CD38 inhibiting compound and application

Abstract

The invention relates to a CD38 inhibiting compound and application thereof. The structural formula of the CD38 inhibiting compound is as follows: # imgabs0. The free form and pharmaceutically acceptable salt or solvate of the CD38 inhibiting compound can provide a new therapeutic method for improving the in-vivo NAD < + > level. Experiments prove that the compound with the general formula (I) provided by the invention can inhibit CD38 with high strength, can effectively increase the level of NAD < + > in vivo, and has the prospect of being developed into a medicine.

Description

Technical Field

[0001] The present invention belongs to the field of medicines, and in particular relates to a CD38 inhibitory compound and application thereof. Background Art

[0002] CD38 is a multifunctional protein present in many different cell types. As a type II transmembrane protein, CD38's functions in the body mainly include enzyme catalysis, receptor function, and participation in the conduction of cellular calcium ions. CD38 is commonly found in various tissue cells, such as B cells, T cells, phagocytes, natural killer cells, smooth muscle cells, glial cells, kidneys, brain, liver, and heart. CD38 is associated with the occurrence of many diseases.

[0003] CD38 belongs to the ADP-ribose cyclase family and has the activities of ADP-ribose cyclase and glycohydrolase. + ), nicotinamide adenine dinucleotide phosphate (NADP + ), nicotinamide mononucleotide and other substances as substrates, which can convert NAD + CD38 can also hydrolyze cADPR into ADP-ribose and, under acidic conditions, NADP + CD38 has been shown to be a NAD + level is a key regulatory factor.

[0004] So far, more than 300 enzymes are known to use NAD + As a substrate for biochemical reactions, NAD + It is a mediator of cell function and metabolism, involved in metabolic pathways, DNA maintenance and repair, and redox homeostasis. + As an important coenzyme factor in cell regulation and energy metabolism in the body, there are two ways to increase NAD + Level: One is NAD + The other is to inhibit NAD + It can generate or inhibit the consumption of NAD via the nicotinamide precursor synthesis pathway. + enzymes to reduce NAD + Consumption of NAD + Precursor nicotinamide riboside and nicotinamide mononucleotide synthesis restores NAD + level, the former synthesis pathway can be obtained through diet. CD38 is NAD + Therefore, it is possible to restore individual NAD by inhibiting CD38 activity. + .

[0005] NAD in the body + NAD levels play an important role in physiological functions. + Levels of NAD have been linked to a variety of diseases. + In humans and animals, NAD is required during mitochondrial myopathy, aging, cardiovascular disease, inflammation, metabolic diseases, including dermatitis, diarrhea, obesity, multiple myeloma, glioma, breast cancer, prostate cancer, melanoma, lung cancer, systemic lupus erythematosus, rheumatoid arthritis, hypertension, atherosclerosis, chronic lymphocytic leukemia, etc. + Levels tend to decrease. In the context of relevant diseases, increasing NAD in cells + Concentration is beneficial. (Haffner CD, Becherer JD, Boros EE, et al. Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors[J]. J Med Chem, 2015, 58(8): 3548-71.)

[0006] Due to the current shortage of CD38 inhibitors, it is necessary to find and discover new and highly effective CD38 inhibitors. Summary of the invention

[0007] In view of the above problems, the present invention provides a CD38 inhibitory compound and application.

[0008] In the first aspect, the present invention provides a CD38 inhibitory compound, the structural formula of which is as follows:

[0009]

[0010] Where R is

[0011] More specifically, the structural formula of the CD38 inhibitory compound is one of the following structural formulas:

[0012]

[0013]

[0014]

[0015] The preparation process of the compound is as follows:

[0016]

[0017] 1. Add 7-bromo-3,4-dihydro-2H-1,4-benzoxazine (15.0 g, 70.07 mmol, 1.0 equiv.) to cycloisopropyl malonate (20.2 g, 140.14 mmol, 2.0 equiv.). Heat to 80°C and react for 4.5 h. After the reaction is completed, add ethyl acetate (50 mL) to the reaction solution, add saturated sodium bicarbonate aqueous solution (75 mL), separate the layers to obtain an aqueous layer, add hydrochloric acid to the aqueous layer, adjust the pH to 1-2, add DCM solution (150 mL), separate the layers to obtain an organic layer, dry over anhydrous sodium sulfate, spin dry the organic solvent to obtain a white solid, add Eaton's reagent (75 g, 5.0 equiv.), react at 60°C for 2 h, after the reaction is completed, add an ice-water mixture, filter, and dry to obtain a red product, i.e., a compound of formula (II).

