, 22.2 mmol) in dichloromethane (100 mL) was slowly added dropwise, and the mixture was reacted at -78 ° C for 15 minutes, diisopropylethylamine (14.3 g, 111 mmol) was added dropwise, and the mixture was added to the room. The temperature was reacted for 3 hours. Dichloromethane (100 mL) and a saturated ammonium chloride solution (100 mL) were added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium chloride (100 mL×1), dried over anhydrous sodium sulfate, filtered and evaporated. The yellow liquid 31b (5.8 g, yield 76%) was obtained.

MS m/z (ESI): 3421. [M+H ⁺ ].

Third step: tert-butyl 2-((3-hydroxypropyl)thio)-4,6-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-formate ( 31c )

Tert-butyl 2-((3-hydroxypropyl)thio)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

31b (5.8g, 17mmol) was dissolved in a mixed solvent of tetrahydrofuran (60mL) and water (20mL), and lithium hydroxide (0.898g, 20.4mmol) was added in portions, and the reaction was carried out at room temperature. hour. Water (500 mL) was added to the reaction mixture, and the mixture was combined with methylene chloride (300 mL × 3). The yellow solid 31c (4.28 g, yield 84%) was obtained.

MS m/z (ESI): 300.1 [M+H ⁺ ].

Fourth step: tert-butyl 2-((3-bromopropyl)thio)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 31d )

Tert-butyl 2-((3-bromopropyl)thio)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

31c (1.0g, 3.3mmol) and carbon tetrabromide (1.33g, 4.0mmol) were dissolved in dichloromethane (30mL), cooled to 0 ° C, and triphenylphosphorus was added dropwise to the reaction solution. A solution of (1.3 g, 4.95 mmol) in dichloromethane (20 mL). Water (50 mL) and dichloromethane (100 mL) were added to the mixture, and the organic layer was washed with brine (50 mL×1), dried over anhydrous sodium sulfate The tertiary 31d crude product (1.19 g) was used directly in the next step.

MS m/z (ESI): 362.0 [M+H ⁺ ].

Step 5: Tert-butyl 3,4,6,8-tetrahydropyrrolo[3',4':4,5]imidazo[2,1-b][1,3]thiazine-7 ( 2H)-formate ( 31e )

Tert-butyl 3,4,6,8-tetrahydropyrrolo[3',4':4,5]imidazo[2,1-b][1,3]thiazine-7(2H)-carboxylate

31d crude product (1.19g, 3.3mmol) was dissolved in acetonitrile (50mL), potassium carbonate (0.544g, 4.0mmol) was added, and the reaction was carried out at 60 ° C for 12 hours. The reaction mixture was filtered under reduced pressure, and the filtrate was spin-dried silica gel column chromatography (methylene chloride / methanol (v / v) = 80: 1), to give a yellow solid 31e (0.745g, 80% yield).

MS m/z (ESI): 2821. [M+H ⁺ ].

Step 6: 2,3,4,6,7,8-hexahydropyrrolo[3',4':4,5]imidazo[2,1-b][1,3]thiazinenesulfonic acid Salt ( 31f )

2,3,4,6,7,8-hexahydropyrrolo[3',4':4,5]imidazo[2,1-b][1,3]thiazine benzenesulfonate

31e (0.745 g, 2.65 mmol) and benzenesulfonic acid 1.5 H ₂ O (0.736 g, 3.97 mmol) were dissolved in dichloromethane (40 mL). The reaction mixture was concentrated under reduced pressure to give a yellow solid 31f (0.478g).

MS m/z (ESI): 1821. [M+H ⁺ ].

Step 7: Tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3,4-dihydropyrrolo[3',4':4, 5]Imidazo[2,1-b][1,3]thiazine-7(2H,6H,8H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 31 g )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3,4-dihydropyrrolo[3',4':4,5]imidazo[2,1-b][ 1,3]thiazin-7(2H,6H,8H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

31f (0.479g, 1.0mmol) was dissolved in N,N-dimethylacetamide (30mL), then added to intermediate 1 (0.954g, 2.9mmol), and stirred at room temperature for 60 minutes. . Sodium tris(ethyloxy)borohydride (1.8 g, 8.6 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The temperature was lowered to 0 ° C, and water (200 mL) and aqueous ammonia (10 mL) were successively added to adjust the pH to 8 and extracted with dichloromethane (100 mL×3). The organic phase was combined and washed with a saturated aqueous solution of brine (100 mL×1). dried, filtered, and the filtrate was spin-dried silica gel column chromatography (methylene chloride / methanol (v / v) = 30: 1) was purified as a white solid 31g (0.360g, 27% yield).

MS m/z (ESI): 493.1 [M+H ⁺ ].

The eighth step: the third butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1,1-dioxy-3,4-dihydropyrrolo[3 ',4':4,5]Imidazo[2,1-b][1,3]thiazine-7(2H,6H,8H)-yl)tetrahydro-2H-pyran-3-yl)amino Formate ( 31h )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1,1-dioxido-3,4-dihydropyrrolo[3',4':4,5]imidazo[2 , 1-b][1,3]thiazin-7(2H,6H,8H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

31 g (0.36 g, 1.0 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (0.25 g, 3.0 mmol) was added at room temperature, and m-chloroperoxybenzoic acid (0.378 g, 2.2 mmol) was added portionwise. ), the reaction was carried out at room temperature for 12 hours. The reaction mixture was quenched with saturated sodium thiosulfate solution (10 mL), and the mixture was adjusted to pH 8 with saturated sodium hydrogen carbonate solution (10 mL), and extracted with dichloromethane (100 mL×3). (50 mL × 1) washing. Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 40: 1), to give a white solid 31h (0.198g, 51% yield).

MS m/z (ESI): 524.1 [M+H ⁺ ].

Step 9: 7-((3R,5S,6R)-5-amine-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-2,3,4, 6,7,8-hexahydropyrrolo[3',4':4,5]imidazo[2,1-b][1,3]thiazine 1,1-dioxide ( compound 31 )

7-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-2,3,4,6,7,8-hexahydropyrrolo[3 ',4':4,5]imidazo[2,1-b][1,3]thiazine 1,1-dioxide

31h (0.198g, 0.38mmol) was dissolved in dichloromethane (12mL), cooled to 0 ° C, added trifluoroacetic acid (6mL), added, and then reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure and water (50 mL) was evaporated. The aqueous phase was adjusted to pH 8 with a saturated aqueous sodium hydrogen carbonate solution (20 mL) and dichloromethane (30mL×3). The organic phases were combined and washed with brine brine (50 mL×1). The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

MS m/z (ESI): 425.1 [M+H ⁺ ].

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.17-6.95 (m, 3H), 4.24-4.20 (m, 2H), 4.11-4.08 (t, 2H), 3.94-3.94 (m, 2H), 3.89- 3.89 (m, 2H), 3.51-3.48 (m, 2H), 3.43-3.37 (t, 1H), 3.10-3.01 (m, 1H), 2.88-2.82 (m, 1H), 2.77-2.71 (m, 2H) ), 2.44-2.41 (m, 1H), 1.51-1.42 (q, 1H).

Example 32

(2R,3S,5R)-5-(2-(cyclopropanesulfonyl)-1-methylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2- (2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 32 )

(2R,3S,5R)-5-(2-(cyclopropylsulfonyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl) tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-((3-hydroxypropyl)thio)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Acid ester ( 32a )

Tert-butyl 2-((3-hydroxypropyl)thio)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

31c (2.4g, 8.0mmol) was dissolved in N,N-dimethylformamide (50mL) at room temperature, added potassium carbonate (1.33g, 9.6mmol) for 5 minutes, adding methyl iodide (1.35g) , 9.6 mmol), and reacted at room temperature for 12 hours. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (300 mL×3). The organic phase was combined, washed with a saturated aqueous sodium chloride solution (100 mL×1), dried over anhydrous sodium sulfate Separation by hydrazine column chromatography (dichloromethane / methanol (v/v) = 60:1) afforded a yellow solid 32a (1.0 g, yield 40%).

MS m/z (ESI): 314.1 [M+H ⁺ ].

Second step: tert-butyl 2-((3-hydroxypropyl)sulfonyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Formate ( 32b )

Tert-butyl 2-((3-hydroxypropyl)sulfonyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]i Midazole-5(1H)-carboxylate

32a (0.6 g, 1.9 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and m-chloroperoxybenzoic acid (1.08 g, 6.27 mmol) was added portionwise, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was quenched with saturated sodium thiosulfate solution (5 mL), and the mixture was adjusted to pH 8 with saturated sodium hydrogen carbonate solution (10 mL), and extracted with dichloromethane (50 mL×3). The aqueous solution (50 mL x 1) was washed. Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, silica gel column chromatography (methylene chloride / methanol (v / v) = 50: 1) was purified as a yellow solid 32b (0.437g, 66% yield).

MS m/z (ESI): 346.1 [M+H ⁺ ].

Third step: tert-butyl 2-((3-bromopropyl)sulfonyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Formate ( 32c )

Tert-butyl 2-((3-bromopropyl)sulfonyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

32b (0.437g, 1.27mmol) and carbon tetrabromide (0.504g, 1.5mmol) were dissolved in dichloromethane (10mL), cooled to 0 ° C, triphenylphosphorus was added dropwise to the reaction solution A solution of (0.50 g, 1.9 mmol) in dichloromethane (10 mL). Water (30 mL) and dichloromethane (50 mL) were added to the reaction mixture, and the organic layer was washed with saturated aqueous brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, It was isolated (petroleum ether / ethyl acetate (v/v) = 3:1) to afford white solid 32c (0.21 g, yield 40%).

MS m/z (ESI): 409.1 [M+H ⁺ ].

Fourth step: tert-butyl 2-(cyclopropanesulfonyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 32d) )

Tert-butyl 2-(cyclopropylsulfonyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

32c (0.26g, 0.64mmol) was dissolved in tetrahydrofuran (5mL) at room temperature, cooled to -20 ° C, and a solution of potassium tert-butoxide in tetrahydrofuran (0.76mL, 1mol / L) was added dropwise, kept at -20 ° C Reaction for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL × 3). The organic phase was combined, washed with a saturated aqueous solution of brine (100 mL×1), dried over anhydrous magnesium sulfate, filtered, chromatography (petroleum ether / ethyl acetate (v / v) = 5: 1) , was isolated as a white solid 32d (0.210g).

MS m/z (ESI): 328.1 [M+H ⁺ ].

Step 5: 2-(cyclopropanesulfonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 32e )

2-(cyclopropylsulfonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

32d (0.288g, 0.88mmol) and benzenesulfonic acid 1.5H ₂ O (0.244g, 1.3mmol) were dissolved in dichloromethane (20mL), and then reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give a yellow solid 32e (0.338g).

MS m/z (ESI): 228.1 [M+H ⁺ ].

Step 6: Tert-Butyl ((2R,3S,5R)-5-(2-(cyclopropanesulfonyl)-1-methylpyrrolo[3,4-d]imidazole-5(1H,4H ,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 32f )

Tert-butyl((2R,3S,5R)-5-(2-(cyclopropylsulfonyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2, 5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

32e (0.338 g, 0.88 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and Intermediate 1 (0.317 g, 0.97 mmol) was added and stirred at room temperature for 60 min. . Sodium tris(ethenyloxy)borohydride (0.371 g, 1.76 mmol) was added to the reaction mixture at 0 ° C, and the mixture was allowed to react to room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and then water (20 mL) and aqueous ammonia (10 mL) were added to the mixture to adjust to pH 8 and extracted with dichloromethane (50 mL×3), and the organic phase was combined and washed with a saturated aqueous salt solution (50 mL×1). dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried, column chromatography (dichloromethane / methanol (v / v) = 40: 1) was purified as a yellow solid 32f (0.292g, 61% yield).

MS m/z (ESI): 539.1 [M+H ⁺ ].

Step 7: (2R, 3S, 5R)-5-(2-(cyclopropanesulfonyl)-1-methylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl )-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 32 )

(2R,3S,5R)-5-(2-(cyclopropylsulfonyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl) tetrahydro-2H-pyran-3-amine

32f (0.292 g, 0.54 mmol) was dissolved in dichloromethane (6 mL), cooled to 0 ° C, trifluoroacetic acid (3 mL) was added, and the mixture was reacted at 0 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc)EtOAc. ×3) Extraction. The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by preparative liquid chromatography separation (acetonitrile: water (v / v) = 2/ 3), as a white solid compound 32 (0.120g, 50% yield).

MS m/z (ESI): 439.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.22 - 7.05 (m, 3H), 4.29 - 4.27 (d, 1H), 4.25 - 4.22 (m,1H), 4.02-4.01(t,2H), 3.94(s,3H),3.89-3.87(t,2H),3.43-3.37(t,1H),3.12-3.05(m,1H),2.93 -2.82 (m, 2H), 2.46-2.43 (m, 1H), 1.54-1.46 (q, 1H), 1.31-1.27 (m, 2H), 1.17-1.10 (m, 2H).

Example 33

Ethyl 5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3- 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( compound 33 )

Ethyl 5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1, 4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

First step: ethyl 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( 33a )

Ethyl 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

8A (500 mg, 1.69 mmol) was added to a solution of hydrochloric acid in ethyl acetate (5 mL, 4 mol/L), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was allowed to stand to remove the liquid, and ethyl acetate (5 mL) was added to the residual solid and stirred for 1 minute, and the liquid was allowed to stand. The residual solid was purified by column chromatography (dichloromethane/methanol (v/v) = 20:1, and a small amount of aqueous ammonia) to afford pale yellow solid 33a (330 mg, yield 99%).

Second step: tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-morpholine-3,4-dihydro-2H-pyran-3-yl)amino Formate ( 33b )

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

Intermediate 1 (2.5 g, 7.64 mmol) was added to toluene (40 mL), morpholine (1.30 g, 15.30 mmol) was added, and the mixture 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, filtered, and washed with toluene to afford white solid 33b (2.1 g, yield 70%).

^{1 H NMR (400MHz, DMSO- d} 6): δ7.27-7.12 (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, 5.8 Hz, 4H), 2.41-2.20 (m, 2H), 1.27-1.10 (m, 9H).

Third step: tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-carbonyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3- Carbamate ( 33c )

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

Add 33b (2.3g, 5.80mmol) to N,N-dimethylformamide (30mL), then add 4-dimethylamino (0.070g, 0.58mmol) 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. Water (30 mL) was added to the mixture, and the mixture was evaporated. Purification (petroleum ether/ethyl acetate (v/v) = 10:1),yield of EtOAc (EtOAc) 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 and evaporated. purification by column chromatography (petroleum ether / ethyl acetate (v / v) = 8: 1), to give a pale yellow solid 33c (0.41g, 18% yield).

MS m / z (ESI): 394.0 [MH +]; 1 H NMR (400MHz, DMSO- d 6): δ7.27 (dd, 8.5Hz, 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).

Fourth step: ethyl 5-((2S,3R,5S,6R)-5-((t-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)-2-(trifluoro) Methyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( 33d )

Ethyl 5-((2S,3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

33c (556.8 mg, 1.41 mmol) and 33a (330 mg, 1.69 mmol) were added to toluene (10 mL), and reacted at 140 ° C for 1 hour until the solvent was evaporated to dryness. The residue was dissolved in 1,2-dichloroethane (15 mL), and then sodium tris(ethyloxy) borohydride (1.19 g, 5.64 mmol) and acetic acid (0.16 ml, 2. The reaction was carried out for 3 hours at room temperature. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Separation and purification by hydrazine column chromatography (petrole ether / ethyl acetate (v/v) = 3:1) gave pale yellow foamy solid 33d (455 mg, yield 57%).

Step 5: Ethyl 5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyridyl喃-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( Compound 33 )

Ethyl 5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1, 4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

33d (455mg, 0.79mmol) was dissolved in dichloromethane (6mL) and trifluoroacetic acid (2mL) and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated. The organic phases were combined, dried over anhydrous sodium sulfate and evaporated. Separation and purification by hydrazine column chromatography (dichloromethane/methanol = 30:1) afforded Compound 33 (360 mg, yield 96%).

LC-MS: 475.1 [M + H +]; 1 H NMR (400MHz, DMSO- d 6): δ7.33-7.21 (m, 3H), 4.75-4.65 (m, 1H), 4.50 (d, 1H) , 4.28 (q, 2H), 4.09-4.02 (m, 1H), 3.93 (dd, 2H), 3.87 (s, 3H), 3.75-3.67 (m, 1H), 3.54-3.45 (m, 1H), 3.01 (td, 1H), 2.36-2.27 (m, 1H), 1.89-1.53 (m, 3H), 1.30 (t, 3H).

Example 34

(5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4, 5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)(morpholine)methanone ( Compound 34 )

(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[ 3,4-d]imidazol-2-yl)(morpholino)methanone

First step: 5-(Tertidinoxycarbonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid ( 34a )

5-(tert-butoxycarbonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid

8A (8.6 g, 29 mmol) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and water (30 mL), and the mixture was stirred to dissolve completely, and sodium hydroxide (2.32 g, 58 mmol) was added and stirred at room temperature for 2 hours. The pH was adjusted to 4 with a 1 mol/L hydrochloric acid solution, and the solid was precipitated, filtered, and the filter cake was dried. The filtrate was extracted with ethyl acetate (100 mL×4), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. concentrated and the residue combined with the filter cake to give a white solid 34a (4.9g, 63% yield).

MS m/z (ESI): 268.1 [M+H ⁺ ].

Second step: tert-butyl 1-methyl-2-(morpholin-4-carbonyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 34b )

Tert-butyl 1-methyl-2-(morpholine-4-carbonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

34a (1 g, 3.9 mmol) was dissolved in dichloromethane (20 mL), and then morpholine (412 g, 4.8 mol) and triethylamine (813 μL, 5.8 mmol) were added to the reaction system, and the mixture was stirred at room temperature for 20 minutes. TBTU (1.54 g, 4.8 mmol) was added to the reaction system, and the mixture was reacted at room temperature for 8 hours. The reaction mixture was quenched with water (40 mL), EtOAc (EtOAc)EtOAc. Separation (dichloromethane/methanol (v/v) = 20:1) afforded a yellow liquid product 34b (1.2 g, yield 93%).

MS m/z (ESI): 337.1 [M+H ⁺ ].

The third step: (1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)(morpholine)methylketobenzenesulfonate ( 34c )

(1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)(morpholino)methanone benzenesulfonate

34b (1.2 g, 3.57 mmol) was dissolved in dichloromethane (40 mL), benzenesulfonic acid 1.5 H ₂ O (990 mg, 5.4 mol) was added, and the mixture was warmed to 50 ° C and refluxed for 48 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give a white solid, was added methyl tert-butyl ether was filtered to give the crude product 34c as a white solid, it was used directly in the next step.

MS m/z (ESI): 237.1 [M+H ⁺ ].

Fourth step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(morpholin-4-carbonyl)pyrrolo [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 34d )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(morpholine-4-carbonyl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

At room temperature, the crude product 34c (2.3g, 3.57mmol) was dissolved in N, N- dimethylacetamide (10 mL) was added Intermediate 1 (1.28g, 3.9mmol), the reaction was stirred for 1 hour, the reaction The system was cooled to 0 ° C, and sodium tris(acetic acid) hydride (2.36 g, 11 mmol) was added thereto, and the mixture was reacted at room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and then water (20 mL), aqueous ammonia (2 mL) was added to adjust to pH 9 and extracted with dichloromethane (30 mL × 3), and the organic phase was combined and washed with a saturated aqueous salt solution (50 mL×1). dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography separation (dichloromethane / methanol (v / v) = 30: 1), to give a yellow solid 34d (1.5g, 79% yield).

MS m/z (ESI): 548.2 [M+H ⁺ ].

The fifth step: (5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl- 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)(morpholine)methanone ( Compound 34 )

(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[ 3,4-d]imidazol-2-yl)(morpholino)methanone

34 d (1.0 g, 1.8 mmol) was dissolved in dichloromethane (8 mL), cooled to 0 ° C, trifluoroacetic acid (4 mL) The reaction solution was concentrated under reduced pressure. aqueous sodium hydrogen sulfate (10 mL) was then evaporated. The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 20: 1), to give a white solid compound 34 (398mg, 49% yield).

MS m/z (ESI): 448.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.26-7.14 (m, 1H), 7.05-6.98 (m, 2H), 4.28 - 4.25 ( d, 2H), 4.24 - 4.23 (d, 2H), 3.90 (s, 2H), 3.83 (s, 2H), 3.82 (s, 2H), 3.76 (br, 6H), 3.46-3.41 (m, 1H) , 3.07-3.01 (m, 1H), 2.94-2.89 (m, 1H), 2.48-2.45 (m, 1H), 1.56-1.47 (q, 1H).

Example 35

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfinyl)pyrrolo[3,4-d]imidazole- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 35 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfi) Nyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-methyl-2-(methyl sulfide)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 35a )

Tert-butyl 1-methyl-2-(methylthio)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

6C (0.510g, 2.0mmol) was dissolved in N,N-dimethylformamide (10mL) at room temperature, cooled to 0 ° C, potassium carbonate (0.332g, 2.4mmol) was added and reacted for 10 minutes. Methyl iodide (0.338 g, 2.4 mmol) was added rapidly, and the reaction was carried out at 0 ° C for 2 hours. Water (10 mL) was added dropwise to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. A yellow solid 35a (0.284 g, yield 53%) was obtained.

MS m/z (ESI): 270.1 [M+H+];

Second step: 1-methyl-2-(methylthio)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 35b )

1-methyl-2-(methylthio)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

35a (0.270 g, 1.0 mmol) and benzenesulfonic acid 1.5 H ₂ O (0.278 g, 1.5 mmol) were dissolved in dichloromethane (10 mL). The reaction solution was concentrated under reduced pressure to give 35b (0.327 g).

MS m/z (ESI): 170.1 [M+H+].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylthio)pyrrolo[3, 4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 35c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylthio)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

35b (0.327 g, 1.0 mmol) was dissolved in N,N-dimethylacetamide (6 mL), and Intermediate 1 (0.363 g, 1.1 mmol) was added and stirred at room temperature for 60 min. . Sodium tris(ethyloxy)borohydride (0.303 g, 1.43 mmol) was added to the reaction mixture at 0 ° C, and the mixture was stirred and allowed to react to room temperature for 16 hours. The reaction mixture was cooled to 0 ° C, and water (20 mL) and aqueous ammonia (2 mL) were added to the mixture to adjust to pH 8 and extracted with dichloromethane (50 mL×3), and the organic phase was combined and washed with a saturated aqueous salt solution (50 mL×1). dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried, column chromatography (dichloromethane / methanol (v / v) = 60: 1) was purified as a yellow solid 35c (0.365g, 69% yield).

MS m/z (ESI): 481.1 [M+H ⁺ ].

Fourth step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylindenyl)pyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carboxylate ( 35d )

Tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfinyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)- Yl)tetrahydro-2H-pyran-3-yl)carbamate

35c (0.365g, 1.1mmol) was dissolved in dichloromethane (10mL) at room temperature, added trifluoroacetic acid (0.578g, 0.9mmol) for 20 minutes, cooled to 5 ° C, added m-chloroperoxybenzoic acid (0.471 g, 2.2 mmol), and the reaction was allowed to naturally rise to room temperature for 5 hours. A saturated sodium thiosulfate solution (10 mL) was added dropwise to the reaction mixture, and dichloromethane (50 mL) and water (30 mL) The organic phase was separated, and the organic phase was washed with a saturated aqueous solution chromatography (methylene chloride / methanol (v / v) = 20: 1) to give a yellow solid 35d (0.03g, 5.4% yield).

MS m/z (ESI): 497.1 [M+H ⁺ ].

