CN103172635B - Piperazine or piperidines, its salt, intermediate, preparation method and application - Google Patents

Abstract

The invention discloses piperazine or piperidine compounds or salts thereof. The invention also discloses the preparation of formula I: in a solvent, under the action of alkali, the formula II and R ₇ H are condensed at a temperature of 10°C to 30°C. The present invention also discloses the preparation of formula I salts: formula VII and formula I? When R ₃ ＝H, F or NO ₂ , formula II is subjected to amino protection reaction in sequence to obtain formula V, the above formula V is subjected to ester hydrolysis to obtain formula VI, the above formula VI is subjected to condensation reaction with R ₇ H to obtain formula VII and The above formula VII undergoes deprotection and salt formation; formula VIIR ₃ =NO ₂ and formula I? When R ₃ =NH ₂ , after the condensation, deprotection and salt formation include nitro group reduction. The invention also discloses the preparation method of the intermediate in the compound of formula I. The invention also discloses the intermediates in the method for preparing formula I. The piperazine or piperidine compounds and salts thereof of the present invention provide a new direction for the research and development of DPP-4 inhibitors, and are of great significance to the development of DPP-4 inhibitors.

Description

Piperazine or piperidine compound, its salt, intermediate, preparation method and application

technical field

The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to piperazine or piperidine compounds with novel structure and potential DPP-4 inhibitory activity, intermediates thereof, pharmaceutically acceptable salts thereof, preparation methods and applications thereof.

Background technique

Diabetes is a disease that seriously threatens human health. According to the World Health Organization, there are about 180 million diabetics in the world, 90% of whom are type 2 diabetics, and this number is expected to double by 2030. At present, the treatment of type 2 diabetes is mainly based on small molecule oral drugs. Sulfonylureas, glinides, biguanides and thiazolidinediones are commonly used drugs for the treatment of type 2 diabetes, but long-term use of these hypoglycemic drugs can lead to Adverse reactions such as hypoglycemia, weight gain, and β-cell function damage occurred in patients. The discovery of DPP-4 inhibitors can effectively avoid the deficiency of traditional oral hypoglycemic drugs, and DPP-4 is generally considered to be the most promising new target for the treatment of type 2 diabetes.

DPP-4, also known as CD26, was isolated from rat liver for the first time in 1966, and its three-dimensional protein structure was determined in 2003. DPP-4 is a highly specific serine protease in dimer form, and its natural substrate is pancreatic Glucagon-like peptide-1 (GLP-1) and glucose insulinotropic polypeptide (GIP). GLP-1 has the functions of promoting insulin secretion in a glucose-dependent manner, inhibiting the secretion of glucagon, promoting the regeneration and repair of pancreatic β cells, and delaying postprandial gastric emptying. GIP also has the function of stimulating insulin secretion. DPP-4 can rapidly degrade GLP-1 and GIP in the body to inactivate them. DPP-4 inhibitors reduce the catalytic activity of the enzyme by competitively binding to the DPP-4 activation site, thereby increasing the amount of GLP-1 and GIP in the body to promote insulin secretion. DPP-4 inhibitors can stably control blood sugar, improve β-cell function, and will not cause weight gain in patients, and can avoid the risk of hypoglycemia. They have significant advantages in drug safety and are a promising class of drugs.

Since the report of the crystal structure of DPP-4 in 2003, many DPP-4 inhibitors with new structure types, potency and high selectivity have been listed successively in recent years, such as sitagliptin phosphate (sitagliptinphosphate, 2006) developed by Merck. It was listed in the United States in October), Vildagliptin (vildagliptin, approved by the European Commission in September 2007) researched and developed by Novartis, and saxagliptin (saxagliptin, 2009) jointly developed by Bristol-Myers Squibb and AstraZeneca In August 2010, the U.S. FDA approved for marketing), Takeda’s alogliptin benzoate (alogliptinbenzoate, listed in Japan in April 2010) and BoehringerIngeheim’s Linagliptin (BI-1356, listed in the United States in May 2011).

At present, DPP-4 inhibitors containing aminocycloalkane or piperazine fragments have become a new direction for the development of hypoglycemic drugs. Therefore, the study of compounds with novel structures, piperidine or piperazine fragments is of great significance for the development of potential DPP-4 inhibitors.

Contents of the invention

The technical problem to be solved by the present invention is to provide a piperazine or piperidine compound, its salt, intermediate, preparation method and application. The piperazine or piperidine compounds and salts thereof of the present invention provide a new direction for the research and development of DPP-4 inhibitors, and are of great significance to the development of potential DPP-4 inhibitors.

The present invention provides a piperazine or piperidine compound or salt thereof as shown in formula I,

Formula I

Among them, X is C or N;

R ₁ and R ₅ are independently H, F or NO ₂ (preferably R ₁ and R ₅ wherein one is H or F, and the other is H, F or NO ₂ );

R ₂ and R ₄ are independently H or F;

R ₃ is H, F, NO ₂ or NH ₂ ;

R ₆ is H or NH ₂ ;

R ₇ is 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetra Hydrogen-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4, 3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3 , 1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^{3 ,7} ]decyl)ethylamino, 4-hydroxytricyclo[ ^3,3,1,13,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoro Pyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino.

Said salt is preferably hydrochloride, hydrobromide, sulfate, nitrate or phosphate, more preferably hydrochloride.

The compound of formula I is preferably

X=N, R ₁ =R ₄ =R ₆ =H, R ₂ =R ₃ =R ₅ =F and R ₇ =5,6,7,8-tetrahydro-[1,2,4]triazole[ 4,3-a]pyrazinyl (I-2), 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyridine Azinyl (I-1), 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl (I-3), 3 -Ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl (I-4), tricyclo[3,3,1,1 ^3,7 ] decane amino (I-5), 3-hydroxy tricyclo [3,3,1,1 ^3,7 ] decane-1-amino (I-6), 1-(tricyclo [3, 3,1,1 ^3,7 ]decyl)ethylamino (I-7), 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-amino (I-8), pyridine-2-methylamino, 6-fluoropyridine-3-amino (I-9), 1-oxopyridine-2-amino, 2-cyanopyrrolyl (I-11) or 1 -(1-ethyl-2-pyrrolyl)methylamino (I-10);

or X=N, R2= _R3 =R6=H, R1 _{= NO2} , _R4 = _R5 =F and _R7 = _{5,6,7,8 -} tetrahydro-[1,2,4 ]triazol[4,3-a]pyrazinyl (I-13), 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3 -a]pyrazinyl (I-12), 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl (I- 14), 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl (I-15), tricyclo[3,3 , 1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^{3 ,7} ]decyl)ethylamino (I-16), 4-hydroxytricyclo[ ^3,3,1,13,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methyl Amino, 6-fluoropyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino;

or X=C, R ₁ =R ₂ =F, R ₃ =NO ₂ , R ₄ =R ₅ =H, R ₆ =NH ₂ and R ₇ =5,6,7,8-tetrahydro-[1, 2,4]triazol[4,3-a]pyrazinyl (I-18), 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[ 4,3-a]pyrazinyl (I-17), 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl (I-19), 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl (I-20), tricyclo[ 3,3,1,1 ^3,7 ]decane-1-amino (I-21), 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino (I-22), 1 -(tricyclo[3,3,1,1 ^3,7 ]decane)ethylamino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino(I-23 ), pyridine-2-amino, pyridine-2-methylamino (I-24), 6-fluoropyridine-3-amino, 1-oxopyridine-2-amino (I-25), 2-cyanopyrrolyl Or 1-(1-ethyl-2-pyrrolyl)methylamino;

or X=C, R ₁ =R ₂ =F, R ₃ =NH ₂ , R ₄ =R ₅ =H, R ₆ =NH ₂ and R ₇ =5,6,7,8-tetrahydro-[1, 2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a ]pyrazinyl (I-26), 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl (I-27) , 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl (I-28), tricyclo[3,3,1 , 1 ^3,7 ]decane-1-amino (I-29), 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino (I-30), 1-(tricyclo[ 3,3,1,1 ^3,7 ]decyl)ethylamino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino (I-31), pyridine-2 -amino(I-34), pyridine-2-methylamino(I-32), 6-fluoropyridine-3-amino, 1-oxopyridine-2-amino(I-33), 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino.

