WO2014127745A1

WO2014127745A1 - Dpp-iv-inhibiting compounds and intermediates thereof

Info

Publication number: WO2014127745A1
Application number: PCT/CN2014/072432
Authority: WO
Inventors: 李进; 斯托克斯·迈克尔; 窦登峰; 万金桥; 冯静超; 潘飞; 宋宏梅; 胡晓; 易磊
Original assignee: 成都先导药物开发有限公司
Priority date: 2013-02-22
Filing date: 2014-02-24
Publication date: 2014-08-28
Also published as: CN105669682B; CN104003992A; CN105669682A; CN104003992B

Abstract

Provided are compounds as presented in formulas IA and IB or pharmaceutically acceptable salts thereof, the preparation method therefor, and uses thereof, as well as the intermediates of the compounds and the preparation method therefor. The compounds of as presented in formula IA and IB can effectively inhibit the DPP-4 activity, has good selectivity, and can be made into potential new diabetes medicines.

Description

Compound for inhibiting DPP-IV and intermediate thereof

The present invention relates to a compound which inhibits DPP-IV and an intermediate thereof.

Background technique

Diabetes is a metabolic disorder caused by the combination of genetic and environmental factors, which is a serious threat to human health and life safety. In China, the prevalence of diabetes has increased dramatically with the improvement of quality of life and lifestyle changes. According to the diabetes epidemiological data released by the International Diabetes Federation (IDF) in 2013, the number of adult diabetes patients in China has reached 98.4 million, ranking first in the world, and the situation of prevention and control is grim. Faced with huge market demand, the development of new diabetes treatment drugs has been the focus of domestic and foreign pharmaceutical companies. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are an important research object in this field.

DPP-IV, also known as the T cell surface antigen CD26, is a type II transmembrane glycoprotein composed of 766 amino acid residues. DPP-IV is widely distributed in various tissues and organs in the body, including kidney, liver, lung, small intestine, lymphocytes and vascular endothelial cells (Abbott CA, Baker E, Sutherland GR, McCaughan GW. Genomic organization, exact localization, And tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics. 1994; 40 (5): 331-8), partially present in the plasma in soluble form ( Mentlein R. Dipeptidyl-peptidase IV (CD26)-role In the inactivation of regulatory peptides. Regul Pept. 1999; 85(l): 9-24. DPP-IV is a specific serine protease, and its substrate is a polypeptide with a proline (Pro) or alanine (Ala) at the second end of the N-terminal, which can be cleaved from the N-terminus of such a polypeptide. Peptide. The pharmacological action of DPP-IV inhibitors is mainly achieved by increasing the concentration of active glucagon-like peptide-1 (GLP-1) in vivo. GLP-1 is synthesized and secreted by small intestinal L cells, and is the most potent intestinal peptide hormone that has been found to promote insulin secretion. Food digestion can promote the secretion of GLP-1 and release into the blood, and play a physiological role after interacting with a specific GLP-1 receptor. Studies have shown that GLP-1 can exert hypoglycemic effects in many aspects (Gautier JF, Fetita S, Sobngwi E, Salaun-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005; 31(3 Pt l):233-42. ) : 1) Promotes glucose-dependent insulin secretion, increases tissue uptake of glucose; 2) Promotes transcription of proinsulin genes and enhances mRNA stability Increased biosynthesis; 3) inhibits glucagon secretion and reduces hepatic glucose release; 4) promotes islet β cell proliferation and differentiation, inhibits β cell apoptosis; 5) inhibits gastric emptying, controls appetite, lowers blood sugar, and simultaneously Reduce the risk of weight gain. The above physiological functions of GLP-1 provide an important target for the treatment of type 2 diabetes. However, GLP-1 is easily inactivated by DPP-IV from two amino acid residues in the scorpion, and its plasma half-life is less than 2 minutes, which severely limits its clinical application. DPP-IV is one of the key enzymes that promote the degradation and inactivation of GLP-1 in vivo. Selective inhibition of DPP-IV can increase the plasma level of active GLP-1. Therefore, the development of DPP-IV inhibitors provides a new way to treat diabetes. In 2006, Sitagl iptin developed by Merck was approved by the US Food and Drug Administration (FDA) to become the first DPP-IV inhibitor to be marketed. In addition, currently marketed DPP-IV inhibitors include vildagliptin (vi ldagl iptin), saxagl iptin, alogl iptin, and linagliptin (l inagl iptin). Wait for four. The new DPP-IV inhibitor repagliptin (retagl iptin) was independently developed by Chinese pharmaceutical companies and is currently undergoing a phase III clinical study in China. Clinical studies have shown that DPP-IV inhibitors have good hypoglycemic effects in patients with type 2 diabetes (Argyrakopoulou G, Doupis J. DPP4 inhibitors: from sitagliptin monotherapy to the new alogliptin-pioglitazone combination therapy. Adv Ther. 2009; 26 ( 3): 272-80.), compared with traditional diabetes drugs, has the following advantages [Scheen A丄DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab. 2012;38(2):89-101.; Gallwitz B. Emerging DPP-4 inhibitors: focus on linagliptin for type 2 diabetes. Diabetes Metab Syndr Obes. 2013; 6:1-9.]: 1) Oral administration; 2) blood glucose-dependent incretin secretion, low risk of hypoglycemia; 2) can protect and improve islet β-cell function, prevent beta cell degradation, and help to fundamentally undermine the progression of type 2 diabetes 3) Do not increase weight and weight. Therefore, DPP-IV inhibitors play an increasingly important role in the treatment of type 2 diabetes, and have become a research hotspot of current new anti-diabetic drugs.

Summary of the invention

It is an object of the present invention to provide a compound which inhibits DPP-IV, a process for the preparation thereof and use thereof. Another object of the present invention is to provide an intermediate of the compound and a process for the preparation thereof.

The present invention provides a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof,

R ^{1 is} selected from substituted or unsubstituted phenyl; R ^{2 is} selected from C1-5 alkyl or substituted alkyl, 1-5 heteroalkyl or substituted heteroalkyl, or 1-5 heteroatoms or Substituting a hetero atom; R ^{3 is} selected from H, CN, or Cl-10 alkyl or substituted alkyl; X is selected from N or CH; Y is selected from N or CR ⁶ , wherein R ^{6 is} selected from H, CN, carboxyl or Ester group.

Further, in R ¹ , the substituent of the substituted phenyl group is 1 to 5 R ⁴ , wherein R ^{4 is} selected from the group consisting of CN, halogen, C1-6 alkyl or halogen-substituted alkyl, or C1-6 Alkoxy or halogen substituted alkoxy;

In R ² , the substituent of the substituted alkyl group is selected from halogen, CN, 0H, R ⁵ , 0R ⁵ , NHS0 ₂ R ⁵ , S0 ₂ R ⁵ , COOH or C0 ₂ R ⁷ , substituted hetero atom or substituted hetero The substituent of the alkyl group is halogen, CN, 0H, R ⁵ , OR ⁵ , NHS0 ₂ R ⁵ , S0 ₂ R ⁵ , COOH or C0 ₂ R ⁷ ;

In R ³ , the substituent of the substituted alkyl group is selected from 1 to 5 halogens;

In R ⁶ , the carboxyl group is COOH, and the ester group is C0 ₂ R ⁷ _;

Wherein the hetero atom is 0 or S; R ⁵ is a C1-6 alkyl or substituted alkyl group having a substituent of 1 to 5 halogens, COOH or C0 ₂ R ⁷ ; and R ⁷ is a C 1-6 alkyl group. Further, the heteroalkyl group is a C1-4 fluorenyl group containing one hetero atom.

Further, R ^{1 is} selected from a halogen-substituted phenyl group; R ^{2 is} selected from a heteroalkyl group, 1-2 hetero atoms or a C2-3 alkyl group; and R ^{3 is} selected from a halogen-substituted alkyl group.

Further preferably, the halogen is F or Cl.

Wherein the compound is

, , , , , or , or step by step, RR ^{11 is} selected from the group consisting of a substituted phenylphenyl group from a halohalogen; Alkyl fluorenyl group:: RR ^{66 is} selected from the group consisting of HH, CCNN, and carboxycarboxylate. Further, R ^{6 is} selected from C0 ₂ R ⁷ .

Further preferably, the compound or a pharmaceutically acceptable salt thereof is:

Substituting the five-membered aromatic heterocyclic tetrahydropyrazine for DPP4 inhibitor activity and other members of DPP (DPP2, DPP8,

The selectivity of DPP9) plays a major role, and the substitution of tetrahydropyrazine therein can modulate the activity and selectivity of the compound. However, the addition of substituents will additionally produce multiple chiral isomers, making it difficult to synthesize and identify compounds. In the course of the research, it has been found that the introduction of a substituent group by bridging can not only reduce the complexity of the chiral compound and increase the controllability of chirality, but also increase the rigidity of the compound, and can change the activity and selectivity of the compound. However, it was found during the pre-synthesis process that the substituted five-membered aromatic heterocyclic tetrahydropyrazine was bridged to form a bridge-parallel combination. The material is very challenging in synthesis and needs to solve many technical problems. For example, chiral controlled bridge rings are difficult to form effectively, and bridges and loops cannot be directly formed by corresponding parallel rings (especially for short bridge rings). The construction process of the five-membered aromatic heterocyclic ring is not affected by the tension of the bridged ring, the secondary ammonia of the amino acid and the bridged ring is affected by the steric hindrance, and the intermediate stability of the bridged ring in the formation of the final compound is poor. And other issues. After extensive experimental exploration and analysis, the inventors finally developed an ideal synthetic route, effectively overcoming the difficulties in the synthesis process, successfully synthesizing bridge tetrahydropyrazine and replacing the five-membered aromatic heterocycle. It has been experimentally verified that these compounds have good inhibition and selectivity for DPP4.

