Heterocycle-pyrazole amine derivative, preparation method thereof and application thereof in resisting mycobacterium tuberculosis infection

Abstract

The invention discloses a heterocycle-pyrazole amine derivative and a preparation method and application thereof in resisting mycobacterium tuberculosis infection, the structure of the heterocycle-pyrazole amine derivative is shown as a formula I or a formula II, and R1, R2, R3, V, W, X, Y, Z and L are defined as the specification and the claims. Experiments prove that the heterocyclic-pyrazolamine derivative provided by the invention has obvious anti-mycobacterium tuberculosis activity, and is especially suitable for preparing drugs for preventing and / or treating related diseases caused by mycobacterium tuberculosis. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a class of heterocyclic-pyrazolamine derivatives, or their enantiomers, diastereomers, racemates or mixtures thereof, and pharmaceutically acceptable salts thereof. The present invention also relates to a method for preparing the above compounds and the use of the above compounds as anti-tuberculosis bacilli for preparing drugs. The present invention belongs to the field of pharmaceutical technology. Background Art

[0002] Tuberculosis (TB) is a respiratory infectious disease with relatively high morbidity and mortality caused by Mycobacterium tuberculosis (Mtb) (World Health Organization. Global Tuberculosis Report 2022). Mtb is the pathogen of tuberculosis and a member of the Mycobacterium tuberculosis complex (MTBC). MTBC consists of several subspecies such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, and Mycobacterium microti, and five of them can cause human tuberculosis (Brites D., Loiseau C., Menardo F., et al. A New Phylogenetic Framework for the Animal-Adapted Mycobacterium tuberculosis Complex[J]. Front Microbiol, 2018, 9:2820. Gutierrez M.C., Brisse S., Brosch R., et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis[J]. PLoS Pathog, 2005, 1:e5). Mycobacterium tuberculosis can invade various organs of the human body to form tubercles, infiltrations, caseous changes, or cavities (Patil J. Novel tubercular therapeutic agents: Need of the Day[J]. Pharmacoepidemiol Drug Saf, 2015:e137). Pulmonary tuberculosis is relatively common clinically, and patients often present with symptoms such as cough, low fever, night sweats, fatigue, and hemoptysis. Tuberculosis is usually transmitted from infected individuals to others through droplets produced during coughing, sneezing, or speaking, and it is highly contagious (Wang Y, Luan S, Zhou X, Fan S, Research progress on anti-tuberculosis drugs[J]. Clinical Medication Journal, 2018, 16(4), 9-13).

[0003] The World Health Organization's Global Tuberculosis Report 2022 shows that there were approximately 10.6 million new cases in 2021, a 4.5% increase from 2020. Additionally, its incidence rate increased by 3.6% between 2020 and 2021, reversing the trend of an approximate 2% annual decline over the past 20 years (World Health Organization. Global Tuberculosis Report 2022). Furthermore, the emergence of drug-resistant tuberculosis (DR-TB), multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), and totally drug-resistant tuberculosis (TDR-TB) has increased the challenge of eliminating tuberculosis globally (World Health Organization. Global Tuberculosis Report 2022). According to the 2022 report, in 2021, approximately 3.6% of new patients and 18% of retreatment patients globally were resistant to the first-line anti-tuberculosis drug rifampicin, estimated at 450,000 cases. In 2021, the number of deaths officially classified as caused by tuberculosis globally was almost twice as high as the number of deaths caused by AIDS. In the near future, tuberculosis has the potential to replace COVID-19 and once again become the leading cause of death globally due to a single pathogen (World Health Organization. Global Tuberculosis Report 2022). Additionally, studies have shown that there is also a synergistic effect between SARS-CoV-2 and mycobacterial infections, and tuberculosis may co-infect with other viruses such as SARS-CoV-2 and HIV to cause disease together, exacerbating the damage to the global economy and healthcare system (Mousquer G.T., Peres A., Fiegenbaum M. Pathology of TB / COVID-19 Co-Infection: The phantom menace [J]. Tuberculosis (Edinb), 2021, 126:102020. Tapela K., Ochieng' O.C, Quaye O. Parallels in the pathogenesis of SARS-CoV-2 and M. tuberculosis: a synergistic or antagonistic alliance? [J]. Future Microbiol, 2020, 15:1691-1695.).

[0004] At present, the national essential medicine text stipulates a total of 11 anti-tuberculosis drugs (including compound preparations). These include isoniazid, rifampicin, pyrazinamide, sodium para-aminosalicylate, ethambutol, rifapentine, streptomycin, prothionamide, and isoniazid-rifampicin-pyrazinamide, isoniazid-rifampicin-isoniazid-sodium para-aminosalicylate compound preparations. At present, the standard treatment for drug-susceptible tuberculosis recommended by the WHO is a short-course chemotherapy regimen, using four first-line drugs, isoniazid, rifampicin, ethambutol, and pyrazinamide in the first two months, and then isoniazid and rifampicin in the last four-month consolidation period. However, the treatment of MDR-TB and XDR-TB is more difficult and requires longer treatment with more toxic and more expensive second-line drugs. The main reasons for the emergence of drug-resistant tuberculosis strains in clinical cases include gene mutations in drug targets or drug-activating enzymes, compensatory evolution, and activation of efflux pumps (Miotto P., Zhang Y, Cirillo DM, Yam WC. Drug resistance mechanisms and drug susceptibility testing for tuberculosis. Respirology. 2018 Dec;23(12):1098-1113.). At present, the variety of anti-tuberculosis drugs in clinical practice is limited, leaving limited choices for clinicians. Therefore, there is an urgent need to develop new anti-tuberculosis drugs with new structures and new mechanisms to provide effective support for tuberculosis control. Summary of the Invention

[0005] The object of the present invention is to provide a novel anti-tuberculosis drug and its preparation method and use.

[0006] To achieve the above object, the present invention adopts the following technical means:

[0007] A compound represented by formula Ι or formula II, its enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts,

[0008]

[0009] In formula I and formula II:

[0010] Ring A is selected from an unsaturated five-membered ring, six-membered ring or heteroaromatic fused ring; wherein V, W, X, Y, Z are each independently selected from C, N, S, O, substituted or unsubstituted methylene or methine, carbonyl, substituted or unsubstituted imino; the substituent is selected from halogen, a straight-chain, cyclic or branched alkyl group containing 1-5 carbons, an alkoxy group containing 1-5 carbons, or adjacent substituents and the atoms to which they are attached together form a saturated or unsaturated cyclic structure;

[0011] R 1 ,R 2Each independently selected from H, halogen, a straight-chain, cyclic or branched alkyl group having 1-5 carbon atoms;

[0012] L is a chemical bond or L is selected from methylene, carbonyl, m = 0, 1;

[0013] R 3 Selected from H, halogen, a substituted or unsubstituted straight-chain, cyclic or branched alkyl group having 1-8 carbon atoms, a substituted or unsubstituted straight-chain or branched alkenyl group having 1-8 carbon atoms, a substituted or unsubstituted alkoxy group having 1-8 carbon atoms, a substituted or unsubstituted aryl group or heteroaryl group.

[0014] Among them, preferably, the configuration of each chiral carbon in the compound represented by Formula Ι or Formula II is independently the R configuration or the S configuration.

[0015] Among them, preferably, in Formula Ι, ring A is selected from In Formula II, ring A is selected from

[0016] Wherein R 4 , R 5 Each independently selected from H, halogen, a straight-chain, cyclic or branched alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms.

[0017] Among them, preferably, R 1 , R 2 Each independently selected from H, bromine, chlorine, methyl, ethyl;

[0018] R 3 Selected from an alkyl group or cycloalkyl group having 1-8 carbon atoms, an alkyl group or cycloalkyl group having 1-8 carbon atoms optionally substituted by one or more alkyl groups having 1-5 carbon atoms, cycloalkyl groups having 3-5 carbon atoms, halogen, keto groups, methoxy groups, cyano groups, vinyl, propenyl, butenyl, benzene ring, naphthalene ring, a benzene ring or naphthalene ring optionally substituted by one or more methyl groups, methoxy groups, halogen, trifluoromethyl, nitro, cyano, hydroxy, 3-methyl-4-cyano, 3-fluoro-4-cyano, 3-chloro-4-fluoro, thiophene, thiazole, pyridine, a thiophene, thiazole or pyridine optionally substituted by one or more methyl groups, halogen, nitro.

[0019] Among them, preferably, the compound has a structure represented by General Formula III, IV, V or VI:

[0020]

[0021] Among them, in General Formula III, IV, V, R 4 , R 5 Each independently selected from H, halogen, methyl, ethyl;

[0022] R 1 ,R 2 Each is independently selected from H, bromine, chlorine, methyl, and ethyl;

[0023] R 3 is selected from an alkyl group or cycloalkyl group having 1 - 8 carbon atoms, an alkyl group or cycloalkyl group having 1 - 8 carbon atoms optionally substituted by one or more alkyl groups having 1 - 5 carbon atoms, cycloalkyl groups having 3 - 5 carbon atoms, halogen, keto group, methoxy group, or cyano group, vinyl, propenyl, butenyl, benzene ring, naphthalene ring, a benzene ring or naphthalene ring optionally substituted by one or more methyl groups, methoxy groups, halogen, trifluoromethyl group, nitro group, cyano group, hydroxyl group, 3 - methyl - 4 - cyano, 3 - fluoro - 4 - cyano, 3 - chloro - 4 - fluoro; thiophene, thiazole, pyridine, a thiophene, thiazole, or pyridine optionally substituted by one or more methyl groups, halogen, or nitro group;

[0024] In general formula VI, R 4 ,R 5 Each is independently selected from H, halogen, methyl, and ethyl;

[0025] R 1 ,R 2 Each is independently selected from H, bromine, chlorine, methyl, and ethyl;

[0026] R 3 is selected from an alkylamine or cycloalkylaminoamine having 1 - 6 carbon atoms, an alkylamine or cycloalkylamine having 1 - 6 carbon atoms optionally substituted by one or more alkyl groups having 1 - 6 carbon atoms, cycloalkyl groups having 1 - 6 carbon atoms, halogen, keto group, methoxy group, or cyano group;

[0027] Dihydroisoquinoline optionally substituted or unsubstituted at any position, and the substituents are selected from one or more methyl groups, methoxy groups, halogen, trifluoromethyl group, nitro group, cyano group, hydroxyl group, dimethylamine, diethylamine, thiophene, furan, morpholine, thiomorpholine, piperidine, piperazine, N - methylpiperazine.

[0028] Among them, preferably, the compound is selected from the following compounds:

[0029]

[0030]

[0031]

[0032] Among them, preferably, the pharmaceutically acceptable salt is the hydrochloride, sulfate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, acetate, oxalate, succinate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, pentanedioate, arginate or maleate of the compound represented by Formula I or Formula II.

[0033] Furthermore, the present invention also provides a pharmaceutical composition, which comprises: the compound, its enantiomers, diastereomers, racemates or mixtures, or pharmaceutically acceptable salts; and a pharmaceutically acceptable carrier.

[0034] Still further, the present invention also provides the use of the compound, its enantiomers, diastereomers, racemates or mixtures, or pharmaceutically acceptable salts or the pharmaceutical composition for:

[0035] (1) Preparing a drug for preventing and / or treating tuberculosis infection;

[0036] (2) Preparing a drug for preventing and / or treating drug-resistant tuberculosis infection;

[0037] (3) Preparing a drug for inhibiting the growth of Mycobacterium tuberculosis.

[0038] Even further, the present invention also provides a method for reducing the pathogenicity or toxicity of Mycobacterium tuberculosis, which comprises the step of:

[0039] Contacting Mycobacterium tuberculosis with the compound, its enantiomers, diastereomers, racemates or mixtures, or pharmaceutically acceptable salts or the pharmaceutical composition, thereby reducing the pathogenicity or toxicity of Mycobacterium tuberculosis, and the method is not used for the treatment of diseases.

[0040] Even further, the present invention also provides an anti-Mycobacterium tuberculosis method, that is, administering a safe and effective amount of the compound or the pharmaceutical composition to a desired subject or to the environment.

[0041] Even further, the present invention also provides a method for treating tuberculosis infection, which comprises the following steps: administering a safe and effective amount of the compound or the pharmaceutical composition to a subject infected with Mycobacterium tuberculosis.

[0042] Among them, preferably, the compound or the pharmaceutical composition contacts and acts on bacteria for a period of time, thereby reducing the pathogenicity and / or toxicity of Mycobacterium tuberculosis.

[0043] In the present invention, the manner of administering to the subject is not particularly limited, including but not limited to oral administration, injection, inhalation, topical use.

[0044] In the present invention, "a safe and effective amount" means that the amount of the active ingredient (compound of formula Ι) is sufficient to significantly improve the condition without causing serious side effects.

[0045] In the present invention, the term "alkyl having 1 - 8 carbons" or "alkyl having 1 - 6 carbons" refers to a straight-chain or branched-chain alkyl having 1 to 8 or 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, etc. In the present invention, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0046] Generally, the pharmaceutical composition contains 1 - 2000 mg of the active ingredient per dose, more preferably, 10 - 200 mg of the active ingredient per dose. Preferably, the "per dose" is one tablet.

[0047] "Pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), lubricants (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0048] There is no particular limitation on the administration method of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0049] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0050] In these solid dosage forms, the active ingredient is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or calcium phosphate dibasic, or is admixed with the following components: (a) fillers or solubilizers, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxypropylmethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrants, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, sodium carbonate; (e) slow solvents, e.g., paraffin wax; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glyceryl monostearate; (h) adsorbents, e.g., kaolin; (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0051] The solid dosage forms described above can also be prepared with coatings and capsule materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric materials and wax-like substances.

[0052] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances, etc. In addition to these inert diluents, the compositions may also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0053] In addition to the active ingredient, the suspension may contain suspending agents, e.g., ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum monostearate, and agar, or mixtures of these substances, etc.

[0054] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstituting into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0055] The compounds of the present invention can be administered alone or in combination with other therapeutic agents.

[0056] When using the pharmaceutical composition, a safe and effective amount of the compound of formula Ι of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is an effective dosage considered pharmaceutically. For a person weighing 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 20 - 500 mg. Of course, the specific dosage also needs to consider factors such as the administration route and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0057] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0058] 1. The present invention provides novel heterocyclic - pyrazolamine - type structure derivatives.

[0059] 2. The present invention provides a preparation method for heterocyclic - pyrazolamine - type derivatives, with a simple and efficient process.

[0060] 3. The present invention discovers for the first time a new use of heterocyclic - pyrazolamine - type derivatives, which can be used to prepare anti - tuberculosis drugs. Detailed implementation manners

[0061] To make the objectives, technical solutions, and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of them. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.

[0062] In all embodiments, thin - layer analysis was detected using thin - layer silica gel plates (Merck, TLC Silica gel 60F 254 ); the silica gel (200 - 300 mesh) used for column chromatography was purchased from Qingdao Ocean Chemical Industry, and the boiling range of the petroleum ether used for column chromatography was 60 - 90 °C; all reagents in the experiments were purchased from (Beijing) J&K Scientific Ltd. and Shanghai Bide Pharmaceutical Technology Co., Ltd. unless otherwise specified, and were of analytical purity or chemical purity without further treatment. Before the bioactivity test of each compound, HPLC was used for purity analysis, and chromatographically pure organic solvents and Watsons pure water were used in the analysis. 1 H - NMR, 13 13C - NMR was recorded using a 400M, 500M, or 600M nuclear magnetic resonance spectrometer, and the chemical shift was expressed in δ (ppm).

[0063] Preparation route:

[0064] Route 1:

[0065]

[0066] Route 2:

[0067]

[0068] Route Three:

[0069]

[0070] Route Four:

[0071]

[0072] Route Five:

[0073]

[0074] Route Six:

[0075]

[0076] Preparation of 2-thioxo-5,6-dimethylpyrimidin-4(3H)-one (LSL-8-1):

[0077]

[0078] Ethyl 2-methylacetoacetate (3.0 mL, 20 mmol), thiourea (2.28 g, 30 mmol) and sodium ethoxide (2.72 g, 40 mmol) were dissolved in an appropriate amount of ethanol, and the mixture was heated under reflux in an oil bath for 8 hours. The reaction solution was poured into an appropriate amount of ice water, and its pH value was adjusted to slightly acidic to neutral with a dilute hydrochloric acid solution. Flocculent precipitate was formed, and the mixture was allowed to stand overnight. After filtration, 2.53 g of 2-thioxo-5,6-dimethylpyrimidin-4(3H)-one was obtained with a yield of 81%. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.30 (1H, s), 12.09 (1H, s), 2.11 (3H, s), 1.76 (3H, s); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 174.15, 162.07, 148.58, 110.69, 16.43, 10.11; MS (ESI+) m / z: 157 [M+H] + .

[0079] Preparation of 5,6-dimethyl-2-(methylthio)pyrimidin-4(3H)-one (LSL-8-2A):

[0080]

[0081] At room temperature, potassium hydroxide (305 mg, 5.45 mmol) was dissolved in an appropriate amount of ethanol. 2-Thioxo-5,6-dimethylpyrimidin-4(3H)-one (850 mg, 5.45 mmol) was added to the above solution. After stirring for about 30 minutes, methyl iodide (0.34 mL, 5.45 mmol) was added dropwise to the above reaction solution. The reaction was continued overnight. After concentrating the reaction solution, an appropriate amount of ice water was added, and a white precipitate was formed. After filtration, 567 mg of pure 5,6-dimethyl-2-(methylthio)pyrimidin-4(3H)-one was obtained, with a yield of 61.2%. 1 HNMR(DMSO-d 6 , 400 MHz) δ (ppm) 12.48 (1H, s), 2.46 (3H, s), 2.19 (3H, s), 1.87 (3H, s); 13 CNMR(DMSO-d 6 , 101 MHz) δ (ppm) 174.15, 162.07, 148.57, 110.69, 22.05, 16.43, 10.11; MS(ESI+) m / z: 171 [M + H] + .

[0082] Preparation of 2-hydrazino-5,6-dimethylpyrimidin-4(3H)-one (LSL-8-10):

[0083]

[0084] 5,6-Dimethyl-2-(methylthio)pyrimidin-4(3H)-one (340 mg, 2.0 mmol) and hydrazine hydrate (0.96 mL, 20.0 mmol) were dissolved in 5 mL of ethanol. Under microwave irradiation at 130 °C, the reaction was carried out for 1.5 hours, and then it was transferred to room temperature and stirred overnight. After filtration, 210 mg of pure white 2-hydrazino-5,6-dimethylpyrimidin-4(3H)-one was obtained, with a yield of 68.2%. 1 HNMR(DMSO-d 6 , 400 MHz) δ (ppm) 8.18 (1H, s), 4.41 (2H, s), 2.06 (3H, s), 1.79 (3H, s); 13 CNMR(DMSO-d 6 , 101 MHz) δ (ppm) 162.71, 161.58, 155.07, 106.25, 22.21, 10.75; MS(ESI+) m / z: 155 [M + H] + .

[0085] Preparation of 2-(5-amino-3-methyl-1H-pyrazol-1-yl)-5,6-dimethylpyrimidin-4(3H)-one (LSL-8-11):

[0086]

[0087] At room temperature, 3-aminobutenenitrile (164 mg, 2.0 mmol) was added in portions to a solution of 2-hydrazino-5,6-dimethylpyrimidin-4(3H)-one (154 mg, 1.0 mmol) in ethanol (5 mL). The mixture was heated under reflux in an oil bath overnight, then transferred to room temperature. A white solid precipitate was formed, filtered, and 144 mg of pure LSL-8-11 was obtained with a yield of 65.7%. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.27 (1H, s), 6.85 (2H, s), 5.26 (1H, s), 2.26 (3H, s), 2.09 (3H, s), 1.92 (3H, s); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 152.06, 150.87, 88.82, 21.88, 14.31, 11.01; MS (ESI+) m / z: 220 [M+H] + .