Step 5: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(1-methyl-2-(methylindenyl)pyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 35 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfinyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

35d (0.03g, 0.06mmol) was dissolved in dichloromethane (3mL), cooled to 0 ° C, added trifluoroacetic acid (1mL), added, and reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and sodium hydrogen carbonate solution (5 mL) was added dropwise, and the mixture was adjusted to pH 8 and extracted with dichloromethane (20 mL × 3). The organic phases were combined and washed with brine brine (20 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. ).

MS m/z (ESI): 397.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.24-7.10 (m, 3H), 4.36-4.34 (d, 1H), 4.28-4.24 (m, 1H), 4.02-4.01 (m, 2H), 3.90 (s, 3H), 3.89-3.87 (m, 2H), 3.48-3.29 (t, 1H), 3.15-3.14 (m, 1H), 3.11 (s, 3H), 3.09-3.00 (m, 1H), 2.49-2.46 (m, 1H), 1.60-1.51 (q, 1H).

Example 36

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-cyclopropyl-1-methyl -1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 36 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-cyclopropyl-1-methyl-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

First step: 5-((3R,5S,6R)-5-((t-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid ( 36a )

5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluoro Phenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid

7b (3.7 g, 7.2 mmol) was dissolved in tetrahydrofuran (40 mL), then sodium hydroxide (0.58 g, 14.6 mmol) was added to the reaction system and allowed to react at room temperature for 2 hours. The reaction system was cooled to 0 ° C, and a 1 mol/L hydrochloric acid solution was slowly added thereto to adjust the pH to 4, and the solid was precipitated and filtered to give a pale-yellow solid product 36a (2.36 g, yield: 65%). .

MS m/z (ESI): 479.0 [M+H ⁺ ].

Second step: tert-butyl ((2R,3S,5R)-5-(2-(cyclopropylethyl)-1-methylpyrrolo[3,4-d]imidazole-5 (1H, 4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 36b )

Tert-butyl((2R,3S,5R)-5-(2-(cyclopropylcarbamoyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2, 5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

36a (70 mg, 0.146 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and triethylamine (30 μL, 0.22 mmol) and cyclopropylamine (15 μL, 0.19 mmol) were added to the reaction system, room temperature. The reaction was stirred for 30 minutes. TBTU (60 mg, 0.19 mmol) was added to the reaction system, and the reaction was continued for 24 hours. 10 mL of water was added to the reaction system, and the mixture was extracted with dichloromethane (15 mL×3), and the organic phase was combined and washed with brine (50 mL×1). over sodium sulfate, and the filtrate was concentrated and purified by column chromatography separation (dichloromethane / methanol (v / v) = 30: 1), to give a white solid 36b (0.069g, 91% yield).

MS m/z (ESI): 518.1 [M+H ⁺ ].

Third step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-cyclopropyl- 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 36 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-p Yran-3-yl)-N-cyclopropyl-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

36b (0.069g, 0.13mmol) was dissolved in dichloromethane (5mL), cooled to 0 ° C, trifluoroacetic acid (1mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. aqueous sodium hydrogen sulfate (10 mL) was then evaporated and evaporated. The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 20: 1), to give a white solid compound 36 (33mg, 60% yield).

MS m/z (ESI): 418.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.13-7.17 (m, 1H), 7.04-6.98 (m, 1H), 4.32-4.30 (d , 1H), 4.24-4.2 (q, 1H), 3.97 (s, 3H), 3.94 (s, 1H), 3.84 (s, 1H), 3.47-3.42 (t, 1H), 3.06-3.04 (m, 1H) ), 2.84-2.80 (m, 1H), 2.47-2.50 (d, 1H), 0.88-0.81 (m, 2H), 0.64-0.6 (m, 2H).

Example 37

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-isopropyl-1,4, 5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 37 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-isopropyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxamide

First step: 5-t-butyl 2-ethyl 1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylic acid ( 37a )

5-tert-butyl 2-ethyl 1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

Intermediate 5 (0.5 g, 2 mmol) was dissolved in N,N-dimethylformamide (10 mL) at rt, cooled to 0 ° C, EtOAc (0.694 g, 2.1 mmol) Iodoisopropane (0.357 g, 2.1 mmol) was quickly added, and the reaction was carried out for 12 hours at room temperature. Water (200 mL) was added dropwise to the reaction mixture, and the mixture was extracted with methyl t-butyl ether (200 mL × 3). The organic phase was combined, washed with saturated aqueous sodium chloride (200 mL×1), dried over anhydrous sodium sulfate after column chromatography purification (petroleum ether / ethyl acetate (v / v) = 5: 1) pressure was concentrated to give a yellow solid 37a (0.5g, 83.3% yield).

MS m/z (ESI): 324.4 [M+H ⁺ ].

Second step: ethyl 1-isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-carboxybenzenesulfonate ( 37b )

Ethyl 1-isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate benzenesulfonate

37a (1.5 g, 4.6 mmol) and benzenesulfonic acid 1.5 H ₂ O (1.3 g, 8.2 mmol) were dissolved in dichloromethane (30 mL). The reaction solution was concentrated under reduced pressure to give 37b (yel.

MS m/z (ESI): 224.1 [M+H ⁺ ].

Third step: ethyl 5-((3R,5S,6R)-5-((t-butoxycarbonyl)amine)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-yl)-1-isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( 37c )

Ethyl 5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-isopropyl-1,4 ,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

37b (1.8g, 4.7mmol) was dissolved in N,N-dimethylacetamide (20mL), then intermediate 1 (1.7g, 5.2mmol) was added and stirred at room temperature for 1 hour. . Sodium tris(ethyloxy)borohydride (3.15 g, 14.9 mmol) was added to the reaction mixture at 0 ° C, and the mixture was allowed to react to room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and water (100 mL) and aqueous ammonia (10 mL) were successively added to adjust the pH to 8 to precipitate a brown solid, which was filtered and purified by column chromatography ( petroleum ether / ethyl acetate (v/v) ) = 1:1) gave a yellow solid 37c (1.6 g, yield 70%).

MS m/z (ESI): 535.1 [M+H ⁺ ].

Fourth step: tert-butyl ((2R,3S,5R)-5-(2-carbamoyl-1-isopropylpyrrolo[3,4-d]imidazole-5(1H,4H,6H )-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 37d )

Tert-butyl((2R,3S,5R)-5-(2-carbamoyl-1-isopropylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5- Difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

37c (1.4g, 2.6mmol) was dissolved in a methanol solution of ammonia (20 mL, 7 mol/L) at room temperature, and the reaction was sealed at 100 ° C for 8 hours. The reaction mixture was concentrated under reduced pressure and purified (jjjjjjjjjjjjjjj

MS m/z (ESI): 506.1 [M+H ⁺ ].

Step 5: 5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-isopropyl- 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 37 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-isopropyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxamide

37d (0.837g, 1.66mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C, then trifluoroacetic acid (5 mL) was added and the mixture was reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced vacuoluent. EtOAc (EtOAc) (EtOAc) 3) Extraction. The organic phases were combined and washed with brine brine (100 mL×1). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 50: 1), to give a white solid compound 37 (0.515g, yield 76.7%) .

MS m/z (ESI): 406.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.22 - 7.05 (m, 3H), 5.80 - 5.70 (m, 1H), 4.29 - 4.24 (m,2H),4.12-4.06(m,2H),3.80-3.79(t,2H),3.43-3.38(t,1H),3.12-3.05(m,1H),2.93-2.86(m,1H) , 2.49-2.43 (m, 1H), 1.54-1.45 (q, 1H), 1.42 (s, 3H), 1.41 (s, 3H).

Example 38

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,N-diethyl-1- Methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 38 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-p Yran-3-yl)-N,N-diethyl-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

First step: tert-butyl ((2R,3S,5R)-5-(2-(diethylcarbamoyl)-1-methylpyrrolo[3,4-d]imidazole-5 (1H) ,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 38a )

Tert-butyl((2R,3S,5R)-5-(2-(diethylcarbamoyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2, 5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

36a (0.6 g, 1.25 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and triethylamine (189 μL, 1.87 mmol) and cyclopropylamine (109.5 μL, 1.5 mmol) were added to the reaction system in that order. The reaction was stirred at room temperature for 30 minutes. TBTU (0.48 g, 1.5 mmol) was added to the reaction system, the reaction was continued for 24 hours, 30 mL of water was added to the reaction system, and dichloromethane (30 mL×3) was extracted, and the organic phase was combined and washed with brine (50 mL×1). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 30:1) to afford white solid 38a (0.6 g, yield 90%).

MS m/z (ESI): 534.1 [M+H ⁺ ].

Second step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,N-diethyl -1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-indoleamine ( compound 38 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,N-diethyl-1-methyl-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

38a (0.6 g, 1.2 mmol) was dissolved in dichloromethane (8 mL), cooled to 0 ° C, trifluoroacetic acid (4 mL) The reaction solution was concentrated under reduced pressure. aqueous sodium hydrogen sulfate (10 mL) was then evaporated and evaporated. The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 20: 1), to give a white solid compound 38 (298mg, yield 62%).

MS m/z (ESI): 434.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl3): δ 7.19-7.16 (m, 1H), 7.14-6.96 (m, 2H), 4.27-4.23 (m, 1H), 3.98 (s, 2H), 3.93 (s, 2H), 3.81-3.77 (m, 4H), 3.45-3.43 (m, 2H), 3.09-3.05 (t, 1H), 2.87-2.84 (m, 1H), 2.48-2.45 (m, 2H), 1.52-1.47 (m, 1H), 1.27-1.22 (m, 6H).

Example 39

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(isopropylsulfonyl)-1-methylpyrrolo[3,4-d]imidazole- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 39 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(isopropylsulfonyl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-(isopropylthio)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 39a )

Tert-butyl 2-(isopropylthio)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

6A (1.0 g, 4.10 mmol) was dissolved in ethanol (150 mL) at room temperature, and the mixture was warmed to 35 ° C, and iodoisopropane (1.05 g, 6.18 mmol) was quickly added, and the mixture was refluxed at 89 ° C for 12 hours. The reaction mixture was concentrated to give EtOAc (EtOAc) (EtOAc). (100mL × 3) and extracted with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride (100mL × 1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid 39a (0.89g, yield 75.8 %).

MS m/z (ESI): 286.3 [M+H ⁺ ].

Second step: tert-butyl 2-(isopropylthio)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 39b )

Tert-butyl 2-(isopropylthio)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbox Ylate

The grass chloroform (5.43 g, 42.8 mmol) was dissolved in dichloromethane (100 mL) at room temperature under a nitrogen atmosphere, and the temperature was lowered to -78 ° C, and dichloromethane (60 mL) was slowly added dropwise to dissolve dimethyl hydrazine. (6.7 g, 19.6 mmol), and the reaction was maintained at -78 ° C for 30 minutes. A solution of 39a (8.12 g, 28.5 mmol) in dichloromethane (40 mL) was slowly added dropwise and the mixture was reacted at -78 ° C for 15 min. Diisopropylethylamine (18.4 g, 142.6 mmol) was added to the reaction solution, and the mixture was allowed to react to room temperature for 3 hours. Dichloromethane (200 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium chloride (200 mL×3), and the organic layer was washed with saturated aqueous sodium chloride (100 mL×1), dried over anhydrous sodium sulfate and filtered. concentrated under reduced pressure to give a yellow solid, was added diisopropyl ether (100 mL) beating, and filtered to give a yellow solid 39b (5.9g, yield 73.7%).

MS m/z (ESI): 284.1 [M+H ⁺ ].

Third step: tert-butyl 2-(isopropylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate ( 39c )

Tert-butyl 2-(isopropylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

39b (5.9g, 21mmol) was dissolved in a mixed solution of tetrahydrofuran (60mL), methanol (60mL) and water (60mL), cooled to 0 ° C, added potassium persulfate complex salt (53.35g) , 739.9 mmol), and the reaction was allowed to warm to room temperature for 12 hours. The reaction mixture was poured into water (300 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Solid 39c . (5.17 g, yield 78.8%).

MS m/z (ESI): 316.1 [M+H ⁺ ].

Fourth step: tert-butyl 1-methyl-2-(isopropylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 39d )

Tertbutyl 1-methyl-2-(isopropylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

39c (1.5g, 4.8mmol) was dissolved in N,N-dimethylformamide (15mL), cooled to 0 ° C, added potassium carbonate (0.788g, 7.87mmol), and reacted for 10 minutes. Methyl iodide (0.804 g, 1.2 mmol) was added rapidly, and the reaction was carried out at 0 ° C for 1 hour. Water (30 mL) was added dropwise to the reaction mixture, and the mixture was stirred for 10 minutes, and a white solid was precipitated and filtered to give a white cake 39d (1,5 g, yield: 79.0%).

MS m/z (ESI): 330.0 [M+H ⁺ ].

Step 5: 1-Methyl-2-(isopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 39e )

1-methyl-2-(isopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

39d (1.19g, 3.61mmol) and benzenesulfonic acid 1.5H ₂ O (2.9g, 10.5mmol) were dissolved in dichloromethane (30mL), and the reaction was refluxed at 45 ° C for 8 hours. The reaction solution was concentrated under reduced pressure to give 39e ( yel .

MS m/z (ESI): 230.1 [M+H ⁺ ].

Step 6: Tert-Butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(isopropylsulfonyl)pyrrole [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (39f)

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

39e (1.393 g, 3.595 mmol) was dissolved in N,N-dimethylacetamide (20 mL) at rt. Intermediate 1 (1.14 g, 3. . Sodium tris(ethyloxy)borohydride (2.5 g, 12 mmol) was added to the reaction mixture at 0 ° C, and the mixture was reacted at room temperature for 16 hours. The reaction solution was cooled to 0 ° C, and water (20 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 8 to precipitate a white solid, which was filtered to give a white cake, which was purified by column chromatography (dichloromethane/methanol (v) /v) = 100: 1) Purified to give a white solid 39f (1 g, yield 52.6%).

MS m/z (ESI): 541.1 [M+H ⁺ ].

Step 7: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(1-methyl-2-(isopropylsulfonyl)pyrrolo[3,4- d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( compound 39 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

39f (1 g, 1.8 mmol) was dissolved in dichloromethane (15 mL), cooled to 0 ° C, then trifluoroacetic acid (8 mL). The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc) The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 40: 1), to give a white solid compound 39 (0.678g, yield 81.9%) .

MS m/z (ESI): 441.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ7.22-7.07 (m, 3H), 4.29-4.22 (m, 2H), 4.02-4.01 (t, 2H), 3.93 (s, 3H), 3.89-3.88 (t, 2H), 3.51-3.44 (m, 1H), 3.42-3.37 (t, 1H), 3.12-3.05 (m, 1H), 2.93 - 2.87 (m, 1H), 2.47-2.36 (m, 1H), 1.54-1.45 (q, 1H), 1.32 (s, 3H), 1.30 (s, 3H).

Example 40

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazole- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 40 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-(isopropylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 40a )

Tert-butyl 1-ethyl-2-(isopropylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

39c (1.5g, 4.8mmol) was dissolved in N,N-dimethylformamide (15mL), cooled to 0 ° C, added potassium carbonate (0.788g, 7.87mmol), and reacted for 10 minutes. Iodoethane (0.871 g, 5.58 mmol) was quickly added, and the reaction was carried out at 0 ° C for 1 hour. Water (30 mL) was added dropwise to the reaction mixture, and the mixture was stirred for 10 minutes, and a white solid was precipitated and filtered to give white cake 40a (1 g, yield 61%).

MS m/z (ESI): 344.0 [M+H ⁺ ].

Second step: 1-ethyl-2-(isopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium sulfonate ( 40b )

1-ethyl-2-(isopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

40a (1.19 g, 3.61 mmol) and benzenesulfonic acid 1.5 H ₂ O (2.9 g, 10.5 mmol) were dissolved in dichloromethane (30 mL) and refluxed at 45 ° C for 8 hours. The reaction solution was concentrated under reduced pressure to give 40b (yel.

MS m/z (ESI): 244.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(isopropylsulfonyl)pyrrolo [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 40c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

40b (1.162 g, 2.894 mmol) was dissolved in N,N-dimethylacetamide (15 mL) at rt. Intermediate 1 (1.14 g, 3.48 mmol). . Sodium tris(ethyloxy)borohydride (2.0 g, 9.4 mmol) was added to the reaction mixture at 0 ° C, and the mixture was allowed to react to room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and water (20 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 8 to precipitate a white solid, which was filtered to give a white cake, which was purified by column chromatography (dichloromethane/methanol (v) /v) = 100: 1) gave a white solid 40c (0.68 g, yield 42.5%).

MS m/z (ESI): 555.0 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(isopropylsulfonyl)pyrrolo[3,4- d] imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( compound 40 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

40c (0.68g, 1.2mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C, then trifluoroacetic acid (5 mL) was added and reacted at 0 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc) The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 40: 1), to give a white solid compound 40 (0.522g, 94% yield) .

MS m/z (ESI): 455.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.24 - 7.09 (m, 3H), 4.47 - 4.38 (q, 2H), 4.29 - 4.25 (m, 2H), 4.10-4.07 (t, 2H), 3.90-3.89 (t, 2H), 3.57-3.52 (m, 1H), 3.45-3.39 (t, 1H), 3.16-3.08 (m, 1H) , 2.95-2.89 (m, 1H), 2.50-2.45 (m, 1H), 1.56-1.50 (m, 1H), 1.47-1.44 (t, 3H), 1.34 (s, 3H), 1.32 (s, 3H) .

Example 41

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazole -5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 41 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-isopropyl-2-(isopropylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate ( 41a )

Tert-butyl 1-isopropy-2-(isopropylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

39c (1.5g, 4.8mmol) was dissolved in N,N-dimethylformamide (15mL), cooled to 0 ° C, added potassium carbonate (1.86g, 9.59mmol), and reacted for 10 minutes. Iodoisopropane (0.969 g, 5.70 mmol) was quickly added, and the reaction was carried out at 0 ° C for 8 hours. Water (30 mL) was added dropwise to the reaction mixture, and the mixture was stirred for 10 minutes, and a yellow solid was precipitated and filtered to give a yellow solid 41a (1.5 g, yield 88%).

MS m/z (ESI): 358.1 [M+H ⁺ ].

Second step: 1-isopropyl-2-(isopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium sulfonate ( 41b )

1-isopropy-2-(isopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

41a (1.5 g, 4.2 mmol) and benzenesulfonic acid 1.5 H ₂ O (2.7 g, 11 mmol) were dissolved in dichloromethane (30 mL) and refluxed at 45 ° C for 8 hours. The reaction solution was concentrated under reduced pressure to give 41b (yel.

MS m/z (ESI): 258.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(isopropylsulfonyl)pyrrole And [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 41c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropy-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

A mixture of 41b (1.743g, 4.195mmol) was dissolved in N, N- dimethylacetamide (15mL) was added Intermediate 1 (2.1g, 6.4mmol), the addition was completed stirring at rt for 1 h . Sodium tris(ethyloxy)borohydride (3.3 g, 16 mmol) was added to the reaction mixture at 0 ° C, and the mixture was allowed to react to room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and water (20 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 8 to precipitate a white solid, which was filtered to give a white cake, which was purified by column chromatography (dichloromethane/methanol (v) /v) = 60: 1) gave white solid 41c (1.45 g, yield 41%).

MS m/z (ESI): 569.0 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(isopropylsulfonyl)pyrrolo[3,4 -d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 41 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropy-2-(isopropylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

41c (1.45 g, 2.55 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C, trifluoroacetic acid (5 mL), and the mixture was reacted at 0 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc) The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 40: 1), to give a white solid compound 41 (0.78g, 65% yield) .

MS m/z (ESI): 455.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.21 - 7.06 (m, 3H), 5.34 - 5.31 (m, 1H), 4.29 - 4.23 (m,2H), 4.15-4.14(t,2H),3.83-3.82(t,2H),3.58-3.46(m,1H),3.43-3.37(t,1H),3.13-3.06(m,1H) , 2.92-2.86 (m, 1H), 2.48-2.42 (m, 1H), 1.54-1.48 (m, 1H), 1.47 (s, 3H), 1.45 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H).

Example 42

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazole- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 42 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-isopropyl-2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d] Imidazole-5(1H)-formate (42a)

Tert-butyl 1-isopropy-2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 6 (1.5 g, 5.2 mmol) was dissolved in N,N-dimethylformamide (15 mL), cooled to 0 ° C, EtOAc (2 g, 6.1 mmol) Iodine-isopropane (1.7 g, 5.2 mmol) was quickly added, and the reaction was carried out at 60 ° C for 8 hours. Water (200 mL) was added dropwise to the reaction mixture, and the mixture was extracted with methyl tributyl ether (200 mL × 3), and the organic phase was combined, washed with brine (200 mL×1), dried over anhydrous sodium sulfate Concentration gave a yellow solid 42a (1.7 g, yield 99%).

MS m/z (ESI): 330.0 [M+H ⁺ ].

Second step: 1-isopropyl-2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 42b )

1-isopropy-2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

42a (1.7 g, 5.2 mmol) and benzenesulfonic acid 1.5 H ₂ O (2.2 g, 14 mmol) were dissolved in dichloromethane (30 mL). The reaction solution was concentrated under reduced pressure to give 42b (yel.

MS m/z (ESI): 230.1 [M+H ⁺ ].

The third step: the third butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(methylsulfonyl)pyrrole [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 42c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropy-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

42b (1.99 g, 5.14 mmol) was dissolved in N,N-dimethylacetamide (20 mL) at rt. Intermediate 1 (2.2 g, 6.7 mmol). . Sodium tris(ethyloxy)borohydride (3.8 g, 19 mmol) was added to the reaction mixture at 0 ° C, and the mixture was reacted at room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and water (100 mL) and aqueous ammonia (10 mL) were added to adjust the pH to 8 to precipitate a white solid. After filtration, the solid column was chromatographed and purified (dichloromethane/methanol (v/v) = 20:1) gave white solid 42c (1 g, yield 36%).

MS m/z (ESI): 541.1 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(methylsulfonyl)pyrrolo[3,4- d] imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( compound 42 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropy-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

42c (1.2 g, 2.2 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C, trifluoroacetic acid (5 mL), and the mixture was reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) 3) Extraction. The organic phases were combined and washed with brine brine (100 mL×1). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 40: 1), to give a white solid compound 42 (0.82g, 84% yield) .

MS m/z (ESI): 441.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.22-7.05 (m, 3H), 5.31-5.24 (m, 1H), 4.29-4.22 (m, 2H), 4.14 - 4.13 (t, 2H), 3.83 - 3.82 (t, 2H), 3.43 - 3.38 (m, 1H), 3.33 (s, 3H), 3.13 - 3.05 (m, 1H), 2.93 - 2.87 (m, 1H), 2.48-2.44 (m, 1H), 1.54-1.51 (m, 1H), 1.48 (t, 3H), 1.47 (t, 3H).

Example 43

(5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4, 5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)(pyrrolidin-1-yl)methyl ketone ( Compound 43 )

(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[ 3,4-d]imidazol-2-yl)(pyrrolidin-1-yl)methanone

First step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(pyrrolidin-1-carbonyl)pyrrolo [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 43a )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(pyrrolidine-1-carbonyl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

36a (0.6g, 1.25mmol) was dissolved in dichloromethane (10mL) at room temperature, and triethylamine (189mg, 1.87mmol), cyclopropylamine (125μL, 1.87mmol) was added to the reaction system in turn, room The reaction was stirred at temperature for 30 minutes. TBTU (481 mg, 1.5 mmol) was added to the reaction system, the reaction was continued for 24 hours, 30 mL of water was added to the reaction system, and dichloromethane (30 mL×3) was extracted, and the organic phase was combined, washed with brine (50 mL×1), and dried. over sodium sulfate, and the filtrate was concentrated and purified by column chromatography separation (dichloromethane / methanol (v / v) = 30: 1), to give a white solid 43a (0.34g, 63% yield).

MS m/z (ESI): 5321. [M+H ⁺ ].

