Pteridinone compound and application thereof

Abstract

The invention provides a pteridinone compound and application thereof. The structure of the pteridinone compound is as shown in formula I in the specification. The pteridinone compound provided by the invention can effectively inhibit mTOR kinase, has an excellent anti-tumor effect, and is low in toxicity, small in harm to organs, safe and efficient.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and specifically relates to a pteridinone compound and applications thereof. Background Art

[0002] Tumors are diseases caused by abnormal cell proliferation. Unlimited tumor cells invade and destroy normal tissues and organs, affecting physiological functions and ultimately leading to death. Tumors are serious diseases that pose a serious threat to human life and health. Existing treatment options primarily include surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. With the advancement of molecular biology, tumor treatment strategies have gradually shifted from traditional chemotherapy to precision targeted therapies targeting specific molecular phenotypes or signaling pathways. Targeted drugs have become a hot topic in anti-tumor drug research and development.

[0003] The PI3K / AKT / mTOR signaling pathway is abnormally activated in various malignancies and plays a crucial role in cell growth, proliferation, differentiation, and apoptosis. Therefore, targeting the PI3K / AKT / mTOR signaling pathway is a promising strategy for cancer therapy. mTOR, a key serine-threonine protein kinase downstream of PI3K / AKT, exists as two protein complexes (mTORC1 and mTORC2) and participates in biological processes such as gene transcription, protein translation, and ribosome biogenesis. It plays a crucial role in cell growth, apoptosis, autophagy, and metabolism. Sustained overactivation of mTOR signaling can lead to elevated cellular metabolism, sustained growth and proliferation, prolonged cell lifespan, and even cell immortalization, directly or indirectly inducing malignancy. Inhibiting this state can effectively delay or treat malignancies and other diseases caused by mTOR overactivation. Consequently, the development of mTOR inhibitors has attracted widespread attention, and many candidate drugs have entered clinical trials.

[0004] Existing mTOR inhibitors are generally classified into mTOR allosteric inhibitors and ATP-competitive inhibitors based on their site of action. Allosteric inhibitors, represented by rapamycin and its derivatives, only inhibit mTORC1 and do not affect mTORC2 activity. With long-term use, the negative feedback loop of mTORC1 on AKT activates upstream pathways of this signaling pathway, leading to drug resistance. Furthermore, these inhibitors suffer from drawbacks such as low bioavailability and difficulty in synthesis, limiting their clinical application. ATP-competitive mTOR inhibitors act directly at the ATP binding site of the mTOR kinase catalytic domain, inhibiting both mTORC1 and mTORC2 and suppressing feedback activation of AKT. These inhibitors overcome the shortcomings of rapamycin and offer greater therapeutic potential. However, the reduced selectivity between mTORC1 and mTORC2 can lead to increased toxic side effects. The main drawback of ATP-competitive inhibitors is their significant toxicity. For example, PI-103, MLN0128, and AZD8055 have been associated with side effects such as diarrhea, anemia, neutropenia, and non-infectious pneumonia. Furthermore, long-term use of the same mTOR inhibitor can still lead to the development of drug resistance. Existing mTOR inhibitors cannot achieve ideal clinical therapeutic effects. Therefore, it is still necessary to develop novel, safe, efficient and resistant mTOR inhibitors. Summary of the Invention

[0005] In response to the shortcomings of the prior art, the present invention aims to provide a pteridinone compound and its application. The pteridinone compound provided by the present invention can effectively inhibit mTOR kinase, has excellent anti-tumor effects, and is low in toxicity, has little damage to organs, and is safe and highly effective.

[0006] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0007] In a first aspect, the present invention provides a pteridinone compound, the structure of which is shown in Formula I:

[0008]

[0009] Among them, R 1 is selected from substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C12 heteroaryl;

[0010] R 2 Any one selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, or substituted or unsubstituted C3-C12 cycloalkyl; the carbon atoms in the C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or C3-C12 cycloalkyl are independently unsubstituted or at least one carbon atom is replaced by any one of O, S, or N;

[0011] R 3 、R 4 Independently selected from substituted or unsubstituted C1-C6 alkyl.

[0012] The above-mentioned pteridinone compounds with specific structures can effectively inhibit mTOR kinase and have excellent anti-tumor effects. At the same time, they have low toxicity, little damage to organs, and are safe and efficient.

[0013] Preferably, the substituted substituent is selected from any one of halogen, hydroxyl, acyl, carboxyl, amino, nitro, thiol, aldehyde, C1-C6 alkoxy, C6-C20 aryl, C3-C20 heteroaryl, C1-C6 alkyl, C3-C12 cycloalkyl, amide or cyano.