[0088] Preparation of 2-((1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)amino)-2-oxalyl chloride (LSL-8-14):

[0089]

[0090] Under an ice bath, a solution of 2-(5-amino-3-methyl-1H-pyrazol-1-yl)-5,6-dimethylpyrimidin-4(3H)-one (120 mg, 0.55 mmol) dissolved in an appropriate amount of dichloromethane was added dropwise to a dichloromethane solution of oxalyl chloride (0.465 mL, 0.55 mmol). The mixture was transferred to room temperature and stirred for another 24 hours. After concentrating the reaction solution, an appropriate amount of ice water was added, and a yellow flocculent precipitate was formed. After filtration, 160 mg of pure 2-((1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)amino)-2-oxalyl chloride was obtained with a yield of 94.1%. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.94 (1H, s), 6.71 (2H, s), 2.62 (3H, s), 2.33 (3H, s), 2.25 (3H, s); 13 CNMR (DMSO-d 6, 101 MHz) δ (ppm) 169.22, 161.22, 161.13, 154.29, 153.56, 151.71, 139.23, 125.14, 98.44, 23.12, 14.75, 14.31; MS(ESI+) m / z: 310, 312 [M+H] + .

[0091] Preparation of 2-(5-amino-4-chloro-3-methylpyrazol-1-yl)-5,6-dimethylpyrimidin-4(1H)-one (K-3-27):

[0092]

[0093] Dissolve 2-hydrazino-5,6-dimethylpyrimidin-4-(3H)-one (219 mg, 1 mmol) and N-chlorosuccinimide (166 mg, 1.25 mmol) in an appropriate amount of acetonitrile and stir at room temperature for 2 h. After monitoring the reaction by TLC and completion, add an appropriate amount of NaHCO 3 Quench the reaction solution, let it stand overnight at room temperature, a white solid precipitates, filter to obtain 160 mg of pure 2-(5-amino-4-chloro-3-methyl-1H-pyrazol-1-yl)-5,6-dimethylpyrimidin-4(1H)-one, yield: 63%. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 7.06 (2H, s), 2.10 (3H, s), 2.07 (3H, s), 1.84 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 173.08, 156.72, 156.21, 145.73, 144.47, 112.82, 88.49, 21.71, 12.10, 11.98; MS(ESI+) m / z: 254 [M+H] + .

[0094] Preparation of 2-(5-amino-4-bromo-3-methylpyrazol-1-yl)-5,6-dimethylpyrimidin-4(1H)-one (K-3-29):

[0095]

[0096] Dissolve 2-hydrazino-5,6-dimethylpyrimidin-4-(3H)-one (219 mg, 1 mmol) and N-bromosuccinimide (221 mg, 1.25 mmol) in an appropriate amount of acetonitrile and stir at room temperature for 2 h. After monitoring the reaction by TLC and completion, add an appropriate amount of NaHCO 3The quenching reaction solution was precipitated overnight at room temperature, and a pale yellow solid was precipitated. After filtration, 180 mg of pure 2-(5-amino-4-bromo-3-methyl-1H-pyrazol-1-yl)-5,6-dimethylpyrimidin-4(1H)-one was obtained, with a yield of 60%. 1 HNMR(DMSO-d 6 , 600 MHz) δ (ppm) 7.05 (2H, s), 2.11 (3H, s), 2.06 (3H, s), 1.84 (3H, s); 13 CNMR(DMSO-d 6 , 150 MHz) δ (ppm) 172.63, 156.90, 155.89, 147.16, 145.78, 112.80, 74.61, 21.70, 12.89, 12.07; MS(ESI+) m / z: 298 [M+H] + .

[0097] Preparation of 3,5-dimethyl-N-(3-methylpyrazol-5-yl)benzamide (K-3-37):

[0098]

[0099] 3-Methyl-1H-pyrazol-5-amine (97 mg, 1 mmol) was dissolved in an appropriate amount of anhydrous dichloromethane, 0.5 mL of triethylamine was added, and 3,5-dimethylbenzoyl chloride (250 mg, 1.5 mmol) was slowly added dropwise under nitrogen protection. The reaction solution was stirred at room temperature for 2 h. After the reaction was monitored by TLC and completed, the reaction solution was extracted three times with dichloromethane, and the organic layer was washed successively with water and saturated brine. The reaction intermediate was obtained by flash column chromatography. The reaction intermediate was dissolved in an appropriate amount of methanol, 1.5 g of potassium carbonate was added, and the mixture was stirred at room temperature for 0.5 h. After the reaction was monitored by TLC and completed, a large amount of water was added, and the pH was adjusted to neutral with 0.1 M dilute hydrochloric acid. After standing, a large amount of solid was precipitated, and 140 mg of pure 3,5-dimethyl-N-(3-methylpyrazol-5-yl)benzamide was obtained by filtration, with a yield of 61%. 1 HNMR(DMSO-d 6 , 600 MHz) δ (ppm) 12.07 (1H, s), 10.51 (1H, s), 7.62 (2H, s), 7.18 (1H, s), 6.39 (1H, s), 2.33 (6H, s), 2.23 (3H, s); 13 CNMR(DMSO-d 6, 150 MHz) δ (ppm) 164.94, 148.00, 138.54, 137.81 × 2, 134.61, 133.13, 125.92 × 2, 96.85, 21.30 × 2, 11.22; MS(ESI+) m / z: 230 [M+H] + .

[0100] General synthetic method for target compounds in Examples 1 - 20:

[0101]

[0102] The reagent containing amino group (1.5 mmol) was dissolved in an appropriate amount of DMF, sodium hydride (48 mg, 1.2 mmol) was added, and after stirring at room temperature for about 30 minutes, LSL-8-14 (309 mg, 1.0 mmol) was added to the above reaction solution. Stirring was continued for 4 - 24 hours. After concentrating the reaction solution, an appropriate amount of ice water was added, and a solid precipitate formed in the reaction solution. It was filtered to obtain the crude product, which was then separated and purified by flash column chromatography to obtain the target compound.

[0103] Synthetic route for intermediates of another series of compounds:

[0104]

[0105] General synthetic method:

[0106] Ethyl acetoacetate (2 equiv), substituted aniline (1 equiv), and potassium hydroxide (2 equiv) were dissolved in an appropriate amount of toluene and heated under reflux in an oil bath for 1 - 48 hours until the raw materials reacted completely. The reaction solution was poured into an appropriate amount of ice water, and extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated and purified by flash chromatography (DCM / MeOH) to obtain the key intermediate.

[0107] Preparation of N-acetylaceto-p-cyanoaniline (LSL-8-50):

[0108]

[0109] Ethyl acetoacetate (260 mg) and 4-cyanoaniline (118 mg) were heated under reflux in an oil bath for 10 hours and separated and purified by flash chromatography (DCM / MeOH = 2%) to obtain 150 mg of the key intermediate N-acetylaceto-p-cyanoaniline, with a yield of 74.2%. 1 HNMR(DMSO-d 6 , 500 MHz) δ (ppm) 10.50 (1H, s), 7.76 - 7.80 (4H, m), 3.63 (2H, s), 2.23 (3H, s);13 CNMR (DMSO-d 6 , 125 MHz) δ (ppm) 200.33, 169.67, 140.74, 131.79×2, 121.81×2, 119.21, 105.57, 55.85, 29.33; MS (ESI+) m / z 203 [M+H] + .

[0110] Preparation of N-acetylaceto-p-trifluoromethylaniline (LSL-12-15):

[0111]

[0112] Ethyl acetoacetate (260 mg) and 4-trifluoromethylaniline (175 mg) were heated under reflux in an oil bath for 24 hours, and purified by flash chromatography (DCM / MeOH = 1.5%) to obtain 160 mg of the key intermediate N-acetylaceto-p-trifluoromethylaniline, with a yield of 65.3%. 1 HNMR (DMSO-d 6 , 500 MHz) δ (ppm) 9.79 (1H, s), 7.64 (2H, d, J = 7.5 Hz), 7.51 (2H, d, J = 7.5 Hz), 3.70 (2H, s), 2.30 (3H, s); 13 CNMR (DMSO-d 6 , 125 MHz) δ (ppm) 200.33, 169.67, 141.26, 126.82 (J C-F = 27.5 Hz), 126.03×2 (J C-F = 6.75 Hz), 124.64×2 (J C-F = 262.5 Hz), 120.33 (J C-F = 3.75 Hz), 55.85, 29.33; MS (ESI+) m / z 246 [M+H] + .

[0113] Preparation of N-acetylaceto-3,5-dimethylaniline (LSL-12-18):

[0114]

[0115] Ethyl acetoacetate (260 mg) and 3,5-dimethylaniline (121 mg) were heated under reflux in an oil bath for 12 hours, and purified by flash chromatography (PE / EtOAc = 25%) to obtain 155 mg of the key intermediate N-acetylaceto-3,5-dimethylaniline, with a yield of 75.6%. 1 HNMR (CDCl 3, 400 MHz) δ (ppm) 8.90 (1H, s), 7.15 (2H, s), 6.75 (1H, s), 3.55 (2H, s), 2.31 (3H, s), 2.28 (6H, s); 13 C NMR (CDCl 3 , 100 MHz) δ (ppm) 205.39, 163.20, 138.75, 137.29, 126.38, 117.95 × 2, 109.98, 49.75, 31.37, 21.38 × 2; MS (ESI+) m / z 206 [M + H] + .

[0116] Preparation of N - acetoacetyl - 2,4 - dichloroaniline (LSL - 12 - 24):

[0117]

[0118] Ethyl acetoacetate (260 mg) and 2,4 - dichloroaniline (162 mg) were heated under reflux in an oil bath for 12 hours, and purified by flash chromatography (PE / EtOAc = 25%) to obtain 75 mg of the key intermediate N - acetoacetyl - 2,4 - dichloroaniline, with a yield of 30.5%. 1 H NMR (CDCl 3 , 400 MHz) δ (ppm) 9.77 (1H, s), 8.32 (1H, d, J = 7.2 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.23 (1H, dd, J = 2.0, 7.2 Hz), 3.65 (2H, s), 2.34 (3H, s); 13 C NMR (CDCl 3 , 100 MHz) δ (ppm) 200.33, 170.74, 133.99, 131.44, 130.57, 129.82, 128.61, 125.47, 55.85, 29.31; MS (ESI+) m / z 247 [M + H] + .

[0119] Preparation of N - acetoacetyl - p - bromoaniline (LSL - 12 - 26):

[0120]

[0121] Ethyl acetoacetate (260 mg) and p - bromoaniline (172 mg) were heated under reflux in an oil bath for 12 hours, and purified by flash chromatography (PE / EtOAc = 25%) to obtain 100 mg of the key intermediate N - acetoacetyl - p - bromoaniline, with a yield of 39.0%. 1 H NMR (CDCl 3, 400 MHz) δ (ppm) 9.25 (1H, s), 7.42 - 7.47 (4H, m), 3.59 (2H, s), 2.33 (3H, s); 13 C NMR (CDCl 3 , 100 MHz) δ (ppm) 200.33, 169.67, 136.21, 131.79×2, 122.19×2, 118.25, 55.85, 29.33; MS (ESI+) m / z 257 [M + H] + .

[0122] Preparation of N - acetoacetyl - p - hydroxyaniline (LSL - 12 - 29):

[0123]

[0124] Ethyl acetoacetate (260 mg) and p - hydroxyaniline (109 mg) were heated under reflux in an oil bath for 12 hours, and then purified by flash chromatography (PE / EtOAc = 70%) to obtain 80 mg of the key intermediate N - acetoacetyl - p - hydroxyaniline, with a yield of 41.2%. 1 H NMR (CDCl 3 , 400 MHz) δ (ppm) 9.01 (1H, s), 7.34 (2H, d, J = 6.8 Hz), 6.77 (2H, d, J = 6.8 Hz), 5.94 (1H, s), 3.57 (2H, s), 2.32 (3H, s); 13 C NMR (CDCl 3 , 100 MHz) δ (ppm) 200.33, 169.67, 155.48, 130.67, 123.31×2, 116.53×2, 55.85, 29.33; MS (ESI+) m / z 194 [M + H] + .

[0125] Preparation of N - acetoacetyl - 3 - methyl - 4 - cyanoaniline (LSY - 22 - 1):

[0126]

[0127] Ethyl acetoacetate (260 mg) and 3 - methyl - 4 - cyanoaniline (132 mg) were heated under reflux in an oil bath for 12 hours, and then purified by flash chromatography (DCM / MeOH = 2.0%) to obtain 32 mg of the key intermediate N - acetoacetyl - 3 - methyl - 4 - cyanoaniline, with a yield of 14.8%. 1 H NMR (CDCl 3, 400 MHz) δ (ppm) 9.45 (1H, s), 7.45 - 7.56 (3H, s), 3.61 (2H, s), 2.51 (3H, s), 2.33 (3H, s); 13 13C NMR (CDCl 3 , 100 MHz) δ (ppm) 200.32, 169.67, 142.72, 140.35, 132.58, 122.40, 121.83, 119.92, 109.37, 55.85, 29.33, 21.50; MS (ESI+) m / z 217 [M + H] + .

[0128] Preparation of N - acetoacetyl - 3 - fluoro - 4 - cyanobenzeneamine (LSY - 22 - 2):

[0129]

[0130] Ethyl acetoacetate (260 mg) and 3 - fluoro - 4 - cyanobenzeneamine (136 mg) were heated under reflux in an oil bath for 12 hours, and purified by flash chromatography (DCM / MeOH = 2.5%) to obtain 114 mg of the key intermediate N - acetoacetyl - 3 - fluoro - 4 - cyanobenzeneamine, yield: 51.8%. 1 1H NMR (CDCl 3 , 400 MHz) δ (ppm) 9.74 (1H, s), 7.77 (1H, d, J = 8.8 Hz), 7.55 (1H, t, J = 6.0 Hz), 7.27 (1H, d, J = 8.0 Hz), 3.63 (2H, s), 2.35 (3H, s); 13 13C NMR (CDCl 3 , 100 MHz) δ (ppm) 200.33, 169.67, 164.40, 143.00, 131.52, 120.65, 117.23, 109.24, 99.93, 55.85, 29.33; MS (ESI+) m / z 221 [M + H] + .

[0131] Preparation of 1 - (5 - nitrothiazol - 2 - yl) pentane - 2,4 - dione (LSL - 12 - 38):

[0132]

[0133] Ethyl acetoacetate (260 mg), 5-nitrothiazol-2-amine (145 mg) were heated under reflux in an oil bath for 12 hours, and purified by flash chromatography (DCM / MeOH = 3.4%) to obtain 90 mg of the key intermediate 1-(5-nitrothiazol-2-yl)pentane-2,4-dione, yield: 39.3%. 1 HNMR(DMSO-d 6 , 500 MHz) δ (ppm) 13.13 (1H, s), 8.65 (1H, s), 3.85 (2H, s), 2.24 (3H, s); 13 CNMR(DMSO-d 6 , 125 MHz) δ (ppm) 200.33, 165.92, 165.17, 144.38, 139.79, 55.43, 29.33; MS(ESI+) m / z 230 [M+H] + .

[0134] General procedure for the synthesis of the target compounds in Examples 21 - 36:

[0135]

[0136] The starting material LSL-8-10 (1.2 equiv), N-acetoacetyl substituted aniline (1 equiv) and Lawesson's reagent (1.2 equiv) were dissolved in a mixed solution of anhydrous dioxane / pyridine (95 / 5). After stirring at room temperature for 15 minutes, the mixture was heated to 55 °C and reacted for 3 hours, and then stirred overnight at room temperature. The reaction mixture was concentrated, dissolved in methanol and dichloromethane, and silica gel was added for sample mixing, and purified by flash chromatography (DCM / MeOH) to obtain the white desired product.

[0137] General procedure for the synthesis of the target compounds in Examples 37 - 39:

[0138]

[0139] Under argon protection, the starting material LSL-8-11 (1 equiv), cesium carbonate (3 equiv) and the halogenated hydrocarbon (1.4 equiv) were dissolved in DMF and reacted at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash chromatography to obtain the target product.

[0140] General procedure for the synthesis of the target compounds in Examples 40 - 80 and Examples 90 - 94:

[0141]

[0142] Weigh 220 mg of 2-(5-amino-3-methyl-1H-pyrazol-1-yl)-5,6-dimethylpyrimidin-4(3H)-one (LSL-8-11) and dissolve it in an appropriate amount of anhydrous dichloromethane. Add 0.5 mL of triethylamine to the reaction solution. At 0 °C, slowly add the corresponding acyl chloride raw material drop by drop. Transfer it to room temperature and stir for 3 h. After monitoring the reaction by LC / MS until completion, extract the reaction solution three times with dichloromethane, and wash the organic layer successively with water and saturated brine. Obtain the reaction intermediate by flash column chromatography. Dissolve the reaction intermediate in an appropriate amount of methanol, add 1.5 g of potassium carbonate, and stir at room temperature for 0.5 h. After monitoring the reaction by LC / MS until completion, add an appropriate amount of water, adjust its pH to neutral with dilute hydrochloric acid, let it stand, a large amount of solid will precipitate, and the target product can be obtained by filtration.

[0143] General method for the synthesis of the target compounds in Examples 81 - 86:

[0144]

[0145] Weigh 1 mmol of 2-(5-amino-4-halo-3-methyl-1H-pyrazol-1-yl)-5,6-dimethylpyrimidin-4(3H)-one and dissolve it in an appropriate amount of anhydrous dichloromethane. Add 0.5 mL of triethylamine to the reaction solution. At 0 °C, slowly add the corresponding acyl chloride raw material drop by drop. Transfer it to room temperature and stir for 3 h. After monitoring the reaction by LC / MS until completion, extract the reaction solution three times with dichloromethane, and wash the organic layer successively with water and saturated brine. Obtain the reaction intermediate by flash column chromatography. Dissolve the reaction intermediate in an appropriate amount of methanol, add 1.5 g of potassium carbonate, and stir at room temperature for 0.5 h. After monitoring the reaction by LC / MS until completion, add an appropriate amount of water, adjust its pH to neutral with dilute hydrochloric acid, let it stand, a large amount of solid will precipitate, and the target product can be obtained by filtration.

[0146] General method for the synthesis of the target compounds in Examples 87 - 89, 95 - 112:

[0147] Dissolve K-3-37 or N-(3-methyl-1H-pyrazol-5-yl)-acetamide or N-(3-methyl-1H-pyrazol-5-yl)-propanamide or N-(3-ethyl-1H-pyrazol-5-yl)-benzamide or N-(3-chloro-1H-pyrazol-5-yl)-benzamide (1 mmol) and the corresponding heterocyclic halogenated raw material in an appropriate amount of anhydrous N,N-dimethylformamide, add 2 mmol of cesium carbonate, and heat to 90 °C for reaction for 12 - 42 h. After monitoring the reaction by LC / MS until completion, quench the reaction with dilute hydrochloric acid, extract the reaction solution three times with dichloromethane, and wash the organic layer successively with water and saturated brine, and dry it with anhydrous sodium sulfate. Obtain the reaction product by flash column chromatography.

[0148] General method for the synthesis of the target compounds in Examples 113 - 120:

[0149] Weigh 220 mg of 2-(5-amino-3-methyl-1H-pyrazol-1-yl)-5,6-dimethylpyrimidin-4(3H)-one (LSL-8-11) and dissolve it in an appropriate amount of acetonitrile. Add 1 mmol of the corresponding isocyanate compound to the reaction solution. Stir at room temperature for 3 h. After monitoring the reaction by LC / MS and the reaction is completed, extract the reaction solution three times with dichloromethane, and wash the organic layer with water and saturated brine in sequence. The target product is obtained by flash column chromatography.