The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a dipeptidyl peptidase-IV inhibitor.

Further, the dipeptidyl peptidase-IV inhibitor is a drug for treating or/and preventing diabetes, hyperglycemia, and insulin resistance.

The present invention also provides a process for the preparation of the above formula or a compound of the formula, characterized in that the reaction comprises the following steps:

Among them, Step 1: using (l S,5R)-3,8-diazabicyclo[3.2.1]heptan-2-one (Tetrahedron, 1992, 23, 4985) as raw material, with di-tert-butyl dicarbonate The ester is reacted under basic conditions to obtain a product which is retained as the next reactant;

Step 2: The product obtained in the previous step is subjected to a thiolation reaction with a Lawson reagent to obtain a product which is left as a next reaction; Step 3: The product obtained in the previous step is added to a strong acid solution to obtain a product which is left as a next reaction. Step 4: The product obtained in Step 3 is reacted with R ³ -substituted acetyl hydrazine under the action of activating reagent R ³ instead of sodium acetate to obtain a product which is left as the next reactant;

Step 5: reacting the product obtained in Step 4, R ¹ -substituted protected β-aminobutyric acid, and a condensation reagent to obtain a product which is reserved as a next step;

Step 6: reacting the product obtained in Step 3, R ¹ -substituted protected β-aminobutyric acid, and a condensation reagent to obtain a product which is reserved as a next step;

Step 7: reacting the product obtained in Step 6 with R ³ -substituted acetohydrazide under the action of activating reagent R ^{3 in} place of sodium acetate, thereby obtaining a product which is left as the next reactant;

Step 8: Take the product of Step 5 or Step 7 and add a strong acid for deprotection to obtain a product of the formula; or, (lR, 5S)-3,8-diazabicyclo[3.2.1]heptane-2 - the ketone is used as a raw material and the same synthetic method is used to obtain the compound hydrazine; or the racemic starting material is used, and after synthesizing according to the above method, the optical isomer is resolved to obtain a compound.

ΠΑ or ΠΒ.

Further, wherein the solvent used in Step 1 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane. Ethyl acetate or tetrahydrofuran, the reaction temperature is 0 ° C to 30 ° C, the reaction time is 2 to 16 hours;

The solvent used in Step 2 is a polar aprotic solvent, and the aprotic solvent is preferably tetrahydrofuran, diethyl ether, diisopropyl ether or toluene, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5-3 hours; It is also possible to use a toluene as a solvent to heat the reaction.

The acid used in Step 3 is a proton strong acid, and the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, the solvent used is preferably dichloromethane or ethyl acetate, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5 to 4 hours. ;

The solvent used in Step 4 is a polar protic solvent, and the polar protic solvent is preferably n-butanol, the reaction temperature is 110 to 130 ° C, preferably 118 ° C, and the reaction time is 2 to 12 hours;

The solvent used in Step 5 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide, the base used is diisopropylethylamine or other organic base, and the condensing agent is 1_ (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, or 2-(7-azobenzotriazole)-ruthenium, osmium, iridium ',Ν'-tetramethylurea hexafluorophosphate, the reaction temperature used is 0 ° C to 30 ° C, the reaction time is 0.5 to 2 hours;

The solvent used in Step 6 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide, the base used is diisopropylethylamine or other organic base, and the condensing agent is 1_ (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole or 2-(7-azobenzotriazole)-Ν,Ν,Ν' , Ν'-tetramethylurea hexafluorophosphate, the reaction temperature is from 0 ° C to 30 ° C, and the reaction time is from 0.5 to 2 hours.

The solvent used in Step 7 is a polar protic solvent, and the polar protic solvent is preferably n-butanol, the reaction temperature is in the range of 110 to 130 ° C, and the reaction time is 2 to 12 hours;

The acid used in Step 8 is a proton strong acid, and the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, and the solvent used is preferably dichloromethane, ethyl acetate or none, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5 to 4 hours.

The present invention also provides a process for the preparation of the above formula or a ruthenium compound, the reaction steps being as follows:

Wherein Step 1 : N-Boc-3-amino-1,2-propanediol is reacted with methyl (-1-nitrobenzyloxycarbonyl-2-aziridinecarboxylate) under Lewis acid catalysis to obtain a product Reserved as the next reactant;

Step 2: The product obtained in the previous step is subjected to an oxidation reaction, and the product is obtained as a reactant for the next step;

Step 3: hydrogenating the product obtained in the previous step to obtain a product which is reserved for the next step;

Step 4 The product obtained in the previous step is deprotected by adding a strong acid solution, and the product is obtained as the next step. Receiving

Step 5: The product obtained in the previous step is added to a strong basic organic solvent to obtain a product which is reserved for the next step;

Step 6: The product obtained in the previous step is reacted with di-tert-butyl dicarbonate under basic conditions to obtain a product which is left as the next reaction;

Step 7: The product obtained in the previous step is added to the Lawson reagent to obtain a product which is left as the next reaction; Step 8: The product obtained in the previous step is added to a strongly acidic solution, and the reaction is obtained, and the product is obtained as the next step. Reactant;

Step 9: reacting the product obtained in the previous step, R ¹ -substituted protected β-aminobutyric acid, and a condensation reagent to obtain a product which is reserved as a next step;

Step 10: reacting the product obtained in the previous step with R ³ -substituted acetyl hydrazine under the activation of R ³ -substituted sodium acetate to obtain a product which is left as the next reactant;

Step 11: adding the product obtained in the previous step to a strong acid reaction to obtain a product of the formula;

Alternatively, the starting material is replaced by (R)-l-p-nitrobenzyloxycarbonyl-2-aziridinecarboxylic acid methyl ester, and the compound oxime is prepared according to the above synthesis method; or, the racemic N-Boc-serine is used. Methyl ester, after synthesis according to the above method, the optical isomer is resolved to obtain the compound hydrazine or hydrazine.

Further, wherein the solvent used in Step 1 is a non-polar solvent, the non-polar solvent is preferably toluene or xylene, the Lewis acid is preferably boron trifluoride etherate, the reaction temperature is 20 to 30 ° C, and the reaction time is 0.5 to 2 hours;

The solvent used in Step 2 is a polar aprotic solvent, and the polar aprotic solvent is preferably dichloromethane or tetrahydrofuran, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 1 to 2 hours;

The solvent used in Step 3 is a polar solvent, the polar solvent is preferably ethyl acetate or methanol, the catalyst used is a metal catalyst, the metal catalyst is preferably palladium carbon, the reaction temperature is 20 to 30 ° C, and the reaction time is 2 Up to 4 hours;

The solvent used in Step 4 is a polar aprotic solvent, and the polar aprotic solvent is preferably dichloromethane or ethyl acetate. The acid used is a strong acid, preferably trifluoroacetic acid or hydrochloric acid, and the reaction temperature is 0 ° C to 30 ° C. °C, the reaction time is 2 to 4 hours;

The solvent used in Step 5 is a polar protic solvent, preferably methanol, and the strong base used is preferably sodium methoxide, the reaction temperature is 20 to 30 ° C, and the reaction time is 4 to 16 hours;

Step 6 The solvent is a polar protic solvent, preferably methanol, and the base is preferably a tertiary amine, and the reaction time is 2 to 10 hours;

The solvent used in Step 7 is a polar aprotic solvent, and the aprotic solvent is preferably tetrahydrofuran, diethyl ether or diisopropyl ether, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5 to 3 hours;

The solvent used in Step 8 is a polar aprotic solvent, and the polar aprotic solvent is preferably dichloromethane or ethyl acetate. The acid used is a strong acid, preferably trifluoroacetic acid, and the reaction temperature is 0 ° C to 30 ° C. , the reaction time is 2 to 4 hours;

The solvent used in Step 9 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, N, N to dimethylformate. Amide or tetrahydrofuran, the base used is diisopropylethylamine or other organic base, and the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriene Oxazole, or 2-(7-azobenzotriazole)-ruthenium, osmium, iridium, Ν'-tetramethylurea hexafluorophosphate, reaction temperature of 0 ° C to 30 ° C, reaction time 0.5 to 2 hours;

The solvent used in Step 10 is a polar protic solvent, and the polar protic solvent is preferably n-butanol, the reaction temperature is 110 to 130 ° C, preferably 118 ° C, and the reaction time is 2 to 12 hours;

The solvent used in Step 11 is a polar aprotic solvent, and the polar aprotic solvent is preferably dichloromethane or ethyl acetate. The acid used is a strong acid, preferably trifluoroacetic acid, and the reaction temperature is 0 ° C to 30 ° C. , the reaction time is 0.5 to 2 hours;

An intermediate of IA and IB compounds, which has the following structural formula:

Wherein R ² ' is selected from C1-5 alkyl or substituted alkyl; R ² " is selected from 1 to 5 heteroalkyl- or substituted heteroalkyl, 1-5 heteroatoms or substituted heteroatoms; ^{3 is} selected from H, CN, or Cl-10 alkyl or substituted alkyl; X is selected from N or CH; and R ^{6 is} selected from H, CN, carboxyl or ester groups.

