Compound as well as application and pharmaceutical composition thereof

Abstract

The invention discloses a compound, application thereof and a pharmaceutical composition, and belongs to the technical field of pharmaceutical chemistry. The structure of the compound is shown as a formula (I), a ring A is selected from # imgabs0 # imgabs1 #, R1 and R2 are independently selected from one or more of hydrogen, C1-C20 straight chain or branched chain alkyl, C3-C20 cycloalkyl, C1-C10 alkoxy, substituted C1-C20 straight chain or branched chain alkyl, substituted C3-C20 cycloalkyl, substituted C1-C10 alkoxy, amino, halogen, nitrile group and nitryl; m and n respectively represent the numbers of R1 and R2, m + n = 5, and m > = 1; l is selected from a thioformamido group, a formamido group, a sulfonamido group, a sulfonylurea group, an ester group or a carbonyl group. The compound is unique and novel in structure, and has relatively strong inhibitory activity and excellent analgesic effect as a TRPV1 inhibitor. # imgabs2 #

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular, to a compound, its application and a pharmaceutical composition. Background Art

[0002] Pain is a common clinical symptom, and approximately 500 million people suffer from various pains every year. At present, the most commonly used analgesics in clinical practice are mainly divided into two categories: one is narcotic analgesics that directly activate opioid receptors, and the other is antipyretic analgesics represented by non-steroidal anti-inflammatory drugs (NSAIDs). Although these drugs have good clinical effects, they also have obvious side effects, such as the addiction of opioid drugs and the gastrointestinal side effects of non-steroidal anti-inflammatory drugs. In addition, existing drugs cannot effectively control chronic and neuropathic pain.

[0003] In recent years, with the development of related disciplines and the application of new technologies, certain progress has been made in the research on various receptors related to pain conduction and their selective ligands. TRPV1 is highly expressed in primary sensory neurons and is a non-specific cation channel that can be activated by hydrogen ions (pH < 5.5), high temperature (> 42 °C), and other endogenous and exogenous ligands, and plays an important role in the body's perception of temperature and pain. After TRPV1 is activated, it causes calcium ion influx, leading to the release of substance P and calcitonin gene-related peptide from nerve endings, thereby triggering pain. Downregulating TRPV1 expression or using TRPV1 antagonists can effectively prevent TRPV1 activation, inhibit the conduction of pain signals from peripheral nerves to central nerves, and relieve pain caused by various nerve injuries. Because developing TRPV1 inhibitors can simultaneously exert analgesic and uric acid-lowering effects and is expected to achieve the effect of treating both the symptoms and the root cause, the research on TRPV1 antagonists has become one of the most promising research directions for analgesics at present. However, there is currently no TRPV1 inhibitor on the market, and multiple drugs are in the II / III clinical stage and are mostly used for the treatment of toothache, post-herpetic neuralgia, and osteoarthritis pain.

[0004] Therefore, it is of great significance to research and develop a new type of TRPV1 inhibitor drug. Summary of the Invention

[0005] In view of this, the technical problem to be solved by the present invention is to provide a compound, its application and a pharmaceutical composition. The structure of the compound is unique and novel, and it has strong inhibitory activity and excellent analgesic effect as a TRPV1 inhibitor.

[0006] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] The present invention provides a compound, the structure of which is shown in formula (I):

[0008]

[0009] Among them, ring A is selected from

[0010] R1 and R2 are independently selected from hydrogen, C1-C 20 linear or branched alkyl, C3-C 20 cycloalkyl, C1-C 10 alkoxy, substituted C1-C 20 linear or branched alkyl, substituted C3-C 20 cycloalkyl, substituted C1-C 10 alkoxy, amino, halogen, nitrile, nitro, or one or more of them;

[0011] The substituted C1-C 20 linear or branched alkyl substituents are selected from halogen or nitrile;

[0012] The substituted C3-C 20 cycloalkyl and substituted C1-C 10 alkoxy substituents are independently selected from halogen, nitrile, amino, nitro, C1-C6 linear or branched alkyl, or one or more of them;

[0013] m and n respectively represent the numbers of R1 and R2, and m + n = 5, m ≥ 1;

[0014] L is selected from thiocarboxamide group, carboxamide group, sulfonamide group, sulfonylurea group, ester group or carbonyl group.

[0015] Preferably in the present invention, R1 and R2 are independently selected from hydrogen, C1-C 10 linear or branched alkyl, C3-C 12 cycloalkyl, C1-C 10 alkoxy, substituted C1-C 10 linear or branched alkyl, substituted C3-C 12 cycloalkyl, substituted C1-C 10 alkoxy, amino, halogen, nitrile, nitro, or one or more of them;

[0016] The C1-C 10 linear or branched alkyl includes but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.

[0017] The C3-C 12 cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0018] The C1-C 10The alkoxy group includes, but is not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, etc.

[0019] Preferably, the substituent of the substituted C1-C 10 The substituent of the straight-chain or branched-chain alkyl group is selected from halogen or nitrile group;

[0020] The substituted C1-C 10 The number of substituents of the straight-chain or branched-chain alkyl group is one or more.

[0021] Preferably, the substituent of the substituted C3-C 12 The substituent of the cycloalkyl group and the substituted C1-C 10 The substituent of the alkoxy group is independently selected from one or more of halogen, nitrile group, and C1-C3 straight-chain or branched-chain alkyl group;

[0022] Preferably, L is selected from thioformamide group, formamide group, sulfonamide group or sulfonylurea group.

[0023] More preferably in the present invention, R1 and R2 are independently selected from one or more of hydrogen, C1-C6 straight-chain or branched-chain alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, substituted C1-C6 straight-chain or branched-chain alkyl group, substituted C3-C6 cycloalkyl group, substituted C1-C6 alkoxy group, amino group, halogen, nitrile group, nitro group;

[0024] More preferably, the substituent of the substituted C1-C6 straight-chain or branched-chain alkyl group is selected from halogen;

[0025] More preferably, the substituents of the substituted C3-C6 cycloalkyl group and the substituted C1-C6 alkoxy group are independently selected from one or more of halogen and C1-C3 straight-chain or branched-chain alkyl group.

[0026] The C1-C6 straight-chain or branched-chain alkyl group is preferably a C1-C3 straight-chain or branched-chain alkyl group, which specifically includes, but is not limited to, methyl, ethyl, propyl, isopropyl, etc.

[0027] Even more preferably in the present invention, R1 and R2 are independently selected from one or more of hydrogen, C1-C4 straight-chain or branched-chain alkyl group, substituted C1-C4 straight-chain or branched-chain alkyl group, and halogen;

[0028] Even more preferably, the substituents of the substituted C1-C4 straight-chain or branched-chain alkyl group are independently selected from halogen;

[0029] Even more preferably, L is selected from thioformamide group or formamide group.

[0030] Even more preferably in the present invention, the halogen is selected from fluorine or chlorine;

[0031] More preferably, the number of substituents of the substituted C1-C4 linear or branched alkyl is an integer between 1 and 3.

[0032] More preferably, R1 and R2 are independently selected from one or more of hydrogen, methyl, trifluoromethyl, fluorine, and chlorine.

[0033] More preferably, the compound is selected from any one or more of the following:

[0034] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-chlorophenyl)-2-methylpiperazine-1-carboxamide (I-1);

[0035] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-2-methylpiperazine-1-carboxamide (I-2);

[0036] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-2-methylpiperazine-1-carboxamide (I-3);

[0037] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-2-methylpiperazine-1-carboxamide (I-4);

[0038] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-3-methylpiperazine-1-carboxamide (I-5);

[0039] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-3-methylpiperazine-1-carboxamide (I-6);

[0040] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3-methylpiperazine-1-carboxamide (I-7);

[0041] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-8);

[0042] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-9);

[0043] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-10);

[0044] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (I-11);

[0045] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (I-12);

[0046] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (I-13);

[0047] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (I-14);

[0048] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (I-15);

[0049] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (I-16);

[0050] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-2-methylpiperazine-1-carboxamide (I-17);

[0051] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-dichlorophenyl)-2-methylpiperazine-1-carboxamide (I-18);

[0052] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-2-methylpiperazine-1-carboxamide (I-19);

[0053] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-2-methylpiperazine-1-carboxamide (I-20);

[0054] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-2-methylpiperazine-1-carboxamide (I-21);

[0055] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-3-methylpiperazine-1-carboxamide (I-22);

[0056] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-3-methylpiperazine-1-carboxamide (I-23);

[0057] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,3-dichlorophenyl)-3-methylpiperazine-1-carbothioamide (I-24);

[0058] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-3-methylpiperazine-1-carboxamide (I-25);

[0059] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-3-methylpiperazine-1-carboxamide (I-26);

[0060] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-27);

[0061] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-28);

[0062] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-29);

[0063] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,3-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbothioamide (I-30);

[0064] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-31);

[0065] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-32).