[0150] Example 1 N 1 -Cyclopentyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-15)

[0151]

[0152] Cyclopentylamine (127.5 mg, 1.5 mmol) reacts with LSL-8-14, and is separated and purified by flash column (DCM / MeOH = 20%) to obtain 183 mg of a white solid, yield: 51%, mp. 167 - 169 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.13 (1H, s), 8.05 (1H, s), 6.72 (1H, d, J = 6.4 Hz), 6.62 (1H, s), 4.58 - 4.70 (1H, m), 2.38 (3H, s), 2.21 (3H, s), 2.01 (3H, s), 1.47 - 1.78 (8H, m); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 161.88, 160.28, 154.57, 149.22, 139.89, 107.89, 96.61, 52.44, 32.55×2, 31.12, 24.19×2, 23.94, 21.72, 14.48, 11.72; MS(ESI+) m / z 359.2 [M + H] + .

[0153] Example 2 2-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-oxoacetamide (LSL-8-16)

[0154]

[0155] 1,2,3,4-Tetrahydroisoquinoline (160 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 15%) to obtain 244 mg of a white solid, yield: 60%, mp. 235 - 237 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.69 (1H, s), 7.33 (1H, s), 7.15 - 7.22 (4H, m), 6.64 (1H, s), 4.71 (2H, s), 3.65 (2H, t, J = 4.8 Hz), 3.03 (2H, t, J = 4.8 Hz), 2.48 (3H, s), 2.23 (6H, s); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 166.54, 166.08, 163.42, 161.75, 153.81, 149.78, 140.16, 134.77, 134.65, 129.01, 127.33, 126.72, 126.31, 112.74, 96.48, 50.21, 47.29, 28.97, 22.57, 14.89, 14.46; MS(ESI+) m / z 407.2 [M+H] + .

[0156] Example 3 N 1 -propyl-N 2 -(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-18)

[0157]

[0158] Propylamine (89 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 21%) to obtain 150 mg of a white solid, yield: 45%, mp. 210 - 212 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.12 (1H, s), 6.99 (1H, t, J = 4.8 Hz), 6.61 (1H, s), 3.45 - 3.51 (2H, m), 3.17 (1H, s), 2.38 (3H, s), 2.21 (3H, s), 2.10 (3H, s), 1.56 - 1.66 (2H, m), 0.90 (3H, t, J = 7.2 Hz); 13 CNMR (DMSO-d 6, 101 MHz) δ (ppm) 162.23, 161.73, 160.17, 154.62, 149.20, 147.41, 139.92, 107.80, 96.52, 42.82, 22.41, 21.67, 14.46, 11.91, 11.62; MS(ESI+) m / z 333.1 [M+H] + .

[0159] Example 4 N 1 -Methyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-19)

[0160]

[0161] Methylamine (47 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 22%) to obtain 122 mg of white solid, yield: 40%, mp. 267 - 269 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.93 (1H, s), 7.10 (1H, q), 6.61 (1H, s), 2.99 (3H, d, J = 4.8 Hz), 2.37 (3H, s), 2.21 (3H, s), 2.00 (3H, s); 13 13C NMR (DMSO-d 6 , 101 MHz) δ (ppm) 163.47, 162.60, 161.88, 160.17, 154.62, 149.15, 139.98, 107.96, 96.33, 28.61, 21.66, 14.41, 11.57; MS(ESI+) m / z 407.2 [M+H] + .

[0162] Example 5 N 1 -Cyclobutyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-20)

[0163]

[0164] Cyclobutylamine (107 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 20%) to obtain 275 mg of white solid, yield: 80%, mp. 265 - 267 °C.1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.95 (1H, s), 7.06 (1H, d, J = 7.2 Hz), 6.60 (1H, s), 4.80 - 4.91 (1H, m), 2.38 (3H, s), 2.24 - 2.32 (2H, m), 2.21 (3H, s), 2.05 - 2.13 (2H, m), 2.02 (3H, s); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 163.51, 161.89, 161.10, 160.91, 154.55, 149.19, 140.20, 107.60, 96.27, 45.96, 30.81×2, 21.80, 15.03, 14.47, 11.68; MS(ESI+) m / z 345.2 [M + H] + .

[0165] Example 6 N 1 -Cyclopropyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-22)

[0166]

[0167] Cyclopropylamine (86 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 20%) to obtain 158 mg of a white solid, yield: 48%, mp. 199 - 201 °C. 1 HNMR (DMSO-d 6 , 600 MHz) δ (ppm) 13.29 (1H, s), 7.13 (1H, d, J = 4.2 Hz), 6.68 (1H, s), 3.12 - 3.17 (1H, m), 2.36 (3H, s), 2.23 (3H, s), 1.98 (3H, s), 0.72 - 0.96 (2H, m), 0.57 - 0.61 (2H, m). 13 CNMR (DMSO-d 6 , 150 MHz) δ (ppm) 163.20, 161.50, 160.25, 154.49, 150.83, 149.52, 138.94, 108.38, 97.76, 24.72, 21.66, 14.40, 11.67, 6.79×2; MS(ESI+) m / z 331.1 [M + H] + .

[0168] Example 7N 1 -Dimethyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-23)

[0169]

[0170] Dimethylamine (68 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 22%) to obtain 124 mg of white solid, yield: 39%, mp. 223 - 225 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.82 (1H, s), 6.61 (1H, s), 3.07 (6H, s), 2.44 (3H, s), 2.20 (3H, s), 2.18 (3H, s); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 166.41, 165.19, 163.46, 161.77, 153.56, 149.51, 140.08, 110.68, 96.37, 41.06×2, 22.47, 15.39, 14.42; MS(ESI+) m / z 319.1 [M+H] + .

[0171] Example 8N 1 -Diethyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-24)

[0172]

[0173] Diethylamine (110 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 20%) to obtain 121 mg of white solid, yield: 35%, mp. 167 - 169 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.92 (1H, s), 7.08 (1H, q), 5.88 (1H, s), 3.09 (3H, s), 3.07 (6H, s), 2.32 (3H, s), 2.19 (3H, s); 13 CNMR (DMSO-d 6, 101 MHz) δ (ppm) 163.62, 157.49, 156.33, 155.59, 149.93, 142.00, 140.39, 102.79, 96.11, 42.14×2, 19.07, 13.98, 13.87, 13.17×2; MS(ESI+) m / z 347.2 [M+H] + .

[0174] Example 9 N 1 -Ethyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-27)

[0175]

[0176] Ethylamine (68 mg, 1.5 mmol) was reacted with LSL-8-14 and purified by flash column (DCM / MeOH = 22%) to obtain 150 mg of white solid, yield: 47%, mp. 232 - 234 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.13 (1H, s), 8.04 (1H, s), 7.05 (1H, t, J = 4.4 Hz), 6.61 (1H, s), 3.51 - 3.58 (2H, m), 2.38 (3H, s), 2.21 (3H, s), 2.01 (3H, s), 1.17 (3H, t, J = 7.2 Hz); 13 13C NMR (DMSO-d 6 , 101 MHz) δ (ppm) 162.04, 160.20, 154.63, 149.23, 139.87, 107.87, 96.56, 35.95, 34.48, 21.68, 15.11, 14.45, 12.98, 11.62; MS(ESI+) m / z 319.1 [M+H] + .

[0177] Example 10 N 1 -(2-Thienyl)methyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-29)

[0178]

[0179] 2-Thiophenemethanamine (170 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 20%) to obtain 154 mg of a white solid, yield: 40%, mp. 106 - 108 °C. 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.10 (1H, s), 8.16 (1H, s), 7.73 (1H, t, J = 5.6 Hz), 7.58 (1H, dd, J = 4.8, 0.8 Hz), 7.24 (1H, d, J = 2.8 Hz), 7.06 - 7.09 (1H, m), 6.63 (1H, s), 4.92 (2H, d, J = 5.6 Hz), 2.39 (3H, s), 2.21 (3H, s), 2.02 (3H, s); 13 C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 161.95, 161.11, 154.41, 149.46, 143.23, 139.95, 135.92, 129.45, 127.71, 127.00, 125.21, 108.09, 96.56, 37.31, 21.76, 14.47, 11.57; MS (ESI+) m / z 387.1 [M+H] + .

[0180] Example 11 N 1 -(2-Furyl)methyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-30)

[0181]

[0182] 2-Furfurylamine (145 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 20%) to obtain 130 mg of a white solid, yield: 35%, mp. 120 - 122 °C. 1 H NMR (DMSO-d 6, 400 MHz) δ (ppm) 13.04 (1H, s), 8.07 (1H, s), 7.55 (1H, t, J = 5.6 Hz), 6.62 (1H, s), 6.53 (1H, d, J = 2.8 Hz), 6.50 (1H, dd, J = 7.2, 1.6 Hz), 6.39 - 6.41 (1H, m), 4.74 (2H, d, J = 5.6 Hz), 2.39 (3H, s), 2.21 (3H, s), 2.02 (3H, s); 13 C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 162.00, 161.35, 154.39, 149.42, 144.07, 142.69, 142.17, 140.20, 111.39, 110.95, 110.59, 108.14, 96.29, 37.74, 21.76, 14.47, 11.56; MS (ESI+) m / z 371.1 [M + H] + .

[0183] Example 12 N 1 -Cyclopentyl-N 2 -(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-oxamide (LSL-8-31)

[0184]

[0185] Cyclopentylamine (150 mg, 1.5 mmol) was reacted with LSL-8-14, and purified by flash column (DCM / MeOH = 20%) to obtain 130 mg of white solid, yield: 35%, mp. 167 - 169 °C. 1 HNMR (DMSO-d 6 , 600 MHz) δ (ppm) 13.55 (1H, s), 6.67 (1H, t, J = 7.8 Hz), 6.65 (1H, s), 4.10 - 4.17 (1H, m), 2.37 (3H, s), 2.23 (3H, s), 2.01 (3H, s), 1.86 - 1.88 (2H, m), 1.73 - 1.76 (2H, m), 1.62 - 1.65 (1H, m), 1.30 - 1.42 (4H, m), 1.11 - 1.17 (1H, m); 13 C NMR (DMSO-d 6, 150 MHz) δ (ppm) 161.49, 161.41, 159.81, 158.34, 154.60, 149.48, 139.01, 108.02, 97.61, 49.63, 32.66×2, 25.77, 25.44×2, 21.58, 14.48, 11.68; MS(ESI+) m / z 373.2 [M+H] + .

[0186] Example 13 2-(6-Hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-oxoacetamide (LSL-8-33)

[0187]

[0188] 6-Hydroxy-1,2,3,4-tetrahydroisoquinoline (224 mg, 1.5 mmol) was reacted with LSL-8-14 and purified by flash column (DCM / MeOH = 20%) to give 169 mg of a white solid, yield: 40%, mp. 260 - 262 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.10 (1H, s), 7.05 (1H, d, J = 7.5 Hz), 6.61 (1H, d, J = 1.5 Hz), 6.57 (1H, d, J = 1.5, 7.5 Hz), 6.40 (1H, s), 5.45 (1H, s), 4.41 (2H, s), 4.02 (2H, t, J = 5.5 Hz), 3.14 (3H, s), 2.92 (2H, t, J = 5.5 Hz), 2.36 (3H, s), 2.18 (3H, s); 13 13C NMR (DMSO-d 6 , 101 MHz) δ (ppm) 163.62, 156.33, 155.59, 154.91, 153.94, 149.78, 142.00, 140.39, 132.93, 129.39, 124.23, 117.55, 115.11, 102.79, 96.11, 47.01, 43.68, 28.43, 19.07, 13.98, 13.87; MS(ESI+) m / z 423.2 [M+H] + .

[0189] Example 14 2-(6-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-oxoacetamide (LSL-8-34)

[0190]

[0191] 6-Bromo-1,2,3,4-tetrahydroisoquinoline (316 mg, 1.5 mmol) was reacted with LSL-8-14 and purified by flash column (DCM / MeOH = 15%) to give 121 mg of a white solid, yield: 25%, mp. 170 - 172 °C. 1 HNMR(DMSO-d 6 , 600 MHz) δ (ppm) 13.08 (1H, s), 7.43 (1H, d, J = 1.8 Hz), 7.37 (1H, dd, J = 8.4, 1.8 Hz), 7.25 (1H, d, J = 8.4 Hz), 6.68 (1H, s), 4.63 (2H, s), 3.64 (2H, t, J = 6.0 Hz), 3.03 (2H, t, J = 6.0 Hz), 2.47 (3H, s), 2.25 (3H, s), 2.22 (3H, s); 13 CNMR(DMSO-d 6 , 150 MHz) δ (ppm) 166.44, 165.59, 161.49, 153.75, 150.07, 139.14, 137.77, 133.93, 131.59, 129.38, 129.19, 119.67, 112.88, 97.74, 49.76, 46.68, 28.64, 22.47, 14.90, 14.44; MS(ESI+) m / z 485.1 [M + H] + .

[0192] Example 15 2-(6-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-oxoacetamide (LSL-8-35)

[0193]

[0194] 6-Methoxy-1,2,3,4-tetrahydroisoquinoline (245 mg, 1.5 mmol) was reacted with LSL-8-14 and purified by flash column (DCM / MeOH = 18%) to give 131 mg of a white solid, yield: 30%, mp. 160 - 162 °C. 1HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.15 (1H, s), 8.15 (1H, s), 7.18 (1H, d, J = 8.8 Hz), 6.78 (1H, d, J = 1.8 Hz), 6.76 (1H, dd, J = 8.8, 1.8 Hz), 6.69 (1H, s), 4.59 (2H, s), 3.73 (3H, s), 3.65 (2H, t, J = 6.0 Hz), 3.00 (2H, t, J = 5.6 Hz), 2.47 (3H, s), 2.25 (3H, s), 2.22 (3H, s); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 166.47, 165.31, 163.52, 161.49, 158.22, 153.75, 150.01, 139.12, 136.07, 128.09, 126.42, 113.60, 112.82, 112.60, 97.72, 55.49, 49.71, 46.93, 29.11, 22.44, 14.98, 14.44; MS (ESI+) m / z 437.2 [M+H] + .

[0195] Example 16 2-Morpholino-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-oxoacetamide (LSL-8-36)

[0196]

[0197] Morpholine (131 mg, 1.5 mmol) was reacted with LSL-8-14 and purified by flash column (DCM / MeOH = 25%) to give 133 mg of a white solid, yield: 37%, mp. 210 - 212 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.19 (1H, s), 6.68 (1H, s), 3.74 (4H, t, J = 4.4 Hz), 3.41 (4H, t, J = 4.4 Hz), 2.47 (3H, s), 2.24 (3H, s), 2.16 (3H, s); 13 CNMR (DMSO-d 6, 101 MHz) δ (ppm) 166.44, 165.70, 161.38, 155.31, 153.84, 150.12, 139.09, 113.13, 97.81, 66.43 × 2, 49.03 × 2, 22.41, 14.97, 14.39; MS(ESI+) m / z 361.1 [M + H] + .

[0198] Example 17 2-Thiomorpholinyl-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-oxoacetamide (LSL-8-37)

[0199]

[0200] Thiomorpholine (155 mg, 1.5 mmol) was reacted with LSL-8-14 for 10 h, and purified by flash column (DCM / MeOH = 23%) to obtain 109 mg of white solid, yield: 29%, mp. 175 - 177 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 13.00 (1H, s), 6.59 (1H, s), 3.57 - 3.59 (4H, m), 2.68 - 2.71 (4H, m), 2.40 (3H, s), 2.15 (3H, s), 2.06 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 166.00, 165.11, 161.42, 155.28, 153.48, 150.02, 139.86, 113.40, 99.99, 51.19 × 2, 26.98 × 2, 22.50, 14.90, 14.41; MS(ESI+) m / z 377.1 [M + H] + .

[0201] Example 18 2-(4-(1-Pyrrolidinyl))piperidinyl-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-oxoacetamide (LSL-8-38)

[0202]

[0203] 4-(1-Pyrrolidinyl)piperidine (231 mg, 1.5 mmol) was reacted with LSL-8-14 for 10 h, and purified by flash column (DCM / MeOH = 15%) to obtain 85 mg of white solid, yield: 20%, mp. 216 - 218 °C.1 HNMR(DMSO-d 6 , 600 MHz) δ (ppm) 12.55 (1H, s), 8.24 (1H, s), 6.59 (1H, s), 3.77 - 3.83 (2H, m), 2.96 - 3.03 (2H, m), 2.60 - 2.66 (2H, m), 2.44 (3H, s), 2.27 - 2.31 (2H, m), 2.22 - 2.25 (1H, m), 2.19 (3H, s), 2.14 (3H, s), 1.92 - 1.98 (4H, m), 1.67 - 1.75 (4H, m); 13 CNMR(DMSO-d 6 , 150 MHz) δ (ppm) 163.62, 156.33, 155.59, 155.41, 149.78, 142.00, 140.39, 102.79, 96.11, 61.96, 54.41×2, 43.66×2, 25.96×2, 24.76×2, 19.07, 13.98, 13.87; MS(ESI+) m / z 428.2 [M + H] + .

[0204] Example 192 - Piperazinyl - N-(1-(4,5 - dimethyl - 6 - oxo - 1,6 - dihydropyrimidin - 2 - yl)-3 - methyl - 1H - pyrazol - 5 - yl)-2 - oxoacetamide (LSL - 8 - 40)

[0205]

[0206] Piperazine (129 mg, 1.5 mmol) was reacted with LSL - 8 - 14 for 10 hours, and purified by flash column (DCM / MeOH = 23%) to obtain 90 mg of white solid, yield: 25%, mp. 251 - 253 °C. 1 HNMR(DMSO-d 6 , 600 MHz) δ (ppm) 12.65 (1H, s), 8.14 (1H, s), 6.60 (1H, s), 2.60 - 2.62 (4H, m), 2.45 (3H, s), 2.38 - 2.40 (4H, m), 2.19 (3H, s), 2.14 (3H, s); 13 CNMR(DMSO-d 6, 150 MHz) δ (ppm) 163.62, 156.33, 155.59, 155.41, 149.78, 142.00, 140.39, 102.79, 96.11, 46.14 × 2, 44.92 × 2, 19.07, 13.98, 13.87; MS(ESI+) m / z 360.2 [M + H] + .

[0207] Example 20 2-(1-Methyl)piperazinyl-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-oxoacetamide (LSL-8-41)

[0208]

[0209] N-Methylpiperazine (150 mg, 1.5 mmol) was reacted with LSL-8-14 for 10 hours, and purified by flash column (DCM / MeOH = 20%) to obtain 112 mg of white solid, yield: 30%, mp. 271 - 273 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 12.60 (1H, s), 8.17 (1H, s), 6.61 (1H, s), 2.60 - 2.62 (4H, m), 2.46 (3H, s), 2.37 - 2.40 (4H, m), 2.19 (3H, s), 2.15 (3H, s), 2.06 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 163.60, 156.35, 155.59, 155.41, 149.78, 142.00, 140.39, 102.79, 96.11, 52.66 × 2, 46.05, 44.80 × 2, 19.07, 13.98, 13.87; MS(ESI+) m / z 374 [M + H] + .

[0210] Example 21 2-(3-Methyl-5-p-tolylamino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-8-44)

[0211]

[0212] The raw materials LSL-8-10 (185 mg) and N-acetylaceto-p-toluidide (191 mg) were reacted for 3 hours, then stirred overnight at room temperature, and purified by flash column (DCM / MeOH = 2.0%) to obtain 90 mg of white solid, yield: 29.1%, mp. 190.9 - 191.8 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.85 (1H, s), 10.39 (1H, s), 7.17 (2H, d, J = 7.2 Hz), 7.12 (2H, d, J = 7.2 Hz), 5.99 (1H, s), 2.35 (3H, s), 2.28 (3H, s), 2.19 (3H, s), 1.96 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 151.83, 146.34, 138.24, 131.23, 130.37×2, 118.06×2, 90.57, 21.90, 20.76, 14.34, 11.06; MS(ESI+) m / z 310 [M+H] + .

