CN106699692A - Piperazinyl urea derivative as well as preparation method and application thereof - Google Patents

Abstract

The invention provides a piperazinyl urea derivative, a preparation method thereof, pharmaceutical composition containing the derivative and an application of the derivative as 11 beta-hydroxysteroid dehydrogenase type 1 inhibitor. The piperazinyl urea derivative has a general formula (V) shown in the specification.

Description

A piperazinyl urea derivative, its preparation method and application

Technical field:

The invention provides a piperazinyl urea derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as an inhibitor of 11β-hydroxysteroid dehydrogenase 1.

Background technique:

11β-hydroxysteroid dehydrogenase (11-βhydroxysteroid dehydrogenase, 11β-HSD) is a microsomal complex enzyme in the human body, a member of the short-chain alcohol dehydrogenase superfamily, and a glycoprotein. Catalyzes the conversion of the active 11-oxycorticosteroid, cortisol (hydrocortisone), to the inactive metabolite corticosteroid (cortisone) and their interconversion, thereby modulating local organ cortisol levels. It is widely distributed in the body, mainly in the brain, liver, kidney, heart, blood vessel, lung, testis, colon and placenta, especially in the liver and kidney, and plays different physiological roles.

11β-HSD mainly has two different isoenzymes in the body: 11β-HSD1 and 11β-HSD2, which are obviously different in protein molecular size, cofactor, gene structure, distribution in vivo and balance direction of chemical reaction. 11β-HSD1 was first discovered and has bidirectional catalytic activity, that is, it has bidirectional dehydrogenation and reduction effects. It is mainly distributed in the liver, followed by a certain amount of distribution in the blood vessels. In the liver, it mainly plays the role of catalytic reduction, and can convert oral corticosteroids into active cortisol to play a role. 11β-HSD2 does not have bidirectional enzymatic activity, it can only catalyze the dehydrogenation of the substrate in one direction, that is, the dehydrogenation and oxidation of cortisol into inactive corticosteroids, without the characteristics of reductase. It is mainly distributed in the kidney and placenta; blood vessels also have a certain amount of distribution.

Glucocorticoids play an important role in the metabolism of sugar, fat, protein, water and salt in the body. Abnormal glucocorticoids in blood circulation can lead to insulin resistance, high blood pressure, abnormal lipid metabolism and other diseases. The content of glucocorticoids in tissues is related to 11β-HSD1. Inhibition of 11β-HSD1 can prevent or reduce the tissue-specific amplification of glucocorticoid effects, which is beneficial to patients with non-insulin-dependent diabetes mellitus, insulin resistance, obesity, lipid disorders, metabolic syndrome and other glucocorticoid-mediated diseases. All diseases have benefits.

Several 11β-HSD1 inhibitors have been disclosed in the prior art, for example,

Patent document CN 104125960 A (WO2013/111150) discloses azaadamantane compounds of the following general formula:

Patent literature CN 101448785A (WO2007/113634) discloses compounds of the following general formula:

Patent literature CN 101137616A (WO2006/074244) discloses compounds of the following general formula:

An important defect of these compounds is that most of them contain large hydrophobic group adamantane rings or azaadamantane rings, amide bonds, and large heterocycles in their structures. Poor properties, poor druggability.

Contents of the invention

Aiming at the above-mentioned shortcomings in the prior art, the present invention aims to obtain a series of compounds with inhibitory 11β-HSD1 activity through drug design and synthesis means, and to carry out in vitro enzyme inhibition and in vivo tests of the compounds to find out the compounds that are more water-soluble than those in the current prior art. Better and more promising compounds for inhibiting 11β-HSD1 activity.

The invention provides a piperazinyl urea derivative, its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially an 11β-HSD1 inhibitor. In addition, the present invention also provides a method for treating diseases related to 11β-HSD1 by inhibiting 11β-HSD1, and the use of the piperazinyl urea derivatives in preparing medicine and treating diseases related to 11β-HSD1.

Aiming at the shortcomings of poor water solubility of compounds in the prior art, this application constructs piperazinyl urea derivatives, introduces a piperazine ring, and significantly improves the water solubility of the compound through salt formation. The pharmacokinetics are better, so the druggability Well, it is beneficial for the subsequent development, administration and disease treatment of compounds.

According to one aspect of the application, the application provides a compound as shown in general formula (V), and a pharmaceutically acceptable tautomer, solvate, hydrate or salt thereof:

Wherein, A ¹ , A ² , A ³ and A ⁴ are each independently selected from hydrogen, alkenyl, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxy ring Alkyl, cyano, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroaryl arylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkyl, heterocyclooxyalkyl, heterocyclesulfonyl, halogen, haloalkyl, -NR ⁴ -[C(R ⁵ R ⁶ )] _P - C(O)-R ⁷ , -O-[C(R ⁸ R ⁹ )] _q -C(O)-R ¹⁰ , -OR ¹¹ , -S-alkyl-, -S(O)-alkyl- , -N(R ¹² R ¹³ ), -CO ₂ R ¹⁴ , -C(O)-N(R ¹⁵ R ¹⁶ ), -C(R ¹⁷ R ¹⁸ )-OR ¹⁹ , -C(R ²⁰ R ²¹ ) -N(R ²² R ²³ ), -C(=NOH)-N(H) ₂ , -C(R ^17a R ^18a )-C(O)N(R ²² R ²³ ), -S(O) ₂ - N(R ²⁴ )R ²⁵ or -C(R ^17a R ^18a )-S(O) ₂ -N(R ²⁴ R ²⁵ );

p is 0 or 1; q is 0 or 1;

n=1, 2, 3, 4 or 5; m=1, 2, 3, 4 or 5;

B is selected from hydrogen, alkenyl, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cyano, cycloalkyl, cycloalkylcarbonyl, Cycloalkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycle Alkyl, heterooxyalkylene, or heterocyclic sulfonyl;

R is selected from hydrogen or alkyl _;

R and _R are each independently selected from _hydrogen , alkyl, cycloalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroaryl Ring or heterocycloalkyl, or R ₂ and R ₃ together with the atoms they are connected to form a ring selected from cycloalkyl and heterocycle;

R is selected from hydrogen, alkyl, cycloalkyl, carboxyalkyl, ^{carboxycycloalkyl} , aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkane group, heterocycle, heterocycloalkyl and heterooxyalkylene;

R ⁵ and R ⁶ are each independently selected from hydrogen and an alkyl group; or R ⁵ and R ⁶ form a ring selected from a cycloalkyl group and a heterocyclic ring together with the atoms connected to them;

R is selected from hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, ^{carboxycycloalkyl} , aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkane Oxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heterooxyalkylene or -N(R ²⁶ R ²⁷ );

R ⁸ and R ⁹ are each independently selected from hydrogen and an alkyl group; or R ⁵ and R ⁶ form a ring selected from a cycloalkyl group and a heterocyclic ring together with the atoms connected to them;

R ¹⁰ is selected from hydroxyl or -N(R ²⁸ R ²⁹ );

R is selected from hydrogen, alkyl, carboxyalkyl, cycloalkyl, ^{carboxycycloalkyl} , aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryl Aryloxyalkyl, heterocycle, heterocycloalkyl or heterooxyalkyl;

^R and R ^are each independently selected from hydrogen, alkyl, alkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylsulfonyl, carboxyalkyl, cycloalkyl, carboxycycloalkane radical, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocycloalkyl, heteroepoxyalkyl or heterocyclesulfonyl;

R is selected from hydrogen, alkyl, carboxyalkyl, cycloalkyl, ^{carboxycycloalkyl} , aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryl Aryloxyalkyl, heterocycle, heterocycloalkyl or heterooxyalkyl;

^R and R ^are each independently selected from hydrogen, alkyl, alkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylsulfonyl, carboxyl, carboxyalkyl, cycloalkyl, carboxyl Cycloalkyl, Cycloalkylsulfonyl, Heteroaryl, Heteroarylalkyl, Heteroaryloxy, Heteroarylsulfonyl, Heterocycle, Heterocycloalkyl, Heteroepoxyalkyl, Heteroepoxy , heterocyclic sulfonyl, hydroxyl or alkyl-C(O)N(R ²⁰¹ R ²⁰² ), or R ¹⁵ and R ¹⁶ form a heterocyclic ring with the atoms they are connected to;

R ²⁰¹ and R ²⁰² are each independently selected from hydrogen and alkyl;

R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected from hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkane group, heterocycle or heterocycloalkyl;

R ^17a and R ^18a are each independently selected from hydrogen and alkyl;

R ²⁰ and R ²¹ are each independently selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, cycloalkyl, carboxyalkyl, carboxycycloalkyl, ring Alkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocycle carbonyl or heterocycle sulfonyl;

^R and R ^are each independently selected from hydrogen, alkyl, alkylcarbonyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyl Alkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkoxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, Heteroepoxy group, heteroarylsulfonyl group or hydroxyl group, or R ²² and R ²³ form a ring selected from heteroaryl and heterocycle together with the atoms they are connected to;

^R and R ^are each independently selected from hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, carboxyl, arylsulfonyl, carboxyl Alkyl, carboxycycloalkyl, cycloalkyl, cycloalkoxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocycloalkane A group, a heterocyclic epoxy group, a heteroarylsulfonyl group or a hydroxyl group, or R ²⁴ and R ²⁵ form a heterocyclic ring together with the atoms they are connected to;

R ²⁶ and R ²⁷ are each independently selected from hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, carboxyl, arylsulfonyl, carboxyl Alkyl, carboxycycloalkyl, cycloalkyl, cycloalkoxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocycloalkane A group, a heterocyclic epoxy group, a heteroarylsulfonyl group or a hydroxyl group, or R ²⁶ and R ²⁷ form a heterocyclic ring together with the atoms they are connected to;

R ²⁸ and R ²⁹ are each independently selected from hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, carboxyl, arylsulfonyl, carboxyl Alkyl, carboxycycloalkyl, cycloalkyl, cycloalkoxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocycloalkane group, heterocyclyloxy group, heteroarylsulfonyl group or hydroxyl group, or R ²⁸ and R ²⁹ together with the atoms to which they are attached form a heterocyclic ring.

In a preferred embodiment of the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, A ² , A ³ and A ⁴ are hydrogen ; R ₁ , R ₂ and R ₃ are hydrogen.

The compound represented by the above general formula (V), and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, in a preferred embodiment, ^A is selected from H, F, OH, _NH2CO- , _{NH2SO2- or CH3SO2- .}

A preferred embodiment of the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, m=n=2.

The compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, a preferred embodiment, B is selected from H, aryl, aryl Alkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkyl, heteroepoxyalkyl, hetero Cyclosulfonyl.

A preferred embodiment, the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein, A ¹ , A ² , A ³ and ^A4 are hydrogen _; R1, R2 and _R3 are _hydrogen . A more preferred embodiment is the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein m=n=2. The most preferred embodiment, such as the compound shown in the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein, B is selected from H, aryl, Arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkyl, heterooxyalkyl , Heterocyclic sulfonyl.

A preferred embodiment, the compound represented by the above general formula (V), and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein A1 is fluorine ( ^F ) ; A ² , A ³ and A ⁴ are hydrogen; R ₁ , R ₂ and R ₃ are hydrogen. A more preferred embodiment is the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein m=n=2. The most preferred embodiment, the compound shown in the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein, B is selected from H, aryl, Arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkyl, heterooxyalkyl , Heterocyclic sulfonyl.

A preferred embodiment, the compound shown in the above general formula (V), and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein ^A is hydroxyl (-OH ); A ² , A ³ and A ⁴ are hydrogen; R ₁ , R ₂ and R ₃ are hydrogen. A more preferred embodiment is the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein m=n=2. The most preferred embodiment, the compound shown in the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein, B is selected from H, aryl, Arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkyl, heterooxyalkyl , Heterocyclic sulfonyl.

A preferred embodiment, the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein A ¹ is NH ₂ CO- ; A ² , A ³ and A ⁴ are hydrogen; R ₁ , R ₂ and R ₃ are hydrogen. A more preferred embodiment is the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein m=n=2. The most preferred embodiment, the compound shown in the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein, B is selected from H, aryl, Arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkyl, heterooxyalkyl , Heterocyclic sulfonyl.

A preferred embodiment, the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein A ¹ is NH ₂ SO ₂ ^- _; A2, A3 and ^A4 are hydrogen _; R1, R2 and ^R3 are _hydrogen . A more preferred embodiment is the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein m=n=2. The most preferred embodiment, such as the compound shown in the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein, B is selected from H, aryl, Arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkyl, heterooxyalkyl , Heterocyclic sulfonyl.

A preferred embodiment, the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein A ¹ is CH ₃ SO ₂ ^- _; A2, A3 and ^A4 are hydrogen _; R1, R2 and ^R3 are _hydrogen . A more preferred embodiment is the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein m=n=2. The most preferred embodiment, the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein, B is selected from H, aryl, Arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkyl, heterooxyalkyl , Heterocyclic sulfonyl.

The compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, a preferred embodiment, B is selected from H, aryl, aryl Alkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl.

The compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, a preferred embodiment, the aryl, arylalkyl, The aryl in the arylsulfonyl is preferably selected from substituted or unsubstituted phenyl or naphthyl; the aryl in the heteroaryl, heteroarylalkyl, and heteroarylsulfonyl is preferably selected from substituted or unsubstituted The pyridyl.

The compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, a preferred embodiment, the substituted phenyl or naphthyl and The substituents on the substituted pyridyl are each independently selected from halogen, alkyl with 1 to 5 carbons, cycloalkyl, hydroxyl, cyano, alkoxy, amino, substituted amino, mercapto, substituted mercapto, carbonyl, alkylsulfonyl or sulfonyl.

The compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, a preferred embodiment, the substituted phenyl or naphthyl and The substituents on the substituted pyridyl are each independently selected from F, Cl, Br, I; hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy thiol, trifluoromethoxy, difluoromethoxy; mercapto, methylmercapto, ethylmercapto, propylmercapto, butylmercapto; cyano; methyl, ethyl, propyl, butyl, tert-butyl, isopropyl , trifluoromethyl, difluoromethyl; amino, methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, formamido, acetamido; methylsulfonyl, ethylsulfonyl, propane Sulfonyl, sulfonic acid; carboxyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl.

A preferred embodiment, the compound represented by the above general formula (V), and its pharmaceutically acceptable tautomers, solvates, hydrates or salts, wherein,

A ² , A ³ and A ⁴ are hydrogen, R ₁ , R ₂ and R ₃ are hydrogen, A ¹ is selected from H, F, OH, NH ₂ CO-, NH ₂ SO ₂ - or CH ₃ SO ₂ -; B Preferably selected from H, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkane group, heterooxyalkylene group, heterocyclic sulfonyl group.

