WO2009052708A1 - 1-(3-amino-propyl)-piperidin-4-yl-amides, pharmaceutical compositions, processes for their preparation and uses - Google Patents

Abstract

1-(3-Amino-propyl)-piperidin-4-yl-amides as the following formula, pharmaceutically acceptable salts thereof , compositions thereof, and processes for preparing them. These compounds or their pharmaceutically acceptable salts could be used as antagonists of CCR5, are used to prepare drugs for treatment of CCR5 mediated diseases or HIV infection, asthma, rheumatoidarthritis, autoimmune diseases, chronic obstructive pulmonary disease(COPD).

Description

 L-(3-aminopropyl)piperidine-4-aminoamide compound, pharmaceutical composition thereof

 And preparation method and use thereof

 The present invention relates to a 1-(3-aminopropyl)piperidin-4-aminoamide compound, a pharmaceutical composition thereof, and a process for the preparation thereof and use thereof, which are useful as CCR5 antagonists.

 Background technique

 Chemokines are a class of cytokines that direct the directed migration of lymphocytes and play an important role in inflammatory responses, leukocyte extravasation, tissue infiltration, tumorigenesis, and embryonic development. Chemokines are a large family of secretory signaling molecules with a molecular weight of approximately 8 to 14 kD. There are currently about 45 members of this family, and their common features are: Containing four conserved cysteines (Cys). The family is divided into four categories based on whether they contain other amino acids between the two Cys near the N-terminus: C-C, C-X-C, C-Xs-C, and C. Among them, CC (also known as β-chemokine) and CXC (also known as (X-chemokine)) are the two most important categories.

 The function of chemokines in vivo is mediated through chemokine receptors. The current standard nomenclature for chemokine receptors is characterized by their specific binding to chemokines (for example, if the ligand is a CC-like chemokine subfamily, it is named CCR). The receptor for chemokines belongs to the 7-transmembrane G-protein coupled receptor family (GPCR), which has an N-terminus outside the cell and a C-terminus in the cell, containing seven very conserved Transmembrane regions. They bind to G proteins when bound to agonists, allowing extracellular signals to be delivered to the cells. Under the action of agonists, chemokine receptors can cause a series of intracellular Signaling and altering cell behavior, such as inhibition of adenylate cyclase (AC), mobilize intracellular calcium release, activate a series of protein kinases, direct cell-directed migration (chemotaxis), and affect cytokine release.

There are currently 19 chemokine receptors found, which are CCR1-11, CXCR1-6, XCR1, CX ₃ CR1. Chemokine receptors are thought to be important mediators of inflammatory and autoimmune diseases (Gerard et al., Nature Immunology, 2, 108-15 (2001)), and therefore, modulators of chemokine receptors ( Including agonists and antagonists) can be used in a variety of diseases, such as inflammation or allergic diseases, allergic reactions, autoimmune diseases, inflammatory bowel disease, scleroderma, eosinophilic myositis, tumorigenesis and metastasis Wait.

As a member of the chemokine receptor family, CCR5, its endogenous agonist is RANTES, ΜΙΡ-1α ΜΙΡ-Ι β, which is expressed in peripheral blood-derived dendritic cells, sputum lymphocytes, monocytes, giant Phagocytes and immune cells and inflammatory cells involved in maintaining long-term inflammatory responses. Therefore, regulation of CCR5 may regulate the recruitment of sputum cells to inflammatory response lesions, providing a new target for the treatment of inflammatory and autoimmune diseases. For example, CCR5 deletion protects mice from DSS-induced severe Inflammation and mucosal damage (Andres et al., Journal of Immunology, 164, 6303-12 (2000)); in mice, TCR-779, a small molecule antagonist of CCR5, inhibits collagen-induced arthritis (Yang et al) , European Journal of Immunology, 32, 2124-32 (2002) ) o Therefore, antagonists of CCR5 can be used in the treatment of the following diseases: asthma and local disorders (such as local dermatitis, local allergies), rheumatoid arthritis , arteriosclerosis, psoriasis, sarcoidosis and other fibrotic diseases, autoimmune diseases (such as multiple sclerosis, inflammatory bowel disease). In addition, since CD ⁸⁺ T cells are associated with chronic obstructive pulmonary disease (COPD) (Cosio et al., Chest, 121, 160S-165S, (2002)), therefore, CCR5 is antagonistic. Anti-agents may also be used in the treatment of COPD.

 In addition to their role in inflammation and immune responses, chemokine receptors may also be important receptors for certain parasites and viral invasion cells. For example, the Duffy receptor is a receptor for Plasmodium to enter red blood cells, and people who lack Duffy receptors are less susceptible to malaria. More importantly, several chemokine receptors are involved in the invasion of HIV, known as the co-receptor of HIV into the host.

 Studies have shown that CD4 molecules on Th cells are essential for HIV invasion, but only CD4 is not sufficient to mediate HIV-cell fusion. Further studies have revealed that another molecule known as HIV invading co-receptors is CCR5, CXCR4, CCR2b, CCR3, CCR8 and orphan receptors V28, STRL-33, GPR1, GPR15, AP J in chemokine receptors. (Domes et al., Virology, 235, 179-90, (1997)). In vivo, CCR5 and CXCR4 are the major co-receptors of HIV entry, and CCR3 may also be involved in the entry of some HIV. CCR5 is a co-receptor of macrophage tropism (M-tropic) HIV-1 and CXCR4 is a T cell tropism (T-tropic) co-receptor of HIV-1. Therefore, CCR5 plays an important role in the spread of HIV. The substances that regulate CCR5 can affect the spread of M-tropic HIV-1 in the human population and control the disease in the early stage. In vitro, chemokines RANTES, ΜΙΡ-1α and ΜΙΡ-1 β, which bind to CCR5, were found to inhibit HIV infection by inhibiting the entry of HIV-1 into the cell. Some small molecule compounds that bind to CCR5 and antagonize CCR5 function are also very effective in inhibiting HIV invading cells in vitro.

 In summary, there is an urgent need in the art to develop compounds that are CCR5 antagonists with potential pharmaceutical uses. Summary of the invention

 The present inventors have extensively and intensively studied a compound having CCR5 antagonistic activity, and have designed and synthesized a compound of the formula I. The test results show that these compounds are potent CCR5 antagonists, can be used as an entry inhibitor of HIV virus, and can be developed into an anti-AIDS drug, on the basis of which the present invention has been completed.

 Accordingly, it is an object of the present invention to provide a class of 1-(3-aminopropyl)piperidin-4-aminoamide compounds which are CCR5 antagonists.

 Another object of the present invention is to provide a process for the preparation of the above compounds.

 A further object of the invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I or a pharmaceutically acceptable salt thereof.

 A further object of the present invention is to provide the use of such compounds as CCR5 antagonists in the manufacture of a medicament for the treatment of diseases mediated by CCR5.

 In a first aspect of the invention, there is provided a 1-(3-aminopropyl)piperidin-4-aminoamide compound of formula I or a pharmaceutically acceptable salt thereof,

In the formula, and the following groups each independently hydrogen or unsubstituted or substituted by 1 to 3 substituents: Ci-C ₆ Ci-Cs, alkoxy, C ₂ -C ₆ ; i-hik, C ₂ -C _{6 3⁄4} : group, C ₃ -Cs ring-based, C ₃ -Cs ring-based oxy, amine, phenyl, benzyl, naphthyl, C ₅ -C _1Q aromatic heterocyclic or c ₄ a -c ₇ saturated heterocyclic group, said heterocyclic ring comprising 1-3 heteroatoms selected from N, 0 and S, the substituents being selected from the group consisting of dC ₆ alkyl, dC ₆ alkoxy dC ₆ alkyl, -3⁄4 cycloalkyl, Halogen, sulfhydryl, hydroxyl, CF ₃ , CN, N0 ₂ , NR6R ₇ ,

NR6COOR ₇ , NR6S0 ₂ R ₇ , COOR ₇ , COR ₇ , CONR^ S0 ₂ R ₇ , S0 ₂ NR6R ₇ , OR? and OCOR ₇ ;

G is OCO, CO, NR ₇ CO or S0 ₂ ;

NR6S0₂R₇、 COOR₇、 COR₇、 CONR6R₇、 S0₂R₇、 OR?禾卩 OCOR₇， 其中 d-C₆烷基、 C₂-C₆烯基、 C₂-C₆ 块基、 C₃-C₇环烷基、 d-C₆烷氧基或 d-C₆烷巯基可选择性地被 ^素、羟基、氨基、 C₃-Cv 环烷基、 氰基或巯基取代； R ₂ is an unsubstituted or substituted group of 1 to 3 substituents: phenyl, benzyl, naphthyl or C ₅ -C _{1 ()} aromatic heterocyclic group, said heterocyclic ring includes 1- 3 heteroatoms selected from N, 0 and S, the substituents being selected from the group consisting of the following atoms or groups: CC ₆ alkyl, dC ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C _6- block, C ₃ -C ₇ cycloalkyl, dC ₆ alkyl fluorenyl, halogen, fluorenyl, hydroxy, CF ₃ , CN, N0 ₂ , NR6R ₇ ,

NR6S0 ₂ R ₇ , COOR ₇ , COR ₇ , CONR6R ₇ , S0 ₂ R ₇ , OR? and OCOR ₇ , wherein dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ block, C ₃ -C ₇ cycloalkyl, dC ₆ alkoxy or dC ₆ alkyl fluorenyl may be optionally substituted by a hydrazine, a hydroxy group, an amino group, a C ₃ -Cv cycloalkyl group, a cyano group or a decyl group;

 X is not present, 0, CO or NH;

R4 is an unsubstituted or substituted group of 1-3 substituents: dC ₆ alkylene, dC ₆ alkoxy dC ₆ alkylene, dC ₆ alkylenecarbonyl, dC ₆ alkyleneoxy, a c ₂ -c ₆ alkenylene group or a c ₂ -c ₆ subunit group, said substituent being selected from the group consisting of: dC ₆ alkyl, dC ₆ alkoxy, halogen, amino, nitro, nitrile Base, thiol and hydroxy;

R ₅ is an unsubstituted or substituted group of 1 to 3 substituents: ₈ cycloalkyl, adamantyl, phenyl, phenol, benzyl, naphthyl, C ₅ -C _1Q aromatic heterocyclic Or a C ₄ -C ₇ saturated heterocyclic group, said heterocyclic ring comprising 1-3 heteroatoms selected from N, 0 and S, said substituent being selected from the group consisting of the following atoms or groups: dC ₆ alkane Base, dC ₆ alkoxy, halogen, fluorenyl, hydroxy, CF ₃ , CN, N0 ₂ , NR6R ₇ , NReCOR^ NReCOOR^ NR6S0 ₂ R ₇ , COOR ₇ , COR ₇ , CONR6R ₇ , S0 ₂ R ₇ , S0 ₂ NR6R ₇ , OR? and OCOR ₇ , and NR^R? can together form a cyclic amine;

R6 is hydrogen, hydroxy or CC ₆ alkyl;

R ₇ is hydrogen or an unsubstituted or substituted by 1-3 substituents the following groups: dC ₆ alkyl, dC ₆ alkoxy _{¾ Ci-C 6 ¾¾¾ Ci-} C 6 C 2 -C 6; i Hickey , C ₂ -C _{6 3⁄4} : group, C ₃ -Cs i 3⁄43⁄4 group, phenyl group, ⁼ ^ group, Tecaki, C ₅ -C _1Q aromatic heterocyclic group or C ₄ -C ₇ saturated heterocyclic group, The heterocyclic ring includes 1 to 3 hetero atoms selected from N, 0 and S, and the substituent is selected from the group consisting of dC ₆ alkyl, dC ₆ alkoxy dC ₆ alkyl, halogen , amino, nitro, thiol, hydroxy, CN and CF ₃ .

 In a preferred embodiment of the invention, the compound of the invention is a compound of formula II below:

 (II)

Wherein R ₃ is hydrogen, dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ block or C ₃ -C ₇ cycloalkyl, wherein dC ₆ alkyl is optionally halogen, hydroxy , dC ₄ alkoxy, c ₃ -c ₇ cycloalkyl, cyano, decyl, amino, nitro Or a dc ₄ alkyl thiol group;

The definitions of X, R4, and R ₅ are as described above;

And independently hydrogen, halogen, hydroxy, cyano, decyl, nitro, dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ block, C ₃ -C ₇ cycloalkyl, dC ₆ Alkoxy or dC ₆ alkylalkyl, wherein dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ block, C ₃ -C ₇ cycloalkyl, dC ₆ alkoxy or dC ₆ alkenyl It may be optionally substituted by halogen, hydroxy, amino, C ₃ -C ₇ cycloalkyl, cyano or thiol.

 For the compound of formula II, it is more preferred that:

 R3 is a C1-C4 fluorenyl group;

 X is not present;

R4 is dC ₄ alkylene;

S0₂R₇、 S0₂NR6R₇、 OR₇禾 B OCOR₇， 且 NR6R₇可共同组成环胺， 其中 R«为氢或 C C₆烷基， R₇ 为氢、 C C₆烷基或 d-C₆烷氧基； R ₅ is an unsubstituted or substituted group of 1 to 3 substituents: phenyl, phenol, naphthyl, adamantyl, morpholinyl, piperazinyl, piperidinyl, pyrrolyl, thienyl , imidazolyl, triazolyl, tetrazolyl, furyl, pyranyl or fluorenyl, quinolyl, benzopyranyl, benzothienyl, benzofuranyl, benzimidazolyl or benzo a triazolyl group, the substituent is selected from the group consisting of lower-C ₄ alkyl, dC ₄ alkoxy, halogen, hydroxy, CF ₃ , NO ₂ , NR ₆ R ₇ , NR ₆ COR ₇ ,

S0 ₂ R ₇ , S0 ₂ NR6R ₇ , OR _{7 and} B OCOR ₇ , and NR6R ₇ may together form a cyclic amine, wherein R« is hydrogen or CC ₆ alkyl, R ₇ is hydrogen, CC ₆ alkyl or dC ₆ alkane Oxylate

R ₈ is hydrogen, halogen or CrC ₄ alkyl;

R ₉ is hydrogen or halogen.

 In the present invention, particularly preferred compounds are the compounds listed in Table 1.

 A pharmaceutically acceptable salt of the 1-(3-aminopropyl)piperidin-4-aminoamide compound of the present invention, which is a compound of the present invention and hydrochloric acid, tartaric acid, hydrazine according to a pharmaceutically conventional salt formation method a salt formed from an acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid or methanesulfonic acid.