[0213] Example 22 2-(3-Methyl-5-p-chlorophenylamino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-8-47)

[0214]

[0215] The raw materials LSL-8-10 (185 mg) and N-acetylaceto-p-chloroaniline (211 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.0%) to obtain 90 mg of white solid, yield: 29.1%, mp. 213.9 - 214.4 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.12 (1H, s), 10.80 (1H, s), 7.39 (2H, d, J = 7.2 Hz), 7.25 (2H, d, J = 7.2 Hz), 6.13 (1H, s), 2.34 (3H, s), 2.16 (3H, s), 1.95 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 151.73, 145.41, 139.55, 129.77×2, 125.63, 119.31×2, 91.78, 21.75, 14.06, 11.22; MS(ESI+) m / z 330 [M+H] +.

[0216] Example 23 2-(3-Methyl-5-phenylamino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-8-48)

[0217]

[0218] The raw material LSL-8-10 (185 mg) and acetoacetanilide (177 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 1.5%) to obtain 85 mg of white solid, yield: 28.8%, mp. 272.1 - 272.5 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.95 (1H, s), 10.53 (1H, s), 7.34 - 7.39 (2H, m), 7.20 - 7.25 (2H, m), 6.99 - 7.02 (1H, m), 6.08 (1H, s), 2.36 (3H, s), 2.21 (3H, s), 1.96 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 151.95, 145.89, 140.72, 129.99×2, 122.11, 117.69×2, 91.11, 18.76, 14.37, 11.04; MS(ESI+) m / z 296 [M+H] + .

[0219] Example 24 2-(3-Methyl-5-p-methoxyphenylamino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-12)

[0220]

[0221] The raw material LSL-8-10 (185 mg) and acetoacetanisidine (207 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.0%) to obtain 90 mg of white solid, yield: 27.7%, mp. 172.2 - 172.9 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.75 (1H, s), 10.09 (1H, s), 7.18 (2H, d, J = 8.0 Hz), 6.94 (2H, d, J = 7.2 Hz), 5.83 (1H, s), 3.75 (3H, s), 2.34 (3H, s), 2.18 (3H, s), 1.96 (3H, s);13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 155.24, 151.88, 147.39, 134.06, 120.52 × 2, 115.18 × 2, 89.60, 55.76, 21.90, 14.39, 11.02; MS (ESI+) m / z 326 [M+H] + .

[0222] Example 25 2-(3-Methyl-5-p-cyanophenylamino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-13)

[0223]

[0224] The raw material LSL-8-10 (185 mg) and N-acetylaceto-p-cyanoaniline (202 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 3.2%) to obtain 110 mg of white solid, yield: 34.4%, mp. 238.6 - 239.1 °C. 1 HNMR (CDCl 3 , 500 MHz) δ (ppm) 10.89 (1H, s), 9.61 (1H, s), 7.65 (2H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.5 Hz), 6.00 (1H, s), 2.40 (3H, s), 2.31 (3H, s), 2.11 (3H, s); 13 CNMR (CDCl 3 , 125 MHz) δ (ppm) 153.05, 144.21, 143.87, 133.91 × 3, 133.30, 120.00, 119.16, 116.80, 116.73 × 2, 104.41, 92.49, 21.89, 14.24, 10.94. MS (ESI+) m / z 321 [M+H] + .

[0225] Example 26 2-(3-Methyl-5-o-tolylamino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-16)

[0226]

[0227] The raw materials LSL-8-10 (185 mg) and N-acetylaceto-2-methylaniline (191 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.5%) to obtain 85 mg of white solid, yield: 27.5%, mp. 176.4 - 177.1 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.76 (1H, s), 10.20 (1H, s), 7.39 (1H, d, J = 8.0 Hz), 7.24 (2H, m), 6.94 (1H, t, J = 7.6 Hz), 6.03 (1H, s), 2.35 (3H, s), 2.33 (3H, s), 2.21 (3H, s), 1.96 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 152.15, 148.66, 146.17, 139.22, 131.12, 126.57, 122.16, 116.25, 114.65, 90.67, 21.65, 18.47, 14.41, 11.06; MS(ESI+) m / z 310 [M + H] + .

[0228] Example 275,6-dimethyl-2-(3-methyl-5-o-methoxyphenylamino-1H-pyrazol-1-yl)-4(3H)-pyrimidinone (LSL-12-17)

[0229]

[0230] The raw materials LSL-8-10 (185 mg) and N-acetylaceto-2-methoxyaniline (207 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.5%) to obtain 125 mg of white solid, yield: 38.5%, mp. 225.6 - 226.8 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.73 (1H, s), 10.97 (1H, s), 7.36 (1H, dd, J = 7.2, 1.6 Hz), 7.08 (1H, dd, J = 7.2, 1.6 Hz), 6.92 - 7.00 (2H, m), 6.21 (1H, s), 3.93 (3H, s), 2.38 (3H, s), 2.23 (3H, s), 1.98 (3H, s); 13 CNMR (DMSO-d 6, 100 MHz) δ (ppm) 148.00, 145.13, 130.07, 121.50, 114.21, 111.30, 91.11, 91.08, 56.22, 21.71, 14.15, 11.04; MS(ESI+) m / z 326 [M+H] + .

[0231] Example 28 2-(3-Methyl-5-(3,5-dimethylphenyl)amino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-20)

[0232]

[0233] The raw material LSL-8-10 (185 mg) and N-acetylaceto-3,5-dimethylaniline (205 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.5%) to obtain 120 mg of white solid, yield: 37.1%, mp. 173.9 - 174.5 °C. 1 1H NMR(CDCl 3 , 400 MHz) δ (ppm) 10.11(1H, s), 6.75(2H, s), 6.68(1H, s), 5.79(1H, s), 2.33(3H, s), 2.31(6H, s), 2.22(3H, s), 2.05(3H, s); 13 13C NMR(CDCl 3 , 100 MHz) δ (ppm) 161.87, 158.29, 153.06, 146.85, 146.27, 140.06, 139.34×2, 124.51, 116.11, 115.94, 90.20, 21.90, 21.49×2, 14.19, 10.89; MS(ESI+) m / z 324 [M+H] + .

[0234] Example 29 2-(3-Methyl-5-(4-trifluoromethylphenyl)amino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-22)

[0235]

[0236] The raw material LSL-8-10 (185 mg) and N-acetylaceto-p-trifluoroaniline (245 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.5%) to obtain 50 mg of white solid, yield: 13.8%, mp. 226.3 - 226.5 °C. 1 1H NMR(CDCl3 , 600 MHz) δ (ppm) 10.63 (1H, s), 7.57 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.4 Hz), 5.90 (1H, s), 2.34 (3H, s), 2.25 (3H, s), 2.05 (3H, s); 13 C NMR (CDCl 3 , 150 MHz) δ (ppm) 153.03, 146.16, 145.14, 143.07, 126.88 (q, J = 3.75 Hz), 125.14, (123.99, 123.77, 123.55, 123.34), 116.84×2, 116.53×2, 91.57, 21.82, 14.20, 10.89; MS (ESI+) m / z 364 [M + H] + .

[0237] Example 30 2-(3-Methyl-5-(p-fluorophenylamino)-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-23)

[0238]

[0239] The raw material LSL-8-10 (185 mg) and N-acetylaceto-p-fluoroaniline (195 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.0%) to obtain 94 mg of white solid, yield: 30.3%, mp. 190.6 - 191.8 °C. 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.94 (1H, s), 10.31 (1H, s), 7.24 - 7.27 (2H, m), 7.16 - 7.21 (2H, m), 5.98 (1H, s), 2.35 (3H, s), 2.19 (3H, s), 1.97 (3H, s); 13 C NMR (DMSO-d 6 , 101 MHz) δ (ppm) 158.97, 156.60, 151.76, 149.24, 146.33, 137.30, 119.90 (C-F, J = 32 Hz), 116.61×2, 116.39×2, 114.07, 90.54, 21.88, 14.39, 11.00; MS (ESI+) m / z 314 [M + H] + .

[0240] Example 3 12-(3-Methyl-5-(2,4-dichlorophenyl)amino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-28)

[0241]

[0242] The raw material LSL-8-10 (185 mg) and N-acetylaceto-p-chloroaniline (246 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.3%) to obtain 229 mg of white solid, yield: 63.1%, mp. 224.4 - 224.8 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.95 (1H, s), 10.92 (1H, s), 7.71 (1H, d, J = 1.6 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.41 (1H, dd, J = 1.6, 8.4 Hz), 6.25 (1H, s), 2.36 (3H, s), 2.24 (3H, s), 1.97 (3H, s); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 151.94, 143.91, 136.65, 129.51, 128.82, 125.29, 125.13, 122.27, 117.59, 92.48, 21.70, 14.41, 11.01; MS(ESI+) m / z 364 [M + H] + .

[0243] Example 32 2-(3-Methyl-5-(4-bromophenyl)amino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-30)

[0244]

[0245] The raw material LSL-8-10 (185 mg) and N-acetylaceto-p-bromoaniline (256 mg) were reacted for 3 hours and purified by flash column (DCM / MeOH = 2.0%) to obtain 120 mg of white solid, yield: 32.2%, mp. 231.9 - 232.4 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.96 (1H, s), 10.51 (1H, s), 7.51 (2H, d, J = 7.2 Hz), 7.20 (2H, d, J = 7.2 Hz), 6.10 (1H, s), 2.37 (3H, s), 2.22 (3H, s), 1.98 (3H, s);13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 165.91, 151.69, 145.18, 140.18, 138.76, 132.60×2, 132.08, 121.46, 119.52×2, 113.10, 91.70, 21.91, 14.40, 11.00; MS (ESI+) m / z 374 [M+H] + .

[0246] Example 33 2-(3-Methyl-5-(4-hydroxyphenylamino)-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-33)

[0247]

[0248] The raw material LSL-8-10 (185 mg) and N-acetylaceto-p-hydroxyaniline (193 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 3.0%) to obtain 110 mg of white solid, yield: 35.4%, mp. 241.5 - 242.0 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.81 (1H, s), 9.95 (1H, s), 9.24 (1H, s), 7.07 (2H, d, J = 8.4 Hz), 6.76–6.79 (2H, m), 5.74 (1H, s), 2.33 (3H, s), 2.16 (3H, s), 1.96 (3H, s); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 163.61, 153.51, 151.94, 147.91, 132.49, 121.11×2, 116.38×2, 89.20, 21.92, 14.39, 11.02; MS (ESI+) m / z 312 [M+H] + .

[0249] Example 34 2-(3-Methyl-5-(3-methyl-4-cyanophenyl)amino)-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-34)

[0250]

[0251] The raw materials LSL-8-10 (185 mg) and N-acetoacetyl-3-methyl-4-cyanoaniline (216 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.5%) to obtain 125 mg of white solid, yield: 37.4%, mp. 236.8 - 237.4 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.12 (1H, s), 10.81 (1H, s), 7.66 (1H, d, J = 8.4 Hz), 7.17 (1H, d, J = 1.2 Hz), 7.11 (1H, dd, J = 8.4, 1.2 Hz), 6.31 (1H, s), 2.47 (3H, s), 2.37 (3H, s), 2.24 (3H, s), 1.97 (3H, s); 13 CNMR (DMSO-d 6 , 101 MHz) δ (ppm) 151.48, 149.58, 144.58, 143.89, 143.50, 134.49, 119.04, 117.24, 114.53, 114.13, 103.34, 93.85, 21.90, 20.57, 14.40, 10.98; MS(ESI+) m / z 335 [M+H] + .

[0252] Example 35 2-(3-Methyl-5-(3-fluoro-4-cyanophenyl)amino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-35)

[0253]

[0254] The raw materials LSL-8-10 (185 mg) and N-acetoacetyl-3-fluoro-4-cyanoaniline (220 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 2.5%) to obtain 101 mg of white solid, yield: 30%, mp. 253.5 - 254.6 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.32 (1H, s), 10.85 (1H, s), 7.78 (1H, t, J = 8.4 Hz), 7.22 (1H, d, J = 12.0 Hz), 7.12 (1H, d, J = 8.4 Hz), 6.39 (1H, s), 2.37 (3H, s), 2.24 (3H, s), 1.99 (3H, s); 13 CNMR (DMSO-d 6, 101 MHz) δ (ppm) 165.68, 163.17, 151.20, 147.50, 147.40, 142.29, 135.09, 115.21, 113.31, 103.04, 102.80, 95.50, 90.72, 90.57, 21.86, 14.37, 10.94; MS(ESI+) m / z 339 [M + H] + .

[0255] Example 36 2-(3-Methyl-5-((5-nitrothiazol-2-yl)amino)-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-40)

[0256]

[0257] The raw material LSL-8-10 (185 mg) and 1-(5-nitrothiazol-2-yl)pentane-2,4-dione (229 mg) were reacted for 3 hours, and purified by flash column (DCM / MeOH = 4.0%) to obtain 100 mg of white solid, yield: 29.0%, mp. 169.3 - 170.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.92 (1H, s), 8.85 (1H, s), 8.39 (1H, s), 6.13 (1H, s), 2.23 (3H, s), 1.93 (3H, s), 1.24 (3H, s); 13 13C NMR (DMSO-d 6 , 101 MHz) δ (ppm) 174.14, 151.27, 149.78, 147.96, 130.15, 115.08, 22.00, 14.67, 11.18; MS(ESI+) m / z 314 [M + H] + .

[0258] Example 37 2-(3-Methyl-5-methylamino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-31)

[0259]

[0260] The raw material LSL-8-11 (219 mg) and methyl iodide (197 mg) were purified by flash column (DCM / MeOH = 3.0%) to obtain 40 mg of white solid, yield: 17.2%, mp. 220.5 - 221.6 °C. 1 1H NMR (DMSO-d 6, 500 MHz) δ (ppm) 9.52 (1H, s), 7.89 (1H, s), 5.13 (1H, s), 3.12 (3H, s), 3.07 (3H, s), 2.33 (3H, s), 2.13 (3H, s); 13 C NMR (DMSO-d 6 , 125 MHz) δ (ppm) 163.62, 158.52, 156.33, 155.59, 140.39, 102.79, 82.86, 30.23, 19.07, 13.98, 13.87; MS (ESI+) m / z 234 [M + H] + .

[0261] Example 38 2-(3-Methyl-5-ethylamino-1H-pyrazol-1-yl)-5,6-dimethyl-4(3H)-pyrimidinone (LSL-12-42)

[0262]

[0263] Starting material LSL-8-11 (219 mg) and iodoethane (218 mg) were separated and purified by flash column (DCM / MeOH = 3.0%) to obtain 50 mg of white solid, yield: 14.4%, mp. 241 - 243 °C. 1 1H NMR (DMSO-d 6 , 500 MHz) δ (ppm) 10.88 (1H, s), 7.85 (1H, s), 5.15 (1H, s), 3.50 (2H, q, J = 6.0 Hz), 3.12 (3H, s), 2.32 (3H, s), 2.14 (3H, s), 1.28 (3H, t, J = 6.0 Hz); 13 C NMR (DMSO-d 6 , 125 MHz) δ (ppm) 163.62, 157.81, 156.33, 155.59, 140.39, 102.79, 83.68, 39.47, 19.07, 14.27, 13.98, 13.86; MS (ESI+) m / z 248 [M + H] + .

[0264] Example 39 2-(5-(Hexylamino)-3-methyl-1H-pyrazol-1-yl)-5,6-dimethylpyrimidin-4(3H)-one (LSL-12-43)

[0265]

[0266] Starting materials LSL-8-11 (219 mg) and iodohexane (311 mg) were separated and purified by flash column (DCM / MeOH = 3.0%) to obtain 120 mg of white solid, yield: 39.6%, mp. 290.2 - 291.6 °C. 1 1H NMR (DMSO-d 6 , 500 MHz) δ (ppm) 6.61 (2H, s), 5.24 (1H, s), 4.35 (2H, t, J = 6.4 Hz), 2.40 (3H, s), 2.07 (6H, s), 1.70–1.79 (2H, m), 1.40–1.48 (2H, m), 1.28–1.38 (4H, m), 0.88 (3H, t, J = 6.4 Hz); 13 13C NMR (DMSO-d 6 , 125 MHz) δ (ppm) 167.89, 165.45, 154.54, 150.69, 150.23, 110.31, 88.68, 67.06, 31.38, 28.63, 25.61, 22.49, 21.98, 14.47, 14.34, 10.40; MS (ESI+) m / z 304 [M+H] + .

[0267] Example 40 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)acetamide (LSL-8-46)

[0268]

[0269] Acetyl chloride (236 mg, 3 mmol) was reacted with LSL-8-11 and separated and purified by flash column (DCM / MeOH = 2%) to obtain 104 mg of white solid, yield: 40%, mp. 199.4–201.0 °C. 1 1H NMR (CDCl 3 , 400 MHz) δ (ppm) 11.57 (1H, s), 10.25 (1H, s), 6.73 (1H, s), 2.37 (3H, s), 2.30 (3H, s), 2.28 (3H, s), 2.11 (3H, s); 13 13C NMR (CDCl 3 , 100 MHz) δ (ppm) 166.43, 161.30, 157.50, 153.35, 145.83, 140.45, 116.95, 98.65, 24.40, 21.89, 14.14, 10.94; MS (ESI+) m / z 262 [M+H] + .

[0270] Example 41 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (K-2-58)

[0271]

[0272] Benzoyl chloride (420 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2%) to obtain 70 mg of a white solid, yield: 47%, mp. 249.8–251.0 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 12.66 (1H, s), 8.01 (2H, d, J = 7.50 Hz), 7.59 (1H, t, J = 6.48 Hz), 7.52 (2H, t, J = 7.08 Hz), 6.86 (1H, s), 2.37 (3H, s), 2.19 (3H, s), 2.01 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 158.77, 157.45, 136.26, 134.32, 128.78, 127.75, 124.06, 122.62, 99.99, 94.02, 24.91, 16.74, 6.25; MS (ESI+) m / z 324 [M+H] + .

[0273] Example 42 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)propanamide (K-2-64)

[0274]

[0275] Propionyl chloride (276 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2.4%) to obtain 58 mg of a white solid, yield: 40%, mp. 167.5–168.6 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 12.73 (1H, s), 6.72 (1H, s), 2.50 (2H, q), 2.30 (3H, s), 1.90 (6H, s), 1.32 (3H, t, J = 7.50 Hz); 13 13C NMR (DMSO-d 6, 150 MHz) δ (ppm) 172.76, 167.03, 152.51, 150.73, 145.45, 136.95, 102.38, 92.46, 29.00, 18.01, 14.03, 11.72, 9.01; MS(ESI+) m / z 276 [M + H]+.

[0277] Example 43 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl) tert-butylamide (K-2-65)

[0278]

[0279] Isobutyryl chloride (318 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 2.2%) to obtain 60 mg of white solid, yield: 41%, mp. 157.7–158.6 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 12.71 (1H, s), 6.74 (1H, s), 2.65 (1H, dd, J = 13.86, 6.96 Hz), 2.31 (3H, s), 1.88 (3H, s), 1.84 (3H, s), 1.34 (3H, s), 1.33 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 172.69, 161.35, 157.51, 153.38, 145.89, 140.51, 116.89, 98.62, 52.38, 25.66, 21.81, 14.14, 12.07, 10.94; MS(ESI+) m / z 290 [M + H] + .