Second step: (5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)(pyrrolidin-1-yl)methyl ketone ( Compound 43 )

(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[ 3,4-d]imidazol-2-yl)(pyrrolidin-1-yl)methanone

43a (0.34 g, 1.0 mmol) was dissolved in dichloromethane (8 mL), cooled to 0 ° C, trifluoroacetic acid (4 mL) The reaction solution was concentrated under reduced pressure. aqueous sodium hydrogen sulfate (10 mL) was then evaporated. The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by column chromatography (dichloromethane / methanol (v / v) = 20: 1), to give a white foamy solid Compound 43 (249mg, yield 91% ).

MS m/z (ESI): 432.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.18-7.14 (m, 1H), 7.06-6.97 (m, 2H), 4.27-4.24 (t , 2H), 3.97-3.92 (m, 4H), 3.89 (s, 4H), 3.62-3.61 (m, 1H), 3.46-3.43 (t, 1H), 3.09-3.04 (m, 1H), 2.84-2.83 (m, 1H), 2.49-2.45 (m, 1H), 1.94-1.87 (m, 4H), 1.59-1.46 (m, 6H).

Example 44

5-((2S,3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 44 )

5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4 ,5,6-tetrahydropyrr Olo[3,4-d]imidazole-2-carboxamide

First step: tert-butyl ((2R,3S,5R,6S)-5-(2-aminomethylmethyl-1-methylpyrrolo[3,4-d]imidazole-5 (1H, 4H, 6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate ( 44a )

Tert-butyl((2R,3S,5R,6S)-5-(2-carbamoyl-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2, 5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

33d (350mg, 0.61mmol) was added to a solution of ammonia in methanol (10 mL, 0.5 mol/L), and the mixture was allowed to react at 80 ° C for 16 hours. The reaction solution was concentrated, and the obtained crude product 44a was directly transferred to the next reaction.

Second step: 5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran- 3-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 44 )

5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1-methyl-1,4 ,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

The crude product of 44a obtained in the previous step was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2mL), and stirred at room temperature for 1 hour. The reaction was quenched with EtOAc EtOAc EtOAc. Separation and purification by hydrazine column chromatography (dichloromethane/methanol (v/v) = 30:1) gave Compound 44 (yield:

MS m/z (ESI): 446.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.62 (s, 1H), 7.33-7.19 (m, 4H), 4.68 (tt, 7.5 Hz) , 1H), 4.49 (d, 1H), 4.04 (dd, 1H), 3.95-3.85 (m, 5H), 3.73-3.65 (m, 1H), 3.48 (ddd, 1H), 3.00 (td, 4.4 Hz, 1H), 2.31 (ddd, 1H), 1.86-1.65 (m, 3H).

Example 45

(2R,3S,5R)-5-(1-(Difluoromethyl)-2-(methylsulfonyl)pyrrolo[3,4-d]imidazolyl-5(1H,4H,6H)- 2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 45 )

(2R,3S,5R)-5-(1-(difluoromethyl)-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5 -difluorophenyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-(difluoromethyl)-2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-amino Formate ( 45a )

Tert-butyl 1-(difluoromethyl)-2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 6 (1.0 g, 4.0 mmol) was dissolved in acetonitrile (30 mL), cooled to 0 ° C, then added potassium hydroxide (4.49 g, 80.0 mmol) and water (30 mL). Dibromofluoromethylphosphonic acid diethyl ester (2.14 g, 8.0 mmol) was added, and the reaction was carried out at 0 ° C for 2 hours. The reaction mixture was diluted with water (30 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Concentration gave a white solid 45a (1.2 g, yield 88.9%).

MS m/z (ESI): 338.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.05-7.75 (m, 1H), 4.69-4.65 (d, 2H), 4.47-4.41 ( d, 2H), 3.36-3.35 (d, 3H), 1.52 (s, 9H).

Step 2: 1-(Difluoromethyl)-2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolebenzenesulfonate ( 45b )

1-(difluoromethyl)-2-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

45a (1.2 g, 3.56 mmol) and benzenesulfonic acid 1.5 H ₂ O (0.99 g, 5.34 mmol) were dissolved in dichloromethane (25 mL). The reaction solution was concentrated under reduced pressure to give 45b (l.

MS m/z (ESI): 238.0 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-5-(1-(difluoromethyl)-2-(methylsulfonyl)pyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)-2-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)carbamate ( 45c )

Tert-butyl((2R,3S,5R)-5-(1-(difluoromethyl)-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2- (2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

A mixture of 45b (1.41g, 3.56mmol) was dissolved in N, N- dimethylacetamide (20mL) was added Intermediate 1 (1.11g, 3.39mmol), stirred at room temperature for 60 minutes. Sodium tris(ethyloxy)borohydride (1.13 g, 5.34 mmol) was added to the reaction mixture at 0 ° C, and the mixture was stirred at room temperature for 4 hours. The reaction solution was cooled to 0 ° C, water (30 mL) and aqueous ammonia (1.5 mL) were successively added to adjust pH to 8 and extracted with dichloromethane (50 mL×3). The organic phase was combined and washed with a saturated aqueous solution of brine (50 mL×1) Drying with anhydrous magnesium sulfate, filtering, and drying the filtrate, and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) = 100:1 to 70:1) to obtain pale yellow solid 45c (1.3 g, The yield was 66.7%).

MS m/z (ESI): 549.0 [M+H ⁺ ].

Step 4: (2R, 3S, 5R)-5-(1-(Difluoromethyl)-2-(methylsulfonyl)pyrrolo[3,4-d]imidazolyl-5(1H,4H ,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 45 )

(2R,3S,5R)-5-(1-(difluoromethyl)-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5 -difluorophenyl)tetrahydro-2H-pyran-3-amine

45 C (1.0 g, 1.82 mmol) was dissolved in dichloromethane (16 mL), cooled to 0 ° C, trifluoroacetic acid (8 mL) was added, and the mixture was reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure. sodium hydrogen sulfate aqueous solution (10 mL) was evaporated, and the mixture was adjusted to pH 8 and extracted with dichloromethane (30mL×4). The organic phases were combined and washed with brine brine (30 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane/methanol (v/v) = 50:1 to 30:1) to give a light gray solid compound 45 (0.65 g, Yield 79.8%).

MS m/z (ESI): 449.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.09-7.79 (t, 1H), 7.11-6.97 (m, 3H), 4.18-14 (m, 2H), 4.08-4.06 (t, 2H), 3.81 (s, 2H), 3.34-3.29 (t, 1H), 3.27 (s, 3H), 3.05-2.99 (m, 1H), 2.84-2.78 (m, 1H), 2.37-2.33 (m, 1H), 1.45-1.37 (q, 1H).

Example 46

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-N-methyl- 1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 46 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-N-methyl-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

First step: tert-butyl-((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methylindenyl)pyrrolo[3 ,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 46a )

Tert-butyl-((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methylcarbamoyl)pyrrolo[3,4-d]imidazol-5(1H,4H ,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

10c (0.4 g, 1.15 mmol) was dissolved in an amine methanol solution (3.8 mL, 7 mol/L), and the mixture was sealed at 90 ° C for 8 hours. The solvent methanol was removed under reduced pressure to give solid 46a (0.4 g).

MS m/z (ESI): 506.1 [M+H ⁺ ].

Second step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-N -methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 46 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-N-methyl-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

46a (0.4 g, 1.15 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and trifluoroacetic acid (2 mL) was added at 0 ° C, and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure to remove trifluoroacetic acid, and water and aqueous ammonia was added to the reaction mixture to adjust to pH 9. The mixture was extracted with dichloromethane (30 mL × 3), and the organic phase was combined, washed with saturated aqueous sodium chloride (50 mL × 1), dried over anhydrous sodium sulfate The filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 30:1) to afford compound 46 (102 mg, yield 39%).

MS m/z (ESI): 406.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.10-7.07 (m, 1H), 6.98-6.90 (m, 2H), 4.44 - 4.40 (m) , 2H), 4.28-4.16 (m, 2H), 3.89 (s, 2H), 3.77 (s, 2H), 3.39-3.44 (t, 3H), 3.01-2.96 (m, 1H), 2.82 (s, 3H) ), 2.42-2.40 (d, 1H), 1.50-1.44 (m, 1H), 1.34-1.32 (m, 3H).

Example 47

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,1-diethyl-1, 4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 47 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,1-diethyl-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazole-2-carboxamide

First step: 5-((3R,5S,6R)-5-((t-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid ( 47a )

5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4, 5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid

10c (6g, 11.5mmol) was dissolved in tetrahydrofuran (40 mL) and sodium hydroxide (0.92 g, 23 mmol). The reaction was carried out for 2 hours at room temperature. The reaction system was cooled to 0 ° C, and a 1 mol/L hydrochloric acid solution was slowly added dropwise to adjust the pH to 4, and solid compound 47a (4 g, yield 65%) was precipitated and used directly to the next step.

MS m/z (ESI): 493.1 [M+H ⁺ ].

Second step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(ethylaminomethylmethyl)pyrrolo [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 47b )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(ethylcarbamoyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

47a (400 mg, 0.81 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and triethylamine (226 μL, 1.6 mmol) and ethylamine hydrochloride (0.13 g, 1.6 mmol) were sequentially added to the reaction system. The reaction was stirred at room temperature for 30 minutes. TBTU (521 mg, 1.6 mmol) was added to the reaction system, and the reaction was continued for 24 hours. Water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (30 mL×3). The organic phase was combined, washed with saturated aqueous brine (50 mL×1), dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography. (Dichloromethane/methanol (v/v) = 30:1) gave white solid 47b (0.53 g, yield 66%).

MS m/z (ESI): 520.1 [M+H ⁺ ].

The third step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,1-diethyl 1,-,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 47 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,1-diethyl-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazole-2-carboxamide

47b (0.53g, 1.0mmol) was dissolved in dichloromethane (8 mL), cooled to 0 ° C, then trifluoroacetic acid (4 mL). The reaction solution was concentrated under reduced pressure. aqueous sodium hydrogen sulfate (10 mL) was then evaporated. The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 20: 1), to give a white solid compound 47 (345mg, yield 80.7%).

MS m/z (ESI): 420.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.18-7.14 (m, 1H), 7.06-6.97 (m, 2H), 4.50-4.45 (m) , 2H), 4.28-4.23 (m, 2H), 3.97 (s, 2H), 3.85 (s, 2H), 3.43-3.40 (m, 3H), 3.08-3.04 (m, 1H), 2.92 (s, 1H) ), 2.52-2.48 (d, 1H), 1.39-1.36 (m, 3H), 1.28-1.21 (m, 3H).

Example 48

(2R,3S,5R)-5-(2-cyclopropyl-1-ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5 -difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 48 )

(2R,3S,5R)-5-(2-cyclopropyl-1-ethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro- 2H-pyran-3-amine

First step: tert-butyl 2-cyclopropyl-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 48a )

Tert-butyl 2-cyclopropyl-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

27b (747.9mg, 3.0mmol) was dissolved in tetrahydrofuran (20mL) at room temperature, cooled to -20 ° C, sodium hexamethyldidecylamino (1.8mL, 2mol / L, 3.6mmol) was added dropwise In the reaction mixture, stirring was continued for 30 minutes. While maintaining the temperature below -20 ° C, ethyl iodide (608.3 mg, 3.9 mmol) was added dropwise to the reaction liquid, and the reaction was carried out at -20 ° C for 1 hour. The reaction was continued to room temperature for 4 hours. After completion of the reaction, saturated sodium hydrogencarbonate (20 mL) was added dropwise to the reaction mixture, and extracted with dichloromethane (30 mL×3), and the organic phase was combined, and then saturated sodium thiosulfate solution (30 mL×1) (30 mL × 1) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuo to give brown liquid 48a (840mg).

MS m/z (ESI): 278.1 [M+H ⁺ ].

Second step: 2-cyclopropyl-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-benzenesulfonate ( 48b )

2-cyclopropyl-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

48a (832.08 mg, 3 mmoL) was dissolved in dichloromethane (20 mL), and benzenesulfonic acid 1.5 H ₂ O (833.4 mg, 4.5 mmoL) was added, and the reaction was refluxed for 8 hours. After completion of the reaction, the reaction mixture was concentrated to dryness to give crystals: jjjjj

MS m/z (ESI): 178.1 [M+H ⁺ ].

The third step: tert-butyl ((2R,3S,5R)-5-(2-cyclopropyl-1-ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)- 2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 48c )

Tert-butyl((2R,3S,5R)-5-(2-cyclopropyl-1-ethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5- Difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

48b (1.01g, 3.0mmol) was dissolved in N,N-dimethylacetamide (20mL), and intermediate 1 (1.08g, 3.0mmol) was added and stirred at room temperature for 1 hour. . Sodium tris(ethyloxy)borohydride (953.7 mg, 4.5 mmol) was added to the reaction mixture at 0 ° C, and the mixture was allowed to react at room temperature for 3 hours. The mixture was cooled to 0 ° C, and then water (30 mL) and EtOAc (EtOAc) (EtOAc) Filtration, concentration of the filtrate under reduced pressure, rotary drying, purification by column chromatography (dichloromethane / methanol (v / v) = 100:1, a small amount of aqueous ammonia), to obtain a pale yellow solid 48c (600 mg, yield 40.8%) .

MS m/z (ESI): 489.1 [M+H ⁺ ].

Fourth step: (2R, 3S, 5R)-5-(2-cyclopropyl-1-ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2- (2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 48 )

(2R,3S,5R)-5-(2-cyclopropyl-1-ethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro- 2H-pyran-3-amine

48c (550 mg, 1.13 mmol) was added to dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was dried with EtOAc (EtOAc) (EtOAc). The organic phase was combined, washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and dried, and purified by thin layer chromatography (dichloromethane/ethanol (v/v) = 10:1) Compound 48 (320 mg, yield 73.2%) was obtained as pale yellow solid.

MS m/z (ESI): 389.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.21-7.05 (m, 3H), 4.28-4.21 (m, 2H), 4.10-4.04 (q, 2H), 3.96-3.95 (t, 2H), 3.77-3.76 (t, 2H), 3.38-3.31 (t, 1H), 3.08-3.02 (m, 1H), 2.91-2.85 (m, 1H) , 2.46-2.42 (m, 1H), 1.94-1.89 (m, 1H), 1.46-1.43 (t, 1H) 1.40-1.46 (t, 3H), 1.28 (s, 1H), 0.97-0.94 (m, 2H) ), 0.89-0.84 (m, 2H).

Example 49

(2R,3S,5R)-5-(2-cyclopropyl-1-isopropylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2, 5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 49 )

(2R,3S,5R)-5-(2-cyclopropyl-1-isopropylpyrrolo[3,4-d]imidaz Ol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-cyclopropyl-1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 49a )

Tert-butyl 2-cyclopropyl-1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

27b (747.9mg, 3.0mmol) was dissolved in tetrahydrofuran (20mL) at room temperature, cooled to -20 ° C, sodium hexamethyldidecylamino (1.8mL, 2mol / L, 3.6mmol) was added dropwise Stirring was continued for 30 minutes in the reaction mixture. While maintaining the temperature at -20 ° C, iodoisopropane (510.0 mg, 3.9 mmol) was added dropwise to the reaction solution, and the reaction was carried out at -20 ° C for 1 hour. The reaction was continued to room temperature for 4 hours. After completion of the reaction, saturated sodium hydrogencarbonate (20 mL) was added dropwise to the reaction mixture, and extracted with dichloromethane (30 mL×3), and the organic phase was combined, and then saturated sodium thiosulfate solution (30 mL×1) (30 mL × 1) was washed with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to afford brown liquid 49a (880mg).

MS m/z (ESI): 29.21. [M+H ⁺ ].

Second step: 2-cyclopropyl-1-isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-benzenesulfonate ( 49b )

2-cyclopropyl-1-isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesμLfonate

49a (874.2 mg, 3 mmoL) was dissolved in dichloromethane (20 mL), and benzenesulfonic acid 1.5 H ₂ O (833.4 mg, 4.5 mmoL) was added, and the mixture was refluxed for 8 hours. After completion of the reaction, the reaction mixture was concentrated and dried to give a yellow solid (yield: 41 g).

MS m/z (ESI): 1921. [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-5-(2-cyclopropyl-1-isopropylpyrrolo[3,4-d]imidazole-5(1H,4H,6H) -yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 49c )

Tert-butyl((2R,3S,5R)-5-(2-cyclopropyl-1-isopropylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5- Difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

49b (1.05g, 3.0mmol) was dissolved in N,N-dimethylacetamide (20mL), and intermediate 1 (0.981g, 3.0mmol) was added and stirred at room temperature for 1 hour. . Sodium tris(ethyloxy)borohydride (1.59 g, 7.5 mmol) was added to the reaction mixture at 0 ° C, and the mixture was allowed to react to room temperature for 3 hours. The temperature was lowered to 0 ° C, and water (30 mL) and aqueous ammonia (1.5 mL) were successively added, and the mixture was extracted with dichloromethane (50 mL×4), and the organic phase was combined, washed with a saturated aqueous sodium chloride solution (30 mL×1), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, rotary dried, and purified by column chromatography (dichloromethane/methanol (v/v) = 100:1 to 70:1) to give pale yellow solid 49c (580 mg, yield 38.4%) .

MS m/z (ESI): 503.1 [M+H ⁺ ].

Step 4: (2R, 3S, 5R)-5-(2-cyclopropyl-1-isopropylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2 -(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 49 )

(2R,3S,5R)-5-(2-cyclopropyl-1-isopropylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro- 2H-pyran-3-amine

49c (502.6 mg, 1.0 mmoL) was added to dichloromethane (20 mL) at 0 ° C or less, trifluoroacetic acid (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was dried with EtOAc (EtOAc) (EtOAc). The combined organic layers were washed with brine (30 mL×1), dried over anhydrous sodium sulfate Compound 49 (200 mg, yield 49.6%) was obtained as white solid.

MS m/z (ESI): 403.1 [M+H+]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.20-7.06 (m, 3H), 4.77-4.72 (m, 1H), 4.30-4.23 ( m, 2H), 4.04-4.03 (t, 2H), 3.75-3.74 (t, 2H), 3.32-3.31 (t, 1H), 3.05-3.03 (m, 1H), 2.90-2.87 (m, 1H), 2.47-2.44 (m, 1H), 1.95-1.93 (m, 1H), 1.46-1.44 (t, 1H) 1.42-1.38 (d, 6H), 0.99-0.94 (m, 2H), 0.93-0.85 (m, 3H).

Example 50

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-cyclopropyl-1-ethyl -1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 50 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-cyclopropyl-1-ethyl-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

First step: tert-butyl ((2R,3S,5R)-5-(2-(cyclopropylcarbamoyl)-1-ethylpyrrolo[3,4-d]imidazole-5 (1H) ,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 50a )

Tert-butyl((2R,3S,5R)-5-(2-(cyclopropylcarbamoyl)-1-ethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2, 5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

47a (0.4 g, 0.81 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and triethylamine (169 μL, 1.2 mmol) and cyclopropylamine (112 μL, 1.6 mmol) were added to the reaction system in this order. The reaction was stirred at temperature for 30 minutes. TBTU (390 g, 1.2 mmol) was added to the reaction system, and the reaction was continued for 24 hours. Water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (30 mL×3). The organic phase was combined, washed with brine (50mL×1), dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography. Dichloromethane/methanol (v/v) = 30:1) gave a yellow solid 50a (140 mg, yield 30%).

MS m/z (ESI): 5321. [M+H ⁺ ].

Second step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-cyclopropyl- 1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 50 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-cyclopropyl-1-ethyl-1,4,5,6 -tetrahydropyrrolo[3,4-d]i Midazole-2-carboxamide

50a (140 mg, 0.37 mmol) was dissolved in dichloromethane (8 mL), cooled to 0 ° C, trifluoroacetic acid (2 mL) The reaction solution was concentrated under reduced pressure. aqueous sodium hydrogen sulfate (10 mL) was then evaporated and evaporated. The organic phase was combined, washed with brine brine (50 mL×1), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane/methanol (v/v) = 20:1) Compound ( 50 mg, yield 50%) was obtained as white solid.

MS m/z (ESI): 432.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.17-7.17 (m, 1H), 7.04-6.98 (m, 2H), 4.50-4.45 (m) , 2H), 4.27-4.22 (m, 2H), 3.95 (s, 1H), 3.83 (s, 3H), 3.46-2.41 (t, 2H), 3.40 (s, 1H), 2.84-2.80 (m, 1H) ), 2.49-2.47 (d, 2H), 1.39-1.37 (m, 3H), 0.88-0.80 (m, 4H), 0.62-0.60 (m, 2H).

Example 51

1-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1, 4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)ethanone ( Compound 51 )

1-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6- Tetrahydropyrrolo[3,4-d]imidazol-2-yl)ethanone

First step: 5-(Tertidinoxycarbonyl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid ( 51a )

5-(tert-butoxycarbonyl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylic acid

10a (2g, 6.4mmol) was dissolved in a tetrahydrofuran/water mixed solution (16 mL, v/v = 1:1), and sodium hydroxide (0.51 g, 12.8 mol) was added and allowed to react at room temperature for 2 hours. Ethyl acetate (20mL × 5). The combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated to give a light yellow solid 51a (1.3g, 74%), it was used directly in the next step.

MS m/z (ESI): 2821. [M+H ⁺ ].

Second step: tert-butyl 1-ethyl-2-(methoxy(methyl)carbamoyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H) -formate ( 51b )

Tert-butyl1-ethyl-2-(methoxy(methyl)carbamoyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

51a (1g, 3.55mmol) was dissolved in N,N-dimethylformamide (8mL), N,N'-carbonyldiimidazole (0.75g, 4.6mmol) was added, the temperature was lowered to 0 ° C, and the reaction was stirred for 1.5 hours. N,O-dimethylhydroxylamine hydrochloride (0.75 g, 4.6 mmol) was added portionwise and allowed to react at room temperature overnight. The reaction system was poured into 20 mL of water, extracted with ethyl acetate (30 mL×3), and the organic phase was combined, washed with saturated aqueous brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Ether: ethyl acetate (v/v) = 1:1) afforded a yellow solid 51b (0.94 g, yield 83%).

MS m/z (ESI): 325.1 [M+H ⁺ ].

The third step: 1-ethyl-N-methoxy-N-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-nonylamine benzene sulfonate ( 51c )

1-ethyl-N-methoxy-N-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide benzenesulfonate

51b (0.94 g, 2.92 mmol) was dissolved in dichloromethane (20 mL), benzenesulfonic acid 1.5 H ₂ O (0.81 g, 4.39 mmol) was added, and the mixture was warmed to 50 ° C and reflux for 24 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to give a white solid 51c (2.22g crude), was used directly in the next step.

MS m/z (ESI): 225.1 [M+H ⁺ ].

Fourth step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methoxy)methylcarbamate Mercapto)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 51d )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(methoxy(methyl)carbamoyl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

51c (2.22 g, 2.92 mmol) was dissolved in N,N-dimethylacetamide (10 mL) at room temperature. Intermediate 1 (1.05 g, 3.2 mmol) was added to the reaction system at room temperature, reaction 30 minute. The reaction system was cooled to 0 ° C, and sodium triacetate triacetate (1.6 g, 7.6 mmol) was added to react for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and water (20 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 9 to precipitate a solid, which was washed with water (50 mL × 3), dissolved in dichloromethane, methylene chloride (50 mL) ×3), the organic phase is combined, washed with a saturated aqueous solution of brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 30 :1), a yellow solid 51d (1.28 g, yield 82%).

MS m/z (ESI): 536.2 [M+H ⁺ ].