Further, in R ² ', the substituent of the substituted alkyl group is selected from halogen, CN, OH, R ⁵ , OR ⁵ , NHS0 ₂ R ⁵ , S0 ₂ R ⁵ , COOH or C0 ₂ R ⁷ ; R ² " Wherein the hetero atom is selected as g N, S or 0, and the substituent replacing the hetero atom or the substituted heteroalkyl group is halogen, CN, OH, R ⁵ , OR ⁵ , NHS0 ₂ R ⁵ , S0 ₂ R ⁵ , COOH Or C0 ₂ R ⁷ ;

Wherein R ⁵ is an alkyl group or a substituted alkyl group of Cl-6, and the substituent is 1-5 halogens, COOH or C0 ₂ R ⁷ ; and R ⁷ is a C1-6 alkyl group.

In one step, the intermediate is:

Among them, the following steps are included:

Step 1: Using (lS,5R)-3,8-diazabicyclo[3.2.1]heptan-2-one (re ra/^i raw, 1992, 23, 4985) as raw material and di-dicarbonate Butyl ester is reacted in an alkaline solution to obtain a product which is left as the next reactant;

Step 2: The product obtained in the previous step is added to the Lawson reagent to obtain a product which is left as the next reactant; Step 3: The product obtained in the previous step is added to a strong acid solution to obtain a product which is reserved for the next step. Step 4: reacting the product obtained in the previous step, R ³ -substituted acetohydrazide with sodium acetate or R ³ -substituted sodium acetate to obtain a product which is left as the next reactant; Alternatively, the starting material is replaced by (lR,5S)-3,8-diazabicyclo[3.2.1]heptan-2-one, and the compound oxime is prepared according to the above method; or, using the racemic starting material, After the above method is synthesized, the optical isomer is resolved to obtain the compound IIAA or hydrazine.

Further, the reaction steps are as follows:

The reaction process includes the following steps:

Step 1 : reacting N-Boc-3-amino-1,2-propanediol with methyl (-1-nitrobenzyloxycarbonyl-2-aziridinecarboxylate) in a solvent to obtain a product for the next step. Reactant;

Step 2: The product obtained in the previous step is reacted with a Dess-Martin reagent to obtain a product which is reserved for the next step; Step 3: The product obtained in the previous step is subjected to hydrogenation reaction to obtain a product which is left as a next step; 4: The product obtained in the previous step is added to a strong acid solution, and the reaction is carried out to obtain a product which is left as the next step; Step 5: The product obtained in the previous step is reacted by adding sodium methoxide in a solvent to obtain a product for the next step. Reactant;

Step 6: The product obtained in the previous step is added to di-tert-butyl dicarbonate and a tertiary amine to obtain a product which is left as the next reaction;

Step 7: The product obtained in the previous step is added to the Lawson reagent to obtain a product which is left as the next reactant; Step 8: The product obtained in the previous step is added to a strong acid solution, and the reaction is carried out to obtain a product for the next reaction. Alternatively, the starting material is replaced by (R)-l-p-nitrobenzyloxycarbonyl-2-aziridinecarboxylic acid methyl ester, and the compound hydrazine is prepared according to the above method; or, using the racemic amino acid methyl ester, After synthesis according to the above method, the optical isomer is resolved to obtain the compound ruthenium or osmium.

The compounds and derivatives provided herein may be based on IUPAC (International Union of Pure and Applied Chemistry) or

CAS (Chemical Abstracts Service, Columbus, OH) naming system nomenclature.

Definition of terms of use in connection with the present invention. Unless otherwise indicated, the initial definitions provided herein for groups or terms apply to the group or terminology throughout the specification. For terms that are not specifically defined herein, the meanings that those skilled in the art can give to them should be given in light of the disclosure and context.

"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, for example, the prefix (Ca-b)alkyl group indicates any alkyl group having "a" to "b" carbon atoms. For example, (C1-4)alkyl means an alkyl group containing from 1 to 4 carbon atoms. The term "pharmaceutically acceptable" means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.

The terms "salt" and "pharmaceutically acceptable salt" are the acid and I or basic salts which form the compound or its stereoisomers with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal salts). Also included are quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It may also be obtained by mixing a compound, or a stereoisomer thereof, with a suitable amount (e.g., equivalent) of a certain amount of an acid or a base. These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium. The salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound. Acid, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.

In one embodiment of the invention, the invention includes isotopically-labeled compounds of formula (IA) or (IB), said isotopically-labeled compound being the same as the compounds listed herein, but one or more of the atoms are Another atom is substituted, the atomic mass or mass of which is different from the atomic mass or mass number that is common in nature. Isotopes which may be introduced into the compound of formula (IA) or (IB) include hydrogen, carbon, nitrogen, oxygen, sulfur, ie 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S o Compounds of formula (IA) or (IB) containing the above isotopes and I or other atomic isotopes, and stereoisomers thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers, are intended to be encompassed within the scope of the invention .

The key intermediates and compounds in the present invention are isolated and purified in a manner which is commonly used in organic chemistry for separation and purification and examples of such methods include filtration, extraction, drying, spin drying, and various types of chromatography. Alternatively, the intermediate can be subjected to the next reaction without purification.

In certain embodiments, one or more compounds of the invention may be used in combination with one another. Alternatively, the compounds of the present invention can be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds can be administered simultaneously, separately or sequentially to the subject.

The compound of the present invention is effective for inhibiting DPP-IV activity, and is a member of the DPP family, DPP2, DPP8,

DPP9 has reasonable selectivity. These compounds can be used to treat a variety of DPP-4-related diseases such as diabetes, providing new options for clinical use.

detailed description

Example 1 (R)-3-Amino-1-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, 2,4] Triazolo[4,3-a]azepine-10-meryl)-4-(2,4,5-trifluorophenyl)butanone trifluoroacetate (Compound 1 Preparation

Step 1: L-pyroglutamic acid methyl ester (compound lb)

Thionyl chloride (65 mL, 900 mmol) was added dropwise to 100 mL of methanol in an ice bath, then L-pyroglutamic acid la (58 g, 449 mmol). The reaction mixture was stirred at room temperature for 16 h and then evaporated. Ethyl acetate (200 mL), sodium carbonate (50 g) and water (100 mL) were added and stirred for one hour. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and evaporated

MS (ESI) m/z: 144 (M+l); ¹ H NMR (400 Hz, CDCl ₃ ): 52.20 - 2.60 (m, 4H), 3.78 (s, 3H), 4.23-4.30 (m, lH), 6.23 (br, lH).

Step 2: N-Benzyl-L-pyroglutamic acid methyl ester (compound lc)

Compound lb (20 g, 140 mmol) was dissolved in 80 mL of dry DMF, and sodium hydrogen chloride (4 g, <RTI ID=0.0>> The ice bath was removed and stirred at room temperature overnight. Extract with dichloromethane (100 mL) and wash with saturated sodium bicarbonate (100 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dry. The crude product was purified by column chromatography eluting with silica gel

MS (ESI) m / z: 234 (M + 1); ¹ H NMR (400 Hz, CDCl ₃ ): 52.00 - 2.63 (m, 4H), 3.67 (s, 3H), 3.96-4.04 (m, 2H), 5.02 (dJ=14Hz, lH), 7.18-7.36(m,5H)o

Step 3: (5) -N-Benzyl-5-thiopyrrolidone-2-carboxylic acid methyl ester (Compound Id)

Compound lc was dissolved in 80 mL of dry tetrahydrofuran, and Lawson's reagent (12.5 g, 30 mmol) was added with vigorous stirring. After 3 hours, tetrahydrofuran was evaporated under reduced pressure and ethyl acetate (150 mL) was evaporated and evaporated. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (lululuEtOAcEtOAcEtOAcEtOAc

MS (ESI) m / s: 250 (M + 1); ¹ H NMR (400 Hz, CDCl ₃ ): 52.17 (m, lH), 2.27 (m, lH), 3.15 (m, 2H), 3. 69 (s , 3H), 4.30 (dd, lH), 4.37 (d, lH), 5.73 (d, lH), 7.32 (m, 5H).