The compound of formula I is more preferably

X=N, R ₁ =R ₄ =R ₆ =H, R ₂ =R ₃ =R ₅ =F and R ₇ =5,6,7,8-tetrahydro-[1,2,4]triazole[ 4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3- Methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro- [1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1, 1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^3,7 ]decyl)ethylamino, pyridine-2-amino, 6-fluoropyridine-3-amino , 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino;

or X=N, R2= _R3 =R6=H, R1 _{= NO2} , _R4 = _R5 =F and _R7 = _{5,6,7,8 -} tetrahydro-[1,2,4 ]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine Base, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8 -tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl or 1-(tricyclo[ ^3,3,1,13,7 ]decyl)ethylamino;

or X=C, R ₁ =R ₂ =F, R ₃ =NO ₂ , R ₄ =R ₅ =H, R ₆ =NH ₂ and R ₇ =5,6,7,8-tetrahydro-[1, 2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a ]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6, 7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[ ^3,3,1,13,7 ]decaneamino, 3-hydroxytricyclic [3,3,1,1 ^3,7 ]decane-1-amino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-methylamino or 1-oxopyridin-2-amino;

or X=C, R1 ₌ R2=F, _R3 = _NH2 , R4= _R5 =H, R6= _NH2 and _R7 = _{3 -} trifluoromethyl _- 5,6,7,8 -tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[ 4,3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3 ,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 4-hydroxytricyclo[3,3,1, 1 ^3,7 ] Decane-1-amino, pyridine-2-amino, pyridine-2-methylamino or 1-oxopyridin-2-amino.

The present invention also provides a preparation method of piperazine or piperidine compound (formula I), which comprises the following steps: in a solvent, under the action of a base, the compound of formula II is condensed with R ₇ H, and the reaction temperature is 10 ℃ ~ 30 ℃, it can be;

Formula II Formula I

Among them, X is N;

R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F, NO ₂ or NH ₂ ;

R ₆ is H or NH ₂ ;

Y is Cl;

R ₇ is 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetra Hydrogen-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4, 3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3 , 1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^{3 ,7} ]decyl)ethylamino, 4-hydroxytricyclo[ ^3,3,1,13,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoro Pyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino.

The R ₁ is preferably H or NO ₂ , R ₂ is preferably H or F, R ₃ is preferably H or F, R ₄ is preferably H or F, R ₅ is preferably F, R ₆ is preferably H, R ₇ is preferably 5, 6, 7 , 8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4 ]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-Ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3,1,1 ^3,7 ] Decane amino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^3,7 ]decyl)ethyl Amino, pyridine-2-amino, 6-fluoropyridin-3-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino.

The compound of formula II is preferably

X=N, R ₁ =R ₄ =R ₆ =H, R ₂ =R ₃ =R ₅ =F and R ₇ =5,6,7,8-tetrahydro-[1,2,4]triazole[ 4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3- Methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro- [1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1, 1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^3,7 ]decyl)ethylamino, 4-hydroxytricyclo[3,3,1,1 ^{3 , 7} ] Decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoropyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1 -(1-ethyl-2-pyrrolyl)methylamino;

or X=N, R2= _R3 =R6=H, R1 _{= NO2} , _R4 = _R5 =F and _R7 = _{5,6,7,8 -} tetrahydro-[1,2,4 ]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine Base, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8 -tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[ ^3,3,1,13,7 ]decaneamino, 3-hydroxytricyclo[3, 3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^3,7 ]decyl)ethylamino, 4-hydroxytricyclo[3,3, 1,1 ^3,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoropyridine-3-amino, 1-oxopyridine-2-amino, 2-cyano pyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino.

The compound of formula II is more preferably

X=N, R ₁ =R ₄ =R ₆ =H, R ₂ =R ₃ =R ₅ =F and R ₇ =5,6,7,8-tetrahydro-[1,2,4]triazole[ 4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3- Methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro- [1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1, 1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^3,7 ]decyl)ethylamino, pyridine-2-amino, 6-fluoropyridine-3-amino , 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino;

or X=N, R2= _R3 =R6=H, R1 _{= NO2} , _R4 = _R5 =F and _R7 = _{5,6,7,8 -} tetrahydro-[1,2,4 ]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine Base, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8 - tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl or 1-(tricyclo[ ^3,3,1,13,7 ]decyl)ethylamino.

The condensation reaction may be a conventional condensation reaction in the art. The present invention particularly preferably following reaction condition:

The condensation reaction preferably includes the following steps: mixing the solution of the compound of formula II with R ₇ H and a base to carry out the condensation reaction at a reaction temperature of 10°C to 30°C. The solvent is preferably one or more of dichloromethane, tetrahydrofuran and acetonitrile, more preferably dichloromethane; the amount of the solvent is preferably 10-50mL/g formula II compound, more preferably 20-40mL/g formula II II compound. The base is preferably pyridine, triethylamine or 1,8-diazabicyclic-bicyclic (5,4,0)-7-undecene (DBU for short), more preferably triethylamine or DBU; The molar ratio of the base to the compound of formula II is preferably 1.0 to 3.0:1, more preferably 1.2:1. The molar ratio of the compound of formula II to R ₇ H is preferably 1:1-2, more preferably 1:1. The reaction temperature of the condensation reaction is preferably 15°C to 25°C. The reaction progress of the condensation reaction can be monitored by HPLC or TLC. Generally, the disappearance of the compound of formula II is used as the reaction end point, preferably 18h-25h, more preferably 15h-25h. The post-treatment method of the condensation reaction preferably includes the following steps: mixing the reaction system with saturated aqueous sodium bicarbonate solution, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, suction filtering, concentrating, and purifying by column chromatography , that is, the eluent used in the column chromatography is petroleum ether: ethyl acetate=1:1; the method of the column chromatography can be selected according to the conventional method of column chromatography in the art.

The compound of formula I can also be reacted with an acid to prepare a salt of the compound of formula I above. The acid may be a conventional acid in the art, preferably hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, more preferably hydrochloric acid.

The compound of formula II can be prepared by the following method: acylating the compound of formula III with an acylating agent under the action of a base in a solvent at a reaction temperature of -20°C to 10°C;

Formula III Formula II

Among them, X is N;

R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F, NO ₂ or NH ₂ ;

R ₆ is H or NH ₂ ;

Y is Cl.

The R ₁ is preferably H or NO ₂ , R ₂ is preferably H or F, R ₃ is preferably H or F, R ₄ is preferably H or F, R ₅ is preferably F, and R ₆ is preferably H. The compound of formula III is preferably R ₁ =R ₄ =R ₆ =H and R ₂ =R ₃ =R ₅ =F; or R ₂ =R ₃ =R ₆ =H, R ₁ =NO ₂ and R ₄ = R ₅ =F.

The acylation reaction may be a conventional acylation reaction in the art. The present invention preferably following reaction conditions:

The acylation reaction preferably includes the following steps: at -20°C to 10°C, mix the solution of the acylating reagent with the solution of the base and the compound of formula III to carry out the acylation reaction. The acylation reaction more preferably includes the following steps: at -5°C to 0°C, the solution of the base and the compound of formula III is added dropwise into the solution of the acylating reagent to carry out the acylation reaction.

The solvent is preferably one or more of methylene chloride, tetrahydrofuran and acetonitrile, more preferably methylene chloride; the amount of the solvent is preferably 10-50mL/g compound of formula III, more preferably 20mL/g compound of formula III . The base is preferably pyridine or triethylamine, more preferably pyridine; the molar ratio of the base to the compound of formula III is preferably 1-3:1, more preferably 1.2:1. The acylating agent is preferably phosgene or triphosgene (BTC for short), more preferably triphosgene; the molar ratio of the acylating agent to the compound of formula III is preferably 0.3-3:1, more preferably 0.4:1. The reaction temperature of the acylation reaction is preferably -10°C to 0°C, more preferably -5°C to 0°C. The reaction progress of the acylation reaction can be monitored by TLC, and generally the end point of the reaction is when the compound of formula III disappears, preferably 0.5h-3h, more preferably 1h.

The present invention also provides a kind of preparation method of the salt of piperazine or piperidine compound, it comprises the following steps:

When R ₃ in the compound of formula VII and formula I = H, F or NO ₂ , the compound of formula H is subjected to an amino protection reaction to obtain the compound of formula V, and the compound of formula V is subjected to ester hydrolysis reaction to obtain the compound of formula VI, and the compound of formula V is obtained by subjecting the compound of formula V to Compound VI is condensed with R ₇ H to obtain a compound of formula VII, and the compound of formula VII is subjected to deprotection and salt-forming reaction to obtain a salt of a compound of formula I;

When R ₃ =NO ₂ in the compound of formula VII and R ₃ =NH ₂ in the compound of formula I, after the condensation reaction, the nitro reduction reaction is also included before the deprotection and salt-forming reaction, and the compound of formula VII The R3 is reduced to amino;

Among them, X=C;

R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₆ is NH ₂ ;

Y is _{OC2H5 ;}

R ₇ is 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetra Hydrogen-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4, 3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3 , 1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^{3 ,7} ]decyl)ethylamino, 4-hydroxytricyclo[ ^3,3,1,13,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoro Pyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino.

The R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, R ₅ is preferably H, R ₇ is preferably 5,6,7,8-tetrahydro-[1,2,4] Triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl , 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8- Tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3 , 1,1 ^3,7 ]decane-1-amino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-methylamino or 1-oxo Pyridine-2-amino.