A preferred embodiment, the compound shown in the above general formula (V), and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein the compound is selected from:

On the other hand, the present application provides a synthetic method for the compound represented by the above-mentioned general formula (V), said method comprising the following steps: 1) an isocyanate compound represented by the general structural formula X1 and an isocyanate compound represented by the general structural formula X2 The representative hydrazine compound generates urea derivative X3 through addition reaction; 2), uses hydrogenation catalyst to remove the benzyl group of the urea derivative X3 by catalytic hydrogenation to obtain compound X4; 3), reacts compound X4 and X5 to obtain compound V1; 4), the compound V1 reacts with X6 to obtain the target compound V; the route is shown in the following general synthesis method (1):

In the above general synthesis method (1): the substituents A ¹ , A ² , A ³ , A ⁴ , R ₁ , R ₂ , R ₃ , B, m, and n in the structural formula of each compound are as defined in the above general formula V ; When R2 is hydrogen, V1=V; X5 is a halogen of B or a boronic acid/boric acid ester substitute, and X6 is a halogen substitute of R2.

In the general synthesis method (1) above, the raw material compounds X1, X2, X5, and X6 used can all be commercially available, that is, purchased through commercial channels.

Among the several reaction steps in the general synthesis method (1) described above, those skilled in the art can properly select specific experimental conditions for each step according to the type of reaction.

For example, in a preferred embodiment of the above-mentioned synthetic general method (1), the hydrogenation catalyst used in the step 2) is selected from a palladium hydrogenation catalyst, a platinum hydrogenation catalyst, etc., such as palladium carbon, palladium hydroxide, platinum carbon, or Ranny Ni et al. From the point of view of economy and experimental operation, palladium carbon is more preferred; 5-10% Pd/C is most preferred.

With respect to the general synthesis method (1) above, further, a preferred experimental condition for implementation is provided below.

step 1)

The hydrazine derivative X2 (0.05mol) was dissolved in 200ml of dichloromethane (CH ₂ Cl ₂ ), placed in an ice bath, and kept at an internal temperature of 0-10°C. Compound X1 (0.05 mol, dissolved in 50 ml CH ₂ Cl ₂ ) was added dropwise. After the addition was completed, it was moved to room temperature for 6h. The reaction solution was transferred into a 500ml beaker, washed three times with 100ml of water, separated, and the organic layer was dried. The dichloromethane was removed under reduced pressure to obtain a white solid, which was recrystallized from ethyl acetate to obtain the target compound X3.

step 2)

Compound X3 (0.05 mol) was dissolved in 120 ml CH ₃ OH, and 10% Palladium charcoal (Pd/C) (3 g) was added. Pressurized hydrogenation at a pressure of 2 MPa and an external temperature of 80° C. overnight. Cool to room temperature, reduce pressure, filter, and remove CH ₃ OH under reduced pressure to obtain a white solid, which is recrystallized from ethyl acetate (2ml: 1g) to obtain the target product X4.

step 3)

X5 is the halogen substitution of B, or the boronic acid/boric acid ester substitution of B is different, and the experimental conditions are appropriately selected, and the specific operation can be performed according to the following steps.

step 3.1

When X5 is an acid chloride, dissolve compound X4 (1 mmol) and DIPEA (2 mmol) in 25 ml CH ₂ Cl ₂ , add acid chloride X5 (1 mmol), react at room temperature overnight. The reaction solution was washed with acid water and separated, and the organic layer was washed in saturated sodium carbonate solution and separated. The organic layer was dried, and the solvent was removed under pressure to obtain a white solid. The target compound V was obtained by recrystallization from ethanol.

reaction 3.2

When X5 is a halogenated compound, dissolve compounds X4 (1mmol), K ₂ CO ₃ (2mmol) and X5 (1mmol) in 50ml CH ₃ CN and heat to reflux overnight. Cool, filter, and remove the solvent under reduced pressure to give the compound as a white solid. The solid was subjected to column separation using ethyl acetate:petroleum ether (10:1) as the eluent to obtain the target compound V.

reaction 3.3

When X5 is an aromatic halide, heteroaryl halide or aryl (heteroaryl) boronic acid/boronic acid ester, hydrazine derivatives X4, X5, palladium catalyst (PdCl2, Pd(OAc)2, XPhos, XantPhos, etc.), base Add (sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium acetate, etc.) into the solvent (toluene, 1,4-dioxane, 1,2-dichloroethane, DMF, DMSO), and replace the air with stirring It is nitrogen, and the temperature is raised to 80-120 degrees to react. After the reaction, the reaction solution was transferred into a 500ml beaker, washed with 100ml of water three times, separated, and the organic layer was dried. The dichloromethane was removed under reduced pressure to obtain a white solid, which was recrystallized from ethyl acetate to obtain the target compound V1.

As for the pharmaceutically acceptable tautomers, solvates, hydrates or salts of the compound represented by general formula (V), it can be obtained according to conventional technical methods in the art.

For example: the compound of formula V structure reacts with inorganic acid (or inorganic base), organic acid (or organic base), and the salt of the compound of formula V structure is precipitated by cooling.

According to certain embodiments of the present application, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the compound and its pharmaceutically acceptable tautomer, solvate, hydrate or salt, and a pharmaceutically acceptable carrier.

According to some embodiments of the present application, the present application provides a method for preparing the pharmaceutical composition, the method comprising the compound or its pharmaceutically acceptable tautomer, solvate, hydrate Or the salt is prepared by mixing with a pharmaceutically acceptable carrier.

According to some embodiments of the present application, the present application provides a kit comprising the compound and a pharmaceutically acceptable tautomer, solvate, hydrate or salt thereof.

According to certain embodiments of the present application, the present application provides a method for inhibiting 11β-hydroxysteroid dehydrogenase 1 in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound and a pharmaceutically acceptable tautomorphism thereof Constructs, solvates, hydrates or salts.

According to certain embodiments of the present application, the present application provides a method for treating a disease associated with 11β-hydroxysteroid dehydrogenase 1 in a subject by inhibiting 11β-hydroxysteroid dehydrogenase 1, the method comprising administering to the subject the treatment An effective amount of the compound and a pharmaceutically acceptable tautomer, solvate, hydrate or salt thereof.

According to some embodiments of the present application, the diseases related to 11β-hydroxysteroid dehydrogenase 1 include non-insulin-dependent diabetes mellitus, insulin resistance, glucose intolerance, obesity, lipid disorder, metabolic syndrome, high Blood sugar, hypertension, hyperlipidemia, glaucoma, cardiovascular disorders, osteoporosis, inflammation, dementia, depression, cognitive impairment, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, androgen excess, or polycystic ovary syndrome.

According to some embodiments of the present application, the present application provides the use of the compound and its pharmaceutically acceptable tautomer, solvate, hydrate or salt in the preparation of a medicament.

According to some embodiments of the present application, the present application provides the inhibition of 11β-hydroxysteroid dehydrogenase 1 in the subject by the compound and its pharmaceutically acceptable tautomer, solvate, hydrate or salt the use of.

According to certain embodiments of the present application, the present application provides that the compound and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof inhibit 11β-hydroxysteroid dehydrogenase 1 in a subject. Use for treating diseases associated with 11β-hydroxysteroid dehydrogenase 1.

According to some embodiments of the present application, the present application provides that the diseases related to 11β-hydroxysteroid dehydrogenase 1 include non-insulin-dependent diabetes mellitus, insulin resistance, glucose intolerance, obesity, lipid disorder, metabolic syndrome, hyperglycemia, hypertension, hyperlipidemia, glaucoma, cardiovascular disorders, osteoporosis, inflammation, dementia, depression, cognitive impairment, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, Angina pectoris, peripheral vascular disease, androgen excess, or polycystic ovary syndrome.

Accordingly, the present invention provides a piperazinyl urea derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially an inhibitor of 11β-hydroxysteroid dehydrogenase 1.

definition

Unless otherwise defined, all technical terms or specialized words used herein have the meanings commonly understood by those of ordinary skill in the technical field of the present invention.

The meanings of some abbreviations used in this application are as follows: "n-" means positive, "i-" means different, "s-" or "sec" means secondary (secondary), "t-" or "tert-" means tertiary ), "o-" refers to the ortho position (ortho), "m-" refers to the meta position, "p-" refers to the para position (para), "(E)-" refers to the E-isomer, "(Z)- " refers to the Z-isomer, "cis-" refers to the cis-isomer, "trans-" refers to the trans-isomer, "rac" refers to the racemate, and "Ph" refers to the benzene group, "Me" means a methyl group, and "Et" means an ethyl group.

The term "Ca-b" when used in front of a chemical group refers to a group containing a to b carbon atoms, where a is the minimum number of carbon atoms in the substituent and b is the maximum number. For example, "C1-6" alkyl refers to an alkyl group containing 1-6 carbon atoms; for example, "C2-6 alkenyl" refers to an alkenyl group containing 2-6 carbon atoms.

The term "alkyl" refers to a saturated hydrocarbon substituent containing 1-20 carbon atoms, and the alkyl group may be a straight-chain alkyl group or a branched-chain alkyl group. In some embodiments of the present application, the alkyl group has 1-16 carbon atoms. In certain embodiments of the present application, the alkyl group has 1-12 carbon atoms. In certain embodiments of the present application, the alkyl group has 1-10 carbon atoms. In certain embodiments of the present application, the alkyl group has 1-8 carbon atoms. In certain embodiments of the present application, the alkyl group has 1-7 carbon atoms. In certain embodiments of the present application, the alkyl group has 1-6 carbon atoms. In certain embodiments of the present application, the alkyl group has 1-5 carbon atoms. In certain embodiments of the present application, the alkyl group has 1-4 carbon atoms. In certain embodiments of the present application, the alkyl group has 1-3 carbon atoms. In certain embodiments of the present application, the alkyl group has 1-2 carbon atoms. In some embodiments of the present application, examples of the alkyl group include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.

The term "alkylene" refers to a divalent alkyl group formed by removing a hydrogen atom from the above-mentioned alkyl group. The alkylene group can be straight or branched, such as methylene, ethylene, propylene, etc. .

The term "alkenyl" refers to an unsaturated hydrocarbon substituent containing 2-20 carbon atoms and one or more double bonds, and the alkenyl group may be straight chain or branched. In certain embodiments of the present application, the term "alkenyl" may include substituents in the "E" or "Z" direction. In certain embodiments of the present application, the term "alkenyl" may encompass either a "cis" or "trans" conformation. In certain embodiments of the present application, the alkenyl group has 2-16 carbon atoms. In certain embodiments of the present application, the alkenyl group has 2-14 carbon atoms. In certain embodiments of the present application, the alkenyl group has 2-12 carbon atoms. In certain embodiments of the present application, the alkenyl group has 2-10 carbon atoms. In certain embodiments of the present application, the alkenyl group has 2-8 carbon atoms. In certain embodiments of the present application, the alkenyl group has 2-7 carbon atoms. In certain embodiments of the present application, the alkenyl group has 2-6 carbon atoms. In certain embodiments of the present application, the alkenyl group has 2-5 carbon atoms. In certain embodiments of the present application, the alkenyl group has 2-4 carbon atoms. In certain embodiments of the present application, examples of the alkenyl group include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl, etc.

The term "alkenylene" refers to a divalent alkenyl group formed by removing a hydrogen atom from the above-mentioned alkenyl group. The alkenylene group can be straight or branched, such as vinylidene, ethylene-1,1-diyl , propene-1,2-diyl, etc.

The term "alkynyl" refers to an unsaturated hydrocarbon substituent containing 2-20 carbon atoms and one or more triple bonds, and the alkynyl group may be straight or branched. In some embodiments of the present application, the alkynyl group has 2-16 carbon atoms. In some embodiments of the present application, the alkynyl group has 2-14 carbon atoms. In some embodiments of the present application, the alkynyl group has 2-12 carbon atoms. In certain embodiments of the present application, the alkynyl group has 2-10 carbon atoms. In certain embodiments of the present application, the alkynyl group has 2-8 carbon atoms. In certain embodiments of the present application, the alkynyl group has 2-7 carbon atoms. In certain embodiments of the present application, the alkynyl group has 2-6 carbon atoms. In certain embodiments of the present application, the alkynyl group has 2-5 carbon atoms. In certain embodiments of the present application, the alkynyl group has 2-4 carbon atoms. In some embodiments of the present application, examples of the alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, 1-butynyl and the like.

The term "alkynylene" refers to a divalent alkynyl group formed by removing a hydrogen atom from the above-mentioned alkynyl group. The alkynylene group can be straight or branched, such as acetylene-1,2-diyl, propyne- 1,2-diradical, etc.

The term "alkoxy" refers to -O-alkyl, wherein the term "alkyl" is as defined above. In certain embodiments of the present application, examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy Base etc.

The term "halogen" or "halogen atom" refers to a fluorine (F) atom, chlorine (Cl) atom, bromine (Br) atom or iodine (I) atom.

The term "halo" when used in front of a chemical group means that said substituent is substituted with one or more halogen substituents. The term "haloalkyl" means that in the above-mentioned alkyl group, one or more hydrogen atoms at any position are replaced by one or more same or different halogen atoms. In certain embodiments of the present application, examples of haloalkyl include, but are not limited to, CHCl ₂ , CHF ₂ , CF ₃ , C ₂ F ₅ and the like. The term "trifluoromethyl" is _CF3 .

The term "n-membered" (n is an integer) is generally used to describe the number n of atoms forming a ring in one moiety of a compound. For example, furyl is a 5-membered heterocycloalkyl, and pyridyl is a 6-membered heterocycloalkyl.

The term "m-n membered" when used in front of a chemical group refers to a monocyclic or polycyclic cycloalkyl group containing m-n ring-forming atoms, where m is the minimum number of atoms in the ring portion of the substituent and n is the maximum number. For example, "5-6 membered aromatic heterocyclic group" refers to an aromatic heterocyclic group containing 5-6 ring-forming atoms.

The term "cycloalkyl" refers to a monocyclic or polycyclic ring formed by carbon atoms, and the cycloalkyl may be saturated or partially saturated. In certain embodiments of the present application, the cycloalkyl group includes 3-20 members (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 membered) cycloalkyl, eg 3-membered monocyclic, 5-membered monocyclic or 12-membered bicyclic ring. Examples of cycloalkyl groups include cyclobutyl, cyclopentyl, cycloheptyl, cyclohexenyl, and the like.

The term "aryl" refers to a carbocyclic aromatic ring comprising a single ring or multiple rings (eg 2, 3 or 4 fused rings). In some embodiments of the present application, examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, indenyl, and the like. In certain embodiments of the present application, the aryl group includes 5-14 membered (eg, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 membered) aryl groups.