Step 4: ) Small benzyl -2-(methoxycarbonyl)-5-(methylthio)-3,4-dihydro-2H-pyrrole small iodinating gun (combination le)

The compound Id ( llg, 44 mmol) was dissolved in 40 mL of EtOAc. The product le, yellow solid 16g, yield 93%.

MS (ESI) m/z: 264 (M+l); ¹ H NMR (400 Hz, CDCl ₃ ): 52.24 (m, lH), 3.04 (s, 3H), 3.16 (m, lH), 3.25 (m) , lH), 3.63 (s, 3H), 4.29 (dd, lH), 4.72 (d, lH), 4.89 (dd, lH), 5.14 (d, lH), 7.43 (m, 3H), 7.51 (m, 2H).

Step 5: trans-Wl-benzyl-(nitroalkenyl)-pyrrole-2-carboxylic acid methyl ester (Compound If) Compound le (8 g, 20.5 mmol) was dissolved in 50 mL of dry DMF, and nitromethane was added. (7.5 g, 123 mmol) and triethylamine (4 mL, 29 mmol). It was then reacted at 60 ° C for 5 hours. The solvent was evaporated under reduced pressure and then purified tolululululululu

MS (ESI) m / s: 277 (M + 1); ¹ H NMR (400 Hz, CDCl ₃ ): 2.22 (m, lH), 2.34 (m, lH), 3.39 (5, lH), 3.7 4 (dd, lH), 3 2 (s, 3H), 4.24 (dd, lH), 430 (d, lH), 4.51 (d, lH), 6.87 (s, lH), 7 6 (dd, 2H), 7 5 ( m

Step 6: (M,5R)-3,8-azabicyclobicyclo[3.2.1]octanoyl-2-one (compound lg)

The compound lf (2.1 g, 7.6 mmol) was hydrogenated in a mixed solution of ethyl acetate and acetic acid (10 mL + 10 mL) for 4 hours under catalysis of 10% palladium carbon. The palladium carbon catalyst was filtered off with diatomaceous earth and concentrated to dryness. The residue (1.8 g, 7.3 mmol) was dissolved in 15 mL of methanol, and then evaporated. The palladium carbon catalyst was filtered off with celite, and then concentrated to dryness to give compound lg, white solid, 0.9 g, yield 94%.

MS (ESI) m/z: 127 (M+l); ¹ H NMR (400 Hz, CDCl ₃ ): 51.75 (m, lH), 2.05 (m, 3H), 2.45 (bs, lH), 3 , J = 2.0, 9.0 Hz, lH), 3.48 (dd, J = 4.0, 9.0 Hz, lH), 3.74 (m, 2H), 6.35 (s, lH).

Step 7: (M,5R)-8-tert-Butoxycarbonyl-3,8-azabicyclobicyclo[3.2.1]octan-2-one (compound lh) to an lg (2 g, To a solution of 15.9 mmol) in 40 mL of dichloromethane was added di-tert-butyl dicarbonate ( 5.19 g, 23.8 mmol) and triethylamine (0.66 mL, 4.8 mmol) and allowed to warm to room temperature overnight. After the solvent was evaporated under reduced pressure, EtOAc mjjjjjjjjjjjjj

MSiESpm/z SYiM+l); ¹ leg MR (400 mHz, CDCl ₃ ): S1.45 (s, 9H) 1.77-1.84 (m, lH), 2.10-2.16 (m, 2H), 2.18-2.26 (m, lH), 3.03 (ddJ = 2.4, 10.8 Hz, lH), 4.42 (s, lH), 4.48 (s, lH), 5.73 (s, lH).

Step 8: (M,5R)-8-tert-Butoxycarbonyl-3,8-azabicyclobicyclo[3.2.1]octanoyl-2-thioketone (Compound li) Compound lh (40 mg, 0.18 mmol) Dissolved in 5 mL of tetrahydrofuran and added Lawson's reagent (43 mg, 0.1 mmol) with vigorous stirring. After the reaction mixture was stirred for 3 hours, the reaction mixture was evaporated to dryness and then evaporated and evaporated. The organic layer was washed with saturated sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate The crude product was purified by column chromatography eluting elut elut elut elut MS (ESI) m / z: 243 (M + 1).

Step 9: (M,5R)-3,8-azabicyclobicyclo[3.2.1]octanoyl-2-thioketone (compound lj)

The compound li (40 mg, 0.16 mmol) was dissolved in 0.2 mL of methanol, then 4N hydrochloric acid ethyl acetate (4 mL), and stirred overnight at room temperature. Excessive hydrochloric acid and a solvent were distilled under pressure to obtain a compound lj, a white solid (23 mg, yield 98%). MS (ESI) m/z: 143 (M+l)

Step 10: (6R,9S)-3-(Trifluoromethyl)-6,7,8,9-tetrahydro-5H-6,9-cycloimine[1,2,4]triazole [4 ,3-a]吖庚

City annihilation 3⁄4 糊 s Θfairchuan E.Ior9S0Γ69ε)ΐεεζH---- --- - annihilation $^齄蝶3⁄43⁄4i 3⁄4 ^匾 33⁄4 J川i川 Hςνζ) (unpt≤[- -----

Step 1: (2S)-3-(3-tert-Butoxycarbonylamino-2-hydroxypropoxy)-2-p-nitrobenzyloxycarbonylamino-propionic acid methyl ester (Compound 2b)

To a solution of Compound 21 (6.82 g, 35.7 mmol) and Compound 2a (5 g, 17.8 mmol) in toluene (80 mL) was added dropwise boron trifluoroether (0.3 mL, 48%). After stirring at room temperature for 2 hours, the solvent was evaporated, evaporated, mjjjjjjjjjj

MS (ESI) m / z: 472 (M + 1), 416 (M - 56 + 1); ¹ H NMR (400 Hz, CDCl ₃ ): 58.22 (d, / = 8.4 Hz, 2H), 7.5 2 (dJ = 8.4 Hz, 2H), 5.08-5.13 (m, lH), 5.19-5.26 (m, 2H), 4.42-4.58 (m, lH), 3.91-3.94 (m, lH), 3.78 (s, 3H), 3.73 -3.83 (m, 2H), 3.54 - 3.62 (m, 2H), 3.42 - 3.50 (m, 2H), 1.44 (s, 9H).

Step 2: (3S)-3-(3-tert-Butoxycarbonylamino-2-carbonylpropoxy)-2-p-nitrobenzyloxycarbonylamino-propionic acid methyl ester (Compound 2c)

To a solution of compound 2b (4.7 g, 10 mmol) in dichloromethane (150 mL), EtOAc (EtOAc) After 1 h of reaction, a solution of Na ₂ S ₂ O ₃ (2N, 120 mL) was added to the mixture, and the mixture was evaporated and evaporated. The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (350 mL) and brine (350 mL). The organic phase was dried, filtered, dried and purified eluted elut elut elut

MS (ESI) m / z: 470 (M + l), 414 (M - 56 + 1); ¹ H NMR (400 Hz, CDCl ₃ ): 58.22 (d, / = 8.4 Hz, 2H), 7.5 2 (dJ = 8.4 Hz, 2H), 5.17-5.28 (m, 3H), 4.18 (s, 2H), 4.04 (d, / = 8.4 Hz, lH), 4.00 (dd, / = 5.6 Hz, 2.4 Hz, lH), 3.82 (s, 3H), 3.75-3.80 (m, lH), 1.45 (s, 9H).

Step 3: (3 5 -5-tert-Butoxycarbonylamidomethyl-morpholine-3-carboxylic acid methyl ester (Compound 2d)

Palladium on carbon (0.5 g, 10%) was added to a solution of compound 2c (2.0 g, 4.26 mmol) in ethyl acetate (50 mL). 2d, colorless oil 0.6 g, yield 51.3%.

MS (ESI) m / z: 275, 219 (M - 56 + 1); 1H-NMR (400 mHz, CDCl ₃ ): 54.97 (s, lH), 4.11 (dd, / = 11.12 Hz, 3.6 Hz, lH), 3.82 (ddJ=11.2Hz, 3.6Hz, lH), 3J5(s, 3H), 3Jl (dd, /=10.4Hz, 3.6Hz, lH), 3.39 (tJ=10.8 Hz, lH), 3.16-3.22 (m, lH), 3.16 (t, / = 10.8 Hz, lH), 3.00 - 3.11 (m, 2H), 1.45 (s, 9H). Step 4: (3S,5-5-Aminomethyl-morpholine-3-carboxylic acid methyl ester (Compound 2e)

Trifluoroacetic acid (10 mL) was added dropwise to a solution of Compound 2d (500 mg, 1. <RTI ID=0.0></RTI> , yield 100%.

MS (ESI) m/z: 175 (M+l)

Step 5: 3-oxo-7,9-diazabicyclo [3.3.1] decane-6-one (compound 20

Compound 2e (317 mg, 1.82 mmol) and sodium methoxide (491 mg, 9.1 mmol) were dissolved in meOH (20 mL) and stirred overnight, filtered, and the filtrate (Compound 2f solution) was directly used for the next reaction. MS (ESI) m/z: 143 (M+1).