[0014] Preferably, the R 2 Selected from any one of the following groups:

[0015]

[0016] Preferably, the R 1 Selected from any one of the following groups:

[0017]

[0018]

[0019] Preferably, the R 3 、R 4 Independently selected from C1-C6 alkyl, preferably methyl, ethyl, n-propyl or isopropyl.

[0020] Preferably, the pteridinone compound is selected from any one of the following compounds (corresponding to Examples 1-109, respectively):

[0021]

[0022]

[0023]

[0024]

[0025]

[0026] In a second aspect, the present invention provides use of the pteridinone compound described above in the preparation of an mTOR inhibitor.

[0027] In a third aspect, the present invention provides use of the pteridinone compounds described above in the preparation of drugs for treating and / or preventing diseases involving the mTOR signaling pathway.

[0028] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the pteridinone compound as described above.

[0029] In a fifth aspect, the present invention also provides the use of the pteridinone compounds described above in the preparation of drugs for treating and / or preventing tumors.

[0030] Preferably, the tumor includes colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, cervical cancer, esophageal cancer, gallbladder cancer, malignant glioma, myeloproliferative disease, leukemia or lymphoma.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The present invention provides a pteridinone compound with a specific structure, which can effectively inhibit mTOR kinase and has excellent anti-tumor effects. At the same time, it has low toxicity, little damage to organs, and is safe and efficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the HE staining result of the compound's in vivo toxicology / safety study. DETAILED DESCRIPTION

[0034] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0035] The following examples provide pteridinone compounds with different structures.

[0036] Example 1. trans-4-(4-amino-6-(6-hydroxybenzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR133)

[0037] The synthesis method comprises the following steps:

[0038] Step 1. Synthesis of 5-nitrosopyrimidine-4,6-diamine

[0039]

[0040] To a solution of 4,6-diaminopyrimidine (8.0 g, 72.65 mmol) in hydrochloric acid (2N, 250 mL) was added aqueous sodium nitrite (4.2 g, 15 mL of water) at 0°C, stirred at 20°C for 2 hours, and quenched with saturated aqueous sodium carbonate at 0°C (adjusted to pH > 7). A blue solid was obtained by filtration, and the filter cake was washed with water and methanol, then dried under reduced pressure to give the title compound (4.5 g, yield: 45%). 1 H NMR (500MHz, DMSO-d6) δ10.05(s,1H),9.10(s,1H),8.42(s,1H),8.03(s,1H),7.93(s,1H).

[0041] Step 2. Synthesis of cis-4-((methylsulfonyl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0042]

[0043] To a solution of cis-4-hydroxycyclohexane-1-carboxylic acid methyl ester (5.0 g, 31.64 mmol) in dichloromethane (60 mL) was added triethylamine (6.8 mL, 63.29 mmol) and methanesulfonyl chloride (5.44 g, 47.46 mmol) at 0°C. The mixture was stirred at 20°C overnight and then quenched with water. The aqueous phase was extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (6.4 g, yield: 86%) was isolated as a white solid by flash column chromatography (petroleum ether / ethyl acetate: 80 / 20). 1 H NMR(500MHz,Chloroform-d)δ4.90(br s,1H),3.68(s,3H),3.01(s,3H),2.40(td,J=9.8,4.4Hz,1H),2.08–1.99(m,2H),1.96–1.87(m,2H),1.82–1.75(m,2H),1.74–1.65(m,2H).

[0044] Step 3. Synthesis of methyl 2-(6-hydroxybenzofuran-3-yl)acetate

[0045]

[0046] To a methanol solution (250 mL) of 2-(6-hydroxybenzofuran-3-yl)acetic acid (15.0 g, 78.06 mmol) was added thionyl chloride (6.78 mL, 93.67 mmol) at 0°C. The mixture was then stirred at 20°C for 2 hours. Most of the solvent was removed under reduced pressure, and the residue was diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 x 150 mL). The organic phases were combined, washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (15.2 g, 95% yield) as a white solid. The product was used in the next step without further purification.