The term "heterocycloalkyl" means that one or more ring-forming carbon atoms in the above-mentioned cycloalkyl group are replaced by heteroatoms such as S, O or N atoms. The "heterocycloalkyl" may be a monocyclic or polycyclic heterocycloalkane. Examples of the "heterocycloalkyl" include pyrazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl and the like. In some embodiments of the present application, the heterocycloalkyl group has 1-20 (such as 2-20, 3-20, 4-20, 5-20, 6-20, 7- 20, 8-20, 9-20, 10-20, 15-20, 2-18, 3-18, 4-18, 5-18, 6-18, 7- 18, 8-18, 9-18, 10-18, 15-18, 2-15, 3-15, 4-15, 5-15, 6-15, 7- 15, 8-15, 9-15, 10-15, 2-10, 3-10, 4-10, 5-10, 6-10, 7-10, 8- 10, 9-10, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 2-7, 3-7, 4- 7, 5-7, 6-7, 2-6, 3-6, 4-6, 5-6, 2-5, 3-5, 4-5, 2- 4, 3-4, or 2-3) carbon atoms. In some embodiments of the present application, the heterocycloalkyl has 1-5 (1-4, 1-3, 1-2, 2-5, 2-4, 2-3 , 3-5, 3-4) heteroatoms.

The term "heteroaryl" means that one or more ring-forming carbon atoms in the above-mentioned aryl group are replaced by heteroatoms such as S, O or N atoms. The "heteroaryl" may be monocyclic or polycyclic heteroaryl. Examples of the "heteroaryl" include, but are not limited to, furyl, pyridyl, pyrimidyl, imidazolyl, indolyl, pyrrolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, , pyrazolyl, purinyl, benzimidazolyl, etc. In some embodiments of the present application, the heterocycloalkyl group has 1-20 (such as 2-20, 3-20, 4-20, 5-20, 6-20, 7- 20, 8-20, 9-20, 10-20, 15-20, 2-18, 3-18, 4-18, 5-18, 6-18, 7- 18, 8-18, 9-18, 10-18, 15-18, 2-15, 3-15, 4-15, 5-15, 6-15, 7- 15, 8-15, 9-15, 10-15, 2-10, 3-10, 4-10, 5-10, 6-10, 7-10, 8- 10, 9-10, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 2-7, 3-7, 4- 7, 5-7, 6-7, 2-6, 3-6, 4-6, 5-6, 2-5, 3-5, 4-5, 2- 4, 3-4, or 2-3) carbon atoms. In some embodiments of the present application, the heterocycloalkyl has 1-5 (1-4, 1-3, 1-2, 2-5, 2-4, 2-3 , 3-5, 3-4) heteroatoms.

The term "piperazinyl urea", the chemical formula is C ₅ H ₁₂ N ₄ O, and the structural formula is shown in formula (I):

The term "ureido" as used herein refers to alkyl-NCON-, cycloalkyl-NCON-, heterocycloalkyl-NCON-, aryl-NCON- or heteroaryl-NCON-, wherein alkyl, cycloalkyl , heterocycloalkyl, aryl and heteroaryl are as described herein.

The term "piperazine" refers to Piperazine is easily soluble in water and glycerin.

The term "hydroxyl" refers to -OH.

The term "amino" refers to -NH2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO2.

The term "carbonyl" refers to -C(O)-.

The term "oxo" refers to =O.

The term "oxy" refers to an ether substituent (-O-).

In certain embodiments of the present application, the above-mentioned alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl or heteroaryl groups may be substituted or unsubstituted. In certain embodiments of the present application, the substituents may be one or more, and the substituents are independently selected from halogen, nitro, cyano, alkoxy, alkyl, alkenyl, alkynyl, hydroxyl, Amino, etc.

The terms "substituent", "radical" or "group" are used interchangeably in this application. If a group of substituents is "optionally substituted" with one or more substituents, it means that the substituents may be unsubstituted or substituted with substituents.

When the term "independently selected from" is used to describe a substituent, it means that each substituent is independently selected from each other, and one substituent may be the same as or different from other substituents.

The compounds provided herein may also include all isotopes of atoms present in intermediates or products. Examples of isotopes in the compounds described herein include, but are not limited to, isotopes of elements such as hydrogen, carbon, nitrogen, fluorine, chlorine, oxygen, sulfur, or phosphorus, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³⁶ Cl, ¹⁸ O, ¹⁷ O, ³⁵ S, ³¹ P or ³² P, etc.

Compounds described herein also include tautomeric forms of the compounds, such as keto-enol tautomers.

The compounds described herein include anhydrous and unsolvated forms of the compounds, as well as hydrates and solvates of the compounds. The term "solvate" in this application refers to a molecule comprising the compound and one or more molecules of a pharmaceutically acceptable solvent such as ethanol. According to some embodiments of the present application, the solvate may contain, for example, 1-8 solvent molecules, such as 1-6, 1-4, 1-3, 1-2, 2-6 , 2-4, 2-3, 3-6 or 3-4. Where the solvent is water, the solvate is a hydrate.

The term "pharmaceutical composition" means containing a therapeutically effective amount of one or more of the compounds and their pharmaceutically acceptable tautomers, solvates, hydrates or salts, and other pharmaceutically acceptable carriers mixture. The purpose of preparing the compound into a pharmaceutical composition is to more conveniently administer it to a subject.

The pharmaceutical composition described in the present application can be tablets, pills, capsules, granules, powders, suppositories, powders, ointments, patches, injections, solutions, suspensions, sprays, lotions, drops, wipes, etc. agent. The pharmaceutical composition can be prepared as a dry powder and mixed with sterile water or buffer to prepare a solution before administration. The pH of the buffer is usually 3-11, preferably 5-9, more preferably 7-8.

The terms "kit" or "kit" are used interchangeably in this application. The present application discloses a kit comprising a therapeutically effective amount of the therapeutic agent or pharmaceutical composition. According to some embodiments of the present application, the kit further comprises one or more other therapeutic agents. According to some embodiments of the present application, the kit further includes instructions for use. According to some embodiments of the present application, the kit further includes devices for corresponding administration methods, such as but not limited to needles.

The terms "administering", "administering" or "administering" refer to administering a certain dose of a compound or pharmaceutical composition to a subject through a suitable administration method.

The "administration method" includes but not limited to oral administration, intravenous administration, intrarespiratory administration, sublingual administration, topical administration, intramuscular administration, intraocular administration, transdermal absorption, gastrointestinal administration, etc. Any administration methods known in the art such as external administration, intraperitoneal administration, vaginal administration, buccal administration, rectal administration, etc. Those skilled in the art will understand that the mode of administration to a subject depends on many factors, including the location of the disease, the age of the subject, the severity of the disease, and the ingredients of the pharmaceutical composition, among others.

The compounds or pharmaceutical compositions described herein can be administered at any time. For example, the compound or pharmaceutical composition can be administered before, during, or after the onset of the disease in the subject, for example, about 1 hour, about 2 hours, about 4 hours, about 5 hours, about 8 hours, about 12 hours, about 24 hours, about 2 days, about 4 days, about 8 days, about 16 days, about 30 days or 1 month, about 2 months, about 4 months, about 6 months medicine.

The compounds or pharmaceutical compositions described in this application can be administered once or multiple times. When multiple doses are administered, it can be at any time interval, for example, the interval between the subsequent dose and the previous dose is about 8 weeks, about 4 weeks, about 2 weeks, about 1 week, about 5 days, about 3 days, about 2 days. days, about 24 hours, about 12 hours, about 8 hours, about 6 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 30 minutes or less.

The compounds or pharmaceutical compositions described in this application can be administered alone or in combination with other suitable drugs. The combined administration may be, for example, simultaneous or sequential administration with other drugs. When administered sequentially, it may be at any interval.

The term "effective amount" or "therapeutically effective amount" of the compound refers to an amount sufficient to obtain the desired therapeutic effect after administration to a subject. The therapeutic effects include effectively inhibiting the activity of 11β-hydroxysteroid dehydrogenase 1, and effectively improving or treating 11βHSD1-related diseases in the subject. The 11βHSD1-related diseases include but are not limited to non-insulin-dependent diabetes mellitus, insulin resistance, glucose intolerance, obesity, lipid disorders, metabolic syndrome, hyperglycemia, hypertension, hyperlipidemia, glaucoma, cardiovascular disorders , osteoporosis, inflammation, dementia, depression, cognitive impairment, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina pectoris, peripheral vascular disease, androgen excess (e.g. hirsutism, menstrual irregularities, hyperandrogenism) or polycystic ovary syndrome (PCOS). Those skilled in the art will understand that the appropriate dosage of the compound depends on many factors, including but not limited to the weight, age and sex of the subject to be treated, the time of administration, the severity of the disease to be treated, and the like.

The terms "treat" or "treatment" refer to the fact that a disease, disorder or condition in a subject can be "prevented", "prevented", "inhibited", "improved" or "cured" after administration of the drug.

The terms "subject", "subject" or "patient" are used interchangeably in this application and have a broad meaning including human or non-human mammals such as dogs, cats, mice, rats, sheep, pigs , goats, cows, non-human primates; or birds, such as chickens, ducks, geese; including other vertebrates, invertebrates, as well as in vitro tissues, prokaryotic cells or eukaryotic cells, etc. According to some embodiments of the present application, the subject is a mammal. According to some embodiments of the present application, the subject is a primate. According to some embodiments of the present application, the subject is a human.

When the subject is a human, common doses for systemic administration include, but are not limited to, 10 ng/kg-100 mg/kg, such as 10-100 ng/kg, 10-500 ng/kg, 10-1000 ng/kg, 50-500 ng/kg, 50 -1000ng/kg, 1-10μg/kg, 5-50μg/kg, 10-100μg/kg, 100-500μg/kg, 250-750μg/kg, 10-1000μg/kg, 100-1000μg/kg, 500-1000 μg/kg, 1-10mg/kg, 5-50mg/kg, 20-50mg/kg, 25-75mg/kg, 1-100mg/kg, 20-100mg/kg, 50-100mg/kg, 75-100mg/kg kg, 1mg/kg, 5mg/kg, 10mg/kg, 20mg/kg, 30mg/kg, 40mg/kg, 50mg/kg, 75mg/kg, 100mg/kg, etc.

The term "pharmaceutically acceptable carrier" is a pharmaceutically acceptable component or medium, including but not limited to solvents, excipients, diluents, adjuvants, fillers and the like. Common pharmaceutically acceptable carriers include physiological saline, buffers, sugars, gelatin, starch, Ringer's solution, cellulose and the like. The pH of the carrier is usually 3-11, preferably 5-9, more preferably 7-8.

The term "pharmaceutically acceptable salt" refers to an acid addition salt or a base addition salt formed by the compound. The acid forming the acid addition salt can be an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, etc., or an organic acid such as acetic acid, propionic acid, butyric acid, or organic acid. acid, malonic acid, oxalic acid, glycolic acid, benzoic acid, citric acid, salicylic acid, etc. Bases forming base addition salts can be inorganic bases such as sodium, potassium, calcium, magnesium, iron, zinc, aluminum, ammonium, etc., or organic bases such as primary amines, secondary amines, etc. , tertiary amines, cyclic amines, etc.

The term "half-inhibitory concentration (IC ₅₀ )", or "half-inhibition rate", refers to the concentration of the inhibitor when the activity of the target substance is inhibited to half during the process of inhibiting the target substance. In general, the stronger the inhibitory ability of an inhibitor, the lower the _IC50 . According to some embodiments of the present application, the _IC50 of the compound described herein is the concentration of the compound when 11β-HSD1 activity is inhibited by 50%.

In this application, when "about" is used to modify a numerical value, it means that the numerical value can fluctuate ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, within ±3%, ±2%, or ±1%.

Unless otherwise stated in this application or clearly contradicted by context, when used in the context of describing this application, including in the context of the claims, the terms "a", "an", "the", "the" and "At least one" and similar references are construed to cover both the singular and the plural. Unless otherwise stated in this application or clearly contradicted by context, the terms "comprising", "having", "including" and "containing" as used in this application are to be construed as open-ended terms (i.e. "including but not limited to" ). Unless otherwise stated in this application or clearly contradicted by the context, all methods described in this application can be performed in any suitable order according to the understanding of those skilled in the art.

All patents, patent applications, and literature references cited in this application are hereby incorporated by reference in their entirety into this application to the same extent as if each were individually incorporated by reference. In the event of a conflict between this application and the documents provided herein, the content of this application shall control.

Description of drawings

The accompanying drawings, which are incorporated herein and form a part of this specification, illustrate the invention and, together with the description, further serve to explain the principles of the invention and to enable those skilled in the relevant art to make and use the invention. Embodiments of the present invention are described with reference to the drawings by way of example only.

Figure 1 shows a computer simulation of the interaction of compounds described herein with 11β-HSD1, wherein Figure 1A is compound V-15, Figure 1B is compound V-30, Figure 1C is compound V-19, and Figure 1D is compound V -31;

Figure 2 shows the impact of the compounds described in the application on the content of hydrocortisone (cortisol) in mouse plasma, wherein Figure 2A is a positive control (glycyrrhetinic acid, referred to as GA), and the compound V-15 (SIPI7291) of 30mpk , V-19 (SIPI7295) and positive control-glycyrrhetinic acid (abbreviated as GA) on the effect of hydrocortisone content in plasma, Figure 2B is the positive control (glycyrrhetinic acid), and the compound V-23 (SIPI7299) of 30mpk , V-30 (SIPI7349) and V-31 (SIPI7336) on the plasma hydrocortisone content.

Combined with the above description, it can be seen that the semicarbazide series compounds applied for by the patent have: 1) novel structure and improved water solubility; 2) different enzyme action site and previously reported compounds, with a new mode of action; 3) higher activity , good physical and chemical properties and activity are more druggable.

detailed description

This application describes preferred implementation modes and examples, and those skilled in the art can make appropriate changes to the implementation modes and examples described in this application on the basis of reading this application. Therefore, the content claimed in this application includes all equivalent modifications and changes to the subject matter in the claims of this application within the scope permitted by law.

Use above-mentioned general method (I) to obtain following compound shown in table 1 in the present application:

Table 1: Piperazinyl urea compounds obtained in this application.