The compound of formula II is preferably R ₁ =R ₂ =F, R ₃ =NO ₂ , R ₄ =R ₅ =H and R ₇ =5,6,7,8-tetrahydro-[1,2,4] Triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl , 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8- Tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3 , 1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^3,7 ]decyl)ethylamino, 4-hydroxytricyclo[3,3,1 , 1 3, ⁷ ] Decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoropyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrole Base or 1-(1-ethyl-2-pyrrolyl)methylamino;

The compound of formula II is more preferably R ₁ =R ₂ =F, R ₃ =NO ₂ , R ₄ =R ₅ =H and R ₇ =5,6,7,8-tetrahydro-[1,2,4 ]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine Base, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8 -tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[ ^3,3,1,13,7 ]decaneamino, 3-hydroxytricyclo[3, 3,1,1 ^3,7 ]decane-1-amino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-methylamino, 1-oxo Substituted pyridine-2-amino.

The compound of formula II can be prepared by the above-mentioned method for preparing the compound of formula II.

The amino protection reaction, ester hydrolysis reaction, condensation reaction and deprotection and salt formation reaction can be conventional amino protection reaction, ester hydrolysis reaction, condensation reaction and deprotection and salt formation reaction in the art. The present invention particularly preferably following reaction conditions:

The amino protection reaction preferably includes the following steps: in a solvent, under the action of a base, carry out an amino protection reaction with the compound of formula II and an amino protection reagent, and the reaction temperature is 10°C to 30°C. The amino protection reaction more preferably includes the following steps: after mixing the solution of the compound of formula II with a base, carry out an amino protection reaction with an amino protection reagent at a reaction temperature of 10°C to 30°C.

In the amino protection reaction, the solvent is preferably one or more of ethyl acetate, dichloromethane and tetrahydrofuran, more preferably dichloromethane, and the amount of the solvent is preferably 10 mL/g of the compound of formula II. Described base is preferably one or more in pyridine, diisopropylethylamine and triethylamine, more preferably triethylamine; The molar ratio of described base and formula II compound is preferably 1～2: 1, more preferably 1.2:1 is preferred. The amino-protecting reagent is preferably benzyl chloroformate or di-tert-butyl dicarbonate, more preferably di-tert-butyl dicarbonate; the molar ratio of the amino-protecting reagent to the compound of formula II is preferably 1 to 2:1, more preferably 1.2:1. The reaction temperature of the amino protection reaction is preferably 15°C to 25°C. The reaction progress of the amino protection reaction can be monitored by TLC or HPLC, and the end point of the reaction is generally when the compound of formula II disappears, preferably 1 h to 5 h, more preferably 3 h. The post-treatment method of the amino protection reaction preferably includes the following steps: decompressing to remove the solvent, and purifying by column chromatography; the eluent used in the column chromatography is preferably petroleum ether: ethyl acetate=2 : 1.

The ester hydrolysis reaction preferably includes the following steps: in a solvent, under the action of a base, the compound of formula V is subjected to an ester hydrolysis reaction, then acidified to pH = 3 to 4, and the reaction temperature is 10°C to 30°C, that is Can. The ester hydrolysis reaction more preferably includes the following steps: mixing the solution of the compound of formula V with a base, performing ester hydrolysis reaction, acidifying to pH=3-4, and the reaction temperature is 10°C-30°C.

In the described ester hydrolysis reaction, the solvent is preferably one or more of water, acetonitrile, ethanol and tetrahydrofuran, more preferably tetrahydrofuran: water=1:1 (V/V); the amount of the solvent is preferably 20 mL/g compound of formula V. Described alkali is preferably one or more in sodium hydroxide, sodium carbonate and potassium hydroxide, more preferably sodium hydroxide; The molar ratio of described alkali and formula V compound is preferably 1～10:1, more preferably 3 : 1. Described acid is preferably one or more in sulfuric acid, hydrochloric acid and phosphoric acid, more preferably hydrochloric acid; Described acid preferably participates in reaction with the form of aqueous solution; The concentration of the aqueous solution of described acid is preferably 1～12mol/L, more preferably Preferably 6mol/L. The reaction temperature of the ester hydrolysis reaction is preferably 10°C to 30°C. The reaction process of the ester hydrolysis reaction can be monitored by TLC or HPLC, and the end point of the reaction is generally when the compound of formula V disappears, preferably 0.5h to 5h, more preferably 2h. The post-treatment method of the ester hydrolysis reaction preferably includes the following steps: extract the reaction system with dichloromethane, dry the organic phase with anhydrous sodium sulfate, suction filter, and concentrate.

The condensation reaction preferably includes the following steps: in a solvent, under the action of a condensation reagent, conduct a condensation reaction between the compound of formula VI and R ₇ H at a reaction temperature of 0°C to 50°C. The condensation reaction more preferably includes the following steps: mixing the solution of the compound of formula VI and R ₇ H with a condensation reagent to carry out the condensation reaction at a reaction temperature of 10°C to 40°C. The condensation reaction most preferably includes the following steps: mixing a solution of the compound of formula VI and R ₇ H with a condensation reagent, and reacting at 10°C to 30°C for 1 to 24 hours.

In the condensation reaction, the solvent is preferably one or more of dichloromethane, ethyl acetate, tetrahydrofuran and N,N-dimethylformamide, more preferably N,N-dimethylformamide ; The preferred amount of the solvent is 10mL/g formula VI compound. The condensation reagent is preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (abbreviated as HATU), benzotriazole-N , N, N', N'-tetramethyluronium hexafluorophosphate (referred to as HBTU), 1-hydroxybenzotriazole (referred to as HOBt)/1-ethyl-(3-dimethylaminopropyl) carbon Imide hydrochloride (abbreviated as EDC·HCl), dicyclohexylcarbodiimide (abbreviated as DCC), Carter condensing agent (abbreviated as BOP-reagent) and 1H-benzotriazol-1-yloxytripyrrolidine One or more of base hexafluorophosphate (abbreviated as PyBOP), preferably HATU and/or HOBt/EDC HCl; the molar ratio of the condensation reagent to the compound of formula VI is preferably 1 to 2:1, more preferably 1.14 : 1. The reaction temperature of the condensation reaction is preferably 10°C to 30°C. The reaction progress of the condensation reaction can be monitored by TLC or HPLC, and generally the end point of the reaction is when the compound of formula VI disappears, preferably 10h-25h, more preferably 12h-20h. The post-treatment method of the described condensation reaction preferably comprises the following steps: the reaction system is mixed with water and an organic solvent, the organic phase is washed three times with water successively, and the saturated sodium carbonate aqueous solution is washed three times, the organic phase is dried with anhydrous sodium sulfate, pumped Filter, concentrate, get final product; The preferred ethyl acetate or dichloromethane of described organic solvent; After described water washing, also can wash with saturated sodium chloride aqueous solution before washing with saturated sodium carbonate aqueous solution; Described water and ethyl acetate The volume ratio of the water and the solvent in the condensation reaction is preferably 1:1; the volume ratio of the water and the condensation reaction is preferably 1:1.

The deprotection and salt-forming reaction preferably include the following steps: deprotecting and salt-forming the compound of formula VII in an acidic C ₁ -C ₄ alcohol solution, and the reaction temperature is 10°C-30°C. .

In the deprotection and salt-forming reaction, the acid is preferably hydrochloric acid; the C ₁ -C ₄ alcohol is preferably methanol and/or ethanol, more preferably methanol; the C ₁ -C ₄ alcohol of the acid The concentration of the alcohol solution is preferably 2 mol/L-10 mol/L, more preferably 2 mol/L-3 mol/L; the amount of the C ₁ -C ₄ alcohol solution of the acid is preferably 10 mL/g of the compound of formula VII. The reaction temperature of the deprotection and salt formation reaction is preferably 15°C to 25°C. The reaction progress of the deprotection and salt-forming reaction can be monitored by HPLC or TLC, and generally the end point of the reaction is when the compound of formula VII disappears, preferably 1h-5h, more preferably 1h-2h. The post-treatment method of the deprotection and salt formation reaction preferably includes the following steps: distilling off the solvent under reduced pressure, recrystallizing with a mixed solution of methanol and isopropanol or methanol and ether, and suction filtration.

The nitro reduction reaction can be a conventional nitro reduction reaction in the art. The present invention particularly preferably following condition:

The nitro reduction reaction preferably includes the following steps: in a solvent, under the action of a catalyst, the compound of formula VII and a reducing agent are subjected to a nitro reduction reaction. The nitro group reduction reaction more preferably includes the following steps: mixing the solution of the compound of formula VII with a catalyst, and then mixing it with a reducing agent to carry out the nitro group reduction reaction.