[0066] More preferably, the compound of the present invention is selected from any one or more of the following:

[0067] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-10);

[0068] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (I-16);

[0069] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-2-methylpiperazine-1-carboxamide (I-19);

[0070] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-2-methylpiperazine-1-carboxamide (I-20);

[0071] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-2-methylpiperazine-1-carboxamide (I-21);

[0072] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-3-methylpiperazine-1-carboxamide (I-23);

[0073] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-3-methylpiperazine-1-carboxamide (I-25);

[0074] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-3-methylpiperazine-1-carboxamide (I-26);

[0075] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-27);

[0076] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-31);

[0077] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-32). The present invention also provides the use of the above compounds as TRPV1 antagonists in the preparation of analgesic drugs.

[0078] The compounds described in the present invention have excellent inhibitory activity against TRPV1 and analgesic efficacy as TRPV1 antagonists.

[0079] Among them, in some specific embodiments of the present invention, I-10, I-16, I-19, I-20, I-21, I-23, I-25, I-26, I-27, I-31 and I-32 among the above specific compounds have good inhibitory activity against TRPV1, comparable to the positive control N-(4-(tert-butyl)phenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC).

[0080] I-19, I-20, I-25 and I-32 among the above specific compounds can significantly inhibit the pain response induced by acetic acid. Among them, compounds I-19 and I-25 have the strongest analgesic activity, superior to the analgesic activity of the positive control BCTC. Compounds I-19, I-20, I-25 and I-32 can also significantly inhibit the inflammatory pain induced by formalin, and the analgesic activities of compounds I-19 and I-25 are superior to the positive control BCTC.

[0081] The present invention also provides a pharmaceutical composition comprising the above compounds or their pharmaceutically acceptable salts.

[0082] Preferably, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier and adjuvant.

[0083] The adjuvant includes but is not limited to diluents or excipients, etc.

[0084] Compared with the prior art, the compound provided by the present invention has a structure as shown in formula (I), wherein ring A is selected from R1 and R2 are independently selected from hydrogen, C1-C 20 linear or branched alkyl, C3-C 20 cycloalkyl, C1-C 10 alkoxy, substituted C1-C 20 linear or branched alkyl, substituted C3-C 20 cycloalkyl, substituted C1-C 10 alkoxy, amino, halogen, nitrile, nitro, or one or more of them; the substituent of the substituted C1-C 20 linear or branched alkyl is selected from halogen or nitrile; the substituents of the substituted C3-C 20 cycloalkyl and the substituted C1-C 10 alkoxy are independently selected from halogen, nitrile, amino, nitro, C1-C6 linear or branched alkyl, or one or more of them; m and n respectively represent the number of R1 and R2, and m + n = 5, m ≥ 1; L is selected from thiocarboxamide group, carboxamide group, sulfonamide group, sulfonylurea group, ester group or carbonyl group. The structure of the compound is unique and novel, and it has strong inhibitory activity and excellent analgesic effect as a TRPV1 inhibitor. Detailed implementation manners

[0085] In order to further illustrate the present invention, the compounds, their applications and pharmaceutical compositions provided by the present invention will be described in detail below with reference to examples.

[0086] In the following examples, unless otherwise specified, the raw materials used are ordinary commercially available products that can be directly purchased or can be prepared by conventional methods in the art. Room temperature refers to 25 ± 5 °C.

[0087] Example 1

[0088] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-chlorophenyl)-2-methylpiperazine-1-carboxamide (I-1)

[0089]

[0090] 2,2-Difluoro-1,3-benzodioxole-5-carbaldehyde (II-1, 0.2 g, 1.07 mmol) was dissolved in 20 ml of anhydrous dichloromethane. (II-2, 0.21 g, 1.07 mmol) and sodium triacetoxyborohydride (0.68 g, 3.21 mmol) were added. After reacting at room temperature for 3 hours, 10 ml of water was added to quench the reaction. After evaporating the organic solvent under reduced pressure, the pH was adjusted to 8 - 9 with saturated sodium carbonate aqueous solution. It was extracted with ethyl acetate (20 ml × 3). The organic phases were combined, washed with saturated brine (15 ml × 2), dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to obtain 0.29 g of II-3 with a yield of 74%.

[0091] II-3 (0.29 g, 0.79 mmol) was dissolved in 20 ml of anhydrous dichloromethane. After ice-bathing for 20 minutes, 10 ml of a prepared dichloromethane / trifluoroacetic acid = 1:1 trifluoroacetic acid solution was slowly added dropwise into the reaction system from a constant-pressure dropping funnel. After the addition was complete, the reaction was carried out at room temperature for 3 hours. The solvent was evaporated under reduced pressure. After dilution with water, the pH was adjusted to 8 - 9 with saturated sodium carbonate aqueous solution. It was extracted with ethyl acetate (20 ml × 3). The organic phases were combined, washed with saturated brine (15 ml × 2), dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was evaporated under reduced pressure to obtain 0.17 g of II-4 with a yield of 85%.

[0092] II-4 (0.17 g, 0.63 mmol) was dissolved in 15 ml of anhydrous dichloromethane. The anhydrous dichloromethane solution of II-5 (0.1 g, 0.65 mmol) was slowly added dropwise under ice-bathing. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to obtain 0.18 g of white solid I-1 with a melting point of 125 - 127 °C and a yield of 67%.

[0093] 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.56–7.42 (m, 2H), 7.36 (dd, J = 4.9, 3.3 Hz, 2H), 7.29–7.23 (m, 2H), 7.17 (dd, J = 8.3, 1.6 Hz, 1H), 4.30 (q, J = 5.8 Hz, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.55 (d, J = 13.6 Hz, 2H), 3.10 (m, 1H), 2.86–2.72 (m, 1H), 2.63 (m, 1H), 2.12 (m, 1H), 1.99 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 154.99, 143.31, 142.14, 140.07, 135.84, 131.64, 129.13, 128.54, 125.68, 124.73, 121.56, 120.24, 110.44, 61.50, 57.36, 53.13, 46.88, 16.09. ESI-HRMS m / z: [M+H] + calcd for C 20 H 20 ClF2N3O3, 423.1161; found, 424.1205.

[0094] Example 2

[0095] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-2-methylpiperazine-1-carboxamide (I-2)

[0096]

[0097] The synthesis method is the same as that of I-1, except that the starting material II-5 is replaced with m-tolyl isocyanate to obtain 0.21 g of a white solid, melting point 102 - 104 °C, yield 45%, and the spectral data are as follows.

[0098] 1 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.36 (dd, J = 4.9, 3.3 Hz, 2H), 7.28 (d, J = 1.9 Hz, 1H), 7.24 (dd, J = 7.9, 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 1.6 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 4.31 (q, J = 5.8 Hz, 1H), 3.85 (d, J = 13.1 Hz, 1H), 3.59–3.41 (m, 2H), 3.08 (m, 1H), 2.80 (d, J = 11.5 Hz, 1H), 2.63 (m, 1H), 2.24 (s, 2H), 2.12 (m, 1H), 1.98 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 155.25, 143.31, 142.13, 140.90, 137.70, 135.88, 134.15, 131.64, 129.14, 128.53, 124.72, 122.85, 120.81, 117.36, 110.44, 61.53, 57.43, 53.19, 46.87, 28.52, 21.64, 16.04. ESI-HRMS m / z: [M+H] + calcd for C 21 H 23 F2N3O3, 403.1707; found, 404.1742。

[0099] Example 3

[0100] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-2-methylpiperazine-1-carboxamide (I-3)

[0101]

[0102] The synthesis method was the same as that of I-1, except that the starting material II-5 was replaced with p-fluorophenyl isocyanate to obtain 0.2 g of white solid I-3, with a melting point of 120 - 122 °C and a yield of 65%.

[0103] 1 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.45 (dd, J = 8.9, 5.0 Hz, 2H), 7.36 (dd, J = 4.8, 3.4 Hz, 2H), 7.23–7.14 (m, 1H), 7.06 (t, J = 8.9 Hz, 2H), 4.30 (p, J = 6.5 Hz, 1H), 3.85 (d, J = 13.0 Hz, 1H), 3.55 (d, J = 13.6 Hz, 1H), 3.45 (d, J = 13.6 Hz, 1H), 3.09 (m, 1H), 2.80 (d, J = 11.0 Hz, 1H), 2.63 (d, J = 11.1 Hz, 1H), 2.12 (m, 1H), 1.99 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H). 13CNMR(101MHz, DMSO-d6) δ 158.99, 156.62, 155.26, 143.31, 142.14, 137.31, 137.28, 135.87, 134.15, 131.64, 129.14, 124.72, 121.99, 121.92, 115.26, 115.04, 110.43, 110.11, 61.52, 57.40, 53.16, 46.84, 16.04. ESI-HRMS m / z: [M+H] + calcd for C 20 H 20 F3N3O3, 407.1457; found, 408.1479。

[0104] Example 4

[0105] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-2-methylpiperazine-1-carboxamide (I-4)

[0106]

[0107] The synthesis method is the same as that of I-1, except that the starting material II-5 is replaced with p-trifluoromethylphenyl isocyanate, and 0.19 g of white solid is obtained, with a melting point of 118 - 120 °C and a yield of 78%. The spectral data are as follows.

