A cd38 inhibiting compound and uses thereof

Abstract

A CD38 inhibiting compound and application, the structural formula is as follows: the free form and the pharmaceutically acceptable salt or solvate of the CD38 inhibiting compound can be used to improve the NAD + Level provides a new treatment method. It is proved by experiment that the compound with general formula (I) provided by the application can inhibit CD38 with high intensity, can effectively increase the NAD + Level in vivo, and has the prospect of being developed into a drug.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a CD38 inhibitory compound and its application. 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 include enzyme catalysis, receptor function, and participation in cellular calcium ion conduction. CD38 is ubiquitous in various tissue cells, such as B cells, T cells, phagocytes, natural killer cells, smooth muscle cells, glial cells, and cells in the kidney, brain, liver, and heart. CD38 has been implicated in the development of numerous diseases.

[0003] CD38 belongs to the ADP-ribose cyclase family and has the activities of ADP-ribose cyclase and glycohydrolase. It uses nicotinamide adenine dinucleotide (NAD + ), 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, into NADP-ribose. + CD38 has been shown to be a NAD + levels of key regulatory factors.

[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 synthesis. + It can produce or inhibit the consumption of NAD through the nicotinamide precursor synthesis pathway. + enzymes to reduce NAD + Consumption, using NAD + Synthesis of the precursors nicotinamide riboside and nicotinamide mononucleotide 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 for the development of 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 are decreasing. 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 response to the above problems, the present invention provides a CD38 inhibitory compound and its application.

[0008] In a 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] The preparation process of the compound is as follows:

[0015]

[0016] 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 completion, add ethyl acetate (50 mL) to the reaction solution, followed by saturated sodium bicarbonate solution (75 mL). Separate the layers to obtain an aqueous layer. Add hydrochloric acid to the aqueous layer to adjust the pH to 1-2. Add DCM solution (150 mL), separate the layers to obtain an organic layer, dry over anhydrous sodium sulfate, and spin-dry the organic solvent to obtain a white solid. Add Eaton's reagent (75 g, 5.0 equiv.) and react at 60°C for 2 h. After completion, add ice-water mixture, filter, and dry to obtain a red product, namely, compound of formula (II).

[0017] 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 completion of the reaction, slowly add the reaction solution dropwise to an aqueous solution (50 mL). Stir for 30 minutes, then add DCM (200 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and spin-dry the organic solvent to obtain a brown solid, namely, the compound of formula (III).

[0018] 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.), and potassium carbonate (20.0 g, 144.72 mmol, 3.0 equiv.) to a two-necked flask. The atmosphere in the flask was replaced with nitrogen three times. 1,4-dioxane / water (50 mL v / v 4:1) was added. The reaction was allowed to react at 105°C for 16 h. After completion of the reaction, DCM (100 mL) and water (50 mL) were added to the reaction mixture. 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 100:1 as the eluent. The organic solvent containing the target product was collected, concentrated and dried to obtain a yellow solid product, namely the compound of formula (IV).

[0019] 4. The compound of formula (IV) (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.), and sodium tert-butoxide (33.4 mg, 0.58 mmol, 3.55 equiv.) were added to a two-necked flask. The atmosphere in the flask was replaced with nitrogen three times, and RNH2 (0.25 mmol, 1.5 equiv.) and anhydrous 1,4-dioxane were added. The reaction was carried out at 115°C for 20 h. After completion of the reaction, DCM (25 ml) and water (10 mL) were added to the reaction mixture. 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, and the organic solvent containing the target product was collected and concentrated to dryness to obtain the final product.

[0020] where R is

[0021] Preferably, the protection scope of the present invention covers the free form and pharmaceutically acceptable salt or solvate of a CD38 inhibitory compound.

[0022] In a second aspect, the present invention provides a CD38 inhibitory compound for use as a drug for treating a CD38-mediated disease, wherein the CD38-mediated disease is one of a myocardial disease or condition, a metabolic disease, aging, atherosclerosis, cardiovascular disease, multiple myeloma, stromal cell carcinoma, gastric cancer, breast cancer, lung 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.

[0023] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned CD38 inhibitory compound and a pharmaceutically acceptable carrier.

[0024] The CD38 inhibitor of the present invention can increase the NAD + The present invention provides a new treatment method. The compound of formula (I) provided by the present invention can inhibit CD38 with high intensity and effectively increase NAD + level, and has the prospect of being developed into a drug. DETAILED DESCRIPTION

[0025] Example 1

[0026]

[0027] The following compounds were prepared:

[0028]

[0029] 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 completion, add ethyl acetate (50 mL) to the reaction solution, followed by saturated sodium bicarbonate solution (75 mL). Separate the layers to obtain an aqueous layer. Add hydrochloric acid to the aqueous layer to adjust the pH to 1-2. Add DCM solution (150 mL), separate the layers to obtain an organic layer, dry over anhydrous sodium sulfate, and spin-dry the organic solvent to obtain a white solid. Add Eaton's reagent (75 g, 5.0 equiv.) and react at 60°C for 2 h. After completion, add ice-water mixture, filter, and dry to obtain 15.6 g of a red product, compound of formula (II), in a yield of 78.9%. 1 H NMR (400MHz, DMSO-d6) δ 11.64 (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] + .