[0280] Example 44 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-methylbenzamide (K-2-71)

[0281]

[0282] 4-Methylbenzoyl chloride (462 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.8%) to obtain 75 mg of white solid, yield: 44%, mp. 249.9–250.4 °C. 1 1H NMR (DMSO-d 6, 600 MHz) δ (ppm) 12.37 (1H, s), 10.61 (1H, s), 7.92 (2H, d, J = 9.72 Hz), 7.36 (2H, d, J = 9.36 Hz), 6.88 (1H, s), 2.49 (3H, s), 2.43 (3H, s), 2.34 (3H, s), 2.13 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 166.96, 153.53, 142.77, 131.60, 129.47×2, 128.09×2, 104.21, 95.45, 21.58, 19.76, 13.66, 13.01; MS (ESI+) m / z 338 [M+H] + .

[0283] Example 45 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-methylbenzamide (K-2-72)

[0284]

[0285] 3-Methylbenzoyl chloride (462 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.9%) to obtain 80 mg of a white solid, yield: 47%, mp. 186.3–187.4 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 12.21 (1H, s), 10.01 (H, s), 7.72 (1H, t, J = 5.21 Hz), 7.64 (1H, s), 7.45 (2H, d, J = 5.01 Hz), 6.75 (1H, s), 2.86 (3H, s), 2.43 (3H, s), 2.40 (3H, s), 2.16 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 167.23, 163.98, 154.02, 151.98, 141.10, 140.25, 137.01, 133.81, 129.88, 128.02, 127.45, 126.50, 103.88, 95.01, 22.13×2, 14.50, 12.01; MS (ESI+) m / z 338 [M+H] + .

[0286] Example 46 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-chlorobenzamide (K-2-74)

[0287]

[0288] 2-Chlorobenzoyl chloride (525 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to give 75 mg of a white solid, yield: 40%, mp. 203.1–204.2 °C. 1 HNMR(DMSO-d 6 , 600 MHz) δ (ppm) 7.77–7.71 (1H, m), 7.47–7.39 (2H, m), 7.27 (1H, m), 6.56 (1H, s), 2.33 (3H, s), 2.28 (3H, s), 2.01 (3H, s); 13 CNMR(DMSO-d 6 , 150 MHz) δ (ppm) 167.03, 163.37, 152.51, 150.73, 145.45, 140.45, 134.05, 134.02, 131.12, 129.52, 128.12, 127.58, 102.38, 94.49, 18.01, 14.13, 11.72; MS(ESI+) m / z 358 [M+H] + .

[0289] Example 47 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3,5-dimethylbenzamide (K-2-75)

[0290]

[0291] 3,5-Dimethylbenzoyl chloride (462 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to give 70 mg of a white solid, yield: 40%, mp. 259.6–260.1 °C. 1 HNMR(DMSO-d 6 , 600 MHz) δ (ppm) 12.33 (1H, s), 7.64 (2H, s), 7.30 (1H, s), 6.89 (1H, s), 2.44 (9H, s), 2.33 (3H, s), 2.12 (3H, s); 13 CNMR(DMSO-d 6, 150 MHz) δ (ppm) 164.83, 145.45, 137.98, 138.23 × 2, 135.11, 133.98, 133.62, 130.02, 127.19, 126.20 × 2, 114.21, 107.19, 89.50, 21.26, 21.15, 12.19, 12.05, 10.85; MS(ESI+) m / z 352 [M + H] + .

[0292] Example 48 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-chlorobenzenesulfonamide (K-2-76)

[0293]

[0294] 4-Chlorobenzenesulfonyl chloride (633 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2.6%) to give 65 mg of a white solid, yield: 33%, mp. 243.4–244.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.66 (1H, s), 10.13 (1H, s), 8.90 (1H, s), 7.72–7.66 (2H, m), 7.64–7.58 (2H, m), 6.22 (1H, s), 2.97 (3H, s), 2.20 (3H, s), 2.11 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 165.02, 154.20, 152.46, 141.03, 133.95 × 2, 133.22, 130.15 × 2, 103.89, 91.00, 20.75, 13.65, 12.01; MS(ESI+) m / z 374 [M + H] + .

[0295] Example 49 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-nitrobenzamide (K-2-78)

[0296]

[0297] 4-Nitrobenzoyl chloride (555 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2.4%) to give 75 mg of a yellow solid, yield: 41%, mp. 380.1–381.2 °C. 1 HNMR (DMSO-d 6 , 600 MHz) δ (ppm) 8.44 (2H, d, J = 12.02 Hz), 8.34 (2H, d, J = 12.53 Hz), 6.62 (1H, s), 2.22 (3H, s), 2.16 (3H, s), 1.90 (3H, s); 13 CNMR (DMSO-d 6 , 150 MHz) δ (ppm) 170.28, 161.03, 157.57, 155.12, 149.74, 148.43, 142.50, 140.41, 129.45, 124.24, 113.63, 96.32, 21.76, 14.47, 11.95; MS (ESI+) m / z 369 [M+H] + .

[0298] Example 50 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-chloro-4-fluorobenzamide (K-2-79)

[0299]

[0300] 3-Chloro-4-fluorobenzoyl chloride (579 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to give 65 mg of a white solid, yield: 35%, mp. 340.5–341.6 °C. 1 HNMR (DMSO-d 6 , 600 MHz) δ (ppm) 8.27 (2H, m), 7.59 (1H, t, J = 8.70 Hz), 6.58 (1H, s), 2.20 (3H, s), 2.15 (3H, s), 1.89 (3H, s); 13 CNMR (DMSO-d 6 , 150 MHz) δ (ppm) 170.82, 160.47, 158.98, 157.25, 155.56, 148.11, 141.85, 132.26, 130.44, 129.02, 120.92, 117.71, 113.54, 96.07, 21.73, 14.45, 12.02; MS (ESI+) m / z 376 [M+H] + .

[0301] Example 51 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-methoxybenzamide (K-2-80)

[0302]

[0303] 3-Methoxybenzoyl chloride (510 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2.1%) to give 85 mg of a white solid, yield: 48%, mp. 379.0–380.1 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 14.94 (1H, s), 7.75 (1H, d, J = 6.00 Hz), 7.56 (1H, t, J = 18.00 Hz), 7.48 (1H, t, J = 7.98 Hz), 7.20 (1H, dd, J = 8.22, 2.52 Hz), 6.66 (1H, s), 3.90 (3H, s), 2.24 (3H, s), 2.18 (3H, s), 1.89 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 162.54, 162.52, 160.13, 155.94, 149.92, 148.62, 141.13, 135.47, 130.47, 119.98, 118.86, 113.64, 112.64, 96.30, 55.97, 21.58, 14.37, 12.05; MS (ESI+) m / z 354 [M+H] + .

[0304] Example 52 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-chloromethylbenzamide (K-2-81)

[0305]

[0306] 3-Chloromethylbenzoyl chloride (567 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to give 80 mg of a white solid, yield: 43%, mp. 310.9–311.4 °C. 1 1H NMR (DMSO-d 6, 600 MHz) δ (ppm) 14.94 (1H, s), 8.38 (1H, s), 8.14 (1H, d, J = 7.80 Hz), 7.71 (1H, d, J = 7.68 Hz), 7.58 (1H, t, J = 7.68 Hz), 6.59 (1H, s), 4.98 (3H, s), 2.21 (3H, s), 2.16 (3H, s), 1.90 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 161.91, 155.21, 148.45, 141.17, 139.18, 134.16, 133.01, 129.86, 128.23, 127.87, 113.59, 96.10, 45.97, 21.65, 14.43, 11.97; MS (ESI+) m / z 372 [M + H] + .

[0307] Example 53 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-thiophene-2-carboxamide (K-2-82)

[0308]

[0309] 2-Thiophenecarbonyl chloride (438 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.5%) to obtain 66 mg of a white solid, yield: 40%, mp. 324.8–325.4 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 15.70 (1H, s), 8.20 (1H, d, J = 3.3 Hz), 7.88 (1H, d, J = 3.96 Hz), 7.23 (1H, d, J = 3.78 Hz), 6.48 (1H, s), 2.18 (3H, s), 2.14 (3H, s), 1.88 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 170.89, 157.87, 157.44, 155.69, 148.02, 141.35, 140.54, 132.47, 129.39, 128.89, 113.46, 95.60, 21.74, 14.42, 12.01; MS (ESI+) m / z 330 [M + H] + .

[0310] Example 54 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)piperazine-1-carboxamide (K-2-83)

[0311]

[0312] 1-Piperidinecarbonyl chloride (441 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.5%) to obtain 71 mg of a white solid, yield: 43%, mp. 183.2–184.1 °C. 1 HNMR (DMSO-d 6 , 600 MHz) δ (ppm) 6.58 (2H, s), 5.23 (1H, s), 3.56 (2H, s), 3.45 (2H, s), 2.51 (3H, s), 2.10 (3H, s), 2.06 (3H, s), 1.59 (6H, m); 13 CNMR (DMSO-d 6 , 150 MHz) δ (ppm) 170.14, 164.18, 154.49, 150.94, 150.81, 150.77, 115.23, 88.63, 45.99, 45.24, 26.03, 25.51, 24.02, 22.56, 14.38, 10.96; MS(ESI+) m / z 331 [M+H] + .

[0313] Example 55 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-(4-methoxyphenyl)acetamide (K-2-84)

[0314]

[0315] 4-Methoxyphenylacetyl chloride (552 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.9%) to obtain 65 mg of a white solid, yield: 35%, mp. 175.4–176.5 °C. 1 HNMR (DMSO-d 6 , 600 MHz) δ (ppm) 14.94 (1H, s), 7.72 (1H, s), 7.36 (1H, d, J = 1.23 Hz), 6.84–6.78 (2H, m), 6.55 (1H, s), 3.82 (3H, s), 3.71 (2H, d, J = 1.25 Hz), 2.25 (3H, s), 2.19 (3H, s), 1.87 (3H, s);13 CNMR (DMSO-d 6 , 150 MHz) δ (ppm) 167.53, 164.09, 158.39, 153.84, 152.51, 140.92, 136.95, 129.16, 127.67, 113.41, 104.07, 92.46, 55.35, 46.46, 21.02, 14.03, 11.83; MS (ESI+) m / z 368 [M+H] + .

[0316] Example 56 5-Chloro-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)thiophene-2-carboxamide (K-2-85)

[0317]

[0318] 5-Chloro-2-thiophenecarbonyl chloride (543 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2.0%) to obtain 70 mg of a white solid, yield: 38%, mp. 370.2–371.5 °C. 1 HNMR (DMSO-d 6 , 600 MHz) δ (ppm) 7.97 (1H, d, J = 4.02 Hz), 7.25 (1H, d, J = 4.02 Hz), 6.45 (1H, s), 2.17 (3H, s), 2.15 (3H, s), 1.89 (3H, s); 13 CNMR (DMSO-d 6 , 150 MHz) δ (ppm) 128.87, 128.73, 113.58, 99.99, 95.97, 21.79, 14.47, 11.79; MS (ESI+) m / z 364 [M+H] + .

[0319] Example 57 2-Chloro-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)nicotinamide (K-2-86)

[0320]

[0321] 2-Chloro-3-pyridinecarbonyl chloride (528 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.6%) to obtain 75 mg of a white solid, yield: 42%, mp. 359.2–360.1 °C. 1 HNMR (DMSO-d6 , 600 MHz) δ (ppm) 12.48 (1H, s), 8.61 (1H, dd, J = 4.74, 1.8 Hz), 8.26 (1H, d, J = 6.06), 7.63 (1H, dd, J = 7.56, 4.8 Hz), 6.77 (1H, s), 2.27 (3H, s), 2.20 (3H, s), 1.98 (3H, s); 13 C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 161.41, 152.25, 146.97, 140.52, 140.50, 139.98, 139.71, 139.64, 139.55, 131.59, 123.96, 98.62, 21.66, 14.26, 10.86; MS (ESI+) m / z 359 [M + H] + .

[0322] Example 58 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-methylbenzamide (K-2-87)

[0323]

[0324] 2-Methylbenzoyl chloride (462 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to obtain 72 mg of a white solid, yield: 43%, mp. 358.4–360.1 °C. 1 H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 14.37 (1H, s), 7.70 (1H, d, J = 7.08 Hz), 7.44 (1H, t, J = 8.64 Hz), 7.33 (2H, m), 6.62 (1H, s), 2.53 (3H, s), 2.20 (3H, s), 2.03 (3H, s), 1.81 (3H, s). 13 C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 172.10, 164.88, 156.21, 156.17, 147.72, 140.62, 137.18, 135.60, 131.84, 131.00, 128.11, 126.54, 113.30, 95.91, 21.47, 20.66, 14.41, 12.01. MS (ESI+) m / z 338 [M + H] + .

[0325] Example 59 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-nitrobenzamide (K-2-88)

[0326]

[0327] 3-Nitrobenzoyl chloride (555 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.9%) to obtain 70 mg of a yellow solid, yield: 38%, mp. 345.1–346.3 °C. 1 HNMR(DMSO-d 6 , 500 MHz) δ (ppm) 12.72 (1H, s), 8.79 (1H, s), 8.50 (1H, d, J = 8.15 Hz), 8.43 (1H, d, J = 7.75 Hz), 7.80 (1H, t, J = 8.00 Hz), 6.92 (1H, s), 2.46 (3H, s), 2,35 (3H, s), 2.11 (3H, s); 13 CNMR(DMSO-d 6 , 150 MHz) δ (ppm) 167.20, 153.53, 147.80, 141.06, 131.13, 129.59, 125.19, 123.23, 104.21, 95.45, 19.76, 13.66, 13.01; MS(ESI+) m / z 369 [M+H] + .

[0328] Example 60 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)pentanediamide (K-2-89)

[0329]

[0330] Pivaloyl chloride (462 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.5%) to obtain 66 mg of a white solid, yield: 43%, mp. 240.4–241.1 °C. 1 HNMR(DMSO-d 6 , 500 MHz) δ (ppm) 11.84 (1H, s), 6.64 (1H, s), 2.34 (3H, s), 2.23 (3H, s), 1.98 (3H, s), 1.28 (9H, s); 13 CNMR(DMSO-d 6, 150 MHz) δ (ppm) 175.16, 97.69, 27.55×3, 14.28×2, 11.02; MS(ESI+) m / z 304 [M+H] + .

[0331] Example 61 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-ethylbenzamide (K-2-90)

[0332]

[0333] 4-Ethylbenzoyl chloride (504 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.8%) to obtain 70 mg of white solid, yield: 40%, mp. 295.1–296.2 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 8.04 (2H, d, J = 7.86 Hz), 7.41 (2H, d, J = 8.10 Hz), 6.66 (1H, s), 2.71 (2H, dd, J = 15.18, 7.56 Hz), 2.24 (3H, s), 2.22 (3H, s), 1.92 (3H, s), 1.23 (3H, t, J = 7.56 Hz); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 162.59, 157.22, 153.22, 148.98, 141.07, 131.31, 128.74, 127.97, 102.31, 96.58, 28.53, 21.39, 15.67, 14.40, 11.67; MS(ESI+) m / z 352 [M+H] + .

[0334] Example 62 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3,5-dichlorobenzamide (K-2-91)

[0335]

[0336] 3,5-Dichlorobenzoyl chloride (627 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to obtain 70 mg of white solid, yield: 40%, mp. 325.6–326.7 °C. 1 1H NMR (DMSO-d 6, 600 MHz) δ (ppm) 8.09 (2H, d, J = 7.86 Hz), 7.86 (1H, s), 6.63 (1H, s), 2.21 (3H, s), 2.19 (3H, s), 1.90 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 169.40, 161.62, 160.60, 154.37, 148.73, 143.04, 138.53, 135.28×2, 131.54, 126.60×2, 113.67, 96.68, 21.74, 14.47, 11.89; MS (ESI+) m / z 392 [M + H] + .

[0337] Example 63 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-naphthamide (K-2-92)

[0338]

[0339] 2-Naphthoyl chloride (570 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.9%) to give 68 mg of a white solid, yield: 37%, mp. 298.0–298.9 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 8.37 (1H, d, J = 1.65 Hz), 8.09 (1H, dd, J = 7.60, 1.58 Hz, 1H), 7.94 (1H, d, J = 7.36 Hz), 7.88 (1H, d, J = 7.43 Hz), 7.64–7.60 (2H, m), 7.55–7.51 (1H, m), 6.61 (1H, s), 2.20 (3H, s), 2.11 (3H, s), 1.89 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 166.59, 164.09, 152.51, 140.45, 133.50, 133.40, 132.19, 129.44, 127.84, 127.57, 127.00, 126.11, 124.04, 104.07, 94.49, 21.02, 14.03, 11.83; MS (ESI+) m / z 374 [M + H] + .

[0340] Example 64 4-Chloro-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-nitrobenzamide (K-2-93)

[0341]

[0342] 4-Chloro-3-nitrobenzoyl chloride (660 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.8%) to obtain 80 mg of a yellow solid, yield: 40%, mp. 301.0–302.4 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 8.63 (1H, d, J = 1.96 Hz), 8.47 (1H, dd, J = 8.36, 1.80 Hz), 7.94 (1H, d, J = 8.40 Hz), 6.63 (1H, s), 2.22 (3H, s), 2.20 (3H, s), 1.91 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 168.63, 160.49, 153.62, 149.21, 148.40, 143.42, 135.69, 132.58, 132.47, 128.33, 124.89×2, 113.72, 96.81, 21.73, 14.47, 11.72; MS (ESI+) m / z 403 [M+H] + .

[0343] Example 65 N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)acrylamide (K-2-94)

[0344]

[0345] Acryloyl chloride (270 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.5%) to obtain 60 mg of a white solid, yield: 44%, mp. 151.2–152.9 °C. 1 HNMR (DMSO-d 6 , 600 MHz) δ (ppm) 8.09 (2H, d, J = 7.86 Hz), 7.86 (1H, s), 6.63 (1H, s), 2.21 (3H, s), 2.19 (3H, s), 1.90 (3H, s); 13 CNMR (DMSO-d 6, 150 MHz) δ (ppm) 164.09, 163.79, 153.84, 152.51, 140.92, 139.38, 127.67, 126.24, 104.07, 93.78, 21.02, 14.03, 11.83; MS(ESI+) m / z 274 [M+H] + .

[0346] Example 66 N-(1-(4,5-Dimethyl-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)methacrylamide (K-2-95)

[0347]

[0348] Methacryloyl chloride (312 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.6%) to give 58 mg of a white solid, yield: 40%, mp. 150.2–151.0 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 8.09 (2H, d, J = 7.86 Hz), 7.86 (1H, s), 6.63 (1H, s), 2.21 (3H, s), 2.19 (3H, s), 1.90 (3H, s); 13 13C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 166.78, 165.19, 154.04, 152.62, 141.12, 139.45, 137.78, 124.10, 103.96, 94.01, 20.98, 18.01, 13.86, 11.75; MS(ESI+) m / z 288 [M+H] + .

[0349] Example 67 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)but-2-enamide (K-2-97)

[0350]

[0351] Crotonoyl chloride (312 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to give 62 mg of a white solid, yield: 43%, mp. 190.1–191.3 °C. 1 1H NMR (DMSO-d 6, 400 MHz) δ (ppm) 12.49 (1H, s), 11.84 (1H, s), 6.94–6.87 (1H, m), 6.66 (1H, s), 6.17 (1H, d, J=14.48 Hz), 2.38 (3H, s), 2.23 (3H, s), 1.99 (3H, s), 1.90 (3H, s); 13 C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 161.89, 142.45×2, 140.56, 125.84, 97.94, 18.09×2, 14.26, 11.00; MS (ESI+) m / z 288 [M+H] + .