Step 6: 6-Hexyl-3-oxo-7,9-diazabicyclo[3.3.1]non-9-carboxylic acid tert-butyl ester (Compound 2g) br. br. N,N-Diisopropylethylamine (470 mg, 3.64 mmol) and di-tert-butyl dicarbonate (476 mg, 2.2 mmol) were added to a solution of methanol (20 mL). After reacting at room temperature for 2 h, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Column chromatography (silica gel, ethyl acetate: petroleum ether = 1 : 1) gave product 2 g, white solid, 0.22 g, yield 50%.

MS (ESI) m/z: 243 (M+l); ¹ H NMR (400 Hz, CDCl ₃ ): 56.00 (s, lH), 4.42 (s, lH), 4.28 (s, lH), 4.03 (dJ = 10.8) , lH), 3.94 (d, / = 11.6 Hz, lH), 3.79 (d, / = 12.0 Hz, 2H), 3.66 (d, / = 10.8 Hz, lH), 3.41 (dd, J = 12.0 Hz, 2.8 Hz, lH), 1.48 (s, 9H).

Step 7: 6-sulfanyl-3-oxo-7,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (Compound 2h) Lawson's reagent (367 mg, 0.91 mmol) was added to The compound 2g (220 mg, 0.91 mmol), EtOAc (EtOAc, m. (20 mL). The organic phase was dried, filtered, concentrated and purified tolululululululululululu

MS (ESI) m / s: 259 (M + 1); ¹ H NMR (400 Hz, CDCl ₃ ): 54.87 (s, lH), 4.18 (d, / = 10.8 Hz, lH), 3.94 (d, /=11.6) Hz, lH), 3.79 (dJ = 11.6 Hz, 2H), 3.70-3.75 (m, 3H), 3.42 (dd, /=13.6 Hz, 2.8 Hz, lH), 1.48 (s, 9H) °

Step 8: 3-oxo-7,9-diazabicyclo [3.3.1] 壬垸 -6-thione (Compound 2i)

Trifluoroacetic acid (3 mL) was added dropwise to a solution of EtOAc (3 mL). The yield is 100%.

MS (ESI) m/z: 159 (M+l

Step 9: ((2R)-4-carbonyl-4-(6-thioindol-3-oxo-7,9-diazabicyclo[3.3.1]壬-9-fluorenyl) small (2, Benzyl 4,5-trifluorophenyl)butan-2-ylcarbamate (Compound 2j)

To a solution of the compound 2i (71 mg, 0.45 mmol) in dichloromethane (10 mL), EtOAc (EtOAc, EtOAc, After reacting for two hours, the reaction mixture was washed with saturated sodium hydrogen sulfate (8 mL) and brine (8 mL). The organic phase was dried, filtered, concentrated and purified by column chromatography (EtOAc,EtOAcEtOAc

MS (ESI) m/z: 508 (M+l); ¹ H NMR (400 Hz, CDCl ₃ ): 57.29-7.35 (m, 5H), 7.06 (dd, /=17.6 Hz, 9. 2Hz, lH), 6.86 (dd, /=14.4Hz, 8.4Hz, lH), 5.46-5.54(m,lH), 3.85-3.94(m,lH),4.51(d,/=12.0,lH),4 16-4.25(m,lH),3.85-3.94(m,lH),3.74-3.77(m,lH),3.60-3.64(m,lH ),3.37-3.49(m,2H ),3.13-3.2 0 (m, lH ), 2.87-2.95 (m, lH ), 2.78-2.83 (m, lH ), 2.53-2.59 (m, lH ).

Step 10: ((2R)-4-carbonyl-4-(3-trifluoromethyl-6,7,9,10-tetrahydro-5H-6,10-cycloimine[1,2,4]3 Benzazo[3,4-d][l,5]oxazolyl-11-fluorenyl)-1-(2,4,5-trifluorophenyl)-2-butyl)carbamate (compound) 2k )

Compound 2j (132 mg, 0.26 mmol), trifluoroacetyl hydrazide (100 mg, 0.78 mmol), and sodium acetate (64 mg, 0.78 mmol) were dissolved in n-butanol (5 mL) and then evaporated to reflux overnight. The reaction mixture was concentrated and purified byjjjjjjlilililililililililili

MS (ESI) m/z: 584 (M+l); ¹ H NMR (400 Hz, CDCl ₃ ): 57.29-7.35 (m, 5H), 7.01 (dd, /=17.2 Hz, 9.6 Hz, lH), 6.71 (dd, /=12.0 Hz, 7.6 Hz, lH), 5.78 (d, /=9.2 Hz, lH), 5.35 (s, lH), 5.01 (dJ = 4.0 Hz, lH), 4.3 4-4.44 (m, lH ), 4.25-4.30 (m, lH), 4.17-4.19 (m, lH), 3.97-4.01 (m, lH), 3.87 (d, / = 10.8 Hz, lH), 3.80 (d, /=12.6 Hz) , lH), 2.87-3.05 (m, 2H), 2.77-2.82 (m, lH), 2.54-2.63 (m, lH).

Step 11: (3R)-3-Amino-l-(3-trifluoromethyl-6,7,9,10-tetrahydro-5H-6,10-cycloimine[1,2,4]triazole And [3,4-d][l,5]oxazolyl-11-fluorenyl)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate (Compound 2 )

Palladium carbon (32 mg, 10%) was added to a solution of compound 2k (30 mg, 0.089 mmol) in ethyl acetate (5 mL). White solid 15 mg, yield 24%.

MS (ESI) m / z: 450 (M + 1); 1H-NMR (400 mHz, CDCl ₃ ): 57.20 (ddJ = 16.8 Hz, 8.8 Hz, lH), 6.97-7. 08 (m, lH ), 5.91 (s, 0.51H), 5.40 (s, 0.46H), 4.92 (s, 0.55H), 4.44 (s, lH), 4.40 (s, 0.48H), 4.33-4.36 (m, lH), 4.04 (tJ =9.2 Hz, lH), 3.72-3.84 (m, 4H), 2.94 (t, J = 7.6, lH), 2.87 (dd, J = 17.6, 3.2 Hz, 0.51H), 2.77 (d, / = 10.0 Hz) , lH), 2.51 (ddJ=17.2Hz, 8.0Hz, 0.46H

Example 3 (R)-3-Amino-1-((6R,95)-3-methyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1,2, 4] Triazolo[4,3-a]azepine-10-indole)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate (compound 3 Preparation

Step 1: ((R)-4-carbonyl-4-((lS,5R)-2-thiocarbonyl-3,8-diazabicyclo[3.2.1]-8-octyl) small (2,4, tert-Butyl 5-trifluorophenyl)-2-butyl)carbamate (Compound 3a)

To (R) -3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butanoic acid (347 mg, 1.04 mmol) in 10 mL of dichloromethane was added diisopropylethylamine (diisopropylethylamine) 593 mg, 4.6 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg, 1.38 mmol), l-hydroxybenzotriazole (186 mg, 1.38 mmol), Stir at room temperature for 1 hour. Compound lj (150 mg) was then added to the reaction system and stirred at room temperature overnight. The reaction solution was washed with brine, dried and concentrated. The crude product was purified by silica gel column chromatography (dichloromethanol: EtOAc = EtOAc) MS (ESI) M/Z: 495 (M+H), 358 [(M+H)-Boc]. Step 2: ((R)-4-((6R,9S)-3-methyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine[1,2,4]3 Zoxao[4,3-a] azepine-10-yl)-4-yl-small (2,4,5-trifluorophenyl)-2-butyl)carbamic acid tert-butyl ester (compound 3b)

To a solution of the compound 3a (120 mg, 0.372 mmol) in 15 mL of n-butanol, acetohydrazide (82 mg, 1.1 mmol) and sodium acetate C 152 mg (1.86 mmol) were sequentially added and then refluxed for 18 hours. After the n-butanol was removed in vacuo, the residue was dissolved in dichloromethane (10 mL) and washed with brine. The organic phase was dried and concentrated to give a crude material. mjjjjjjjj

MS m / z (ESI): 480 (M + H) ⁺ , 380 [(M+H) + -Boc].

Step 3 (R ) -3-amino-1-(( 6R,9S ) -3-methyl-6,7,8,9-tetrahydro-5H-6,9-cyclic imine [1,2,4 Triazolo[4,3-a]azepine-10-alkyl)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate (compound 3)

Under ice-cooling, 3 mL of trifluoroacetic acid was added to compound 3b (80 mg, 0.15 mmol), and the mixture was stirred at room temperature for 30 minutes. After the trifluoroacetic acid was removed by distillation under reduced pressure, the residue was purified to purified crystals to afford compound 3 as a white solid.