[0047] Step 4. Synthesis of methyl 2-(6-(benzyloxy)benzofuran-3-yl)acetate

[0048]

[0049] To a solution of methyl 2-(6-hydroxybenzofuran-3-yl)acetate (15.2 g, 73.79 mmol) in acetone (250 mL) was added potassium carbonate (30.55 g, 221.37 mmol) and benzyl bromide (15.14 g, 88.55 mmol) at 0°C. The mixture was stirred at 20°C overnight. Upon completion of the reaction, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (2 x 180 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (16.4 g, 75% yield) was isolated as a white solid by flash column chromatography (petroleum ether / ethyl acetate: 80 / 20). 1 H NMR(500MHz,Chloroform-d)δ7.53(d,J=1.2Hz,1H),7.45(d,J=7.1Hz,2H),7.43(d,J=8.6Hz,1H),7.39(t,J=7.6Hz ,2H),7.36–7.30(m,1H),7.08(d,J=2.2Hz,1H),6.98(dd,J=8.6,2.2Hz,1H),5.11(s,2H),3.73(s,3H),3.67(s,2H).

[0050] Step 5. Synthesis of 4-amino-6-(6-(benzyloxy)benzofuran-3-yl)pteridin-7(8H)-one

[0051]

[0052] To a solution of methyl 2-(6-(benzyloxy)benzofuran-3-yl)acetate (7.2 g, 24.32 mmol) and 5-nitrosopyrimidine-4,6-diamine (2.7 g, 19.42 mmol) in anhydrous ethanol (150 mL) was added a 20% ethanolic solution of sodium ethoxide (15.1 g, 43.50 mmol) at 0°C. The mixture was refluxed and stirred for 3 hours. After cooling, the mixture was filtered, and the filter cake was washed with ethanol, dichloromethane, and methanol, respectively, and dried to obtain the title compound (4.56 g, yield: 61%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.25(s,1H),8.62(d,J=8.6Hz,1H),8.09(s,1H),7.51(d,J=7.5Hz,2H ),7.41(t,J=7.5Hz,2H),7.36–7.31(m,1H),7.31(s,1H),7.05(dd,J=8.7,2.4Hz,1H),6.76(br s,2H),5.19(s,2H).

[0053] Step 6. Synthesis of trans-4-(4-amino-6-(6-(benzyloxy)benzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid methyl ester

[0054]

[0055] To a solution of 4-amino-6-(6-(benzyloxy)benzofuran-3-yl)pteridin-7(8H)-one (300 mg, 0.78 mmol) in N,N-dimethylformamide (6.0 mL) were added cesium carbonate (282 mg, 0.86 mmol) and methyl 4-((methylsulfonyl)oxy)cyclohexane-1-carboxylate (199 mg, 0.86 mmol), and the mixture was stirred at 80°C for 2 hours. Then, methyl 4-((methylsulfonyl)oxy)cyclohexane-1-carboxylate (199 mg, 0.86 mmol) was added. After stirring at 80°C for 2 hours, methyl 4-((methylsulfonyl)oxy)cyclohexane-1-carboxylate (199 mg, 0.86 mmol) was further added, and stirring was continued at 80°C for 2 hours. The reaction solution was cooled to 20°C, diluted with water, and extracted with ethyl acetate (2×180 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (135 mg, yield: 33%) was obtained by separation using flash column chromatography (petroleum ether / ethyl acetate: 3 / 1 to DCM / MeOH: 100 / 1) to afford a yellow solid. 1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.42(s,1H),8.26(d,J=8.7Hz,1H),7 .50(d,J=6.3Hz,2H),7.42(d,J=7.8Hz,2H),7.37–7.33(m,1H),7.28(s,1H),7.1 9(d,J=2.3Hz,1H),5.54(br,1H),5.17(s,2H),3.73(s,3H),2.89–2.84(br,2H), 2.60–2.48(m,1H),2.21(d,J=12.8Hz,2H),1.87–1.80(m,2H),1.76–1.72(m,2H).

[0056] Step 7. Synthesis of trans-4-(4-amino-6-(6-hydroxybenzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid methyl ester

[0057]

[0058] To a solution of methyl trans-4-(4-amino-6-(6-(benzyloxy)benzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylate (1.2 g, 2.29 mmol) and ammonium acetate (2.89 g, 45.89 mmol) in methanol (30 mL) was added palladium on carbon (1.0 g, 50% weight), and the mixture was stirred at reflux for 1 hour. After cooling, the mixture was filtered through celite, and the filtrate was concentrated and separated by flash column chromatography (DCM / MeOH: 80 / 1) to give a yellow solid, the title compound (647 mg, yield: 65%). 1 HNMR(500MHz,DMSO-d6)δ9.69(s,1H),9.02(s,1H),8.45(d,J=8.6Hz,1H),8.34(s,1H),7.94(br s,1H),7.24(br s,1H),6.99(d,J=2.1Hz,1H),6.91(dd,J=8.6,2.2Hz,1H),5.42(brs,1H),3.64(s,3H),2.73(d,J= 12.7Hz, 2H), 2.48–2.36 (m, 1H), 2.09 (d, J = 13.0Hz, 2H), 1.75 (d, J = 12.2Hz, 2H), 1.60–1.44 (m, 2H).