[0018] 2. Add the compound of formula (II) (15.0 g, 53.17 mmol, 1.0 equiv.) and DMF (0.5 mL) to POCl3 (10 mL). Heat to 90°C and react for 6 h. After the reaction is completed, slowly add the reaction solution to the aqueous solution (50 mL), stir for 30 minutes, add DCM (200 mL×3), combine the organic layers, add anhydrous sodium sulfate to the organic layers and dry them, spin dry the organic solvent to obtain a brown solid, i.e., the compound of formula (III).

[0019] 3. Add the compound of formula (III) (14.5 g, 48.24 mmol, 1.0 equiv.), thiazole-5-boronic acid pinacol ester (12.3 g, 57.89 mmol, 1.2 equiv.), Pd(dppf)Cl2 (3.5 g, 4.82 mmol, 0.1 equiv.), potassium carbonate (20.0 g, 144.72 mmol, 3.0 equiv.) to a double-necked flask, replace the gas in the flask with nitrogen three times, add 1,4-dioxane / water (50 mL v / v 4:1). React at 105 ° C for 16 h. After the reaction is completed, add DCM (100 ml) to the reaction solution, add water (50 mL), separate the layers, dry the organic layer with anhydrous sodium sulfate, and filter. After concentration, the product was purified by silica gel column chromatography using a mixture of dichloromethane and methanol in a volume ratio of 100:1 as the eluent, and the organic solvent containing the target product was collected, concentrated and dried to obtain a yellow solid product, namely the compound of formula (VI).

[0020] 4. Add the compound of formula (VI) (30.0 mg, 0.16 mmol, 1.0 equiv.), Pd2(dba)3 (25.5 mg, 0.016 mmol, 0.1 equiv.), BrettPhos (13.5 mg, 0.41 mmol, 0.25 equiv.), sodium tert-butoxide (33.4 mg, 0.58 mmol, 3.55 equiv.) into a double-necked flask, replace the gas in the flask with nitrogen three times, and add compound RNH 2 (0.25mmol, 1.5equiv.) and anhydrous 1,4-dioxane. The reaction was carried out at 115°C for 20h. After the reaction was completed, DCM (25ml) and water (10mL) were added to the reaction solution, the layers were separated, and the organic layer was dried over anhydrous sodium sulfate and filtered. After concentration, the product was purified by silica gel column chromatography using a mixture of dichloromethane and methanol in a volume ratio of 100:6 as the eluent. The organic solvent containing the target product was collected and concentrated to obtain the final product.

[0021] Where R is

[0022] Preferably, the protection scope of the present invention covers a free form and a pharmaceutically acceptable salt or solvate of a CD38 inhibitory compound.

[0023] In a second aspect, the present invention proposes the use of a CD38 inhibitory compound as a drug for treating a CD38-mediated disease, wherein the CD38-mediated disease is one of myocardial disease or disease, metabolic disease, aging, atherosclerosis, cardiovascular disease, multiple myeloma, blastoma, gastric cancer, breast cancer, lung cancer, liver cancer, colon cancer, liver cancer, melanoma, bladder cancer, lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, rheumatoid arthritis, systemic lupus erythematosus and mitochondrial myopathy.

[0024] In a third aspect, the present invention provides a pharmaceutical composition consisting of the above-mentioned CD38 inhibitory compound and a pharmaceutically acceptable carrier.