 In a second aspect of the invention, there is provided a process for the preparation of a compound of the invention which can be prepared by the following scheme:

General process:

Wherein, R ₂ , R ₃ , R 4 and R ₅ are as defined above;

P is a common protecting group for an amino group, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), 9-fluorenylmethoxycarbonyl (Fmoc), CH ₃ CO or CH ₃ OCO. Step a): in the presence of a base, R ₂ NH ₂ and 1-bromo-3-chloropropane nucleophilic substitution reaction, to obtain N-substituted 3-chloropropylamine compound I;

 Step b): N-substituted 3-chloropropylamine compound I undergoes reductive amination reaction with aldehyde or ketone, or coupling reaction with acid, or nucleophilic substitution reaction with halogenated hydrocarbon to obtain N-trisubstituted 3- Chloropropylamine compound II;

 Step c): nucleophilic substitution reaction of a primary or secondary amine compound with an N-trisubstituted 3-chloropropylamine compound II in the presence of a base to give 4-N-protected 1-(3-aminopropyl)piperidin Pyridine-4-amino compound III;

Step d): Compound III is acid-hydrolyzed (for Boc, Ac or CH ₃ OCO) or base hydrolysis (for Fmoc) or hydrogenolysis (for Cbz or Bn) according to the protecting group of the amino group, deamination protecting group to give compound IV;

 Step e): coupling reaction of the free amine compound IV with an acid (acid chloride method, activated ester method or mixed acid anhydride method) to form 1-(3-aminopropyl)-piperidine-4-aminoamide VI;

 Step f): in the presence of a base, the free amine compound IV and the chloroacetyl chloride form a chloroacetamide compound V; Step g): the base, the chloroacetamide compound V and the hetero atom-containing compound undergo a nucleophilic substitution reaction to obtain 1-( 3-Aminopropyl)piperidine-4-aminoamide VI.

The preparation of the primary or secondary amine compound in the above step c), i.e., the intermediate 4-N-substituted-4-aminopiperidine compound, is as follows.

Preparation process of intermediate 4-V-substituted-4-aminopiperidine

Where R ₃ is defined as above; and! ^ is a common protecting group for amino groups, such as Boc, Cbz, Bn, Fmoc, CH ₃ CO or CH ₃ OCO; etc.; 1-N-protected 4-piperidone is protected by reductive amination to give - piperidine VII, via 4 - an amino protecting group (to give compound VIII), and compound VIII via a 1-amino deprotecting group to give the intermediate 4-N-substituted-4-aminopiperidine IX.

 In a third aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I, or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable carrier, Protease inhibitors and/or reverse transcriptase inhibitors may also be included.

 In a fourth aspect of the invention, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt of the invention, as an antagonist of CCR5, for the manufacture of a medicament for the treatment of a disease mediated by CCR5. Specifically, it is used for the preparation of a medicament for treating HIV infection, asthma, rheumatoid arthritis, autoimmune diseases, and chronic obstructive pulmonary disease (COPD).

 Detailed ways

 The invention is further described below in conjunction with specific embodiments. It is to be understood that the examples are only intended to illustrate the invention and not to limit the scope of the invention.

 Preparation example

 Example 1

Compound 1: 1-acetyl-N-(3-chlorophenyl)-N-(3-(4-(N-ethyl-2-phenylacetamido)piperidinyl)propyl)piperidine -4-carboxamide

 Step 1: 1-Benzyl-4-ethylaminopiperidine

To a solution of 1-benzyl-4-piperidone (5.67 g, 30 mmol) in THF (50 mL), EtOAc (EtOAc) Stir at room temperature for 10 minutes. Sodium triacetoxyborohydride (8.90 g, 42 mmol) was then added portion wise and the mixture was stirred at room temperature for 1.5 h. After addition of 2M sodium hydroxide solution (50 mL) quenched the reaction and the resulting mixture was extracted three times with ether (30 mL), combined organic phase was extracted, dried over anhydrous Na ₂ S0 _4, and removed by rotary evaporation The solvent gave i-benzyl-4-ethylaminopiperidine (5.03 g, yield 77%) as a yellow oil.

 Step 2: N-( 1-Benzyl-4-piperidinyl)-N-ethyl-2-phenylacetamide

To a solution of 1-benzyl-4-ethylaminopiperidine (4.59 g, 21 mmol) in dichloromethane was added triethylamine (7.3 mL) with stirring to ensure complete dissolution. The mixture was added dropwise with phenylacetyl chloride (4.3 mL) under ice-cooling, and then the mixture was stirred at this temperature for 2 hr. The solvent was evaporated, the residue was diluted with addition of ethyl acetate (50 mL), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ S0 _4, and the solvent was removed by rotary evaporation. The quantitatively obtained white solid was directly subjected to the next reaction without purification.

 Step 3: N-(4-piperidinyl)ethyl-2-phenylacetamide

 To a solution of N-( 1-benzyl-4-piperidinyl)ethyl-2-phenylacetamide (440 mg, 1.3 mmol) in ethanol (10 mL), EtOAc. ). Further, 10% palladium on carbon (88 mg) was added to the mixture and nitrogen gas was charged. The resulting mixture was stirred at reflux for 12 hours then cooled and filtered. Evaporation of the filtrate gave a pale yellow thick oil which was subtitled (225 mg, yield 70%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) 7.33-7.23 (m, 5H), 3.75-3.70 (d, J = 14.4Hz, 2H), 3.32-3.24 (m, 2H), 3.16-3.03 (m, J = 15.3 Hz, 12.3Hz, 2H), 2.74-2.65 (m, 1H), 2.48-2.41 (m, 3H), 1.71-1.53 (m, 3H), 1.36-1.24 (d, J=12.3Hz, 1H), 1.21 -1.11 (m, 3H); EI-MS: mlz 247 [M+l] ⁺ , 246 [M]+, 164, 155, 127, 98, 91, 83, 72.

 Step 4: N-(3-Chloropropyl)-3-chloroaniline

1-Chloro-3-chloropropane (5.08 mL, 50 mmol) and potassium carbonate (4.14 g) were added to a solution of 3-chloroaniline (1.05 mL, 10 mmol) in acetonitrile (20 mL). After the mixture was stirred at reflux for 15 hours, 1-bromo-3-chloropropane (OO mL) was further added, followed by stirring under reflux for 72 hours. After the solvent was evaporated, EtOAc (EtOAc)EtOAc. After separating the organic phase, the aqueous phase was extracted three times with ethyl acetate (20 mL). Combined The organic phase was washed once with brine, dried over sodium sulfate and evaporated The concentrate was separated by column chromatography (EtOAc/EtOAc (EtOAc:EtOAc)

^{! HNMR (CDCI3, 300 MHz)} 7.09-7.04 (t, J = 8.1Hz, 1H), 6.67-6.65 (d, J = 8.1Hz, 1H), 6.59 (s, 1H), 6.49-6.46 (dd, J =2.4Hz, 5.7Hz, 1H), 3.84 (br-s, 1H), 3.66-3.62 (t, J=6.3Hz, 2H), 3.33-3.29 (t, J=6.6Hz, 2H), 2.13-2.01 (m, 2H).

 Step 5: 1-Acetyl-N-(3-chlorophenyl)-N-(3-chloropropyl)-4-piperidinecarboxamide

 N-(3-Chloropropyl)-3-chloroaniline (144 mg, 0.71 mmol) was dissolved in dichloromethane (5 mL), and then triethylamine (0.4 mL, 2. And 1-acetyl-4-piperidinecarbonyl chloride (400 mg, 2.11 mmol) o The mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate (5 mL) was evaporated and evaporated. The concentrate was separated by column chromatography (dichloromethane/ethyl acetate =l/l (v/v)) to afford white solid (211 mg, yield 84%).

^{! HNMR (CDCI3, 300 MHz)} 7.42-7.41 (d, J = 4.5, 2H), 7.20 (s, 1H), 7.10-7.08 (t, J = 4.2Hz, 3.6Hz, 1H), 4.54-4.50 (d , J=12.6Hz, 1H), 3.81-3.77 (t, J=6.0Hz, 7.8Hz, 4H), 3.56-3.52 (t, J=6.6Hz, 2H), 3.52-3.44 (m, 1H), 2.89 -2.80 (m, 1H), 2.39-2.32 (t, J = 10.2 Hz, 11.1 Hz, 2H), 2.12-1.97 (m, 4H), 2.05 (s, 3H); EI-MS: mlz 356 [M] +, 338, 295, 247, 204, 149, 127, 1 12, 82, 57; Mp: 129-132 ⁰ C.

 Step 6: 1-Acetyl-N-(3-chlorophenyl)-N-(3-(4-(N-ethyl-2-phenylacetamido)-1-piperidinyl)propyl) Piperidine-4-carboxamide (Compound 1)

 1-acetyl-N-(3-chlorophenyl)-N-(3-chloropropyl)-4-piperidinecarboxamide (79 mg, 0.22 mmol), N-(4-piperidinyl)-N -ethyl-2-phenylacetamide (60 mg, 0.24 mmol), a mixture of potassium iodide (40 mg, 0.24 mmol) and potassium carbonate (91 mg, 0.66 mmol) dissolved in acetonitrile (5 mL). 12 hours. The solvent was evaporated to dryness. EtOAc EtOAc m. The concentrate was separated by column chromatography (dichloromethane /methanol = 30/1 / / / / / / / / / / / / / / / / / /

^{! HNMR (CDCI3, 300 MHz)} 7.39-7.06 (m, 9H), 4.55-4.50 (d, J = 13.2Hz, 1H), 3.78-3.62 (m, 5H), 3.58-3.46 (m, 1H), 3.31 -3.23 (m, 2H), 3.07 (br-s, 1H), 2.87-2.79 (t, J=11.4Hz, 2H), 2.47 (br-s, 1H), 2.36-2.21 (m, 3H), 2.05 (s, 3H), 1.77-1.54 (m, 10H), 1.30-1.09 (m, 5H); EI-MS: mlz 566 [M]+, 523, 475, 447, 259, 82, 57; HREI calculated C ₃₂ H ₄₃ C1 ₄ 0 ₃ (M+): 566.3024, Measured: 566.3012.

 Example 2

Compound 2: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-phenylacetamido)-1-piperidine Phenyl) piperidine-4-carboxamide

 Step 1: 1-Benzylpiperidinyl-4-ethylcarbamic acid tert-butyl ester

The crude 1-benzyl-4-ethylaminopiperidine (see step 1 of Example 1) was dissolved in 1,4-dioxane (80 mL) and water (30 mL). Triethylamine (13.0 mL, 100 mmol), and Boc ₂ O (1. 9 g, 50 mmol) were added, and stirring was continued at room temperature for 6 hours. The solvent was evaporated to dryness EtOAc EtOAc m. The product obtained (14.15 g, a two-step yield of 89%) was taken directly to the next step without further purification.

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.06-1.10 (3Η, t, J = 6.9Hz), 1.46 (9H, s), 1.61-1.77 (4H, m), 1.98-2.06 (2H, t, J = Ll.lHz), 2.90-2.94 (2H, br-d, J=11.7Hz), 3.12-3.15 (2H, br-d, J=6.6Hz), 3.48 (2H, s), 3.95 (1H, br- s), 7.30 (5H, m).

 Step 2: N-(4-piperidinyl)-N-ethylformic acid tert-butyl ester

 To a solution of N-(1-benzyl-4-piperidinyl)-N-ethylformic acid tert-butyl ester (14.15 g, 44.46 mmol) in methanol (120 mL) 440 mmol). Further, 10% palladium carbon (1.41 g) was added to the mixture and nitrogen gas was charged. The resulting mixture was stirred under reflux for 12 hours, and the pressure was gradually reduced during the reaction to release the generated gas. It was then cooled and filtered, and the filtrate was evaporated to give a white crystallite.

^{! HNMR (CDCI3, 300 MHz)} δ 1.07-1.12 (3Η, t, J = 6.9Hz), 1.46 (9H, s), 1.50-1.70 (5H, m), 2.09 (1H, s), 2.61-2.68 ( 2H, t, J = 11.7 Hz), 3.10-3.13 (4H, br-d, J = 10.5 Hz).

 Step 3: N-(3-Chloropropyl)-3-chloro-4-methylaniline

Add 1-bromo-3-chloropropane (30.5 mL, 300 mmol), potassium iodide (1.66 g, 10 mmol) to 3-chloro-4-methylaniline (14.16 g, 100 mmol) in DMF (10 mL) And triethylamine (60 mL). The mixture was stirred at room temperature for 3 days. The solvent was evaporated to dryness EtOAc EtOAc m. Separation of the concentrate by column chromatography (petroleum ether / ethyl acetate) =25/1 (v/v)) gave the product as a pale brown oil ( 18.64 g, yield 86%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 2.01-2.09 (2Η, m), 2.45 (3Η, s), 3.27-3.31 (2H, t, J = 6.6Hz), 3.62-3.66 (2H, t, J = 6.3 Hz), 6.42-6.46 (1H, dd, J = 2.4 Hz, 5.7 Hz), 6.63-6.64 (1H, d, J = 2.4 Hz), 6.98-7.01 (1H, d, J = 8.1 Hz).

 Step 4: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)-4-piperidinecarboxamide

 N-(3-chloropropyl)-3-chloro-4-methylaniline (18.64 g, 85.9 mmol) was dissolved in dichloromethane (350 mL) with stirring, and three were added to the solution under ice cooling. Ethylamine (47.9 mL, 343.6 mmol), then 1-acetyl-4-piperidinecarbonyl chloride (48.72 g, 257.7 mmol) was added portionwise at this temperature. After the addition was completed, the mixture was stirred at the same temperature for 1 hour, and the mixture was further stirred at room temperature for 3 hours. A saturated aqueous solution of sodium hydrogencarbonate (100 mL) was added, and the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (60 mL). The combined organic phases were dried with sodium sulfate and evaporated. The concentrate was separated by column chromatography (dichloromethane / ethyl acetate =l /l (v/vp) to give the product as light brown oil (26.37 g, yield 83%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.54-1.84 (4H, m), 2.00 (3Η, m), 2.05 (3H, s), 2.34-2.41 (2H, m), 2.43 (3H, s), 2.85 ( 1H, br-s), 3.51-3.55 (2H, t, J=6.3Hz), 3.74-3.79 (2H, t, J=7.2Hz), 4.50-4.53 (1H, m), 6.96-6.99 (1H, Dd, J = 1.8 Hz, 6.0 Hz), 7.18 (1H, d, J = 2.1 Hz), 7.30-7.33 (1H, d, J = 8.1 Hz).

 Step 5: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-N-ethylcarbamic acid tert-butyl ester-1-piperidinyl)propyl Piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)-4-piperidinecarboxamide (10. 3 g, 27.8 mmol), N- (4- a mixture of tert-butyl-N-ethylformamate (6.3 g, 27.8 mmol), potassium iodide (4.6 g, 27.8 mmol) and triethylamine (7.75 mL, 55.6 mmol) in acetonitrile (70 mL) The solution was stirred at reflux for 13 hours. Then, the solvent was evaporated to dryness, evaporated, evaporated, evaporated The concentrate was separated by column chromatography (dichloromethane / methanol = 100/1 to 50/l Cv/v) to afford product as white powder (9.3 g, yield 60%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.05-1.09 (3Η, t, J = 6.9Hz), 1.45 (9H, s), 1.45-1.80 (12H, m), 1.91-1.99 (2H, m), 2.04 ( 3H, s), 2.26-2.39 (4H, m), 2.42 (3H, s), 2.80-3.12 (4H, m), 3.62-3.67 (2H, q, J=5.4Hz, 3.0Hz), 3.74-3.78 (1H, br-d, J=13.2Hz), 4.49-4.53 (1H, br-d, J=13.5Hz), 6.94-6.98 (1H, dd, J=2.4Hz, 5.7Hz), 7.18 (1H, d, J = 2.1 Hz), 7.28-7.30 (1H, d, J = 8.1 Hz). EI-MS: mlz 562 [M]+, 416, 378, 364, 335, 241, 227, 154, 98, 82.