Part I: Synthetic Examples

General synthetic route:

step 1)

The hydrazine derivative X2 (0.05mol) was dissolved in 200ml of dichloromethane (CH ₂ Cl ₂ ), placed in an ice bath, and kept at an internal temperature of 0-10°C. Compound X1 (0.05 mol, dissolved in 50 ml CH ₂ Cl ₂ ) was added dropwise. After the addition was completed, it was moved to room temperature for 6h. The reaction solution was transferred into a 500ml beaker, washed three times with 100ml of water, separated, and the organic layer was dried. The dichloromethane was removed under reduced pressure to obtain a white solid, which was recrystallized from ethyl acetate to obtain the target compound X3.

step 2)

Compound X3 (0.05 mol) was dissolved in 120 ml CH ₃ OH, and 10% Palladium charcoal (Pd/C) (3 g) was added. Pressurized hydrogenation at a pressure of 2 MPa and an external temperature of 80° C. overnight. Cool to room temperature, reduce pressure, filter, and remove CH ₃ OH under reduced pressure to obtain a white solid, which is recrystallized from ethyl acetate (2ml: 1g) to obtain the target product X4.

step 3)

X5 is the halogen substitution of B, or the boronic acid/boric acid ester substitution of B is different, and the experimental conditions are appropriately selected, and the specific operation can be performed according to the following steps.

step 3.1

When X5 is an acid chloride, dissolve compound X4 (1 mmol) and DIPEA (2 mmol) in 25 ml CH ₂ Cl ₂ , add acid chloride X5 (1 mmol), react at room temperature overnight. The reaction solution was washed with acid water and separated, and the organic layer was washed in saturated sodium carbonate solution and separated. The organic layer was dried, and the solvent was removed under pressure to obtain a white solid. The target compound V was obtained by recrystallization from ethanol.

reaction 3.2

When X5 is a halogenated compound, dissolve compounds X4 (1mmol), K ₂ CO ₃ (2mmol) and X5 (1mmol) in 50ml CH ₃ CN and heat to reflux overnight. Cool, filter, and remove the solvent under reduced pressure to give the compound as a white solid. The solid was subjected to column separation using ethyl acetate:petroleum ether (10:1) as the eluent to obtain the target compound V.

reaction 3.3

When X5 is aromatic halide, heteroaryl halide or aryl (heteroaryl) boronic acid/boronic acid ester, hydrazine derivative X4, X5, palladium catalyst (PdCl2, Pd(OAc)2, XPhos, XantPhos, etc.), base Add (sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium acetate, etc.) into the solvent (toluene, 1,4-dioxane, 1,2-dichloroethane, DMF, DMSO), and replace the air with stirring It is nitrogen, and the temperature is raised to 80-120 degrees to react. After the reaction, the reaction solution was transferred into a 500ml beaker, washed with 100ml of water three times, separated, and the organic layer was dried. The dichloromethane was removed under reduced pressure to obtain a white solid, which was recrystallized from ethyl acetate to obtain the target compound V1.

Example 1 : V-7 1-( Adamantane -2- base )-3-(4- Benzylpiperazine -1- base ) Urea

Take 1-amino-4 benzylpiperazine (10.79g, 56.4mmol), 2-adamantane isocyanate (10g, 56.4mmol) and CH ₂ Cl ₂ (250ml), and follow the general synthesis method (1) to obtain compound V -7. The yield of the reaction was 95%.

ESI-MS[M+H] ⁺ : m/z=369.26;

1H NMR (600MHz, CDCl3) δ7.31(d, J=6.3Hz, 4H), 7.26(d, J=6.7Hz, 1H), 6.58(d, J=8.5Hz, 1H), 3.91(d, J =8.5Hz,1H),3.52(s,2H),2.98(s,2H),2.83(s,2H),2.57(s,2H),2.26(s,2H),1.91(s,2H),1.83 (d, J=10.2Hz, 7H), 1.73 (d, J=18.4Hz, 4H), 1.65 (d, J=12.8Hz, 2H).

Example 2 : V-5 1-( Adamantane -2- base )-3- Piperazinyl urea

1-(adamantane-2-yl)-3-(4-benzylpiperazin-1-yl)urea (15g), according to the reaction 2 of the general synthesis method (1), carried out hydrogenation to remove the benzyl group to obtain the target product V-5. The yield of the reaction was 98%.

ESI-MS[M+H] ⁺ : m/z=279.21;

1H NMR (600MHz, CDCl3) δ6.58(d, J=8.0Hz, 1H), 5.29(s, 1H), 3.92(d, J=8.6Hz, 1H), 2.98(d, J=46.7Hz, 6H ), 2.45(s, 2H), 1.92(s, 2H), 1.85(s, 7H), 1.75(s, 4H), 1.65(d, J=12.7Hz, 2H).].

Example 3 : V-6 1-( Adamantane -2- base )-3-(4-(2- pyridyl methylene ) Piperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₂ -bromomethylpyridine (0.17g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3 CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-6. The yield of the reaction was 92%.

ESI-MS[M+H] ⁺ : m/z=369.25;

1H NMR (600MHz, CDCl3) δ8.57(d, J=4.7Hz, 1H), 7.66(t, J=7.6Hz, 1H), 7.40(d, J=7.8Hz, 1H), 7.20–7.15(m ,1H),6.58(d,J=8.5Hz,1H),3.91(d,J=8.6Hz,1H),3.68(s,2H),3.00(s,2H),2.85(s,2H),2.63 (s, 2H), 2.38 (s, 2H), 1.92 (s, 2H), 1.84 (s, 7H), 1.75 (s, 4H), 1.65 (d, J=12.8Hz, 2H).

Example 4 : V-8 1-( Adamantane -2- base )-3-((4- phenethyl ) Piperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ( ₂ -bromoethyl)benzene (0.179g, 1mmol), K2CO3 ₍ 0.28g, 2mmol), CH ₃ CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-8. The yield of the reaction was 90%.

ESI-MS[M+H]+: m/z=369.25;

1H NMR (600MHz, CDCl3) δ7.29(t, J=7.5Hz, 2H), 7.20(d, J=7.0Hz, 3H), 6.56(d, J=8.3Hz, 1H), 3.92(d, J =8.6Hz,1H),2.99(d,J=56.9Hz,4H),2.78(d,J=8.5Hz,2H),2.62(dd,J=21.1,13.3Hz,4H),2.30(s,2H ),1.92(s,2H),1.85(s,7H),1.75(s,4H), 1.67(s,2H).

Example 5 : V-9 1-( Adamantane -2- base )-3-(4-((3- Methoxycarbonyl ) Benzyl ) Piperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₃ -methoxycarbonylbenzyl bromide (0.23g, 1mmol), K2CO3 (0.28g, 2mmol), _{CH 3} CN (50ml) was operated according to the reaction 3.2 of the general synthesis method (1) to obtain the target compound V-9. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=427.28;

1H NMR (600MHz, CDCl3) δ7.97–7.93(m, 2H), 7.53(d, J=7.3Hz, 1H), 7.40(t, J=7.6Hz, 1H), 6.57(d, J=8.5Hz ,1H),4.38(q,J=7.1Hz,1H),3.92(s,3H),3.57(s,2H),2.99(s,2H),2.80(s,2H),2.59(s,2H) , 2.28 (s, 2H), 1.92 (s, 2H), 1.84 (s, 7H), 1.75 (s, 4H), 1.65 (d, J=12.9Hz, 2H).

Example 6 : V-10 1-( Adamantane -2- base )-3-(4-(3- Trifluoromethyl ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), 3-trifluoromethylbenzyl bromide (0.24g, 1mmol), K2CO3 (0.28g, 2mmol), _CH3CN (50ml) According to the reaction 3.2 of the general synthesis method (1), the target compound V-10 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H]+: m/z=437.26;

1H NMR (600MHz, CDCl3) δ7.57(s, 1H), 7.52(t, J=6.7Hz, 2H), 7.44(t, J=7.6Hz, 1H), 6.57(d, J=8.5Hz, 1H ),3.91(d,J＝8.6Hz,1H),3.57(s,2H),3.00(s,2H),2.81(s,2H),2.58(s,2H),2.29(s,2H),1.92 (s, 2H), 1.84 (s, 7H), 1.75 (s, 4H), 1.66 (d, J=12.7Hz, 2H).

Example 7 : V-11 1-( Adamantane -2- base )-3-(4-(3,5- two ( Trifluoromethyl )) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinyl urea (0.3g, 1mmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.31g, 1mmol), K2CO3 (0.28g, 2mmol ), CH ₃ CN (50ml) according to the reaction 3.2 of the general synthesis method (1), the target compound V-11 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=505.23;

1H NMR (600MHz, CDCl3) δ7.79(d, J=7.0Hz, 3H), 6.56(d, J=8.5Hz, 1H), 3.92(d, J=8.6Hz, 1H), 3.64(s, 2H ),3.02(s,2H),2.80(s,2H),2.62(s,2H),2.35(s,2H),1.92(s,2H),1.85(s,7H),1.76(s,4H) , 1.66 (d, J=12.8Hz, 2H).

Example 8 : V-12 1-( Adamantane -2- base )-3-(4-(4- cyano ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₄ -cyanobenzyl bromide (0.20g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3 CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-12. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=394.26;

1H NMR (600MHz, CDCl3) δ7.61(d, J=8.2Hz, 2H), 7.44(d, J=8.1Hz, 2H), 6.55(d, J=8.5Hz, 1H), 3.91(d, J =8.6Hz,1H),3.58(s,2H),3.01(s,2H),2.78(s,2H),2.58(s,2H),2.31(s,2H),1.92(s,2H),1.84 (s, 7H), 1.74 (d, J=11.7Hz, 4H), 1.65 (d, J=12.7Hz, 2H).

Example 9 : V-13 1-( Adamantane -2- base )-3-(4-(4- tert-butyl ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₄ -tert-butylbenzyl bromide (0.23g, 1mmol), K2CO3 (0.28g, 2mmol), _{CH 3} CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-13. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=425.32;

1H NMR (600MHz, CDCl3) δ7.26(d, J=8.2Hz, 2H), 7.15(d, J=8.2Hz, 2H), 6.51(d, J=8.5Hz, 1H), 3.84(d, J =8.6Hz,1H),3.41(s,2H),2.92(s,2H),2.76(s,2H),2.49(s,2H),2.16(s,2H),1.84(s,2H),1.77 (s, 7H), 1.68 (s, 4H), 1.58 (d, J=12.8Hz, 2H), 1.24 (s, 9H).

Example 10 : V-14 1-( Adamantane -2- base )-3-(4-(3,4- Difluoro ) Benzylpiperazine -1- base ) Urea

1-(adamantan- ₂ -yl)-3-piperazinylurea (0.3g, 1mmol), 3,4-difluorobenzyl bromide (0.21g, 1mmol), K2CO3 ₍ 0.28g, 2mmol), CH ₃ CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-14. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=405.25;

1H NMR (600MHz, CDCl3) δ7.11–7.06 (m, 1H), 7.02 (dd, J = 18.3, 8.2Hz, 1H), 6.95 (s, 1H), 6.49 (d, J = 8.5Hz, 1H) ,3.84(d,J＝8.5Hz,1H),3.39(s,2H),2.93(s,2H),2.72(s,2H),2.50(s,2H),2.19(s,2H),1.85( s, 2H), 1.77 (s, 7H), 1.68 (s, 4H), 1.58 (d, J=12.8Hz, 2H).

Example 11 : V-15 1-( Adamantane -2- base )-3-(4-(2,4- Difluoro ) Benzylpiperazine -1- base ) Urea

1-(adamantan- ₂ -yl)-3-piperazinylurea (0.3g, 1mmol), 2,4-difluorobenzyl bromide (0.21g, 1mmol), K2CO3 ₍ 0.28g, 2mmol), CH ₃ CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-15. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=405.25;

1H NMR (600MHz, CDCl3) δ7.34(dd, J=15.1, 8.3Hz, 1H), 6.85(t, J=8.3Hz, 1H), 6.79(t, J=9.4Hz, 1H), 6.55(d ,J=8.5Hz,1H),3.91(d,J=8.5Hz,1H),3.54(s,2H),3.00(s,2H),2.81(s,2H),2.57(s,2H),2.31 (s, 2H), 1.92 (s, 2H), 1.84 (s, 7H), 1.75 (s, 4H), 1.65 (d, J=12.8Hz, 2H).

Example 12 : V-16 1-( Adamantane -2- base )-3-(4-(2- fluorine -6- Trifluoromethyl ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), 2-fluoro-6-trifluoromethylbenzyl bromide (0.26g, 1mmol), K ₂ CO ₃ (0.28g , 2mmol), CH ₃ CN (50ml) according to the reaction 3.2 of the general synthesis method (1), the target compound V-16 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=455.23;

1H NMR (600MHz, CDCl3) δ7.41 (d, J = 7.9Hz, 1H), 7.31 (dd, J = 13.4, 7.9Hz, 1H), 7.19 (dd, J = 16.6, 7.7Hz, 1H), 6.51 (d,J=8.5Hz,1H),3.84(d,J=8.6Hz,1H),3.62(s,2H),2.88(s,2H),2.71(s,2H),2.42(s,2H) , 2.33 (s, 2H), 1.85 (s, 2H), 1.77 (s, 7H), 1.68 (s, 4H), 1.58 (d, J=12.8Hz, 2H).

Example 13 : V-17 1-( Adamantane -2- base )-3-(4-(2- Trifluoromethoxy ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₂ -trifluoromethoxybenzyl bromide (0.26g, 1mmol), K2CO3 ₍ 0.28g, 2mmol) , CH ₃ CN (50ml) according to the reaction 3.2 of the general synthesis method (1), the target compound V-17 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=453.24;

1H NMR (600MHz, CDCl3) δ7.52(dd, J=7.0, 2.1Hz, 1H), 7.29(d, J=4.9Hz, 2H), 7.23(d, J=7.5Hz, 1H), 6.57(d ,J=8.4Hz,1H),3.92(d,J=8.5Hz,1H),3.60(s,2H),3.00(s,2H),2.81(s,2H),2.57(s,2H),2.33 (s, 2H), 1.92 (s, 2H), 1.85 (s, 7H), 1.75 (s, 4H), 1.65 (d, J=12.9Hz, 2H).

Example 14 : V-18 1-( Adamantane -2- base )-3-(4-(4- chlorine ) Benzylpiperazine -1- base ) Urea

1-(Adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₄ -chlorobenzyl bromide (0.21g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3CN (50ml) According to the reaction 3.2 of the general synthesis method (1), the target compound V-18 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=403.21;

1H NMR (600MHz, CDCl3) δ7.33(s, 4H), 6.55(d, J=8.1Hz, 1H), 3.88(d, J=7.4Hz, 1H), 3.58(s, 2H), 2.86(d ,J=138.5Hz,6H),2.34(s,2H),1.92(s,2H),1.85(d,J=8.3Hz,7H),1.75(s,4H),1.66(d,J=12.8Hz ,2H).