In the nitro reduction reaction, the solvent is preferably ethanol and/or methanol, more preferably methanol; the amount of the solvent used is preferably 10 mL/g of the compound of formula VII. The preferred palladium-carbon (Pd/C) of the catalyst; the preferred mass fraction of palladium in the described palladium-carbon is 10%; the mass ratio of the catalyst to the compound of formula VII is preferably 1～3:10, more preferably 1: 10. The reducing agent is preferably ammonium formate or hydrogen; the molar ratio of the reducing agent to the compound of formula VII is preferably 1-10:1, more preferably 3:1. When the reducing agent is ammonium formate, the reaction temperature of the nitro reduction reaction is preferably 20°C to 70°C, more preferably 55°C to 65°C; when the reducing agent is hydrogen, the reaction temperature of the nitro reduction reaction Preferably 20°C to 80°C, more preferably 70°C (external temperature). The reaction process of the nitro reduction reaction can be monitored by TLC or HPLC, and the end point of the reaction is generally when the compound of formula VII disappears, preferably 2h-40h, more preferably 3h-30h. The post-treatment method of the nitro reduction reaction preferably includes the following steps: distilling off the solvent under reduced pressure, dissolving in ethyl acetate, washing with water three times, drying the organic phase with anhydrous sodium sulfate, suction filtering, and concentrating.

The salt of the compound of formula I can be further reacted with a base to prepare the compound of formula I. The base can be a conventional base in the art. The conditions of the reaction can be selected according to the conventional acid-base neutralization reaction conditions in the art.

The compound of formula II can be prepared by the following method: reducing the compound of formula IV with a reducing agent in a solvent, and the reaction temperature is 0°C to 50°C;

Formula IV Formula II

Among them, X is C;

R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F or NO ₂ ;

R ₆ is NH ₂ ;

_Y is _OC2H5 .

Said R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, and R ₅ is preferably H. The compound of formula IV is preferably R ₁ =R ₂ =F, R ₃ =NO ₂ and R ₄ =R ₅ =H.

The reduction reaction can be a conventional reduction reaction in the art. The present invention particularly preferably following reaction condition:

The reduction reaction preferably includes the following steps: mixing the solution of the compound of formula IV with a reducing agent at 0° C. to 50° C. to carry out the reduction reaction.

Described solvent is preferably one or more in methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and acetonitrile, more preferably 1,2-dichloroethane and/or acetonitrile; The amount of said solvent is preferably 5-20mL/g compound of formula IV, more preferably 8mL/g compound of formula IV. The reducing agent is preferably sodium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride, more preferably sodium triacetoxy borohydride or sodium borohydride; the molar ratio of the reducing agent to the compound of formula IV Preferably 1-5:1, more preferably 3:1. The reaction temperature of the reduction reaction is preferably 10°C to 20°C. The reaction progress of the reduction reaction can be monitored by HPLC or TLC, generally the end point of the reaction is when the compound of formula IV disappears, preferably 12h-16h, more preferably 14h. The post-treatment method of the reduction reaction preferably includes the following steps: mixing the reaction system with aqueous hydrochloric acid, stirring, separating the water phase, mixing it with dichloromethane, and adjusting the pH of the system to 8-9 with alkali, The organic phase was separated, washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered with suction, and concentrated; the concentration of the aqueous hydrochloric acid solution was 2 mol/L. The volume ratio of the hydrochloric acid to the solvent in the reduction reaction is preferably 1 to 3:1, more preferably 1:1; the volume ratio of the dichloromethane to hydrochloric acid is preferably 1 to 3:1, more preferably 1:1; Described base is preferably inorganic bases such as anhydrous sodium carbonate or anhydrous potassium carbonate, more preferably anhydrous sodium carbonate.

The compound of formula IV can be prepared by the following method: in a solvent, the compound of formula IX and ammonium acetate are subjected to enamination reaction;

Wherein, R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F or NO ₂ .

Said R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, and R ₅ is preferably H. The compound of formula IX is preferably R ₁ =R ₂ =F, R ₃ =NO ₂ and R ₄ =R ₅ =H.

The ene amination reaction can be a conventional ene amination reaction in the art, and the following reaction conditions are particularly preferred in the present invention:

The enamination reaction preferably includes the following steps: mixing the solution of the compound of formula IX with ammonium acetate, and carrying out the enamination reaction.

The solvent is preferably one or more of isopropanol, ethanol and methanol, more preferably methanol; the amount of the solvent is preferably 10 mL/g of the compound of formula IX. The molar ratio of the ammonium acetate to the compound of formula IX is preferably 1-5:1, more preferably 3:1. The reaction temperature of the ene amination reaction is preferably 20°C to 80°C, more preferably 50°C to 70°C. The reaction progress of the ene amination reaction can be monitored by TLC or HPLC, and generally the end point of the reaction is when the compound of formula IX disappears, preferably 3h. The aftertreatment method of described ene amination reaction preferably comprises the following steps: evaporate the solvent under reduced pressure, add ethyl acetate to dissolve, and wash the organic phase with saturated sodium carbonate aqueous solution 3 times successively, and wash the organic phase with saturated sodium chloride aqueous solution for 1 Once, the organic phases were combined, dried with anhydrous sodium sulfate, filtered with suction, and concentrated.

The compound of formula IX can be prepared by the following method: under the protection of an inert gas, in a solvent, under the action of a base, the compound of formula XII is subjected to nucleophilic substitution with 4-ethoxycarbonylpiperidin-3-one hydrochloride Reaction, the reaction temperature is -20°C ~ 30°C;

Wherein, R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F or NO ₂ .

Said R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, and R ₅ is preferably H. The compound of formula XII is preferably R ₁ =R ₂ =F, R ₃ =NO ₂ and R ₄ =R ₅ =H.

The nucleophilic substitution reaction may be a conventional nucleophilic substitution reaction in the art. The present invention particularly preferably following reaction condition:

The nucleophilic substitution reaction preferably comprises the following steps: under the protection of an inert gas, after mixing the solution of 4-ethoxycarbonylpiperidin-3-one hydrochloride with a base, mixing with the compound of formula XII to carry out the nucleophilic substitution reaction, The reaction temperature is -20°C to 30°C. The nucleophilic substitution reaction more preferably includes the following steps: under the protection of an inert gas, mix the solution of 4-ethoxycarbonylpiperidin-3-one hydrochloride with a base at -15°C to -5°C for 10min to 20min , at -10°C to 0°C, dropwise add the compound of formula XII to carry out nucleophilic substitution reaction.

The solvent is preferably toluene, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, acetone, alcohols with 1 to 4 carbons, N, N-dimethylformamide, dimethylsulfoxide and N-methylpyrrolidone One or more of them, more preferably N-methylpyrrolidone; the amount of said solvent is preferably 8mL/g compound of formula XII. The base is preferably triethylamine, pyridine, diisopropylethylamine or DBU, more preferably diisopropylethylamine; the molar ratio of the base to the compound of formula XII is preferably 1 to 5:1, more preferably 2.1 : 1. The molar ratio of the compound of formula XII to 4-ethoxycarbonylpiperidin-3-one hydrochloride is preferably 1:1-3, more preferably 1:1.1. The inert gas is preferably nitrogen. The reaction temperature of the nucleophilic substitution reaction is preferably -10°C to 25°C. The reaction progress of the nucleophilic substitution reaction can be monitored by HPLC or TLC, and the end point of the reaction is generally when the compound of formula XII disappears, preferably 4h-6h. The post-treatment method of the nucleophilic substitution reaction preferably includes the following steps: mixing the reaction system with ice water, suction filtration, washing the filter cake with water and petroleum ether successively, and drying; the drying temperature is preferably 50℃～65℃.

The present invention also provides a method for preparing intermediate II of piperazine or piperidine compounds or their salts, which is prepared by any of the following methods,

Method 1: In a solvent, under the action of a base, the compound of formula III is acylated with an acylating agent, and the reaction temperature is -20°C to 10°C;

Formula III Formula II

Among them, X is N;

R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F, NO ₂ or NH ₂ ;

R ₆ is H or NH ₂ ;

Y is Cl;

Method 2: In a solvent, the compound of formula IV is subjected to a reduction reaction with a reducing agent, and the reaction temperature is 0°C to 50°C;

Formula IV Formula II

Among them, X is C;

R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F or NO ₂ ;

R ₆ is NH ₂ ;

Y is _{OC2H5 ;}

The reaction conditions are the same as the reaction conditions in the preparation method of the compound of formula II above.

The present invention also provides intermediates of piperazine or piperidine compounds or salts thereof as shown in formula II, formula IX, formula IV, formula V, formula VI or formula VII,

Formula II

Wherein, Y is Cl or OC ₂ H ₅ ;

X is C or N;

R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F, NO ₂ or NH ₂ ;

R ₆ is H or NH ₂ ;

Formula IX

Wherein, R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F or NO ₂ ;

Formula IV

Wherein, R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F or NO ₂ ;

Formula V

Wherein, R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F or NO ₂ ;

Formula VI

Wherein, R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F or NO ₂ ;

Formula VII

Wherein, R ₁ and R ₅ are independently H, F or NO ₂ ;

R ₂ and R ₄ are independently H or F;

R ₃ is H, F or NO ₂ ;

R ₇ is 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetra Hydrogen-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4, 3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3 , 1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^{3 ,7} ]decyl)ethylamino, 4-hydroxytricyclo[ ^3,3,1,13,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoro Pyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino.