[0108] 1 H NMR(400MHz, DMSO-d6) δ 8.85(s, 1H), 7.72(d, J = 8.5Hz, 2H), 7.60(d, J = 8.6Hz, 2H), 7.44–7.32(m, 2H), 7.20(d, J = 8.4Hz, 1H), 4.37(p, J = 6.5Hz, 1H), 3.92(d, J = 13.1Hz, 1H), 3.58(d, J = 13.6Hz, 1H), 3.48(d, J = 13.6Hz, 1H), 3.16(m, 1H), 2.84(d, J = 11.1Hz, 1H), 2.67(d, J = 11.1Hz, 1H), 2.16(m, 1H), 2.03(m, 1H), 1.26(d, J = 6.7Hz, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 154.77, 144.92, 143.32, 142.15, 135.80, 134.15, 131.64, 129.13, 126.51, 125.97, 124.69, 123.73, 122.15, 121.84, 119.44, 118.55, 110.40, 61.49, 57.32, 53.11, 47.00, 16.12. ESI-HRMS m / z: [M+H] + calcd for C 21 H 20 F5N3O3, 457.1425; found, 458.1473。

[0109] Example 5

[0110] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-3-methylpiperazine-1-carboxamide (I-5)

[0111]

[0112] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced by 4-N-Boc-3-methylpiperazine and the starting material II-5 is replaced by p-trifluoromethylphenyl isocyanate, to obtain 0.23 g of white solid I-5, with a melting point of 106 - 108 °C and a yield of 68%. The spectral data are as follows.

[0113] 1 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.44–7.37 (m, 2H), 7.36–7.27 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 3.99 (d, J = 13.8 Hz, 1H), 3.80 (m, 2H), 3.31 (d, J = 13.7 Hz, 1H), 3.12 (m, 1H), 2.93 (m, 1H), 2.66 (m, 1H), 2.47 (m, 1H), 2.29 (s, 3H), 2.18–2.05 (m, 1H), 1.14 (d, J = 6.2 Hz, 3H). 1313C NMR(101MHz, DMSO-d6) δ 155.21, 143.27, 142.03, 140.86, 137.74, 136.60, 134.15, 131.65, 129.14, 128.57, 124.83, 122.85, 120.66, 117.22, 110.61, 57.04, 55.37, 54.94, 50.62, 44.25, 21.65, 15.68. ESI-HRMS m / z: [M+H] + calcd for C 21 H 23 F2N3O3, 403.1707; found, 404.1749。

[0114] Example 6

[0115] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-3-methylpiperazine-1-carboxamide (I-6)

[0116]

[0117] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced with 4-N-Boc-3-methylpiperazine and the starting material II-5 is replaced with 4-fluorophenyl isocyanate, to obtain 0.23 g of white solid I-6, with a melting point of 140 - 142 °C and a yield of 65%. The spectral data is as follows.

[0118] 1 1H NMR(400MHz, DMSO-d6) δ 8.52(s, 1H), 7.51–7.42(m, 2H), 7.42–7.27(m, 2H), 7.16(dd, J = 8.2, 1.6 Hz, 1H), 7.06(t, J = 8.9 Hz, 2H), 3.94(d, J = 13.8 Hz, 1H), 3.85–3.66(m, 2H), 3.26(d, J = 13.8 Hz, 1H), 3.08(m, 1H), 2.89(m, 1H), 2.62(m, 1H), 2.43(s, 1H), 2.10(s, 1H), 1.09(d, J = 6.2 Hz, 3H). 1313C NMR(101MHz,DMSO-d6)δ158.97,156.61,155.26,143.27,142.04,137.27,136.58,134.15,131.65,129.14,124.82,121.84,115.30,110.60,57.02,54.92,50.54,44.20,15.66.ESI-HRMS m / z:[M+H] + calcd for C 20 H 20 F3N3O3,407.1457;found,408.1494。

[0119] Example 7

[0120] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3-methylpiperazine-1-carboxamide (I-7)

[0121]

[0122] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced by 4-N-Boc-3-methylpiperazine and the starting material II-5 was replaced by 4-(trifluoromethyl)phenyl isocyanate, to obtain 0.23 g of white solid I-7, with a melting point of 116-118 °C and a yield of 72%. The spectral data are as follows.

[0123] 1 1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.61(d,J=8.5Hz,2H),7.50(d,J=8.6Hz,2H),7.37–7.21(m,2H),7.09(dd,J=8.3,1.5Hz,1H),3.87(d,J=13.8Hz,1H),3.71(m,2H),3.19(d,J=13.8Hz,1H),3.05(m,1H),2.86(m,1H),2.57(m,1H),2.37(m,1H),2.04(m,1H),1.03(d,J=6.1Hz,3H). 1313C NMR (101 MHz, DMSO-d6) δ 154.74, 144.88, 143.28, 142.05, 136.52, 134.15, 131.64, 129.14, 126.42, 125.99 (q, J = 4.04 Hz), 124.79, 123.73, 121.98 (q, J = 32.32 Hz), 119.32, 110.57, 109.99, 56.99, 54.89, 50.55, 50.30, 44.29, 15.57. ESI-HRMS m / z: [M+H] + calcd for C 21 H 20 F5N3O3, 457.1425; found, 458.1441.

[0124] Example 8

[0125] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-8)

[0126]

[0127] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced with tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, and the starting material II-5 was replaced with m-tolyl isocyanate, to obtain 0.23 g of white solid I-8, melting point 108 - 110 °C, yield 71%, and the spectral data are as follows.

[0128] 1 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.40–7.33 (m, 3H), 7.22 (dd, J = 8.3, 1.5 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 4.54 (s, 1H), 3.77 (s, 2H), 3.63–3.52 (m, 2H), 3.31 (dd, J = 9.7, 2.2 Hz, 1H), 2.85 (dd, J = 9.4, 2.1 Hz, 1H), 2.59 (s, 1H), 2.29 (s, 3H), 1.89 (d, J = 9.5 Hz, 1H), 1.73 (d, J = 9.4 Hz, 1H), 1.28 (d, J = 4.7 Hz, 1H). 1313C NMR (101 MHz, DMSO-d6) δ 154.21, 143.30, 141.96, 140.83, 137.74, 137.50, 134.15, 131.64, 129.13, 128.57, 124.24, 122.71, 120.34, 116.92, 110.22, 110.03, 61.16, 60.02, 57.60, 57.26, 50.84, 35.52, 21.66. ESI-HRMS m / z: [M+H] + calcd for C 21 H 21 F2N3O3, 401.1551; found, 402.1582。

[0129] Example 9

[0130] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-9)

[0131]

[0132] The synthesis method was the same as that of I-3, except that the starting material II-2 was replaced with tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, and the starting material II-5 was replaced with 4-fluorophenyl isocyanate, to obtain 0.15 g of white solid I-9, melting point 110 - 112 °C, yield 63%, and the spectral data are as follows.

[0133] 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.09 (dd, J = 8.8, 5.1 Hz, 2H), 6.94 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.64 (t, J = 8.7 Hz, 2H), 4.07 (s, 1H), 3.10 (d, J = 9.2 Hz, 2H), 2.90–2.80 (m, 1H), 2.17–2.03 (m, 2H), 1.42 (d, J = 9.6 Hz, 2H), 1.26 (d, J = 9.6 Hz, 1H), 0.80 (s, 1H). 1313C NMR (101 MHz, DMSO-d6) δ 158.86, 156.50, 154.20, 153.81, 143.30, 141.97, 137.48, 137.28, 137.25, 134.14, 131.64, 129.13, 124.23, 121.45, 121.38, 115.28, 115.06, 110.21, 110.01, 61.17, 60.00, 57.60, 57.26, 50.86, 46.06, 35.49, 25.39, 11.50. ESI-HRMS m / z: [M+H] + calcd for C 20 H 18 F3N3O3, 405.1300; found, 406.1333.

[0134] Example 10

[0135] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-10)

[0136]

[0137] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced with tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, and the starting material II-5 was replaced with 4-(trifluoromethyl)phenyl isocyanate, to obtain 0.15 g of white solid I-10, with a melting point of 114 - 116 °C and a yield of 58%. The spectral data are as follows.