Example 15 : V-19 1-( Adamantane -2- base )-3-(4-(2- methyl ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₂ -methylbenzyl bromide (0.19g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3 CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-19. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=383.27;

1H NMR (600MHz, CDCl3) δ7.22(d, J=7.3Hz, 1H), 7.15(dd, J=10.6, 4.8Hz, 3H), 6.60(d, J=8.1Hz, 1H), 3.91(d ,J＝8.6Hz,1H),3.47(s,2H),2.97(s,2H),2.80(s,2H),2.53(s,2H),2.35(s,3H),2.27(s,2H) , 1.92 (s, 2H), 1.84 (s, 7H), 1.75 (s, 4H), 1.65 (d, J=12.7Hz, 2H).

Example 16 : V-20 1-( Adamantane -2- base )-3-(4-(4- Trifluoromethyl ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₄ -trifluoromethylbenzyl bromide (0.24g, 1mmol), K2CO3 ₍ 0.28g, 2mmol), CH ₃ CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-20. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=436.24;

1H NMR (600MHz, CDCl3) δ7.57(d, J=8.1Hz, 2H), 7.44(d, J=8.0Hz, 2H), 6.56(d, J=8.5Hz, 1H), 3.92(d, J =8.6Hz,1H),3.57(s,2H),3.00(s,2H),2.80(s,2H),2.59(s,2H),2.30(s,2H),1.92(s,2H),1.85 (s, 7H), 1.75 (s, 4H), 1.65 (d, J=12.8Hz, 2H).

Example 17 : V-21 1-( Adamantane -2- base )-3-(4-(2,5- Difluoro ) Benzylpiperazine -1- base ) Urea

1-(adamantan- ₂ -yl)-3-piperazinylurea (0.3g, 1mmol), 2,5-difluorobenzyl bromide (0.21g, 1mmol), K2CO3 ₍ 0.28g, 2mmol), CH ₃ CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-21. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=405.25;

1H NMR (600MHz, CDCl3) δ7.12(m, 1H), 6.99(m, 1H), 6.92(m, 1H), 6.55(d, J=8.4Hz, 1H), 3.91(d, J=8.5Hz ,1H),3.56(s,2H),3.01(s,2H),2.83(s,2H),2.59(s,2H),2.34(s,2H),1.92(s,2H),1.85(s, 7H), 1.75(s, 4H), 1.65(d, J=12.8Hz, 2H).

Example 18 : V-22 1-( Adamantane -2- base )-3-(4-(3- chlorine ) Benzylpiperazine -1- base ) Urea

1-(Adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₃ -chlorobenzyl bromide (0.21g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3CN (50ml) According to the reaction 3.2 of the general synthesis method (1), the target compound V-22 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H]+: m/z=403.21;

1H NMR (600MHz, CDCl3) δ7.32(s, 1H), 7.24(m, 2H), 7.19(m, 1H), 6.56(d, J=8.4Hz, 1H), 3.91(d, J=8.6Hz ,1H),3.49(s,2H),3.00(s,2H),2.81(s,2H),2.57(s,2H),2.27(s,2H),1.92(s,2H),1.84(m, 7H), 1.75 (m, 4H), 1.65 (d, J=13.3Hz, 2H).

Example 19 : V-23 1-( Adamantane -2- base )-3-(4-(2- cyano ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₂ -cyanobenzyl bromide (0.20g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3 CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-23. The yield of the reaction was 90%.

ESI-MS[M+H]+: m/z=394.26;

1H NMR (600MHz, CDCl3) δ7.65(d, J=7.6Hz, 1H), 7.59–7.52(m, 2H), 7.37(t, J=7.5Hz, 1H), 6.57(d, J=8.5Hz ,1H),3.91(d,J＝8.6Hz,1H),3.73(s,2H),3.00(s,2H),2.82(s,2H),2.59(s,2H),2.42(s,2H) , 1.92 (s, 2H), 1.85 (s, 7H), 1.75 (s, 4H), 1.66 (d, J=12.8Hz, 2H).

Example 20 : V-24 1-( Adamantane -2- base )-3-(4-(3- fluorine ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₃ -fluorobenzyl bromide (0.19g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3CN (50ml) According to the reaction 3.2 of the general synthesis method (1), the target compound V-24 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=387.24;

1H NMR (600MHz, CDCl3) δ7.26(m, 1H), 7.08–7.03(m, 2H), 6.95(m, 1H), 6.57(d, J=8.3Hz, 1H), 3.91(d, J= 8.6Hz,1H),3.51(s,2H),3.00(s,2H),2.81(s,2H),2.58(s,2H),2.28(s,2H),1.92(s,2H),1.84( s, 7H), 1.75 (s, 4H), 1.65 (d, J=12.8Hz, 2H).

Example twenty one : V-25 1-( Adamantane -2- base )-3-(4-(4- fluorine ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₄ -fluorobenzyl bromide (0.19g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3CN (50ml) According to the reaction 3.2 of the general synthesis method (1), the target compound V-25 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=387.25;

1H NMR (600MHz, CDCl3) δ7.81-7.57 (m, 2H), 7.21–7.03 (m, 2H), 6.53 (d, J = 8.3Hz, 1H), 3.89 (d, J = 8.6Hz, 1H) ,3.50(s,2H),3.03(s,2H),2.82(s,2H),2.56(s,2H),2.27(s,2H),1.91(s,2H),1.82(s,7H), 1.73 (s, 4H), 1.65 (d, J=12.8Hz, 2H).

Example twenty two : V-26 1-( Adamantane -2- base )-3-(4-(2- chlorine ) Benzylpiperazine -1- base ) Urea

1-(Adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₂ -chlorobenzyl bromide (0.21g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3CN (50ml) According to the reaction 3.2 of the general synthesis method (1), the target compound V-26 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=403.22;

1H NMR (600MHz, CDCl3) δ7.44(d, J=8.6Hz, 1H), 7.35(d, J=7.9Hz, 1H), 7.24(t, J=6.9Hz, 1H), 7.19(t, J =7.6Hz,1H),6.58(d,J=8.5Hz,1H),3.92(d,J=8.5Hz,1H),3.64(s,2H),3.00(s,2H),2.85(s,2H ),2.58(s,2H),2.38(s,2H),1.92(s,2H),1.85(s,7H),1.76(d,J=12.0Hz,4H),1.66(d,J=12.8Hz ,2H).

Example twenty three : V-27 1-( Adamantane -2- base )-3-(4-(3,5- Difluoro ) Benzylpiperazine -1- base ) Urea

1-(adamantan- ₂ -yl)-3-piperazinylurea (0.3g, 1mmol), _3,5 -difluorobenzyl bromide (0.21g, 1mmol), K2CO3 (0.28g, 2mmol), CH ₃ CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-27. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=405.24;

1H NMR (600MHz, CDCl3) δ6.87(s, 2H), 6.70(s, 1H), 6.56(d, J=8.2Hz, 1H), 3.91(d, J=8.0Hz, 1H), 3.50(s ,2H),3.01(s,2H),2.81(s,2H),2.60(s,2H),2.30(s,2H),1.92(s,2H),1.84(s,7H),1.74(d, J=9.1Hz, 4H), 1.65(d, J=12.8Hz, 2H).

Example twenty four : V-28 1-( Adamantane -2- base )-3-(4-(3,4 – Dichloro ) Benzylpiperazine -1- base ) Urea

1-(adamantan- ₂ -yl)-3-piperazinylurea (0.3g, 1mmol), 3,4-dichlorobenzyl bromide (0.24g, 1mmol), K2CO3 ₍ 0.28g, 2mmol), CH ₃ CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-28. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=437.18;

1H NMR (600MHz, CDCl3) δ7.42(d, J=1.8Hz, 1H), 7.38(d, J=8.2Hz, 1H), 7.15(dd, J=8.2, 1.9Hz, 1H), 6.55(d ,J=8.5Hz,1H),3.91(d,J=8.6Hz,1H),3.46(s,2H),3.00(s,2H),2.79(s,2H),2.58(s,2H),2.27 (s, 2H), 1.92 (s, 2H), 1.84 (s, 7H), 1.74 (d, J=9.2Hz, 4H), 1.65 (d, J=12.7Hz, 2H).

Example 25 : V-29 1-( Adamantane -2- base )-3-(4-(2 – Trifluoromethyl ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₂ -trifluoromethylbenzyl bromide (0.24g, 1mmol), K2CO3 ₍ 0.28g, 2mmol), CH ₃ CN (50ml) was operated according to Reaction 3.2 of General Synthesis (1) to obtain the target compound V-29. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=437.26;

1H NMR (600MHz, CDCl3) δ7.76(d, J=7.8Hz, 1H), 7.63(d, J=7.8Hz, 1H), 7.52(t, J=7.6Hz, 1H), 7.34(t, J =7.6Hz,1H),6.59(d,J=8.5Hz,1H),3.92(d,J=8.5Hz,1H),3.69(s,2H),3.00(s,2H),2.81(s,2H ),2.59(s,2H),2.36(s,2H),1.92(s,2H),1.85(s,7H),1.76(d,J=12.5Hz,4H),1.66(d,J=12.8Hz ,2H).

Example 26 : V-30 1-( Adamantane -2- base )-3-(4-(2- fluorine ) Benzylpiperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), ₂ -fluorobenzyl bromide (0.19g, 1mmol), K2CO3 (0.28g, 2mmol ₎ , _CH3CN (50ml) According to the reaction 3.2 of the general synthesis method (1), the target compound V-30 was obtained. The yield of the reaction was 90%.

ESI-MS[M+H] ⁺ : m/z=387.26;

1H NMR (400MHz, CDCl3) δ7.29(t, J=8.2Hz, 1H), 7.21–7.15(m, 1H), 7.04(t, J=7.1Hz, 1H), 6.96(t, J=9.4Hz ,1H),6.49(d,J=8.5Hz,1H),3.83(d,J=8.6Hz,1H),3.52(s,2H),2.91(s,2H),2.76(s,2H),2.51 (s, 2H), 2.25 (s, 2H), 1.84 (s, 2H), 1.77 (s, 7H), 1.67 (s, 4H), 1.57 (d, J=12.9Hz, 2H).

Example 27 : V-31 1-( Adamantane -2- base )-3-(4-(2- pyridyl ) Piperazine -1- base ) Urea

1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), 2-bromopyridine (0.16g, 1mmol), PdCl ₂ (0.01g, 0.05mmol), cesium carbonate (1g, 3mmol) in toluene (50ml), according to the reaction 3.3 in the general synthesis method (1), the compound V31 was obtained. The reaction yield is 72%.

ESI-MS[M+H] ⁺ : m/z=356.24;

1H NMR (400MHz, CDCl3) δ8.13(d, J=3.8Hz, 1H), 7.46–7.40(m, 1H), 6.60(t, J=6.2Hz, 2H), 6.56(d, J=8.6Hz ,1H),4.13(s,2H),3.87(d,J=8.6Hz,1H),2.81(m,6H),1.87(s,2H),1.78(s,7H),1.69(d,J= 11.1Hz, 4H), 1.59 (d, J = 12.9Hz, 2H).

Example 28 : V-32 1-( Adamantane -2- base )-3-(4-(3- Trifluoromethylphenyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), 1-bromo-3-trifluoromethylbenzene (0.23g, 1mmol), palladium acetylacetonate (0.02g, 0.05mmol), cesium carbonate (1g, 3mmol) was added to toluene (50ml), and the compound V32 was obtained according to reaction 3.3 in general synthesis method (1).

ESI-MS[M+H] ⁺ : m/z=423.24;

1H NMR (400MHz, CDCl3) δ7.37(t, J=8.2Hz, 1H), 7.12(d, J=6.5Hz, 2H), 7.08(d, J=8.5Hz, 1H), 6.58(d, J =8.6Hz,1H),3.94(d,J=8.6Hz,1H),3.16(m,8H),1.94(s,2H),1.85(s,7H),1.75(s,4H),1.66(d , J=12.9Hz, 2H).

Example 29 : V-33 1-( Adamantane -2- base )-3-(4-(3,4- Dichlorophenyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), 1-bromo-3,4-dichlorobenzene (0.23g, 1mmol), palladium acetylacetonate (0.02g, 0.05mmol), cesium carbonate (1g, 3mmol) was added to toluene (50ml), and the compound V33 was obtained according to reaction 3.3 in general synthesis method (1). The reaction yield is 75%.

ESI-MS[M+K] ⁺ : m/z=462.29;

1H NMR (400MHz, CDCl3) δ7.22(m, 1H), 6.85(m, 2H), 6.57(d, J=8.6Hz, 1H), 3.94(d, J=8.6Hz, 1H), 3.11(m , 8H), 1.93 (s, 2H), 1.85 (s, 7H), 1.74 (d, J=9.5Hz, 4H), 1.66 (d, J=12.4Hz, 2H).

Example 30 : V-34 1-( Adamantane -2- base )-3-(4-(4- cyanobenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve in 25ml CH ₂ Cl ₂ , add 4-cyanobenzenesulfonyl chloride ( 0.20g, 1mmol), according to the reaction 3.1 operation of the general synthesis method (1), the target compound V-34 was obtained. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=444.21;

1H NMR (400MHz, CDCl3) δ7.94–7.85 (m, 4H), 6.22 (d, J = 8.3Hz, 1H), 3.87 (dt, J = 8.2, 2.7Hz, 1H), 3.27 (m, 8H) ,1.89–1.77(m,9H),1.72(s,2H),1.60(s,4H).

Example 31 : V-35 1-( Adamantane -2- base )-3-(4-(2- Methylbenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve in 25ml CH ₂ Cl ₂ , add 2-methylbenzenesulfonyl chloride ( 0.19g, 1mmol), according to the reaction 3.1 operation of the general synthesis method (1), the target compound V-35 was obtained. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=433.22;

1H NMR (400MHz, CDCl3) δ7.94 (dd, J = 8.2, 1.1Hz, 1H), 7.50 (td, J = 7.5, 1.2Hz, 1H), 7.35 (dd, J = 7.3, 3.3Hz, 2H) ,6.40(d,J=8.5Hz,1H),3.90(d,J=8.5Hz,1H),3.60(s,2H),3.01(s,4H),2.63(m,5H),1.86(d, J=24.0Hz, 9H), 1.74(s, 2H), 1.69–1.60(m, 4H).

Example 32 : V-36 1-( Adamantane -2- base )-3-(4-(4- chlorine -2- Trifluoromethylbenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) dissolved in 25ml CH ₂ Cl ₂ , add 4-chloro-2- Trifluoromethylbenzenesulfonyl chloride (0.28 g, 1 mmol) was operated according to Reaction 3.1 of General Synthesis (1) to obtain the target compound V-36. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=521.15;

1H NMR (400MHz, CDCl3) δ8.21–8.14 (m, 1H), 7.96–7.89 (m, 1H), 7.78–7.70 (m, 2H), 6.39 (d, J=8.4Hz, 1H), 3.90 ( d,J=8.5Hz,1H), 3.72(s,2H), 2.84(m,6H), 1.91–1.78(m,9H), 1.74(s,2H), 1.70–1.60(m,4H).