In the compound of formula II, when X=N, said R ₁ is preferably H or NO ₂ , R ₂ is preferably H or F, R ₃ is preferably H or F, R ₄ is preferably H or F, R ₅ is preferably F, R ₆ H is preferred, and Y is preferably Cl. When X=C, said R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, R ₅ is preferably H, R ₆ is preferably NH ₂ , and Y is preferably OC ₂ H ₅ .

The compound of formula II is preferably X=N, R ₁ =R ₄ =R ₆ =H, R ₂ =R ₃ =R ₅ =F and Y=Cl;

or X=N, R2= _{R3 =} R6=H, R1 _{= NO2} , _R4 = _R5 =F and Y= _Cl ;

Or X=C, R ₁ =R ₂ =F, R ₃ =NO ₂ , R ₄ =R ₅ =H and Y=OC ₂ H ₅ .

In the compound of formula IX, said R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, and R ₅ is preferably H. The compound of formula IX is preferably R ₁ =F, R ₂ =F, R ₃ =NO ₂ , R ₄ =H and R ₅ =H.

In the compound of formula IV, said R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, and R ₅ is preferably H. The compound of formula IV is preferably R ₁ =F, R ₂ =F, R ₃ =NO ₂ , R ₄ =H and R ₅ =H.

In the compound of formula V, said R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, and R ₅ is preferably H. The compound of formula V is preferably R ₁ =F, R ₂ =F, R ₃ =NO ₂ , R ₄ =H and R ₅ =H.

In the compound of formula VI, said R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, and R ₅ is preferably H. The compound of formula VI is preferably R ₁ =F, R ₂ =F, R ₃ =NO ₂ , R ₄ =H and R ₅ =H.

In the compound of formula VII, said R ₁ is preferably F, R ₂ is preferably F, R ₃ is preferably NO ₂ , R ₄ is preferably H, R ₅ is preferably H, R ₇ is preferably 5,6,7,8-tetrahydro-[1 ,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3- a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6 , 7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[ ^3,3,1,13,7 ]decaneamino, 3-hydroxytri Cyclo[3,3,1,1 ^3,7 ]decane-1-amino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-methylamino or 1-oxopyridin-2-amino.

The compound of formula VII is preferably R ₁ =F, R ₂ =F, R ₃ =NO ₂ , R ₄ =H, R ₅ =H and R ₇ =5,6,7,8-tetrahydro-[1, 2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a ]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6, 7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[ ^3,3,1,13,7 ]decaneamino, 3-hydroxytricyclic [3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^3,7 ]decyl)ethylamino, 4-hydroxytricyclo[3 , 3,1,1 ^3,7 ] Decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoropyridine-3-amino, 1-oxopyridine-2-amino, 2 - cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino;

The compound of formula VII is more preferably R ₁ =F, R ₂ =F, R ₃ =NO ₂ , R ₄ =H, R ₅ =H and R ₇ =5,6,7,8-tetrahydro-[1 ,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3- a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6 , 7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[ ^3,3,1,13,7 ]decaneamino, 3-hydroxytri Cyclo[3,3,1,1 ^3,7 ]decane-1-amino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-methylamino or 1-oxopyridin-2-amino.

The present invention also provides the above-mentioned piperazine or aminopiperidine compounds, their pharmaceutically acceptable salts, optical isomers or polymorphs used for the treatment and/or prevention of diabetes, hyperglycemia and insulin resistance application in medicine.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive and progressive effect of the present invention is that the piperazine or piperidine compounds and their salts of the present invention provide a new direction for the research and development of DPP-4 inhibitors, and are of great significance to the development of potential DPP-4 inhibitors.

detailed description

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

In the following examples, undefined abbreviations have their generally accepted meanings, and unless otherwise stated, all room temperature refers to a temperature of 20°C to 30°C. Table 1, Table 2, Table 3 and Table 4 are the physical and chemical data of compounds I-1 ~ I-11, the physical and chemical data of compounds I-12 ~ I-16, the physical and chemical data of compounds I-17 ~ I-25 and the compound Physical and chemical data of I-26~I-34.

Method Example 1

Synthesis of 1-chloroformyl-4-(2,4,5-trifluorophenyl)piperazine(II)

Dissolve triphosgene (254mg, 0.9mmol) in 10ml of dichloromethane, cool in an ice-salt bath, lower the internal temperature to -5°C to 0°C, slowly add pyridine (219mg, 2.8mmol) and 1-(2, 4,5-Trifluorophenyl)piperazine (500mg, 2.3mmol) in dichloromethane solution, the temperature was controlled below 0°C, the addition was completed in 10 minutes, and the reaction was maintained at 0°C for 1h, the TLC raw material disappeared completely, due to the activity of the acid chloride Higher, difficult to separate II put into the next reaction in the form of crude product.

Method Example 2

Synthesis of 1-chloroformyl-4-(2,4,5-trifluorophenyl)piperazine(II)

Pour excess phosgene into 10ml of dichloromethane, cool in an ice-salt bath, lower the internal temperature to -5°C to 0°C, slowly add triethylamine (282mg, 2.8mmol) and 1-(2,4, 5-Trifluorophenyl)piperazine (500mg, 2.3mmol) in dichloromethane solution, temperature control below 0°C, 10min to complete the addition, maintained at 0°C for 1h, the TLC raw material completely disappeared, due to the high activity of acid chloride , it is not easy to separate II into the next reaction in the form of crude product.

Method Example 3

(4-(2,4,5-trifluorophenyl)-1-piperazinyl)(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazol[4,3 Synthesis of -a]-7(8H)-pyrazinyl)methanone (I-1)

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine (444mg, 2.3mmol) and Triethylamine (273 mg, 2.7 mmol), the reaction temperature was raised to room temperature, and stirred for 20 h. Add 20ml of saturated sodium bicarbonate solution to terminate the reaction, extract with dichloromethane (20ml×2), combine the organic phases, dry over anhydrous sodium sulfate, filter with suction, concentrate, and perform column chromatography (petroleum ether: ethyl acetate = 1:1) 575 mg of white powdery solid was obtained, and the two-step yield was 57.2%.

The synthesis method of I-2～I-10 is the same as that of I-1; I-11 is obtained by the condensation reaction between the acylated product and prolinamide, and finally the amide is dehydrated with acetic anhydride; I-6 and I-7 are obtained through condensation DBU is used as a base during the reaction; I-10 is an oily substance, which can be easily preserved by salting it with hydrochloric acid.

Method Example 4

(4-(2,3-difluoro-6-nitrophenyl)-1-piperazinyl)(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazole[ Synthesis of 4,3-a]-7(8H)-pyrazinyl)methanone (I-12)

Anhydrous piperazine (0.535g, 6.2mmol) was dissolved in 10ml of toluene, 2,3,4-trifluoronitrobenzene (1.000g, 5.6mmol) was added dropwise with stirring, and stirred at room temperature for 1h. Add 15ml of 2mol/L HCl aqueous solution, stir for 30min, wash the aqueous phase with toluene three times, separate the aqueous phase, add an appropriate amount of dichloromethane, stir, adjust the pH to 8-9 with anhydrous sodium carbonate, separate the dichloromethane layer, wash once with water, organic The phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated to obtain 1.013 g of crude 1-(2,3-difluoro-6-nitrophenyl)piperazine as an orange-yellow oil, with a crude yield of 73.8%.

Dissolve bis(trichloromethyl)carbonate (BTC for short) (495 mg, 1.7 mmol) in 10 ml of dichloromethane, cool in an ice-salt bath to lower the internal temperature to -5°C to 0°C, and slowly add pyridine dropwise ( 725mg, 9.2mmol) and 1-(2,3-difluoro-6-nitrophenyl)piperazine crude product (1.013g, 4.2mmol) mixture, the temperature was controlled below 0°C, the addition was completed in 10min, and maintained at React at 0°C for 1 h, and proceed directly to the next step.

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine (800mg, 4.2mmol) and Triethylamine (842 mg, 8.4 mmol), the temperature of the reaction system was raised to room temperature, and stirred for 20 h. Add 20ml of saturated sodium bicarbonate solution to terminate the reaction, extract with dichloromethane (20ml×2), combine the organic phases, dry over anhydrous sodium sulfate, filter with suction, concentrate, and perform column chromatography (petroleum ether:ethyl acetate=3:2) 1.254 g of yellow solid was obtained, and the three-step yield was 48.1%.

The synthesis method of I-13～I-16 is the same as that of I-12.

Method Example 5

(4-(2,3-difluoro-6-nitrophenyl)-1-piperazinyl)(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazole[ Synthesis of 4,3-a]-7(8H)-pyrazinyl)methanone (I-12)

Anhydrous piperazine (0.535g, 6.2mmol) was dissolved in 10ml of N,N-dimethylformamide, and 2,3,4-trifluoronitrobenzene (1.000g, 5.6mmol) and triethylamine (0.566 g, 5.6mmol), stirred at room temperature for 1h. Add 15ml of 2mol/L HCl aqueous solution, stir for 30min, wash the aqueous phase with ethyl acetate three times, separate the aqueous phase, add an appropriate amount of dichloromethane, stir, adjust the pH to 8-9 with anhydrous sodium carbonate, separate the dichloromethane layer, and wash the organic phase with water Three times, the organic phase was dried with anhydrous sodium sulfate, suction filtered, and concentrated to obtain 1.213 g of crude orange-yellow oil 1-(2,3-difluoro-6-nitrophenyl)piperazine, and the crude yield was 89.2%.