 Step 6: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-ethylamine-1-piperidinyl)propyl)piperidine-4-methyl Amide

 The product of Step 5 (9.4 g, 16.63 mmol) was dissolved in tetrahydrofuran (40 mL) with stirring, and 4N hydrochloric acid (40 mL) was added dropwise to the solution at room temperature, then the mixture was stirred at 40 ° C. hour. Thereafter, the THF in the solution was evaporated, the aqueous phase was extracted with ethyl acetate (60 mL), and then the pH of the solution was adjusted to 10 with a 2N sodium hydroxide solution. The aqueous phase was extracted three times with dichloromethane (30 mL). EtOAc (EtOAc m. Purification, the next step can be directly carried out.

Step 7: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-phenylacetamido)-1- Piperidinyl)propyl) piperidine-4-carboxamide (compound 2)

 When stirring, add HBTU (152 mg, a solution of the product (95 mg, 0.2 mmol), phenylacetic acid (27 mg, 0.2 mmol), and triethylamine (0.08 mL, 0.6 mmol) in DMF (4 mL). 0.4 mmol). This mixture was stirred at room temperature for 24 hours. It was then diluted with ethyl acetate (15 mL) and brine and brine evaporated. The concentrate was separated by column chromatography (dichloromethane/methanol = 30/1 (v/v)) to give the product as a white foam (71 mg, yield 60%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.08-1.16 (3Η, m), 1.45-1.79 (11H, m), 2.04 (3H, s), 2.17-2.51 (5H, m), 2.41 (3H, s) , 2.79-2.87 (2H, m), 3.07-3.11 (1H, br-d, J=10.5Hz), 3.17-3.26 (2H, m), 3.48-3.77 (6H, m), 4.48-4.53 (1H, Br-d, J=14.1Hz), 6.93-6.99 (1H, m), 7.14-7.33 (7H, m); EI-MS: mlz 580 [M]+, 489, 416, 378, 364, 335, 259 , 154, 141, 98, 82; HREI calcd for C ₃₃ H ₄₅ C1 ₄ 0 ₃ (M+): 580.3180, Measured: 580.3185.

 The reaction conditions of the following Examples 3-16 were similar to those of Example 2, and the last step was to replace the phenylacetic acid with a derivative of phenylacetic acid.

 Example 3

 Compound 3: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3,4-dichlorophenyl)) Amido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 3,4-Dichlorophenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in Step 2 of Example 2 to give a white foam (82 mg, yield 71%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.20-1.25 (3Η, t, J = 6.9Hz), 1.57-1.81 (11H, m), 2.04 (3H, s), 2.30-2.42 (4H, m), 2.42 ( 3H, s), 2.63 (1H, br-s), 2.80-2.88 (1H, t, J=11.7Hz), 2.97 (1H, br-s), 3.13-3.20 (1H, m), 3.25-3.34 ( 2H, m), 3.63-3.78 (6H, m), 4.50-4.54 (1H, br-d, J=12.9Hz), 6.96-7.12 (2H, m), 7.19 (1H, br-s), 7.28- 7.39 (3H, m); EI-MS: mlz 648 [M]+, 489, 416, 378, 364, 335, 327, 236, 160, 1 12, 98, 82; HREI calculated C ₃₃ H ₄₃ C1 ₃ N ₄ 0 ₃ (M+): 648.2401, Measured: 648.2395

 Example 4

 Compound 4: 1-acetyl-indole-(3-chloro-4-methylphenyl)-indole-(3-(4-(indolyl-2-(3,4,5-trimethoxybenzene) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide

 Instead of phenylacetic acid, 3,4,5-trimethoxyphenylacetic acid was used in the same manner as in the step 7 of Example 2 to give a yellowish foamy solid (72 mg, yield 49%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.18-1.23 (3Η, t, J = 6.9Hz), 1.11-1.25 (2H, m), 1.62-1.84 (8H, m), 2.04 (3H, s), 2.29- 2.42 (2H, m), 2.42 (3H, s), 2.49-3.03 (5H, m), 3.19-3.35 (2H, m), 3.44-3.51 (2H, q, J=6.9Hz), 3.63-3.79 ( 6H, m), 3.81 (3H, s), 3.83 (6H, s), 4.48-4.53 (1H, br-d, J=13.2Hz), 6.45-6.50 (2H, d, J=15.3Hz), 6.97 -7.05 (1H, br-s), 7.18-7.22 (1H, m), 7.30-7.34 (1H, m); EI-MS: mlz 670 [M]+, 489, 416, 378, 349, 335, 236 , 208, 181, 141, 1 12, 98, 82; HREI calculated C ₃₆ H ₅₁ C1 ₄ 0 ₆ (M ⁺ ): 670.3497, Measured: 670.3501.

 Example 5

 Compound 5: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3,4-dimethoxyphenyl) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide

3,4-dimethoxyphenylacetic acid was used instead of phenylacetic acid, and the reaction process was the same as in the step 7 of Example 2 to obtain a yellowish Color foamy solid (82mg, yield 65%)

^{! HNMR (CDCI3, 300 MHz)} δ 1.10-1.23 (3H, m), 1.60-1.81 (11H, m), 2.04 (3H, s), 2.29-2.39 (4H, m), 2.39 (3H, s), 2.67 (1H, br-s), 2.80-2.96 (2H, m), 3.15-3.34 (3H, m), 3.63-3.79 (6H, m), 3.86 (6H, s), 4.50-4.54 (1H, br -d, J = 12.6 Hz), 6.72-6.83 (3H, m), 6.96-7.04 (1H, m), 7.18-7.19 (1H, m), 7.29-7.34 (1H, m); EI-MS: mlz 640 [M]+, 489, 416, 364, 335, 319, 236, 151, 141, 1 12, 98, 82; HREI calculated C ₃₅ H ₄₉ C1 ₄ 0 ₅ (M+) : 640.3391 , Measured value: 640.3383 .

 Example ό

 Compound 6: 1-acetyl-indole-(3-chloro-4-methylphenyl)-indole-(3-(4-(Ν-ethyl-2-(4-trifluoromethylphenyl)) Amido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 4-Phosphoric acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in Step 2 of Example 2 to give a pale yellow foamy solid (64 mg, yield 52%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.20-1.25 (4H, m), 1.57-1.82 (10Η, m), 2.04 (3H, s), 2.33-2.42 (4H, m), 2.42 (3H, s), 2.46-2.58 (1H, m), 2.68-2.88 (1H, m), 2.96-3.00 (1H, br-s),

3.20- 3.36 (3H, m), 3.59-3.79 (6H, m), 4.50-4.54 (1H, d, J = 12.9Hz), 6.97-7.05 (1H, q, J=7.5Hz), 7.19(1H, Br-s), 7.28-7.41 (3H, m), 7.56-7.58 (2H, d, J=8.1Hz); EI-MS: mlz 648 [M]+, 550, 489, 416, 364, 327, 284 , 236, 167, 1 12, 98, 82; HREI calcd for C ₃₄ H ₄₄ C1F ₃ N ₄ 0 ₃ (M ⁺ ): 648.3054, Measured: 648.3062.

 Example 7

 Compound 7: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-hydroxyphenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

 4-Phenylphenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in Step 2 of Example 2 to give a pale yellow foamy solid (120 mg, yield 67%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.08-1.25 (4H, m), 1.62-1.78 (11Η, m), 2.05 (3H, s), 2.36-2.42 (4H, m), 2.42 (3H, s), 2.56 (1H, br-s), 2.80-2.93 (2H, m), 3.09-3.13 (1H, m),

3.21- 3.28 (2H, m), 3.59-3.79 (6H, m), 4.49-4.54 (1H, br-d, J=13.5Hz), 6.75-6.78 (2H, m), 6.96-7.09 (3H, m ), 7.18-7.19 (1H, m), 7.26-7.33 (1H, m); EI-MS: mlz 596 [M]+, 489, 364, 335, 319, 275, 141, 127, 98, 57; HREI For C ₃₃ H ₄₅ C1 ₄ 0 ₄ (M+): 596.3129, Measured: 596.3144.

 Example 8

 Compound 8: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methoxyphenyl)acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide

 4-Phenoxyphenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in Step 2 of Example 2 to give a pale yellow foam (yield: 59 mg, yield: 42%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.10-1.25 (3Η, m), 1.58-1.88 (11H, m), 2.04 (3H, s), 2.20-2.42 (5H, m), 2.42 (3H, s), 2.70-2.88 (2H, m), 3.02-3.04 (1H, m), 3.22-3.32 (2H, m), 3.62-3.78 (6H, m), 3.78 (3H, s), 4.50-4.55 (1H, br -d, J = 13.2 Hz), 6.83-6.86 (2H, d, J = 8.4 Hz), 6.99-7.08 (1H, m), 7.12-7.20 (3H, m), 7.27-7.36 (1H, m); EI-MS: mlz 610 [M]+, 489, 416, 364, 335, 319, 289,236, 141, 121, 1 12, 98, 82, 57; HREI calculated C ₃₄ H ₄₇ C1 ₄ 0 ₄ (M+) : 610.3286, measured value: 610.3288 ο

 Example 9

 Compound 9: 1-acetyl-indole-(3-chloro-4-methylphenyl)-indole-(3-(4-(indole-ethyl-2-(3-indolyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

 Instead of phenylacetic acid, 3-mercaptoacetic acid was used in the same manner as in Step 2 of Example 2 to give a slightly brown foam (45 mg, yield 43%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.18-1.25 (3Η, m), 1.29-1.34 (1H, br-d, J = 12.3Hz), 1.61-1.90 (10H, m), 2.04 (3H, s) , 2.22-2.41 (5H, m), 2.41 (3H, s), 2.79-2.88 (2H, m), 2.95-2.99 (1H, m), 3.23-3.35 (2H, m), 3.56-3.84 (6H, m), 4.49-4.54 (1H, br-d, J=13.5Hz), 6.93-7.02 (1H, ddd, J=2.1Hz, 7.8Hz, 9.6Hz), 7.10-7.21 (4H, m), 7.26- 7.38 (2H, m), 7.54-7.64 (1H, dd, J=7.2Hz, 17.4Hz), 8.21-8.41 (1H, br-d); EI-MS: mlz 619 [M]+, 489, 463, 364, 335, 298, 202, 141, 130, 112, 98, 57; HREI calculated C ₃₅ H ₄₆ C1 ₅ 0 ₃ (M+): 619.3289, Measured: 619.3287.

 Example 10

 Compound 10: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-fluorophenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

 4-Phenylphenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in Step 2 of Example 2 to give a pale yellow foam (83 mg, yield 68%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.14-1.26 (4H, m), 1.57-1.82 (10Η, m), 2.04 (3H, s), 2.29-2.42 (5H, m), 2.42 (3H, s), 2.79-2.97 (2H, m), 3.11-3.18 (1H, br-s), 3.22-3.31 (2H, m), 3.58-3.78 (6H, m), 4.49-4.54 (1H, m), 6.97-7.02 (3H, t, J=8.4Hz), 7.18-7.24 (3H, m), 7.28-7.33 (1H, m); EI-MS: mlz 598 [M]+, 489, 416, 364, 335, 291, ^{</ RTI></RTI></RTI></RTI></ RTI} ></RTI></RTI><RTIgt;

 Example 11

 Compound 11: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-chlorophenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

 4-Phenylphenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in Step 2 of Example 2 to give a pale yellow foam (77 mg, yield 62%)

^{! HNMR (CDCI3, 300 MHz)} δ 1.18-1.25 (3Η, m), 1.42 (1H, m), 1.57-1.84 (10H, m), 2.04 (3H, s), 2.29-2.47 (4H, m), 2.42 (3H, s), 2.62-2.69 (1H, br-s), 2.79-2.88 (1H, m), 2.94-2.99 (1H, br-s), 3.15-3.33 (3H, m), 3.58-3.79 (6H, m), 4.48-4.54 (1H, m), 6.96-7.04 (1H, ddd, J=1.8Hz, 8.4Hz, 6.3Hz), 7.14-7.21 (3H, m), 7.26-7.33 (3H, m); EI-MS: mlz 614 [M]+, 489, 416, 364, 335, 293, 1 12, 98, 82, 57; HREI calculated C ₃₃ H ₄₄ C1 ₂ N ₄ 0 ₃ (M+): 614.2790, measured value: 614.2773.

 Example 12

 Compound 12: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-nitrophenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

4-Nitrophenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in the step 7 of Example 2 to give a red-brown foam (143 mg, yield 59%). 'HNMR (CDCI3, 300 MHz) δ 1.11-1.28 (4H, m), 1.53-1.87 (10H, m), 2.04 (3H, s), 2.13-2.45 (3H, m), 2.41 (3H, s), 2.58-2.87 (4H, m), 3.23-3.38 (3H, m), 3.62-3.86 (6H, m), 4.49-4.53 (1H, br-d, J=13.2Hz), 7.01-7.04 (1H, m ), 7.19-7.20 (1H, d, J=1.8Hz), 7.31-7.34 (1H, d, J=8.1Hz), 7.40-7.50 (2H, m), 8.16-8.19 (2H, d, J=8.7 Hz); EI-MS: mlz 625 [M]+, 489, 416, 364, 335, 304, 236, 141, 137, 112, 98, 82; HREI calculated C ₃₃ H ₄₄ C1 ₅ 0 ₅ (M+) : 625.3031 , Measured value: 625.3036.

 Example 13

 Compound 13: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-naphthyl)acetamide)) 1-piperidinyl)propyl)piperidine-4-carboxamide

 The phenylacetic acid was replaced by 1-naphthylacetic acid, and the reaction was carried out in the same manner as in the step 7 of Example 2 to give a pale yellow foam (82 mg, yield: 65%).

^{! HNMR (CDCI3, 400 MHz)} δ 1.04-1.24 (4H, m), 1.44-1.93 (10Η, m), 1.97 (3H, s), 1.98-2.12 (2H, m), 2.23-2.34 (3H, m ), 2.34 (3H, s), 2.66-2.92 (3H, m), 3.21-3.27 (2H, m), 3.39-3.81 (4H, m), 4.05-4.08 (2H, d, J=13.6Hz), 4.41-4.45 (1H, d, J = 17.6Hz), 6.83-6.91 (1H, m), 7.07-7.10 (1H, m), 7.19-7.23 (2H, m), 7.28-7.49 (3H, m), 7.60-7.99 (3H, m); EI-MS: mlz 631 [M+l]+, 489, 416, 335, 309, 141, 85, 57; HREI calculated C ₃₇ H ₄₈ C1 ₄ 0 ₃ (M+ 1+): 631.3415, measured value: 631.3400ο

 Example 14

 Compound 14: 1-acetyl-indole-(3-chloro-4-methylphenyl)-indole-(3-(4-(indol-ethyl-2-(4-nitrosapinyl))acetamide -1-piperidinyl) propyl) piperidine-4-carboxamide

 4-Nitro-1-naphthylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in the step 7 of Example 2 to give a pale brown foam (72 mg, yield 53%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.12-1.33 (3Η, m), 1.60-1.90 (11H, m), 2.04 (3H, s), 2.09-2.34 (5H, m), 2.42 (3H, s), 2.78-2.88 (2H, m), 3.02-3.09 (1H, m), 3.27-3.51 (3H, m),

3.55- 3.78 (3H, m), 4.11-4.20 (2H, m), 4.49-4.54 (1H, m), 6.92-7.03 (1H, m), 7.17-7.19 (1H, m), 7.28-7.31 (1H , m), 7.38-7.78 (3H, m), 7.85-7.96 (1H, m), 8.03-8.59 (2H, m); EI-MS: mlz 675 [M]+, 645, 630, 489, 462, 416, 364, 335, 309, 141, 112, 98, 82; HREI calculated C ₃₇ H ₄₆ C1 ₅ 0 ₅ (M+): 675.3187, Measured: 675.3188.