The fifth step: the third butyl ((2R,3S,5R)-5-(2-acetamido-1-ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)- 2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 51e )

Tert-butyl((2R,3S,5R)-5-(2-acetyl-1-ethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5- Difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

51d (0.28g, 0.53mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and methylmagnesium bromide reagent (0.44 mL, 3 mol/L) was added at -10 °C for 1 hour. The ammonium chloride solution (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL×3). Column chromatography and purification (dichloromethane/methanol (v/v) = 15:1) afforded 51e (0.19 g, yield 73%).

MS m/z (ESI): 491.1 [M+H ⁺ ].

Step 6: 1-(5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-B 1,-,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)ethanone ( Compound 51 )

1-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6- Tetrahydropyrrolo[3,4-d]imidazol-2-yl)ethanone

51e (0.19 g, 0.387 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and trifluoroacetic acid (2 mL) was added at 0 ° C, and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure to remove trifluoroacetic acid, and water and aqueous ammonia was added to the reaction mixture to adjust to pH 9. The mixture was extracted with dichloromethane (30 mL × 3), and the organic phase was combined, washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate The filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 30:1) to afford Compound 51 (0.101 g, yield 78%).

MS m/z (ESI): 391.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.16-7.13 (m, 1H), 7.10-7.01 (m, 2H), 4.31-4.27 (m) , 3H), 4.17-4.20 (m, 1H), 3.95 (s, 2H), 3.87 (s, 2H), 3.05-2.95 (m, 2H), 2.45 (s, 3H), 1.53-1.42 (m, 1H) ), 1.29-1.19 (m, 3H).

Example 52

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-N-isopropyl -1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 5 2)

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-N-isopropyl-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

First step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-isopropylcarbamoyl)pyrrole [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 52a )

Tert-butyl-((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(isopropylcarbamoyl)pyrrolo[3,4-d]imidazol-5(1H,4H ,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

10c (400mg, 0.813mmol) was dissolved in dichloromethane (10mL) at room temperature, and triethylamine (169μL, 1.21mmol), cyclopropylamine (139μL, 1.62mmol), and room temperature were added to the reaction system at room temperature. The reaction was stirred for 30 minutes. TBTU (398 mg, 1.21 mmol) was added to the reaction system, and the reaction was continued for 24 hours. Water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (30 mL×3). The organic phase was combined, washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography. (Dichloromethane/methanol (v/v) = 30:1) gave white solid 52a (304mg, yield 70%).

MS m/z (ESI): 534.1 [M+H ⁺ ].

Second step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-N -isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 52 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-N-isopropyl-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

52a (304 mg, 0.56 mmol) was dissolved in dichloromethane (6 mL), cooled to 0 ° C, trifluoroacetic acid (2 mL) The reaction solution was concentrated under reduced pressure. aqueous sodium hydrogen sulfate (10 mL) was then evaporated. The organic phases were combined and washed with brine brine (50 mL×1). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 20: 1), to obtain a solid compound 52 (68mg, 27% yield).

MS m/z (ESI): 434.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.20-6.93 (m, 3H), 4.43-4.38 (m, 2H), 4.22-4.08 (m) , 2H), 3.91 (s, 2H), 3.79 (s, 2H), 3.41-3.35 (m, 1H), 3.01 (m, 1H), 2.87 (m, 1H), 2.43-2.40 (d, 1H), 1.31-1.33 (m, 3H), 1.19-1.17 (m, 3H).

Example 53

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(ethylsulfonyl)pyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 53 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(ethylsulfonyl) Pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-(ethylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 53a )

Tert-butyl 1-ethyl-2-(ethylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

30c (1.5g, 5.0mmol) was dissolved in N,N-dimethylformamide (15mL), cooled to 0 ° C, added potassium carbonate (0.825g, 8.24mmol), and reacted for 10 minutes. Iodoethane (0.936 g, 6.0 mmol) was quickly added, and the reaction was carried out at room temperature for 12 hours. Water (200 mL) was added dropwise to the reaction mixture, and the mixture was extracted with methyl tributyl ether (200 mL × 3), and the organic phase was combined, washed with brine (200 mL×1), dried over anhydrous sodium sulfate Concentration gave a yellow solid 53a (1.4 g, yield 85%).

MS m/z (ESI): 330.1 [M+H ⁺ ].

Second step: 1-ethyl-2-(ethylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium benzene sulfonate ( 53b )

1-ethyl-2-(ethylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

53a (1.4 g, 4.3 mmol) and benzenesulfonic acid 1.5 H ₂ O (3 g, 12.6 mmol) were dissolved in dichloromethane (30 mL). The reaction solution was concentrated under reduced pressure to give 53b (yel.

MS m/z (ESI): 230.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(ethylsulfonyl)pyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 53c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(ethylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

53b (1.644g, 4.24mmol) was dissolved in N,N-dimethylacetamide (20mL), and intermediate 1 (1.2g, 5.1mmol) was added and stirred at room temperature for 1 hour. . Sodium tris(ethyloxy)borohydride (3.2 g, 14 mmol) was added to the reaction mixture at 0 ° C, and the mixture was allowed to react to room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and water (100 mL) and aqueous ammonia (10 mL) were successively added to adjust the pH to 8 to precipitate a brown solid. After filtration, the white solid column was chromatographed and purified (dichloromethane/methanol (v/v) ) = 150: 1) gave a yellow solid 53c (1 g, yield 44%).

MS m/z (ESI): 541.1 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(ethylsulfonyl)pyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 53 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(ethylsulfonyl) Pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

53c (1 g, 1.85 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C, trifluoroacetic acid (5 mL), and the mixture was reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure. EtOAc EtOAc (EtOAc) (EtOAc) )extraction. The organic phases were combined and washed with brine brine (100 mL×1). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 50: 1), to give a white solid compound 53 (0.64g, 79% yield) .

MS m/z (ESI): 441.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ7.22-7.05 (m, 3H), 4.41-4.36 (q, 2H), 4.29-4.22 (m, 2H), 4.05-4.04 (t, 2H), 3.87-3.86 (t, 2H), 3.42-3.37 (m, 3H), 3.13-3.06 (m, 1H), 2.93-2.87 (m, 1H) , 2.48-2.42 (m, 1H), 1.54-1.51 (m, 1H), 1.45-1.42 (t, 3H), 1.31-1.27 (t, 3H).

Example 54

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(ethylsulfonyl)-1-isopropylpyrrolo[3,4-d]imidazole- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 54 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)-1-isopropylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-isopropyl-2-(ethylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 54a )

Tert-butyl 1-isopropy-2-(ethylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

30c (1.5g, 5.0mmol) was dissolved in N,N-dimethylformamide (15mL), cooled to 0 ° C, cesium carbonate (1.95g, 5.98mmol) was added and reacted for 10 minutes. Iodoisopropane (1.109 g, 6.524 mmol) was quickly added, and the reaction was carried out for 12 hours at room temperature. Water (200 mL) was added dropwise to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The yellow solid 54a (1.5 g, yield 88%).

MS m/z (ESI): 344.1 [M+H ⁺ ].

Second step: 1-isopropyl-2-(ethylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium sulfonate ( 54b )

1-isopropy-2-(ethylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

54a (1.4 g, 4.4 mmol) and benzenesulfonic acid 1.5 H ₂ O (2.9 g, 13 mmol) were dissolved in dichloromethane (30 mL). The reaction solution was concentrated under reduced pressure to give 54b (2.6 g of crude material).

MS m/z (ESI): 244.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(ethylsulfonyl)pyrrolo [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 54c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropy-2-(ethylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

54b (1.752 g, 4.364 mmol) was dissolved in N,N-dimethylacetamide (20 mL) at rt. Intermediate 1 (1.2 g, 5.2 mmol). . Sodium tris(ethyloxy)borohydride (3.2 g, 14 mmol) was added to the reaction mixture at 0 ° C, and the mixture was allowed to react to room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and water (100 mL) and aqueous ammonia (10 mL) were successively added to adjust the pH to 8 to precipitate a brown solid. After filtration, the solid column was separated and purified (dichloromethane/methanol (v/v). = 150: 1) Purified yellow solid 54c (1.1 g, yield 45%).

MS m/z (ESI): 555.1 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(ethylsulfonyl)pyrrolo[3,4- d] imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( compound 54 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropy-2-(ethylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine

54c (1.1 g, 2.0 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C, trifluoroacetic acid (5 mL), and then reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure. EtOAc EtOAc (EtOAc) (EtOAc) )extraction. The organic phases were combined and washed with a saturated aqueous solution of brine (100 mL×1). Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, Purification by column chromatography (dichloromethane / methanol (v / v) = 50: 1), to give a white solid compound 54 (0.77g, 85% yield) .

MS m/z (ESI): 455.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23-7.08 (m, 3H), 5.35-5.28 (m, 1H), 4.30-4.25 ( m,2H), 4.16-4.14(t,2H),3.84-3.83(t,2H), 3.46-3.38(m,3H),3.13-3.08(m,1H),2.94-2.88(m,1H), 2.48-2.45 (m, 1H), 1.55-1.52 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H), 1..4-1.30 (q, 3H).

Example 55

3-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1, 4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-4-methyl-1,2,4-oxadiazol-5(4H)-one ( Compound 55 )

3-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6- Tetrahydropyrrolo[3,4-d]imidazol-2-yl)-4-methyl-1,2,4-oxadiazol-5(4H)-one

First step: tert-butyl 1-ethyl 2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,6-dihydropyrrolo[ 3,4-d]imidazole-5(1H)-formate ( 55a )

Tert-butyl1-ethyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H) -carboxylate

25a (2.1 g, 7.39 mmol) was dissolved in methanol (20 mL), and sodium hydrogencarbonate (0.84 g, 14 mmol) and hydroxyamine hydrochloride (1.02 g, 14 mmol) were added to the reaction system, and the mixture was heated to reflux for 1.5 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure to give a yellow oily compound, which was dissolved in 1,4-dioxane (30mL), and 1,8-diazabicyclounde-carbon- 7-ene (1.35 g, 8.87 mmol) and N,N'-carbonyldiimidazole (1.44 g, 8.87 mmol), warmed to 80 ° C for 4 hours, cooled to room temperature and concentrated under reduced pressure to give compound 55a. (1.9 g, yield 73%). Used directly in the next step.

MS m/z (ESI): 322.0 [M+H ⁺ ].

Second step: tert-butyl 1-ethyl-2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4, 6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 55b )

Tert-butyl1-ethyl-2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole- 5(1H)-carboxylate

55a (1.3 g, 4 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (1.85 g, 8.1 mmol) and methyl iodide (500 μL, 8.1 mmol) were added to the reaction system in this order. The temperature was reacted for 2 hours. Water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL×3), and the organic layer was combined, washed with saturated aqueous sodium chloride (50 mL×6), dried over anhydrous sodium sulfate Purification by column chromatography (dichloromethane/methanol (v/v) = 20:1) afforded pale yellow solid 55b (0.60 g, yield 52%).

MS m/z (ESI): 336.0 [M+H ⁺ ].

The third step: 3-(1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-4-methyl-1,2,4-oxa Diazol-5(4H) -ketobenzenesulfonate ( 55c )

3-(1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-4-m Ethyl-1,2,4-oxadiazol-5(4H)-one benzenesulfonate

55b (0.60g, 1.78mol) was dissolved in dichloromethane (20mL), benzenesulfonic acid 1.5 H ₂ O (0.49g, 24.9mol) was added to warm to 50 ° C for 8 hours, cooled to room temperature, concentrated under reduced pressure. A yellow solid 55c (1.09 g of crude) was obtained which was used directly to the next step.

MS m/z (ESI): 236.1 [M+H ⁺ ].

The fourth step: the third butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(4-methyl-5-oxo) -4,5-dihydro-1,2,4-oxadiazol-3-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyridyl喃-3-yl)carbamate ( 55d )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(4-methyl-5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

55c (1.09 g, 1.78 mmol) was dissolved in N,N-dimethylacetamide (15 mL), and Intermediate 1 (0.64 g, 1.95 mmol) was added to the reaction system at room temperature for 30 minutes. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (0.65 g, 3.47 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 9 to precipitate a solid, which was washed with water (50 mL×3), dissolved in dichloromethane, methylene chloride (50 mL) ×3) extraction, the organic phase was combined, washed with a saturated aqueous solution of brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 20 :1), a yellow solid 55d (0.68 g, yield 70%).

MS m/z (ESI): 547.1 [M+H ⁺ ].

Step 5: 3-(5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-B 1,-,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-4-methyl-1,2,4-oxadiazol-5(4H)-one ( Compound 55 )

3-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2 H-pyran-3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-4-methyl-1,2,4-oxadiazol-5( 4H)-one

55d (0.68g, 1.2mmol) was dissolved in dichloromethane (10mL) at room temperature, trifluoroacetic acid (2mL) was added at 0 °C, and the mixture was warmed to room temperature and stirred for 2 hours. Concentrated under reduced pressure to remove trifluoroacetic acid, water (15 mL) was added to the reaction system, and aqueous ammonia was added dropwise to adjust the pH to 9, and extracted with dichloromethane (30 mL × 3), and the organic phase was combined with a saturated aqueous salt solution (50 mL × 1) , dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography separation (dichloromethane / methanol (v / v) = 30: 1), to give an orange solid compound 55 (0.347g, 66% yield).

MS m/z (ESI): 447.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.01-6.84 (m, 3H), 4.13-4.04 (m, 4H), 3.90-3.86 (d , 2H), 3.31 (s, 3H), 3.10-3.09 (m, 5H), 2.90-2.84 (m, 1H), 2.70-2.67 (m, 1H), 2.28-2.24 (m, 1H), 1.32-1.07 (m, 3H).

Example 56

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3 , 4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 56 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formic acid Ester ( 56a )

Tert-butyl 1-ethyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylatete

25a (7.5g, 28.626mmoL) was dissolved in N,N-dimethylformamide (150mL), sodium azide (5.58g, 85.878mmoL) and ammonium acetate (6.3619g, 85.878mmoL) were added, and the temperature was raised. The reaction was allowed to go to 120 ° C overnight. The reaction solution was cooled to room temperature, and water (200 mL) was added to a 1 mol/L hydrochloric acid solution to adjust pH 1-2, and filtered to obtain a yellow solid. The filtrate was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, and the resulting solid was filtered combined and dried to give a yellow solid 56a (7g, 80% yield).

MS m/z (ESI): 306.1 [M+H ⁺ ].

Second step: tert-butyl 1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 ( 1H)-formate ( 56b-1 )

Tert-butyl 1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imi Dazole-5(1H)-carboxylate

Third butyl 1-ethyl-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-A Acid ester (56b-2)

Tert-butyl 1-ethyl-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

56a (4000 mg, 13.11 mmol) was dissolved in N,N-dimethylformamide (100 mL), and sodium hydrogen hydride (629 mg, 60%, 15.73 mmol) was added and the mixture was stirred for 0.5 hour. Methyl iodide (2230 mg, 15.73 mmol) was added and the reaction was allowed to warm overnight. The reaction solution was slowly added to ice water (500 g), sodium chloride was added to saturate, and ethyl acetate (100 mL × 4) was extracted. The organic phase was combined, washed with a saturated sodium chloride solution (200 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated to dryness. = 2: 1 to 1:1) gave white solid 56b-1 (2500 mg, yield 59.8%) and white solid 56b-2 (1100 mg, yield: 26.3%).

Compound 56b-1: MS m/z (ESI): 320.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 4.62-4.59 (d, 2H), 4.50-4.45 (q, 2H) ), 4.38-4.36 (d, 2H), 4.34 - 4.33 (d, 3H), 1.47-1.46 (d, 9H), 1.39-1.36 (t, 3H); Compound 56b-2: MS m/z (ESI) :320.1[M+H ⁺ ]; ¹ H NMR (400MHz, DMSO- d ₆ ): δ 4.58-4.55 (d, 2H), 4.44 (s, 3H), 4.39-4.31 (m, 4H), 1.47 ( d, 9H), 1.35-1.32 (m, 3H).

The third step: 1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium Acid salt ( 56c )

1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole dibenzenesulfonate

Tert-butyl 1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Formate ( 56b-1 ) (2500 mg, 7.863 mmol), benzenesulfonic acid 1.5 H ₂ O (2900 mg, 15.672 mmol) were dissolved in dichloromethane (25 mL) and warmed to 40 ° C overnight. The reaction solution was concentrated to dryness and dried in vacuo to give 1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4- d] Imidazole dibenzenesulfonate ( 56c ) (4190 mg) was directly reacted with the next step.

MS m/z (ESI): 2221. [M+H ⁺ ].

The fourth step: the third butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-tetrazole) -5-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 56d )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

56c (3200mg, 5.98mmoL) and intermediate 1 (2350mg, 7.18mmoL) were dissolved in N,N-dimethylacetamide (10mL), stirred at room temperature for 0.5 hours, and added to the ice bath. Sodium borohydride (3420 mg, 16.15 mmol) was stirred at 0 ° C for 0.5 h and then warmed to room temperature and stirred for 2 h. Intermediate 1 (2300 mg, 7.033 mmol) and sodium tris(acetoxy)borohydride (3420 mg, 16.146 mmol) were added and allowed to react at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (100 mL), and stirred for 0.5 hr, filtered, filtered, washed with water (20 mL × 3) The residue was purified with EtOAc EtOAc EtOAc (EtOAc (EtOAc)

MS m/z (ESI): 531.1 [M+H ⁺ ].

The fifth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-tetrazol-5-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 56 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

56d (1200mg, 2.26mmoL) was added to dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added, and the mixture was allowed to react to room temperature for 2 hours. The reaction solution was spin-dried, and a saturated sodium hydrogen carbonate solution (200 mL) was added to adjust pH 7-8, and the aqueous phase was extracted with dichloromethane (60 mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, the residue was purified by silica gel column chromatography separation (dichloromethane / methanol (v / v) = 30: 1, adding a small amount of ammonia), to give a yellow solid compound 56 (420 mg, yield 43%).

MS m/z (ESI): 431.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.24-7.20 (m, 1H), 7.18-7.06 (m, 2H), 4.55-4.49 (q, 2H), 4.38 (s, 3H), 4.32-4.27 (m, 2H), 4.12-4.11 (t, 2H), 3.94-3.93 (t, 2H), 3.47-3.41 (t, 1H), 3.17 -3.10 (m, 1H), 2.97-2.90 (m, 1H), 2.51-2.48 (dd, 1H), 1.58-1.49 (q, 1H), 1.47-1.44 (t, 3H).

Example 57

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(2-methyl-2H-tetrazol-5-yl 1)pyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 57 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: 1-ethyl-2-(2-methyl-2H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium Acid salt ( 57a )

1-ethyl-2-(2-methyl-2H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole dibenzenesulfonate

56b-2 (1000 mg, 3.13 mmoL), benzenesulfonic acid 1.5 H ₂ O (1590 mg, 6.26 mmol) was dissolved in dichloromethane (10 mL), and the mixture was warmed to 40 ° C overnight. The reaction mixture was concentrated to dryness and dried in vacuo to afford 57a (1670mg).

MS m/z (ESI): 2221. [M+H ⁺ ].

Second step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(2-methyl-2H-tetrazole) -5-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 57b )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

57a (1670mg, 3.13mmoL) and intermediate 1 (1230mg, 3.76mmoL) were dissolved in N,N-dimethylacetamide (10mL), stirred at room temperature for 0.5 hours, and added to the ice bath. Sodium borohydride (1800 mg, 8.45 mmol) was stirred at 0 ° C for 0.5 h and then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (100 mL), and stirred for 0.5 hr, filtered, filtered, washed with water (20 mL × 3) The residue was purified by silica gel column chromatography separation (dichloromethane / methanol (v / v) = 60: 1) to give a yellow solid 57b (605mg, 36.5% yield).

MS m/z (ESI): 531.1 [M+H ⁺ ].

The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(2-methyl-2H-tetrazol-5-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 57 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

57b (580 mg, 1.09 mmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added and the mixture was warmed to room temperature for 2 hours. The reaction solution was spin-dried, and a saturated sodium hydrogen carbonate aqueous solution (100 mL) was added to adjust pH to 7-8, and the aqueous phase was extracted with dichloromethane (30mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, the residue was purified by silica gel column chromatography separation (dichloromethane / methanol (v / v) = 30: 1, adding a small amount of ammonia), to give a yellow solid compound 57 (300 mg, yield 63%).

MS m/z (ESI): 431.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.24-7.20 (m, 1H), 7.18-7.06 (m, 2H), 4.51-4.46 (q, 2H), 4.45 (s, 3H), 4.32-4.27 (m, 2H), 4.10-4.09 (t, 2H), 3.93-3.92 (t, 2H), 3.48-3.41 (t, 1H), 3.17 -3.10 (m, 1H), 2.96-2.90 (m, 1H), 2.50-2.47 (m, 1H), 1.58-1.49 (dd, 1H), 1.46-1.42 (t, 3H).

Example 58

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine dihydrochloride ( Compound 58 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine dihydrochloride

First step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine dihydrochloride ( Compound 58 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )tetrahydro-2H-pyran-3-amine dihydrochloride

Compound 2 (500 mg, 1.21 mmol) was dissolved in dry ethyl acetate (15 mL), cooled to 0 ° C, and ethyl hydrogen chloride solution (5 mL, 3 mol / L) was added dropwise to the reaction mixture. The reaction was carried out at 0 ° C for 1 hour. A white solid precipitated, was filtered, the cake was washed with ethyl acetate (15mL × 3) washed and sucked dry to give a white solid compound 58 (520mg, yield 88.6%).

MS m/z (ESI): 413.1 [M+H ⁺ ].

¹ H NMR (400 MHz, CD ₃ OD): δ 7.25-7.13 (m, 3H), 4.80 (s, 2H), 4.69-4.66 (d, 2H), 4.62-4.55 (t, 2H), 4.45-4.42 (d, 2H), 4.42-4.01 (m, 1H), 3.89 (s, 3H), 3.86-3.83 (t, 1H), 3.61-3.58 (t, 1H), 3.26 (s, 1H), 2.80-2.77 (m, 1H), 2.23 - 2.14 (q, 1H).

Example 59

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazol-2-carboxamide dihydrochloride ( Compound 59 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxamide dihydrochloride

First step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-carboxamide dihydrochloride ( Compound 59 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-2-carboxamide dihydrochloride

Compound 10 (300 mg, 1.21 mmol) was dissolved in dry ethyl acetate (8 mL), cooled to 0 ° C, and ethyl hydrogen chloride (4 mL, 3 mol / L) was added dropwise to the reaction mixture. The reaction was carried out at 0 ° C for 1 hour. A white solid precipitated, was filtered, the cake was washed with ethyl acetate (15mL × 3) washed and sucked dry to give a white solid compound 59 (300mg, yield 84.5%).

MS m/z (ESI): 392.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.26-7.13 (m, 3H), 4.84 (s, 2H), 4.70-4.62 (d) , 2H), 4.59-4.52 (t, 2H), 4.46-4.60 (m, 3H), 4.11-4.05 (m, 1H), 3.88-3.83 (t, 1H), 3.63-3.57 (s, 3H), 2.82 -2.79 (m, 1H), 2.22 - 2.14 (m, 1H), 1.34-1.14 (t, 3H).

Example 60

3-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1, 4,5,6 tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1,2,4-oxadiazol-5(4H)-one ( Compound 60 )

3-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6- Tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1,2,4-oxadiazol-5(4H)-one

First step: tert-butyl 1-ethyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,6-tetrahydropyrrole [3,4-d]imidazole-5(1H)-formate ( 60a )

Tert-butyl1-ethyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H) -carboxylate

25a (2.1g, 7.39mmol) was dissolved in methanol (20mL), sodium hydrogencarbonate (0.84g, 14mmol), hydroxylamine hydrochloride (1.02g, 14mmol) was added to the reaction system, and the mixture was heated to reflux for 1.5 hours, cooled to room temperature. Concentration under reduced pressure gave a yellow oily compound. Compound was dissolved in 1,4-dioxane (30mL), and 1,8-diazabicycloundec-7-ene was added to the reaction system. (1.35g, 8.87mmol) and N, N'- carbonyldiimidazole (1.44g, 8.87mmol), the reaction temperature was raised to 80 ℃ 4 hours, cooled to room temperature and concentrated under reduced pressure to give a yellow oily compound 60a (1.9g, Yield 73%) was used directly in the next step.