[0025] The CD38 inhibitor of the present invention can be used to increase NAD + The compound of the general formula (I) provided by the present invention can inhibit CD38 with high intensity and effectively increase NAD + level, with the prospect of being developed into a drug. DETAILED DESCRIPTION

[0026] Embodiment 1

[0027]

[0028] The following compounds were prepared:

[0029]

[0030] 1. Add 7-bromo-3,4-dihydro-2H-1,4-benzoxazine (15.0 g, 70.07 mmol, 1.0 equiv.) to cycloisopropyl malonate (20.2 g, 140.14 mmol, 2.0 equiv.). Heat to 80°C and react for 4.5 h. After the reaction is completed, add ethyl acetate (50 mL) to the reaction solution, add saturated sodium bicarbonate aqueous solution (75 mL), separate the layers to obtain an aqueous layer, add hydrochloric acid to the aqueous layer, adjust the pH to 1-2, add DCM solution (150 mL), separate the layers to obtain an organic layer, dry over anhydrous sodium sulfate, spin dry the organic solvent to obtain a white solid, add Eaton's reagent (75 g, 5.0 equiv.), react at 60°C for 2 h, after the reaction is completed, add an ice-water mixture, filter, and dry to obtain 15.6 g of a red product, i.e., a compound of formula (II), with a yield of 78.9%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.64(s,1H),7.49(d,J=2.0Hz,1H),7.28(d,J=2.0Hz,1H),5.85(s,1H),4.32(t,J=4.6Hz,2H),3.99(t,J=4.6Hz,2H). ESI-MS: m / z=283.19[M+H] + .

[0031] 2. Add the compound of formula (II) (15.0 g, 53.17 mmol, 1.0 equiv.) and DMF (0.5 mL) to POCl 3 (10mL). Heat to 90°C and react for 6h. After the reaction is completed, slowly add the reaction solution to the aqueous solution (50mL), stir for 30 minutes, add DCM (200mL×3), combine the organic layers, add anhydrous sodium sulfate to the organic layer and dry it, spin dry the organic solvent to obtain 14.8g of brown solid, i.e., compound of formula (III), with a yield of 92.6%. 1 HNMR (400 MHz, DMSO-d 6 )δ7.58(s,1H),7.44(d,J=1.8Hz,1H),7.02(s,1H),4.38(t,J=4.6Hz,2H),4.08(t,J=4.6Hz,2H). ESI-MS:m / z=301.48[M+H] + .

[0032] 3. Compound (III) (14.5 g, 48.24 mmol, 1.0 equiv.), thiazole-5-boronic acid pinacol ester (12.3 g, 57.89 mmol, 1.2 equiv.), Pd(dppf)Cl 2 (3.5g, 4.82mmol, 0.1equiv.), potassium carbonate (20.0g, 144.72mmol, 3.0equiv.) were added to a double-necked flask, the gas in the flask was replaced with nitrogen three times, and 1,4-dioxane / water (50mLv / v 4:1) was added. The reaction was carried out at 105°C for 16h. After the reaction was completed, DCM (100ml) and water (50mL) were added to the reaction solution, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, and filtered. After concentration, it was purified by silica gel column chromatography, eluted with a mixed solution of dichloromethane and methanol in a volume ratio of 100:1 as the eluent, and the organic solvent containing the target product was collected, concentrated and dried to obtain 8.56g of a yellow solid product, i.e., the compound of formula (IV), with a yield of 58.2%. 1 HNMR (400MHz, CDCl 3 )δ8.78(s,1H),8.10(s,1H),7.75(s,1H),7.39(s,1H),6.92(s,1H),4.41(t,J=4.6Hz,2H),4.27(t,J=4.8Hz,2H). ESI-MS: m / z=305.84[M+H] + .