Pour excess phosgene into 10ml of dichloromethane, cool in an ice-salt bath, lower the internal temperature to -5°C to 0°C, slowly add pyridine (725mg, 9.2mmol) and 1-(2,3-difluoro- The mixed solution of crude 6-nitrophenyl)piperazine (1.213g, 5.0mmol) was controlled at a temperature below 0°C, and the addition was completed within 10 minutes. The reaction was maintained at 0°C for 1 hour, and the next reaction was carried out directly.

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine (800mg, 4.2mmol) and Triethylamine (842 mg, 8.4 mmol), the temperature of the reaction system was raised to room temperature, and stirred for 20 h. Add 20ml of saturated sodium bicarbonate solution to terminate the reaction, extract with dichloromethane (20ml×2), combine the organic phases, dry over anhydrous sodium sulfate, filter with suction, concentrate, and perform column chromatography (petroleum ether:ethyl acetate=3:2) 1.345 g of yellow solid was obtained, and the three-step yield was 52.1%.

Method Example 6

Synthesis of 1-(2,3-difluoro-4-nitrophenyl)-4-ethoxycarbonylpiperidin-3-one (IX)

4-Ethoxycarbonylpiperidin-3-one hydrochloride (50.000g, 0.24lmol) was dissolved in 400ml of N-methylpyrrolidone, cooled in an ice-salt bath, cooled to -10°C, and diisopropylethyl was added under nitrogen protection Amine (59.300g, 0.460mol), stirred for 15min, and added dropwise 2,3,4-trifluoronitrobenzene (38.800g, 0.219mol) at about -5°C under temperature control, and reacted at 0°C for 2h after the addition was completed. Stirring was continued at room temperature for 2 h. The reaction solution was poured into 2L of ice water, a brownish-yellow solid was precipitated, filtered with suction, the filter cake was washed with a large amount of water and petroleum ether, and the dried brownish-yellow solid was 59.310g, and the yield of the crude product was 82.5%. mp: 117-120°C, ¹ H-NMR (CDCl ₃ ), δ (ppm): 7.88-7.83 (m, 1H, J=9.6, 7.6, 2.2), 6.67-6.63 (m, 1H, J=9.6, 8.0, 2.0), 4.26(q, 2H, J=6.8), 3.97(s, 2H), 3.54(t, 2H, J=4.8), 2.51-2.49(m, 2H), 1.33(t, 3H, J = 6.8).

Method Example 7

Synthesis of 1-(2,3-difluoro-4-nitrophenyl)-4-ethoxycarbonylpiperidin-3-one (IX)

4-Ethoxycarbonylpiperidin-3-one hydrochloride (50.000g, 0.241mol) was dissolved in 400ml of ethanol, cooled in an ice-salt bath, cooled to -10°C, and triethylamine (51.060g, 0.460 mol), stirred for 15 min, and added dropwise 2,3,4-trifluoronitrobenzene (38.800 g, 0.219 mol) at about -5 °C under temperature control, reacted at 0 °C for 2 h after the addition was completed, and continued to stir at room temperature for 2 h. The reaction solution was poured into 2L of ice water to precipitate a brownish yellow solid, which was filtered with suction, and the filter cake was washed with a large amount of water and petroleum ether. The dried brownish yellow solid was 60.110g, and the yield of the crude product was 83.6%.

Method Example 8

Synthesis of 1-(2,3-difluoro-4-nitrophenyl)-3-amino-4-ethoxycarbonyl-1,2,5,6-tetrahydropyridine (IV)

The IX crude product (59.310 g, 0.181 mol) was dissolved in 600 ml of methanol, and ammonium acetate (41.770 g, 0.542 mol) was added to reflux for 3 h. Evaporate the solvent under reduced pressure, add 1L ethyl acetate to dissolve, wash the organic phase with saturated sodium carbonate solution (500ml×3), wash once with 800ml saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, filter with suction, and concentrate to obtain The orange-red solid crude product was 60.400 g, and the yield of the crude product was about 100%. mp: 106-110°C, ¹ H-NMR (CDCl ₃ ), δ (ppm): 7.88-7.84 (m, 1H), 6.69-6.64 (m, 1H), 4.20 (q, 2H, J=6.4), 3.99 (s, 2H), 3.57-3.54 (t, 2H, J=5.6), 2.52 (t, 2H, J=5.2), 1.37-1.28 (m, 3H).

Method Example 9

Synthesis of 1-(2,3-difluoro-4-nitrophenyl)-3-amino-4-ethoxycarbonylpiperidine (II)

Cool 500ml of glacial acetic acid in an ice-water bath to 10°C-20°C, add sodium borohydride (20.9g, 0.550mol) in batches, control the temperature at 10-20°C, and stir for 1h to prepare sodium triacetoxyborohydride. Add 60.400 g of the crude IV above and 500 ml of 1,2-dichloroethane, and stir at room temperature for 14 h. Add 400ml of 2mol/L HCl aqueous solution, stir at room temperature for 1h, separate the aqueous phase, then add 500ml of dichloromethane and alkalinize the pH8-9 with anhydrous sodium carbonate, separate the organic phase, wash the organic phase with saturated aqueous sodium chloride solution, and wash with anhydrous sulfuric acid Dry over sodium, filter with suction, and concentrate to obtain 46.700 g of a yellow solid, with a crude yield of 77.3%. mp: 87-90°C. ¹ H-NMR (CDCl ₃ ), δ (ppm): 7.86-7.81 (m, 1H), 6.75-6.70 (m, 1H), 4.22 (q, 2H, J=6.4), 3.70-3.52 (m, 2H ), 3.52 (m, 1H), 3.19-2.98 (m, 2H), 2.71-2.66 (m, 1H), 2.23-1.94 (m, 2H), 1.31 (t, 3H, J=6.4).

Method Example 10

Synthesis of 1-(2,3-difluoro-4-nitrophenyl)-3-amino-4-ethoxycarbonylpiperidine (II)

60.400 g of the crude IV above was dissolved in 500 ml of acetonitrile, sodium borohydride (20.9 g, 0.550 mol) was added in batches, the temperature was controlled at about 0°C, and after the addition was completed, the temperature was raised to room temperature and stirred for 14 h. Add 400ml of 2mol/L HCl aqueous solution, stir at room temperature for 1h, separate the aqueous phase, then add 500ml of dichloromethane and alkalinize the pH8-9 with anhydrous sodium carbonate, separate the organic phase, wash the organic phase with saturated aqueous sodium chloride solution, and wash with anhydrous sulfuric acid Dry over sodium, filter with suction, and concentrate to obtain 46.700 g of a yellow solid, with a crude yield of 77.3%. mp: 87-90°C. ¹ H-NMR (CDCl ₃ ), δ (ppm): 7.86-7.81 (m, 1H), 6.75-6.70 (m, 1H), 4.22 (q, 2H, J=6.4), 3.70-3.52 (m, 2H ), 3.52 (m, 1H), 3.19-2.98 (m, 2H), 2.71-2.66 (m, 1H), 2.23-1.94 (m, 2H), 1.31 (t, 3H, J=6.4).

Method Example 11

Synthesis of 1-(2,3-difluoro-4-nitrophenyl)-3-tert-butoxycarbonylamino-4-ethoxycarbonylpiperidine (V)

The above crude product II (46.700g, 0.142mol) was dissolved in 500ml of dichloromethane, triethylamine (17.170g, 0.170mol) was added, and finally di-tert-butyl dicarbonate (37.133g, 0.170mol) was added, and stirred at room temperature for 3h. The solvent was distilled off under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 2:1) gave 54.751 g of a yellow solid. The total yield of the four steps of nucleophilic substitution, ene amination, reduction and amino protection was 58.2%. mp: 126-129°C. ¹ H-NMR (CDCl ₃ ), δ (ppm): 7.87-7.83 (m, 1H), 6.76-6.71 (m, 1H), 5.26 (s, 1H), 4.30-4.19 (m, 3H), 3.67- 3.47(m, 2H), 3.26-3.15(m, 2H), 2.85-2.81(m, 1H), 2.20-1.96(m, 2H), 1.58-1.44(m, 9H), 1.33-1.29(m, 3H ).