[0030] 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 completion of the reaction, slowly add the reaction solution dropwise to an aqueous solution (50 mL). After stirring for 30 minutes, add DCM (200 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and spin dry the organic solvent to obtain 14.8 g of a brown solid, compound of formula (III), in a 92.6% yield. 1 H NMR (400MHz, DMSO-d6) δ7.58 (s, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.02 (s, 1H), 4.38 (t, J = 4.6 Hz, 2H), 4.08 (t, J = 4.6 Hz, 2H). ESI-MS:m / z=301.48[M+H] + .

[0031] 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.), and potassium carbonate (20.0 g, 144.72 mmol, 3.0 equiv.) to a two-necked flask. The atmosphere in the flask was replaced with nitrogen three times. 1,4-dioxane / water (50 mL v / v 4:1) was added. The reaction was allowed to react at 105°C for 16 h. After completion of the reaction, DCM (100 mL) and water (50 mL) were added to the reaction mixture. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and filtered. After concentration, the residue was purified by silica gel column chromatography using a mixture of dichloromethane and methanol in a volume ratio of 100:1 as the eluent. The organic solvent containing the target product was collected, concentrated and dried to obtain 8.56 g of a yellow solid product, namely the compound of formula (IV), with a yield of 58.2%. 1 H NMR (400MHz, CDCl3) δ 8.78 (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] + .

[0032] 4. The compound of formula (IV) (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.), and sodium tert-butoxide (33.4 mg, 0.58 mmol, 3.55 equiv.) were added to a two-necked flask. The atmosphere in the flask was replaced with nitrogen three times, and trans-4-trifluoromethylcyclohexylamine (41.1 mg, 0.25 mmol, 1.5 equiv.) and anhydrous 1,4-dioxane were added. The reaction was carried out at 115°C for 20 h. After completion of the reaction, DCM (25 ml) and water (10 mL) were added to the reaction mixture. 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, concentrated and dried to obtain 10 mg of a light yellow solid product, namely the compound of formula (H1), with a yield of 14%. 1H NMR (400MHz, 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] + .

[0033] Example 2

[0034] The following compounds were prepared:

[0035]

[0036] 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 the product, i.e., compound (H2), with a yield of 19.3%. 1 H NMR (400MHz, CDCl3) 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] + .

[0037] Example 3

[0038] The following compounds were prepared:

[0039]

[0040] This example adopts the same implementation method as Example 1, except that 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, i.e., compound (H3), with a yield of 43.1%.1 H NMR (400MHz, CDCl3) 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] + .

[0041] Example 4

[0042] The following compounds were prepared:

[0043]

[0044] 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 the product, namely, compound (H4), with a yield of 41.6%. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0045] Example 5

[0046] The following compounds were prepared:

[0047]

[0048] 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 the product, i.e., compound (H5), with a yield of 23.1%. 1H NMR (400MHz, CDCl3) 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] + .

[0049] Example 6

[0050] The following compounds were prepared:

[0051]

[0052] This example adopts the same implementation method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with 1-methanesulfonyl-4-aminopiperidine (70 mg, 0.39 mmol, 1.5 equiv.) to obtain 35.6 mg of the product, namely, the compound of formula (H6), with a yield of 30.4%. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0053] Example 7

[0054] The following compounds were prepared:

[0055]

[0056] 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 the product, i.e., compound (H7), with a yield of 16.9%. 1 H NMR (400MHz, CDCl3) 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),3.43-3.30(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] + .

[0057] Example 8

[0058] The following compounds were prepared:

[0059]

[0060] 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 the product, i.e., compound (H8), with a yield of 18%. 1 H NMR (400MHz, CDCl3) δ8.77(s,1H),8.07(s,1H),7.34(s,1H),7.31(s,1H),5.78(s,1H),4.9 6(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),3.9 1(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=1 2.4Hz, 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] + .

[0061] Example Nine

[0062] The following compound was prepared:

[0063]

[0064] This example employed the same procedure as Example 1 except that in Step 4, trans-4-trifluoromethylcyclohexylamine was replaced with N-aminomorpholine (30 μL, 0.29 mmol, 1.1 equiv.) to give 30.4 mg of product, the (H9) compound, in 31.3% yield. 1 H NMR (400 MHz, CDC13) δ 8.75 (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 = 4.6 Hz, 2H), 4.26 (t, J = 4.6 Hz, 2H), 3.87 - 3.83 (m, 4H), 3.07 - 2.73 (m, 4H). ESI-MS: m / z = 371.12 [M+H] + .