[0138] 1 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.30 (s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 4.48 (s, 1H), 3.66 (s, 2H), 3.51 (d, J = 9.8 Hz, 1H), 3.46 (s, 1H), 3.27–3.18 (m, 1H), 2.75 (dd, J = 9.7, 2.1 Hz, 1H), 2.49 (d, J = 9.5 Hz, 1H), 1.79 (d, J = 9.7 Hz, 1H), 1.64 (d, J = 9.5 Hz, 1H). 1313C NMR(101MHz,DMSO-d6)δ153.68,144.80,143.30,141.97,137.45,134.14,131.63,129.13,126.44,126.02(q,J=4.04Hz),124.24,123.75,122.02,121.70,119.05,110.22,110.01,61.10,59.97,57.57,57.41,50.96.ESI-HRMSm / z:[M+H] + calcd for C 21 H 18 F5N3O3,455.1268;found,456.1294。

[0139] Example 11

[0140] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (I-11)

[0141]

[0142] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced with 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.3.1]heptane, and the starting material II-5 was replaced with m-tolyl isocyanate, to obtain 0.15 g of white solid I-11, with a melting point of 138 - 140 °C and a yield of 62%. The spectral data are as follows.

[0143] 1 1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.38(d,J=1.9Hz,1H),7.35–7.29(m,1H),7.23(d,J=1.5Hz,1H),7.18–7.09(m,2H),7.06(dd,J=8.2,1.5Hz,1H),6.82–6.74(m,1H),4.20(d,J=5.9Hz,2H),3.65(s,2H),3.16(dd,J=10.4,2.5Hz,2H),2.63(d,J=10.4Hz,2H),2.40(s,1H),2.27(s,3H),1.53(d,J=7.8Hz,1H). 1313C NMR (101 MHz, DMSO-d6) δ 157.79, 143.33, 141.94, 140.46, 137.96, 136.32, 134.09, 131.59, 128.72, 124.21, 122.79, 119.66, 116.30, 110.06, 109.75, 59.44, 58.83, 51.29, 30.03, 21.63. ESI-HRMS m / z: [M+H] + calcd for C 21 H 21 F2N3O3, 401.1551; found, 402.1571.

[0144] Example 12

[0145] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (I-12)

[0146]

[0147] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced with 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.3.1]heptane, and the starting material II-5 was replaced with 4-fluorophenyl isocyanate, to obtain 0.17 g of a white solid, melting point 152 - 154 °C, yield 58%, and the spectral data are as follows.

[0148] 1 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.64–7.43 (m, 2H), 7.23–7.14 (m, 2H), 7.14–6.97 (m, 3H), 4.20 (d, J = 5.9 Hz, 2H), 3.66 (s, 2H), 3.24–3.10 (m, 2H), 2.64 (d, J = 10.4 Hz, 2H), 2.40 (q, J = 6.6 Hz, 1H), 1.56 (d, J = 7.9 Hz, 1H). 13 13C NMR (101 MHz, DMSO-d6) δ 158.90, 157.72, 156.54, 143.28, 141.96, 136.86, 136.83, 136.23, 134.07, 131.56, 129.06, 124.26, 120.70, 120.63, 115.44, 115.22, 110.11, 109.75, 59.47, 58.81, 51.23, 29.94. ESI-HRMS m / z: [M+H] +Calculated for C 20 H 18 F3N3O3, 405.1330; found, 406.1336.

[0149] Example 13

[0150] 3 - ((2,2 - Difluorobenzo[d][1,3]dioxol - 5 - yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3,6 - diazabicyclo[3.1.1]heptane - 6 - carboxamide (I - 13)

[0151]

[0152] The synthesis method is the same as that of I - 1, except that the starting material II - 2 is replaced by 6 - (tert - butoxycarbonyl)-3,6 - diazabicyclo[3.3.1]heptane, and the starting material II - 5 is replaced by 4 - (trifluoromethyl)phenyl isocyanate, to obtain 0.25 g of a white solid, melting point 170 - 172 °C, yield 46%, and the spectral data are as follows.

[0153] 1 H NMR (400 MHz, DMSO - d6) δ 8.88 (s, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.24 (d, J = 5.8 Hz, 2H), 3.65 (s, 2H), 3.17 (d, J = 10.5 Hz, 2H), 2.63 (d, J = 10.4 Hz, 2H), 2.43 (q, J = 6.7 Hz, 1H), 1.51 (d, J = 8.0 Hz, 1H). 13 C NMR (101 MHz, DMSO - d6) δ 157.75, 144.27, 143.28, 141.96, 136.17, 134.01, 131.50, 129.00, 126.44, 126.22 (q, J = 4.04 Hz), 124.17, 123.75, 122.11 (q, J = 32.32 Hz), 118.40, 109.98, 109.64, 58.62, 51.31, 30.39. ESI - HRMS m / z: [M + H] + Calculated for C 21 H 18 F5N3O3, 455.1268; found, 456.1293.

[0154] Example 14

[0155] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (I-14)

[0156]

[0157] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced by tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate, and the starting material II-5 was replaced by m-tolyl isocyanate, to obtain 0.17 g of a yellow solid with a yield of 42%. The spectral data are as follows.

[0158] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.34 (dd, J = 4.8, 3.1 Hz, 3H), 7.31–7.25 (m, 1H), 7.18–7.11 (m, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 4.43–4.30 (m, 2H), 3.47 (s, 2H), 2.58 (dd, J = 10.8, 2.5 Hz, 2H), 2.26 (s, 1H), 2.25 (s, 3H), 2.24 (s, 1H), 1.86 (q, J = 6.0, 5.1 Hz, 2H), 1.83–1.68 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 154.01, 143.31, 142.10, 140.79, 137.79, 136.16, 134.14, 131.64, 129.13, 128.61, 124.68, 122.79, 120.28, 116.87, 110.42, 110.05, 60.82, 57.59, 54.07, 28.20, 21.66. ESI-HRMS m / z: [M+H] + calcd for C 22 H 23 F2N3O3, 415.1707; found, 416.1703.

[0159] Example 15

[0160] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (I-15)

[0161]

[0162] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced by tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate, and the starting material II-5 is replaced by p-fluorophenyl isocyanate, obtaining 0.12 g of a white solid with a melting point of 190-192 °C and a yield of 75%. The spectral data are as follows.

[0163] 1 H NMR(400MHz,Chloroform-d)δ7.34–7.24(m,2H),7.02(s,1H),6.96–6.86(m,4H),4.14(d,J=3.8Hz,2H),3.39(s,2H),2.57(dd,J=11.1,2.5Hz,2H),2.32(dd,J=10.9,1.6Hz,2H),1.88(dt,J=11.8,8.3Hz,4H). 13 C NMR(101MHz,Chloroform-d)δ160.03,157.63,153.34,144.01,142.82,134.91,134.81,131.63,123.44,121.55,121.47,115.60,115.37,109.57,108.97,61.36,57.53,54.70,28.25.ESI-HRMSm / z:[M+H] + calcd forC 21 H 20 F3N3O3,419.1457;found,420.1468。

[0164] Example 16

[0165] 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (I-16)

[0166]

[0167] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced by tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate, and the starting material II-5 is replaced by p-trifluoromethylphenyl isocyanate, obtaining 0.15 g of a white solid with a melting point of 182-184 °C and a yield of 73%. The spectral data are as follows.

[0168] 11H NMR (400 MHz, Chloroform-d) δ 7.44 (s, 4H), 7.01 (s, 1H), 6.90 (s, 2H), 4.18 (d, J = 4.9 Hz, 2H), 3.39 (s, 2H), 2.59 (dd, J = 11.1, 2.5 Hz, 2H), 2.31 (dd, J = 10.9, 1.6 Hz, 2H), 1.95–1.80 (m, 4H). 13 13C NMR (101 MHz, Chloroform-d) δ 152.58, 144.02, 142.86, 142.13, 134.76, 134.17, 131.63, 129.10, 126.08 (q, J = 4.04 Hz), 125.59, 124.87, 124.54, 123.46, 122.89, 118.82, 118.41, 109.55, 109.00, 61.30, 57.61, 54.80, 31.94, 29.71, 29.38, 28.22, 22.71, 14.14. ESI-HRMS m / z: [M+H] + calcd for C 22 H 20 F5N3O3, 470.1423; found, 471.1436。

[0169] Example 17

[0170] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-2-methylpiperazine-1-carboxamide (I-17)

[0171]

[0172] The synthesis method is the same as that of I-1, except that the starting material II-5 is replaced with 2,4-dichlorophenyl isocyanate, and 0.15 g of white solid is obtained, with a melting point of 125 - 127 °C and a yield of 71%. The spectral data are as follows.