MS (ESI) m/z: 380 (M+H); ¹ H NMR (400m, CD3OD): 57.36-7.29 (m, lH), 7.25-7.16 (m, lH), 5.82 (d, 0.5H), 5.52 (d, 0.5H), 5.16-5.14 (m, 0.5H), 4.32-4.27 (m, lH), 4.14-4.07 (m, lH), 3.91-3.86 (m, lH), 3. 09-3.02 ( m, 2H), 2.91-2.89 (m, lH), 2.69-2.56 (m, 4H), 2.52-2.50 (m, 0.5H), 2.47-2.26 (m, 1.5H), 2.17- 1.95 (m, 2H) ) o

Example 4 (R)-3-Amino-1-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, Preparation of 2,4]triazolo[4,3-a]azepine-10-indolyl-4-(2-methylphenyl)butanone trifluoroacetate (compound 4)

Step 1: ((R)-4-carbonyl-4-((lS,5R)-2-thiol-3,8-diazabicyclo[3.2.1]-8-octyl) small (2 -methylphenyl)-2-butyl)carbamic acid tert-butyl ester (compound 4a)

Add diisopropylethylamine to (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butanoic acid (74.22 mg, 0.25 mmol) in 5 mL of dichloromethane (89 mg, 0.69 mm _O l), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65.90 mg, 0.35 mmol), l-hydroxybenzotriazole (37.26 mg) , 0.28 mmol), stirred at room temperature for 0.5 hours. Compound lj (32.71 mg, 0.23 mmol) was then added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was added with 10 mL of saturated brine, and extracted with dichloromethane (15mIX3). The crude product was purified by silica gel column chromatography (dichloromethanol:methanol = 100:1) to afford compound 4a as a white solid (yield: 62%).

MS (ESI) M/Z: 418 (M+H), 372 (M-tBu).

Step 2: ((R)-4-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1,2,4 Triazolo[4,3-a]azepine-10-yl)-4-yl-1-(2-methylphenyl)-2-butyl)carbamic acid tert-butyl ester (compound 4b)

In a solution of compound 4a (60 mg, 0.14 mmol) in 3 mL of n-butanol, 2,2,2-trifluoroacetyl hydrazide was sequentially added.

(55.20 mg, 0.43 mmol) and sodium acetate (35 mg, 0.43 mol) then refluxed overnight. After reducing the pressure of n-butanol, The residue was taken up in ethyl acetate (5 mL). The organic phase was dried and concentrated to give a crystallite crystallite. MS (ESI) M/Z: 494 (M+H), 438 (M-tBu).

Step 3: (R)-3-Amino-1-((6R,95)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, 2,4] Triazolo[4,3-a]azepine-10-indole)-4-(2-methylphenyl)butanone trifluoroacetate (compound 4)

Under ice-cooling, 3 mL of trifluoroacetic acid was added to Compound 4b (23 mg, 0.046 mmol), and the mixture was stirred at room temperature for 30 min. After the trifluoroacetic acid was removed by distillation under reduced pressure, the residue was purified to crystals to afford compound 4 as a colorless oil (yield: 55%).

MS (ESI) M / Z: 394 (M + H); ¹ H NMR (400 Hz, CD ₃ OD): 57.21-7.10 (m, 4H), 5.86-5.84 (d, 0.5H), 5.5 0-5.48 (d , 0.5H), 5.11 (s, 0.5H), 4.80 (s, 0.5H), 4.40-4.22 (d, lH), 4.22-4.16 (t, lH), 3.87 (s, lH), 3.33-3.31 ( m, 3.6H), 2.82-2.76 (m, lH), 2.53-2.51 (d, 4H), 2.39-2.34 (m, 0.5H), 2.12 (s, 3 H), 2.07-2.05 (m, lH) .

Example 5 (R)-3-Amino-1-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, Preparation of 2,4]triazolo[4,3-a]azepine-10-indolyl-4-(2-fluorophenyl)butanone trifluoroacetate (compound 5)

Step 1: ((R)-4-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1,2,4 Triazolo[4,3-a]azepine-10-yl)-4-yl(t-fluorophenyl)-2-butyl)carbamic acid tert-butyl ester (compound 5a)

Add diisopropylethylamine to (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butanoic acid (50.97 mg, 0.17 mmol) in 5 mL of dichloromethane (60.31 mg, 0.47 mm _O l), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44.65 mg, 0.23 mmol), l-hydroxybenzotriazole (25.25) Mg, 0.18 mmol), stirred at room temperature for 0.5 hours. Compound lk (34.00 mg, 0.15 mmol) was then added to the reaction mixture and stirred at room temperature overnight. The reaction solution was added to 10 mL of saturated brine, and extracted with dichloromethane (15mIX3). The crude product was purified by silica gel column (dichlorodichlorobenzene:methanol = 100:1) to afford compound 5a as white solid (yield: 41.28%).

MS (ESI) M/Z: 495 (M+H), 442 (M-tBu).

Step 2: (R) -3-Amino-1-((6R,9S -3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1,2 , 4] triazolo[4,3-a]azepine-10-alkyl)-4-(2-fluorophenyl)butanone trifluoroacetate (compound 5)

To the compound 5a (32.00 mg, 0.064 mmol) was added 3 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 min. After the trifluoroacetic acid was removed by distillation under reduced pressure, the residue was purified to crystals to afford compound 5 as colorless oil (yield 40%).

MS (ESI) m / z: 398 (M+H); ¹ H NMR (400 Hz, CD ₃ OD): 57.38-7.24 (m, 2H), 7.20-7.11 (m, lH), 7.0 4-6.95 (t, lH), 5.84-5.82 (d, 0.5H), 5.51-5.48 (d, 0.5H), 4.42-4.36 (t, lH), 4.22-4.16 (t, lH), 3.90-3.80 (d, lH), 3.16-2.98 (m, 2H), 2.97-2.78 (m, 1.5H), 2.50-2.34 (m, 2.5H), 2.18-2.10 (m, lH), 2.07-1.92 (m, lH) Example 6 (R)-3-Amino-1-((6R,95)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, Preparation of 2,4]triazolo[4,-a]azepine--alkyl)-4-(3-chlorophenyl)butanone trifluoroacetate (compound 6)

Step 1: ((R)-4-Methyl-4-((lS,5R)-2-thiolcyl-3,8-diazabicyclo[3.2.1]-8-octyl) Small (3- Chlorophenyl)-2-butyl)carbamic acid tert-butyl ester (compound 6a)

Diethylethylamine was added to (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butanoic acid (69.03 mg, 0.22 mmol) in 5 mL of dichloromethane. (85.1413⁄4, 0.661^^1), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63.03 mg, 0.33 mmol), l-hydroxybenzotriazole (44.55) Mg, 0.33 mmol), stirred at room temperature for 0.5 hours. Then, the compound lj (31.29 mg, 0.22 mmol) was added to the reaction mixture, and stirred at room temperature overnight. The reaction solution was added with 10 mL of brine, and then evaporated, evaporated, The crude product was purified by silica gel column (dichloromethane:methanol = 100:1) to yield compound 6a, white solid 50mg, yield 52%.

MS (ESI) M/Z: 438 (M+H), 382 (M-tBu) o

Step 2: ((R)-4-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1,2,4 Triazolo[4,3-a]azepine-10-yl)-4-yl-small (3-chlorophenyl)-2-butyl)carbamic acid tert-butyl ester (compound 6b)

To a solution of the compound 6a (50 mg, 0.11 mmol) in 5 mL of n-butanol, 2,2,2-trifluoroacetylhydrazide (55.20 mg, 0.43 mmol) and sodium acetate (28 mg, 0.34 mol) were sequentially added, and then refluxed overnight. After the n-butanol was removed under reduced pressure, the residue was evaporated to mjjjjjjjjjjjjj The organic phase was dried and concentrated to give a crystallite crystallite crystallitelitelitelitelitelitelitelitelitelitelitelite MS (ESI) M/Z: 495 (M+H), 458 (M-tBu+l).

Step 3: (R)-3-Amino-1-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, 2,4]triazolo[4,3-a]azepine-10-mercapto)-4-(3-chlorophenyl)butanone trifluoroacetate (compound 6)

Under an ice bath, 3 mL of trifluoroacetic acid was added to the compound 6b (12 mg, 0.023 mmol), and the mixture was stirred at room temperature for 30 minutes. After the trifluoroacetic acid was removed by distillation under reduced pressure, the residue was purified to crystals to afford compound 6 as a colorless oil (yield: 83%).

MS (ESI) m / z: 414 (M + H); NMR (400 Hz, CD ₃ OD) 57.37-7.19 (d, 4H), 5.88-5.86 (d, 0.5H), 5.55-5 • 54 (d, 0.5H), 5.13(s,0.5H), 4.82(s,0.5H),4.44-4.36(t,lH),4.22-4.19(m,lH),3.90(s,lH),3.14-2.98(m , 3.5H), 2.56-2.18 (m, 1.5H), 2.14-2.0 (m, 2.5H), 1.96-1.94 (m, lH).

Example 7 (R)-3-Amino-1-C(6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, 2,4]triazolo[4,3-a]azepine-10-phenyl)-4-(2,5-difluorophenyl)butanone trifluoroacetate (compound 7) preparation

Teng%8 inch.

To a solution of the free amino compound 1 (10 mg, 0.023 mmol) in 1 mL of methanol, 0.11M hydrobromic acid (0.209 ml) water and methanol (methanol: water = 4:1) was added and stirred for 30 min. The compound 8a was obtained as a white solid (11.8 mg, yield: 100%).