Method Example 12

Synthesis of 1-(2,3-difluoro-4-nitrophenyl)-3-tert-butoxycarbonylamino-4-carboxylic acid piperidine (VI)

V (26.504g, 0.062mol) was dissolved in 520ml of tetrahydrofuran/water (V/V=1:1), solid sodium hydroxide (7.414g, 0.185mol) was added, and stirred at room temperature for 2h. The 6mol/L HCl aqueous solution was acidified to pH 3-4, extracted with dichloromethane (100ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction and concentrated to give 24.200g of a light yellow solid with a yield of 97.6%. mp: 188-191°C. ¹ H-NMR (DMSO), δ (ppm): 7.89-7.84 (m, 1H), 6.94-6.90 (m, 1H), 6.60-6.59 (m, 1H), 4.07 (m, 1H), 3.83-3.41 (m, 2H), 3.15-3.01 (m, 2H), 2.81-2.77 (m, 1H), 2.10-1.72 (m, 2H), 1.32 (s, 9H).

Method Example 13

(3-amino-1-(2,3-difluoro-4-nitrophenyl)-4-piperidinyl)(3-trifluoromethyl-5,6-dihydro-[1,2,4 Synthesis of ]triazol[4,3-a]-7(8H)-pyrazinyl)methanone hydrochloride (I-17)

VI (2.0g, 5.0mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine (0.912g , 4.7mmol) was dissolved in 20ml of anhydrous N,N-dimethylformamide, HOBt (0.770g, 5.7mmol) and EDC·HCl (1.092g, 5.7mmol) were added, and stirred at room temperature for 20h. After the reaction, 20ml of water and 20ml of ethyl acetate were added, the organic phase was washed 3 times with water and saturated aqueous sodium carbonate solution 3 times, the organic phase was dried with anhydrous sodium sulfate, suction filtered and concentrated to obtain 2.967g of a yellow foamy solid, and the yield of the crude product was > 100%, recrystallized from ethyl acetate, suction filtered, and dried to obtain 1.827 g of a yellow solid, with a recrystallization yield of 63.6%. ¹ H-NMR (CDCl ₃ +D ₂ O), δ (ppm): 7.89-7.84 (m, 1H), 6.77-6.73 (m, 1H), 5.29-5.00 (m, 2H), 4.57-4.11 (m , 5H), 3.68-3.65 (m, 2H), 3.22-3.03 (m, 3H), 2.43-1.81 (m, 2H), 1.37 (s, 9H).

The yellow solid (1.000g, 1.7mmol) obtained above was dissolved in 10ml 2-3mol/LHCl/MeOH, stirred at room temperature for 1h, the solvent was evaporated under reduced pressure, recrystallized from methanol/isopropanol, and 0.503g of yellow solid was obtained by suction filtration, recrystallized Yield 56.5%.

Take 100 mg of the above-mentioned yellow solid pure product, put it in 5 ml of dichloromethane and 5 ml of saturated aqueous sodium hydroxide solution, stir for 1 hour, separate the organic phase, extract the water phase with dichloromethane twice, combine the organic phases, and dry over anhydrous sodium sulfate The organic phase was suction filtered and concentrated to obtain 85 mg of the free base of compound I-1 as a yellow oil. Since the free base is an oil, it is not conducive to preservation. saved in the form.

The synthesis method of I-18～I-24 is the same as that of I-17. I-25 uses HATU as the condensation agent and DIEA as the base.

Method Example 14

(3-amino-1-(4-amino-2,3-difluorophenyl)-4-piperidinyl)(3-trifluoromethyl-5,6-dihydro-[1,2,4] Synthesis of triazol[4,3-a]-7(8H)-pyrazinyl)methanone hydrochloride (I-26)

VI (2.0g, 5.0mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine (0.912g , 4.7mmol) was dissolved in 20ml of anhydrous N,N-dimethylformamide, HOBt (0.770g, 5.7mmol) and EDC·HCL (1.092g, 5.7mmol) were added, and stirred at room temperature for 20h. After the reaction, 20ml of water and 20ml of ethyl acetate were added, the organic phase was washed 3 times with water and saturated aqueous sodium carbonate solution 3 times, the organic phase was dried with anhydrous sodium sulfate, suction filtered and concentrated to obtain 2.967g of a yellow foamy solid. The yield of the crude product was > 100%, recrystallized from ethyl acetate, suction filtered, and dried to obtain 1.827 g of a yellow solid, with a recrystallization yield of 63.6%.

The above yellow solid (1.827g, 3.2mmol) was dissolved in 20ml of methanol, 182mg of 10% Pd/C and ammonium formate (0.605g, 9.6mmol) were added, and refluxed for 3h. Evaporate the solvent under reduced pressure, dissolve in 20ml of ethyl acetate, wash the organic phase 3 times with water, dry the organic phase with anhydrous sodium sulfate, suction filter and concentrate to obtain 1.700 g of a purple foamy solid crude product, which is directly carried out to the next step reaction. 1.700 g of the crude purple foamy solid was dissolved in 17 ml of 2-3 mol/L HCl/MeOH, and stirred at room temperature for 1 h. Methanol/ether crystallization gave 1.261 g of lavender solid, with a two-step yield of 76.6%.

Compounds I-27～I-32 are synthesized in the same way as above.

Method Example 15

Synthesis of 2-(3-amino-1-(2,3-difluoro-4-aminophenyl)-4-piperidinecarboxamido)-1-oxopyridine hydrochloride (I-33)

VI (0.900g, 2.2mmol) was dissolved in 10ml of anhydrous N,N-dimethylformamide, DIEA (1.419g, 11mmol), 1-oxo-2-aminopyridine hydrochloride (0.352g, 2.4mmol) and HATU (0.988g, 2.6mmol), first reacted at 0°C for 2h, then rose to room temperature for 10h. Add water and dichloromethane, wash the organic phase with water, wash with saturated sodium chloride, and wash with saturated sodium carbonate, dry the organic phase with anhydrous sodium sulfate, filter with suction, and concentrate to obtain 1.311 g of a yellow solid crude product, which is recrystallized from ethyl acetate to obtain 0.798 g , The recrystallization yield was 72.2%. The above yellow solid (0.798 g, 1.6 mmol) was dissolved in 40 ml of methanol, 80 mg of 10% Pd/C was added, hydrogenated by hydrogen at normal pressure, and stirred for 6 h. Suction filtration and evaporation of the solvent under reduced pressure gave 0.786 g of a gray crude product, which was directly carried out to the next reaction. 0.786 g of the gray crude product was dissolved in 7 ml of 2-3 mol/L HCl/MeOH, stirred for 1 h, the solvent was evaporated under reduced pressure, and recrystallized from methanol/ether to obtain 0.413 mg of a gray solid, the two-step yield was 58.5%.

Method Example 16

Synthesis of 2-(3-amino-1-(2,3-difluoro-4-aminophenyl)-4-piperidinecarboxamido)pyridine hydrochloride (I-34)

VI (2.000g, 5.0mmol) was dissolved in 20ml of anhydrous N, N-dimethylformamide, DIEA (3.225g, 25mmol), 1-oxo-2-aminopyridine hydrochloride (0.803g, 5.5mmol) and HATU (2.280g, 6.0mmol), first reacted at 0°C for 2h, then rose to room temperature for 10h. Add water and dichloromethane, wash the organic phase with water, saturated sodium chloride, and saturated sodium carbonate, dry the organic phase with anhydrous sodium sulfate, filter with suction, and concentrate to obtain 2.800 g of a yellow solid crude product, which is recrystallized from ethyl acetate to obtain 2.007 g , The recrystallization yield was 81.6%. The above yellow solid (0.500 g, 1.0 mmol) was dissolved in 20 ml of ethanol, 0.050 g of 10% Pd/C was added, hydrogenated under pressure (1 MPa), and stirred at external temperature (70° C.) for 30 h. Suction filtration and evaporation of the solvent under reduced pressure gave 0.463 g of a gray crude product, which was directly carried out to the next reaction. 0.463 g of the gray crude product was dissolved in 5 ml of 2-3 mol/L HCl/MeOH, stirred for 2 h, the solvent was evaporated under reduced pressure, and 0.297 g of the gray solid was crystallized from methanol/ether, the two-step yield was 69.7%.

Effect example

Some piperazine or 3-aminopiperidine compounds were tested for DPP-4 enzyme inhibition in vitro

The DPP-4 enzyme activity assay method is a chromogenic method using glycylproline p-nitroanilide (Gly-Pro-p-nitroanilide) as a substrate. Under alkaline conditions, DPP-4 catalyzes the hydrolysis of the substrate Gly-Pro-p-nitroanilide to generate glycylproline and yellow p-nitroaniline, which has a characteristic absorption peak at a wavelength of 405nm. The absorption value measured by a spectrophotometer or a microplate reader at 405nm, that is, the amount of chromophore PNA generated reflects the activity of the enzyme, and the reaction formula is as follows.

The amount of DPP-4 enzyme required to hydrolyze 1 μmol of Gly-Pro-p-nitroanilide in one minute is defined as 1U. In the DPP-4 enzyme activity assay system (substrate 0.4mM, appropriate amount of DPP-4, buffer 50mM Tris-HCl, pH8.3) Add various inhibitors at different concentrations, react at 37°C for one hour, measure the absorbance at 405nm with a spectrophotometer or a microplate reader, and then convert the absorbance at 405nm according to the Beer-Bouguer law into p -production of nitroaniline. For a certain inhibitor, the amount of inhibitor required to inhibit 1U of enzyme activity is defined as a unit of inhibitory activity to evaluate the activity of various inhibitors.