[0173] 11H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.38–7.35 (m, 2H), 7.34 (d, J = 2.8 Hz, 1H), 7.17 (dd, J = 8.3, 1.5 Hz, 1H), 4.27 (dd, J = 7.0, 3.6 Hz, 1H), 3.91–3.75 (m, 1H), 3.55 (d, J = 13.5 Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H), 3.11 (td, J = 12.7, 3.2 Hz, 1H), 2.86–2.75 (m, 1H), 2.64 (dt, J = 11.2, 1.9 Hz, 1H), 2.14 (dd, J = 11.3, 3.7 Hz, 1H), 2.00 (td, J = 11.7, 3.4 Hz, 1H), 1.26 (d, J = 6.6 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 155.03, 143.31, 142.14, 136.45, 135.79, 134.14, 131.64, 129.59, 129.13, 129.05, 128.48, 127.72, 124.74, 110.44, 110.09, 61.51, 57.29, 53.03, 47.26, 16.02. ESI-HRMS m / z: [M+H] + calcd for C 20 H 19 Cl2F2N3O3, 457.0772; found, 458.0777。

[0174] Example 18

[0175] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-dichlorophenyl)-2-methylpiperazine-1-carboxamide (I-18)

[0176]

[0177] The synthesis method was the same as that of I-1, except that the starting material II-5 was replaced with 3,5-dichlorophenyl isocyanate, and 0.15 g of white solid was obtained, with a melting point of 126 - 128 °C and a yield of 65%. The spectral data are as follows.

[0178] 11H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.60 (d, J = 1.9 Hz, 2H), 7.36 (dd, J = 4.9, 3.3 Hz, 2H), 7.17 (dd, J = 8.2, 1.5 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 4.29 (h, J = 5.5, 4.7 Hz, 1H), 3.86 (d, J = 13.1 Hz, 1H), 3.55 (d, J = 13.6 Hz, 1H), 3.45 (d, J = 13.6 Hz, 1H), 3.11 (td, J = 12.7, 3.2 Hz, 1H), 2.81 (d, J = 11.1 Hz, 1H), 2.64 (d, J = 11.2 Hz, 1H), 2.12 (dd, J = 11.3, 3.7 Hz, 1H), 1.99 (td, J = 11.7, 3.3 Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 154.45, 143.68, 143.32, 142.15, 135.79, 134.07, 131.64, 129.13, 124.71, 120.98, 117.67, 110.43, 110.11, 61.46, 57.26, 53.03, 47.02, 16.15. ESI-HRMS m / z: [M+H] + calcd for C 20 H 19 Cl2F2N3O3, 457.0772; found, 458.0784。

[0179] Example 19

[0180] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-2-methylpiperazine-1-carboxamide (I-19)

[0181]

[0182] The synthesis method is the same as that of I-1, except that the starting material II-5 is replaced with 2,4-difluorophenyl isocyanate, and 0.15 g of white solid is obtained, with a melting point of 118 - 120 °C and a yield of 61%. The spectral data are as follows.

[0183] 11H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.36 (h, J = 3.9, 3.3 Hz, 3H), 7.29–7.09 (m, 2H), 7.00 (dt, J = 9.1, 4.6 Hz, 1H), 4.25 (p, J = 6.4 Hz, 1H), 3.81 (d, J = 13.0 Hz, 1H), 3.55 (d, J = 13.6 Hz, 1H), 3.45 (d, J = 13.6 Hz, 1H), 3.09 (td, J = 12.8, 3.3 Hz, 1H), 2.80 (d, J = 11.0 Hz, 1H), 2.63 (d, J = 11.1 Hz, 1H), 2.13 (dd, J = 11.2, 3.8 Hz, 1H), 1.99 (td, J = 11.7, 3.4 Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 158.00, 157.59, 155.45, 155.12, 155.00, 143.32, 142.14, 135.86, 131.64, 128.39 (dd, J = 10.1, 4.04 Hz), 124.74, 124.68, 124.56, 111.14 (dd, J = 22.22, 4.04 Hz), 110.45, 110.12, 104.36 (t, J = 26.26 Hz), 61.53, 57.33, 53.09, 47.11, 15.95. ESI-HRMS m / z: [M+H] + calcd for C 20 H 19 F4N3O3, 425.1363; found, 426.1370。

[0184] Example 20

[0185] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-2-methylpiperazine-1-carboxamide (I-20)

[0186]

[0187] The synthesis method was the same as that of I-1, except that the starting material II-5 was replaced with 2,5-difluorophenyl isocyanate, and 0.15 g of white solid was obtained, with a melting point of 100 - 102 °C and a yield of 69%. The spectral data are as follows.

[0188] 11H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.40 (m, 1H), 7.36 (dd, J = 4.8, 3.3 Hz, 2H), 7.27–7.20 (m, 1H), 7.20–7.11 (m, 1H), 6.90 (m, 1H), 4.36–4.21 (m, 1H), 3.83 (dt, J = 13.1, 2.6 Hz, 1H), 3.55 (d, J = 13.6 Hz, 1H), 3.46 (d, J = 13.4 Hz, 1H), 3.12 (td, J = 12.7, 3.3 Hz, 1H), 2.80 (dt, J = 9.8, 2.1 Hz, 1H), 2.63 (dt, J = 11.2, 1.9 Hz, 1H), 2.14 (dd, J = 11.2, 3.7 Hz, 1H), 2.00 (td, J = 11.7, 3.4 Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 159.22, 156.87, 156.85, 154.85, 152.52, 152.49, 150.11, 143.32, 142.15, 135.81, 134.15, 131.64, 129.60 (dd, J = 14.14, 11.11 Hz), 129.13, 124.72, 116.50 (dd, J = 22.22, 10.1 Hz), 111.92 (dd, J = 27.27, 2.02 Hz), 110.70, 110.62, 110.44, 110.38, 110.10, 61.50, 57.27, 53.04, 47.22, 16.00. ESI-HRMS m / z: [M+H] + calcd for C 20 H 19 F4N3O3, 425.1363; found, 426.1363。

[0189] Example 21

[0190] 4 - ((2,2 - Difluorobenzo[d][1,3]dioxol - 5 - yl)methyl)-N-(3,5 - difluorophenyl)-2 - methylpiperazine - 1 - carboxamide (I - 21)

[0191]

[0192] The synthesis method was the same as that of I - 1, except that the starting material II - 5 was replaced by 3,5 - difluorophenyl isocyanate, and 0.15 g of a white solid was obtained, with a melting point of 136 - 138 °C and a yield of 67%. The spectral data are as follows.

[0193] 1 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.36 (dd, J = 4.9, 3.3 Hz, 2H), 7.30–7.22 (m, 2H), 7.17 (dd, J = 8.3, 1.6 Hz, 1H), 6.71 (tt, J = 9.3, 2.4 Hz, 1H), 4.32 (q, J = 5.7 Hz, 1H), 3.94–3.77 (m, 1H), 3.55 (d, J = 13.6 Hz, 1H), 3.45 (d, J = 13.6 Hz, 1H), 3.12 (td, J = 12.7, 3.2 Hz, 1H), 2.86–2.75 (m, 1H), 2.65 (dt, J = 11.3, 2.0 Hz, 1H), 2.13 (dd, J = 11.2, 3.7 Hz, 1H), 2.00 (td, J = 11.7, 3.4 Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 164.04, 163.88, 161.64, 161.48, 154.51, 143.94 (t, J = 6.06 Hz), 143.32, 142.15, 135.78, 134.15, 131.64, 129.13, 124.68, 110.40, 110.09, 102.19 (q, J = 8.08 Hz), 96.80 (t, J = 26.26 Hz), 61.46, 57.27, 53.05, 46.96, 16.12. ESI-HRMS m / z: [M+H] + calcd for C 20 H 19 F4N3O3, 425.1363; found, 426.1362。

[0194] Example 22

[0195] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-3-methylpiperazine-1-carboxamide (I-22)

[0196]

[0197] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced with 4-N-Boc-3-methylpiperazine and the starting material II-5 was replaced with 2,4-dichlorophenyl isocyanate, to obtain 0.13 g of a white solid, melting point 120-122 °C, yield 65%, and the spectral data are as follows.

[0198] 11H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.38–7.32 (m, 3H), 7.16 (dd, J = 8.3, 1.5 Hz, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.81–3.72 (m, 1H), 3.67 (dt, J = 13.2, 3.9 Hz, 1H), 3.28 (d, J = 13.8 Hz, 1H), 3.14 (ddd, J = 12.7, 9.3, 2.9 Hz, 1H), 2.94 (dd, J = 13.0, 8.3 Hz, 1H), 2.62 (ddd, J = 11.7, 4.8, 3.1 Hz, 1H), 2.49–2.40 (m, 1H), 2.12 (ddd, J = 12.1, 9.3, 3.2 Hz, 1H), 1.09 (d, J = 6.2 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 154.98, 143.27, 142.04, 136.52, 136.44, 131.65, 129.57, 129.14, 129.08, 128.52, 127.74, 124.84, 110.61, 110.02, 57.01, 54.75, 50.63, 50.08, 44.38, 15.38. ESI-HRMS m / z: [M+H] + calcd for C 20 H 19 Cl2F2N3O3, 457.0772; found, 458.0831。

[0199] Example 23

[0200] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-3-methylpiperazine-1-carboxamide (I-23)

[0201]

[0202] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced with 4-N-Boc-3-methylpiperazine and the starting material II-5 was replaced with 2,4-difluorophenyl isocyanate, to obtain 0.17 g of a white solid, melting point 142 - 144 °C, yield 65%, and the spectral data are as follows.