 Example 15

 Compound 15: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(2-naphthyl)acetamide)) 1-piperidinyl)propyl)piperidine-4-carboxamide

 Using 2-naphthylacetic acid instead of phenylacetic acid, the reaction was carried out in the same manner as in the step 7 of Example 2 to give a pale yellow foam (77 mg, yield 61%).

^{! HNMR (CDCI3, 400 MHz)} δ 1.11-1.33 (4H, m), 1.59-1.77 (10Η, m), 2.03 (3H, s), 2.19-2.41 (4H, m), 2.41 (3H, s), 2.78-2.86 (3H, m), 3.00-3.03 (1H, m), 3.25-3.36 (2H, m),

3.56- 3.68 (3H, m), 3.72-3.77 (1H, d, J=13.5Hz), 4.10-4.15 (2H, d, J=15.6Hz), 4.48-4.53 (1H, d, J=13.2Hz) , 6.92-7.01 (1H, m), 7.14-7.18 (1H, m), 7.26-7.56 (5H, m), 7.75-8.05 (3H, m); EI-MS: mlz 630 [M] ⁺ , 489, 416, 335, 309, 268, 141, 98, 85, 71, 57; HREI calculated C37H47CI 4O3 (M ⁺ ): 630.3337, Measured: 630.3339. Compound 16: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-adamantyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

 The 1-adamantylacetic acid was used in place of the phenylacetic acid, and the reaction was carried out in the same manner as in the step 7 of Example 2 to give a white foam (96 mg, yield 78%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.08-1.16 (1H, m), 1.61-1.83 (24Η, m), 1.90-2.05 (5H, m), 2.05 (3H, s), 2.05-2.11 (3H, m), 2.32-2.42 (4H, m), 2.42 (3H, s), 2.80-2.96 (3H, m), 3.24-3.30 (2H, q, J=6.6Hz), 3.60-3.79 (3H, m) , 4.49-4.54 (1H, d, J=13.8Hz), 6.96-6.98 (1H, d, J=8.1Hz), 7.18 (1H, s), 7.28-7.31 (1H, d, J=8.4Hz); EI-MS: mlz 638 [M]+, 540, 416, 335, 331, 317, 221, 141, 135, 98, 82; HREI calculated C ₃₇ H ₅₅ C1 ₄ 0 ₃ (M ⁺ ): 638.3963 , measurement Value: 638.3956.

 Example 17

 Compound 17: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(2-oxoethoxy)) Phenyl) acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 Acetate (0.03 mL, 0.3 mmol) was added dropwise to a solution of compound 7 (120 mg, 0.2 mmol) and triethylamine (0.08 mL, 0.6 mmol) in dichloromethane. This mixture was stirred at room temperature overnight. It was then diluted with ethyl acetate (20 mL) and brine and brine evaporated. The concentrate was separated by column chromatography (dichloromethane/methanol = 30/1 to 25/l (v/v)) to afford product as white powder (53 mg, yield 41%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.10-1.25 (4H, m), 1.56-1.93 (10Η, m), 2.04 (3H, s), 2.26-2.41 (3H, m), 2.28 (3H, s), 2.41 (3H, s), 2.79-2.95 (4H, m), 3.20-3.35 (3H, m), 3.62-3.79 (6H, m), 4.48-4.52 (1H, d, J = 12.9Hz), 6.99- 7.02 (2H, d, J=8.1Hz), 7.08-7.10 (1H, m), 7.18-7.26 (3H, m), 7.34-7.36 (1H, m) ; EI-MS: mlz 638 [M]+, 489, 416, 364, 335, 317, 179, 141, 112, 108, 82, 57; HREI calculated C ₃₅ H ₄₇ C1 ₄ 0 ₅ (M+): 638.3235, Measured: 638.3249.

 Example 18

 Compound 18: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-acetylphenyl))acetamide -1-piperidinyl)propyl)piperidine-4-carboxamide

 Step 1: Ethyl 4-acetylphenylacetate

 Ethyl phenylacetate (3.35 g, 20 mmol) was dissolved in dry carbon disulfide (15 mL), and the obtained mixture was cooled in ice-cooled, and anhydrous aluminum trichloride (6.67 g, 50 mmol) was slowly added while stirring. Thereafter, acetyl chloride (1.85 mL, 26 mmol) was added while stirring at 0 ° C, and the mixture was refluxed for 12 hours and then quenched with crushed ice. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue is placed in a freezer and then the solid obtained by filtration is the product. Ethyl 4-acetylacetophenone was recrystallized from petroleum ether to give white crystals (500 mg, yield 12%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.22-1.27 (3Η, dt, J = 7.2Hz, 1.2Hz), 2.59 (3H, s), 3.67 (2H: s), 4.12-4.19 (2H, q, J = 7.2 Hz, 6.9 Hz), 7.37-7.39 (2H, d, J = 8.1 Hz), 7.90-7.93 (2H, d, J = 8.1 Hz); Mp: 62-64 °C.

 Step 2: 4-Acetylphenylacetic acid

Ethyl 4-acetylacetophenone (234 mg, 1.13 mmol) dissolved in 50% sulfuric acid solution (10 mL) at room temperature Stir overnight. The obtained solid was then filtered, washed with a little ice water and dried to give white powdery solid (198 mg, yield 98%).

 Mp: 106-109 ° C

 Step 3: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-acetylphenyl))acetamide -1-piperidinyl)propyl)piperidine-4-carboxamide (compound 18)

 The phenylacetic acid of the second step of Example 2 was replaced with 4-acetylphenylacetic acid. The reaction was carried out in the same manner as in Step 2 of Example 2 to give a white foam (60 mg, yield: 48%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.10-1.14 (1H, m), 1.18-1.25 (5Η, m), 1.57-1.85 (10Η, m), 2.04 (3H, s), 2.30-2.42 (3H, m), 2.42 (3H, s), 2.59 (3H, s), 2.79-2.92 (2H, m), 3.09-3.17 (1H, br-s), 3.24-3.33 (2H, m), 3.46-3.78 ( 6H, m), 4.49-4.54 (1H, d, J = 12.9Hz), 6.94-7.06 (1H, m), 7.17-7.19 (1H, m), 7.28-7.37 (3H, m), 7.89-7.92 ( 2H, d, J=8.1Hz) ; EI-MS: mlz 622 [M]+, 489, 416, 364, 335, 301, 236, 141, 98, 82; HREI calculated C ₃₃ H ₄₇ C1 ₄ 0 ₄ (M+): 622.3286, Measured: 622.3289.

 Example 19

 Compound 19: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-aminophenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

 Add stannous chloride (2.37 g, 12.5 mmol) to a solution of compound 12 (1.52 g, 2.5 mmol) in EtOAc (20 mL). The mixture was stirred under a nitrogen atmosphere for 3 hrs and then diluted with a 1N caustic solution. The ester (25 mL) was extracted and the insoluble material was filtered off. The organic phase was separated and the aqueous extracted with ethyl acetate (25 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The concentrate was separated by column chromatography (dichloromethane / methanol = 30/1 to 25/l Cv/v) to afford product as a brownish brown powder (926 mg, yield 64%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.07-1.32 (4H, m), 1.56-1.79 (10Η, m), 2.04 (3H, s), 2.23-2.42 (5H, m), 2.42 (3H, s), 2.80-3.01 (5H, m), 3.21-3.28 (2H, q, J=6.9Hz), 3.51-3.78 (6H, m), 4.48-4.53 (1H, d, J=13.5Hz), 6.60-6.65 ( 2H, m), 6.93-7.03 (3H, m), 7.17-7.18 (1H, t, J=2.1Hz), 7.25-7.30 (1H, d, J=8.4Hz); EI-MS: mlz 595 [M ]+, 463, 416, 364, 335, 274, 141, 85, 71, 57; HREI calculated C ₃₃ H ₄₆ C1 ₅ 0 ₃ (M+): 595.3289, Measured: 595.3285.

 Example 20

 Compound 20: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methanesulfonylaminophenyl)) Amido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 Triethylamine (0.043 mL, 0.312 mmol) was added to a solution of compound 19 (93 mg, 0.156 mmol After the mixture was cooled to 0 ° C, methanesulfonyl chloride (0.014 mL, 0.187 mmol) was added dropwise, and the mixture was stirred at room temperature for one hour. The reaction was diluted with methylene chloride (10 mL), brine and evaporated. The concentrate was separated by column chromatography (dichloromethane/methanol = 25/1 to 15/l (v/v)) to afford product as pale yellow foam (79 mg, yield 75%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.10-1.43 (4H, m), 1.57-1.88 (11Η, m), 2.04 (3H, s), 2.30-2.42 (3H, m), 2.42 (3H, s), 2.79-2.89 (1H, m), 3.06-3.13 (1H, m), 3.24-3.39 (2H, m), 3.39 (6H, s), 3.61-3.80 (5H, m), 4.48-4.54 (1H, m ), 6.96-7.08 (1H, br-d), 7.17-7.23 (1H, m), 7.26 (1H, s), 7.29-7.39 (5H, m); EI-MS: mlz 673 [M]+, 489 , 416, 352, 335, 184, 154, 106, 82; HR calcd for C ₃₄ H ₄₈ C1 ₅ 0 ₅ S (M ⁺ ): 673.3065, Measured: 673.3087.

 Example 21

 Compound 21: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-acetamidophenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

 Triethylamine (0.05 mL, 0.356 mmol) was added to a solution of EtOAc (EtOAc). After the mixture was cooled to 0 ° C, acetyl chloride (0.014 mL, 0.195 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 0.5 hour. The reaction was diluted with methylene chloride (15 mL), brine and evaporated. The concentrate was separated by column chromatography (dichloromethane/methanol = 20/1 to 15/l (v/v)) to give the product as a yellowish foam (89 mg, yield 78%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.08-1.36 (5H, m), 1.57-1.84 (11Η, m), 2.04 (3H, s), 2.15 (3H, s), 2.24-2.42 (4H, m) , 2.42 (3H, s), 2.79-2.98 (3H, m), 3.23-3.29 (2H, m), 3.52-3.79 (5H, m), 4.49-4.54 (1H, m), 6.94-7.00 (1H, m), 7.15-7.18 (3H, d, J=7.8Hz), 7.26-7.31 (1H, m), 7.41-7.46 (2H, m), 7.58-7.67 (1H, m); EI-MS: mlz 637 [M]+, 489, 416, 335, 316, 154, 149, 141, 106, 82; HREI calculated C ₃₅ H ₄₈ C1 ₅ 0 ₄ (M ⁺ ): 637.3395 , Measured: 637.3401.

 Example 22

 Compound 22: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methoxyformamidophenyl) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide

 Triethylamine (0.04 mL) was added to a solution of EtOAc (EtOAc). After the mixture was cooled to 0 ° C, methyl chloroformate (0.17 mL, 0.22 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction was diluted with methylene chloride (10 mL), brine and evaporated. The concentrate was separated by column chromatography (dichloromethane/methanol = 25/1 to 10/1 (v/v)) to give the product as a pale yellow foam (66 mg, yield 68%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.08-1.342 (4H, m), 1.60-1.81 (15H, m), 2.04 (3H, s), 2.24-2.41 (3H, m), 2.41 (3H, s), 2.80-2.88 (2H, m), 3.22-3.29 (2H, q, J=6.9Hz), 3.59-3.67 (6H, m), 3.76 (3H, s), 4.52-4.53 (1H, m), 6.63- 6.67 (1H, m), 6.93-7.01 (1H, m), 7.16-7.19 (1H, d, J=7.5Hz), 7.27-7.33 (3H, m); EI-MS: mlz 621 [M-32] ⁺ , 489, 463, 416, 364, 335, 300, 274, 141, 112, 98, 82.

 Example 23

 Compound 23: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(1-pyrrolidinyl))sulfonate Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 Step 1: 4-chlorosulfonylphenylacetate

 To the stirred ethyl phenylacetate (8.2 g, 50 mmol) was added chlorosulfonic acid (16.6 mL, 250 mmol). After the dropwise addition was completed, the mixture was further stirred at room temperature for 0.5 hour. The reaction was poured onto EtOAc (3 mL). The concentrate was separated by column chromatography (EtOAc/EtOAc (EtOAc:EtOAc)

 Step 2: 4-(1-Pyrrolidinyl)sulfonylphenylacetate

A solution of ethyl 4-chlorosulfonyl phenylacetate (524 mg, 2 mmol) in THF (10 mL) was cooled to EtOAc (EtOAc) The mixture was allowed to warm to room temperature and stirring was continued for 1 hour. Counter The mixture was diluted with dichloromethane (20 mL), brine and evaporated. The concentrate was separated by column chromatography (yield: petroleum ether / ethyl acetate = 3/l (v/vp) to afford the product as yellow oil (378 mg, yield 63%).

 Step 3 : 4-G-pyrrolidinyl)sulfonylphenylacetic acid

 4-(1-Pyrrolidinyl)sulfonyl phenylacetate (352 mg, 1.18 mmol) was dissolved in a mixture of 2N sodium hydroxide (10 mL) and methanol (10 mL). . The methanol was evaporated to dryness, diluted with a little water, and ethyl acetate (10 mL) was evaporated. The aqueous phase was adjusted to pH 2 with 1N hydrochloric acid and then extracted three times with dichloromethane (10 mL). The combined organic phases (dichloromethane phase only) were washed with brine, dried over sodium sulfate and evaporated. , yield 98%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.74-1.79 (4Η, ρ, J = 3.3Hz), 3.22-3.26 (4Η, t, J = 6.6Hz), 7.43-7.46 (2Η, d, J = 7.8Hz ), 7.78-7.81 (2H, d, J = 8.1 Hz); Mp: 123-124 °C.