[0352] Example 68 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-1-benzenesulfonamide (K-2-98)

[0353]

[0354] Benzenesulfonyl chloride (570 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to obtain 68 mg of white solid, yield: 36%, mp. 145.1–145.5 °C. 1 1H NMR (DMSO-d 6 , 600 MHz) δ (ppm) 12.59 (1H, s), 11.16 (1H, s), 8.60 (1H, s), 7.36 (4H, d, J=4.85 Hz), 7.26–7.22 (1H, m), 6.13 (1H, s), 4.66 (2H, s), 2.23 (3H, s), 2.03 (3H, s), 1.96 (3H, s); 13 C NMR (DMSO-d 6 , 150 MHz) δ (ppm) 164.09, 153.84, 152.51, 140.92, 130.80, 129.67, 129.53, 128.47, 128.18, 104.07, 93.71, 60.07, 20.98, 15.12, 12.01; MS (ESI+) m / z 374 [M+H] + .

[0355] Example 69 3,4-Dichloro-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (K-3-1)

[0356]

[0357] 3,4-Dichlorobenzoyl chloride (627 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 2.2%) to obtain 75 mg of white solid, yield: 38%, mp. 291.3–292.4 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 8.13 (1H, d, J = 1.96 Hz), 7.95 (1H, dd, J = 8.36, 2.00 Hz), 7.87 (1H, d, J = 8.36 Hz), 6.66 (1H, s), 2.28 (3H, s), 2.22 (3H, s), 1.94 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 174.02, 160.61, 156.94, 155.74, 148.53, 140.45, 135.55, 134.79, 132.42, 131.78, 129.27, 127.87, 112.91, 96.60, 21.52, 14.40, 11.68; MS (ESI+) m / z 392 [M+H] + .

[0358] Example 70 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)hexanamide (K-3-3)

[0359]

[0360] Hexanoyl chloride (402 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.4%) to obtain 70 mg of white solid, yield: 44%, mp. 179.1–180.5 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.38 (1H, s), 11.67 (1H, s), 6.60 (1H, s), 2.44 (2H, t, J = 7.48 Hz), 2.35 (3H, s), 2.22 (3H, s), 1.98 (3H, s), 1.69–1.61 (2H, m), 1.33–1.29 (4H, m), 0.86 (3H, dd, J = 15, 6.76 Hz); 13 CNMR (DMSO-d 6, 100 MHz) δ (ppm) 211.06, 169.71, 151.30, 140.49, 114.04, 97.80, 42.23, 37.11, 31.21, 24.97, 22.31, 14.30, 14.26, 10.98; MS(ESI+) m / z 318 [M+H] + .

[0361] Example 71 N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl) heptanamide (K-3-6)

[0362]

[0363] Heptanoyl chloride (444 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.4%) to obtain 65 mg of a white solid, yield: 39%, mp. 343.1–344.2 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.73 (1H, s), 6.43 (1H, s), 2.35 (2H, t, J = 7.40 Hz), 2.16 (3H, s), 2.12 (3H, s), 1.84 (3H, s), 1.70–1.62 (2H, m), 1.35–1.26 (6H, m), 0.86 (3H, t, J = 6.84 Hz). 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 172.37, 169.04, 156.30, 156.24, 147.47, 140.47, 113.22, 95.61, 37.55, 31.41, 28.76, 25.34, 22.47, 21.61, 14.37×2, 12.09. MS(ESI+) m / z 332 [M+H] + .

[0364] Example 72 N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl) nonanamide (K-3-8)

[0365]

[0366] Nonanoyl chloride (528 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to obtain 67 mg of a white solid, yield: 37%, mp. 290.1–291.2 °C. 1HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.72 (1H, s), 6.43 (1H, s), 2.34 (2H, t, J = 7.44 Hz), 2.15 (3H, s), 2.11 (3H, s), 1.84 (3H, s), 1.69–1.62 (2H, m), 1.27–1.21 (10H, m), 0.85 (3H, dd, J = 10.80, 5.92 Hz); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 172.27, 169.02, 156.29, 156.24, 147.42, 140.44, 113.19, 95.59, 37.54, 31.70, 29.07, 25.37, 22.55, 22.51, 21.61, 14.41, 14.38, 12.08; MS (ESI+) m / z 360 [M+H] + .

[0367] Example 73 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-2-naphthamide (K-3-9)

[0368]

[0369] 1-Naphthoyl chloride (570 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.9%) to give 69 mg of a white solid, yield: 38%, mp. 335.6–336.4 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 14.66 (1H, s), 8.57 (1H, d, J = 9.28 Hz), 8.14 (1H, d, J = 7.64 Hz), 8.03 (2H, t, J = 9.68 Hz), 7.69–7.6727 (3H, m), 6.74 (1H, s), 2.25 (3H, s), 1.95 (3H, s), 1.81 (3H, s); 13 CNMR (DMSO-d 6, 100 MHz) δ (ppm) 172.16, 167.81, 164.63, 156.06, 148.07, 140.80, 133.98, 131.95, 130.39, 128.97, 128.36, 127.76, 126.97, 126.64, 125.74, 125.40, 113.36, 96.14, 52.74, 21.32, 14.45, 11.94; MS(ESI+) m / z 374 [M + H] + .

[0370] Example 74 3-Chloro-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-nitrobenzamide (K-3-10)

[0371]

[0372] 3-Chloro-4-nitrobenzoyl chloride (660 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 2.0%) to obtain 78 mg of a yellow solid, yield: 39%, mp. 306.7–307.8 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 8.64 (1H, d, J = 1.80 Hz), 8.51 (1H, dd, J = 8.56, 1.84 Hz), 7.92 (1H, d, J = 8.40 Hz), 6.60 (1H, s), 2.21 (3H, s), 2.16 (3H, s), 1.90 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 169.14, 160.46, 157.93, 154.26, 148.82, 148.43, 143.92, 135.97, 132.48, 132.44, 128.11, 124.88, 113.68, 96.47, 21.81, 14.50, 11.86; MS(ESI+) m / z 403 [M + H] + .

[0373] Example 75 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3,4-difluorobenzamide (K-3-13)

[0374]

[0375] 3,4-Difluorobenzoyl chloride (528 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.8%) to obtain 70 mg of white solid, yield: 39%, mp. 336.2–337.7 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 15.91 (1H, s), 8.20–8.15 (1H, m), 8.15–8.10 (1H, m), 7.62 (1H, dd, J = 18.52, 8.44 Hz), 6.59 (1H, s), 2.21 (3H, s), 2.16 (3H, s), 1.89 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 170.82, 160.49, 157.45, 155.60, 152.50, 149.92, 148.13, 141.75, 131.96, 125.43, 118.44, 117.34, 113.55, 96.02, 21.72, 14.45, 12.02; MS (ESI+) m / z 360 [M+H] + .

[0376] Example 76 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-methoxybenzamide (K-3-14)

[0377]

[0378] 4-Methoxybenzoyl chloride (510 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.7%) to obtain 64 mg of white solid, yield: 36%, mp. 311.5–312.1 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.72 (1H, s), 7.95 (2H, d, J = 8.72 Hz), 7.14 (2H, d, J = 8.72 Hz), 6.75 (1H, s), 3.87 (3H, s), 2.40 (3H, s), 2.27 (3H, s), 2.00 (3H, s); 13 CNMR (DMSO-d 6, 100 MHz) δ (ppm) 159.38, 159.00, 158.62, 158.25, 141.12, 129.61, 120.01, 117.14 × 2, 114.79, 114.27 × 2, 111.39, 98.97, 97.70, 56.07, 14.31, 11.04, 11.03; MS(ESI+) m / z 354 [M + H] + .

[0379] Example 773 - chloro - N-(1-(4,5 - dimethyl - 6 - oxo - 1,6 - dihydropyrimidin - 2 - yl)-3 - methyl - 1H - pyrazol - 5 - yl)benzamide (K - 3 - 15)

[0380]

[0381] 3 - Chlorobenzoyl chloride (525 mg, 3 mmol) was reacted with LSL - 8 - 11, and purified by flash column (DCM / MeOH = 1.9%) to obtain 68 mg of white solid, yield: 38%, mp. 356.4–357.1 °C. 1 1H NMR (DMSO - d 6 , 400 MHz) δ (ppm) 15.60 (1H, s), 8.20 (1H, d, J = 7.80 Hz), 8.09 (1H, s), 7.70 (1H, dd, J = 7.92, 1.28 Hz), 7.59 (1H, t, J = 7.84 Hz), 6.62 (1H, s), 2.22 (3H, s), 2.17 (3H, s), 1.89 (3H, s); 13 13C NMR (DMSO - d 6 , 100 MHz) δ (ppm) 171.12, 161.17, 157.02, 155.67, 148.13, 141.35, 136.26, 134.30, 132.33, 131.26, 127.73, 126.46, 113.54, 96.20, 21.68, 14.44, 12.04; MS(ESI+) m / z 358 [M + H] + .

[0382] Example 78N-(1-(4,5 - dimethyl - 6 - oxo - 1,6 - dihydropyrimidin - 2 - yl)-3 - methyl - 1H - pyrazol - 5 - yl)-4 - fluorobenzamide (K - 3 - 16)

[0383]

[0384] 4-Fluorobenzoyl chloride (474 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.8%) to obtain 60 mg of white solid, yield: 35%, mp. 375.6–376.4 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 15.49 (1H, s), 8.27 (2H, dd, J = 8.72, 5.44 Hz), 7.38 (2H, t, J = 8.76 Hz), 6.60 (1H, s), 2.22 (3H, s), 2.17 (3H, s), 1.89 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 171.33, 164.84 (J C-F = 248.28 Hz), 161.39, 157.18, 155.86, 148.06, 141.22, 130.67×2 (J C-F = 9.17 Hz), 130.58 (J C-F = 2.78 Hz), 116.25×2 (J C-F = 21.74 Hz), 113.47, 95.89, 21.66, 14.44, 12.04; MS(ESI+) m / z 342 [M+H] + .

[0385] Example 79 4-Chloro-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (K-3-23)

[0386]

[0387] 4-Chlorobenzoyl chloride (525 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.7%) to obtain 60 mg of white solid, yield: 34%, mp. 275.1–276.5 °C. 1 HNMR (CDCL 3 , 400 MHz) δ (ppm) 12.46 (1H, s), 7.98 (2H, d, J = 8.48 Hz), 7.55 (2H, d, J = 8.56 Hz), 6.89 (1H, s), 2.43 (3H, s), 2.35 (3H, s), 2.14 (3H, s); 13 CNMR (CDCL 3, 100 MHz) δ (ppm) 162.42, 161.21, 157.19, 153.58, 146.04, 140.65, 139.12, 131.73, 129.26 × 2, 128.73 × 2, 117.23, 98.85, 21.80, 14.22, 11.02; MS(ESI+) m / z 358 [M+H] + .

[0388] Example 80 3-Bromo-N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (K-3-24)

[0389]

[0390] 3-Bromobenzoyl chloride (657 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to obtain 70 mg of a white solid, yield: 35%, mp. 372.1–373.2 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 15.65 (1H, s), 8.27 (1H, d, J = 7.92 Hz), 8.21 (1H, s), 7.83 (1H, dd, J = 7.84, 1.28 Hz), 7.52 (1H, t, J = 7.88 Hz), 6.61 (1H, s), 2.21 (3H, s), 2.16 (3H, s), 1.89 (3H, s). 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 170.94, 161.08, 157.11, 155.60, 148.05, 141.41, 136.48, 135.21, 131.49, 130.65, 126.80, 122.73, 113.51, 96.19, 21.74, 14.45, 12.04. MS(ESI+) m / z 402 [M+H] + .

[0391] Example 81 3-Chloro-N-(4-chloro-1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-fluorobenzamide (K-3-30)

[0392]

[0393] 3-Chloro-4-fluorobenzoyl chloride (579 mg, 3 mmol) was reacted with K-3-27, and purified by flash column (DCM / MeOH = 2.1%) to give 75 mg of white solid, yield: 37%, mp. 223.2–224.1 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.55 (1H, s), 10.82 (1H, s), 8.20 (1H, dd, J = 7.08, 2.08 Hz), 7.80 (1H, m), 7.63 (1H, t, J = 8.96 Hz), 2.28 (3H, s), 2.09 (3H, s), 1.96 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 165.42, 163.80, 159.97 (J C-F = 250.99 Hz), 146.90, 134.40, 131.24 (J C-F = 35.10 Hz), 130.89×2, 130.86 (J C-F = 48.70 Hz), 129.72 (J C-F = 8.50 Hz), 123.13, 120.42 (J C-F = 18.01 Hz), 117.85 (J C-F = 21.43 Hz), 113.18, 108.56, 21.63, 12.15, 10.95; MS (ESI+) m / z 410 [M+H] + .

[0394] Example 82 N-(4-Bromo-1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-chloro-4-fluorobenzamide (K-3-31)

[0395]

[0396] 3-Chloro-4-fluorobenzoyl chloride (579 mg, 3 mmol) was reacted with K-3-29, and purified by flash column (DCM / MeOH = 2.1%) to give 76 mg of white solid, yield: 33%, mp. 293.4–295.1 °C. 1 HNMR (DMSO-d 6, 400 MHz) δ (ppm) 8.22 (1H, dd, J = 7.16, 2.00 Hz), 8.11 (1H, m), 7.56 (1H, t, J = 8.92 Hz), 2.21 (3H, s), 2.09 (3H, s), 1.86 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 169.58, 162.04, 160.46 (J C-F = 124.93 Hz), 152.77, 147.28, 139.98, 132.88 (J C-F = 3.21 Hz), 130.81, 129.47 (J C-F = 8.29 Hz), 120.39 (J C-F = 17.82 Hz), 117.56 (J C-F = 21.25 Hz), 114.37, 96.16, 90.13, 21.66, 13.20, 11.77; MS (ESI+) m / z 454 [M + H] + .

[0397] Example 83 N-(4-Chloro-1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-nitrobenzamide (K-3-35)

[0398]

[0399] 4-Nitrobenzoyl chloride (555 mg, 3 mmol) was reacted with K-3-27, and purified by flash column (DCM / MeOH = 2.1%) to obtain 80 mg of a yellow solid, yield: 40%, mp. 304.1–305.8 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.40 (1H, s), 8.37 (2H, d, J = 8.88 Hz), 8.25 (2H, d, J = 8.84 Hz), 2.25 (3H, s), 2.10 (3H, s), 1.92 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 167.56, 163.74, 150.76, 149.78, 146.73, 140.31, 137.16, 129.81×2, 124.13×2, 114.35, 109.97, 105.66, 21.72, 12.21, 11.26; MS (ESI+) m / z 403 [M + H] + .

[0400] Example 84 N-(4-Bromo-1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-nitrobenzamide (K-3-36)

[0401]

[0402] 4-Nitrobenzoyl chloride (555 mg, 3 mmol) was reacted with K-3-27, and purified by flash column (DCM / MeOH = 2.0%) to obtain 85 mg of a yellow solid, yield: 38%, mp. 285.7–286.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 8.40 (2H, d, J = 8.76 Hz), 8.21 (2H, d, J = 8.72 Hz), 2.27 (3H, s), 2.08 (3H, s), 1.95 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 164.30, 149.94, 149.63, 148.24, 139.58, 129.81×2, 124.21×2, 118.29, 114.58, 100.24, 95.06, 21.68, 13.13, 11.06; MS (ESI+) m / z 447 [M+H] + .

[0403] Example 85 N-(4-Bromo-1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3,5-dimethylbenzamide (K-3-38)

[0404]

[0405] 3,5-Dimethylbenzoyl chloride (462 mg, 3 mmol) was reacted with K-3-29, and purified by flash column (DCM / MeOH = 2.1%) to obtain 80 mg of a white solid, yield: 37%, mp. 214.3–215.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.53 (1H, s), 10.51 (1H, s), 7.58 (1H, s), 7.27 (1H, s), 6.92 (1H, s), 3.33 (3H, s), 2.36 (3H, s), 2.27 (3H, s), 2.11 (3H, s), 1.96 (3H, s); 13CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 138.18 × 2, 136.82, 133.91, 127.26, 126.02 × 2, 21.27 × 2, 13.14, 12.98, 10.95; MS (ESI+) m / z 430 [M+H] + .

[0406] Example 86 N-(4-Chloro-1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3,5-dimethylbenzamide (K-3-39)

[0407]

[0408] 3,5-Dimethylbenzoyl chloride (462 mg, 3 mmol) was reacted with K-3-27, and purified by flash column (DCM / MeOH = 2.1%) to obtain 82 mg of a white solid, yield: 42%, mp. 215.5–216.1 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.16 (1H, s), 10.60 (1H, s), 7.58 (1H, s), 7.27 (1H, s), 6.95 (1H, s), 3.33 (3H, s), 2.36 (3H, s), 2.31 (3H, s), 2.12 (3H, s), 1.97 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 165.82, 145.85, 138.48, 138.23 × 2, 135.10, 133.96, 133.62, 130.02, 127.25, 126.01 × 2, 114.19, 89.59, 21.26, 21.15, 12.18, 12.07, 10.96; MS (ESI+) m / z 386 [M+H] + .

[0409] Example 87 3,5-Dimethyl-N-(3-methyl-1-(pyrimidin-2-yl)-1H-pyrazol-5-yl)benzamide (K-3-42)

[0410]

[0411] 2-Chloropyrimidine (114 mg, 1 mmol) was reacted with K-3-37, and purified by flash column (DCM / MeOH = 2.1%) to obtain 30 mg of a white solid, yield: 20%, mp. 150.2–151.3 °C.1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 12.43 (1H, s), 8.97 (2H, d, J = 4.64 Hz), 7.57 (2H, s), 7.50 (1H, t, J = 4.64 Hz), 7.31 (1H, s), 6.79 (1H, s), 2.41 (6H, s), 2.28 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 163.07, 159.51×2, 157.23, 151.42, 140.69, 138.91×2, 134.32, 133.57, 125.31×2, 118.95, 98.08, 21.39×2, 14.44; MS (ESI+) m / z 309 [M+H] + .

[0412] Example 883,5-Dimethyl-N-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)benzamide (K-3-44)

[0413]

[0414] 2-Fluoropyridine (97 mg, 1 mmol) was reacted with K-3-37 and purified by flash column (DCM / MeOH = 2.1%) to give 30 mg of a white solid, yield: 20%, mp. 149.2–150.1 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 13.04 (1H, s), 8.58 (1H, d, J = 4.36 Hz), 8.07 (1H, t, J = 7.36 Hz), 7.98 (1H, d, J = 8.32 Hz), 7.57 (2H, s), 7.39 (1H, t, J = 6.16 Hz), 7.32 (1H, s), 6.76 (1H, s), 2.42 (6H, s), 2.28 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 162.99, 154.12, 150.74, 147.25, 140.93, 140.44, 138.96×2, 134.33, 133.52, 125.23×2, 121.30, 113.77, 97.52, 21.41×2, 14.36; MS (ESI+) m / z 307 [M+H] + .

[0415] Example 89 N-(1-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methyl-1H-pyrazol-5-yl)-3,5-dimethylbenzamide (K-3-47)

[0416]

[0417] 6-Chloro-1,3-dimethyluracil (174 mg, 1 mmol) was reacted with K-3-37, and purified by flash column (DCM / MeOH = 2.1%) to obtain 40 mg of white solid, yield: 22%, mp. 173.4–174.1 °C. 1 HNMR(DMSO-d 6 , 400 MHz) δ (ppm) 10.94 (1H, s), 7.63 (2H, s), 7.21 (1H, s), 6.78 (1H, s), 6.04 (1H, s), 3.23 (3H, s), 2.99 (3H, s), 2.33 (9H, s); 13 CNMR(DMSO-d 6 , 100 MHz) δ (ppm) 165.62, 162.13, 151.99, 150.22, 146.72, 142.59, 137.98×2, 134.06, 133.59, 126.06×2, 100.69, 100.05, 32.17, 28.38, 21.28×2, 11.58; MS(ESI+) m / z 368 [M+H] + .