[0203] 11H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.42–7.28 (m, 3H), 7.27–7.13 (m, 2H), 7.00 (tdd, J = 8.6, 2.9, 1.4 Hz, 1H), 3.93 (d, J = 13.8 Hz, 1H), 3.76 (ddd, J = 12.9, 3.3, 1.5 Hz, 1H), 3.71–3.57 (m, 1H), 3.27 (d, J = 13.8 Hz, 1H), 3.10 (td, J = 9.9, 9.5, 5.0 Hz, 1H), 2.91 (dd, J = 13.0, 8.4 Hz, 1H), 2.62 (ddd, J = 11.6, 4.6, 3.1 Hz, 1H), 2.45 (ddd, J = 9.1, 6.2, 3.2 Hz, 1H), 2.10 (ddd, J = 12.2, 9.6, 3.2 Hz, 1H), 1.09 (d, J = 6.2 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 160.35, 160.24, 157.94, 157.82, 157.45, 157.33, 155.35, 154.99, 154.86, 143.28, 142.04, 136.57, 134.15, 131.65, 129.14, 128.19 (dd, J = 11.11, 4.04 Hz), 124.80, 124.57 (dd, J = 12.12, 4.04 Hz), 111.15 (dd, J = 22.22, 3.03 Hz), 110.58, 110.00, 104.37 (dd, J = 26.26, 24.24 Hz), 57.03, 54.84, 50.60, 50.21, 44.27, 15.47. ESI-HRMS m / z: [M+H] + calcd for C 20 H 19 F4N3O3, 425.1363; found, 426.1379。

[0204] Example 24

[0205] 4 - ((2,2 - Difluorobenzo[d][1,3]dioxol - 5 - yl)methyl)-N-(2,3 - dichlorophenyl)-3 - methylpiperazine - 1 - carbothioamide (I - 24)

[0206]

[0207] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced by 4-N-Boc-3-methylpiperazine and the starting material II-5 is replaced by 2,3-dichlorophenyl isothiocyanate, obtaining 0.13 g of a yellow solid with a melting point of 130-132 °C and a yield of 66%. The spectral data are as follows.

[0208] 1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.41–7.30(m,2H),7.29–7.20(m,2H),7.16(dd,J=8.2,1.6Hz,1H),6.72(tt,J=9.3,2.4Hz,1H),3.93(d,J=13.8Hz,1H),3.84–3.64(m,2H),3.27(d,J=13.8Hz,1H),3.11(ddd,J=12.8,9.6,2.9Hz,1H),2.92(dd,J=13.0,8.5Hz,1H),2.63(dt,J=12.0,3.6Hz,1H),2.44(ddd,J=9.0,6.2,3.0Hz,1H),2.10(ddd,J=12.3,9.7,3.2Hz,1H),1.09(d,J=6.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ181.61,143.30,142.09,140.87,136.34,134.16,132.08,131.65,131.25,130.24,129.15,128.61,128.03,124.86,110.63,110.02,56.85,54.84,54.24,49.77,48.67,15.20.ESI-HRMSm / z:[M+H] + calcd for C 20 H 19 Cl2F2N3O2S,473.0543;found,474.0554。

[0209] Example 25

[0210] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-3-methylpiperazine-1-carboxamide (I-25)

[0211]

[0212] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced by 4-N-Boc-3-methylpiperazine and the starting material II-5 is replaced by 2,5-difluorophenyl isothiocyanate, obtaining 0.13 g of a white solid with a melting point of 112-114 °C and a yield of 66%. The spectral data are as follows.

[0213] 1 H NMR(400MHz,DMSO-d6)δ9.33(s,1H),7.52(dd,J=8.0,1.6Hz,1H),7.40–7.31(m,3H),7.28(dd,J=7.9,1.6Hz,1H),7.18(dd,J=8.2,1.6Hz,1H),4.28(dd,J=24.0,13.2Hz,2H),3.93(d,J=13.8Hz,1H),3.58(ddd,J=12.8,9.2,2.9Hz,1H),3.41–3.33(m,2H),2.69(ddd,J=11.9,5.0,3.0Hz,1H),2.57(ddd,J=9.0,6.0,2.8Hz,1H),2.21(ddd,J=12.1,9.2,3.1Hz,1H),1.12(d,J=6.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ164.06,163.90,161.66,161.50,154.50,143.90(t,J=14.14Hz),143.28,142.05,136.50,134.15,131.64,129.13,124.80,110.58,110.01,102.19(dd,J=21.21,9.09Hz),96.81(t,J=26.26Hz),56.96,54.84,50.46,50.24,44.22,15.55.ESI-HRMSm / z:[M+H] + calcd for C 20 H 19 F4N3O3,425.1363;found,426.1347。

[0214] Example 26

[0215] 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-3-methylpiperazine-1-carboxamide (I-26)

[0216]

[0217] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced by 4-N-Boc-3-methylpiperazine and the starting material II-5 is replaced by 3,5-difluorophenyl isothiocyanate, obtaining 0.11 g of a white solid with a melting point of 112-114 °C and a yield of 66%. The spectral data are as follows.

[0218] 1 H NMR(400MHz,Chloroform-d)δ7.88(ddd,J=10.8,6.5,3.2Hz,1H),7.05(d,J=1.4Hz,1H),6.97–6.86(m,3H),6.55(ddt,J=9.0,7.3,3.6Hz,2H),3.91(d,J=13.5Hz,1H),3.68(ddd,J=12.8,3.4,1.6Hz,1H),3.63–3.50(m,1H),3.18(ddd,J=12.8,9.6,3.2Hz,1H),3.12(d,J=13.5Hz,1H),2.95(dd,J=12.8,8.6Hz,1H),2.64(ddd,J=11.8,4.7,3.2Hz,1H),2.50(dqd,J=9.4,6.2,3.2Hz,1H),2.18–2.04(m,1H),1.10(d,J=6.3Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ160.00,157.60,153.54,149.49,147.12,144.00,142.80,134.96,134.17,131.64,129.11,128.57(t,J=12.12Hz),123.62,114.78(dd,J=12.12,10.1Hz),109.84,108.98,108.54,108.46,108.30,108.21,108.02,108.00,57.46,54.82,50.49,49.79,44.30,15.37.ESI-HRMSm / z:[M+H] + calcd for C 20 H 19 F4N3O3,425.1363;found,426.1359。

[0219] Example 27

[0220] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-27)

[0221]

[0222] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced by tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, and the starting material II-5 is replaced by 2,4-dichlorophenyl isocyanate, obtaining 0.23 g of a yellow solid with a melting point of 127 - 129 °C and a yield of 71%. The spectral data are as follows.

[0223] 1 H NMR(400MHz,DMSO-d6)δ8.02–7.81(m,1H),7.68(d,J=8.7Hz,1H),7.60(d,J=2.4Hz,1H),7.37(td,J=4.8,4.4,2.4Hz,2H),7.33(d,J=8.2Hz,1H),7.17(dd,J=8.3,1.6Hz,1H),4.47(s,1H),3.74(s,2H),3.66–3.45(m,2H),3.30(d,J=11.3Hz,1H),2.82(dd,J=9.5,2.1Hz,1H),2.58(d,J=9.5Hz,1H),1.87(d,J=9.6Hz,1H),1.72(d,J=9.5Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ153.81,143.31,141.98,137.43,136.06,134.15,131.64,129.00,128.61,127.80,124.23,110.22,110.06,61.15,59.81,57.54,50.78,35.56.ESI-HRMSm / z:[M+H] + calcd for C 20 H 17 Cl2F2N3O3,455.0615;found,456.0605。

[0224] Example 28

[0225] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-28)

[0226]

[0227] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced by tert-butyl 2,5-azabicyclo[2.2.1]heptane-2-carboxylate, and the starting material II-5 is replaced by 3,5-dichlorophenyl isocyanate, obtaining 0.20 g of a white solid with a melting point of 138-140 °C and a yield of 79%. The spectral data are as follows.