 Step 4: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(l-pyrrolidinyl))) Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide (compound 23)

 4-(1-Pyrrolidinyl)sulfonylphenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in Step 2 of Example 2 to give a pale yellow foam (50 mg, yield: 35%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.12-1.25 (4H, m), 1.63-1.76 (10Η, m), 1.76-2.04 (3H, m), 2.04 (3H, s), 2.15-2.25 (2H, m ), 2.34-2.55 (4H, m), 2.42 (3H, s), 2.76-2.88 (3H, m), 3.24 (4H, br-s), 3.33-3.35 (3H, d, J=6.0Hz), 3.67-3.79 (5H, m), 4.49-4.53 (1H, d, J = 12.9Hz), 6.98-7.09 (1H, m), 7.19 (1H, br-s), 7.27-7.30 (1H, m), 7.38-7.41 (2H, d, J=8.4Hz), 7.76-7.79 (2H, d, J=7.8Hz) ; EI-MS: mlz 713 [M]+, 578, 392, 335, 225, 154, 1 12, 70; HREI calculated C ₃₇ H ₅₂ C1 ₅ 0 ₅ S (M+): 713.3378, Measured: 713.3355.

 Example 24

 Compound 24: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-( 3-(4-(N-ethyl-2-(4-N,N-dimethylamine) Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 Step 1: 4-N,N-Dimethylaminesulfonylphenylacetic acid

 In step 2, dimethylamine was used in place of pyrroline, and the reaction was carried out in the same manner as in Steps 2, 2, and 3 of Example 23 to obtain white needle crystals (450 mg, yield 53%).

^{! HNMR (CDCI3, 300 MHz)} δ 2.71 (6H, s), 3.74 (2Η, s), 7.45-7.48 (2H, d, J = 8.1Hz), 7.73-7.76 (2H, d, J = 8.4Hz) ; Mp: 120-121 °C.

 Step 2: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-( 3-(4-(N-ethyl-2-(4-N,N-dimethylamine) Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide (compound 24)

 4-N,N-dimethylamine sulfonyl phenylacetic acid was used in place of phenylacetic acid, and the reaction was the same as in the step 7 of Example 2 to give a pale yellow foam (77 mg, yield 49%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.18-1.28 (4H, m), 1.61-1.89 (10Η, m), 2.04 (3H, s), 2.20-2.42 (4H, m), 2.42 (3H, s), 2.45-2.50 (1H, m), 2.69 (3H, s), 2.70 (3H, s), 2.80-2.91 (2H, m), 3.05-3.08 (1H, br-s), 3.29-3.33 (2H, m ), 3.50-3.68 (3H, m), 3.74-3.80 (3H, m), 4.48-4.54 (1H, m), 6.95-7.01 (1H, m), 7.17-7.19 (1H, m), 7.29-7.31 (1H, d, J=7.8Hz), 7.40-7.45 (2H, m), 7.71-7.73 (2H, d, J=7.8Hz); EI-MS: mlz 687 [M]+, 644, 489, 419 , 366, 335, 199, 154, 1 12, 98, 82, 57; HREI calculated C ₃₅ H ₅ QC1 ₅ 0 ₅ S (M ⁺ ): 687.3221 , Measured: 687.3204.

 Example 25

 Compound 25: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(1-piperidinyl))sulfonate Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 Step 1: 4-(1-piperidinyl)sulfonylphenylacetic acid

 In the second step, piperidine was used instead of pyrroline, and the reaction was carried out in the same manner as in Steps 1, 2, and 3 of Example 23 to obtain white crystals (323 mg, yield: 34%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.40-1.45 (2Η, m), 1.60-1.67 (4H, m), 2.97-3.00 (4H, t, J = 5.7Hz, 5.1Hz), 3.73 (2H, s ), 7.43-7.46 (2H, d, J = 7.8 Hz), 7.70-7.73 (2H, d, J = 7.8 Hz); Mp: 114-115 °C.

 Step 2: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(l-piperidinyl))sulfonate Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide (compound 25)

 4-(1-piperidinyl)sulfonylphenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in the step 7 of Example 2 to obtain a yellow foam (35 mg, yield: 24%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.13-1.25 (5H, m), 1.63-1.70 (11Η, m), 1.75-1.92 (5H, m), 2.05 (3H, s), 2.19-2.42 (4H, m ), 2.42 (3H, s), 2.75-2.89 (3H, m), 2.97-3.01 (4H, m), 3.27-3.38 (3H, m), 3.64-3.85 (5H, m), 4.50-4.55 (1H , m), 7.03-7.07 (1H, m), 7.21(1H, s), 7.33-7.35 (1H, m), 7.39-7.41 (2H, d, J=7.8Hz), 7.68-7.71 (2H, d , J=7.8Hz); EI-MS: mlz 727 [M]+, 684, 406, 364, 335, 239, 154, 112, 98, 84; HREI calculated C ₃₈ H ₅₄ C1 ₅ 0 ₅ S (M+ ): 727.3534, measured value: 727.3560 ο

 Example 26

 Compound 26: 1-acetyl-indole-(3-chloro-4-methylphenyl)-indole-(3-(4-(indol-ethyl-2-(4-morpholinylsulfonylphenyl)) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide

 Step 1: 4-(1-morpholinyl)sulfonylphenylacetic acid

 In the second step, morpholine was used in place of pyrrolidine, and the reaction was carried out in the same manner as in Steps 1, 2, and 3 of Example 23 to obtain white needle crystals (207 mg, 70%).

¹ HNMR (CDCI3, 300 MHz) δ 2.98-3.02 (4Η, t, J=4.8Hz), 3.73-3.76 (4Η, t), 3.74 (2Η, s), 7.47-7.49 (2H, d, J=8.4 Hz), 7.71-7.73 (2H, d, J=8.1Hz); Mp: 71-73 °C.

 Step 2: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-morpholinylsulfonylphenyl)) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide (Compound 26)

 4-(1-morpholinyl)sulfonylphenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in the step 7 of Example 2 to obtain a pale yellow foam (56 mg, yield: 42%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.20-1.26 (3Η, m), 1.38-1.45 (1H, m), 1.61-1.83 (11H, m), 2.04 (3H, s), 2.25-2.42 (4H, m ), 2.42 (3H, s), 2.80-2.88 (2H, m), 2.96-3.01 (5H, m), 3.26-3.33 (2H, m), 3.61-3.80 (10H, m), 4.49-4.54 (1H , br-d, J=13.2Hz), 6.93-7.01 (1H, m), 7.17-7.20 (1H, m), 7.26-7.31 (1H, m), 7.42-7.45 (2H, d, J=8.1Hz ), 7.68-7.71 (2H, d, J=8.1Hz); EI-MS: mlz 729 [M]+, 489, 408, 364, 335, 319, 236, 141, 112, 98, 82, 57; HREI For C ₃₇ H ₅₂ C1 ₅ 0 ₆ S (M+): 729.3327, Measured: 729.3351. Example 27

 Compound 27: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-n-propylaminesulfonylphenyl)) Amido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 Step 1: 4-n-propylamine sulfonylphenylacetic acid

 In the second step of Example 23, n-propylamine was used in place of pyrrolidine, and the reaction was carried out in the same manner as in Steps 1, 2, and 3 of Example 23 to give white crystals (190 mg, yield: 24%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 0.84-0.89 (3Η, t, J = 7.5Hz), 1.43-1.55 (2H, hex, J = 7.2Hz), 2.88-2.94 (2H, q, J = 6.6Hz ), 3.73 (2H, s), 4.79-4.83 (1H, t, J=6.0Hz), 7.42-7.44 (2H, d, J=7.8Hz), 7.81-7.84 (2H, d, J=7.8Hz) ; Mp: 99-100 °C.

 Step 2: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-n-propylaminesulfonylphenyl)) Amido)-1-piperidinyl)propyl)piperidine-4-carboxamide (Compound 27)

 4-Phenylpropylsulfonylphenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in Step 2 of Example 2 to give a pale yellow foam (65 mg, yield 46%).

^{! HNMR (CDCI3, 300 MHz)} δ 0.83-0.89 (4H, m), 1.10-1.25 (4Η, m), 1.43-1.52 (3Η, m), 1.57-1.84 (8H, m), 1.88-2.00 (2H , m), 2.04 (3H, s), 2.28-2.45 (3H, m), 2.41 (3H, s), 2.50-2.63 (1H, m), 2.85-2.92 (3H, m), 2.98-3.12 (2H , m), 3.25-3.34 (2H, m), 3.60-3.81 (5H, m), 4.49-4.53 (1H, m), 4.83 (1H, br-s), 6.97-7.02 (1H, m), 7.19 (1H, br-s), 7.30-7.44 (3H, m), 7.78-7.80 (2H, d, J=8.1Hz); EI-MS: mlz 701 [M]+, 489, 462, 419, 380, 364, 335, 319, 255, 226, 213, 154, 112, 98, 82; HREI calculated C ₃₆ H ₅₂ C1 ₅ 0 ₅ S (M+): 701.3378, Measured: 701.3373 ο

 Example 28

 Compound 28: 1-acetyl-indole-(3-chloro-4-methylphenyl)-indole-(3-(4-(indolyl-2-(4-tert-butylaminesulfonylphenyl)acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide

 Step 1: 4-tert-butylamine sulfonylphenylacetic acid

 In the second step of Example 23, tert-butylamine was used in place of pyrrolidine, and the reaction was carried out in the same manner as in Steps 1, 2, and 3 of Example 23 to give white crystals (180 mg, yield 21%).

¹ HNMR (CDCI3, 300 MHz) δ 1.21 (9H, s), 3.72 (2Η, s), 5.04 (1H, s), 7.39-7.42 (2H, d, J=8.4Hz), 7.84-7.86 (2H, d, J = 8.4 Hz); Mp: 133-135 °C.

 Step 2: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-tert-butylaminesulfonylphenyl)acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide (compound 28)

 Instead of phenylacetic acid, 4-tert-butylamine sulfonylphenylacetic acid was used in the same manner as in the step 7 of Example 2 to give a pale yellow foam (87 mg, yield 56%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.10-1.21 (2Η, m), 1.21 (9H, s), 1.35-1.42 (1H, m), 1.65-1.82 (12H, m), 2.04 (3H, s), 2.22-2.42 (5H, m), 2.42 (3H, s), 2.80-2.95 (3H, m), 3.27-3.29 (2H, m), 3.44-3.51 (1H, q, J=6.6Hz), 3.63- 3.65 (2H, m), 3.75-3.78 (3H, d, J=9.6Hz), 4.40-4.54 (1H, m), 6.96-6.98 (1H, m), 7.18 (1H, s), 7.28-7.31 ( 1H, d, J=7.8Hz), 7.35-7.38 (2H, d, J=7.8Hz), 7.82-7.84 (2H, m); EI-MS: mlz 715[M]+, 462, 419, 394, 364, 335, 283, 238, 181, 141, 112, 98, 82; HREI calculated C ₃₇ H ₅₄ C1 ₅ 0 ₅ S (M ⁺ ): 715.3534, measured value: Example 29

 Compound 29: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methanesulfonylphenyl)acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide

 Step 1: 4-Methylphenylacetate

 To a stirred solution of ethyl 4-chlorosulfonylphenylacetate (2.62 g, 10 mmol) and zinc powder (3. After the dropwise addition was completed, the mixture was stirred under reflux for 3 hours. The reaction mixture was poured onto EtOAc (3 mL). The concentrate was separated by column chromatography ( petroleum ether / ethyl acetate = 30/1 to 10/l (v/v)) to afford colourless oil ( 1.38 g, yield 70%).

 Step 2: 4-Methylmercaptophenylacetate

 To a stirred solution of ethyl 4-mercaptophenylacetate (1.05 g, 5.34 mmol) and potassium carbonate (1.48 g, 10.68 mmol) in DMF (15 mL), EtOAc (0.5 mL, 8.01 mmol). After the dropwise addition was completed, the mixture was further stirred at room temperature for 15 hours. The reaction was then diluted with EtOAc (EtOAc) EtOAc (EtOAc)EtOAc. The concentrate was separated by column chromatography ( petroleum ether / ethyl acetate = 10 /l (v / v))

 Step 3 : 4-Methanesulfonylphenylacetate

 m-CPBA (m-chloroperoxybenzoic acid) (1540 mg, 7.59 mmol) was added to a solution of EtOAc (EtOAc,EtOAc. The mixture was stirred at room temperature for 3 hours, then diluted with dichloromethane (20 mL), washed with 10% sodium sulfate The concentrate was separated by column chromatography ( petroleum ether / ethyl acetate = 4 / 1 (v / v)), and the residue was recrystallized ( petroleum ether / ethyl acetate) to yield white crystals (224 mg Rate 26%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.24-1.29 (3Η, t, J = 7.2Hz), 3.05 (3H, s), 3.71 (2H, s), 4.14-4.21 (2H, q, J = 7.2Hz ), 7.48-7.51 (2H, d, J=8.1Hz), 7.89-7.92 (2H, d, J=8.1Hz).

 Step 4: 4-Methanesulfonylphenylacetic acid

 The ethyl 4-methyl-pyrolinyl)sulfonyl phenylacetate was replaced by ethyl 4-methanesulfonyl phenylacetate. The reaction was carried out in the same manner as in the step 3 of Example 23 to give white crystals (198 mg, 100%).

^{! HNMR (CDCI3, 300 MHz)} δ 3.05 (3Η, s), 3.77 (2Η, s), 7.49-7.51 (2H, d, J = 8.1Hz), 7.90-7.93 (2H, d, J = 8.4Hz) .

 Step 5: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methanesulfonylphenyl)acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide (compound 29)

 4-Methanesulfonylphenylacetic acid was used in place of phenylacetic acid, and the reaction was carried out in the same manner as in Step 2 of Example 2 to give a pale yellow foam (54 mg, yield 36%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.10-1.25 (3Η, m), 1.44-1.50 (1H, m), 1.56-1.88 (10H, m), 2.01-2.09 (1H, m), 2.04 (3H, s ), 2.31-2.40 (4H, m), 2.42 (3H, s), 2.79-2.99 (3H, m), 3.04 (3H, s), 3.27-3.35 (2H, m), 3.44-3.52 (1H, m ), 3.65-3.68 (2H, m), 3.71-3.82 (3H, m), 4.47-4.53 (1H, m), 6.94-6.98 (1H, m), 7.18 (1H, s), 7.29-7.31 (1H , d, J=5.4Hz), 7.44-7.47 (2H, d, J=8.1Hz), 7.87-7.90 (2H, d, J=8.1Hz); EI-MS: mlz 658 [M]+, 489, 462, 419, 364, 337, 335, 196, 170, 141, 1 12, 98, 82; HREI calculated C ₃₄ H ₄₇ C1 ₄ 0 ₅ S (M+): 658.2956, measured value: 658.2960.

 Example 30

 Compound 30: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-morpholinacetamido)-1-piperidine Phenyl) piperidine-4-carboxamide

 Step 1: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-chloroacetamido)-1-piperidinyl ) propyl) piperidine-4-carboxamide

 The product of Example 6 Step 6 C987 mg, 2.13 mmol) was dissolved in dichloromethane (15 mL), triethylamine (0.9 mL, 6.4 mmol) was added, cooled to 0 ° C, then chloroacetyl chloride was added dropwise ( 0.25 mL, 3.2 mmol). The mixture was slowly warmed to room temperature and stirring was continued for 2 hours. Dichloromethane (20 mL) was diluted and washed with water and brine. The concentrate was separated by column chromatography (methylene chloride / methanol = 30/1 to 15/1 (v/v)) to afford product as pale yellow foam (1.01 g, yield 88%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.10-1.24 (3Η, m), 1.56-1.85 (12H, m), 1.94-2.04 (2H, m),

2.04 (3H, s), 2.30-2.42 (4H, m), 2.42 (3H, s), 2.80-2.98 (2H, m), 3.26-3.36 (2H, m), 3.61-3.68 (2H, m), 3.74-3.78 (1H, d, J=13.5Hz), 4.06 (2H, s), 4.48-4.55 (1H, m), 6.96-6.98 (1H, d, J=7.5Hz), 7.18-7.19 (1H, d, J=1.8 Hz), 7.28-7.31 (1H, d, J=8.1 Hz); EI-MS: mlz 504, 416, 370, 335, 327, 274, 272, 217, 183, 154, 1 12, 98, 82, 57.