[0059] Step 8. Synthesis of trans-4-(4-amino-6-(6-hydroxybenzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid

[0060]

[0061] To a solution of trans-4-(4-amino-6-(6-hydroxybenzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid methyl ester (1.08 g, 2.48 mmol) in tetrahydrofuran (30 mL) / methanol (30 mL) was slowly added sodium hydroxide solution (1N, 30 mL) at 20°C, and the mixture was then stirred at 20°C overnight, quenched with dilute hydrochloric acid (0.5 M) and adjusted to pH 5-6. A yellow solid precipitated, which was filtered, washed with water and cold methanol, and dried to give a yellow solid, the title compound (725 mg, yield: 70%). 1 H NMR (500MHz, DMSO-d6) δ12.16(s,1H),9.71(s,1H),9.03(s,1H),8.45(d,J=8.5Hz,1H),8.34(s,1H),7.97(br s,1H),7.25(br s,1H),6.99(d,J=2.1Hz,1H),6.91(dd,J=8.6,2.1Hz,1H),5.41(br s,1H),2.71(br,2H),2.28(t,J=12.5Hz,1H),2.08(d,J=12.9Hz,2H),1.73(d,J=12.1Hz,2H),1.48(q,J=12.6Hz,2H).

[0062] Example 2. trans-4-(4-amino-6-(2-methylbenzo[d]oxazol-5-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR001)

[0063] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-methylbenzo[d]oxazol-5-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.13(s,1H),8.76(d,J=1.7Hz,1H),8.48(dd,J=8.7,1.7Hz,1H),8.30(s,1H),7.90(br s,1H),7.84(br s,1H),7.71(d,J=8.7Hz,1H),5.35(br,1H),2.75–2.66(m,2H),2.65(s,3H),2.27(t,J=12. 3Hz,1H),2.07(d,J=12.9Hz,2H),1.78–1.67(m,2H),1.47(q,J=13.7,13.1Hz,2H).ESI-MS:C 21 H 20N6O4[MH] - found419.4.

[0064] Example 3. trans-4-(4-amino-7-oxo-6-(pyridin-2-yl)pteridin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR003)

[0065] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(pyridin-2-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.15(br s,1H),8.68(d,J=4.8Hz,1H),8.32(s,1H),8.00–7.87(m,2H),7.85(br s,1H),7.60(br s,1H),7.48(td,J=5.4,2.6Hz,1H),5.32(br s,1H),2.68–2.62(m,2H),2.23(t,J=12.3Hz,1H),2.05(d,J=13.1Hz,2H),1.76–1.66(m,2H),1.56–1.39(m,2H).ESI-MS:C 18 H 18 N6O3[MH] - found 365.2.

[0066] Example 4. trans-4-(4-amino-6-(7-methoxy-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR004)

[0067] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(7-methoxy-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.14(br s,1H),11.70(s,1H),8.63(s,1H),8.29(s,1H),7.85(s,1H),7.77(s,1H) ,7.25(d,J=8.0Hz,1H),6.97(t,J=7.8Hz,1H),6.79(d,J=7.7Hz,1H),5.37 (br,1H),3.99(s,3H),2.75–2.71(m,2H),2.29(t,J=12.6Hz,1H),2.08(d,J=13.0Hz,2H),1.72(d,J=12.6Hz,3H),1.48(q,J=12.8Hz,2H).ESI-MS:C 22 H 22 N6O4[MH]- found 433.6.

[0068] Example 5. trans-4-(4-amino-6-(3-fluoro-4-methoxyphenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR006)

[0069] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(3-fluoro-4-methoxyphenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.14(br,1H),8.49–8.44(m,2H),8.29(s,1H),7.95(br s,1H),7.83(br s,1H),7.23(t,J=9.0Hz,1H),5.34(br s,1H),3.93(s,3H),2.75–2.63(m,2H),2.27(t,J=12.7Hz,1H),2.07(d,J=13.2Hz,2H),1.70(d,J=12.0Hz,2H),1.55–1.41(m,2H).ESI-MS:C 20 H 20 FN5O4[MH] - found 412.2.

[0070] Example 6. trans-4-(4-amino-6-(4-methoxyphenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR007)

[0071] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-methoxyphenyl)acetate. 1 HNMR(500MHz,Methanol-d4)δ8.35(d,J=9.0Hz,2H),8.26(s,1H),7.00(d,J=9.0Hz,2H),5.47(br s,1H),3.87(s,3H),2.87–2.80(m,2H),2.41(tt,J=12.4,3.5Hz,1H),2.22–2.1 2(m,2H),1.78(dd,J=13.0,3.6Hz,2H),1.63(qd,J=13.2,3.7Hz,2H).ESI-MS:C 20 H 21 N5O4[MH] - found 394.2.