[0228] 1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),7.67(d,J=1.9Hz,2H),7.37(d,J=1.5Hz,1H),7.32(d,J=8.3Hz,1H),7.18(dd,J=8.3,1.6Hz,1H),7.09(t,J=1.9Hz,1H),4.50(s,1H),3.73(s,2H),3.55(d,J=10.7Hz,2H),3.28(dd,J=9.8,2.2Hz,1H),2.82(dd,J=9.6,2.1Hz,1H),2.54(d,J=9.6Hz,1H),1.86(d,J=9.6Hz,1H),1.71(d,J=9.5Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ153.81,143.31,141.98,137.43,136.06,134.15,131.64,129.00,128.61,127.80,124.23,110.22,110.06,61.15,59.81,57.54,50.78,35.56.ESI-HRMSm / z:[M+H] + calcd for C 20 H 17 Cl2F2N3O3,455.0615;found,456.0603。

[0229] Example 29

[0230] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-29)

[0231]

[0232] The synthesis method is the same as that of I-1, except that the starting material II-2 is replaced by tert-butyl 2,5-azabicyclo[2.2.1]heptane-2-carboxylate, and the starting material II-5 is replaced by 2,5-difluorophenyl isocyanate, obtaining 0.21 g of a white solid with a melting point of 120-122 °C and a yield of 73%. The spectral data are as follows.

[0233] 1 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.50 (td, J = 9.0, 6.2 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.23 (ddd, J = 10.7, 9.0, 2.9 Hz, 1H), 7.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.01 (tdd, J = 8.8, 3.0, 1.4 Hz, 1H), 4.46 (s, 1H), 3.73 (s, 2H), 3.61–3.46 (m, 2H), 3.26 (d, J = 9.5 Hz, 1H), 2.81 (dd, J = 9.6, 2.1 Hz, 1H), 2.56 (d, J = 9.5 Hz, 1H), 1.86 (d, J = 9.6 Hz, 1H), 1.71 (d, J = 9.5 Hz, 1H). 13 13C NMR (101 MHz, DMSO-d6) δ 160.19, 157.78, 157.67, 154.72, 143.32, 141.99, 137.45, 134.15, 131.65, 129.14, 128.01, 127.91, 124.42, 124.27, 111.14 (dd, J = 21.21, 3.03 Hz), 104.34 (dd, J = 26.26, 24.24 Hz), 61.15, 59.92, 57.65, 50.92, 35.51. ESI-HRMS m / z: [M+H] + calcd for C 20 H 17 F4N3O3, 423.1206; found, 424.1204。

[0234] Example 30

[0235] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,3-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbothioamide (I-30)

[0236]

[0237] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced with tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, and the starting material II-5 was replaced with 2,3-dichlorophenyl isocyanate, to obtain 0.24 g of a yellow solid, melting point 106 - 108 °C, yield 76%, and the spectral data are as follows.

[0238] 1 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 71.1 Hz, 1H), 7.64–7.48 (m, 1H), 7.48–7.27 (m, 4H), 7.18 (d, J = 8.3 Hz, 1H), 4.97 (d, J = 60.9 Hz, 1H), 3.73 (dd, J = 20.3, 7.8 Hz, 3H), 3.60–3.38 (m, 2H), 2.86 (d, J = 9.4 Hz, 1H), 2.69 (d, J = 12.1 Hz, 1H), 1.91 (t, J = 31.5 Hz, 2H). 13 13C NMR (101 MHz, DMSO-d6) δ 178.01, 143.34, 142.03, 140.27, 137.29, 134.16, 132.02, 131.65, 131.34, 130.62, 129.15, 128.79, 127.98, 124.28, 110.28, 110.12, 68.72, 62.81, 61.84, 58.93, 57.74, 53.73, 36.18, 35.13, 28.53. ESI-HRMS m / z: [M+H] + calcd for C 20 H 17 Cl2F2N3O2S, 471.0387; found, 472.0389。

[0239] Example 31

[0240] 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (I-31)

[0241]

[0242] The synthesis method was the same as that of I-1, except that the starting material II-2 was replaced with tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, and the starting material II-5 was replaced with 2,5-difluorophenyl isocyanate, to obtain 0.24 g of a colorless liquid with a yield of 62%. The spectral data are as follows.

[0243] 11H NMR (400 MHz, Chloroform-d) δ 8.04 (m, 1H), 7.14 (s, 1H), 7.08–6.84 (m, 3H), 6.61 (td, J = 8.5, 8.0, 3.8 Hz, 1H), 6.45 (d, J = 4.2 Hz, 1H), 4.56 (s, 1H), 3.72 (s, 2H), 3.69–3.51 (m, 2H), 3.36 (dd, J = 8.5, 2.3 Hz, 1H), 2.88 (dd, J = 9.8, 2.1 Hz, 1H), 2.76 (d, J = 9.7 Hz, 1H), 1.96 (d, J = 9.9 Hz, 1H), 1.79 (d, J = 9.8 Hz, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 159.97, 159.95, 157.58, 157.56, 152.42, 149.29, 149.26, 146.94, 146.91, 143.98, 142.73, 135.61, 134.16, 131.63, 129.11, 128.59 (t, J = 22.22 Hz), 123.08, 114.76 (dd, J = 12.12, 10.1 Hz), 109.58, 108.98, 108.32, 108.24, 108.07, 107.99, 107.70, 107.68, 61.08, 59.65, 58.00, 57.35, 50.21, 35.40, 29.69. ESI-HRMS m / z: [M+H] + calcd for C 20 H 17 F4N3O3, 423.1206;found, 424.1210。

[0244] Example 32

[0245] 5 - ((2,2 - Difluorobenzo[d][1,3]dioxol - 5 - yl)methyl)-N-(3,5 - difluorophenyl)-2,5 - diazabicyclo[2.2.1]heptane - 2 - carboxamide (I - 32)

[0246]

[0247] The synthesis method is the same as that of I - 1, except that the starting material II - 2 is replaced by tert - butyl 2,5 - diazabicyclo[2.2.1]heptane - 2 - carboxylate, and the starting material II - 5 is replaced by 3,5 - difluorophenyl isocyanate, to obtain 0.24 g of a white solid, melting point 102 - 104 °C, yield 62%, and the spectral data are as follows.

[0248] 11H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.37 (d, J = 1.4 Hz, 1H), 7.35–7.25 (m, 3H), 7.18 (dd, J = 8.3, 1.5 Hz, 1H), 6.72 (tt, J = 9.3, 2.5 Hz, 1H), 4.51 (s, 1H), 3.73 (s, 2H), 3.55 (d, J = 9.5 Hz, 2H), 3.32–3.22 (m, 1H), 2.82 (dd, J = 9.6, 2.1 Hz, 1H), 2.54 (d, J = 9.6 Hz, 1H), 1.86 (d, J = 9.6 Hz, 1H), 1.70 (d, J = 9.5 Hz, 1H). 13 13C NMR (101 MHz, DMSO-d6) δ 164.08, 163.92, 161.68, 153.45, 143.83 (t, J = 14.14 Hz), 143.30, 141.98, 137.41, 134.14, 131.64, 129.13, 124.28, 110.25, 110.04, 101.99, 101.78, 96.70 (t, J = 26.26 Hz), 61.10, 59.91, 57.53, 50.91. ESI-HRMS m / z: [M+H] + calcd for C 20 H 17 F4N3O3, 423.1206; found, 424.1211。

[0249] The TRPV1 and URAT1 inhibitory activities, as well as the in vivo analgesic and uric acid-lowering activities of the compounds in the present invention, can be determined by using the assay systems described below. The experimental methods for the specific conditions in the test examples of the present invention are generally carried out under conventional conditions or according to the conditions recommended by the commercial manufacturers. Reagents without specific sources indicated are common reagents purchased from the market.

[0250] Test Example 1

[0251] Inhibitory activity of the compounds of the present invention against hTRPV1-HEK293 (Htrpv1-HEK-293) stable transfected cells

[0252] The present invention uses the following method to determine the hTRPV1 inhibitory activity of the compounds of the present invention.

[0253] HEK293 cells stably expressing hTRPV1 were seeded at 2.5×10 4Inoculate at a density of cells per well into a 96-well black plate, and incubate overnight in a cell culture incubator at 37°C and 5% CO2. The culture medium is DMEM medium supplemented with 10% fetal bovine serum (FBS). Load the Fluo-3AM calcium ion fluorescent probe at room temperature. First, prepare a DMSO stock solution of 2 mM calcium ion fluorescent probe Fluro-3AM. Add 16.5 mg of Pluronic F127 to the Fluo-3AM / DMSO stock solution to prevent the aggregation of Fluo-3AM in HBSS (Hank’s balanced salt solution) and help it enter the cells. Dilute the Fluo-3AM solution with HBSS to prepare a 5 μM Fluo-3AM working solution. Add 10 μL of the above working solution to each well of the cell plate and incubate at 37°C for 30 minutes. Add 50 μL of HBSS containing 1% fetal bovine serum to each well and continue to incubate for 40 minutes. Wash the cells 4 times with the Tyrode's solution. Add 40 μL of samples with different concentrations to each well, and set 3 replicates for each sample concentration. The positive control group adds an equal amount of N-(4-(tert-butyl)phenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC), and the negative control group adds Tyrode's solution. After incubating at 37°C for 30 minutes, capsaicin stimulation (50 nM) is given, and then the absorbance values at λex = 488 nm and λex = 540 nm before and after capsaicin stimulation are measured to characterize the cytoplasmic calcium ion concentration. The results are shown in Table 1. Among them, the IC 50 According to the instructions for classification, in Table 1:

[0254] “+” indicates that the IC 50 measured value is less than 100 μM and greater than or equal to 1 μM;

[0255] “++” indicates that the IC 50 measured value is less than 1 μM and greater than or equal to 100 nM;

[0256] “+++” indicates that the IC 50 measured value is less than 100 nM and greater than or equal to 1 nM.