Example 33 : V-37 1-( Adamantane -2- base )-3-(4-(3- fluorine -4- Methylbenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve it in 25ml CH ₂ Cl ₂ , add 3-chloro-4 methylbenzene Sulfonyl chloride (0.21 g, 1 mmol) was operated according to reaction 3.1 of general synthesis method (1) to obtain the target compound V-37. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=450.21;

1H NMR (400MHz, CDCl3) δ7.43 (dt, J = 14.9, 7.7Hz, 3H), 6.24 (d, J = 8.2Hz, 1H), 3.87 (d, J = 8.3Hz, 1H), 3.23 (m ,8H), 2.39(s,3H), 1.90–1.78(m,9H), 1.72(s,2H), 1.61(s,4H).

Example 34 : V-38 1-( Adamantane -2- base )-3-(4-(4- fluorine -2- Trifluoromethylbenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve in 25ml _CH2Cl2 , add 4-fluoro- ₂ -trifluoro Toluenesulfonyl chloride (0.26 g, 1 mmol) was operated according to Reaction 3.1 of General Synthesis (1) to obtain the target compound V-38. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=505.19;

1H NMR (400MHz, CDCl3) δ8.06(m, 1H), 8.01(m, 1H), 7.44(t, J=9.1Hz, 1H), 6.23(d, J=8.3Hz, 1H), 3.87(d , J=11.1Hz, 1H), 3.28(m, 8H), 1.90–1.76(m, 9H), 1.72(s, 2H), 1.61(s, 4H).

Example 35 : V-39 1-( Adamantane -2- base )-3-(4-(4- Difluoromethoxybenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve it in 25ml CH ₂ Cl ₂ , add 4-difluoromethoxybenzene Sulfonyl chloride (0.24 g, 1 mmol) was operated according to reaction 3.1 of general synthesis method (1) to obtain the target compound V-39. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=5485.22;

1H NMR (400MHz, CDCl3) δ7.81(d, J=8.8Hz, 2H), 7.32–7.26(m, 2H), 6.64(t, J=72.4Hz, 1H), 6.24(d, J=8.3Hz ,1H), 3.87(d,J=8.3Hz,1H), 2.81(m,8H), 1.89–1.77(m,9H), 1.72(s,2H), 1.60(s,4H).

Example 36 : V-40 1-( Adamantane -2- base )-3-(4-(4- bromine -2- Trifluoromethylbenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantane-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) dissolved in 25ml CH ₂ Cl ₂ , add 4-bromo-2-trifluoro Toluenesulfonyl chloride (0.32 g, 1 mmol) was operated according to Reaction 3.1 of General Synthesis (1) to obtain the target compound V-40. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=565.10,567.10;

1H NMR (400MHz, CDCl3) δ8.03(d, J=8.7Hz, 2H), 7.87(dd, J=8.5, 1.9Hz, 1H), 6.37(d, J=8.4Hz, 1H), 3.90(d , J=8.5Hz, 1H), 3.10(m, 8H), 1.87(d, J=25.6Hz, 9H), 1.74(s, 2H), 1.67(t, J=8.8Hz, 4H).

Example 37 : V-41 1-( Adamantane -2- base )-3-(4-(3- methyl -8- Quinolinesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantane-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) dissolved in 25ml CH ₂ Cl ₂ , add 3-methyl-8-quinol Phenylsulfonyl chloride (0.24g, 1mmol), according to the reaction 3.1 of the general synthesis method (1), the target compound V-41 was obtained. The yield of the reaction was 85%.

ESI-MS [M+H] ⁺ : m/z = 484.23.

Example 38 : V-42 1-( Adamantane -2- base )-3-(4-(3- chlorine -2- Fluorobenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantane-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) dissolved in 25ml CH ₂ Cl ₂ , add 3-chloro-2-fluorobenzene Sulfonyl chloride (0.23 g, 1 mmol) was operated according to reaction 3.1 of general synthesis method (1) to obtain the target compound V-42. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=471.15;

1H NMR (400MHz, CDCl3) δ7.77(td, J=6.2, 3.1Hz, 1H), 7.70–7.64(m, 1H), 7.27(dd, J=9.9, 6.1Hz, 1H), 6.32(d, J＝8.4Hz, 1H), 3.90(d, J＝8.4Hz, 1H), 3.37(m, 8H), 1.90(s, 9H), 1.73(s, 2H), 1.64(dd, J＝10.6, 8.0 Hz, 4H).

Example 39 : V-43 1-( Adamantane -2- base )-3-(4-(2- Trifluoromethylbenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantane-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) dissolved in 25ml CH ₂ Cl ₂ , add 2-trifluoromethylbenzenesulfonate Acyl chloride (0.25g, 1mmol), according to reaction 3.1 of general synthesis method (1), the target compound V-43 was obtained. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=487.21;

1H NMR (400MHz, CDCl3) δ8.18 (dd, J = 5.6, 3.7Hz, 1H), 7.93 (dd, J = 5.6, 3.6Hz, 1H), 7.74 (dd, J = 5.9, 3.4Hz, 2H) ,6.39(d,J=8.4Hz,1H),3.90(d,J=8.5Hz,1H),3.13(m,8H),1.92–1.77(m,9H),1.74(s,2H),1.70– 1.60(m,4H).

Example 40 : V-44 1-( Adamantane -2- base )-3-(4-(8- Quinolinesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve in 25ml CH ₂ Cl ₂ , add 8-quinolinesulfonyl chloride (0.23 g, 1 mmol), according to the operation of reaction 3.1 of the general synthesis method (1), the target compound V-44 was obtained. The yield of the reaction was 85%.

ESI-MS [M+H] ⁺ : m/z = 470.22.

Example 41 : V-45 1-( Adamantane -2- base )-3-(4-(2- Fluorobenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve in 25ml CH ₂ Cl ₂ , add 2-fluorobenzenesulfonyl chloride (0.20 g, 1 mmol), according to the operation of reaction 3.1 of the general synthesis method (1), the target compound V-45 was obtained. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=437.19;

1H NMR (400MHz, CDCl3) δ7.75 (dd, J = 8.1, 1.1Hz, 1H), 7.50 (td, J = 7.4, 1.2Hz, 1H), 7.31 (dd, J = 7.3, 3.3Hz, 2H) ,6.37(d,J=8.5Hz,1H),3.89(d,J=8.4Hz,1H),3.35(m,8H),1.87(s,9H),1.74(s,2H),1.67(dd, J = 10.6, 8.0 Hz, 4H).

Example 42 : V-46 1-( Adamantane -2- base )-3-(4-(3- Trifluoromethylbenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantane-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) dissolved in 25ml CH ₂ Cl ₂ , add 3-trifluoromethylbenzenesulfonate Acyl chloride (0.25g, 1mmol), according to reaction 3.1 of general synthesis method (1), the target compound V-46 was obtained. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=486.19;

1H NMR (400MHz, CDCl3) δ8.05(s, 1H), 7.99(d, J=7.9Hz, 1H), 7.92(d, J=7.9Hz, 1H), 7.75(t, J=7.8Hz, 1H ), 6.23(d, J＝8.3Hz, 1H), 3.87(dt, J＝8.2, 2.8Hz, 1H), 3.25(m, 8H), 1.89–1.76(m, 9H), 1.72(s, 2H) ,1.59(s,4H).

Example 43 : V-47 1-( Adamantane -2- base )-3-(4-(2- chlorine -5- pyridinesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve in 25ml CH ₂ Cl ₂ , add 2-chloro-5-pyridine sulfonate Acyl chloride (0.21g, 1mmol), according to the reaction 3.1 of the general synthesis method (1), the target compound V-47 was obtained. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=454.16;

1H NMR (400MHz, CDCl3) δ8.58 (dd, J = 9.8, 2.4Hz, 1H), 7.89 (ddd, J = 8.8, 3.9, 2.6Hz, 1H), 6.87 (dd, J = 12.8, 8.8Hz, 1H), 6.26(d, J=8.5Hz, 1H), 3.87(d, J=8.3Hz, 1H), 3.64(s, 1H), 3.07(m, 7H), 1.85(d, J=21.7Hz, 9H), 1.72(s, 2H), 1.61(s, 4H).

Example 44 : V-48 1-( Adamantane -2- base )-3-(4-(5- fluorine -2- Methoxybenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) dissolved in 25ml CH ₂ Cl ₂ , add 5-fluoro-2-methoxy Benzenesulfonyl chloride (0.23g, 1mmol), according to the reaction 3.1 of the general synthesis method (1), the target compound V-48 was obtained. The yield of the reaction was 85%.

ESI-MS[M+H]+: m/z=467.21;

1H NMR (400MHz, CDCl3) δ7.63 (dd, J = 7.9, 3.2Hz, 1H), 7.27–7.22 (m, 1H), 7.01 (dd, J = 9.1, 3.9Hz, 1H), 6.39 (d, J＝8.4Hz, 1H), 3.94(s, 3H), 3.89(d, J＝8.4Hz, 1H), 3.72(s, 1H), 2.83(m, 7H), 1.90(s, 2H), 1.83( s,7H), 1.74(s,2H), 1.70–1.61(m,4H).

Example 45 : V-49 1-( Adamantane -2- base )-3-(4-(4- Chlorobenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve in 25ml CH ₂ Cl ₂ , add 4-chlorobenzenesulfonyl chloride (0.21 g, 1 mmol), according to the operation of reaction 3.1 of the general synthesis method (1), the target compound V-49 was obtained. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=453.17;

1H NMR (400MHz, CDCl3) δ7.73 (d, J = 8.6Hz, 2H), 7.56 (d, J = 8.6Hz, 2H), 6.24 (d, J = 8.3Hz, 1H), 3.87 (dt, J =8.2, 2.8Hz, 1H), 3.22(m, 8H), 1.84(dd, J=13.9, 7.8Hz, 9H), 1.72(s, 2H), 1.60(s, 4H).

Example 46 : V-50 1-( Adamantane -2- base )-3-(4-(4- Trifluoromethoxybenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinyl urea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve in 25ml CH ₂ Cl ₂ , add 4-trifluoromethoxybenzene Sulfonyl chloride (0.26 g, 1 mmol) was operated according to reaction 3.1 of general synthesis method (1) to obtain the target compound V-50. The yield of the reaction was 85%.

ESI-MS[M+H] ⁺ : m/z=503.20;

1H NMR (400MHz, CDCl3) δ7.78(d, J=8.8Hz, 2H), 7.33(d, J=8.3Hz, 2H), 6.17(d, J=8.3Hz, 1H), 3.80(dt, J =8.2, 2.7Hz, 1H), 3.16(m, 8H), 1.83–1.68(m, 9H), 1.65(s, 2H), 1.52(s, 4H).

Example 47 : V-51 1-( Adamantane -2- base )-3-(4-(4- Methylbenzenesulfonyl ) Piperazine -1- base ) Urea

Take 1-(adamantan-2-yl)-3-piperazinylurea (0.3g, 1mmol), DIPEA (0.26g, 2mmol) and dissolve in 25ml CH ₂ Cl ₂ , add 4-methylbenzenesulfonyl chloride ( 0.19g, 1mmol), according to the reaction 3.1 of the general synthesis method (1), the target compound V-51 was obtained. The yield of the reaction was 87%.

ESI-MS[M+H] ⁺ : m/z=433.22;

1H NMR (600MHz, CDCl3) δ7.67(d, J=8.2Hz, 2H), 7.36(d, J=8.1Hz, 2H), 6.25(d, J=8.3Hz, 1H), 3.86(d, J =8.3Hz,1H),3.22(m,8H),2.46(s,3H),1.82(dd,J=33.8,19.9Hz,9H),1.72(s,2H),1.63–1.56(m,4H) .

Example 48 : V-52 1-(5- Hydroxyadamantane -2- base )-3-(4- Benzylpiperazine -1- base ) Urea

1-Amino-4-benzylpiperazine (0.19g, 1mmol), 4-isocyanatoadamantan-1-ol (0.19g, 1mmol) were dissolved in CH ₂ Cl ₂ (25ml) according to the synthetic general method (1), Compound V-52 was obtained. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=385.25;

1H NMR (600MHz, CDCl3) δ7.79(d, J=7.0Hz, 3H), 6.56(d, J=8.5Hz, 1H), 3.91(d, J=8.6Hz, 1H), 3.63(s, 2H ),3.54(S,1H),3.02(s,2H),2.78(s,2H),2.62(s,2H),2.34(s,2H),1.92(s,2H),1.83(s,6H) , 1.76 (s, 4H), 1.66 (d, J=12.8Hz, 2H).

Example 49 : V-53 1-((5- aminocarbonyl ) Adamantane -2- base )-3-(4- Benzylpiperazine -1- base ) Urea

1-Amino-4-benzylpiperazine (0.19g, 1mmol), 4-isocyanate adamantane-1-carboxamide (0.22g, 1mmol) were dissolved in CH ₂ Cl ₂ (25ml) and operated according to the general synthesis method (1), Compound V-53 was obtained. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=412.26;

1H NMR (600MHz, CDCl3) δ7.78(d, J=7.0Hz, 3H), 6.56(d, J=8.5Hz, 1H), 3.91(d, J=8.6Hz, 1H), 3.63(s, 2H ),3.02(s,2H),2.80(s,2H),2.62(s,2H),2.35(s,2H),1.92(s,2H),1.85(s,6H),1.76(s,4H) , 1.66 (d, J=12.8Hz, 2H), 1.57 (S, 2H).

Example 50 : V-54 1-((5- Aminosulfonyl ) Adamantane -2- base )-3-(4- Benzylpiperazine -1- base ) Urea

1-Amino-4-benzylpiperazine (0.19g, 1mmol), 4-isocyanate adamantane-1-sulfonamide (0.26g, 1mmol) were dissolved in CH ₂ Cl ₂ (25ml) according to the synthetic general method (1) , to obtain compound V-54. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=448.23;

1H NMR (600MHz, CDCl3) δ7.79(d, J=7.0Hz, 3H), 6.56(d, J=8.5Hz, 1H), 3.92(d, J=8.6Hz, 1H), 3.61(s, 2H ),3.02(s,2H),2.80(s,2H),2.62(s,2H),2.35(s,2H),2.04(S,2H),1.92(s,2H),1.85(s,6H) , 1.76 (s, 4H), 1.66 (d, J=12.8Hz, 2H).