[0033] 4. The compound of formula (IV) (30.0 mg, 0.16 mmol, 1.0 equiv.), Pd 2 (dba) 3 (25.5mg, 0.016mmol, 0.1equiv.), BrettPhos (13.5mg, 0.41mmol, 0.25equiv.), sodium tert-butoxide (33.4mg, 0.58mmol, 3.55equiv.) were added to a double-necked flask, the gas in the flask was replaced with nitrogen three times, trans-4-trifluoromethylcyclohexylamine (41.1mg, 0.25mmol, 1.5equiv.) and anhydrous 1,4-dioxane were added. The reaction was carried out at 115°C for 20h. After the reaction was completed, DCM (25ml) was added to the reaction solution, water (10mL) was added, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, and filtered. After concentration, the product was purified by silica gel column chromatography using a mixture of dichloromethane and methanol in a volume ratio of 100:6 as the eluent. The organic solvent containing the target product was collected, concentrated and dried to obtain 10 mg of a light yellow solid product, namely the compound of formula (H1), with a yield of 14%. 1 H NMR (400 MHz, CDCl3 )δ8.75(s,1H),8.05(s,1H),7.31(s,1H),7.29(s,1H),5.74(s,1H),4.97(d,1H),4.35(t,J=4.6Hz,2H),4.21(t,J=4.6Hz ,2H),3.76–3.69(m,1H),3.44–3.34(m,1H),2.39-2.29(m,2H),2.12-2.02(m,2H),1.53-1.44(m,2H),1.40–1.32(m,2H). ESI-MS:m / z=436.13[M+H] + .

[0034] Embodiment 2

[0035] The following compounds were prepared:

[0036]

[0037] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with methyl 4-aminocyclohexanecarboxylate (45.6 mg, 0.29 mmol, 1.1 equiv.) to obtain 21.5 mg of product, namely (H2) compound, with a yield of 19.3%. 1 HNMR (400MHz, CDCl 3 )δ8.77(s,1H),8.06(s,1H),7.31(s,1H),7.23(s,1H),5.78(s,1H),4.73-4.68(m,1H),4.38(t,J=4.6Hz,2H),4.23(t,J= 4.6Hz,2H),4.12-4.10(m,1H),3.72(s,3H),3.66–3.56(m,1H),3.04–2.93(m,2H),2.23–2.14(m,2H),1.33–1.24(m,4H). ESI-MS: m / z=426.12[M+H] + .

[0038] Embodiment 3

[0039] The following compounds were prepared:

[0040]

[0041] This example adopts the same implementation method as Example 1, except that the trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with cyclohexylamine (46 μL, 0.29 mmol, 1.5 equiv.) to obtain 41.5 mg of the product, namely (H3) compound, with a yield of 43.1%. 1 HNMR (400MHz, CDCl 3 )δ8.77(s,1H),8.07(s,1H),7.28(s,1H),7.22(s,1H),5.83(s,1H),4.75(br s,J=9.4,5.0Hz,1H),4.36(t,J=4.6Hz,2H),4.23(t,J=4.8Hz,2H),3.46–3.3 8(m,1H),2.15(t,J=12.0,2.6Hz,2H),1.86–1.76(m,2H),1.46–1.24(m,6H). ESI-MS:m / z=368.14[M+H] + .

[0042] Embodiment 4

[0043] The following compounds were prepared:

[0044]

[0045] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with cyclopentylamine (39 μL, 0.39 mmol, 1.5 equiv.) to obtain 38.5 mg of product, namely (H4) compound, with a yield of 41.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.08(s,1H),8.35(s,1H),7.96(s,1H),7.38(s,1H),6.74(d,J=6.1Hz,1H),5.47(s,1H),4.34( t,J=4.7Hz,2H), 4.04(t,J=3.6Hz,2H), 3.89-3.84(m,1H), 2.06-2.02(m,2H), 1.76–1.53(m,6H). ESI-MS:m / z=354.12[M+H] + .