MS m/z (ESI): 322.0 [M+H ⁺ ].

Second step: 3-(1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1,2,4-oxadiazole-5 ( 4H)-ketobenzenesulfonate ( 60b )

3-(1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1,2,4-oxadiazol-5(4H)-one benzene sulfonate

60a (0.60 g, 1.83 mol) was dissolved in methylene chloride (20 mL), benzenesulfonic acid 1.5 H ₂ O (0.43 g, 2.7 mol) was added and the mixture was warmed to 50 ° C for 8 hr. A yellow solid 60b (1.03 g of crude) was obtained which was used directly to the next step.

MS m/z (ESI): 22.21. [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-oxo-4,5-) Dihydro-1,2,4-oxadiazol-3-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl Carbamate ( 60c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

60b (1.03 g, 1.83 mmol) was dissolved in dimethylacetamide (15 mL). Intermediate 1 (0.61 g, 1 .. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (0.98 g, 4.46 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 9, and the solid was precipitated, washed with water (50 mL × 3), dissolved in dichloromethane, with dichloromethane (50 mL × 3) The organic phase was extracted, washed with a saturated aqueous solution of brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 20:1 The yellow solid 60c (0.57 g, yield 58%).

MS m/z (ESI): 533.1 [M+H ⁺ ].

The fourth step: 3-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-B Base-1,4,5,6 tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1,2,4-oxadiazol-5(4H)-one ( Compound 60 )

3-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4,5,6- Tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1,2,4-oxadiazol-5(4H)-one

60c (0.57 g, 1.06 mmol) was dissolved in dichloromethane (10 mL) at room temperature, trifluoroacetic acid (2 mL) was added at 0 ° C, and the mixture was warmed to room temperature and stirred for 2 hr. The organic phase was extracted with dichloromethane (30 mL×3), and the organic phase was combined and washed with saturated aqueous sodium chloride (50 mL×1). After drying, the filtrate was concentrated and purified by chromatography (methylene chloride/methanol (v/v) = 30:1) to afford compound 60 (0.042 g, yield 10%).

MS m/z (ESI): 433.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.18-7.10 (m, 1H), 7.09-7.05 (m, 2H), 4.43-4.40 ( d, 1H), 4.23-4.19 (m, 3H), 3.93-3.91 (m, 2H), 3.76-3.74 (m, 2H), 3.37-3.34 (m, 1H), 3.09-3.03 (m, 1H), 2.47-2.44 (m, 1H), 1.63-1.54 (m, 1H), 1.30-1.26 (t, 3H).

Example 61

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-1,2,4-triazole-5- Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 61 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolo[3, 4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-carbamoyl-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 61a )

Tert-butyl 2-carbamoyl-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

10a (8 g, 25.8 mmol) was dissolved in a methanol solution of ammonia (55.4 mL, 7 mol/L), and heated to 80 ° C for 8 hours. The reaction solution was concentrated spin-dried to give a yellow solid 61a (7.2g crude) was used directly in the next reaction.

Second step: tert-butyl 1-ethyl-2-(1H-1,2,4-triazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H)-formate ( 61b )

Tert-butyl 1-ethyl-2-(1H-1,2,4-triazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

61a (3.57 g, 6.1 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (20 mL) and heated to reflux for 5 hr. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give crystals crystals crystals crystals crystals Water (40 mL) was added to the reaction system, and extracted with ethyl acetate (50mL × 3), combined organic phases were washed with saturated aqueous sodium chloride solution (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 61b ( 2.1 g, yield 70%), used directly in the next step.

MS m/z (ESI): 205.1 [M+H ⁺ ].

The third step: tert-butyl 1-ethyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4- d] imidazole-5(1H)-formate ( 61c )

Tert-butyl 1-ethyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

61b (1.0 g, 3.2 mmol) was dissolved in N,N-dimethylformamide (10 mL), and hydrazine carbonate (2.13 g, 6.57 mmol) and iodomethane (927 mg, 6.5 mmol) were sequentially added to the reaction system. The reaction was carried out for 4 hours at room temperature. The reaction mixture was extracted with ethyl acetate (50 mL×3). EtOAc (EtOAc m. Methanol (v/v) = 20:1) gave pale yellow solid pyrrolo[ 61c (0.61 g, yield 52%).

MS m/z (ESI): 319.1 [M+H ⁺ ].

The fourth step: 1-ethyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4- d] Imidazobenzenesulfonate ( 61d )

1-ethyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

61c (0.61g, 1.93mol) was dissolved in dichloromethane (20mL), benzenesulfonic acid 1.5 H ₂ O (0.46g, 2.90mol) was added to the solution, and the mixture was heated to 50 ° C for 8 hours, and cooled to room temperature. Concentration under reduced pressure gave a yellow solid (yield: ield :

MS m/z (ESI): 219.1 [M+H ⁺ ].

The fifth step: the third butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-1, 2,4-Triazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 61e )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-1,2,4-triazol-5-yl) Pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

61d (1.02g, 1.93mmol) was dissolved in dimethylacetamide (15 mL), and Intermediate 1 (0.69 g, 2.1 mmol) was added to the reaction system at room temperature for 30 minutes. The reaction system was cooled to 0 ° C, and sodium triacetate triacetate (0.83 g, 3.7 mmol) was added to react for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 9, and the solid was precipitated, washed with water (50 mL × 3), dissolved in dichloromethane, with dichloromethane (50 mL × 3) The organic phase was extracted, washed with a saturated aqueous solution of brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 20:1 The yellow solid 61e (0.534 g, yield 53%).

MS m/z (ESI): 530.2 [M+H ⁺ ].

Step 6: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-1,2,4-tri) Zyrid-5-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 61 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolo[3, 4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

61e (0.53 g, 1 mmol) was dissolved in dichloromethane (10 mL) at room temperature, trifluoroacetic acid (2 mL) was added at 0 ° C, and the mixture was warmed to room temperature and stirred for 2 hours. Concentrated under reduced pressure to remove trifluoroacetic acid, water (15 mL) was added to the reaction system, and aqueous ammonia was added dropwise to adjust the pH to 9 and extracted with dichloromethane (30 mL×3), and the organic phase was combined with a saturated aqueous salt solution (50 mL×1) The organic layer was dried (MgSO4 / MeOH (v/v) = 30:1) (m.

MS m/z (ESI): 430.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.90 (s, 1H), 7.16-7.07 (m, 1H), 7.05-6.97 (m, 2H) ), 4.47-4.39 (m, 2H), 4.30-4.28 (m, 4H), 4.04-3.87 (m, 4H), 3.49-3.44 (t, 1H), 3.12-3.07 (m, 1H), 2.94 - 2.92 (m, 1H), 2.52-2.50 (m, 1H), 1.41-1.39 (t, 3H).

Example 62

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-1,2,4-triazol-3-yl)pyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( compound 62 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-1,2,4-triazol-3-yl)pyrrolo[3,4-d] Imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: 1-ethyl-2-(1H-1,2,4-triazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium Acid salt ( 62a )

1-ethyl-2-(1H-1,2,4-triazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

61b (0.70g, 2.3mmol) was dissolved in dichloromethane (20mL), benzenesulfonic acid 1.5 H ₂ O (0.54g, 3.45mmol) was added to the solution and the mixture was heated to 50 ° C for 8 hours, and cooled to room temperature. Concentration under reduced pressure gave a yellow solid 62a (1.1 g, crude).

MS m/z (ESI): 205.1 [M+H ⁺ ].

Second step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-1,2,4-tri) Zyrid-3-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 62b )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-1,2,4-triazol-3-yl)pyrrolo[3, 4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

62a (1.1 g, 2.3 mmol) was dissolved in dimethylacetamide (15 mL), and Intermediate 1 (0.94 g, 2.89 mmol) was added to the reaction system at room temperature for 30 minutes. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (2.2 g, 10.2 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 9, and the solid was precipitated, washed with water (50 mL×3), and dissolved in dichloromethane, with dichloromethane (50 mL×3) The organic phase was extracted, washed with a saturated aqueous solution of brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 20:1 ), 62b (0.60 g, yield 43%).

MS m/z (ESI): 516.1 [M+H ⁺ ].

The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-1,2,4-triazol-3-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 62 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-1,2,4-triazol-3-yl)pyrrolo[3,4-d] Imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

62b (0.60 g, 1.16 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 2 hours. Concentrated under reduced pressure to remove trifluoroacetic acid, water (15 mL) was added to the reaction system, and aqueous ammonia was added dropwise to adjust the pH to 9 and extracted with dichloromethane (30 mL×3), and the organic phase was combined with a saturated aqueous salt solution (50 mL×1) The organic layer was dried (MgSO4).

MS m/z (ESI): 416.1 [M+H ⁺ ].

Example 63

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 63 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: 5-t-butyl 2-ethyl 1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate ( 63a )

5-tert-butyl 2-ethyl 1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

Intermediate 5 (20.0 g, 71.17 mmol) was dissolved in N,N-dimethylformamide (200 mL), cesium carbonate (27.82 g, 85.41 mmol) was added, and iodoisopropane (14.52 g) was added to the ice bath. , 85.41 mmoL), reacted at 60 ° C for 2 hours. A saturated sodium chloride solution (400 mL) was added to the reaction mixture, and the mixture was combined with ethyl acetate (200 mL×3), and the organic phase was washed with saturated sodium chloride solution (200 mL×4), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, to give a pale yellow solid 63a (21g, 91.3% yield).

MS m/z (ESI): 324.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.69-5.59 (m, 1H), 4.62-4.57 (d, 2H), 4.39-4.33 ( m, 4H), 1.5 (d, 9H), 1.44-1.40 (m, 9H).

The second step: the third butyl 2-carbamoyl-1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 63b )

Tert-butyl 2-carbamoyl-1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

63a (21 g, 65.0 mmol) was dissolved in an ammonia-methanol solution (92.8 mL, 7 mol/L, 650 mmol), and the mixture was warmed to 85 ° C, and the mixture was stirred for 20 hours. The reaction solution was cooled to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, White solid 63b (17 g, yield 89%).

Third step: tert-butyl 2-cyano-1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 63c )

Tert-butyl 2-cyano-1-isopropyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

63b (14.9 g, 50.68 mmol) was dissolved in pyridine (260 mL), cooled to 0 ° C, trifluoroacetic anhydride (20.6 g, 126.70 mmol) was added dropwise with stirring, and the mixture was allowed to react to room temperature for 2 hours. The reaction solution was added to a saturated sodium chloride solution (300 mL), and extracted with ethyl acetate (100 mL×4). The organic phase was combined and washed with a 1 mol/L aqueous solution of citric acid until the aqueous phase was weakly acidic, and brine (100 mL× 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a white solid 63c (13.5g, yield 96.5%).

MS m/z (ESI): 431.1 [M+H ⁺ ].

Fourth step: tert-butyl 1-isopropyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Acid ester ( 63d )

Tert-butyl 1-isopropyl-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

63c (7.0g, 25.36mmoL) was dissolved in N,N-dimethylformamide (150mL), sodium azide (4.95g, 76.09mmoL) and ammonium acetate (5.86g, 76.09mmoL) were added, and the temperature was raised. The reaction was allowed to go to 120 ° C overnight. The reaction solution was cooled to room temperature, water (200 mL) was added, and the mixture was adjusted to pH 1-2 with 1 mol/L hydrochloric acid solution, and filtered to give a yellow solid. The filtrate was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, and the resulting solid was filtered combined, dried, to give a yellow solid 63d (6.8g, 85% yield).

MS m/z (ESI): 320.1 [M+H ⁺ ].

Fifth step: tert-butyl 1-isopropyl-2-(1-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H) -formate ( 63e-1 )

Tert-butyl 1-isopropyl-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Third butyl 1-isopropyl-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Formate ( 63e-2 )

Tert-butyl 1-isopropyl-2-(2-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

63d (6.7g, 21mmoL) was dissolved in N,N-dimethylformamide (150mL), sodium hydride (1008mg, 60%, 25.2mmoL) was added under ice bath, and stirred for 0.5 hour in ice bath, then iodine was added. Methane (3.58 g, 25.2 mmol) was allowed to react overnight. The reaction solution was slowly added to crushed ice (500 g), sodium chloride was added until the reaction mixture was saturated, and extracted with ethyl acetate (100 mL x 4). The organic phase was combined, washed with a saturated sodium chloride solution (200 mL×3), dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography ( petroleum ether/ethyl acetate (v/v) = 2:1 to 1:1), a white solid 63e-1 (2.0 g, yield 28.6%) and a white solid 63e-2 (3.1 g, yield 44.3%) were obtained.

Compound 63e-1: MS m / z (ESI): 334.1 [M + H +]; Compound 63e-2: MS m / z (ESI): 334.1 [M + H +].

Step 6: 1-isopropyl-2-(1-methyl-2H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazolium Acid salt (63f)

1-isopropyl-2-(1-methyl-2H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

63e-2 (2.9g, 8.71mmoL), benzenesulfonic acid 1.5.H ₂ O (3.22g, 17.42mmoL) was dissolved in anhydrous methanol (30mL), and the mixture was heated to 70 ° C for 2 hours. The reaction solution was concentrated to dryness, and ethyl acetate (50 mL) was evaporated. The filter cake was dried in vacuo to give colorless crystals 63f (3.4g crude), used directly in the next reaction.

MS m/z (ESI): 234.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, DMSO): δ 9.94 (s, 2H), 7.60 (s, 2H), 7.31-7.30 (m, 3H), 5.42-5.39 (m, 1H), 4.66 (s, 2H), 4.32-4.31 (m, 5H), 1.45-1.42 (m, 6H).

Step 7: Tert-Butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(1-methyl-2H-tetra) Zyrid-5-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 63 g )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(1-methyl-1H) -tetrazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

63 g (3.7 g, 9.46 mmoL) and Intermediate 1 (3.71 g, 11.35 mmol) were dissolved in N,N-dimethylacetamide (60 mL), stirred at room temperature for 0.5 hour, and added to the ice bath. Sodium ethoxide) sodium borohydride (3.86 g, 18.20 mmol) was stirred at 0 ° C for 0.5 h and then warmed to room and then stirred for 2 h. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (100 mL), and the mixture was stirred for 0.5 hr, filtered, and the filter cake was washed with water (20 mL × 3), dissolved in dichloromethane (100 mL), dried over anhydrous sodium sulfate It was isolated and purified silica gel column chromatography (methylene chloride / methanol (v / v) = 60: 1) to give a yellow solid 63g (3.7g, yield 72.5%).

MS m/z (ESI): 545.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ7.22-7.18 (m, 1H), 7.08-7.01 (ddd, 2H), 5.53-5.45 (m, 1H), 4.40-4.38 (d, 1H), 4.34 (s, 3H), 4.33-4.29 (m, 1H), 4.19 (m, 2H), 3.88 (s, 2H), 3.77-3.72 (t , 1H), 3.45-3.40 (t, 1H), 3.18-3.10 (m, 1H), 2.44-2.41 (d, 1H), 1.71-1.62 (q, 1H), 1.49-1.48 (d, 6H), 1.28 (s, 9H).

Step 8: (2R, 3S, 5R)-2-(2,5-Difluorophenyl)-5-(1-isopropyl-2-(1-methyl-2H-tetrazol-5-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 63 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-isopropyl-2-(1-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

63 g (3.5 g, 6.43 mmol) was added to dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added under ice-cooling, and the mixture was allowed to react to room temperature for 2 hours. The reaction solution was spin-dried, and a saturated sodium hydrogen carbonate solution (200 mL) was added to adjust pH 7-8, and the aqueous phase was extracted with dichloromethane (60 mL×4). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, then evaporated. It was washed with a mixed solvent of ethyl acetate (2 mL) and isopropyl ether (5 mL) to afford Compound (yield: 54 .

MS m/z (ESI): 445.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.29-7.25 (ddd, 1H), 7.22-7.12 (m, 2H), 5.55-5.45 (hept, 1H), 4.47-4.45 (d, 1H), 4.35 (s, 3H), 4.34-4.32 (dd, 1H), 4.21-4.20 (t, 2H), 3.94-3.88 (m, 2H), 3.51 -3.46 (t, 1H), 3.25-3.15 (m, 2H), 2.59-2.55 (m, 1H), 1.70-1.61 (q, 1H), 1.51-1.49 (d, 6H).

Example 64

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(1-ethyl-2-(1H-pyrazol-3-yl)pyrrolo[3,4-d] Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 64 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-pyrazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-(methoxy(methyl)carbamoyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H) -formate ( 64a )

Tert-butyl 1-ethyl-2-(methoxy(methyl)carbamoyl)-4,6-dihydropyrrolo[3,4-d]i Midazole-5(1H)-carboxylate

The compound N,O-dimethylhydroxylamine hydrochloride (9.14 g, 93.78 mmol) was dissolved in dichloromethane (40 mL), and trimethylaluminum (46.9 mL, 93.78 mmoL) was added dropwise with stirring at -10 °C. After stirring for 1 hour, a 10a (14 g, 45.3 mmol) solution of dichloromethane (30 mL) was added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction solution was cooled to -10 ° C, and a saturated ammonium chloride solution was added to the reaction mixture to extract the mixture, and a saturated sodium chloride solution (100 mL), dichloromethane (50 mL × 5) The sodium solution (50 mL x 3) was washed. Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 64a (13g, 88.4% yield).

MS m/z (ESI): 325.1 [M+H ⁺ ].

Second step: tert-butyl 2-ethylindenyl-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole 5(1H)-formate ( 64b )

Tert-butyl 2-acetyl-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

64a (13g, 40.1mmoL) was dissolved in tetrahydrofuran (130 mL), and methylmagnesium bromide (26.7 mL, 80.2 mmol) was added dropwise with stirring at -10 °C, and the reaction was stirred at 0 ° C for 2 hours. The reaction solution was cooled to 0 ° C, and a saturated ammonium chloride solution was added to the reaction mixture to extract the mixture, and then a saturated sodium chloride solution (200 mL), ethyl acetate (50 mL×4), and the organic phase was combined with saturated The sodium solution (100 mL x 3) was washed. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 1:3 to 1:1) to give a white solid 64b (10 g , yield 83%).

MS m/z (ESI): 280.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.54-4.50 (d, 2H), 4.46 - 4.36 (m, 4H), 2.64 (d, 3H), 1.51 (d, 9H), 1.41-1.35 (m, 3H).

Third step: (E)-t-butyl 2-(3-(dimethylamine)propenyl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole- 5(1H)-formate ( 64c )

(E)-tert-butyl 2-(3-(dimethylamino)acryloyl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

64b (5g, 19.92mmoL) was dissolved in N,N-dimethylformamide (8mL), and N,N-dimethylformamide dimethyl acetal (4.26g, 35.8mmoL), 90 The reaction was stirred at ° C for 10 hours. The reaction mixture was cooled to rt. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 1:1 to 1:2) and combined with a yellow solid to give 64c (5 g, yield 83.6%) ).

MS m/z (ESI): 335.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.77-7.74 (dd, 1H), 6.21-6.18 (d, 1H), 4.54-4.41 ( m, 6H), 3.14 (s, 3H), 2.95 (s, 3H), 1.52-1.51 (d, 9H), 1.44-1.36 (td, 3H).

Fourth step: tert-butyl 1-ethyl-2-(1H-pyrazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formic acid Ester ( 64d )

Tert-butyl 1-ethyl-2-(1H-pyrazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

64c (3g, 8.98mmoL) was dissolved in toluene (15mL), hydrazine hydrate (539.4mg, 10.77mmoL) was added, and the reaction was stirred at 50 ° C for 4 hours, supplemented with hydrazine hydrate (2.15g, 43.10mmoL) and p-toluene Sulfonic acid. H ₂ O (341 mg, 1.8 mmol) was added to ethanol (6 mL). The reaction solution was stirred at 90 ° C for 4 hours, cooled to room temperature, saturated sodium chloride solution (50 mL) was added, and extracted with ethyl acetate (50 mL×5), and the organic phase was combined and saturated sodium chloride solution (100 mL×2) ), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford an off-white solid 64d (3g crude).

MS m/z (ESI): 304.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62 (s, 1H), 6.82-6.80 (m, 1H), 4.58-4.44 (ddd, 4H), 4.41-4.36 (q, 2H), 1.53-1.52 (d, 9H), 1.45-1.41 (td, 3H).

Step 5: 1-Ethyl-2-(1H-pyrazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole bis(4-methylbenzenesulfonate Acid salt ( 64e )

1-ethyl-2-(1H-pyrazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole bis(4-methylbenzenesulfonate)

64 d (1 g, 3.3 mmoL) was dissolved in ethanol (15 mL), p-toluenesulfonic acid 1.5 H ₂ O (735 mg, 3.96 mmol) was added, and the reaction was stirred at 80 ° C for 2 hours. Additional p-toluenesulfonic acid 1.5 H ₂ O (735 mg, 3.96 mmol) was added and stirring was continued for 2 hours. The reaction mixture was added ethyl acetate (70 mL) was stirred for 20 minutes, filtered, the filter cake with ethyl acetate (25mL × 2), dried to give an off-white solid 64e (1.6g crude).

MS m / z (ESI): 204.1 [M + H +]; 1 H NMR (400MHz, DMSO- d 6): δ10.01 (s, 2H), 8.01-8.0 (d, 1H), 7.49-7.47 ( d, 4H), 7.12-7.10 (d, 4H), 6.88 (s, 1H), 4.58 (s, 2H), 4.51-4.45 (q, 2H), 4.41 (s, 2H), 2.28 (s, 6H) , 1.37-1.34 (t, 3H).

The sixth step: the third butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-pyrazol-3-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 64f )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-pyrazol-3-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

64e (1.6g, 2.925mmoL) and intermediate 1 (1.15g, 3.51mmoL) were dissolved in N,N-dimethylacetamide (60mL), stirred at room temperature for 1 hour, added tris (oxygen) Sodium borohydride (1.67 g, 7.90 mmol) was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL), and the mixture was stirred for 0.5 hr, filtered, and filtered and washed with water (20mL × 3) and dried to give a yellow solid 64f (1.2 g, yield 80%).

MS m/z (ESI): 515.1 [M+H ⁺ ].

Step 7: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-pyrazol-3-yl)pyrrolo[3, 4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine (Compound 64)

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1H-pyrazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)tetrahydro-2H-pyran-3-amine

64f (1.1g, 2.14mmoL) was added to dichloromethane (5mL), trifluoroacetic acid (4mL) was added, and the reaction was stirred at 40 ° C for 2 hours. The reaction solution was spin-dried, and the pH was adjusted to 7-8 with a saturated sodium hydrogen carbonate solution (200 mL). The aqueous phase was extracted with dichloromethane (60 mL×4), and the organic phase was combined, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 50:1, with a small amount of aqueous ammonia) to give a solid, mixture of dihydromethane (1mL) and petroleum ether (30mL) The solvent was washed to give a yellow solid compound 64 (500 mg, yield 56%).

MS m/z (ESI): 415.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.71-7.70 (d, 1H), 7.24-7.20 (m, 1H), 7.17-7.06 (m, 2H), 6.70 (d, 1H), 4.42 (s, 2H), 4.31-4.28 (t, 2H), 4.06 (s, 2H), 3.90 (s, 2H), 3.46-3.40 (t, 1H) ), 3.15-3.09 (td, 1H), 2.95-2.89 (m, 1H), 2.50-2.47 (d, 1H), 1.57-1.48 (q, 1H), 1.42-1.36 (t, 3H).