Example 51 : V-55 1-((5- Methanesulfonyl ) Adamantane -2- base )-3-(4- Benzylpiperazine -1- base ) Urea

1-Amino-4-benzylpiperazine (0.19 g, 1 mmol), 4-isocyanate adamantane-1-sulfonylmethyl (0.26 g, 1 mmol) were dissolved in CH ₂ Cl ₂ (25 ml) according to the general method of synthesis (1 ) operation to obtain compound V-55. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=447.24;

1H NMR (600MHz, CDCl3) δ7.77(d, J=7.0Hz, 3H), 6.56(d, J=8.5Hz, 1H), 3.92(d, J=8.6Hz, 1H), 3.63(s, 2H ),3.02(s,2H),2.84(S,3H),2.80(s,2H),2.62(s,2H),2.35(s,2H),1.92(s,2H),1.85(s,6H) , 1.76 (s, 4H), 1.66 (d, J=12.8Hz, 2H).

Example 52 : V-56 1-(5- Fluoroadamantane -2- base )-3-(4- Benzylpiperazine -1- base ) Urea

1-Amino-4-benzylpiperazine (0.19 g, 1 mmol), 4-isocyanate adamantane-1-fluoro (0.20 g, 1 mmol) were dissolved in CH ₂ Cl ₂ (25 ml) and operated according to the general synthesis method (1), Compound V-56 is obtained. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=387.25;

1H NMR (600MHz, CDCl3) δ7.79(d, J=7.0Hz, 3H), 6.57(d, J=8.5Hz, 1H), 3.92(d, J=8.6Hz, 1H), 3.64(s, 2H ),3.02(s,2H),2.79(s,2H),2.62(s,2H),2.35(s,2H),1.92(s,2H),1.83(s,6H),1.76(s,4H) , 1.66 (d, J=12.8Hz, 2H).

Example 53 : V-57 1-(5- Hydroxyadamantane -2- base )-3-(4-((2- methyl ) Benzyl ) Piperazine -1- base ) Urea

1-Amino-4-((2-methyl)benzyl)piperazine (0.21g, 1mmol), 4-isocyanatoadamantan-1-ol (0.19g, 1mmol) were dissolved in CH ₂ Cl ₂ (25ml) according to Synthetic general method (1) operation, to obtain compound V-57. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=399.27;

1H NMR (600MHz, CDCl3) δ7.65(d, J=7.6Hz, 1H), 7.57–7.52(m, 2H), 7.37(t, J=7.5Hz, 1H), 6.58(d, J=8.5Hz ,1H),3.91(d,J=8.6Hz,1H),3.72(s,2H),3.61(S,1H),3.00(s,2H),2.82(s,2H),2.59(s,2H) , 2.42 (s, 2H), 1.92 (s, 2H), 1.85 (s, 6H), 1.75 (s, 4H), 1.66 (d, J=12.8Hz, 2H).

Example 54 : V-58 1-((5- aminocarbonyl ) Adamantane -2- base )-3-(4-((2- methyl ) Benzyl ) Piperazine -1- base ) Urea

1-Amino-4-((2-methyl)benzyl)piperazine (0.21 g, 1 mmol), 4-isocyanatoadamantane-1-carboxamide (0.22 g, 1 mmol) dissolved in CH ₂ Cl ₂ (25 ml) According to the general synthesis method (1), the compound V-58 was obtained. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=426.28;

1H NMR (600MHz, CDCl3) δ7.66(d, J=7.6Hz, 1H), 7.58–7.52(m, 2H), 7.37(t, J=7.5Hz, 1H), 6.57(d, J=8.5Hz ,1H),3.91(d,J＝8.6Hz,1H),3.73(s,2H),3.00(s,2H),2.82(s,2H),2.59(s,2H),2.42(s,2H) , 1.92 (s, 2H), 1.85 (s, 6H), 1.75 (s, 4H), 1.66 (d, J=12.8Hz, 2H), 1.57 (S, 2H).

Example 55 : V-59 1-((5- Aminosulfonyl ) Adamantane -2- base )-3-(4-((2- methyl ) Benzyl ) Piperazine -1- base ) Urea

1-Amino-4-((2-methyl)benzyl)piperazine (0.21 g, 1 mmol), 4-isocyanatoadamantane-1-sulfonamide (0.26 g, 1 mmol) dissolved in CH ₂ Cl ₂ (25 ml) According to the general synthesis method (1), the compound V-59 was obtained. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=462.25;

1H NMR (600MHz, CDCl3) δ7.69(d, J=7.6Hz, 1H), 7.59(m, 2H), 7.37(t, J=7.5Hz, 1H), 6.57(d, J=8.5Hz, 1H ),3.91(d,J＝8.6Hz,1H),3.73(s,2H),3.00(s,2H),2.82(s,2H),2.59(s,2H),2.42(s,2H),2.04 (S, 2H), 1.92 (s, 2H), 1.85 (s, 6H), 1.75 (s, 4H), 1.66 (d, J=12.8Hz, 2H).

Example 56 : V-60 1-((5- Methylsulfonyl ) Adamantane -2- base )-3-(4-((2- methyl ) Benzyl ) Piperazine -1- base ) Urea

1-Amino-4-((2-methyl)benzyl)piperazine (0.21 g, 1 mmol), 4-isocyanatoadamantane-1-sulfonylmethyl (0.26 g, 1 mmol) were dissolved in CH ₂ Cl ₂ ( 25ml) according to the general synthesis method (1) to obtain compound V-60. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=461.25;

1H NMR (600MHz, CDCl3) δ7.65(d, J=7.6Hz, 1H), 7.58(m, 2H), 7.37(t, J=7.5Hz, 1H), 6.57(d, J=8.5Hz, 1H ),3.91(d,J＝8.6Hz,1H),3.73(s,2H),3.00(s,2H),2.87(S,3H)2.82(s,2H),2.59(s,2H),2.42( s, 2H), 1.91 (s, 2H), 1.85 (s, 6H), 1.75 (s, 4H), 1.65 (d, J=12.8Hz, 2H).

Example 57 : V-61 1-(5- Fluoroadamantane -2- base )-3-(4-((2- methyl ) Benzyl ) Piperazine -1- base ) Urea

1-Amino-4-((2-methyl)benzyl)piperazine (0.21 g, 1 mmol), 4-isocyanate adamantane-1-fluoro (0.20 g, 1 mmol) were dissolved in CH ₂ Cl ₂ (25 ml) according to Synthetic general method (1) operation, to obtain compound V-61. The yield of the reaction was 80%.

ESI-MS[M+H] ⁺ : m/z=401.26;

1H NMR (600MHz, CDCl3) δ7.66(d, J=7.6Hz, 1H), 7.59–7.51(m, 2H), 7.37(t, J=7.5Hz, 1H), 6.56(d, J=8.5Hz ,1H),3.91(d,J＝8.6Hz,1H),3.73(s,2H),3.00(s,2H),2.82(s,2H),2.61(s,2H),2.42(s,2H) , 1.92 (s, 2H), 1.85 (s, 6H), 1.75 (s, 4H), 1.66 (d, J=12.8Hz, 2H).

Part II: Pharmacological Effects and Pharmaceutical Experimental Examples

Experimental example 1 : compound with 11 beta -HSD1 receptor interaction

This experimental example illustrates that the piperazinyl urea derivatives described in this application interact with Tyr183, coenzymes NAP1292 and Ser170 in the 11β-HSD1 receptor.

The structure of the 11β-HSD1 receptor is known to those skilled in the art. In the process of designing and developing drugs in this field, those skilled in the art usually conduct computer docking experiments to study the mechanism of action. In this application, the eHits software of Canada's SimBioSys Company was used to study the interaction between piperazinyl urea derivatives represented by formula (V) and 11β-HSD1 receptors.

Figure 1 shows the computer simulation of the interaction of the following four compounds with the 11β-HSD1 receptor: V-15 (numbered SIPI7291 in the experiment) (Figure 1A), V-30 (numbered SIPI7349 in the experiment ) (Figure 1B), V-19 (numbered SIPI7295 in the experiment) (Figure 1C) and V-31 (numbered SIPI7336 in the experiment) (Figure 1D). It can be seen from the figure that the two urea-forming amino groups in compounds V-15, V-30 and V-31 form hydrogen bonds with Tyr183 and Ser170 of 11β-HSD1, respectively. And for the three compounds, Tyr183 forms a hydrogen bond with the amino group connected to adamantane, while Ser170 forms a hydrogen bond with another amino group of urea. In compound V19, the two amino groups forming urea form hydrogen bonds with Tyr183, coenzyme NAP1292 and Ser170 respectively.

It can be seen that when interacting with 11β-HSD1, the piperazinyl urea compound provided in the present application forms hydrogen bonds between the two amino groups of urea and Tyr183 and Ser170 of 11β-HSD1 respectively. In some compounds, the two amino groups forming urea form hydrogen bonds with Tyr183, coenzyme NAP1292 and Ser170 respectively. It can be seen that one advantage of the compound described in this application is that the hydrogen bond formed with 11β-HSD1 is generally relatively fixed, that is, Tyr183 forms a hydrogen bond with the amino group connected to adamantane, and Ser170 forms a hydrogen bond with another amino group of urea. Another advantage of the compounds described in the present application is that they can interact with the coenzyme NAP1292. It has been reported in this field that the redox effect of 11β-HSD1 itself has a great relationship with its own coenzyme. The reason why 11β-HSD1 cannot effectively lower blood sugar after negative feedback in clinical practice may be that the compound cannot selectively act on its coenzyme. Therefore, the interaction with the coenzyme has an impact on the selectivity of the compound (see R.Ge et al., 11β-Hydroxysteroid Dehydrogenase 1 Inhibitors as Promising Drugs for the Treatment of Diabetes: Status and Development (11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors as Promising Therapeutic Drugs for Diabetes: Status and Development), Current Medicinal Chemistry, 2010, 17, 412-422). So far, there is no report on other compounds with similar structures and the coenzyme NAP1292 of 11β-HSD1. The present application discloses for the first time that the piperazinyl urea compound can interact with the coenzyme NAP1292, indicating that the compound described in the present application has a unique mechanism of action and also conforms to the development trend of 11β-HSD1 inhibitors.

Experimental example 2 : Determination of the water solubility of compounds

This experimental example shows that the piperazine ring in the compound represented by formula (V) described in this application improves the water solubility of the compound.

In the 2005 and 2010 editions of the Chinese Pharmacopoeia, several categories of "very soluble, easily soluble, soluble, slightly soluble, slightly soluble, very soluble, almost insoluble or insoluble" are used to describe the solubility of drugs in different solvents.

In this application, the following method stipulated in the "Chinese Pharmacopoeia" is used to detect the water solubility of the compound: Weigh 1 g of the test compound that has been ground into a fine powder, and put it in a certain capacity of pure water at 25 °C ± 2 °C, and force it every 5 minutes. Shake for 30 s, observe the dissolution of the test compound within 30 min, and define the water-soluble category according to the following Table 2.

Table 2: Classes of water solubility of compounds

Dissolution category 1g (ml) of solute can be dissolved in less than 1ml of water Very soluble 1g (ml) of solute can be dissolved in 1 to less than 10ml of water soluble 1g (ml) of solute can be dissolved in 10 to less than 30ml of water to dissolve 1g (ml) of solute can be dissolved in 30-less than 100ml of water Slightly soluble lg(ml) of solute can be dissolved in 100-less than 1000ml of water Slightly soluble 1g (ml) of solute can be dissolved in 1000-less than 10000ml of water Very slightly soluble 1g (ml) of solute cannot be completely dissolved in 10000ml of water barely soluble or insoluble

Select seven compounds in the prior art (PR-1: the compound of Example 94 in the application of CN201280070435.2; PR-2: the compound of Example 5 in the application of CN201280070435.2; PR-3: No. 165 of the specification in the application of WO2011060321A1 The second compound on the page; PR-4: the sixth compound on page 165 of the specification in WO2011060321A1 application; PR-5: the compound of Example 31 in the application of CN101137616A; PR-6: the compound of Example 49 in the application of CN101137616A; and PR -7: Example 54 compound in CN101137616A application), as well as the compound described in the present application, under the condition that the compound is not salified and is salified, the water solubility of the compound is detected.

In this example, the compound was formed into the hydrochloride salt. Those skilled in the art should understand that the compound can also be formed into other inorganic acid salts or organic acid salts, or inorganic alkali salts or organic alkali salts according to common methods in the art.

The method for the compound to form a hydrochloride : Take 1 g of the compound to be salified into a fine powder, slowly add it to 20 ml of ethyl acetate hydrogen chloride (1 mol/L) solution, a white solid is precipitated, and stir for 2 hours to fully salt the compound. Filter to obtain a filter cake, and dry the filter cake under reduced pressure at 40° C. for 6 hours to obtain a dry hydrochloride compound.

The water solubility test results of the tested compounds and compound hydrochlorides are shown in Table 3.

Table 3: Test results of water solubility of compounds and compound hydrochlorides

It can be seen that an important advantage of the compounds described in the present application is that, compared with the compounds in the prior art, piperazine rings are introduced into the piperazinyl urea derivatives described in the present application, so that the water solubility of the piperazinyl urea compounds The property is significantly improved, and the pharmacokinetics is better, so the drug-making property is good, which is beneficial to the production, administration and disease treatment of the compound.

Experimental example 3 : Piperazinyl urea derivatives _IC50 Determination of

In this experimental example, the IC ₅₀ of the compounds in Table 1 represented by the formula (V) of the present application when inhibiting the activity of 11β-HSD1 was determined, and the IC ₅₀ of some compounds when the activity of 11β-HSD2 was also tested.

_IC50 is an important parameter for a compound to inhibit a target receptor. For determination of IC50, ₅₀ mM glycyrrhetinic acid in 100% DMSO solution was prepared respectively. Tris assay buffer solutions of 250 μM glycyrrhetinic acid (final concentration 50 μM) were then prepared. The compound to be assayed was dissolved in Tris assay buffer at a ratio of 1:5 to prepare 8 doses, and the experiment was repeated twice with an initial concentration of 50 μM. Transfer 10 μl of all concentrations of the reference compound glycyrrhetinic acid and the compound to be tested into a 96-well plate. Prepare 1.6 mg/ml Tris assay buffer (final concentration 0.32 mg/ml), add 10 μl to a 96-well plate. Tris assay buffer of 1.33 μM Cortisone and 333 μM NADPH was prepared, and 30 ul was added to a 96-well plate. Centrifuge at 1000 rpm for 1 min and incubate the plate at 37°C for 2 hours. Prepare the reconstitution buffer solution (50mM phosphate buffer, PH7.0, 0.8M KF) of each detection conjugate (HTRE cortisone conjugate) according to the drug instruction of cortisone, add 50μl of each conjugate To a 384-well plate, incubate the 384-well plate for 2 hours at room temperature, then use a 665/620 ratio.

The _IC50 values for the compounds described herein are shown in Table 4 below.