[0046] Embodiment 5

[0047] The following compounds were prepared:

[0048]

[0049] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with trans-4-isopropylcyclohexylamine (68 μL, 0.39 mmol, 1.5 equiv.) to obtain 28.5 mg of product, namely (H5) compound, with a yield of 23.1%. 1 HNMR (400MHz, CDCl 3 )δ8.77(d,J=0.4Hz,1H),8.05(d,J=0.4Hz,1H),7.29(d,J=1.6Hz,1H),7.20(d, J=1.6Hz,1H),5.76(s,1H),4.64(d,J=6.8Hz,1H),4.37(t,J=4.8Hz,2H),4.22(t ,J=4.8Hz,2H),3.77–3.68(m,1H),3.41–3.37(m,2H),2.28-2.25(m,2H),2.08-2 .04(m,2H),1.71(d,J=1.0Hz,2H),1.45-1.37(m,2H),1.18(s,3H),1.16(s,3H). ESI-MS: m / z = 426.18 [M+H] + .

[0050] Embodiment 6

[0051] The following compounds were prepared:

[0052]

[0053] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with 1-methylsulfonyl-4-aminopiperidine (70 mg, 0.39 mmol, 1.5 equiv.) to obtain 35.6 mg of product, namely, compound of formula (H6), with a yield of 30.4%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.05(s,1H),8.31(s,1H),7.89(s,1H),7.38(s,1H),6.74(d,J=7.7Hz,1H),5.59(s,1H),4.31(t,J=4.2Hz ,2H),4.04(t,2H),3.62-3.59(m,3H),2.92-2.89(m,2H),2.87(s,3H),2.05-2.02(m,2H),1.66-1.58(m,2H). ESI-MS: m / z=447.11[M+H] + .

[0054] Embodiment 7

[0055] The following compounds were prepared:

[0056]

[0057] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with trans-4-aminocyclohexanecarboxylic acid tert-butyl ester (78 mg, 0.39 mmol, 1.5 equiv.) to obtain 20.8 mg of product, namely (H7) compound, with a yield of 16.9%. 1 HNMR (400MHz, CDCl 3 )δ8.72(s,1H),8.02(s,1H),7.24(s,2H),5.71(s,1H),4.86–4.75(m,1H),4.34(t,J=4.6Hz,2H),4.21(t,J=4.8Hz,2H),3.4 3–3.30(m,1H),2.26-2.16(m,1H),2.06-1.97(m,2H),1.73–1.60(m,2H),1.58-1.51(m,2H),1.43(s,9H),1.31–1.23(m,2H). ESI-MS:m / z=468.19[M+H] + .

[0058] Embodiment 8

[0059] The following compounds were prepared:

[0060]

[0061] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with 1-acetylpiperidin-4-amine (90 μL, 0.66 mmol, 2.5 equiv.) to obtain 19.4 mg of product, namely (H8) compound, with a yield of 18%. 1 H NMR (400 MHz, CDCl 3)δ8.77(s,1H),8.07(s,1H),7.34(s,1H),7.31(s,1H),5.78(s,1H),4.96(d,J=7.2Hz, 1H), 4.68 (d, J = 14.2Hz, 1H), 4.38 (t, J = 4.8Hz, 2H), 4.22 (t, J = 4.8Hz, 2H), 3.91 (d, J = 4. 4Hz,1H),3.67(dd,J=10.6,4.6Hz,1H),3.23(dd,J=14.6,11.0Hz,1H),2.80(t,J=12.4H z, 1H), 2.29 (d, J = 12.0Hz, 1H), 2.18 (d, J = 13.2Hz, 1H), 2.13 (s, 3H), 1.54-1.47 (m, 2H). ESI-MS: m / z=411.14[M+H] + .

[0062] Embodiment 9

[0063] The following compounds were prepared:

[0064]

[0065] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with N-aminomorpholine (30 μL, 0.29 mmol, 1.1 equiv.) to obtain 30.4 mg of product, namely (H9) compound, with a yield of 31.3%. 1 HNMR (400MHz, CDCl 3 )δ8.75(s,1H),8.07(s,1H),7.37(s,1H),7.30(s,1H),6.48(s,1H),6.01(s,1H),4 .38(t,J=4.6Hz,2H), 4.26(t,J=4.6Hz,2H), 3.87-3.83(m,4H), 3.07–2.73(m,4H). ESI-MS:m / z=371.12[M+H] + .