The screening of inhibitor is to form enzyme activity assay system with a certain amount of enzyme, add the various inhibitors of different amounts and blank control, show by table 5 data, some compounds in the present invention have certain DPP-4 inhibitory activity, to In the future, the development of DPP-4 inhibitors with a new structure and structural modification will play a guiding role.

Table 5. Preliminary inhibitory activity experiments of some compounds (100 μg/ml) on DPP-4

compound Inhibition rate(%) I-17 38.0 I-18 23.8 I-19 94.7 I-20 50.3 I-22 14.7 I-24 98.7 I-29 11.9

Claims (15)

1. A piperazine or piperidine compound or a salt thereof, characterized in that: its structure is as shown in formula I: Among them, X is C or N; R ₁ and R ₅ are independently H, F or NO ₂ ; R ₂ and R ₄ are independently H or F; R ₃ is H, F, NO ₂ or NH ₂ ; R ₆ is H or NH ₂ ; R ₇ is 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetra Hydrogen-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4, 3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3 ,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^{3 ,7} ]decyl)ethylamino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoro Pyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino. 2. piperazine or piperidine compound or its salt as claimed in claim 1, is characterized in that: X=N, R ₁ =R ₄ =R ₆ =H, R ₂ =R ₃ =R ₅ =F and R ₇ =5,6,7,8-tetrahydro-[1,2,4]triazole[ 4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3- Methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro- [1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1, 1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^3,7 ]decyl)ethylamino, pyridine-2-amino, 6-fluoropyridine-3-amino , 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino; or X=N, R2= _R3 =R6=H, R1 _{= NO2} , _R4 = _R5 =F and _R7 = _{5,6,7,8 -} tetrahydro-[1,2,4 ]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine Base, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6,7,8 -tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl or 1-(tricyclo[3,3,1,1 ^3,7 ]decyl)ethylamino; or X=C, R ₁ =R ₂ =F, R ₃ =NO ₂ , R ₄ =R ₅ =H, R ₆ =NH ₂ and R ₇ =5,6,7,8-tetrahydro-[1, 2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a ]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6, 7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclic [3,3,1,1 ^3,7 ]decane-1-amino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-methylamino or 1-oxopyridin-2-amino; or X=C, R ₁ =R ₂ =F, R ₃ =NH ₂ , R ₄ =R ₅ =H, R ₆ =NH ₂ and R ₇ =3-trifluoromethyl-5,6,7,8 -tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[ 4,3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3 ,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 4-hydroxytricyclo[3,3,1, 1 ^3,7 ] Decane-1-amino, pyridine-2-amino, pyridine-2-methylamino or 1-oxopyridin-2-amino. 3. The piperazine or piperidine compound or its salt as claimed in claim 1 or 2, characterized in that: said salt is hydrochloride, hydrobromide, sulfate, nitrate or phosphate. 4. A preparation method of a piperazine compound as shown in formula I, characterized in that it comprises the following steps: in a solvent, under the action of a base, the compound of formula II is condensed with R ₇ H, and the reaction temperature is 10 ℃ ~ 30 ℃, can; Among them, X is N; R ₁ and R ₅ are independently H, F or NO ₂ ; R ₂ and R ₄ are independently H or F; R ₃ is H, F, NO ₂ or NH ₂ ; R ₆ is H or NH ₂ ; Y is Cl; R ₇ is 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetra Hydrogen-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4, 3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3 ,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^{3 ,7} ]decyl)ethylamino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoro Pyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino; The base is pyridine, triethylamine or 1,8-diazabicyclo-bicyclo(5,4,0)-7-undecene. 5. The preparation method as claimed in claim 4, characterized in that: said compound of formula II is prepared by the following method: in a solvent, under the action of a base, the compound of formula III is subjected to an acylation reaction with an acylating agent , the reaction temperature is -20°C to 10°C; the acylating agent is phosgene or triphosgene; Among them, X is N; R ₁ and R ₅ are independently H, F or NO ₂ ; R ₂ and R ₄ are independently H or F; R ₃ is H, F, NO ₂ or NH ₂ ; R ₆ is H or NH ₂ ; Y is Cl. 6. The preparation method according to claim 5, characterized in that: in the acylation reaction, the base is pyridine or triethylamine. 7. A preparation method of a salt of piperidine compounds as shown in formula I, characterized in that it comprises the following steps: When R ₃ in the compound of formula VII and formula I = H, F or NO ₂ , the compound of formula II is subjected to amino protection reaction to obtain the compound of formula V, and the compound of formula V is subjected to ester hydrolysis reaction to obtain the compound of formula VI. Condensation reaction of compound VI with R ₇ H to obtain compound of formula VII, deprotection and salt-forming reaction of compound of formula VII above to obtain a salt of compound of formula I; When R ₃ =NO ₂ in the compound of formula VII and R ₃ =NH ₂ in the compound of formula I, after the condensation reaction, the nitro reduction reaction is also included before the deprotection and salt-forming reaction, and the compound of formula VII R ₃ is reduced to amino; Among them, X=C; R ₁ and R ₅ are independently H, F or NO ₂ ; R ₂ and R ₄ are independently H or F; R ₆ is NH ₂ ; Y is _{OC2H5 ;} R ₇ is 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetra Hydrogen-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4, 3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3 ,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^{3 ,7} ]decyl)ethylamino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoro Pyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino. 8. The preparation method according to claim 7, characterized in that: the compound of formula II is prepared by the following method: in a solvent, the compound of formula IV is subjected to a reduction reaction with a reducing agent, and the reaction temperature is 0° C. to 50° C. ℃, that is enough; Among them, X is C; R ₁ and R ₅ are independently H, F or NO ₂ ; R ₂ and R ₄ are independently H or F; R ₃ is H, F or NO ₂ ; R ₆ is NH ₂ ; _Y is _OC2H5 . 9. The preparation method according to claim 8, characterized in that: the solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and acetonitrile. 10. The preparation method according to claim 8, characterized in that: the reducing agent is sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. 11. A method for preparing intermediate II of piperazine compounds or salts thereof, prepared by the following method: In a solvent, under the action of a base, the compound of formula III is subjected to an acylation reaction with an acylating agent at a reaction temperature of -20°C to 10°C; the acylating agent is phosgene or triphosgene; Among them, X is N; R ₁ and R ₅ are independently H, F or NO ₂ ; R ₂ and R ₄ are independently H or F; R ₃ is H, F, NO ₂ or NH ₂ ; R ₆ is H or NH ₂ ; Y is Cl. 12. The preparation method according to claim 11, characterized in that, in the acylation reaction, the base is pyridine or triethylamine. 13. Intermediates of piperazine or piperidine compounds or salts thereof as shown in formula II or formula VII: Wherein, Y is Cl; X is N; R ₁ and R ₅ are independently H, F or NO ₂ ; R ₂ and R ₄ are independently H or F; R ₃ is H, F, NO ₂ or NH ₂ ; R ₆ is H or NH ₂ ; Wherein, R ₁ and R ₅ are independently H, F or NO ₂ ; R ₂ and R ₄ are independently H or F; R ₃ is H, F or NO ₂ ; R ₇ is 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetra Hydrogen-[1,2,4]triazol[4,3-a]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4, 3-a]pyrazinyl, 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3 ,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, 1-(tricyclo[3,3,1,1 ^{3 ,7} ]decyl)ethylamino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-amino, pyridine-2-methylamino, 6-fluoro Pyridine-3-amino, 1-oxopyridine-2-amino, 2-cyanopyrrolyl or 1-(1-ethyl-2-pyrrolyl)methylamino. 14. the intermediate of piperazine or piperidine compound or its salt as claimed in claim 13, it is characterized in that: The compound of formula II is X=N, R ₁ =R ₄ =R ₆ =H, R ₂ =R ₃ =R ₅ =F and Y=Cl; or X=N, R2= _{R3 =} R6=H, R1 _{= NO2} , _R4 = _R5 =F and Y= _Cl ; The compound of formula VII is R ₁ =F, R ₂ =F, R ₃ =NO ₂ , R ₄ =H, R ₅ =H and R ₇ =5,6,7,8-tetrahydro-[1, 2,4]triazol[4,3-a]pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a ]pyrazinyl, 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, 3-ethyl-5,6, 7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl, tricyclo[3,3,1,1 ^3,7 ]decaneamino, 3-hydroxytricyclic [3,3,1,1 ^3,7 ]decane-1-amino, 4-hydroxytricyclo[3,3,1,1 ^3,7 ]decane-1-amino, pyridine-2-methylamino or 1-oxopyridin-2-amino. 15. The piperazine or piperidine compound as described in any one of claims 1 to 3, and its pharmaceutically acceptable salts are used in the preparation of medicines for the treatment and/or prevention of diabetes, hyperglycemia and insulin resistance Applications.