Example 65

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1H-pyrazol-3-yl)pyrrolo[3 ,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 65 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1H-pyrazol-3-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H -pyran-3-amine

First step: (E)-t-butyl 2-(3-(dimethylamino)but-2-enyl)-1-ethyl-4,6-dihydropyrrolo[3,4- d] imidazole-5(1H)-formate ( 65a )

(E)-tert-butyl2-(3-(dimethylamino)but-2-enoyl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

64b (3.5g, 12.54mmoL) and 1,1-dimethoxy-N,N-dimethylethylamine (5g, 37.6mmoL) were added to the reaction flask, and the reaction was stirred at 110 ° C for 8 hours. The reaction mixture was returned to room temperature, rotary dried and concentrated, diethyl ether was added (30mL) was stirred dispersion was filtered, washed with diethyl ether (5mL × 3), to give a yellow solid 65a (2.5g, 58% yield).

MS m/z (ESI): 349.2 [M+H ⁺ ].

Second step: tert-butyl 1-ethyl-2-(5-methyl-1H-pyrazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 ( 1H)-formate ( 65b )

Tert-butyl 1-ethyl-2-(5-methyl-1H-pyrazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imi Dazole-5(1H)-carboxylate

65a (2.3g, 6.61mmoL) was dissolved in absolute ethanol (25mL), hydrazine hydrate (669mg, 13.22mmoL) and p-toluenesulfonic acid.H ₂ O (251mg, 1.32mmoL) were added, and the reaction was stirred at 80 ° C for 2 hours. . The reaction solution was cooled to room temperature, EtOAc EtOAc (EtOAc m. × 3). the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford an off-white solid 65b (2.3g crude).

MS m/z (ESI): 318.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.53-6.52 (d, 1H), 4.56-4.42 (ddd, 4H), 4.39-4. q, 2H), 2.35 (s, 3H), 1.52-1.51 (d, 9H), 1.44-1.39 (td, 3H).

The third step: 1-ethyl-2-(5-methyl1-1H-pyrazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole II 4-methylbenzenesulfonate) ( 65c )

1-ethyl-2-(5-methyl-1H-pyrazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole bis(4-methylbenzenesulfonate)

65b (1g, 3.15mmoL) was dissolved in ethanol (15mL), p-toluenesulfonic acid.H ₂ O (718.2g, 3.78mmoL) was added, and the reaction was stirred at 80 ° C for 2 hours, and p-toluenesulfonic acid.H _{2 was added.} O (718.2mg, 3.78mmoL), reaction was stirred for 2 hours, the reaction solution was added ethyl acetate (70 mL) was stirred for 20 minutes, filtered, the filter cake with ethyl acetate (25mL × 2), dried to give an off-white solid 65c (1.6g Crude product).

MS m/z (ESI): 218.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.99 (s, 2H), 7.49-7.47 (d, 4H), 7.12-7. d, 4H), 6.61 (s, 1H), 4.56 (s, 2H), 4.49-4.43 (q, 2H), 4.40 (s, 2H), 2.32 (s, 3H), 2.28 (s, 6H), 1.34 (t, 3H).

Fourth step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1H-pyrazole) 3-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 65d )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1H-pyrazol-3-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

65c (1.6g, 2.85mmoL) and intermediate 1 (1.12g, 3.42mmoL) were dissolved in N,N-dimethylacetamide (70mL), stirred at room temperature for 1 hour, added tris (oxygen) Sodium borohydride (1.63 g, 7.69 mmol) was stirred at room temperature for 2 hours. The reaction solution was added to a saturated aqueous solution of sodium hydrogencarbonate (100 mL), and stirred for 0.5 hr, filtered, and the filter cake was washed with water (20 mL × 3), dried, and purified by column chromatography (methylene chloride / methanol (v/) v) = 50: 1) gave a yellow solid 65d (650 mg, yield 43.3%).

MS m/z (ESI): 529.1 [M+H ⁺ ].

Step 5: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(1-ethyl-2-(5-methyl-1H-pyrazol-3-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 65 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1H-pyrazol-3-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

65d (650mg, 1.23mmoL) was added to dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the reaction was stirred at 40 ° C for 2 hours. The reaction solution was spin-dried, and the pH was adjusted to 7 to 8 using a saturated sodium hydrogen carbonate aqueous solution (200 mL), and the aqueous phase was extracted with dichloromethane (60 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, the residue was separated and purified by silica gel column chromatography (methylene chloride / methanol (v / v) = 10: 1, adding a small amount of ammonia), to give compound 65 as a yellow solid (100 mg, yield 19%).

MS m/z (ESI): 429.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.24-7.20 (m, 1H), 7.18-7.06 (m, 2H), 6.42 (d) , 1H), 4.38-4.36 (d, 2H), 4.32-4.26 (m, 2H), 4.06-4.04 (t, 2H), 3.89-3.88 (t, 2H), 3.45-3.40 (t, 1H), 3.15 -3.08 (m, 1H), 2.96-2.90 (m, 1H), 2.50-2.47 (dd, 1H), 2.34 (s, 3H), 1.54-1.51 (q, 1H), 1.38-1.35 (t, 3H) .

Example 66

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-pyrazol-3-yl)pyrrolo[3 ,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 66 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-pyrazol-3-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-(1-methyl-1H-pyrazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 ( 1H)-formate ( 66a )

Tert-butyl 1-ethyl-2-(1-methyl-1H-pyrazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

64d (2g, 6.6mmoL) was dissolved in N,N-dimethylformamide (10mL), sodium hydride (291mg, 7.26mmoL) was added, stirred at room temperature for 20 minutes, and iodomethane (1.03g, 7.26) was added. MmoL), the reaction was continued for 2 hours at room temperature. The reaction liquid was slowly added to crushed ice (500 g), sodium chloride was added until the reaction solution was saturated, and extracted with ethyl acetate (30 mL × 4). The organic phase was combined, washed with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was washed with petroleum ether, filtered, filtered, and washed with petroleum ether (20mL×3) 66a (1.5 g, yield 71.7%).

MS m/z (ESI): 318.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.53-6.52 (d, 1H), 4.56-4.42 (ddd, 4H), 4.39-4. q, 2H), 2.35 (s, 3H), 1.52-1.51 (d, 9H), 1.44-1.39 (td, 3H).

Second step: 1-ethyl-2-(1-methyl-1H-pyrazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazobenzenesulfonate Acid salt ( 66b )

1-ethyl-2-(1-methyl-1H-pyrazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole dibenzenesulfonate

66a (1.5 g, 4.73 mmoL) and benzenesulfonic acid 1.5 H ₂ O (1.75 g, 9.464 mmol) were dissolved in anhydrous methanol (15 mL), and the mixture was warmed to 70 ° C for 2 hours. The reaction solution was concentrated to dryness to give 66b (2.5 g of crude material).

MS m/z (ESI): 218.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-pyrazole) 3-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 66c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-pyrazol-3-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-py Ran-3-yl)carbamate

66b (2.52g, 4.73mmoL) and intermediate 1 (1.86g, 5.678mmoL) were dissolved in N,N-dimethylacetamide (20mL), stirred at room temperature for 1 hour, added tris (oxygen) Sodium borohydride (2.71 g, 12.77 mmol) was stirred at room temperature for 2 hours. The reaction solution was added to a saturated aqueous solution of sodium hydrogencarbonate (100 mL), stirred for 0.5 hr, filtered, and the filter cake was washed with water (20 mL×3) and dried to give a yellow solid. (v/v) = 30:1) gave an off-white solid 66c (1 g, yield 40%).

MS m/z (ESI): 529.2 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-pyrazol-3-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 66 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(1-methyl-1H-pyrazol-3-yl)pyrrolo[3,4-d]imidazol- 5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

66c (1 g, 1.89 mmol) was added to dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the reaction was stirred at 40 ° C for 2 hours. The reaction solution was spin-dried, and a saturated sodium hydrogen carbonate solution (200 mL) was added to adjust pH 7-8, and the aqueous phase was extracted with dichloromethane (60 mL×4). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and the residue was purified by chromatography (methylene chloride / methanol (v/v) = 10:1, with a small amount of aqueous ammonia) Solid compound 66 (590 mg, yield 72.8%).

MS m/z (ESI): 429.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.61 (d, 1H), 7.24 - 7.19 (ddd, 1H), 6.17-7.06 (m) , 2H), 6.66-6.65 (d, 1H), 4.45-4.40 (q, 2H), 4.31-4.25 (m, 2H), 4.06-4.04 (t, 2H), 3.95 (s, 3H), 3.89-3.88 (t, 2H), 3.45-3.40 (t, 1H), 3.15-3.07 (tt, 1H), 2.94-2.88 (td, 1H), 2.50-2.47 (m, 1H), 1.56-1.47 (m, 1H) , 1.40-1.37 (t, 3H).

Example 67

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(1,5-dimethyl-1H-pyrazol-3-yl)-1-ethylpyrrole And [3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 67 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(1,5-dimethyl-1H-pyrazol-3-yl)-1-ethylpyrrolo[3,4-d]imidazol -5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-(1,5-dimethyl-1H-pyrazol-3-yl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole -5(1H)-formate ( 67a-1 )

Tert-butyl 2-(1,5-dimethyl-1H-pyrazol-3-yl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Third butyl 2-(1,3-dimethyl-1H-pyrazol-5-yl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H )-formate ( 67a-2 )

Tert-butyl 2-(1,3-dimethyl-1H-pyrazol-5-yl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

66a (1g, 3.15mmoL) was dissolved in N,N-dimethylformamide (10mL), sodium hydride (1511mg, 3.78mmoL) was added, stirred at room temperature for 20 minutes, and iodomethane (537mg, 3.78mmoL) was added. The reaction was continued for 2 hours at room temperature. The reaction solution was slowly added to crushed ice (500 g), sodium chloride was added until the reaction solution was saturated, and ethyl acetate (30 mL×4) was extracted. The organic phase was combined, washed with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography ( petroleum ether/ethyl acetate/methanol (v/v/) v) = 5: 0.3: 0.1) gave 67a-1 (800 mg, yield 77%) and 67a-2 (50 mg, yield 4.8%).

Compound 67a-1 : MS m/z (ESI): 332.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.55-6.53 (d, 1H), 4.55-4.49 (m, 2H) , 4.47-4.40 (m, 4H), 3.80 (d, 3H), 2.30 (s, 3H), 1.52-1.51 (d, 9H), 1.41-1.37 (td, 3H); Compound 67a-2 : MS m/ z (ESI): 332.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.16-6.15 (d, 1H), 4.59-4.45 (dd, 4H), 4.01-3.98 (m, 2H) ), 3.94 (s, 3H), 2.31 (s, 3H), 1.52 (s, 9H), 1.40-1.36 (t, 3H).

Step 2: 2-(1,5-Dimethyl-1H-pyrazol-3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole Diphenyl sulfonate ( 67b )

2-(1,5-dimethyl-1H-pyrazol-3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole dibenzenesulfonate

67a-1 (700 mg, 2.115 mmoL) and benzenesulfonic acid 1.5 H ₂ O (782.5 mg, 4.23 mmol) were dissolved in anhydrous methanol (5 mL), and the mixture was heated to 70 ° C for 2 hours. The reaction solution was concentrated to dryness to give 67b (1.15 g).

MS m/z (ESI): 2321. [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(1,5-dimethyl-1H-pyrazole-3) -yl)-1-ethylpyrrolo[3,4-d]imidazole 1-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 67c )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(1,5-dimethyl-1H-pyrazol-3-yl)-1-ethylpyrrolo[3,4 -d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

67b (1.16g, 2.11mmoL) and Intermediate 1 (830mg, 2.53mmoL) were dissolved in N,N-dimethylacetamide (10mL), stirred at room temperature for 1 hour, added tris(ethoxy)oxy Sodium borohydride (2.71 g, 12.77 mmol) was stirred at room temperature for 2 hours. The reaction solution was added to a saturated aqueous solution of sodium hydrogencarbonate (100 mL), and stirred for 0.5 hr, filtered, and the filter cake was washed with water (20 mL × 3), dried, and purified by column chromatography (methylene chloride / methanol (v/) v) = 50: 1) to give a yellow solid, tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(1,5-dimethyl) -1H-pyrazol-3-yl)-1-ethylpyrrolo[3,4-d]imidazole 1-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl) Carbamate ( 67c ) (800 mg, yield 70%).

MS m/z (ESI): 543.2 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(1,5-dimethyl-1H-pyrazol-3-yl)-1 -ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 67 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(1,5-dimethyl-1H-pyrazol-3-yl)-1-ethylpyrrolo[3,4-d]imidazol -5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

67c (800 mg, 1.47 mmoL) was added to dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the reaction was stirred at 40 ° C for 2 hours. The reaction solution was spin-dried, and the pH was adjusted to 7 to 8 using a saturated sodium hydrogen carbonate aqueous solution (200 mL), and the aqueous phase was extracted with dichloromethane (60 mL × 4). The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness. The residue was purified by chromatography (methylene chloride/methanol (v/v) = 10:1, with a small amount of aqueous ammonia) to give a yellow solid. Compound 67 (300 mg, yield 46%).

MS m/z (ESI): 443.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.24 - 7.19 (ddd, 1H), 7.17-7.06 (m, 2H), 6.43 (d) , 1H), 4.43-4.37 (q, 2H), 4.31-4.25 (m, 2H), 4.05-4.03 (t, 2H), 3.88-3.86 (dd, 2H), 3.82 (s, 3H), 3.45-3.39 (t, 1H), 3.14-3.07 (ddd, 1H), 2.95-2.89 (td, 1H), 2.50-2.46 (m, 1H), 2.33 (s, 3H), 1.56-1.47 (q, 1H), 1.39 -1.35 (t, 3H).

Example 68

(2R,3S,5R)-5-(2-(1-(Difluoromethyl)-1H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d]imidazole-5 ( 1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 68 )

(2R,3S,5R)-5-(2-(1-(difluoromethyl)-1H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)- Yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-(1-(difluoromethyl)-1H-tetrazol-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-d] Imidazole-5(1H)-formate ( 68a-1 )

Tert-butyl 2-(1-(difluoromethyl)-1H-tetrazol-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Tert-butyl 2-(2-(difluoromethyl)-2H-tetrazol-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5 ( 1H)-formate ( 68a-2 )

Tert-butyl 2-(2-(difluoromethyl)-2H-tetrazol-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

14a (2910mg, 10.0mmoL) was dissolved in acetonitrile (30mL), cooled to 0 ° C, added potassium hydroxide (11.2g, 0.20 mol) and water (30mL), reacted for 10 minutes, quickly added bromofluoromethylphosphonic acid Diethyl ester (5.34 g, 20.0 mmol) was reacted at 0 ° C for 2 hours. The reaction mixture was diluted with water (30 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The product was isolated and purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 6:1 to 1:1) to give white solid 68a-1 (0.55mg, yield 16.1%) and white solid 68a -2 (2300 mg, yield 67.4%).

MS m/z (ESI): 342.2 [M+H ⁺ ].

Second step: 2-(1-(difluoromethyl)-1H-tetrazol-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazolium sulfonic acid Salt ( 68b )

2-(1-(difluoromethyl)-1H-tetrazol-5-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

68a-1 (550 mg, 1.61 mmol) and benzenesulfonic acid 1.5 H ₂ O (567 mg, 3.22 mmol) were dissolved in anhydrous methanol (10 mL), and the mixture was heated to 65 ° C for 4 hours. A white solid precipitated, was filtered and dried to give 68b (643mg), used directly in the next reaction.

MS m/z (ESI): 242.1.1 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-5-(2-(1-(difluoromethyl)-1H-tetrazol-5-yl)-1-methylpyrrolo[3 ,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 68c )

Tert-butyl((2R,3S,5R)-5-(2-(1-(difluoromethyl)-1H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H ,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

68b (643 mg, 1.61 mmol) and Intermediate 1 (523 mg, 1.60 mmol) were dissolved in N,N-dimethylacetamide (15 mL) and stirred at room temperature for 1 hour. After 0 ° C or less, sodium tris(ethyloxy)borohydride (443 mg, 2.09 mmol) was added, and the reaction was kept at 0 ° C for 0.5 hour, and naturally raised to room temperature for 2 hours. Water (30 mL) and aqueous ammonia (3 mL) were successively added dropwise to the reaction mixture, stirred for 0.5 hour, and filtered. The filter cake was washed with water (20 mL×3) and petroleum ether (20 mL×3), and evaporated to give a yellow solid 68c (600 mg, yield 67.4%).

MS m / z (ESI): 553.1 [M + H +].

Step 4: (2R, 3S, 5R)-5-(2-(1-(Difluoromethyl)-1H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d] Imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 68 )

(2R,3S,5R)-5-(2-(1-(difluoromethyl)-1H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)- Yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

68c (600 mg, 1.09 mmol) was added to dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added below 0 ° C, and the mixture was allowed to react to room temperature for 2 hours. The reaction solution was spin-dried, and a saturated sodium hydrogen carbonate solution (10 mL) was added to adjust the pH to more than 8, and the aqueous phase was extracted with dichloromethane (30mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, the residue was separated and purified by silica gel column chromatography (methylene chloride / methanol (v / v) = 50: 1 ~ 30: 1), to give a white solid compound 68 (300 mg, yield 60.1%).

MS m/z (ESI): 453.3 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.78-8.50 (t, 1H), 7.04-6.97 (m, 3H), 4.21-4.16 (m, 2H), 3.98-3.97 (m, 5H), 3.85-3.83 (t, 2H), 3.36-3.30 (t, 1H), 3.02-2.96 (m, 1H), 2.82-2.79 (m, 1H) , 2.49-2.36 (m, 1H), 1.47-1.39 (q, 1H).

Example 69

(2R,3S,5R)-5-(2-(2-(Difluoromethyl)-2H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d]imidazole-5 ( 1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 69 )

(2R,3S,5R)-5-(2-(2-(difluoromethyl)-2H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)- Yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

First step: 2-(2-(difluoromethyl)-2H-tetrazol-5-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d] Imidazobenzene sulfonate ( 69a )

2-(2-(difluoromethyl)-2H-tetrazol-5-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

68a-2 (2300 mg, 6.74 mmoL) and benzenesulfonic acid 1.5 H ₂ O (2500 mg, 13.48 mmoL) were dissolved in anhydrous methanol (20 mL), and the mixture was heated to reflux at 65 ° C for 4 hours. The reaction mixture was concentrated under rotary drying, and dried in vacuo to give a yellow solid 69a (2.69g), used directly in the next reaction.

MS m/z (ESI): 2421. [M+H ⁺ ].

Second step: tert-butyl ((2R,3S,5R)-5-(2-(2-(difluoromethyl)-2H-tetrazol-5-yl)-1-methylpyrrolo[3 ,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 69b )

Tert-butyl((2R,3S,5R)-5-(2-(2-(difluoromethyl)-2H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H ,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

69a (2.69g, 6.74mmoL) and intermediate 1 (2.2g, 6.74mmoL) were dissolved in N,N-dimethylacetamide (40mL), stirred at room temperature for 1 hour, and the temperature was less than 0 °C. Sodium tris(ethyloxy)borohydride (1.86 g, 8.76 mmol) was allowed to react to room temperature for 2 hours. Under ice bath, water (30 mL) and aqueous ammonia (2 mL) were added dropwise to the reaction mixture, and the mixture was stirred for 0.5 hour, filtered, and the filter cake was washed with water (20 mL×3) and petroleum ether (20 mL×3), and dried to give yellow. Solid 69b (1.4 g, yield 38%).

MS m / z (ESI): 553.1 [M + H +].

The third step: (2R, 3S, 5R)-5-(2-(2-(difluoromethyl)-2H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d] Imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 69 )

(2R,3S,5R)-5-(2-(2-(difluoromethyl)-2H-tetrazol-5-yl)-1-methylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)- Yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

69b (1400 mg, 2.53 mmol) was added to dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added and the mixture was warmed to room temperature for 2 hours. The reaction solution was spin-dried, dissolved with water (20 mL), and adjusted to pH <RTIgt; The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary drying, the residue was chromatographed by thin layer chromatography (dichloromethane / methanol (v / v) = 50: 1-30: 1), to give a yellow solid compound 69 (600 mg, yield 52.5%).

MS m/z (ESI): 453.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.43 - 8.14 (t, 1H), 7.23 - 7.04 (m, 3H), 4.33-4.28 (m, 2H), 4.09-4.07 (m, 5H), 3.96 (t, 2H), 3.49-3.42 (m, 1H), 3.17-3.14 (m, 1H), 2.94 (m, 1H), 2.52-2.48 (m, 1H), 1.59-1.50 (q, 1H).

Example 70

(2R,3S,5R)-5-(1-(difluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazole-5 ( 1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 70 )

(2R,3S,5R)-5-(1-(difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H) -yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

First step: 5-t-butyl 2-ethyl 1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylic acid Ester ( 70a )

5-tert-butyl 2-ethyl1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

Intermediate 5 (10 g, 35.5 mmol) was dissolved in N,N-dimethylformamide (20 mL). EtOAc (23 g, 71 mmol), sodium chlorodifluoroacetate (10.79 g, 71 ), reacted at 80 ° C for 3 hours. After cooling to room temperature, water (60 mL) was added to the reaction mixture, which was extracted with ethyl acetate (60 mL×3), and the organic phase was combined, washed with saturated aqueous brine (50 mL×4), dried over anhydrous sodium sulfate Concentration and purification by column chromatography (petroleum ether / ethyl acetate (v/v) = 2:1) afforded 70a (8.5 g, yield 70%).

MS m/z (ESI): 3321. [M+H ⁺ ].

Second step: tert-butyl 2-aminoformamidine-1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate (70b )

Tert-butyl 2-carbamoyl-1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

70a (3.0 g, 9.0 mmol) was dissolved in an ammonia-methanol solution (12.8 mL, 7 mol/L), and the mixture was reacted at 90 ° C for 8 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure to remove methanol to give a pale yellow solid 70b (2.23g), was used directly in the next reaction.

MS m/z (ESI): 325.0 [M+H ⁺ ].

Third step: tert-butyl 2-cyano-1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 70c )

Tert-butyl 2-cyano-1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

70b (2.23g, 7.4mol) was dissolved in pyridine (40mL), trifluoroacetic anhydride (5.37g, 18.5mol) was added to the solution at 0 °C, added, and naturally heated to room temperature for 4 hours, minus The solvent was concentrated to remove the solvent pyridine and trifluoroacetic acid anhydride, and water (20 mL) was added to the reaction mixture, and dichloromethane (30 mL×3) was evaporated. Filtration and concentration under reduced pressure gave 70% (yield: <RTIgt;

MS m/z (ESI): 307.0 [M+Na ⁺ ].

Fourth step: tert-butyl 1-(difluoromethyl)-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H )-formate ( 70d )

T-butyl 1-(difluoromethyl)-2-(1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

70c (2.06g, 7.25mmol) was dissolved in N,N-dimethylformamide (30mL), and sodium azide (1.4g, 21.7mmol), ammonium acetate (1.67g, 21.7 mmol), the temperature was raised to 120 ° C for 2 hours. The reaction system was cooled to 0 ° C, hydrochloric acid (3 mol / L) was slowly added to adjust the pH to 4, and the solid was precipitated and filtered to give a white solid 70d (2.1 g, yield 88%).

MS m/z (ESI): 328.0 [M+H ⁺ ].

Step 5: Tert-butyl 1-(difluoromethyl)-2-(1-methyl-1H-tetrazol-5-yl)-4,6-tetrahydropyrrolo[3,4-d] Imidazole-5(1H) -formate ( 70e )

Tert-butyl 1-(difluoromethyl)-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

At room temperature, 70d (2.1g, 6.4mmol) was dissolved in N, N- dimethylformamide (20mL), the conditions 0 ℃ added sodium hydride (0.199g, 8.32mmol), the reaction for 0.5 hours. Methyl iodide (1.18 g, 8.32 mmol) was added, and the mixture was warmed to room temperature and stirred for 3 hours. Water (20 mL) was added to the reaction system, the pH was adjusted to 9 with aqueous ammonia, and extracted with ethyl acetate (30 mL × 3). The organic phase was combined, washed with saturated aqueous sodium chloride (30 mL × 6), dried over anhydrous sodium sulfate Separation and purification by column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) gave white solid 70e (1.1 g, yield 50%).