[0066] Embodiment 10

[0067] The following compounds were prepared:

[0068]

[0069] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with cycloheptylamine (38 μL, 0.30 mmol, 1.5 equiv.) to obtain 33.9 mg of the product, namely (H10) compound, with a yield of 45.2%. 1 HNMR (400MHz, CDCl 3 )δ8.77(s,1H),8.06(s,1H),7.29(s,1H),7.27(s,1H),7.22(s,1H),5.66(s,1H),4 .75-474(m,1H),4.37(t,J=4.0Hz,2H),4.25(t,J=3.8Hz,2H),1.78–1.60(m,12H). ESI-MS: m / z=382.15[M+H] + .

[0070] Embodiment 11

[0071] The following compounds were prepared:

[0072]

[0073] This example adopts the same implementation method as Example 1, except that the trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with 4-amino-1-methylpiperidine (38 μL, 0.29 mmol, 1.0 equiv.) to obtain 13.4 mg of the product, namely, compound (H11), with a yield of 17.8%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.08(s,1H),8.40(s,1H),8.02(s,1H),7.39(s,1H),6.83(s,1H),5.54(s,1H),4.34(t,J=3.8Hz,2H),4.04(t ,J=3.8Hz,2H),3.46-3.64(m,4H),2.94-2.92(m,2H),2.28–2.16(m,2H),1.98-1.95(m,2H),1.80–1.67(m,2H). ESI-MS: m / z=383.15[M+H] + .

[0074] Embodiment 12

[0075] The following compounds were prepared:

[0076]

[0077] This example adopts the same implementation method as Example 1, except that the trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with 4-aminotetrahydropyran (30 μL, 0.29 mmol, 1.5 equiv.) to obtain 26.8 mg of the product, namely (H12) compound, with a yield of 37%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.09(s,1H),8.36(s,1H),7.95(s,1H),7.41(s,1H),6.74(d,J=7.4Hz,1H),5.63(s,1H),4.35(t,J=3.8Hz,2H),4.04 (t,J=3.8Hz,2H),3.93-3.90(m,2H),3.73–3.65(m,1H),3.48(t,J=11.6Hz,2H),1.95-1.92(m,2H),1.70–1.56(m,2H). ESI-MS: m / z=370.12[M+H] + .

[0078] Embodiment 13

[0079] The following compounds were prepared:

[0080]

[0081] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with 3-aminotetrahydrofuran (21 μL, 0.29 mmol, 1.5 equiv.) to obtain 29.3 mg of the product, namely (H13) compound, with a yield of 43.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.05(s,1H),8.31(s,1H),7.95(s,1H),7.36(s,1H),6.94(d,J=5.4Hz,1H),5.45(s,1H),4.31(t,J=3.8Hz,2H),4.13-4.12(m ,1H),4.01(t,J=3.8Hz,2H),3.92–3.83(m,2H),3.78(d,J=7.4Hz,1H),3.73-3.67(m,1H),2.28-2.19(m,1H),2.01–1.91(m,1H). ESI-MS:m / z=356.10[M+H] + .

[0082] Embodiment 14

[0083] The following compounds were prepared:

[0084]

[0085] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with 3-oxetanamine (30 μL, 0.29 mmol, 1.5 equiv.) to obtain 30.1 mg of product, namely (H14) compound, with a yield of 42.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.06(s,1H),8.31(s,1H),7.94(s,1H),7.54(s,1H),7.42(s,1H),5.16(s,1H),4.90(t,J=5 .6Hz,2H),4.66-4.63(m,1H),4.62-4.59(m,2H),4.31(t,J=3.8Hz,2H),4.00(t,J=3.4Hz,2H). ESI-MS:m / z=342.09[M+H] + .