 Step 2: 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-morpholinacetamide)-1-piperidinyl ) propyl)-4-piperidinecarboxamide (compound 30)

 Step 1 The product (1 10 mg, 0.2 mmol), morpholine (0.02 mL, 0.24 mmol) and EtOAc (EtOAc) Then, the solvent was evaporated to dryness. The concentrate was separated by column chromatography (dichloromethane/methanol = 20/1 to 10/1 (v/v)) to give the product as a pale yellow foam (67 mg, yield 55%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.09-1.24 (2Η, m), 1.59-1.74 (12H, m), 2.03 (3H, s), 2.06-2.16 (1H, m), 2.29-2.39 (4H, m ), 2.41 (3H, s), 2.47-2.55 (4H, m), 2.80-2.99 (3H, m), 3.15-3.16 (2H, d, J=3.6Hz), 3.22-3.38 (2H, m), 3.60-3.81 (8H, m), 4.46-4.54 (1H, m), 6.94-7.00 (1H, dt, J = 7.8Hz, 1.8Hz), 7.18 (1H, d, J=2.1Hz), 7.27-7.30 (1H, d, J = 8.1Hz); EI-MS: mlz 589 [M]+, 489, 416, 378, 335, 1 12, 100; HREI calculated C ₃₁ H ₄₈ C1 ₅ 0 ₄ (M+): 589.3395, measured value: 589.3390.

 Example 31

 Compound 31: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(N-methylpiperazine)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

 In the step 2 of Example 30, 1-methylpiperazine was used in place of the morpholine, and the reaction was carried out in the same manner as in the steps 1 and 2 of Example 30 to give a pale yellow foam (31 mg, yield: 26%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.08-1.25 (3Η, m), 1.57-1.83 (10H, m), 1.87-2.01 (2H, m),

2.05 (3H, s), 2.26-2.38 (8H, m), 2.42 (3H, s), 2.47-2.60 (8H, m), 2.80-2.98 (3H, m), 3.15-3.17 (2H, m), 3.21-3.36 (2H, m), 3.60-3.83 (3H, m), 4.50-4.54 (1H, m), 6.95-6.99 (1H, d, J=2.1Hz, 5.7Hz), 7.19 (1H, m) , 7.28-7.31 (1H, d, J = 8.1 Hz); ESI-MS: mlz 603.3 [M+l]+. Example 32

 Compound 32: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-carbomethyl)-piperidine-1- Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide

 In the second step of Example 30, methyl piperidine-4-carboxylate was used in place of morpholine, and the reaction was carried out in the same manner as in Steps 1 and 2 of Example 30 to give a pale yellow foam (15 mg, yield 11%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.09-1.25 (5H, m), 1.59-1.97 (15H, m), 2.05 (3H, s), 2.17-2.39 (7H, m), 2.42 (3H, s) , 2.84-2.91 (4H, m), 3.19 (2H, s), 3.27-3.44 (3H, m), 3.68 (3H, s), 3.69-3.78 (3H, m), 4.50-4.55 (1H, m) , 7.04-7.17 (1H, m), 7.22-7.23 (1H, m), 7.33-7.35 (1H, m); EI-MS: mlz 645 [M]+, 489, 463, 416, 335, 156; HREI For C ₃₄ H ₅₂ C1 ₅ 0 ₅ (M+): 645.3657, Measured: 645.3629.

 Example 33

 Compound 33: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(N-tert-butoxycarbonylpiperazine)) Amido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 In the step 2 of Example 30, tert-butyl piperazine-1-carbonate was used in place of morpholine, and the reaction was carried out in the same manner as in Steps 1 and 2 of Example 30 to give a pale yellow foam (100 mg, yield 20%). .

^{! HNMR (CDCI3, 300 MHz)} δ 1.08-1.25 (3Η, m), 1.45 (9H, s), 1.57-1.95 (12H, m), 2.04 (3H, s), 2.28-2.50 (9H, m), 2.42 (3H, s), 2.80-2.98 (3H, m), 3.16-3.18 (2H, d, J=3.9Hz),

3.23- 3.36 (2H, m), 3.41-3.49 (4H, m), 3.63-3.68 (2H, m), 3.74-3.79 (1H, m), 4.49-4.53 (1H, m), 6.98 (1H, m ), 7.18 (1H, s), 7.28-7.31 (1H, d, J=8.4Hz); EI-MS: mlz 688 [M]+, 489, 463, 416, 335, 199, 143, 99, 57; HREI calculated C ₃₆ H ₅₇ C1 ₆ 0 ₅ (M+): 688.4079, Measured: 688.4054.

 Example 34

 Compound 34: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-piperazinylacetamide)-1-piperidine Phenyl) piperidine-4-carboxamide

 Compound 33 (658 mg, 0.95 mmol) was dissolved in tetrahydrofuran (5 mL), and 4N hydrochloric acid (5 mL) was added dropwise to the solution at room temperature, and then the mixture was stirred at room temperature for 5 hours. Thereafter, the THF in the solution was evaporated, and the aqueous phase was extracted with ethyl acetate (5 mL), and then the pH of the solution was adjusted to 10 with a 2N sodium hydroxide solution. The solution was extracted three times with dichloromethane (5 mL). The organic phase was combined (dichloromethane phase), dried over sodium sulfate, and the concentrate was purified by column chromatography (dichloromethane/methanol = 10/1 to 5/1 (v/v)) gave product as a white foam (185 mg, yield 33%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.06-1.24 (4H, m), 1.55-1.98 (10Η, m), 2.03 (3H, s),

2.24- 2.54 (7H, m), 2.41 (3H, s), 2.79-2.93 (8H, m), 3.13-3.15 (2H, d, J=5.4Hz), 3.19-3.35 (2H, m), 3.42- 3.50 (2H, m), 3.65-3.78 (4H, m), 4.47-4.52 (1H, m), 6.94-6.97 (1H, d, J=7.8Hz), 7.18 (1H, s), 7.27-7.30 ( 1H, d, J=8.1Hz); EI-MS: mlz 588 [M]+, 489, 463, 416, 335, 141, 99, 71, 57; HREI calculated C ₃₁ H ₄₉ C1 ₆ 0 ₃ (M ⁺ ): 588.3555, Measured value: 588.3561.

 Example 35

Compound 35: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(N-methanesulfonylpiperazine)acetamide) Base-1-piperidinyl)propyl)piperidine-4-carboxamide Triethylamine (0.044 mL, 0.32 mmol) was added <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt; ), warm to room temperature and continue to stir for half an hour. The reaction was diluted with dichloromethane (10 mL). The concentrate was separated by column chromatography (dichloromethane/methanol = 30/1 to 15/1 (v/v) to afford product as white powder (83 mg, yield 77%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.08-1.23 (4H, m), 1.54-2.09 (10Η, m), 2.04 (3H, s), 2.31-2.52 (6H, m), 2.42 (3H, s) , 2.73 (3H, s), 2.79-3.16 (10H, m), 3.19-3.35 (2H, m), 3.42-3.50 (2H, m), 3.65-3.78 (4H, m), 4.47-4.48 (1H, m), 7.13-7.16 (1H, m), 7.25 (1H, m), 7.34-7.36 (1H, d, J=8.4Hz); EI-MS: mlz 666 [M]+, 489, 463, 416, 335, 177; HREI calcd for C ₃₂ H ₅₁ C1 ₆ 0 ₅ S (M+): 666.3330, Measured: 666.3327.

 Example 36

 Compound 36: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-indole))acetamido-1 -piperidinyl)propyl)piperidine-4-carboxamide

 Under stirring, a solution of hydrazine (22 mg, 0.18 mmol) in DMF (1 mL) was slowly added to a solution of sodium hydrogen (8 mg, 0.18 mmol, content 60%) in DMF (1 mL). half an hour. Then a solution of the product of Example 30, Step 1 (100 mg, 0.18 mmol) in DMF (3 mL). The reaction was diluted with EtOAc (EtOAc)EtOAc. The concentrate was separated by column chromatography (dichloromethane / methanol = 20/1 (v/v)) to afford product as a white foam (30 mg, yield 26%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.08-1.27 (2Η, m), 1.53-1.83 (10H, m), 1.94-2.00 (2H, m), 2.04 (3H, s), 2.17-2.24 (1H, m ), 2.31-2.42 (4H, m), 2.42 (3H, s), 2.74-2.95 (3H, m), 3.24-3.41 (3H, m), 3.58-3.67 (2H, m), 3.73-3.78 (1H , m), 4.49-4.53 (1H, d, J = 12.9Hz), 4.90-4.91 (2H, d, J=5.1Hz), 6.54-6.55 (1H, d, J=2.7Hz), 6.92-6.97 ( 1H, m), 7.07-7.11 (2H, m), 7.15-7.23 (3H, m), 7.27-7.31 (1H, m), 7.60-7.63 (1H, d, J=7.8Hz); EI-MS: Mlz 619 [M]+, 489, 416, 335, 298, 202, 130, 1 12; HREI calcd for C ₃₅ H ₄₆ C1 ₅ 0 ₃ (M+): 619.3289, Measured: 619.3280.

 Example 37

 Compound 37: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-pyrrole)acetamido-1- Piperidinyl) propyl) piperidine-4-carboxamide

 Pyrrole was used instead of hydrazine, and the reaction was carried out in the same manner as in Example 36 to give a pale yellow foam (29 mg, yield: 25%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.10-1.38 (4H, m), 1.60-1.90 (11Η, m), 2.04 (3H, s), 2.30-2.42 (4H, m), 2.42 (3H, s), 2.90-3.05 (3H, m), 3.24-3.32 (2H, m), 3.39-3.51 (1H, m), 3.63-3.78 (3H, m), 4.50-4.54 (1H, m), 4.69-4.71 (2H , d, J=5.4Hz), 6.16-6.18 (2H, d, J=6.3Hz), 6.66 (2H, s), 6.95-7.01 (1H, m), 7.18 (1H, s), 7.28-7.31 ( 1H, d, J=8.4Hz); EI-MS: mlz 569 [M] ⁺ , 489, 416, 335, 248, 1 12, 82; HREI calculated C ₃₁ H ₄₄ C1 ₅ 0 ₃ (M+): 569.3133 , measured value: 569.3122

 Example 38

Compound 38: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3-nitrophenol))acetamide -1-piperidinyl)propyl)piperidine-4-carboxamide Using 3-nitrophenol instead of hydrazine, the reaction was carried out in the same manner as in Example 36 to give a pale yellow foam (12 mg, yield 10%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.10-1.30 (1H, m), 1.60-2.01 (14H, m), 2.04 (3H, s), 2.34-2.42 (4H, m), 2.42 (3H, s) , 2.80-2.93 (1H, m), 2.96-3.01 (2H, m), 3.29-3.35 (2H, m), 3.44-3.51 (1H, m), 3.61-3.68 (2H, m), 3.72-3.80 ( 1H, m), 4.48-4.54 (1H, m), 4.77-4.79 (2H, m), 6.95-6.98 (1H, d, J=8.1Hz), 7.18 (1H, s), 7.29-7.31 (2H, d, J = 7.8 Hz), 7.42-7.47 (1H, t, J = 8.1 Hz), 7.69-7.72 (1H, d, J = 7.2 Hz), 7.84-7.87 (1H, d, J = 8.1 Hz); EI-MS: mlz 641 [M]+, 624, 489, 416, 335, 320, 277, 154, 1 12, 82; HREI calculated C ₃₃ H ₄₄ C1 ₅ 0 ₆ (M+): 641.2980, Measured value: 641.2975.

 Example 39

 Compound 39: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-acetylpiperidin-4-yl)) Acetylamino-1-piperidinyl)propyl)piperidine-4-carboxamide

 The reaction procedure was similar to that of Example 2. The last step was replaced by (1-acetylpiperidin-4-yl)acetic acid (synthesized according to JU CAem. 2003, 46, 5512-5532) to give phenylacetic acid to give a pale yellow foam. (14 mg, yield 11%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.18-1.29 (4H, m), 1.56-1.69 (13H, m), 1.69-1.74 (2H, m), 1.97-2.07 (5H, m), 2.06 (3H, s ), 2.12 (3H, s), 2.33-2.46 (4H, m), 2.42 (3H, s), 2.80-2.91 (1H, m), 2.96-3.21 (3H, m), 3.28-3.35 (2H, m ), 3.51-3.64 (3H, m), 3.74-3.81 (2H, m), 4.51-4.58 (1H, m), 7.10-7.13 (1H, d, J=8.1Hz), 7.27 (1H, s), 7.36-7.39 (1H, d, J = 8.1 Hz); EI-MS: mlz 504, 416, 406, 335, 197, 183, 140, 82.

 Example 40

 Compound 40: l-(3-(l-Acetyl-N-(3-chloro-4-methylphenyl)piperidin-4-carboxamido)propyl)piperidinyl-4-(ethyl) Benzyl methionate

 The reaction was carried out in the same manner as in Example 2, and the last step was carried out by amidation of benzyloxycarbonyl chloride in place of phenylacetic acid and an amine to give a white foam (27 mg, yield 40%).

^{! HNMR (CDCI3, 300 MHz)} δ 1.08-1.16 (3Η, m), 1.45-1.79 (11H, m), 2.04 (3H, s), 2.17-2.51 (5H, m), 2.41 (3H, s), 2.79-2.87 (2H, m), 3.07-3.11 (1H, br-d, J=10.5Hz), 3.48-3.77 (6H, m), 4.48-4.53 (1H, br-d, J=14.1Hz), 5.17-5.26 (2H, m), 6.68-6.70 (1H, m), 6.93-6.99 (2H, m), 7.33-7.39 (5H, m); EI-MS: mlz 596 ( M ⁺ ).

 Example 41

 Compound 41 : 3-chloro-4-methylphenyl (3-(4-(N-ethyl-2-phenylacetamido)piperidin-1-yl)propyl)methionine cyclohexyl ester

 The reaction procedure was similar to that of Example 2 except that Step 4 was replaced by cyclohexyloxycarbonyl chloride in place of 1-acetyl-4-piperidinyl chloride. Finally a white foam (30 mg, yield 50%) was obtained.

^{! HNMR (CDCI3, 300 MHz)} δ 1.08-1.16 (3Η, m), 1.45-1.79 (11H, m), 2.17-2.51 (5H, m), 2.41 (3H, s), 2.79-2.87 (2H, m ), 3.17-3.26 (2H, m), 3.48-3.77 (6H, m), 3.87-3.91 (1H, br-d, J=10.5Hz), 4.48-4.53 (1H, br-d, J=14.1Hz ), 6.93-6.99 (1H, m), 7.14-7.33 (7H, m); EI-MS: mlz 553 ( M ⁺ ).