[0065] Example Ten

[0066] The following compound was prepared:

[0067]

[0068] This example employed the same procedure as Example 1 except that in Step 4, trans-4-trifluoromethylcyclohexylamine was replaced with N-aminomorpholine (30 μL, 0.29 mmol, 1.1 equiv.) to give 30.4 mg of product, the (H9) compound, in 31.3% yield. 1 H NMR (400 MHz, CDC13) δ 8.75 (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 = 4.6 Hz, 2H), 4.26 (t, J = 4.6 Hz, 2H), 3.87 - 3.83 (m, 4H), 3.07 - 2.73 (m, 4H). ESI-MS: m / z = 371.12 [M+H] + .

[0069] Example Eleven

[0070] The following compound was prepared:

[0071]

[0072] This example adopts the same implementation method as Example 1, except that 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 (400MHz, DMSO-d6) 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,2 H), 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] + .

[0073] Example 12

[0074] The following compounds were prepared:

[0075]

[0076] This example adopts the same implementation method as Example 1, except that 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, i.e., compound (H12), with a yield of 37%. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0077] Example 13

[0078] The following compounds were prepared:

[0079]

[0080] 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, i.e., compound (H13), with a yield of 43.6%. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0081] Example 14

[0082] The following compounds were prepared:

[0083]

[0084] 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 the product, namely, compound (H14), with a yield of 42.6%. 1 H NMR(400MHz,DMSO-d6)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] + .

[0085] Example 15

[0086] The following compounds were prepared:

[0087]

[0088] This example adopts the same implementation method as Example 1, except that 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 H NMR (400MHz, CDCl3) 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 = 4.6 Hz, 2H), 4.20 (t, J = 4.6 Hz, 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] + .

[0089] Example 16

[0090] The following compounds were prepared:

[0091]

[0092] 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 the product, namely, compound (H16), with a yield of 35.4%. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0093] Embodiment 17

[0094] The following compounds were prepared:

[0095]

[0096] This example uses the same method as Example 1, except that trans-4-trifluoromethylcyclohexylamine in step 4 is replaced with N,N-dimethylethylenediamine (54 uL, 0.49 mmol, 1.5 equiv.) to obtain 33.6 mg of the product, i.e., compound (H17), with a yield of 28.6%. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0097] Example 18

[0098] To verify the inhibitory activity of the compounds of Examples 1 to 17 of the present invention against CD38 in practical applications, compounds that inhibit CD38 hydrolase activity were screened using a 384-well fluorescence format. First, a 1x assay buffer was prepared. Then, 200 nL of compound was transferred to an assay plate in 100% DMSO using an echo method, resulting in a final DMSO concentration of 1%. CD38 protein was added to the 1x assay buffer to create a protein mixture. Next, ε-NAD was added to the 1x assay buffer to create a substrate mixture. 10 μL of the 2x protein mixture was added to the assay plate, centrifuged for 30 seconds, shaken for 30 seconds, and incubated at 25°C for 15 minutes. Furthermore, 10 μL of the 2x substrate mixture was added to the assay plate, centrifuged for 30 seconds, shaken for 30 seconds, and incubated at 25°C for 1 hour. The assay plate was then read using a microplate reader on the Ex300 / Em410 collaborative dynamic reader. The data were fitted into Excel, and the inhibition value was calculated according to the following formula: Inhibition rate (%) = (Max-Signal) / (Max-Min)×100, where Max is the value read by the microplate reader for the wells on the assay plate to which DMSO, protein mixture solution, and substrate mixture solution were added; Min is the value read by the microplate reader for the wells on the assay plate to which DMSO and substrate mixture solution were added; and Signal is the value read by the microplate reader for the wells on the assay plate to which CD38 inhibitory compound, protein mixture solution, and substrate mixture solution were added.

[0099] Table 1 Inhibitory activity of the compounds of the present invention on CD38

[0100] Compound <![CDATA[CD38(IC 50 ,nM)]]> Compound <![CDATA[CD38(IC 50 ,nM)]]> H1 50 H10 7.9 H2 11 H11 ＞1000 H3 14 H12 43 H4 48 H13 112 H5 4.4 H14 83 H6 25 H15 66 H7 27 H16 ＞1000 H8 14 H17 ＞1000 H9 89

[0101] From the inhibitory activity data in Table 1, it can be seen 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 having the following structural formula: (Ι) where R is 、 、 、 、 、 、 、 、 、 、 、 、 or .

2. A pharmaceutically acceptable salt of a CD38 inhibitory compound according to claim 1.

3. A pharmaceutical composition, characterized in that: The invention comprises a CD38 inhibitory compound according to claim 1 and a pharmaceutically acceptable carrier.

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

Images