[0086] Embodiment 15

[0087] The following compounds were prepared:

[0088]

[0089] This example adopts the same implementation method as Example 1, except that the trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with n-propylamine (41 μL, 0.49 mmol, 1.5 equiv.) to obtain 52.9 mg of the product, namely, compound (H15), with a yield of 49.4%. 1 HNMR (400MHz, CDCl 3 )δ8.77(s,1H),8.06(s,1H),7.28(d,J=8.8Hz,2H),5.74(s,1H),4.93(d,J=2.8Hz,1H),4.37 (t,J=4.6Hz,2H),4.20(t,J=4.6Hz,2H),3.26–3.18(m,2H),1.83–1.74(m,2H),1.06(t,3H). ESI-MS: m / z=328.12[M+H] + .

[0090] Embodiment 16

[0091] The following compounds were prepared:

[0092]

[0093] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with 2-methoxyethylamine (43 μL, 0.49 mmol, 1.5 equiv.) to obtain 39.8 mg of product, namely (H16) compound, with a yield of 35.4%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.08(s,1H),8.34(s,1H),7.93(s,1H),7.42(s,1H),7.21(t,J=5.0Hz,1H),5.50(s,1H),4.35 (t,J=4.2Hz,2H),4.04(t,J=4.2Hz,2H),3.58(t,J=5.4Hz,2H),3.43–3.39(m,2H),3.30(s,3H). ESI-MS: m / z=344.10[M+H] + .

[0094] Embodiment 17

[0095] The following compounds were prepared:

[0096]

[0097] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with N,N-dimethylethylenediamine (54uL, 0.49mmol, 1.5equiv.) to obtain 33.6mg of product, namely (H17) compound, with a yield of 28.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.08(s,1H),8.36(s,1H),7.92(s,1H),7.42(s,1H),7.15(t,J=4.6Hz,1H),5.50(s,1H),4.35(t,J =4.2Hz, 2H), 4.04 (t, J = 4.2Hz, 2H), 3.37 (dd, J = 12.0, 6.0Hz, 2H), 2.69 (t, J = 6.4Hz, 2H), 2.35 (s, 6H). ESI-MS:m / z=357.13[M+H] + .

[0098] Embodiment 18

[0099] In order to verify the inhibitory activity of the compounds of Examples 1 to 17 of the present invention on CD38 in practical applications, the compounds that inhibit the hydrolase activity of CD38 were screened in the form of fluorescent 384 wells. First, prepare 1 times the detection buffer. Then, transfer 200nL of the compound to the detection plate by Echo in 100% DMSO, and the final fraction of DMSO is 1%; add CD38 protein to the 1 times detection buffer to make a protein mixed solution; then add ε-NAD to the 1 times detection buffer to make a substrate mixed solution; add 10uL 2x protein mixture to the detection plate, centrifuge for 30s, shake for 30s, and incubate at 25°C for 15min; continue to add 10μL 2x substrate mixture to the detection plate, centrifuge for 30s, shake for 30s, and incubate at 25°C for 1h; use an enzyme reader to read the detection plate in the collaborative dynamics of Ex300 / Em410. The data were fitted into Excel, and the inhibition value was obtained according to the following formula: Inhibition rate (%) = (Max-Signal) / (Max-Min)×100, wherein Max is the value read by the microplate reader of the wells on the test plate to which DMSO, protein mixed solution and substrate mixed solution were added, Min is the value read by the microplate reader of the wells on the test plate to which DMSO and substrate mixed solution were added, and Signal is the value read by the microplate reader of the wells on the test plate to which CD38 inhibitory compounds, protein mixed solution and substrate mixed solution were added;

[0100] Table 1 Inhibitory activity of the compounds of the present invention on CD38

[0101]

[0102]

[0103] It can be seen from the inhibitory activity data in Table 1 that H1-H10 and H12-H15 of the present invention exhibit good CD38 inhibitory activity and have good application prospects.

Claims

1. A CD38 inhibitory compound, the structural formula of which is as follows: Where R is 2. A free form, a pharmaceutically acceptable salt or a solvate of a CD38 inhibitory compound according to claim 1.

3. A pharmaceutical composition, characterized in that: It consists of a CD38 inhibitory compound as claimed in claim 1 and a pharmaceutically acceptable carrier.

4. Use of a CD38 inhibitory compound according to claim 1 in inhibiting CD38 hydrolase activity.

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