Table 4: _IC50 binding of compounds described in this application to 11β-HSD1 and 11β-HSD2.

It can be seen from Table 4 that the compounds described in this application have higher activity and better binding to 11β-HSD1, with a lower IC ₅₀ , while the compounds basically do not bind to 11β-HSD2.

The IC ₅₀ of the compounds in the prior art in the field of binding to 11β-HSD1 is basically in the range of 1-500nm, and the activity is relatively appropriate. If the activity is too high or too low, it will not have good druggability, if it is too high, it will easily cause side effects, and if it is too low, it will be difficult to achieve pharmacological activity (see patent applications CN101137616A, US2010222316A1). The compounds described in this application shown in Table 2 are basically between 20 and 500 nm. Therefore, the activity of the compound described in the present application is basically equivalent to the high activity compound in the prior art, and the water solubility is much improved.

Experimental example 4 : Pharmacodynamic experiment of said compound

In this experimental example, the in vivo efficacy of the compound described in this application was detected by detecting the inhibition of cortisol content in the body after oral administration of glucose.

The following compounds were selected for this experiment:

Compound number corresponding compound Molecular weight (MW) 1 V-31 (SIPI7336) 401.55 2 V-30 (SIPI7349) 386.51 3 V-15 (SIPI7291) 404.50 4 V-23 (SIPI7299) 393.53 5 V-19 (SIPI7295) 382.54

Glycyrrhetinic acid (Sigma Aldrich, product number G10105) was used as a positive control. Compounds and controls were dissolved using DMSO 0.5% methylcellulose (abbreviated as MC)

Adult C57BL/6 mice aged 7-8 weeks were purchased from Shanghai Shrek Animal Center. The animals were reared under a 12-hour day and night light cycle, free to drink water and feed, and start the experiment after one week of adaptation to the environment. All mice were fasted overnight, body weight was measured, and then grouped according to body weight. The test was divided into solvent control group, positive compound group and test drug group, with 8 animals in each group.

After fasting for 16 hours, the animals were grouped according to body weight, and then 2 g/kg of glucose was given by intragastric administration; plasma was collected for 90 minutes to determine the content of plasma cortisol, and the blood was sacrificed, and the plasma was stored at -20°C . Hydrocortisone was detected by the following method: 10 μl of plasma was added to a 384-well plate,

5 μL cortisol-d2

5 μL anti-cortisol-Cryptate (ie: labeled hydrocortisone antibody)

Incubate for 1 hour at room temperature. The test results are represented by mean ± standard error (Mean ± SEM), and the t test is used for statistical analysis, and p<0.05 is considered a significant difference.

Figures 2A and B show the effect of the compounds on plasma cortisol levels. As can be seen from the figure, blood was taken to measure hydrocortisone (cortisol) level after 2 hours after administration, and positive control and test compound V-19 (7295) and V-15 (7291) all significantly reduced hydrocortisone in levels in plasma.

Therefore, combined with the in vitro inhibitory effect of test compounds on 11-HSD-1, it can be shown that compounds V-19(7295) and V-15(7291) also have better inhibitory effects on 11-HSD-1 in vivo.

Claims (22)

1. Compounds as shown in general formula (V), and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof: Wherein, A ¹ , A ² , A ³ and A ⁴ are each independently selected from hydrogen, alkenyl, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxy ring Alkyl, cyano, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroaryl arylalkyl, heteroarylsulfonyl, heterocycle, heterocycloalkyl, heterocyclooxyalkyl, heterocyclesulfonyl, halogen, haloalkyl, -NR ⁴ -[C(R ⁵ R ⁶ )] _P - C(O)-R ⁷ , -O-[C(R ⁸ R ⁹ )] _q -C(O)-R ¹⁰ , -OR ¹¹ , -S-alkyl-, -S(O)-alkyl- , -N(R ¹² R ¹³ ), -CO ₂ R ¹⁴ , -C(O)-N(R ¹⁵ R ¹⁶ ), -C(R ¹⁷ R ¹⁸ )-OR ¹⁹ , -C(R ²⁰ R ²¹ ) -N(R ²² R ²³ ), -C(=NOH)-N(H) ₂ , C(R ^17a R ^18a )-C(O)N(R ²² R ²³ ), -S(O) ₂ -N (R ²⁴ )R ²⁵ or -C(R ^17a R ^18a )-S(O) ₂ -N(R ²⁴ R ²⁵ ); p is 0 or 1; q is 0 or 1; n=1, 2, 3, 4 or 5; m=1, 2, 3, 4 or 5; B is selected from hydrogen, alkenyl, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cyano, cycloalkyl, cycloalkylcarbonyl, Cycloalkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycle, heterocycle Alkyl, heterooxyalkylene, or heterocyclic sulfonyl; R is selected from hydrogen or alkyl _; R and _R are each independently selected from _hydrogen , alkyl, cycloalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroaryl Ring or heterocycloalkyl, or R ₂ and R ₃ together with the atoms they are connected to form a ring selected from cycloalkyl and heterocycle; R is selected from hydrogen, alkyl, cycloalkyl, carboxyalkyl, ^{carboxycycloalkyl} , aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkane group, heterocycle, heterocycloalkyl and heterooxyalkylene; R ⁵ and R ⁶ are each independently selected from hydrogen and an alkyl group; or R ⁵ and R ⁶ form a ring selected from a cycloalkyl group and a heterocyclic ring together with the atoms connected to them; R is selected from hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, ^{carboxycycloalkyl} , aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkane Oxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heterooxyalkylene or -N(R ²⁶ R ²⁷ ); R ⁸ and R ⁹ are each independently selected from hydrogen and an alkyl group; or R ⁵ and R ⁶ form a ring selected from a cycloalkyl group and a heterocyclic ring together with the atoms connected to them; R ¹⁰ is selected from hydroxyl or -N(R ²⁸ R ²⁹ ); R is selected from hydrogen, alkyl, carboxyalkyl, cycloalkyl, ^{carboxycycloalkyl} , aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryl Aryloxyalkyl, heterocycle, heterocycloalkyl or heterooxyalkyl; ^R and R ^are each independently selected from hydrogen, alkyl, alkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylsulfonyl, carboxyalkyl, cycloalkyl, carboxycycloalkane radical, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocycloalkyl, heteroepoxyalkyl or heterocyclesulfonyl; R is selected from hydrogen, alkyl, carboxyalkyl, cycloalkyl, ^{carboxycycloalkyl} , aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryl Aryloxyalkyl, heterocycle, heterocycloalkyl or heterooxyalkyl; ^R and R ^are each independently selected from hydrogen, alkyl, alkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylsulfonyl, carboxyl, carboxyalkyl, cycloalkyl, carboxyl Cycloalkyl, Cycloalkylsulfonyl, Heteroaryl, Heteroarylalkyl, Heteroaryloxy, Heteroarylsulfonyl, Heterocycle, Heterocycloalkyl, Heteroepoxyalkyl, Heteroepoxy , heterocyclic sulfonyl, hydroxyl or alkyl-C(O)N(R ²⁰¹ R ²⁰² ), or R15 and R16 form a heterocyclic ring with the atoms they are connected to; R ²⁰¹ and R ²⁰² are each independently selected from hydrogen and alkyl; R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected from hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkane group, heterocycle or heterocycloalkyl; R ^17a and R ^18a are each independently selected from hydrogen and alkyl; R ²⁰ and R ²¹ are each independently selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, cycloalkyl, carboxyalkyl, carboxycycloalkyl, ring Alkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocycle carbonyl or heterocycle sulfonyl; ^R and R ^are each independently selected from hydrogen, alkyl, alkylcarbonyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyl Alkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkoxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, Heteroepoxy group, heteroarylsulfonyl group or hydroxyl group, or R ²² and R ²³ form a ring selected from heteroaryl and heterocycle together with the atoms they are connected to; ^R and R ^are each independently selected from hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, carboxyl, arylsulfonyl, carboxyl Alkyl, carboxycycloalkyl, cycloalkyl, cycloalkoxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocycloalkane A group, a heterocyclic epoxy group, a heteroarylsulfonyl group or a hydroxyl group, or R ²⁴ and R ²⁵ form a heterocyclic ring together with the atoms they are connected to; R ²⁶ and R ²⁷ are each independently selected from hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, carboxyl, arylsulfonyl, carboxyl Alkyl, carboxycycloalkyl, cycloalkyl, cycloalkoxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocycloalkane A group, a heterocyclic epoxy group, a heteroarylsulfonyl group or a hydroxyl group, or R ²⁶ and R ²⁷ form a heterocyclic ring together with the atoms they are connected to; R ²⁸ and R ²⁹ are each independently selected from hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, carboxyl, arylsulfonyl, carboxyl Alkyl, carboxycycloalkyl, cycloalkyl, cycloalkoxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocycloalkane group, heterocyclyloxy group, heteroarylsulfonyl group or hydroxyl group, or R ²⁸ and R ²⁹ together with the atoms to which they are attached form a heterocyclic ring. 2. The compound according to claim 1, and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein A ² , A ³ and A ⁴ are hydrogen; R ₁ , R2 and _R3 are _hydrogen . 3. The compound according to claim 2, and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein ^A is selected from H, F, OH, NH ₂ CO -, NH ₂ SO ₂ - or CH ₃ SO ₂ -. 4. The compound according to claim 2 or 3, and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein m=n=2. 5. The compound according to claim 4, and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein B is selected from H, aryl, arylalkyl, Aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocyclic, heterocycloalkyl, heterooxyalkyl, heterocyclicsulfonyl . 6. The compound according to claim 5, and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein B is selected from H, aryl, arylalkyl, Arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl. 7. The compound according to claim 6, and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein the aryl, arylalkyl, arylsulfonate The aryl in the acyl is preferably selected from substituted or unsubstituted phenyl or naphthyl; the aryl in the heteroaryl, heteroarylalkyl, and heteroarylsulfonyl is preferably selected from substituted or unsubstituted pyridyl . 8. The compound according to claim 7, and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein the substituted phenyl or naphthyl and the substituted The substituents on the pyridyl group are each independently selected from the group consisting of halogen, 1-5 carbon alkyl, cycloalkyl, hydroxyl, cyano, alkoxy, amino, substituted amino, mercapto, substituted mercapto, carbonyl, alkane Sulfonyl or sulfonyl. 9. The compound according to claim 8, and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein the substituted phenyl or naphthyl and the substituted The substituents on the pyridyl are independently selected from F, Cl, Br, I; hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, three Fluoromethoxy, difluoromethoxy; mercapto, methylmercapto, ethylmercapto, propylmercapto, butylmercapto; cyano; methyl, ethyl, propyl, butyl, tert-butyl, isopropyl, trifluoro Methyl, difluoromethyl; amino, methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, formamido, acetamido; methylsulfonyl, ethylsulfonyl, propylsulfonyl , Sulfonic acid group; carboxyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl. 10. The compound according to any one of the above claims, and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof, wherein the compound is selected from: 11. A method for synthesizing the compound shown in general formula (V) described in any one of the above claims, comprising the following steps: 1), the general structural formula is the isocyanate compound represented by X1 and the general structural formula is X2 The representative hydrazine compound generates urea derivative X3 through addition reaction; 2), uses hydrogenation catalyst to remove the benzyl group of the urea derivative X3 by catalytic hydrogenation to obtain compound X4; 3), reacts compound X4 and X5 to obtain compound V1; 4), the compound V1 reacts with X6 to obtain the target compound V; the route is shown in the following general synthesis method (1): In the above general synthesis method (1): the substituents A ¹ , A ² , A ³ , A ⁴ , R ₁ , R ₂ , R ₃ , B, m, and n in the structural formula of each compound are as defined in the above general formula V ; When R ₂ is hydrogen, V1=V; X5 is a halogen or boronic acid/boronate substitution of B, and X6 is a halogen substitution of R2. 12. synthetic method according to claim 11, is characterized in that, described step 2) the hydrogenation catalyst that adopts selects palladium hydrogenation catalyst, platinum hydrogenation catalyst etc., such as palladium carbon, palladium hydroxide, platinum carbon, RannyNi; Palladium on carbon is preferred. 13. The pharmaceutical composition, characterized in that, the pharmaceutical composition is according to the compound according to any one of claims 1-10 and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof , and a pharmaceutically acceptable carrier. 14. The preparation method of the pharmaceutical composition according to claim 13, characterized in that, the compound according to any one of claims 1-10 or its pharmaceutically acceptable tautomer, solvate , hydrate or salt mixed with a pharmaceutically acceptable carrier to prepare. 15. A kit, characterized in that the kit comprises the compound according to any one of claims 1-10 and pharmaceutically acceptable tautomers, solvates, hydrates or Salt. 16. A method of inhibiting 11β-hydroxysteroid dehydrogenase 1 in a subject, characterized in that the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-10 and its pharmaceutical Acceptable tautomers, solvates, hydrates or salts. 17. A method of treating a disease associated with 11β-hydroxysteroid dehydrogenase 1 in a subject by inhibiting 11β-hydroxysteroid dehydrogenase 1, characterized in that the method comprises administering to the subject a therapeutically effective amount of The compound described in any one of Claims 1-10 and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof. 18. The method according to claim 16 or 17, wherein the diseases associated with 11β-hydroxysteroid dehydrogenase 1 include non-insulin-dependent diabetes mellitus, insulin resistance, glucose intolerance, obesity, lipid Diabetic disorders, metabolic syndrome, hyperglycemia, hypertension, hyperlipidemia, glaucoma, cardiovascular disorders, osteoporosis, inflammation, dementia, depression, cognitive impairment, atherosclerosis, arteriosclerosis, coronary artery disease , thrombosis, angina, peripheral vascular disease, androgen excess, or polycystic ovary syndrome. 19. Use of the compound according to any one of claims 1-10 and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof in the preparation of medicaments. 20. The compound according to any one of claims 1-10 and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof inhibit 11β-hydroxysteroid dehydrogenase 1 in subjects the use of. 21. The compound according to any one of claims 1-10 and pharmaceutically acceptable tautomers, solvates, hydrates or salts thereof in subjects by inhibiting 11β-hydroxysteroid dehydrogenase 1 Use for treating diseases associated with 11β-hydroxysteroid dehydrogenase 1. 22. The use according to claim 21, characterized in that the diseases associated with 11β-hydroxysteroid dehydrogenase 1 include non-insulin-dependent diabetes mellitus, insulin resistance, glucose intolerance, obesity, lipid disorders , metabolic syndrome, hyperglycemia, hypertension, hyperlipidemia, glaucoma, cardiovascular disorders, osteoporosis, inflammation, dementia, depression, cognitive impairment, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis syndrome, angina pectoris, peripheral vascular disease, androgen excess, or polycystic ovary syndrome.