[0418] Example 90 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-hydroxy-3-methylbenzamide (JH-1-1)

[0419]

[0420] 4-Hydroxy-3-methylbenzoyl chloride (510 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.7%) to obtain 70 mg of white solid, yield: 40%, mp. 259.5–260.4 °C. 1 HNMR(DMSO-d 6, 400 MHz) δ (ppm) 11.20 (1H, s), 7.54 (1H, d, J = 2.11 Hz), 7.41 (1H, dd, J = 9.13, 2.34 Hz), 6.81 (1H, d, J = 9.1 Hz), 6.59 (1H, s), 6.06 (1H, s), 3.01 (3H, s), 2.24 (4H, s), 2.19 (4H, s), 1.93 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 167.10, 166.59, 154.01, 151.10, 145.25, 141.06, 133.40, 131.01, 129.02, 128.21, 127.56, 126.44, 114.29, 104.15, 95.40, 20.01, 14.03, 12.98, 9.89; MS (ESI+) m / z 354 [M + H] + .

[0421] Example 91 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-4-hydroxy-3-nitrobenzamide (JH-1-2)

[0422]

[0423] 4-Hydroxy-3-nitrobenzoyl chloride (600 mg, 3 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 1.7%) to give 75 mg of a yellow solid, yield: 39%, mp. 245.6–246.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 10.98 (1H, s), 10.54 (1H, s), 9.04 (1H, s), 8.37 (1H, d, J = 2.32 Hz), 7.89 (1H, dd, J = 8.65, 2.24 Hz), 7.17 (1H, d, J = 8.75 Hz), 6.65 (1H, s), 3.05 (3H, s), 2.20 (3H, s), 1.92 (3H, s); 13 13C NMR (DMSO-d 6, 100 MHz) δ (ppm) 166.90, 166.54, 156.10, 152.02, 145.00, 140.88, 134.90, 133.20, 133.01, 131.03, 121.40, 117.85, 103.98, 95.40, 20.01, 13.67, 12.98; MS(ESI+) m / z 385 [M+H] + .

[0424] Example 92 N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-hydroxy-benzamide (JH-1-3)

[0425]

[0426] 3-hydroxybenzoyl chloride (465 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.9%) to obtain 68 mg of white solid, yield: 40%, mp. 232.4–233.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.35 (1H, s), 9.06 (1H, s), 7.39 (1H, dd, J = 8.34, 2.33 Hz), 7.37–7.30 (2H, m), 7.10 (1H, dd, J = 8.65, 2.24 Hz), 6.65 (1H, s), 5.02 (1H, s), 3.04 (3H, s), 2.41 (3H, s), 1.95 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 167.32, 165.98, 156.45, 153.53, 145.02, 140.88, 133.55, 133.20, 130.21, 123.98, 120.02, 112.40, 104.21, 95.42, 19.75, 14.01, 12.90; MS(ESI+) m / z 340 [M+H] + .

[0427] Example 93 N-(1-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl) pentadecanamide (JH-1-4)

[0428]

[0429] Palmitoyl chloride (822 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.5%) to obtain 86 mg of white solid, yield: 38%, mp. 359.6–360.1 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.20 (1H, s), 7.83 (1H, s), 5.45 (1H, s), 3.01 (3H, s), 2.30 (2H, t, J = 10.64 Hz), 2.24 (3H, s), 1.93 (3H, s), 1.59–1.47 (2H, m), 1.35–1.21 (18H, m), 0.89–0.83 (3H, m); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 172.41, 145.29, 138.04, 133.58, 104.21, 92.76, 37.90, 31.75, 29.77, 29.63, 29.59, 29.54, 29.49, 29.43, 29.24, 25.87, 25.50, 22.86, 19.76, 14.17, 13.66, 13.01; MS (ESI+) m / z 444 [M+H] + .

[0430] Example 94 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)heptadecanamide (JH-1-5)

[0431]

[0432] Stearoyl chloride (906 mg, 3 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 1.4%) to obtain 95 mg of white solid, yield: 40%, mp. 351.7–352.3 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.15 (1H, s), 7.62 (1H, s), 5.50 (s, 1H), 3.11 (3H, s), 2.28 (2H, t, J = 10.56 Hz), 2.22 (3H, s), 1.85 (3H, s), 1.61–1.52 (2H, m), 1.40–1.25 (20H, m), 0.91–0.86 (3H, m); 13 CNMR (DMSO-d 6, 100 MHz) δ (ppm) 172.45, 144.98, 138.09, 133.62, 104.15, 93.10, 37.88, 31.95, 29.90, 29.76, 29.71, 29.62, 29.60, 29.50 × 2, 29.40, 29.25, 25.90, 25.45, 22.79, 19.59, 14.11, 13.54, 12.98; MS(ESI+) m / z 472 [M + H] + .

[0433] Example 95 N-(3-Methyl-1-(pyrimidin-2-yl)-1H-pyrazol-5-yl)benzamide N-(1-(2,6-Dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (JH-1-6)

[0434]

[0435] 2-Chloropyrimidine (114 mg, 1 mmol) was reacted with K-3-37 and purified by flash column (DCM / MeOH = 2.1%) to obtain 32 mg of white solid, yield: 21%, mp. 231.6–232.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 9.05 (1H, s), 9.04 (2H, d, J = 1.01 Hz), 7.90–7.84 (3H, m), 7.51–7.42 (3H, m), 5.45 (1H, s), 2.24 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 166.88, 158.42, 157.40, 149.34, 141.10, 134.41, 131.81, 128.29, 111.79, 92.71, 13.64; MS(ESI+) m / z 280 [M + H] + .

[0436] Example 96 N-(1-(2,6-Dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (JH-1-7)

[0437]

[0438] 6-Chloropyrimidine-2,4(1H,3H)-dione (146 mg, 1 mmol) was reacted with K-3-37, and purified by flash column (DCM / MeOH = 2.1%) to obtain 25 mg of white solid, yield: 16%, mp. 222.5–223.1 °C. 1 HNMR(DMSO-d 6 , 400 MHz) δ (ppm) 11.00 (1H, s), 10.80 (1H, s), 9.04 (1H, s), 7.91–7.83 (2H, m), 7.50–7.41 (3H, m), 5.50 (1H, s), 5.43 (1H, s), 2.21 (3H, s); 13 CNMR(DMSO-d 6 , 100 MHz) δ (ppm) 166.96, 161.69, 153.39, 152.81, 135.05, 134.39, 131.80, 128.33, 126.77, 112.36, 97.15, 13.66; MS(ESI+) m / z 312 [M+H] + .

[0439] Example 97 N-(3-Methyl-1-(6-methylpyrazin-3-yl)-1H-pyrazol-5-yl)benzamide (JH-1-8)

[0440]

[0441] 3-Iodo-6-methylpyridazine (220 mg, 1 mmol) was reacted with K-3-37, and purified by flash column (DCM / MeOH = 2.2%) to obtain 20 mg of white solid, yield: 13%, mp. 216.7–217.5 °C. 1 HNMR(DMSO-d 6 , 400 MHz) δ (ppm) 9.04 (1H, s), 8.67 (1H, d, J = 8.32 Hz), 7.89–7.81 (3H, m), 7.49–7.41 (3H, m), 5.43 (1H, s), 2.54 (3H, d, J = 0.8 Hz), 2.23 (3H, s); 13 CNMR(DMSO-d 6 , 100 MHz) δ (ppm) 167.01, 162.00, 157.20, 152.10, 139.84, 134.28, 132.09, 128.23, 127.05, 116.01, 93.56, 21.40, 14.02; MS(ESI+) m / z 294 [M+H] + .

[0442] Example 98 N-(1-(Imidazo[1,2-a]pyrimidin-6-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (JH-1-9)

[0443]

[0444] 6-Bromoimidazo[1,2-A]pyrazine (280 mg, 1 mmol) was reacted with K-3-37 and purified by flash column (DCM / MeOH = 2.2%) to obtain 20 mg of a white solid, yield: 12%, mp. 216.7–217.5 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 9.02 (1H, s), 8.60 (2H, s), 7.93–7.85 (2H, m), 7.55 (1H, d, J = 4.23 Hz), 7.52–7.45 (3H, m), 7.09 (1H, d, J = 4.15 Hz), 5.44 (1H, s), 2.01 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 167.00, 152.35, 151.01, 149.20, 135.17, 135.11, 134.41, 131.78, 130.82, 128.25, 112.59, 110.52, 96.30, 13.43; MS (ESI+) m / z 319 [M+H] + .

[0445] Example 99 N-(3-Methyl-1-(pyrrol-2-yl)-1H-pyrazol-5-yl)benzamide (JH-1-10)

[0446]

[0447] 2-Chloropyrrole (101 mg, 1 mmol) was reacted with K-3-37 and purified by flash column (DCM / MeOH = 2.2%) to obtain 23 mg of a white solid, yield: 17%, mp. 193.7–194.5 °C. 1 1H NMR (DMSO-d 6, 400 MHz) δ (ppm) 9.50 (1H, d, J = 7.5 Hz), 9.03 (1H, s), 7.88–7.80 (2H, m), 7.50–7.44 (3H, m), 6.94–6.92 (1H, m), 6.27 (1H, dd, J = 5.43, 2.62 Hz), 6.19 (1H, dd, J = 5.41, 1.63 Hz), 5.40 (1H, s), 2.19 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 167.01, 152.93, 135.10, 135.06, 134.39, 131.79, 128.35, 123.01, 106.69, 97.11, 91.98, 13.54; MS (ESI+) m / z 267 [M+H] + .

[0448] Example 100 N-(3-Methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)benzamide (JH-1-11)

[0449]

[0450] 2-Chloropyridine (113 mg, 1 mmol) was reacted with K-3-37 and purified by flash column (DCM / MeOH = 2.0%) to obtain 28 mg of a white solid, yield: 20%, mp. 259.6–260.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 9.00 (1H, s), 8.88 (1H, dd, J = 3.72, 1.75 Hz), 8.61 (1H, dd, J = 7.05, 1.32 Hz), 8.32–8.27 (1H, m), 7.91–7.83 (2H, m), 7.68 (1H, dd, J = 7.02, 3.84 Hz), 7.51–7.42 (3H, m), 5.45 (1H, s), 2.24 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 167.01, 154.88, 151.70, 148.01, 140.01, 139.72, 134.40, 131.78, 128.32, 118.20, 111.01, 93.72, 13.71; MS (ESI+) m / z 279 [M+H] + .

[0451] Example 101 N-(3-Methyl-1-(thiophen-3-yl)-1H-pyrazol-5-yl)benzamide (JH-1-12)

[0452]

[0453] 3-Chlorothiophene (118 mg, 1 mmol) was reacted with K-3-37 and purified by flash column (DCM / MeOH = 2.4%) to obtain 24 mg of a white solid, yield: 17%, mp. 194.1–195.3 °C. 1 HNMR(DMSO-d 6 , 400 MHz) δ (ppm) 9.02 (1H, s), 7.94–7.86 (2H, m), 7.55–7.46 (3H, m), 7.36 (1H, dd, J = 6.01, 1.83 Hz), 7.24 (1H, t, J = 1.71 Hz), 7.04 (1H, dd, J = 6.03, 1.61 Hz), 5.55 (1H, s), 2.19 (3H, s). 13 CNMR(DMSO-d 6 , 100 MHz) δ (ppm) 167.01, 154.15, 139.25, 135.30, 134.35, 132.80, 131.78, 128.52, 128.28, 122.02, 94.22, 12.78. MS(ESI+) m / z 284 [M+H] + .

[0454] Example 102 N-(1-(Furan-3-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (JH-1-13)

[0455]

[0456] 3-Iodofuran (194 mg, 1 mmol) was reacted with K-3-37 and purified by flash column (DCM / MeOH = 2.3%) to obtain 25 mg of a white solid, yield: 19%, mp. 194.1–195.3 °C. 1 HNMR(DMSO-d 6 , 400 MHz) δ (ppm) 9.05 (1H, s), 7.88–7.79 (m, 2H), 7.58 (1H, t, J = 1.92 Hz), 7.52–7.43 (3H, m), 7.40–7.36 (1H, m), 6.31 (1H, dd, J = 2.11, 0.85 Hz), 5.46 (1H, s), 2.28 (3H, s); 13 CNMR(DMSO-d 6, 100 MHz) δ (ppm) 166.95, 154.18, 144.67, 139.25, 134.41, 131.82, 128.35, 128.08, 114.14, 111.54, 94.21, 13.69; MS(ESI+) m / z 268 [M+H] + .

[0457] Example 103 N-(3-Methyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)benzamide (JH-1-14)

[0458]

[0459] 6-Chloroquinoline (163 mg, 1 mmol) was reacted with K-3-37 and purified by flash column (DCM / MeOH = 2.2%) to obtain 25 mg of a white solid, yield: 18%, mp. 201.2–201.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 8.99 (1H, s), 8.93 (1H, dd, J = 4.12, 1.85 Hz), 8.60 (1H, d, J = 7.33 Hz), 8.30 (1H, d, J = 8.34 Hz), 8.12 (1H, dd, J = 7.34, 2.12 Hz), 7.95 (1H, t, J = 2.0 Hz), 7.96–7.88 (2H, m), 7.57 (1H, dd, J = 8.35, 4.14 Hz), 7.55–7.49 (3H, m), 5.67 (1H, s), 2.26 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 166.98, 149.01, 149.01, 144.87, 139.80, 137.01, 135.21, 134.41, 131.82, 129.85, 128.42, 128.35, 123.31, 121.28, 117.34, 92.47, 13.69; MS(ESI+) m / z 329 [M+H] + .

[0460] Example 104 N-(1-(1H-Indol-5-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (JH-1-15)

[0461]

[0462] 4-Chloroindole (151 mg, 1 mmol) was reacted with K-3-37, and purified by flash column (DCM / MeOH = 2.2%) to obtain 35 mg of white solid, yield: 22%, mp. 211.2–212.1 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 8.89 (1H, s), 8.23 (1H, d, J = 8.0 Hz), 7.93–7.85 (3H, m), 7.71 (1H, d, J = 8.3 Hz), 7.54–7.46 (3H, m), 7.40 (1H, dd, J = 8.43, 1.91 Hz), 7.26 (1H, dd, J = 8.1, 3.9 Hz), 6.62 (1H, dd, J = 3.8, 1.9 Hz), 5.71 (1H, s), 2.27 (3H, s); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 166.99, 148.93, 139.69, 135.05, 134.42, 134.30, 131.83, 128.35, 125.90, 123.95, 120.01, 116.68, 112.27, 102.87, 92.50, 13.68; MS(ESI+) m / z 317 [M+H] + .

[0463] Example 105 N-(1-(5-Ethyl-4-methyl-6-oxo-1,6-dihydropyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)acetamide (JH-1-16)

[0464]

[0465] 2-Chloro-5-ethyl-6-methylpyridin-4(3H)-one (172 mg, 1 mmol) was reacted with N-(3-methyl-1H-pyrazol-5-yl)acetamide (1 mmol), and purified by flash column (DCM / MeOH = 2.0%) to obtain 30 mg of white solid, yield: 10.9%, mp. 212–214 °C. 1 HNMR (DMSO-d 6 , 500 MHz) δ (ppm) 11.20 (1H, s), 6.64 (1H, s), 3.14 (3H, s), 2.50 (2H, q), 2.21 (3H, s), 2.18 (3H, s), 1.17 (3H, t, J = 6.5 Hz); 13 CNMR (DMSO-d 6, 125 MHz) δ (ppm) 169.73, 164.68, 156.16, 155.59, 141.71, 136.13, 106.01, 93.79, 23.32, 21.46, 18.62, 14.21, 13.87; MS(ESI+) m / z 276 [M+H] + .

[0466] Example 106 N-(1-(5-Ethyl-4-methyl-6-oxo-1,6-dihydropyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)propanamide (JH-1-17)

[0467]

[0468] 2-Chloro-5-ethyl-6-methylpyridin-4(3H)-one (172 mg, 1 mmol) was reacted with N-(3-methyl-1H-pyrazol-5-yl)propanamide (1 mmol), and purified by flash column (DCM / MeOH = 1.9%) to obtain 40 mg of a white solid, yield: 13.8%, mp. 218–220 °C. 1 1H NMR (DMSO-d 6 , 500 MHz) δ (ppm) 11.05 (1H, s), 6.62 (1H, s), 3.14 (3H, s), 2.67 (2H, q), 2.50 (2H, q), 2.18 (3H, s), 1.21 (3H, t, J = 6.5 Hz), 1.17 (3H, t, J = 6.5 Hz); 13 13C NMR (DMSO-d 6 , 125 MHz) δ (ppm) 171.74, 164.68, 156.16, 155.59, 141.71, 136.58, 106.01, 93.56, 28.75, 21.46, 18.62, 14.21, 13.87, 8.67; MS(ESI+) m / z 290 [M+H] + .

[0469] Example 107 N-(1-(5-Chloro-4-methyl-6-oxo-1,6-dihydropyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)acetamide (JH-1-18)

[0470]

[0471] 2,5-Dichloro-6-methylpyridin-4(3H)-one (178 mg, 1 mmol) was reacted with N-(3-methyl-1H-pyrazol-5-yl)acetamide (1 mmol), and purified by flash column (DCM / MeOH = 2.0%) to give 32 mg of a white solid, yield: 11.3%, mp. 220–222 °C. 1 HNMR (DMSO-d 6 , 500 MHz) δ (ppm) 7.44 (1H, s), 6.62 (1H, s), 3.16 (3H, s), 2.21 (3H, s), 2.18 (3H, s); 13 CNMR (DMSO-d 6 , 125 MHz) δ (ppm) 169.73, 162.07, 155.59, 152.96, 143.78, 136.13, 103.03, 93.79, 23.32, 22.00, 13.87; MS (ESI+) m / z 283 [M+H] + .

[0472] Example 108 N-(1-(5-chloro-4-methyl-6-oxo-1,6-dihydropyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (JH-1-19)

[0473]

[0474] 2,5-Dichloro-6-methylpyridin-4(3H)-one (178 mg, 1 mmol) was reacted with K-3-37 (1 mmol), and purified by flash column (DCM / MeOH = 2.0%) to give 35 mg of a white solid, yield: 10.1%, mp. 215–217 °C. 1 HNMR (DMSO-d 6 , 500 MHz) δ (ppm) 10.44 (1H, s), 7.84–7.87 (2H, m), 7.54–7.58 (1H, m), 7.48–7.52 (2H, m), 6.59 (1H, s), 3.20 (3H, s), 2.19 (3H, s); 13 CNMR (DMSO-d 6 , 125 MHz) δ (ppm) 166.55, 162.07, 155.59, 152.96, 143.78, 143.57, 134.97, 131.75, 128.58×2, 128.23×2, 103.03, 97.62, 19.99, 13.87; MS (ESI+) m / z 345 [M+H] + .

[0475] Example 109 N-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyridin-2-yl)-3-ethyl-1H-pyrazol-5-yl)benzamide (JH-1-20)

[0476]

[0477] 2-Chloro-5,6-dimethylpyridin-4(3H)-one (158 mg, 1 mmol) was reacted with N-(3-ethyl-1H-pyrazol-5-yl)benzamide (1 mmol), and purified by flash column (DCM / MeOH = 1.9%) to obtain 35 mg of a white solid, yield: 10.4%, mp. 216–218 °C. 1 1H NMR (DMSO-d 6 , 500 MHz) δ (ppm) 11.00 (1H, s), 7.84–7.86 (2H, m), 7.54–7.57 (1H, m), 7.48–7.52 (2H, m), 6.62 (1H, s), 3.17 (3H, s), 3.06 (2H, q), 2.36 (3H, s), 1.39 (3H, s); 13 13C NMR (DMSO-d 6 , 125 MHz) δ (ppm) 166.55, 163.62, 156.72, 156.33, 142.15, 140.39, 134.97, 131.75, 128.58×2, 128.23×2, 102.79, 99.19, 26.42, 19.07, 13.98, 10.95; MS(ESI+) m / z 338 [M+H] + .