Example 42 Compound 42: NG-HN-3-chloro-4-methylphenyl)benzenesulfonamido)propyl)piperidin-4-yl)-N-ethyl-2-phenylacetamide

 The reaction procedure was similar to that of Example 2 except that Step 4 was replaced with benzenesulfonyl chloride in place of 1-acetyl-4-piperidinecarbonyl chloride. Finally, a pale yellow foam (55 mg, yield 60%) was obtained.

 EI-MS: m/z 596 ( M+) .

 Example 43

 Compound 43 : N-(l-(3-(l-(3-chloro-4-methylphenyl)-3-cyclohexyl)propyl)piperidin-4-yl)-N-ethyl- 2-phenylacetamide

 The reaction procedure was similar to that of Example 2 except that Step 4 was replaced with cyclohexyl isocyanate in place of 1-acetyl-4-piperidinecarbonyl chloride. Finally, a pale yellow foam (35 mg, yield 50%) was obtained.

 EI-MS: m/z 552 ( M+) .

 Example 44

 Compound 44: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-naphthyloxy)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide

 Using 1-naphthyloxyacetic acid in place of phenylacetic acid, the reaction was carried out in the same manner as in Step 2 of Example 2 to give a pale yellow foam (yield: 73 mg, yield: 58%).

_{^{! HNMR (CDC1 3, 300 MHz}} ) δ 1.10-1.14 (2Η, m), 1.26-1.30 (4H, m), 1.61-1.83 (10H, m), 2.04 (3H, s), 2.29-2.37 (4H, m), 2.42 (3H, s), 2.79-2.89 (2H, m), 3.33-3.47 (3H, m), 3.65-3.78 (3H, m), 4.50-4.55 (1H, d, J=16.2Hz) , 4.90 (2H, s), 6.81-7.22 (4H, m), 7.31-7.37 (2H, m), 7.45-7.48 (3H, m), 7.81 (1H, br); EI-MS: m/z 646 (M+).

 Example 45

 Compound 45: 1-acetyl-N-(3-(4-(4-(3-benzyloxyphenyl)-N-ethyl-2,4-dicarbonylbutylamino)-1-piperidinyl )propyl)-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide

 The reaction procedure was similar to that of Example 2, and the last step was carried out using 4-(3-benzyloxyphenyl)-2,4-dicarbonylbutyric acid (synthesized according to J Med. Chem. 2004, 47, 2561-2573) Instead of phenylacetic acid, a pale yellow foam (14 mg, yield 11%) was obtained.

^{! HNMR (CDCI3, 300 MHz)} δ 0.88-1.12 (10Η, m), 1.18-1.32 (4H, m), 1.59-1.66 (5H, m), 1.73-1.89 (3H, m), 2.04 (3H, s ), 2.23-2.37 (4H, m), 2.40 (3H, s), 2.74-2.87 (2H, m), 3.11-3.38 (3H, m), 3.58-3.82 (4H, m), 3.86 (2H, s ), 4.49-4.59 (1H, m), 5.06 (2H, s), 6.93-7.00 (1H, m), 7.14-7.18 (2H, m), 7.28-7.42 (8H, m), 7.55-7.65 (1H , m); EI-MS: mlz 742 ( M+) .

Biological activity test example

 1. Molecular level activity test results

CCR5 belongs to the G-protein coupled receptor (GPCR) family. The development of drug development technology for GPCR is relatively complete, and the experimental techniques such as receptor ligand binding method, GTPyS binding method and Ca ²⁺ flow detection method are widely used in drug screening related to chemokine receptors. The compounds of the present invention were tested for CCR5 inhibitory activity by suction filtration [ ³⁵ S]GTP _Y S binding assay, SPA-WGA method [ ³⁵ S]GTP _Y S binding assay and calcium influx assay. A. [ ³⁵ S]GTP _Y S binding experiment

When CCR5 binds to an agonist, a conformational change occurs, causing CCR5 to interact with the G protein. The G protein is activated. The G protein is a trimer composed of a ct subunit and a βγ subunit. Since (the ability of the subunit to bind to GTP depends on the action of CCR5 and the agonist, the amount of GTP bound to the a subunit can be measured to reflect the agonist's ability to activate CCR5. In the GTPyS binding assay, in order to rule out GTP hydrolysis due to GTPase The amount of GTP that binds to the G protein does not accurately reflect the activation of CCR5, and for the convenience of detection, GTPyS, a structural analog of ³⁵ S-labeled GTP, is substituted for GTP, and GTPyS binds to the activated ct subunit but cannot be hydrolyzed. Thus, when CCR5 is not activated, the subunit binds to GDP; after CCR5 is activated, the α subunit binds to GTPyS, and GTPyS irreversibly binds to the α subunit. Therefore, the α subunit binds to [ ³⁵ S]-GTP _Y S The amount reflects the extent to which CCR5 is activated by the agonist. When an antagonist is added, it will reduce the ability of the agonist to activate CCR5.

In this type of experiment, the free G protein-bound [ ³⁵ S]-GTP _Y S can be isolated by membrane filtration, which is called the suction filtration GTPyS experiment.

 Or use SPA (Scintillation Proximity Assay) technology to detect binding to G proteins.

[ ³⁵ S]-GTPyS is called the SPA-WGA method [ ³⁵ S]GTP _Y S binding experiment. The principle of SPA technology is: Subatomic particles released by the decay process of radioactive atoms, such as beta rays (electrons), can stimulate the microspheres to emit light at a distance close enough to be detected by the photometric instrument. The energy of such rays in an aqueous phase solution is mostly absorbed by the solvent and the propagation distance is very limited. Therefore, if the luminescent microspheres are attached to the cell membrane by wheat germ agglutinin (WGA), only the [ ^35S ]-GTP _Y S bound to the G protein has a sufficiently short distance to excite the microspheres to illuminate, thereby reflecting the receptor. Activation.

 The activation of G protein by CCR5 was determined by the following experiment.

CHO (Chinese Hamster Ovary Cell) Permanent Cell Line (CHO-CCR5) expressing CCR5 was lysed with lysis buffer (5 mM Tris-HCl, H 7.5, 5 mM EDTA and 5 mM EGTA) and centrifuged at 15,000 x g for 10 min. . The cell membrane was resuspended in reaction buffer (5 mM Tris-HCl, pH 7.5, 5 mM MgCl ₂ , 1 mM EGTA, 100 mM NaCl), and Bio-Rad's Bioford legal protein was used. Then, a GTPyS binding experiment was carried out in a reaction buffer, wherein the reaction system was ΙΟΟμ, containing 1 (^g membrane protein, 40 μΜ GDP, 0.5 nM [ ³⁵ S]-GTPyS (1200 Ci/mmol), after adding the compound to be tested. After shaking and mixing, the reaction tube was incubated at 30 ° C for 1 hour. After the reaction was completed, the tube was placed on ice, diluted with PBS to stop the reaction, and immediately vacuum filtered with a GF/C filter. The radioactive activity is added to the scintillation fluid and measured by a liquid scintillation counter. This is the filtered GTPyS experimental method. The previous steps of the SPA-WGA assay are the same as the GTPyS assay, except that after the reaction is terminated by adding PBS to the reaction, the reaction system is added. The SPA-WGA microspheres were further added with the compound to be tested, and the system was mixed, incubated at 30 ° C for 1 hour, and then partially stopped on ice. Centrifugation at room temperature, 1000 rpm, 15 min, followed by measurement using a liquid scintillation counter.

 The bound radioactivity was determined using a liquid scintillation counter. The basal was determined without agonists and the non-specific was determined in the presence of 10 μΜ of non-isotopic GTPyS.

^[35 S] Press _{100x [c.pm. Samp ie-cpm} non _ S pecific] I [cpm basal -cpm non-S p ecific] -GTPyS to calculate the percentage of binding. IC _5Q is a compound that inhibits ΙΟηΜ RA TES (a cytokine that has a strong chemotactic effect on mononuclear-macrophages) caused by [ ³⁵ S]-GTP _Y S binding 50%, concentration curve from compound Get it on.

When studying the concentration-inhibition curve of the compound, the highest CPM value or RFU value under the action of the agonist RANTES is 100%, the background CPM value or the RFU value is 0%, and then fitted by the statistical software Sigmap lot, and the antagonist is obtained. IC _5Q value. When the concentration of the compound is 1 μΜ and the CCR5 ability of the antagonistic assay is less than 90%, a virtual concentration is required for the convenience of mapping. In this study, the virtual point is: when the compound is 1 mM, its antagonistic Compound

 The CCR5 capacity is 100%.

 B. Calcium influx detection experiment

After activation of the G protein, changes in the intracellular cytosolic Ca ²⁺ concentration can be modulated by several different mechanisms to reflect the level at which the GPCR is activated. Invitrogen's Fluo-4 calcium dye is a commonly used fluorescent dye for Ca ²⁺ detection, and signal detection can usually be done using the FlexStation or FLIPR of the molecular device. The present invention achieves activation of the G _q signaling pathway by the G _l/() protein-coupled CCR5 receptor by overexpressing the G _q family protein-G16 in a CHO-CCR5 stable cell line.

 The cells were cultured in serum-free medium 4 hours before the start of the experiment, and the cells were digested with 0.04% EDTA-PBS and washed once with HBSS (Hank's Balanced Salt Solution) buffer. The cells were resuspended in HBSS containing 2.5 mM Probenecid, and a premixed mixture of Fluo-4 AM (fluorescent dye) and Cremophor EL (polyoxyethylene castor oil) was added to the cell suspension. After mixing well, the reaction was carried out in a 37 ° C incubator for 40 min, then centrifuged at 800 rpm for 3 min, the supernatant was discarded, and 5 mL of HBSS was used to wash the cells twice. Use l lmL HBSS suspension cells to plate 96-well plates (ΙΟΟμΙ/well), centrifuge in 96-well plates at 1000 rpm for 3 min, incubate at room temperature for 10 min in the dark, add 50 μl of drug solution, set up the instrument FlexStation, add agonist solution (25μ1Ανε11), Measurement data.

 C. Activity test results

[ ³⁵ S]GTP _Y S binding assay and calcium influx assay showed that a series of compounds of the invention are antagonists of CCR5, which inhibit the binding of GTP _Y S caused by activation of CCR5 by 10 nM RA TES, and its inhibition And IC ₅ o are listed in Table 1 below.

 Table 1

ο

ο

 1-acetyl-N-(3-chloro-4-methylbenzene

Base) Good (3- (4- (N-ethyl -2-)

3.93 (2-naphthyl)acetamido)-1-piper

Pyridyl) propyl) piperidine-4-carboxamide ¹ _α

 1-acetyl-N-(3-chloro-4-methylbenzene ο

Good (3-(4-(N-ethyl-2-(1-adamantyl)acetamido)-1- 25.6 piperidinyl) propyl) piperidine-4-formyl ° y-ci

Amine

 1-acetyl-N-(3-chloro-4-methylbenzene ο

Base (3) (3- (4-(N-ethyl-2-(4-(2-oxoethoxy)phenyl))

Amido)-1-piperidinyl)propyl) _Y J . 3.94 piperidine-4-carboxamide ⁰

 1-acetyl-N-(3-chloro-4-methylbenzene

Base) Good (3- (4- (N-ethyl -2-)

(4-acetylphenyl)acetamido) 4.58 -1-piperidinyl)propyl) piperidine-4-methyl

Amide

 1-acetyl-N-(3-chloro-4-methylbenzene

Good (3-(4-(N-ethyl-2-(4-aminophenyl)acetamido)-1-1-55 piperidinyl) propyl) piperidine-4-formyl

Amine

 1-acetyl-N-(3-chloro-4-methylbenzene

Base) Good (3- (4- (N-ethyl -2- 〇:

 Work

 (4-carboxamidesulfonylaminophenyl) B 5.25 Amido)-1-piperidinyl)propyl)

Piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylbenzene

Base) Good (3- (4- (N-ethyl -2-)

(4-acetamidophenyl)acetamide 3.33 base)-1-piperidinyl)propyl)piperidine

-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylbenzene ° H

Base) Good (3- (4- (N-ethyl -2-)

(4-methoxyformylaminophenyl) rr ^N丫⁰ , 2.22 acetamido)-1-piperidinyl)propyl)

Piperidine-4-carboxamide 丫 . °

 1-acetyl-N-(3-chloro-4-methylbenzene

Base) Good (3- (4- (N-ethyl -2-)

(4-(1-pyrrolidinyl)sulfonylbenzene 3.33 based) acetamido)-1-piperidinyl)

Propyl) piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylbenzene

Base (3) (3-(4-(N-ethyl-2-(4-indole-indole-dimethylaminosulfonylbenzene-3-yl)acetamido)-1-piperidinyl)

Propyl) piperidine-4-carboxamide

 The compound inhibited CCR5 by more than 50% at a concentration of nM; "one" indicates that the compound did not exhibit CCR5 antagonistic activity at a concentration of 300 nM.

The activity data listed in Table 1 fully shows that the screening results obtained by the three experimental methods are mutually validated and very consistent. The compounds of the present invention are all high activity antagonists of the chemokine receptor CCR5, of which 30 compounds are against CCR5. The inhibitory activity of the receptor IC _5Q reached the nM level, the IC _5Q of the 5 compounds reached the level of 10 nM, and the IC _{5Q of the} 8 compounds reached at least the level of 100 nM.

 2. Cell level antiviral activity test results

 H4DA5 cell model: (operating under P3 laboratory conditions)

 1 H4DA5 cells: Hela cells express human CD4, CCR5 receptor and reporter gene Ltr-lacZ,

 2 Place the appropriate number of H4DA5 cells on a 96-well plate and incubate overnight.

 3 adding the test compound and HIV-1 NL (AD8) virus,

 4 incubate for 3 days,

 5 Determination of viral replication using the β-galactosidase assay kit.

The H4DA5 cell model experiments showed that the compound of the present invention is a CCR5 antagonist capable of inhibiting virus replication in a cell model, and its inhibitory activity EC _{5Q is} listed in Table 2 below, and the structures of the corresponding compounds are shown in Table 1.