MS m/z (ESI): 364.0 [M+Na ⁺ ].

Step 6: 1-(Difluoromethyl)-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d] Imidazobenzene sulfonate ( 70f )

1-(difluoromethyl)-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

70e (1.1g, 3.2mol) was dissolved in dichloromethane (20mL), benzenesulfonic acid 1.5 H ₂ O (0.769g, 4.8mol) was added to warm to 50 ° C reflux for 8 hours, cooled to room temperature, concentrated under reduced pressure A white solid 70f (1.78 g of crude product) was obtained, which was used directly for the next reaction.

MS m/z (ESI): 2421. [M+H ⁺ ].

Step 7: Tert-butyl ((2R,3S,5R)-5-(1-(difluoromethyl)-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3 ,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 70g )

Tert-butyl((2R,3S,5R)-5-(1-(difluoromethyl)-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

70f (1.78 g, 3.2 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and Intermediate 1 (1.15 g, 3.52 mmol) was added and allowed to react at room temperature for 30 minutes. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (1.37 g, 6.24 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 9 to precipitate a solid, which was washed with water (50 mL×3), dissolved in dichloromethane, dichloromethane (50 mL×3) The organic phase was extracted, washed with a saturated aqueous solution of brine (50 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated and purified by chromatography (methylene chloride/methanol (v/v) = 20:1) A white solid 70 g (1.15 g, yield 85%) was obtained.

MS m / z (ESI): 553.1 [M + H +].

Step 8: (2R, 3S, 5R)-5-(1-(Difluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d] Imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 70 )

(2R,3S,5R)-5-(1-(difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H) -yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

70 g (1.15 g, 2.72 mmol) was dissolved in dichloromethane (8 mL) at room temperature, trifluoroacetic acid (2 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 2 hr. The organic phase was extracted with dichloromethane (30 mL×3), and the organic phase was combined and washed with saturated brine (50 mL×1). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 30:1) to afford compound 70 (0.576 g, yield 61%).

MS m / z (ESI): 453.0 [M + H +]; 1 H NMR (400MHz, CDCl 3): δ 8.46 (s, 0.2H), 8.31 (s, 0.4 H), 8.16 (s, 0.2H) , 7.14-6.96 (m, 3H), 4.33 (s, 3H), 4.21-4.16 (m, 2H), 4.11 (s, 2H), 3.77 (s, 2H), 3.36-3.31 (m, 1H), 3.06 -3.01 (m, 1H), 2.82-2.79 (m, 1H), 2.41-2.36 (m, 1H), 1.48-1.39 (m, 1H).

Example 71

(2R,3S,5R)-5-(1-(Difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazole-5 ( 1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrazole-2H-pyran-3-amine ( Compound 71 )

(2R,3S,5R)-5-(1-(difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H) -yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-(difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d] Imidazole-5(1H)-formate ( 71a )

Tert-butyl-1-(difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

A mixture of 70d (2.1g, 6.4mmol) was dissolved in N, N- dimethylformamide (20mL), the conditions 0 ℃ added sodium hydride (0.199g, 8.32mmol), the reaction for 0.5 hours. Methyl iodide (1.18 g, 8.32 mmol) was added, and the reaction was stirred at room temperature for 3 hours. To the reaction liquid reaction system, water (20 mL) was added, and the pH was adjusted to 9 with ammonia water, and extracted with ethyl acetate (30 mL×3). The organic phase was combined, washed with a saturated aqueous solution of brine (30 mL×6), dried over anhydrous sodium sulfate The filtrate was concentrated, purification by column chromatography (petroleum ether / ethyl acetate (v / v) = 3: 1), to give a white solid 71a (0.735g, 33% yield).

MS m/z (ESI): 342.0 [M+H ⁺ ].

Second step: 1-(difluoromethyl)-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d] Imidazobenzene sulfonate ( 71b )

1-(difluoromethyl)-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

71a (0.735 g, 2.15 mol) was dissolved in dichloromethane (20 mL), benzenesulfonic acid 1.5 H ₂ O (0.51 g, 3.23 mol) was added, and the mixture was warmed to 50 ° C and refluxed for 8 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give a white solid 71b (1.21g, crude) was used directly in the next step.

MS m/z (ESI): 2421. [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-5-(1-(difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3 ,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 71c )

Tert-butyl((2R,3S,5R)-5-(1-(difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

71b (1.21 g, 2.15 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and Intermediate 1 (0.771 g, 2. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (0.884 g, 4.19 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust pH to 9, and solids were separated, and water (50 mL × 3) was washed. The solid was dissolved in dichloromethane, dichloromethane (30 mL×3), and the organic phase was combined, washed with saturated aqueous sodium chloride (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography. Methyl chloride/methanol (v/v) = 20:1) gave white solid 71c (0.89 g, yield 75%).

MS m/z (ESI): 553.2 [M+H ⁺ ].

Fourth step: (2R, 3S, 5R)-5-(1-(difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d] Imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 71 )

(2R,3S,5R)-5-(1-(difluoromethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H) -yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

71c (0.89 g, 1.61 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (3 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The organic phase was extracted with aq. After drying, the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 30:1) to afford compound 71 (0.402 g, yield 55%).

MS m/z (ESI): 453.3 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.36 (s, 0.2H), 8.21 (s, 0.4 H), 8.06 (s, 0.2H) , 7.13-6.99 (m, 3H), 4.38 (s, 3H), 4.22-4.13 (m, 2H), 4.11-4.10 (m, 2H), 3.75 (s, 2H), 3.36-3.31 (m, 1H) , 3.04-3.02 (m, 1H), 2.82-2.79 (m, 1H), 2.40-2.36 (m, 1H), 1.48-1.39 (m, 1H).

Example 72

5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(difluoromethyl)-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 72 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(difluoromethyl)-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazole-2-carboxamide

First step: ethyl 1-(difluoromethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate benzenesulfonate ( 72a )

Ethyl 1-(difluoromethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate benzene sulfonate

70a (2.5 g, 7.5 mol) was dissolved in dichloromethane (20 mL), benzenesulfonic acid 1.5 H ₂ O (1.79 g, 11.3 mol) was added, and the mixture was warmed to 50 ° C and refluxed for 8 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to give 72a (4.29g crude), was used directly in the next step.

MS m/z (ESI): 232.0 [M+H ⁺ ].

Second step: ethyl 5-((3R,5S,6R)-5-((t-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-yl)-1-(difluoromethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate ( 72b )

Ethyl 5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(difluoromethyl)-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate

72a (4.29 g, 7.5 mmol) was dissolved in N,N-dimethylacetamide (15 mL), and Intermediate 1 (2.69 g, 8.25 mmol) was added at room temperature for 30 min. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (3.23 g, 14.6 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 9 to precipitate a solid, which was washed with water (50 mL×3), and dissolved in dichloromethane, with dichloromethane (50 mL× 3) Extraction, the organic phase is combined, washed with a saturated aqueous solution of brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and purified by column chromatography (dichloromethane / methanol (v / v) = 20:1) , 72b (2.3g, yield 57%).

MS m/z (ESI): 543.1 [M+H ⁺ ].

The third step: the third butyl ((2R, 3S, 5R)-5-(2-aminomethyl decyl-1-(difluoromethyl)pyrrolo[3,4-d]imidazole-5 (1H, 4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 72c )

Tert-butyl((2R,3S,5R)-5-(2-carbamoyl-1-(difluoromethyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2 ,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

72b (1.1g, 2.0mmol) was dissolved in ammonia-methanol (2.8mL, 7mol / L), the reaction was sealed at 100 ° C for 8 hours, the reaction system was cooled to room temperature, concentrated under reduced pressure to remove methanol. 72c (1.02g). Direct next step.

MS m/z (ESI): 514.0 [M+H ⁺ ].

The fourth step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(difluoromethyl) -1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 72 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(difluoromethyl)-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazole-2-carboxamide

72c (1.02 g, 2.0 mmol) was dissolved in dichloromethane (10 mL) at room temperature, trifluoroacetic acid (4 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. Concentrated under reduced pressure to remove trifluoroacetic acid, water (10 mL) was added to the reaction system, pH was adjusted to 9 with aqueous ammonia, and extracted with dichloromethane (20 mL × 3). The organic phase was combined and washed with saturated aqueous sodium chloride (30 mL) sodium sulfate, and the filtrate was concentrated and purified by column chromatography separation (dichloromethane / methanol (v / v) = 30: 1), to give compound 72 (0.638g, 77% yield).

MS m/z (ESI): 414.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.41 (s, 0.3H), 8.25 (s, 0.5 H), 8.25 (s, 0.3H) , 7.11-6.95 (m, 3H), 4.20-4.13 (m, 2H), 4.04-4.03 (m, 2H), 3.77 (s, 2H), 3.34-3.29 (m, 1H), 3.01-2.98 (m, 1H), 2.78-2.67 (m, 1H), 2.38-2.34 (m, 1H), 1.46-1.37 (m, 1H).

Example 73

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(difluoromethyl)-N -methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 73 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(difluoromethyl)-N-methyl-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

First step: tert-butyl ((2R,3S,5R)-5-(1-(difluoromethyl-2-(methylaminocarbamimido)pyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate ( 73a )

Tert-butyl((2R,3S,5R)-5-(1-(difluoromethyl)-2-(methylcarbamoyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2- (2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

72b (1.0 g, 1.84 mmol) was dissolved in a methanol solution of methylamine (2.6 mL, 2 mol/L), and the reaction was sealed at 90 ° C for 8 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure to remove methanol to afford 73a (0.969g). Used directly in the next step.

MS m/z (ESI): 528.1 [M+H ⁺ ].

Second step: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(difluoromethyl) -N-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 73 )

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-(difluoromethyl)-N-methyl-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

73a (0.969 g, 1.84 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (4 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The organic phase was extracted with dichloromethane (30 mL×3), and the organic phase was combined and washed with saturated brine (30 mL×1). dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography separation (dichloromethane / methanol (v / v) = 30: 1), to give a pale yellow solid compound 73 (0.609g, 77% yield).

MS m/z (ESI): 428.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.42 (s, 0.2H), 8.27 (s, 0.4 H), 8.12 (s, 0.2H) , 7.12-6.96 (m, 3H), 4.20-4.13 (m, 2H), 4.03-4.02 (m, 2H), 3.76 (s, 2H), 3.31-3.21 (m, 1H), 3.20 (s, 4H) , 3.02-2.97 (m, 1H), 2.37-2.33 (m, 1H), 2.38-2.34 (m, 1H), 1.45-1.36 (m, 1H).

Example 74

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1,3,4-oxadiazol-2-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 74 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-(carbonylindenyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 74a )

Tert-butyl 1-ethyl-2-(hydrazinecarbonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

10a (2 g, 6.47 mmol) was dissolved in a methanol (20 mL) solution, and hydrazine hydrate (2.26 g) was added to the reaction system, and the mixture was heated under reflux for 8 hours. The reaction system was cooled to room temperature, methanol was removed under reduced pressure to give a white solid 74a (1.8g crude). Used directly in the next step.

MS m/z (ESI): 296.1 [M+H ⁺ ].

Second step: tert-butyl 2-(2-ethylhydrazinecarbonyl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole 5(1H)-formate ( 74b )

Tert-butyl 2-(2-acetylhydrazinecarbonyl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

74a (1.5 g, 5 mmol) was dissolved in toluene (20 mL), and acetic anhydride (1.55 g, 15 mmol) was added to the reaction system, and the mixture was reacted at room temperature for 30 minutes. Water (20 mL) was added to the reaction mixture, and the mixture was combined with methylene chloride (30 mL×3). 74b (1.45 g, yield 86%).

MS m/z (ESI): 338.0 [M+H ⁺ ].

The third step: tert-butyl 1-ethyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)-4,6-dihydropyrrolo[3,4-d Imidazole-5(1H) -formate ( 74c )

Tert-butyl 1-ethyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

74b (0.61 g, 4.3 mol) was dissolved in tetrahydrofuran (10 mL), and the temperature was controlled under microwave conditions at 100 ° C for 0.5 hour. The reaction mixture was cooled to room temperature, and water (30 mL) was evaporated, evaporated, evaporated. Light yellow solid 74c (0.68 g, yield 49%).

MS m/z (ESI): 320.1 [M+H ⁺ ].

Fourth step: 2-(1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-5-methyl-1,3,4-oxa Diazole trifluoroacetate ( 74d )

2-(1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-5-methyl-1,3,4-oxadiazole trifluoroacetate

The 74c (1.065g, 3.3mol) was dissolved in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL), at room temperature for 3 hours, concentrated under reduced pressure to give a yellow oil 74d (1.21g crude), direct Used in the next step.

MS m/z (ESI): 2221. [M+H ⁺ ].

The fifth step: the third butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1,3, 4-oxadiazol-2-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 74e )

Tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyrrolo[3,4 -d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

74d (1.21 g, 3.3 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and Intermediate 1 (1.18 g, 3.63 mmol) was added and reacted for 30 minutes. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (0.802 g, 3.63 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust pH to 9, and solids were precipitated and washed with water (50 mL × 3). The solid compound was dissolved in dichloromethane, and extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with saturated aqueous brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, purification (dichloromethane / methanol (v / v) = 20: 1), to give a white solid 74e (0.297g).

MS m / z (ESI): 531.2 [M + H +].

Step 6: (2R, 3S, 5R)-2-(2,5-Difluorophenyl)-5-(1-ethyl-2-(5-methyl-1,3,4-oxadiazole) -2-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 74 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyrrolo[3,4- d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

74e (0.297 g, 0.56 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hr. The organic phase was extracted with aq. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 30:1) to afford compound 74 (0.102 g, yield 42%).

MS m/z (ESI): 431.0 [M+H ⁺ ].

Example 75

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-(trifluoromethyl)-1,3,4-oxadiazole -2-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 75 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrrolo[3, 4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-(2-(2,2,2-trifluoroethyl)indolyl)-4,6-dihydropyrrolo[3,4-d Imidazole 5(1H)-formate ( 75a )

Tert-butyl 1-ethyl-2-(2-(2,2,2-trifluoroacetyl)hydrazinecarbonyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

74a (2 g, 6.7 mmol) was dissolved in dichloromethane (20 mL), and then triethylamine (2.8 mL, 20.3 mmol) and trifluoroacetic acid anhydride (4.2 g, 20.3 mmol) were added. Water (20 mL) was added to the reaction system, and the mixture was combined with methylene chloride (20 mL×3). Solid 75a (3.28 g of crude product).

MS m/z (ESI): 392.0 [M+H ⁺ ].

Second step: tert-butyl 1-ethyl-2-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-4,6-dihydropyrrolo[3 ,4-d]imidazole-5(1H)-formate ( 75b )

Tert-butyl 1-ethyl-2-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

75a (3.28 g, 8.3 mmol) was dissolved in tetrahydrofuran (8 mL), and the mixture was reacted under microwave conditions at 100 ° C for 0.5 hour. After cooling to room temperature, water (30 mL) was added to the reaction mixture, and the mixture was combined with methylene chloride (20 mL×3). Column chromatography (petroleum ether / ethyl acetate (v/v) = 2:1) gave white solid 75b (1.64 g, yield 55%).

MS m/z (ESI): 374.1 [M+H ⁺ ].

The third step: 2-(1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-5-(trifluoromethyl)-1,3 , 4-oxadiazole besylate ( 75c )

2-(1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole benzenesulfonate

75b (1.64 g, 4.2 mmol) was dissolved in dichloromethane (10 mL), benzenesulfonic acid (1 g, 6.3 mmol) was added, and the mixture was warmed to 50 ° C and reflux for 8 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to give a white solid 75c (2.65g crude), was used directly in the next step.

MS m/z (ESI): 274.0 [M+H ⁺ ].

Fourth step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-(trifluoro))-1 ,3,4-oxadiazol-2-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamic acid Ester ( 75d )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl) Pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

75c (2.65 g, 4.2 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and Intermediate 1 (1.51 g, 4. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (1.8 g, 8.19 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and water (20 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH to 9, and the solid was precipitated, washed with water (20 mL × 1), and dissolved in dichloromethane, methylene chloride (20 mL × 3) The organic phase is extracted, washed with a saturated aqueous solution of brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and purified by column chromatography (dichloromethane/methanol (v/v) = 30: 1) A white solid 75d (0.972 g, yield 39%).

MS m/z (ESI): 585.1 [M+H ⁺ ].

Step 5: (2R, 3S, 5R)-2-(2,5-Difluorophenyl)-5-(1-ethyl-2-(5-(trifluoromethyl)-1,3,4 -oxadiazol-2-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 75 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrrolo[3, 4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

75d (0.612g, 1.05mmol) was dissolved in dichloromethane (10 mL) at room temperature, trifluoroacetic acid (4 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The organic phase was extracted with dichloromethane (30 mL×3), and the organic phase was combined and washed with a saturated brine solution (30 mL×1). After drying over anhydrous sodium sulfate, the filtrate was concentrated and purified by chromatography (methylene chloride/methanol (v/v) = 30:1) to afford compound 75 (0.212 g, yield 41%).

MS m/z (ESI): 485.0 [M+H ⁺ ].

Example 76

(2R,3S,5R)-2-(2,5-difluorophenyl-5-(2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)- 1-ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 76 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-1-ethylpyrrolo[3 ,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 1-ethyl-2-(3-methyl-1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4- d] imidazole-5(1H)-formate ( 76a )

Tert-butyl 1-ethyl-2-(3-methyl-1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

61a (7.2 g, 25.3 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylethylamine (20 mL). The reaction solution was cooled to room temperature and concentrated under reduced vacuo. The oil was dissolved in acetic acid (20 mL) and EtOAc (1. Water (40 mL) was added to the reaction mixture,yield white solid, which was filtered to afford white solid product 76a (6.8 g, yield 85%).

MS m/z (ESI): 319.3 [M+H ⁺ ].

Second step: tert-butyl 2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-1-ethyl-4,6-dihydropyrrolo[3 , 4-d]imidazole-5(1H)-formate ( 76b )

Tert-butyl 2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Carboxylate

76a (1.1 g, 3.4 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (1.66 g, 5.1 mmol) and iodomethane (539 mg, 3,8 mmol) were sequentially added to the reaction system. The reaction was carried out at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate (50 mL×3). EtOAc evaporated. Petroleum ether (v/v) = 20:1) gave pale yellow solid 76b (0.531 g, yield 47%).

MS m/z (ESI): 333.1 [M+H ⁺ ].

The third step: 2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3 , 4-d]imidazole benzene sulfonate ( 76c )

2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

76b (0.531 g, 1.6 mmol) was dissolved in methanol (10 mL), benzenesulfonic acid (0.445 g, 2.90 mmol) was added, and the mixture was warmed to 50 ° C and refluxed for 8 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to give a yellow solid 76c (0.96g, crude) was used directly in the next step.

MS m/z (ESI): 233.1 [M+H ⁺ ].

The fourth step: the third butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(1,3-dimethyl-1H-1,2, 4-triazol-5-yl)-1-ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate Acid ester ( 76d )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-1 -ethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

76c (0.96 g, 1.6 mmol) was dissolved in N,N-dimethylacetamide (15 mL), and Intermediate 1 (0.57 g, 1.76 mmol) was added at room temperature for 30 min. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (0.67 g, 3.2 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and water (10 mL) and aqueous ammonia (3 mL) were successively added to adjust the pH of the reaction mixture to 9, and the solid compound was precipitated and washed with water (50 mL × 3). The solid compound was dissolved in dichloromethane, and extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with saturated aqueous brine (50 mL×1), dried over anhydrous sodium sulfate purification (dichloromethane / methanol (v / v) = 20: 1), to give a yellow solid 76d (0.54g, yield 62%).

MS m/z (ESI): 544.2 [M+H ⁺ ].

Step 5: (2R, 3S, 5R)-2-(2,5-Difluorophenyl-5-(2-(1,3-dimethyl-1H-1,2,4-triazole-5) -yl)-1-ethylpyrrole[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 76 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-1-ethylpyrrolo[3 ,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

76 d (0.53 g, 1 mmol) was dissolved in dichloromethane (10 mL) at room temperature, trifluoroacetic acid (2 mL) was added at 0 ° C, and the mixture was warmed to room temperature and stirred for 2 hr. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid, and the mixture was adjusted to pH 9 with water and aqueous ammonia. The mixture was extracted with dichloromethane (30 mL×3), EtOAc (EtOAc) v) = 30: 1) gave compound 76 (0.304 g, yield 68.6%) as pale yellow solid.

MS m/z (ESI): 444.1 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.24-7.06 (m, 3H), 4.40 - 4.35 (q, 2H), 4.31-4.27 (m) , 2H), 4.09 (s, 2H), 4.04 (s, 3H), 3.91 (s, 2H), 3.45-3.40 (t, 1H), 3.13 - 3.09 (m, 1H), 2.94 - 2.89 (m, 1H) ), 2.50-2.47 (m, 1H), 1.57-1.51 (q, 1H), 1.40-1.36 (t, 3H).

Example 77

(2R,3S,5R)-5-(2-(1-(Difluoromethyl)-3-methyl-1H-1,2,4-triazol-5-yl)-1-ethylpyrrolo [3,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 77 )

(2R,3S,5R)-5-(2-(1-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5-yl)-1-ethylpyrrolo[3,4-d]imidazol -5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

First step: tert-butyl 2-(1-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5-yl)-1-ethyl-4,6- Dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 77a )

Tert-butyl 2-(1-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5-yl)-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H)-carboxylate

76a (1.0 g, 3.1 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and cesium carbonate (2.04 g, 6.3 mmol) and sodium difluoroacetate (957 mg, 6.3 mmol) were sequentially added to the reaction system. ), reacted at 80 ° C for 3 hours. The reaction solution was cooled, water (20 mL) was added, and ethyl acetate (50 mL×3) was evaporated, and the organic phase was combined, washed with a saturated aqueous salt solution (50 mL×6), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The mixture was separated and purified (ethyl acetate / petroleum ether (v/v) = 2:1) to afford white solid 77a (0.6 g, yield 52%).

MS m/z (ESI): 369.1 [M+H ⁺ ].

The second step: 2-(1-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5-yl)-1-ethyl-1,4,5,6- Tetrahydropyrrolo[3,4-d]imidazolium benzene sulfonate ( 77b )

2-(1-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

77a (0.60 g, 1.6 mmol) was dissolved in methanol (10 mL), benzenesulfonic acid (0.45 g, 2.444 mmol) was added, and the mixture was warmed to 80 ° C and refluxed for 8 hours. The reaction solution was cooled to room temperature and evaporated to dryness crystall

MS m/z (ESI): 269.0 [M+H ⁺ ].

Third step: tert-butyl ((2R,3S,5R)-5-(2-(1-(difluoromethyl)-3-methyl-1H-1,2,4-triazole-5- 1-ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-yl)carbamate ( 77c )

Tert-butyl((2R,3S,5R)-5-(2-(1-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5-yl)-1-ethylpyrrolo[3,4 -d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluoropheny l) tetrahydro-2H-pyran-3-yl)carbamate

77b (1.53 g, 1.6 mmol) was dissolved in NN-dimethylformamide (15 mL). Intermediate 1 (0.53 g, 1.6 mmol). The reaction system was cooled to 0 ° C, sodium borohydride triacetate (0.67 g, 3.17 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and water (10 mL) and aqueous ammonia (3 mL) were successively added to adjust the pH of the reaction mixture to 9, and a solid compound was precipitated and washed with water (50 mL × 3). The solid compound was dissolved in dichloromethane, and extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with saturated aqueous brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, Purification (dichloromethane/methanol (v/v) = 20:1) afforded white solid 77c (0.62 g, yield 61%).