[0478] Example 110 N-(3-Chloro-1-(4,5-dimethyl-6-oxo-1,6-dihydropyridin-2-yl)-1H-pyrazol-5-yl)benzamide (JH-1-21)

[0479]

[0480] 2-Chloro-5,6-dimethylpyridin-4(3H)-one (158 mg, 1 mmol) was reacted with N-(3-chloro-1H-pyrazol-5-yl)benzamide (1 mmol), and purified by flash column (DCM / MeOH = 1.8%) to obtain 40 mg of a white solid, yield: 11.6%, mp. 205–207 °C. 1 1H NMR (DMSO-d 6, 500 MHz) δ (ppm) 10.79 (1H, s), 7.84–7.86 (2H, m), 7.53–7.57 (1H, m), 7.48–7.52 (2H, m), 6.77 (1H, s), 3.16 (3H, s), 2.36 (3H, s); 13 13C NMR (DMSO-d 6 , 125 MHz) δ (ppm) 166.55, 163.62, 156.33, 146.53, 140.39, 135.68, 134.97, 131.75, 128.57×2, 128.23×2, 107.70, 102.79, 19.07, 13.98; MS (ESI+) m / z 345 [M+H] + .

[0481] Example 111 N-(1-(4-Ethyl-5-methyl-6-oxo-1,6-dihydropyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (JH-1-22)

[0482]

[0483] 2-Chloro-6-ethyl-5-methylpyridin-4(3H)-one (172 mg, 1 mmol) was reacted with K-3-37 (1 mmol), and purified by flash column (DCM / MeOH = 2.1%) to obtain 42 mg of white solid, yield: 12.4%, mp. 228–230 °C. 1 1H NMR (DMSO-d 6 , 500 MHz) δ (ppm) 10.85 (1H, s), 7.83–7.85 (2H, m), 7.53–7.56 (1H, m), 7.49–7.53 (2H, m), 6.48 (1H, s), 2.38 (3H, s), 2.31–2.35 (2H, m), 2.19 (3H, s), 1.23 (3H, t, J = 6.5 Hz); 13 13C NMR (DMSO-d 6 , 125 MHz) δ (ppm) 166.55, 166.54, 162.45, 155.59, 143.57, 139.82, 134.97, 131.75, 128.58×2, 128.23×2, 104.44, 97.62, 23.77, 13.87, 13.69, 12.07; MS (ESI+) m / z 338 [M+H] + .

[0484] Example 112 N-(1-(4-chloro-5-methyl-6-oxo-1,6-dihydropyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzamide (JH-1-23)

[0485]

[0486] 2,6-Dichloro-5-methylpyridin-4(3H)-one (178 mg, 1 mmol) was reacted with K-3-37 (1 mmol), and purified by flash column (DCM / MeOH = 1.9%) to obtain 36 mg of a white solid, yield: 10.4%, mp. 231–232 °C. 1 HNMR(DMSO-d 6 , 500 MHz) δ (ppm) 11.05 (1H, s), 7.83–7.85 (2H, m), 7.53–7.56 (1H, m), 7.49–7.53 (2H, m), 6.48 (1H, s), 2.38 (3H, s), 2.31–2.35 (2H, m), 2.19 (3H, s), 1.23 (3H, t, J = 6.5 Hz); 13 CNMR(DMSO-d 6 , 125 MHz) δ (ppm) 166.55, 158.14, 155.59, 143.57, 139.67, 134.97, 131.75, 128.58×2, 128.23×2, 107.33, 97.62, 15.05, 13.87; MS(ESI+) m / z 345 [M+H] + .

[0487] Example 113 1-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-phenylurea (JH-2-1)

[0488]

[0489] Phenyl isocyanate (119 mg, 1 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 2.2%) to obtain 30 mg of a white solid, yield: 18%, mp. 253.3–254.1 °C. 1 HNMR(DMSO-d 6, 400 MHz) δ (ppm) 11.22 (1H, s), 9.72 (1H, s), 7.81 (1H, s), 7.40–7.36 (3H, m), 7.25–7.15 (3H, m), 6.90 (1H, t, J=7.32 Hz), 5.46 (1H, s), 3.04 (s, 3H), 2.21 (4H, s), 1.96 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 166.61, 154.62, 153.53, 145.29, 139.54, 138.32, 133.58, 128.76, 123.09, 118.30, 104.21, 96.79, 19.76, 13.66, 13.01; MS(ESI+) m / z 339 [M+H] + .

[0490] Example 114 1-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-ethylurea (JH-2-2)

[0491]

[0492] Ethyl isocyanate (71 mg, 1 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2.4%) to obtain 32 mg of a white solid, yield: 22%, mp. 234.6–235.2 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.24 (1H, s), 9.68 (1H, s), 8.39 (1H, t, J = 5.83 Hz), 5.47 (1H, s), 3.06–2.99 (7H, m), 2.26 (4H, s), 1.96 (3H, s), 0.91 (4H, t, J = 5.82 Hz); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 166.63, 156.92, 153.55, 145.32, 138.35, 133.60, 104.23, 96.82, 34.35, 19.79, 14.90, 13.59, 13.05; MS(ESI+) m / z 291 [M+H] + .

[0493] Example 115 1-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-vinylurea (JH-2-3)

[0494]

[0495] Vinyl isocyanate (69 mg, 1 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2.3%) to obtain 35 mg of a white solid, yield: 24%, mp. 225.5–226.0 °C. 1 HNMR(DMSO-d 6 , 400 MHz) δ (ppm) 11.18 (1H, s), 9.71 (1H, s), 7.35 (1H, t, J = 16.73 Hz), 6.01 (1H, d, J = 9.12 Hz), 5.50 (1H, s), 4.11 (2H, d, J = 16.82 Hz), 3.03 (3H, s), 2.20 (4H, s), 1.89 (3H, s); 13 CNMR(DMSO-d 6 , 100 MHz) δ (ppm) 166.61, 156.58, 153.53, 145.28, 138.31, 133.59, 129.34, 104.23, 96.80, 95.31, 19.67, 13.66, 13.03; MS(ESI+) m / z 289 [M+H] + .

[0496] Example 116 1-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-(thiophen-2-yl)urea (JH-2-4)

[0497]

[0498] 2-Thiophene isocyanate (125 mg, 1 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2.1%) to obtain 30 mg of a white solid, yield: 17%, mp. 233.2–233.9 °C. 1 HNMR(DMSO-d 6, 400 MHz) δ (ppm) 11.19 (1H, s), 9.68 (1H, s), 9.02 (1H, s), 7.38 (1H, dd, J = 6.92, 1.71 Hz), 7.21 (1H, dd, J = 6.72, 4.93 Hz), 7.05 (1H, dd, J = 5.12, 1.71 Hz), 5.50 (1H, s), 3.02 (3H, s), 2.25 (3H, s), 1.96 (3H, s); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 166.63, 154.11, 153.55, 153.24, 145.31, 138.34, 133.59, 127.84, 126.40, 115.92, 104.23, 96.81, 19.78, 13.68, 12.99; MS (ESI+) m / z 345 [M+H] + .

[0499] Example 117 1-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-(pyridin-2-ylmethyl)urea (JH-2-5)

[0500]

[0501] 2-Isocyanatopyridine (120 mg, 1 mmol) was reacted with LSL-8-11 and purified by flash column (DCM / MeOH = 2.1%) to give 35 mg of a white solid, yield: 20%, mp. 246.5–247.4 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.20 (1H, s), 9.69 (1H, s), 8.53 (1H, dd, J = 4.31, 1.85 Hz), 7.73 (1H, t, J = 7.49 Hz), 7.28 (1H, dd, J = 7.78, 1.32 Hz), 7.17 (1H, dd, J = 7.81, 4.39 Hz), 5.96 (1H, t, J = 8.32 Hz), 5.48 (s, 1H), 4.07 (2H, d, J = 8.31 Hz), 3.00 (2H, s), 2.26 (3H, s), 1.89 (2H, s); 13 13C NMR (DMSO-d 6, 100 MHz) δ (ppm) 166.62, 157.44, 157.10, 153.63, 149.39, 145.30, 138.31, 137.80, 133.59, 123.48, 123.41, 104.20, 96.81, 43.38, 19.78, 13.65, 13.03; MS(ESI+) m / z 354 [M+H] + .

[0502] Example 118 1-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-hexylurea (JH-2-6)

[0503]

[0504] Hexyl isocyanate (127 mg, 1 mmol) was reacted with LSL-8-11, and purified by flash column (DCM / MeOH = 2.0%) to obtain 32 mg of white solid, yield: 20%, mp. 234.7–235.1 °C. 1 1H NMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.16 (1H, s), 9.71 (1H, s), 8.44 (1H, t, J = 6.01 Hz), 5.46 (1H, s), 3.03 (3H, s), 2.82 (2H, t, J = 6.82 Hz), 2.25 (3H, s), 1.96 (3H, s), 1.48–1.38 (2H, m), 1.37–1.25 (6H, m), 0.98–0.85 (3H, m); 13 13C NMR (DMSO-d 6 , 100 MHz) δ (ppm) 166.63, 157.11, 153.55, 145.31, 138.35, 133.60, 104.24, 96.82, 39.56, 31.37, 29.00, 27.58, 22.95, 19.74, 14.19, 13.65, 12.98; MS(ESI+) m / z 347 [M+H] + .

[0505] Example 119 1-(1-(4,5-Dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3-octylurea (JH-2-7)

[0506]

[0507] Octyl isocyanate (155 mg, 1 mmol) was reacted with LSL-8-11, and the product was purified by flash column chromatography (DCM / MeOH = 2.0%) to give 40 mg of a white solid, yield: 21%, mp. 241.3–241.9 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.25 (1H, s), 9.65 (1H, s), 8.46 (1H, t, J = 6.02 Hz), 5.51 (1H, s), 2.99 (3H, s), 2.86 (2H, t, J = 6.78 Hz), 2.19 (3H, s), 1.89 (3H, s), 1.51–1.40 (2H, m), 1.36–1.21 (9H, m), 0.90–0.82 (3H, m); 13 CNMR (DMSO-d 6 , 100 MHz) δ (ppm) 166.64, 157.06, 153.49, 145.28, 138.32, 133.58, 104.22, 96.78, 39.54, 31.76, 28.99, 28.65, 28.29, 26.74, 22.85, 19.77, 14.18, 13.68, 13.05; MS(ESI+) m / z 375 [M+H] + .

[0508] Example 120 1-(4-Chlorophenyl)-3-(1-(4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)urea (JH-2-8)

[0509]

[0510] 4-Chlorophenyl isocyanate (153 mg, 1 mmol) was reacted with LSL-8-11, and the product was purified by flash column chromatography (DCM / MeOH = 2.1%) to give 38 mg of a white solid, yield: 21%, mp. 256.8–257.4 °C. 1 HNMR (DMSO-d 6 , 400 MHz) δ (ppm) 11.22 (1H, s), 9.71 (1H, s), 7.80 (1H, s), 7.44–7.38 (2H, m), 7.17–7.11 (2H, m), 5.55 (1H, s), 3.03 (3H, s), 2.30 (3H, s), 1.95 (3H, s); 13 CNMR (DMSO-d 6, 100 MHz) δ (ppm) 166.76, 154.58, 153.49, 145.33, 138.79, 138.28, 133.62, 127.20, 126.29, 119.89, 104.18, 96.83, 19.80, 13.71, 13.04; MS(ESI+) m / z 373 [M+H] + .

[0511] Experimental Example 1 Minimum Inhibitory Concentration Test of Mycobacterium tuberculosis H37Rv

[0512] The strain MTB H37Rv (ATCC 27294) was preserved by the Bacteriology and Immunology Laboratory of Beijing Chest Hospital Affiliated to Capital Medical University & Beijing Institute of Tuberculosis and Thoracic Tumors. The media 7H9, 7H10 for culturing mycobacteria and their additive OADC were purchased from BD.

[0513] A inoculation loop was used to dip MTB H37Rv stored at -80 °C and streaked on 7H10 solid medium (containing 10% OADC), and statically cultured at 37 °C until single colonies grew out; single colonies were picked and inoculated into 5 mL of 7H9 medium (containing 10% OADC and 0.05% Tween80), and statically cultured for 10 - 14 d until the late logarithmic phase.

[0514] The minimum inhibitory concentration (MIC) of the compound against Mtb H37Rv was determined by the two-fold dilution method in a 96-well plate. 200 μL of 7H9 medium was added to the first row and the eighth row to prevent drying. The logarithmic-phase strain was inoculated into fresh 7H9 medium to a final concentration of OD600 of 0.005. The highest concentration of the test sample was 64 μg / mL, and the lowest was 0.016 μg / mL (3 parallels). The solvent DMSO was used as the negative control, and isoniazid (INH) and rifampicin (RFP) were used as the positive controls. The 96-well plate was placed in an incubator and statically cultured at 37 °C for about 10 d, and the growth of the strain was observed. The drug concentration at which there was no obvious change in the light absorption of the culture solution was taken as the minimum inhibitory concentration.

[0515] Table 1. Inhibitory Activity Data of Some Compounds against Mycobacterium tuberculosis MIC (unit: μg / mL)

[0516]

[0517]

[0518]

[0519] As can be seen from the data in Table 1, most of the compounds of the present invention have good anti-tuberculosis activity. In particular, the MICs of compounds LSL-8-44, LSL-8-47, LSL-8-48, LSL-12-23, LSL-12-28, LSL-12-30, LSL-12-34, LSL-12-35, K-2-88, K-2-89, K-2-90, K-2-91, K-2-92, K-2-93, K-2-95, K-3-1, K-3-3, K-3-6, K-3-8, K-3-9, K-3-13, K-3-14, K-3-15, K-3-16, K-3-23 and K-3-24 against Mycobacterium tuberculosis are less than 0.13 μg / mL.

[0520] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound represented by Formula Ι or Formula II, its enantiomers, diastereomers, racemates or mixtures thereof, or a pharmaceutically acceptable salt, characterized in that, in Formula I and Formula II: Ring A is selected from an unsaturated five-membered ring, six-membered ring or heteroaromatic fused ring; wherein V, W, X, Y, Z are each independently selected from C, N, S, O, substituted or unsubstituted methylene or methine, carbonyl, substituted or unsubstituted imino; the substituents are selected from halogen, straight-chain, cyclic or branched alkyl containing 1-5 carbons, alkoxy containing 1-5 carbons or adjacent substituents and the connected atoms together form a saturated or unsaturated cyclic structure; R 1 ,R 2 each independently selected from H, halogen, a straight-chain, cyclic or branched alkyl group having 1 to 5 carbons; L is a chemical bond or L is selected from methylene, carbonyl, m = 0, 1; R 3 selected from H, a halogen, a substituted or unsubstituted straight-chain, cyclic or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted straight-chain or branched alkenyl group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted aryl group or a heteroaryl group.

2. The compound according to claim 1, characterized in that, the configuration of each chiral carbon in the compound represented by Formula Ι or Formula II is independently R configuration or S configuration.

3. The compound according to claim 1, characterized in that, In Formula Ι, ring A is selected from In Formula II, ring A is selected from wherein R 4 , R 5 are each independently selected from H, halogen, a straight-chain, cyclic or branched alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms.

4. The compound according to claim 1, its enantiomers, diastereomers, racemates or mixtures thereof, or a pharmaceutically acceptable salt, characterized in that: R 1 ,R 2 each independently selected from H, bromine, chlorine, methyl, ethyl; R 3 selected from an alkyl or cycloalkyl group having 1 to 8 carbon atoms, an alkyl or cycloalkyl group having 1 to 8 carbon atoms optionally substituted by one or more alkyl groups having 1 to 5 carbon atoms, cycloalkyl groups having 3 to 5 carbon atoms, halogens, keto groups, methoxy groups, or cyano groups, vinyl, propenyl, butenyl, benzene ring, naphthalene ring, a benzene ring or naphthalene ring optionally substituted by one or more methyl groups, methoxy groups, halogens, trifluoromethyl groups, nitro groups, cyano groups, hydroxy groups, 3-methyl-4-cyano, 3-fluoro-4-cyano, 3-chloro-4-fluoro, thiophene, thiazole, pyridine, a thiophene, thiazole or pyridine optionally substituted by one or more methyl groups, halogens, or nitro groups.

5. The compound according to claim 1, characterized in that: the compound has a structure represented by General Formula III, IV, V or VI: Among them, in General Formulas III, IV, and V, R 4 , R 5 are each independently selected from H, halogen, methyl, and ethyl; R 1 ,R 2 each independently selected from H, bromine, chlorine, methyl, ethyl; R 3 selected from an alkyl or cycloalkyl group having 1 to 8 carbon atoms, an alkyl or cycloalkyl group having 1 to 8 carbon atoms optionally substituted by one or more alkyl groups having 1 to 5 carbon atoms, cycloalkyl groups having 3 to 5 carbon atoms, halogens, keto groups, methoxy groups, or cyano groups, vinyl, propenyl, butenyl, benzene ring, naphthalene ring, a benzene ring or naphthalene ring optionally substituted by one or more methyl groups, methoxy groups, halogens, trifluoromethyl groups, nitro groups, cyano groups, hydroxy groups, 3-methyl-4-cyano, 3-fluoro-4-cyano, 3-chloro-4-fluoro, thiophene, thiazole, pyridine, a thiophene, thiazole or pyridine optionally substituted by one or more methyl groups, halogens or nitro groups; In general formula VI, R 4 , R 5 are each independently selected from H, halogen, methyl, ethyl; R 1 ,R 2 each independently selected from H, bromine, chlorine, methyl, ethyl; R 3 selected from alkylamines or cycloalkylaminoamines having 1 to 6 carbon atoms or alkylamines or cycloalkylamines having 1 to 6 carbon atoms substituted by one or more alkyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 1 to 6 carbon atoms, halogen atoms, keto groups, methoxy groups, or cyano groups; dihydroisoquinoline optionally substituted at any position, and the substituents are selected from 1 or more methyl, methoxy, halogen, trifluoromethyl, nitro, cyano, hydroxyl, dimethylamine, diethylamine, thiophene, furan, morpholine, thiomorpholine, piperidine, piperazine, N-methylpiperazine.

6. The compound according to claim 1, its enantiomers, diastereomers, racemates or mixtures thereof, or a pharmaceutically acceptable salt, characterized in that, the compound is selected from the following compounds:

7. The compound according to claim 1, its enantiomers, diastereomers, racemates or mixtures thereof, or a pharmaceutically acceptable salt, characterized in that, the pharmaceutically acceptable salt is hydrochloride, sulfate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, acetate, oxalate, succinate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, pentanedioate, arginate or maleate of the compound represented by Formula Ι or Formula II.

8. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises: the compound according to claim 1, its enantiomers, diastereomers, racemates or mixtures, or a pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier.

9. The use of the compound according to claim 1, its enantiomers, diastereomers, racemates or mixtures, or a pharmaceutically acceptable salt or the pharmaceutical composition according to claim 8, characterized in that, for: (1) preparing a drug for preventing and / or treating tuberculosis infection; (2) preparing a drug for preventing and / or treating drug-resistant tuberculosis infection; (3) preparing a drug for inhibiting the growth of Mycobacterium tuberculosis.

10. A method for reducing the pathogenicity or toxicity of Mycobacterium tuberculosis, characterized in that, comprises the steps: Contact Mycobacterium tuberculosis with the compound according to any one of claims 1-7, its enantiomers, diastereomers, racemates or mixtures, or a pharmaceutically acceptable salt or the pharmaceutical composition according to claim 8, so as to reduce the pathogenicity or toxicity of Mycobacterium tuberculosis, and the said method is not used for the treatment of diseases.

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