MS (ESI) m/z: 434.13 (M+H); ¹ H NMR (400 Hz, CD ₃ OD) 57.39-7.09 (m, 2H), 5.87 (d, 0.5H), 5.59 (d, 0.5H), 5.12 -4.98(s, 0.5H), 4.51-4.40 (m, lH), 4.25-4.20 (m, lH), 3.09-2.92 (m, 4H), 2.60-2.54 (m, lH), 2.54 (m, l .5H), 2.17-2.12 (m, 2H).

Compound 8b

To a solution of the free amino compound 1 (10 mg, 0.023 mmol) in 1 mL of methanol, 0.11 M of acetic acid (0.209 ml) of water and a methanol solution (methanol: water = 4:1), stirred for 30 minutes, and concentrated to dryness Compound 8b, white solid 11.3 mg, yield 100%.

MS (ESI) m / z: 434.13 (M+H); ¹ H NMR (400 Hz, CD3OD) 57.30-7.06 (m, 2H), 5.83 (d, 0.5H), 5.54 (d, 0.5H), 5.09 (s) , 0.5H), 4.40-4.36 (m, lH), 4.22-4.16 (t, lH), 3.61-3.60 (m, lH), 2.93-2.70 (m, 4H), 2.47- 2.36 (m, 2.5H) , 2.14 - 2.04 (m, 2H), 1.91 (s, 3H).

Compound 8c

To a solution of the free amino compound 1 (10 mg, 0.023 mmol) in 1 mL of methanol, (2.67 mg, 0.023 mmol) of maleic acid was added, stirred for 30 minutes, and concentrated to dryness to give compound 8c as a white solid 13 mg, yield 100% .

MS (ESI) m/z: 434.13 (M+H); ¹ H NMR (400 Hz, CD ₃ OD): 57.23-7.00 (m, 2H), 6.17 (s, 2H), 5.75 (s, 0.5H), 5.43 (s, 0.5H), 5.00 (s, 0.5H), 4.76 (m, 0.5H), 4.35-4.20 (m, lH), 4.12-4.09 (m, lH), 3.75-3.71 (m, l H) , 2.97-2.78 (m, 3H), 2.44 - 2.27 (m, 2.5H), 2.12 - 2.04 (m, lH), 2.00-1.82 (m, 1.5H).

Compound 8d

(1. 7 mg, 0.023 mmol) of succinic acid was added to a solution of the free amino compound 1 (10 mg, 0.023 mmol) in 1 mL of methanol, stirred for 30 minutes, and concentrated to dryness to give compound 8d, white solid 12.6 mg, yield 100 %).

MS (ESI) m/z: 434.13 (M+H) ⁺ ; ¹ H NMR (400 Hz, CD ₃ OD): 57.35-7.10 (m, 2H), 5.86 (s, 0.5H), 5.55 (s, 0.5H) , 5.12-5.05 (m, lH), 4.46-4.39 (m, lH), 4.24-4.20 (m, lH), 3.84-3.78 (m, lH), 3.04-2.92 (m, 2.5 H), 2.84-2.81 (m, lH), 2.53-2.48 (m, 6H), 2.43-2.39 (m, lH), 2.28-2.22 (m, lH), 2.19-2.02 (m, lH), 1.95-

Compound 8e

(3.08 mg, 0.023 mmol) of malic acid was added to a solution of the free amino compound l (10 mg, 0.023 mmol) in 1 mL of methanol, stirred for 30 min, and concentrated to dryness to give compound 8e as a white solid (yield: 100%).

MS (ESI) m / z: 434.13 (M+H); ¹ H NMR (400 Hz, CD ₃ OD): 57.25-7.21 (m, lH), 7.11-7.09 (m, 0.5H), 7.01-6.98 (m, 0.5H), 5.74 (d, 0.5H), 5.43 (d, 0.5H), 5.01-4.99 (m, 0.5H), 4.32-4.24 (m, lH), 4.22-4.19 (m, lH), 4.11 4.08 (m, lH), 3.75-3.72 (m, lH), 3.25 (s, 0.5H), 2.96-2.85 (m, 2.5H), 2.76-2.66 (m, 2H), 2.4 8-2.38 (m, 2H), 2.31-2.24 (m, lH), 2.15-2..03 (m, 1 · 5 Η), 1.96-1.85 (m, 1.5H).

Compound 8f

To a solution of the free amino compound lC 10 mg, 0.023 mmol) in 1 mL of methanol, (3.45 mg, 0.023 mmol) of tartaric acid was added, and the mixture was stirred for 30 minutes, and concentrated to dryness to give compound 8f, white white solid (yield: 100%).

MS (ESI) m / z: 434.13 (M+H); ¹ H NMR (400 Hz, CD3OD) 57.15-7.05 (m, 2H), 5.82 (d, 0.5H), 5.53 (d, 0.5H), 5.09 (s) , 0.5H), 4.45-4.37 (m, 2.5H), 4.21-4.17 (m, lH), 3.82 (s, lH), 3.34 (m, lH), 3.07-2.85 (m, 4 H), 2.58- 2.52 (m, lH), 2.41-2.36 (m, lH), 2.35-1.92 (m, 3H). The beneficial effects of the present invention will be specifically described below by way of test examples.

Test example 1

DPP-4, DPP-2, DPP-8, and DPP-9 are members of the DPP family. Studies have shown that inhibition of other enzymes other than DPP-4 may cause side effects on the body, such as inhibition of DPP-8, DPP. When the -9 enzyme is active, it will cause a series of toxic side effects such as dormant T cell death, gastrointestinal toxicity and immune function. Therefore, in the development of DPP-4 (DPP-IV) enzyme inhibitor, it is required to increase the inhibitor pair. The selectivity of DPP-4, while reducing the selectivity to other DPP families, reduces the toxic side effects of the inhibitor. The present invention determines the inhibitory effect of the compound of the present invention on the DPP family by the following test.

In vitro activity detection of DPP-4, DPP-2 DPP-8, DPP-9

The test compound was dissolved in dimethyl sulfoxide, followed by a buffer solution (DPP4: 100 mM HEPES, pH 7.5, 0.1 mg/mL BSA; DPP2: 100 mM HEPES, pH 5. 5, 0.1 mg /mL BSA; DPP8: 50 mM Tris-HC1, pH 7.5, 0.1 mg/mL BSA; DPP9: 25 mM Tris-HCl, pH 7.5, 0.1 mg/mL BSA) A series of working solutions. Recombinant human DPP-4 (final concentration approximately 180 ng/mL) or DPP-2 (final concentration approximately 100 ng/mL) or DPP-8 (final concentration approximately 200 ng/mL) or DPP-9 (final Concentration of approximately 50 ng/mL) mixed with the above series of compound working solutions, then added to Gly-Pro-AMC (final concentration DPP4 is 50 μΜ, DPP2/8/9 is 20 μΜ) (total reaction volume is ΙΟΟμΐΛ immediately continuous The released AMC (excitation wavelength 360 nm, emission wavelength 460 nm) was detected for 15 minutes. The IC50 of the half inhibition concentration was calculated using SigmaPlot software, and the results are shown in the table below.

Table 1 Compound inhibition of DPP-4

Compound IC50 (ηΜ) Compound IC50 (nM)

Sitagliptin 14.2±0.7 8a 25±1

1 39.4±0.9 8b 15±1.2

Γ 29.7±1.2 8c 11.7±1.3

2 128.7±6.5 8d 12.7±0.9

3 32.4±1.7 8e 8.4±1.8

4 96.6±6.5 8f 17±0.5

5 108±1.7

6 31±0.8

7 57±1.2 Table 2 compounds inhibiting the DPP family

IC50

DPP-4(nM) ϋΡΡ-2(μΜ) ϋΡΡ-8(μΜ) ϋΡΡ-9(μΜ)

Sitagliptin 14.2±0.7 194±13 66±15 110±18

1 39.4±0.9 74.2±6.3 157±2.6 154±1.9

Γ 29.7±1.2 49.6±0.5 55.9±2.1 58.3±2.5

2 128.7 ± 6.5 > 100 > 100 > 100 The above results indicate that the compound of the present invention can effectively inhibit DPP-IV activity and has good selectivity to members of the DPP family, DPP-2, DPP-8, and DPP-9. These compounds can be used to treat a variety of DPP-4-related diseases such as diabetes, providing new options for clinical use.