MS m/z (ESI): 580.1 [M+H ⁺ ].

The fourth step: (2R, 3S, 5R)-5-(2-(1-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5-yl)-1- Ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( compound) 77 )

(2R,3S,5R)-5-(2-(1-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5-yl)-1-ethylpyrrolo[3,4-d]imidazol -5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

77c (0.62 g, 1.07 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added at 0 ° C, and the mixture was warmed to room temperature and stirred for 2 hr. The organic phase was extracted with dichloromethane (30 mL×3), and the organic phase was combined and washed with saturated brine (50 mL×1). over sodium sulfate, and the filtrate was concentrated and purified by column chromatography separation (dichloromethane / methanol (v / v) = 30: 1), to give a pale yellow solid compound 77 (0.323g, 627.% yield).

MS m/z (ESI): 480.3 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.93-7.64 (t,1H), 7.28-7.11 (m,3H), 4.55-4.52 (m) , 2H), 4.31-4.27 (m, 2H), 4.31 (s, 2H), 4.12 (s, 2H), 3.51-3.45 (m, 1H), 3.15-3.12 (m, 1H), 2.94-2.89 (m , 1H), 2.55-2.52 (m, 1H), 1.62-1.53 (q, 1H), 1.49-1.40 (t, 3H).

Example 78

(2R,3S,5R)-5-(1-(Difluoromethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolo[3,4- d] imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( compound 78 )

(2R,3S,5R)-5-(1-(difluoromethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

First step: 5-t-butyl 2-ethyl 1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-formate ( 78a )

5-tert-butyl 2-ethyl 1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

Intermediate 5 (10 g, 35.5 mmol) was dissolved in N,N-dimethylformamide (20 mL). EtOAc (EtOAc (EtOAc,EtOAc) The reaction was carried out at ° C for 3 hours. The reaction mixture was cooled to room temperature. Water (60 mL), EtOAc (EtOAc (EtOAc) Column chromatography and purification (petroleum ether / ethyl acetate (v / v) = 2:1) gave 78a (8.5 g, yield 70%).

MS m/z (ESI): 3321. [M+H ⁺ ].

Second step: tert-butyl 2-aminomethylindol-1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 78b )

Tert-butyl 2-carbamoyl-1-(difluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

78a (2.1 g, 6.3 mmol) was dissolved in an ammonia methanol solution (14 mL, 7 mol/L), and the reaction was sealed at 90 ° C for 8 hours. The reaction mixture was cooled to room temperature, methanol was removed under reduced pressure and concentrated to give a light yellow solid 78b (1.85g, 100% yield), the next step directly.

MS m/z (ESI): 325.0 [M+H ⁺ ].

Third step: tert-butyl 1-(difluoromethyl)-2-(1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4-d Imidazole-5(1H) -formate ( 78c )

Tert-butyl 1-(difluoromethyl)-2-(1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

78b (1.9 g, 6.3 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (20 mL). The reaction solution was cooled to room temperature, and then evaporated to dryness crystals crystals crystalsssssssssssssssss Water (40 mL) was added to the reaction mixture, and a white solid was precipitated, filtered, and washed with water (30mL × 2) to give solid compound 78c (1.7 g, yield 89%).

MS m/z (ESI): 327.1 [M+H ⁺ ].

Fourth step: tert-butyl 1-(difluoromethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[ 3,4-d]imidazole-5(1H) -formate ( 78d )

Tert-butyl 1-(difluoromethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)- Carboxylate

78c (1.7 g, 8.2 mmol) was dissolved in N,N-dimethylformamide (30 mL). EtOAc (5.37 g, 16.4 mmol) 3 hours. The reaction mixture was extracted with ethyl acetate (50 mL×3), and the organic layer was evaporated. (v/v) = 20:1) gave 78d (0.65g, yield 36%).

MS m/z (ESI): 341.0 [M+H ⁺ ].

Step 5: 1-(Difluoromethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)-1,4,5,6-tetrahydropyrrolo[ 3,4-d]imidazole benzene sulfonate ( 78e )

1-(difluoromethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzenesulfonate

78 d (0.56 g, 1.9 mmol) was dissolved in methanol (10 mL) at room temperature, benzenesulfonic acid (0.7 g, 2.86 mmol) was added, and the mixture was warmed to reflux at 80 ° C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give 78e (0.7 g, yield 93%).

MS m / z (ESI): 241.1 [M + H +].

The sixth step: the third butyl ((2R, 3S, 5R)-5-(1-(difluoromethyl)-2-(1-methyl-1H-1,2,4-triazole-5- Pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)amino Formate ( 78f )

Tert-butyl((2R,3S,5R)-5-(1-(difluoromethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolo[3,4-d] Imidazol-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

78e (0.69 g, 1.7 mmol) was dissolved in N,N-dimethylacetamide (15 mL), and Intermediate 1 (0.566 g, 1.7 mmol) was added at room temperature for 30 min. The reaction system was cooled to 0 ° C, sodium borohydride triacetate (0.468 g, 2.21 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust the pH of the reaction mixture to 9, and a solid compound was precipitated and washed with water (50 mL × 3). The solid compound was dissolved in dichloromethane, and extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with saturated aqueous brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, Purification (dichloromethane/methanol (v/v) = 20:1) gave 78f (0.7 g, yield 70%).

MS m/z (ESI): 5521. [M+H ⁺ ].

Step 7: (2R, 3S, 5R)-5-(1-(Difluoromethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolo[ 3,4-d]imidazole-5(1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ( Compound 78 )

(2R,3S,5R)-5-(1-(difluoromethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

78f (0.7 g, 1.26 mmol) was dissolved in ethanol (10 mL) at room temperature, concentrated hydrochloric acid (2 mL) was added, and the mixture was warmed to 60 ° C and stirred for 3 hours. The product was separated by white solid. The filtered product was dissolved in dichloromethane (10 mL). ×3). The combined organic phases were washed with brine (50mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 78 (0.27g, 47% yield).

MS m/z (ESI): 452.0 [M+H ⁺ ]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.66 (s, 0.25H), 8.51 (s, 0.50H), 8.36 (s, 0.25H) , 7.98 (s, 1H), 7.21 - 7.08 (m, 3H), 4.31-4.19 (m, 5H), 4.18 (s, 2H), 394 (s, 3H), 3.46-3.41 (m, 1H), 3.18 -3.10 (m, 1H), 2.95-2.89 (m, 1H), 2.50-2.46 (m, 1H), 1.58-1.49 (m, 1H).

Example 79

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-1,2,4-triazole-5- Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 79 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolo[3, 4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

First step: 5-t-butyl 2-ethyl 1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-formate ( 79a )

5-tert-butyl 2-ethyl 1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

Intermediate 5 (3.98 g, 14.2 mmol) was dissolved in N,N-dimethylformamide (20 mL), EtOAc (EtOAc:EtOAc: The reaction was carried out for 5 hours at room temperature. The reaction mixture was cooled to room temperature, water (60 mL) was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Separation and purification by gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2:1) to give 5-t-butyl 2-ethyl 1-methyl-4,6-dihydropyrrole [3,4-d]imidazole-2,5(1H) -formate 79a (4.18 g).

MS m/z (ESI): 295.1 [M+H ⁺ ].

Second step: tert-butyl 2-aminoethenyl-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 79b )

Tert-butyl 2-carbamoyl-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

79a (4.18 g, 14.2 mmol) was dissolved in an ammonia methanol solution (20 mL, 7 mol/L), and the reaction was sealed at 90 ° C for 8 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure to dryness to affordd to pale crystals of yel .

MS m/z (ESI): 267.1 [M+H ⁺ ].

The third step: the third butyl 1-methyl-2-(1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H) -formate ( 79c )

Tert-butyl 1-methyl-2-(1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imida Zole-5(1H)-carboxylate

79b (4.18 g, 14.2 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (17 mL) and heated to reflux for 5 hr. The mixture was cooled to room temperature and evaporated to dryness crystals crystals crystals crystals Water (40 mL) was added to the reaction mixture, and a white solid was precipitated, filtered, and washed with water (30mL × 2) to give solid compound 79c (3.58 g, yield 79%).

MS m/z (ESI): 29.21. [M+H ⁺ ].

The fourth step: the third butyl 1-methyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4- d] imidazole-5(1H) -formate ( 79d )

Tert-butyl 1-methyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

79c (3.58g, 10.7mmol) was dissolved in N,N-dimethylformamide (30mL), then cesium carbonate (3.5g, 21.4mmol), iodomethane (732uL, 11.7mmol) 3 hours. The reaction mixture was diluted with water (30 mL), EtOAc (EtOAc) Column chromatography and purification (dichloromethane/methanol (v/v) = 20:1) afforded 79d (0.75 g, yield 21%).

MS m/z (ESI): 305.1 [M+H ⁺ ].

Step 5: 1-Methyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4- d] imidazolium sulfonate ( 79e )

1-methyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole benzene sulfonate

79 d (0.75 g, 2.46 mmol) was dissolved in methanol (10 mL) at room temperature, and benzenesulfonic acid (0.9 g, 4.9 mmol) was added to the solution, and the mixture was heated to reflux at 80 ° C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give EtOAc (EtOAc, m .

MS m/z (ESI): 205.1 [M+H ⁺ ].

The sixth step: the third butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-1, 2,4-Triazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate ( 79f )

Tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-1,2,4-triazol-5-yl) Pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

79e (1.5 g, 2.46 mmol) was dissolved in N,N-dimethylacetamide (15 mL), and Intermediate 1 (0.884 g, 2.76 mmol) was added at room temperature for 30 min. The reaction solution was cooled to 0 ° C, sodium borohydride triacetate (1.35 g, 6.39 mmol) was added, and the mixture was reacted for 30 minutes, and the reaction was continued to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, and water (40 mL) and aqueous ammonia (5 mL) were successively added to adjust pH to 9, solid compound was precipitated, and water (50 mL × 3) was washed. The solid compound was dissolved in dichloromethane, and extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate Isolation and purification (dichloromethane/methanol (v/v) = 20:1) afforded 79f (0.857 g, yield 68%).

MS m/z (ESI): 516.1 [M+H ⁺ ].

Step 7: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-1,2,4-tri) Zyrid-5-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine ( Compound 79 )

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-1,2,4-triazol-5-yl)pyrrolo[3, 4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

79f (0.857 g, 1.4 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was evaporated under reduced pressure of trifluoroacetic acid, and water (15 mL) and aqueous ammonia (5 mL) was added, and the mixture was extracted with dichloromethane (30 mL×3). Filtration, the filtrate was concentrated, and purified by column chromatography (dichloromethane/methanol (v/v) = 20:1) to afford compound 79 (0.38 g, yield 57%).

MS m/z (ESI): 416.1 [M+H ⁺ ].

Example 80

5-((2S,3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) 1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 80 )

5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4 ,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

First step: tert-butyl 2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate ( 80a )

Tert-butyl 2-carbamoyl-1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

10a (3.09 g, 10 mmol) was added to a methanol solution of ammonia (100 mL, 0.5 mol/L), and the reaction was sealed at 80 ° C for 16 hours. After completion of the reaction and concentration, the obtained crude product of 80a was directly poured into the next reaction.

Second step: 1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( 80b )

1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

The crude product of 80a obtained in the above reaction was added to a solution of hydrochloric acid in ethyl acetate (4 mol/L, 20 mL), and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was allowed to stand, and the liquid was removed. The mixture was stirred for 1 minute with ethyl acetate, and then the mixture was allowed to stand to remove liquid. Separation and purification by hydrazine column chromatography (dichloromethane/methanol (v/v) = 20:1, and a small amount of aqueous ammonia) afforded a yellow solid, 80b (1.55 g, yield of 86% in two steps).

The third step: the third butyl ((2R, 3S, 5R, 6S)-5-(2-carbamoyl-1-ethylpyrrolo[3,4-d]imidazole-5 (1H, 4H, 6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate ( 80c )

Tert-butyl((2R,3S,5R,6S)-5-(2-carbamoyl-1-ethylpyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-2-(2, 5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

33c (2.61 g, 6.61 mmol) and 80b (1.55 g, 8.60 mmol) were added to 1,2-dichloroethane (12 mL) and refluxed for 7 hr. The reaction solution was cooled to room temperature and diluted with 1,2-dichloroethane (40 mL). Sodium tri(acetoxy)borohydride (4.89 g, 23.14 mmol) and acetic acid (0.83 mL, 14.54 mmol) were sequentially added, and the mixture was reacted at room temperature for 3 hr. A saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added and the mixture was evaporated. Separation and purification by hydrazine column chromatography (petrole ether / ethyl acetate (v/v) = 2:1) afforded pale yellow foamy solid 80c (1.84 g, yield 50%).

Fourth step: 5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran- 3-yl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide ( Compound 80 )

5-((2S,3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1,4 ,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide

80c (1.80 g, 3.22 mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (6 mL). After the reaction was completed, aq. EtOAc EtOAc. Separation and purification by hydrazine column chromatography (ethyl acetate/methanol (v/v) = 100:1) afforded Compound (yel.

LC-MS (ESI): 460.1 [M + 1]; 1 HNMR (400MHz, DMSO- d 6): δ 8.34 (s, 2H), 7.64 (s, 1H), 7.46 (dt, 1H), 7.39-7.25 (m, 3H), 4.96-4.80 (m, 2H), 4.41 (q, 2H), 4.07 (dt, 1H), 3.96 (d, 1H), 3.93-3.66 (m, 3H), 3.65-3.50 (m , 1H), 2.62-2.53 (m, 1H), 2.19-2.03 (m, 1H), 1.29 (t, 3H).

Example 81

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrole [3,4-d]imidazole-5(1H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine ( Compound 81 )

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4-d] Imidazol-5(1H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

First step: 1-methyl-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole ( 81a )

1-methyl-2-(1-methyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole

14b-1 (3.05 g, 10 mmol) was added to a solution of hydrochloric acid in ethyl acetate (4 mol/L, 20 mL), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was allowed to stand, and the liquid was removed. The mixture was stirred for 1 minute with ethyl acetate, and then the mixture was allowed to stand to remove liquid. Separation and purification by hydrazine column chromatography (dichloromethane/methanol (v/v) = 20:1, a small amount of aqueous ammonia) to afford a yellow solid 81a (1.87 g, yield 91%).

Second step: tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-) Tetrazol-5-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Carbamate ( 81b )

Tert-butyl((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H) -tetrazol-5-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate

33c (2.77 g, 7.00 mmol) and 81a (1.87 g, 9.10 mmol) were added to 1,2-dichloroethane (12 mL) and refluxed for 3 hr. The reaction solution was cooled to room temperature and diluted with 1,2-dichloroethane (40 mL). Sodium tri(acetoxy)borohydride (5.2 g, 24.5 mmol) and acetic acid (1.0 mL, 17.5 mmol) were successively added under a nitrogen atmosphere, and reacted at room temperature for 3 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Separation and purification by hydrazine column chromatography (petrole ether / ethyl acetate (v/v) = 4:1) gave pale yellow foamy solid 81b (1.85 g, yield 46%).

The third step: (2R, 3S, 5R, 6S)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazole-5-) Pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine ( Compound 81 )

(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazol-5-yl)pyrrolo[3,4-d] Imidazol-5(1H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine

81b (1.84 g, 3.15 mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (6 mL). After completion of the reaction, aq. EtOAc EtOAc. Separation and purification by hydrazine column chromatography (ethyl acetate/methanol (v/v) = 100:1) afforded white solid compound 81 (1.1 g, yield 72.5%).

LC-MS (ESI): 485.1 [M+1]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.35-7.17 (m, 3H), 4.77-4.64 (m, 1H), 4.51 (d, 1H) ), 4.33 (s, 3H), 4.17-4.08 (m, 1H), 4.06-3.92 (m, 5H), 3.84-3.75 (m, 1H), 3.60-3.46 (m, 1H), 3.02 (td, 1H) ), 2.39-2.26 (m, 1H), 1.83 (q, 1H), 1.54 (s, 2H).

Example 82

Third butyl ((2R,3S)-2-(2,3,5-trifluorophenyl)-5-carbonyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Carbamate ( compound 82 )

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 (82A)

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) gave white solid 82A (27 g, yield 82.6%).

Second step: tert-butyl ((1R,2S)-1-hydroxy-1-(2,4,5-trifluorophenyl)pentyl-4-yn-2-yl)carbamate ( 82B )

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

82A (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 (diro flower hydrocarbon) ruthenium (II) (ie RuCl(p-cymene)(R,R)-FSDPEN) (0.57g, 0.8mmol), added with formic acid (22.8g) , 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 82B (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 ( 82C )

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

82B (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 powdery solid 82C (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 ( 82D )

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

82C (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 82D ( 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 ( 82E )

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

82D (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 rose 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 82E (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 ( 82F )

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

82E (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 82F (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 ( compound 82 )

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

Add 82F (6.7g, 16.2mmol) to N,N-dimethylformamide (70mL), add 4-dimethylaminopyridine (0.19g, 1.62mmol), under anhydrous, oxygen-free, nitrogen-protected conditions Next, s-(trifluoromethyl)dibenzothiophenetrifluoromethanesulfonate (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 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 compound 82 (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).

Biological test

1, DPP-IV in vitro enzyme activity assay

The in vitro enzymatic activity of the DPP-IV of the compounds of the invention was determined by enzymatic reaction of recombinant human DPP-IV and H-Ala-Pro-AFC. The buffer, the sample working solution to be tested, the DPP-IV enzyme dilution, and the AFC substrate dilution were prepared according to the DPP-IV Fluorescent Activity Assay Kit (BPS Bioscience).

A 96-well plate was prepared, and 80 μL of buffer was added to each well, followed by the addition of 5 μL of DPP-AFC-substrate. Add different concentrations of the test solution to the test solution, 5 μL per well, and add 5 μL of buffer to the blank group. Finally, 10 μL of DPP-IV enzyme was added to the test group, and 10 μL of the buffer was added to the blank control group. Statistical analysis of the data was performed using Origin 7.5 software to obtain IC ₅₀ values for each test compound. The results are shown in Table 1.

Conclusion: The compounds of the present invention have significant inhibitory activity against DPP-IV enzymes.

2. Rat plasma DPP-IV enzymatic screening experiment

The experimental animals were SD rats, 8 weeks old, male, purchased from Chengdu Dashuo Biotechnology Co., Ltd., and the animal production certificate number SOXK (chuan)-2008-24. 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 minutes, 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 minutes of reaction, the value was measured with a microplate reader (excitation wavelength Excitation = 405 nM; emission wavelength Emission = 535 nM), using Oregon 7.5 for statistical analysis, calculating the inhibition rate of test compound on plasma DPP-IV activity The duration of 70% is shown in Table 2.

Conclusion: The compound of the present invention can significantly inhibit the plasma DPP-IV activity in rats after a single oral administration.

3. 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, and the blank control group was administered with a 5% DMSO-95% physiological saline solution blank reagent. After 60 minutes of administration, a 50% aqueous glucose solution (5 g/kg) was administered, and the blood glucose level of each mouse was measured at 0, 15, 30, 45, 60, and 120 minutes using a Johnson & Johnson blood glucose meter. Calculate the area under the curve of the drug-time curve (AUC), and calculate the formula: [(blank control area - test group area) / blank control area] × 100%.

The experimental results are shown in Table 3.

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

4. Long-term OGTT experiment

The long-term 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 Vital Lihua Experimental Animal Technology Co., Ltd. According to the basic blood sugar value after fasting, it was divided into 5 groups, 24 in each group. The test compound was formulated into a suspension of 1 mg/mL. Oral administration, the dose was 10 mg/kg, and the blank control group was given. 5% DMSO-95% physiological saline solution. After the animals were housed normally for 48 hours and 72 hours, 10 animals in each group were subjected to OGTT experiments. Animals were fasted for 14 hours before the OGTT experiment; fasting blood glucose values were measured 30 minutes before the sugar load; then 50% aqueous glucose solution (5 g/kg) was administered, and strong growth was used at 0, 15, 30, 45, 60, and 120 minutes. The blood glucose level of each mouse was measured by a blood glucose meter, and the area under the medicine-time curve (AUC) was calculated. The calculation formula was: [(blank control area - test group area) / blank control area] × 100%.

The experimental results are shown in Table 4.

Conclusion: The compound of the present invention still has a significant hypoglycemic effect after 48 hours and 72 hours of administration in mice, indicating that the compound of the present invention has a long-term hypoglycemic effect potential.

Claims (10)

A pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof: Wherein R ^{1 is} selected from methyl, ethyl, -CHF ₂ or isopropyl; R ^{2 is} selected from cyano, methyl, cyclopropyl, methylsulfonyl, ethylsulfonyl, cyclopropylsulfonate Sulfhydryl, isopropylsulfonyl, , , , , , R ³ is H; R ⁴ is H; and R ⁵ is H. A pyrroloimidazole ring derivative represented by the formula (I) according to the first aspect of the patent application, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the pyrroloimidazole ring derivative is selected from the group consisting of: , , or . An intermediate of a pyrroloimidazole ring derivative represented by the following formula (II-B) or a stereoisomer or pharmaceutically acceptable salt thereof, or a stereoisomer thereof: Wherein: R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined in the first claim; P is an amino protecting group. A method for producing a pyrrolomidazole ring derivative represented by the formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, as described in claim 1, wherein the method comprises: Reductive amination reaction of a compound of the formula ( IA ) with a compound of the formula ( II-C ) to give a compound of the formula ( II-B ); Deprotection of the compound of the formula ( II-B ) to give the compound of the formula (I); wherein: R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in the first item of the patent application; P is an amino protecting group. A method for producing a pyrrolomidazole ring derivative represented by the formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, as described in claim 1, wherein the method comprises: Reductive amination reaction of a compound of the formula ( IA ) with a compound of the formula ( II-A9 ) to obtain a compound of the formula ( II-B' ); The alkylation or oximation reaction of the formula ( II-B' ) with R ¹ -X ¹ gives the compound of the formula ( II-B ); Deprotection of the compound of the formula ( II-B ) to give the compound of the formula (I); wherein: R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in the first item of the patent application; X ^{1 is} selected from halogen; P is an amino protecting group. A method for producing a pyrrolomidazole ring derivative represented by the formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, as described in claim 1, wherein the method comprises: Hydrolysis of a compound of the formula ( II-D ) to give a compound of the formula ( II-E ); a condensation reaction of the formula ( II-E ) to give a compound of the formula ( II-F ); Removal of the amino protecting group of the formula ( II-F ) gives the compound of the formula ( I ); as the case, the formula ( II-F ) is obtained by aminolysis of the formula ( II-D ): Wherein: R ² is -C(=O)-NR ⁷ R ⁸ , -C(=O)-NR ⁷ R ^{8 is} selected from , , , R ¹ , R ³ , R ⁴ , and R ⁵ are the same as the first item of the patent application; R ¹³ is a C _1-8 alkoxy group; and P is an amino protecting group. A pharmaceutical composition comprising: an effective amount of a pyrroloimidazole ring derivative represented by the formula (I) according to the first or second aspect of the patent application, or a stereoisomer thereof, or pharmaceutically acceptable The salt, or further comprising one or more additional therapeutic agents, and a pharmaceutically acceptable carrier or excipient. A pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to the first or second aspect of the patent application, or a composition according to claim 7 Use for the preparation of dipeptidyl peptidase-IV inhibitors. a pyrroloimidazole ring derivative represented by the formula (I) in the first or second aspect of the patent application, or a stereoisomer or pharmaceutically acceptable salt thereof or The use of the composition described in claim 7 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 levels, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension . According to the use of claim 9, wherein the diabetes is type II diabetes.