 Table 2

 Chemical

合 化合物名称

Compound name

 Object

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-phenylacetamido))

 2 240 -1-piperidinyl) propyl) piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3,4-dichlorobenzene)

 3 4 base) acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3, 4, 5-)

 4 120 methoxyphenyl) acetamido)-1-piperidinyl) propyl) piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-trifluoromethyl))

 6 32 phenyl) acetamido)-1-piperidinyl) propyl) piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3-indenyl))

9 90 acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-nitrophenyl))

 12 28 acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-adamantyl))

 16 2.5 acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methoxy))

 22 160 acylaminophenyl) acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-N,N-dimethyl)

 24 2.5 Aminesulfonylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(1-piperidinyl)))

 25 4 sulfonylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-morpholinyl)sulfonate

 26 9 acylphenyl) acetamido)-1-piperidinyl) propyl) piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-morpholinylacetamide)

 30 38 -1-piperidinyl) propyl) piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-piperazinylacetamide)

 34 >1000 -1-piperidinyl)propyl) piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(N-methanesulfonyl))

 35 >1000 piperazine)acetamido-1-piperidinyl)propyl)piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-indole)acetamide)

 36 390 base -1-piperidinyl) propyl) piperidine-4-carboxamide

 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3-nitrophenol))

 38 18 acetamido-1-piperidinyl)propyl)piperidine-4-carboxamide

The activity data listed in Table 2 shows that the compounds of the present invention have potent inhibitory effects on viral replication at the cellular level, wherein the inhibitory activity of five compounds against the H4DA5 cell model reaches the nM level of EC _5Q , and five compounds against H4DA5 cells. inhibitory activity EC _5Q model reaches ΙΟηΜ level of inhibitory activity of compounds 4 EC _5Q H4DA5 cell model reaches ΙΟΟηΜ level.

Therefore, the compound of the present invention is a potent CCR5 antagonist and can be used as a therapeutic agent for CCR5-mediated diseases such as HIV-1 virus invasion inhibitor, autoimmune disease, asthma, rheumatoid arthritis, chronic obstructive pulmonary disease, etc. .

Claims

Rights request A 1-(3-aminopropyl)piperidin-4-aminoamide compound of the formula I or a pharmaceutically acceptable salt thereof,

In the formula, and the following groups each independently hydrogen or unsubstituted or substituted by 1 to 3 substituents: Ci-C ₆ Ci-Cs, alkoxy, C ₂ -C ₆ ; i-hik, C ₂ -C _{6 3⁄4} : group, C ₃ -Cs ring-based, C ₃ -Cs ring-based oxy, amine, phenyl, benzyl, naphthyl, C ₅ -C _1Q aromatic heterocyclic or c ₄ a _{-7 7-} saturated heterocyclic group, said heterocyclic ring comprising 1 to 3 hetero atoms selected from N, 0 and S, said substituent being selected from the group consisting of: dC ₆ alkyl, dC ₆ Alkoxy dC ₆ alkyl, -3⁄4 cycloalkyl, halogen, fluorenyl, hydroxy, CF ₃ , CN, N0 ₂ , NR6R ₇ ,

NR6COOR ₇ , NR6S0 ₂ R ₇ , COOR ₇ , COR ₇ , CONR^ S0 ₂ R ₇ , S0 ₂ NR6R ₇ , OR? and OCOR ₇ ; G is OCO, CO, NR ₇ CO or S0 ₂ ; R ₂ is an unsubstituted or substituted group of 1 to 3 substituents: phenyl, benzyl, naphthyl or C ₅ -C _{1 ()} aromatic heterocyclic group, said heterocyclic ring includes 1- 3 heteroatoms selected from N, 0 and S, the substituents being selected from the group consisting of the following atoms or groups: CC ₆ alkyl, dC ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C _6- block, C ₃ -C ₇ cycloalkyl, dC ₆ alkyl fluorenyl, halogen, fluorenyl, hydroxy, CF ₃ , CN, N0 ₂ , NR6R ₇ ,

NR6S0 ₂ R ₇ , COOR ₇ , COR ₇ , CONR6R ₇ , S0 ₂ R ₇ , OR? and OCOR ₇ , wherein dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ block, C ₃ -C ₇ cycloalkyl, dC ₆ alkoxy or dC ₆ alkyl fluorenyl may be optionally substituted by a hydrazine, a hydroxy group, an amino group, a C ₃ -Cv cycloalkyl group, a cyano group or a decyl group;  X is not present, 0, CO or NH; R4 is an unsubstituted or substituted group of 1-3 substituents: dC ₆ alkylene, dC ₆ alkoxy dC ₆ alkylene, dC ₆ alkylenecarbonyl, dC ₆ alkyleneoxy, a c ₂ -c ₆ alkenylene group or a c ₂ -c ₆ subunit group, said substituent being selected from the group consisting of: dC ₆ alkyl, dC ₆ alkoxy, halogen, amino, nitro, nitrile Base, thiol and hydroxy; R ₅ is an unsubstituted or substituted group of 1 to 3 substituents: ₈ cycloalkyl, adamantyl, phenyl, phenol, benzyl, naphthyl, C ₅ -C _1Q aromatic heterocyclic Or a C ₄ -C ₇ saturated heterocyclic group, said heterocyclic ring comprising 1-3 heteroatoms selected from N, 0 and S, said substituent being selected from the group consisting of the following atoms or groups: dC ₆ alkane Base, dC ₆ alkoxy, halogen, fluorenyl, hydroxy, CF ₃ , CN, N0 ₂ , NR6R ₇ , NReCOR^ NReCOOR^ NR6S0 ₂ R ₇ , COOR ₇ , COR ₇ , CONR6R ₇ , S0 ₂ R ₇ , S0 ₂ NR6R ₇ , OR? and OCOR ₇ , and NR^R? can together form a cyclic amine; R6 is hydrogen, hydroxy or CC ₆ alkyl; R ₇ is hydrogen or the following groups which are unsubstituted or substituted by 1 to 3 substituents: dC ₆ alkyl, dC ₆ alkoxy Ci-C ₆ Ci-C ₆ C ₂ -C ₆ ; C ₂ -C _{6 3⁄4} : group, C ₃ -Cs ring, phenyl, ⁼ ^ group, Tsai, C ₅ -d. An aromatic heterocyclic group or a C ₄ -C ₇ saturated heterocyclic group, the heterocyclic ring comprising 1-3 selected from the group consisting of N, 0 and S A hetero atom, said substituent being selected from the group consisting of dC ₆ alkyl, dC ₆ alkoxy dC ₆ alkyl, halogen, amino, nitro, decyl, hydroxy, CN and CF ₃ .  The 1-(3-aminopropyl)piperidin-4-aminoamide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by the following formula II. compound of:

Wherein R ₃ is hydrogen, dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ block or C ₃ -C ₇ cycloalkyl, wherein dC ₆ alkyl is optionally halogen, hydroxy a dC ₄ alkoxy group, a C ₃ -C ₇ cycloalkyl group, a cyano group, a decyl group, an amino group, a nitro group or a dC ₄ alkyl fluorenyl group; The definitions of X, R4, and R ₅ are the same as those in claim 1; And independently hydrogen, halogen, hydroxy, cyano, decyl, nitro, dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ block, C ₃ -C ₇ cycloalkyl, dC ₆ Alkoxy or dC ₆ alkylalkyl, wherein dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ block, C ₃ -C ₇ cycloalkyl, dC ₆ alkoxy or dC ₆ alkenyl It may be optionally substituted by halogen, hydroxy, amino, C ₃ -C ₇ cycloalkyl, cyano or thiol.  The 1-(3-aminopropyl)piperidin-4-aminoamide compound according to Claim 2 or a pharmaceutically acceptable salt thereof, characterized in that  R3 is a C1-C4 fluorenyl group;  X is not present; R4 is dC ₄ alkylene; R ₅ is an unsubstituted or substituted group of 1 to 3 substituents: phenyl, phenol, naphthyl, adamantyl, morpholinyl, piperazinyl, piperidinyl, pyrrolyl, thienyl , imidazolyl, triazolyl, tetrazolyl, furyl, pyranyl or fluorenyl, quinolyl, benzopyranyl, benzothienyl, benzofuranyl, benzimidazolyl or benzo a triazolyl group, the substituent is selected from the group consisting of dC ₄ alkyl, dC ₄ alkoxy, halogen, hydroxy, CF ₃ , N0 ₂ , NR6R ₇ , NR6COR ₇ ,

S0 ₂ R ₇ , S0 ₂ NR6R ₇ , OR _{7 and} B OCOR ₇ , and NR6R ₇ may together form a cyclic amine, wherein R« is hydrogen or CC ₆ alkyl, R ₇ is hydrogen, CC ₆ alkyl or dC ₆ alkane Oxylate R ₈ is hydrogen, halogen or CrC ₄ alkyl; R ₉ is hydrogen or halogen.  The 1-(3-aminopropyl)piperidin-4-aminoamide compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the compound is one of the following compounds:  1-acetyl-N-(3-chlorophenyl)-N-(3-(4-(N-ethyl-2-phenylacetamido)-1-piperidinyl)propyl)piperidine- 4-formamide, 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-phenylacetamido)piperidinyl) Propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3,4-dichlorophenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3,4,5-trimethoxyphenyl)) Amido)-1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3,4-dimethoxyphenyl)acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-trifluoromethylphenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-hydroxyphenyl)acetamide)-1-piperidyl Pyridyl) propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methoxyphenyl)acetamido)) 1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3-indolyl)acetamide)-1- Piperidinyl)propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-fluorophenyl)acetamide)-1- Piperidinyl)propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-chlorophenyl)acetamide)-1- Piperidinyl)propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-nitrophenyl)acetamido)-1 -piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-naphthyl)acetamido)-1-piperidyl Pyridyl) propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-nitro-1-naphthalenyl))acetamide -1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(2-naphthyl)acetamide)-1-piperidyl Pyridyl) propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-adamantyl)acetamide)-1- Piperidinyl)propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(2-oxoethoxy))phenyl) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-acetylphenyl)acetamide)-1 -piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-aminophenyl)acetamide)-1- Piperidinyl)propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methanesulfonylaminophenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide, 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-acetamidophenyl))acetyl Amino)-1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methoxyformamidophenyl)acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(1-pyrrolidinyl))sulfonylphenyl) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-N,N-dimethylaminesulfonylphenyl) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(1-piperidinyl))sulfonylphenyl) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-morpholinylsulfonylphenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-n-propylaminesulfonylphenyl)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-tert-butylaminesulfonylphenyl)acetamide)) 1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methanesulfonylphenyl)acetamide)) 1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-morpholinacetamido)piperidinyl)propyl) Piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(N-methylpiperazine)acetamide)-1 -piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methyl carboxamide)pyranyl) acetamide -1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(N-tert-butoxycarbonylpiperazine)acetamide) -1-piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-piperazinylacetamide)piperidinyl)propyl) Piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(N-methanesulfonylpiperazine)acetamido-i) -piperidinyl)propyl)piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-indole)acetamidopiperidinyl) Propyl) piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-pyrrole)acetamide)piperidinyl) Piperidine-4-carboxamide,  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(3-nitrophenol))acetamido-1- Piperidinyl)propyl) piperidine-4-carboxamide and 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(1-acetylpiperidin-4-yl)acetamide) Base-i-piperidinyl)propyl)piperidine-4-carboxamide. The 1-(3-aminopropyl)piperidin-4-aminoamide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is one of the following compounds:  1-(3-(1-acetyl-N-(3-chloro-4-methylphenyl)piperidin-4-carboxamido)propyl)piperidinyl-4-(ethyl) valine Benzyl ester,  3-Chloro-4-methylphenyl (3-(4-(indolyl-2-phenylacetylamino)piperidin-1-yl)propyl)methionine cyclohexyl ester, Ν-(1 -(3-(Ν-(3-chloro-4-methylphenyl)benzenesulfonamido)propyl)piperidin-4-yl)-indole-ethyl-2-phenylacetamide, N-(l -(3-(l-(3-chloro-4-methylphenyl)-3-cyclohexylureido)propyl)piperidin-4-yl)-indole-ethyl-2-phenylacetamide, 1 -acetyl-indole-(3-chloro-4-methylphenyl)-indole-(3-(4-(indolyl-2-(1-naphthyloxy)acetamido)-1-piperidyl Pyridyl)propyl) piperidine-4-carboxamide, and  1-acetyl-indole-(3-(4-(4-(3-benzyloxyphenyl)-indole-ethyl-2,4-dicarbonylbutylamino)piperidinyl)propyl) Ν-(3-Chloro-4-methylphenyl) piperidine-4-carboxamide.  The 1-(3-aminopropyl)piperidin-4-aminoamide compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical The acceptable salt is 1-(3-aminopropyl)piperidine-4-aminoamide compound with hydrochloric acid, tartaric acid, citric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid or methanesulfonic acid. The salt formed.  A method for producing a 1-(3-aminopropyl)piperidin-4-aminoamide compound according to claim 1, which comprises the steps of:

Wherein, R ₂ , R ₃ , R 4 and R _{5 have} the same definitions as in claim 1; P is an amino protecting group of one of tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 9-fluorenylmethoxycarbonyl, CH ₃ CO or CH ₃ OCO; Step a): in the presence of a base, R ₂ NH ₂ and 1-bromo-3-chloropropane nucleophilic substitution reaction, to obtain N-substituted 3-chloropropylamine compound I;  Step b): N-substituted 3-chloropropylamine compound I undergoes reductive amination reaction with aldehyde or ketone, or coupling reaction with acid, or nucleophilic substitution reaction with halogenated hydrocarbon to obtain N-trisubstituted 3- Chloropropylamine compound II;  Step c): nucleophilic substitution reaction of a primary or secondary amine compound with an N-trisubstituted 3-chloropropylamine compound II in the presence of a base to give 4-N-protected 1-(3-aminopropyl)piperidin Pyridine-4-amino compound III;  Step d): Compound III is subjected to acid hydrolysis or base hydrolysis or hydrogenolysis according to the amino protecting group, and the deamination protecting group is given to compound IV; Step e): Coupling of free amine compound IV with an acid to form 1-(3-aminopropyl)-piperidin-4-aminoamide VI;  Or,  Step f): in the presence of a base, the free amine compound IV and the chloroacetyl chloride form a chloroacetamide compound V; Step g): the base, the chloroacetamide compound V and the hetero atom-containing compound undergo a nucleophilic substitution reaction to obtain 1-( 3-Aminopropyl)piperidine-4-aminoamide VI. 8. The preparation method according to claim 7, wherein the preparation step of the primary or secondary amine compound 4-N-substituted-4-aminopiperidine in the step c) is as follows:

Wherein R _{3 has} the same definition as claim 1; Pi and! ^ is an amino protecting group of one of tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 9-fluorenylmethoxycarbonyl, CH ₃ CO or CH ₃ OCO;  1-N-protected 4-piperidone is subjected to reductive amination to give 1-N-protected-piperidine VII, 4-amino-protected group to give compound VIII, and compound VIII is obtained from 1-amino-deprotected to afford intermediate 4 -N-substituted-4-aminopiperidine IX.  A pharmaceutical composition for treating a disease mediated by CCR5 comprising a therapeutically effective amount of one or more compounds of formula I or a pharmaceutically acceptable salt thereof, and comprising a pharmaceutically acceptable carrier.  10. The pharmaceutical composition according to claim 9, wherein the composition further comprises a protease inhibitor and/or a reverse transcriptase inhibitor.  The 1-(3-aminopropyl)piperidin-4-aminoamide compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an antagonist of CCR5 in the preparation of a therapeutic agent by CCR5 The use of drugs that mediate diseases.  12. Use according to claim 11, characterized by the use in the manufacture of a medicament for the treatment of HIV infection, asthma, rheumatoid arthritis, autoimmune disease or chronic obstructive pulmonary disease.