Claims

Claim

1. A compound of the formula IA or formula IB or a pharmaceutically acceptable salt thereof,

(IA) (IB)

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized by:

In R ¹ , the substituent of the substituted phenyl group is 1 to 5 R ⁴ , wherein R ^{4 is} selected from the group consisting of CN, halogen, C1-6 alkyl or halogen-substituted alkyl, or C1-6 alkoxy Or a halogen-substituted alkoxy group;

In R ² , the substituent of the substituted alkyl group is selected from halogen, CN, OH, R ⁵ , OR ⁵ , NHS0 ₂ R ⁵ , S0 ₂ R ⁵ , COOH or C0 ₂ R ⁷ , substituted hetero atom or substituted hetero The substituent of the alkyl group is halogen, CN, OH, R ⁵ , OR ⁵ , NHS0 ₂ R ⁵ , S0 ₂ R ⁵ , COOH or C0 ₂ R ⁷ ;

In R ⁶ , the carboxyl group is COOH, and the ester group is C0 ₂ R ⁷ _;

Wherein the hetero atom is 0 or S; R ⁵ is a C1-6 alkyl or substituted alkyl group having a substituent of 1 to 5 halogens, COOH or C0 ₂ R ⁷ ;

R ⁷ is a C1-6 alkyl group.

The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from a halogen-substituted phenyl group; R ^{2 is} selected from a C1-3 alkyl group, a heteroalkyl group, Or 1-2 heteroatoms; R ^{3 is} selected from halogen substituted alkyl.

The compound according to any one of claims 1 to 3, wherein the heteroalkyl group is a C1-4 alkyl group having one hetero atom, or a pharmaceutically acceptable salt thereof.

The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the halogen is F or Cl.

The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is

(HA) (IIB) (IIIA), (II IB) wherein R ^{1 is} selected from halogen-substituted phenyl; R ^{3 is} selected from halogen-substituted alkyl; R ^{6 is} selected from H, CN, carboxyl or

The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ^{6 is} selected from C _{2 2} R ⁷ .

The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is:

The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride, a sulfate or a citrate of a compound. , besylate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, horse Acidate, tartrate or trifluoroacetate.

10. Use of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for the manufacture of a dipeptidyl peptidase-IV inhibitor.

The use according to claim 10, wherein the dipeptidyl peptidase-IV inhibitor is for treating or/preventing diabetes, hyperglycemia , insulin resistant drugs.

12. A process for the preparation of a compound of formula IIA or hydrazine according to claim 6 wherein: the reaction comprises the following:

Among them, Step l : (1S,5R 3,8-diazabicyclo[3.2.1]heptan-2-one as raw material, and di-tert-butyl dicarbonate are reacted under alkaline conditions to obtain a product The next reactant;

Step 2: The product obtained in the previous step is subjected to a thiolation reaction with a Lawson reagent to obtain a product which is left as a next reaction; Step 3: The product obtained in the previous step is added to a strong acid solution to obtain a product which is left as a next reaction. Step 4: reacting the product obtained in Step 3 with R ³ substituted formyl hydrazide under the action of activating reagent R ³ substituted sodium formate to obtain a product which is reserved for the next step;

Step 7: reacting the product obtained in Step 6 with R ³ substituted formyl hydrazide under the action of activating reagent R ³ substituted sodium formate to obtain a product which is reserved for the next step;

ΠΑ or ΠΒ.

13. A process for the preparation of a compound hydrazine or a hydrazine according to claim 12, wherein:

The solvent used in Step 1 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, ethyl acetate or tetrahydrofuran, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 2 to 18 hours;

The solvent used in Step 2 is a polar aprotic solvent, and the aprotic solvent is preferably tetrahydrofuran, diethyl ether, diisopropyl ether or toluene, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5-3 hours;

The strong acid used in Step 3 is a proton strong acid, and the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, the solvent used is preferably dichloromethane or ethyl acetate, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5 to 4 hours. ;

The solvent used in Step 5 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide, the base used is an organic base, and the organic base is preferably diisopropylethylamine. The condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, or 2-(7-azobenzotriazole) - Ν, Ν, Ν ', Ν '-tetramethyl urea hexafluorophosphate, the reaction temperature is 0 ° C to 30 ° C, the reaction time is 0.5 to 2 hours;

The solvent used in Step 6 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide, the base used is diisopropylethylamine or other organic base, and the condensing agent is 1_ (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole or 2-(7-azobenzotriazole)-Ν,Ν,Ν' , Ν'-tetramethylurea hexafluorophosphate, the reaction temperature used is 0 ° C to 30 ° C, the reaction time is 0.5 to 2 hours; The solvent used in Step 7 is a polar protic solvent, the polar protic solvent is preferably n-butanol, the reaction temperature ranges from 110 to 130 ° C, and the reaction time is 2-12 hours;

The acid used in Step 8 is a proton strong acid, and the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, the solvent used is preferably dichloromethane or ethyl acetate, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5 to 4 hours. .

A method of producing a ruthenium or osmium compound according to claim 6, wherein the reaction step is as follows:

Step 4: The product obtained in the previous step is deprotected by adding a strong acid solution to obtain a product which is reserved for the next step;

Step 7: The product obtained in the previous step is added to the Lawson reagent, and the reaction is carried out to obtain the product as the next reaction; Step 8: The product obtained in the previous step is added to the strongly acidic solution, and the reaction is carried out to obtain the product as the next step. Reactant

A process for the preparation of a compound hydrazine or a hydrazine according to claim 14, wherein:

The solvent used in Step 1 is a non-polar solvent, the non-polar solvent is preferably toluene or xylene, the Lewis acid is preferably boron trifluoride etherate, the reaction temperature is 20 to 30 ° C, and the reaction time is 0.5 to 2 Hour

The solvent used in Step 3 is a polar solvent, the polar solvent is preferably ethyl acetate or methanol, the catalyst used is a metal catalyst, the metal catalyst is preferably a palladium carbon catalyst, the reaction temperature is 20 to 30 ° C, and the reaction time is 2 to 4 hours;

The solvent used in Step 7 is a polar aprotic solvent, and the aprotic solvent is preferably tetrahydrofuran, diethyl ether or diisopropyl ether, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5-3 hours;

The solvent used in Step 9 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, N, N-dimethylformamide or tetrahydrofuran, the base used is diisopropylethylamine or other organic base, and the condensing agent is 1_ (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, or 2-(7-azobenzotriazole)-ruthenium, osmium, iridium ',Ν'-tetramethylurea hexafluorophosphate, the reaction temperature used is 0 ° C to 30 ° C, the reaction time is 0.5 to 2 hours;

The solvent used in Step 11 is a polar aprotic solvent, and the polar aprotic solvent is preferably dichloromethane or ethyl acetate. The acid used is a strong acid, preferably trifluoroacetic acid, and the reaction temperature is 0 ° C to 30 ° C. , the reaction time is 0.5 to 2 hours.

16. An intermediate of a compound of formula IA and IB according to claim 1 which has the formula:

Wherein R ² ' is selected from C1-5 alkyl or substituted alkyl; R ² " is selected from 1 to 5 heteroalkyl- or substituted heteroalkyl, 1-5 heteroatoms or substituted heteroatoms; ^{3 is} selected from H, CN, or Cl-10 alkyl or substituted alkyl; X is selected from N or CH; R ^{6 is} selected from H, CN, carboxyl or ester groups.

The intermediate according to claim 16, wherein: in R ² ', the substituent of the substituted alkyl group is selected from the group consisting of halogen, CN, OH, R ⁵ , OR ⁵ , NHS0 ₂ R ⁵ , S0 ₂ R ⁵ , COOH or C0 ₂ R ⁷ ; R ² , wherein the hetero atom is selected from N, S or 0, and the substituent which substitutes a hetero atom or a substituted heteroalkyl group is halogen, CN, 0H, R ⁵ , 0R ⁵ , NHS0 ₂ R ⁵ , S0 ₂ R ⁵ , COOH or C0 ₂ R ⁷ ;

Body, characterized in that: the intermediate is:

(IIAA), (IIBA), (quantity IIAA) or (IIIBA).

19. A process for the preparation of a ruthenium or osmium compound according to claim 18, wherein: the reaction step is as

ΠΑΑ

Among them, the following steps are included:

Step 2: The product obtained in the previous step is added to the Lawson reagent to obtain a product which is left as the next reactant; Step 3: The product obtained in the previous step is added to a strong acid solution to obtain a product which is reserved for the next step. Step 4: reacting the product obtained in the previous step, R ³ -substituted acetohydrazide with sodium acetate or R ³ -substituted sodium acetate to obtain a product which is left as the next reactant;

Alternatively, the starting material is replaced by (lR,5S)-3,8-diazabicyclo[3.2.1]heptan-2-one, and the compound oxime is prepared according to the above method; or, using the racemic starting material, After the above method is synthesized, the optical isomer is resolved to obtain the compound II AA or hydrazine.

A method of producing a ruthenium and osmium compound according to claim 18, wherein the reaction step is as follows:

The reaction process includes the following steps:

Step 7: The product obtained in the previous step is added to the Lawson reagent, and the reaction is carried out to obtain the product as the next reaction;

Step 8: The product obtained in the previous step is added with a strong acid, and the reaction is carried out to obtain the product as the next reaction; or, the starting material is replaced by (R)-l-p-nitrobenzyloxycarbonyl-2-aziridine. The methyl carboxylate is prepared by the above method to obtain the compound hydrazine; or, by using the racemic amino acid methyl ester, after synthesizing according to the above method, the optical isomer is resolved to obtain the compound hydrazine or hydrazine.