[0257] Table 1 hTRPV1 receptor inhibitory activity

[0258] Compound number IC50 Compound number IC50 I-1 + I-17 ++ I-2 + I-18 ++ I-3 + I-19 +++ I-4 + I-20 +++ I-5 ++ I-21 +++ I-6 + I-22 ++ I-7 + I-23 +++ I-8 ++ I-24 ++ I-9 + I-25 +++ I-10 +++ I-26 +++ I-11 + I-27 +++ I-12 + I-28 ++ I-13 + I-29 ++ I-14 + I-30 ++ I-15 ++ I-31 +++ I-16 +++ I-32 +++ BCTC +++

[0259] As can be seen from Table 1: The compounds described in the present invention have different degrees of inhibitory activity against TRPV1. Among them, compounds I-10, I-16, I-19, I-20, I-21, I-23, I-25, I-26, I-27, I-31, and I-32 have better inhibitory activity, which is comparable to the positive control BCTC.

[0260] Test Example 2

[0261] The in vivo analgesic activity of the compounds of the present invention can be determined by using two mouse pain model assay systems described as follows:

[0262] (1) Acetic acid-induced writhing test

[0263] Kunming strain clean-grade mice at 10 weeks of age, weighing 22 - 25 g, male, were randomly grouped according to body weight, with 6 mice in each group. 30 min before the test, the compounds of the present invention were administered by gavage at a dose of 20 mg / kg, and the blank control group was given an equal volume of 0.5% sodium carboxymethylcellulose solution. During the test, the mice were intraperitoneally injected with 0.6% acetic acid solution, and the number of writhing responses (abdomen indented, hind limbs extended, hips elevated) of the mice within 15 minutes was recorded. The results are shown in Table 2.

[0264] (2) Formalin-induced pain model experiment

[0265] After adaptive feeding of 8-week-old clean-grade ICR mice, they were randomly grouped according to body weight, with 6 mice in each group. Before the experiment, the compounds of the present invention were administered by gavage to the mice. The dosing dose of the experimental group was 20 mg / kg, and the blank control group was given an equal volume of 0.5% sodium carboxymethylcellulose solution. 1 h later, a formalin solution was subcutaneously injected into the right hind toe, and the licking foot time of the I phase (0 - 5 min) and the II phase (15 - 45 min) responses were recorded respectively.

[0266] Table 2 Effects of some compounds on acetic acid- and formalin-induced mouse behavior ( n = 6)

[0267] Experimental group Writhing times Phase I reaction time Phase II reaction time Blank control 27.16±3.15 2.06±0.18 5.89±0.58 BCTC 17.46±1.32* 1.89±0.20 5.52±0.60 I-19 13.25±2.47*# 1.52±0.13*# 4.18±0.48*# I-20 15.78±1.41* 1.58±0.15* 4.63±0.47* I-25 15.12±0.95*# 1.54±0.14*# 4.32±0.36*# I-32 16.21±1.34* 1.62±0.13* 4.85±0.36*

[0268] Note: *P≤0.05 is the result of Student's t-test relative to the blank control group, and #P≤0.05 is the result of Student's t-test relative to the BCTC group.

[0269] The test results in Table 2 show that I-19, I-20, I-25, and I-32 of the present invention can significantly inhibit the pain response induced by acetic acid. Among them, compounds I-19 and I-25 have the strongest analgesic activity, which is better than the positive control BCTC. In addition, compounds I-19, I-20, I-25, and I-32 can also significantly inhibit the inflammatory pain induced by formalin, and compounds I-19 and I-25 are better than the positive control BCTC.

[0270] In summary, the compounds of the present invention, as TRPV1 antagonists, have excellent inhibitory activity against TRPV1, have good analgesic effects on the pain response induced by acetic acid and the inflammatory pain induced by formalin, and can be used to prepare analgesic drugs.

[0271] The description of the above embodiments is only used to help understand the method and its core idea of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A compound, characterized in that, The structure is as shown in formula (I): Among them, ring A is selected from R1 and R2 are independently selected from one or more of hydrogen, C1-C 20 linear or branched alkyl, C3-C 20 cycloalkyl, C1-C 10 alkoxy, substituted C1-C 20 linear or branched alkyl, substituted C3-C 20 cycloalkyl, substituted C1-C 10 alkoxy, amino, halogen, nitrile, nitro; The substituted C1-C 20 The straight-chain or branched-chain alkyl substituent is selected from halogen or cyano group; The substituted C3-C 20 cycloalkyl and the substituents of the substituted C1-C 10 alkoxy are independently selected from one or more of halogen, cyano, amino, nitro, C1-C6 linear or branched alkyl; m and n respectively represent the numbers of R1 and R2, and m + n = 5, m ≥ 1; L is selected from thiocarboxamido, carboxamido, sulfonamido, sulfonylurea group, ester group or carbonyl group.

2. The compound according to claim 1, wherein R1 and R2 are independently selected from hydrogen, C1-C 10 linear or branched alkyl, C3-C 12 cycloalkyl, C1-C 10 alkoxy, substituted C1-C 10 linear or branched alkyl, substituted C3-C 12 cycloalkyl, substituted C1-C 10 alkoxy, amino, halogen, nitrile, nitro, or one or more of them; The substituents of the substituted C1-C 10 The substituents of the straight-chain or branched alkyl are selected from halogen or nitrile groups; The substituted C3-C 12 cycloalkyl and the substituents of the substituted C1-C 10 alkoxy are independently selected from one or more of halogen, cyano, and C1-C3 straight-chain or branched-chain alkyl; The said L is selected from thiocarboxamido, carboxamido, sulfonamido or sulfonylurea group.

3. The compound according to claim 2, wherein, The said R1 and R2 are independently selected from one or more of hydrogen, C1-C6 straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, substituted C1-C6 straight-chain or branched-chain alkyl, substituted C3-C6 cycloalkyl, substituted C1-C6 alkoxy, amino, halogen, nitrile group, nitro; The substituent of the said substituted C1-C6 straight-chain or branched-chain alkyl is selected from halogen; The substituents of the said substituted C3-C6 cycloalkyl and substituted C1-C6 alkoxy are independently selected from one or more of halogen, C1-C3 straight-chain or branched-chain alkyl.

4. The compound according to claim 3, characterized in that, The said R1 and R2 are independently selected from one or more of hydrogen, C1-C4 straight-chain or branched-chain alkyl, substituted C1-C4 straight-chain or branched-chain alkyl, halogen; The substituent of the said substituted C1-C4 straight-chain or branched-chain alkyl is independently selected from halogen; The said L is selected from thiocarboxamido or carboxamido.

5. The compound according to claim 3 or 4, characterized in that, The said halogen is selected from fluorine or chlorine; The number of substituents of the said substituted C1-C4 straight-chain or branched-chain alkyl is an integer between 1 and 3.

6. The compound according to claim 5, wherein, The said R1 and R2 are independently selected from one or more of hydrogen, methyl, trifluoromethyl, fluorine, chlorine.

7. The compound according to claim 1, characterized in that, The said compound is selected from any one or more of the following: 4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-chlorophenyl)-2-methylpiperazine-1-carboxamide; 4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-2-methylpiperazine-1-carboxamide; 4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-2-methylpiperazine-1-carboxamide; 4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-2-methylpiperazine-1-carboxamide; 4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-3-methylpiperazine-1-carboxamide; 4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-3-methylpiperazine-1-carboxamide; 4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3-methylpiperazine-1-carboxamide; 5-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; 5-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide; 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide; 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide; 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(m-tolyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide; 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide; 3-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-2-methylpiperazine-1-carboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-dichlorophenyl)-2-methylpiperazine-1-carboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-2-methylpiperazine-1-carboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-2-methylpiperazine-1-carboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-2-methylpiperazine-1-carboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-3-methylpiperazine-1-carboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-3-methylpiperazine-1-carboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,3-dichlorophenyl)-3-methylpiperazine-1-thiocarboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-3-methylpiperazine-1-carboxamide; 4-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-3-methylpiperazine-1-carboxamide; 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,4-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,3-dichlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-thiocarboxamide; 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(2,5-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; 5-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(3,5-difluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide. Use of the compound according to any one of claims 1-7 as a TRPV1 antagonist in the preparation of an analgesic drug.

9. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9, characterized in that, The pharmaceutical composition further comprises a pharmaceutically acceptable carrier and adjuvant.

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