[0072] Example 7. 4-Amino-8-(3-fluorobenzyl)-6-(4-methoxyphenyl)pterin-7(8H)-one (TOR008)

[0073] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-methoxyphenyl)acetate, and the halide or methanesulfonyl compound used is 1-(bromomethyl)-3-fluorobenzene. 1 H NMR(500MHz,DMSO-d6)δ8.55(d,J=8.9Hz,2H),8.24(s,1H),7.88(s,2H),7.32–7.2 6(m,1H),7.25–7.18(m,1H),7.10–6.98(m,4H),5.53(s,2H),3.83(s,3H).ESI-MS:C 20 H 16 FN5O2[M+H] + found 378.5.

[0074] Example 8. trans-4-(4-amino-6-(6-methoxypyridin-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR009)

[0075] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-methoxypyridin-3-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.14(s,1H),9.31(s,1H),8.78(dd,J=8.9,2.1Hz,1H),8.30(s,1H),7.89(br s,1H),7.84(br s,1H),6.91(d,J=8.8Hz,1H),5.34(br s,1H),3.94(s,3H),2.75–2.65(m,2H),2.27(t,J=12.6Hz,1H),2.07(d,J=13.1Hz,2H),1.71(d,J=11.6Hz,2H),1.55–1.41(m,2H).ESI-MS:C 19 H 20 N6O4[MH] - ,found 395.4.

[0076] Example 9. trans-4-(4-amino-7-oxo-6-(1H-pyrazol-3-yl)pteridin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR010)

[0077] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(1H-pyrazol-3-yl)acetate. 1 HNMR(500MHz,DMSO-d6)δ13.59(s,1H),12.11(br,1H),8.32(s,1H),7.97(s,1H),7.92(s,1H),7.64(s,1H),7.25(s,1H),5.33( s,1H),2.72–2.65(br,2H),2.27(t,J=12.6Hz,1H),2.07(d,J=13.0Hz,2H),1.70(d,J=12.2Hz,2H),1.56–1.40(m,2H).ESI-MS:C 16 H 17 N7O3[MH] - found354.4.

[0078] Example 10. 4-Amino-6-(1H-pyrazol-3-yl)-8-(tetrahydro-2H-pyran-4-yl)pterin-7(8H)-one (TOR011)

[0079] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(1H-pyrazol-3-yl)acetate, and the halide or methanesulfonyl compound used is tetrahydro-2H-pyran-4-yl methanesulfonate. 1 H NMR(500MHz,DMSO-d6)δ13.58(s,1H),8.32(s,1H),7.97(s,1H),7.93(s,1H),7.64(s,1H),7.25(s,1H),5.58(br s,1H),3.99(d,J=11.9Hz,2H),3.43(t,J=11.9Hz,2H),2.90(d,J=13.2Hz,2H),1.56(d,J=12.5Hz,2H).ESI-MS:C 14 H 15 N7O[MH] - found 312.3.

[0080] Example 11. trans-4-(4-amino-6-(5-methoxy-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR013)

[0081] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(5-methoxy-1H-indol-2-yl)acetate. 1H NMR(500MHz,DMSO-d6)δ12.14(br s,1H),11.56(s,1H),8.30(s,1H),8.06(s,1H),7.92(s,1H),7.65(s,1H ),7.35(d,J=8.5Hz,1H),7.16(s,1H),6.91(d,J=9.0Hz,1H),5.35(br,1H ),3.79(d,J=2.0Hz,3H),2.73(br,2H),2.28(t,J=12.6Hz,1H),2.08(d,J=12.8Hz,2H),1.73(d,J=12.6Hz,3H),1.48(q,J=12.8Hz,2H).ESI-MS:C 22 H 22 N6O4[MH] - found 433.6.

[0082] Example 12. trans-4-(4-amino-6-(4-(dimethylamino)phenyl)-7-oxopterin-8(7H)yl)cyclohexane-1-carboxylic acid (TOR014)

[0083] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(dimethylamino)phenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.12(br s,1H),8.47(d,J=8.9Hz,2H),8.24(s,1H),7.65(br s,2H),6.74(d,J=8.9Hz,2H),5.33(br s,1H),3.33(s,6H),2.71(d,J=13.5Hz,2H),2.32–2.23(m,1H),2.10–2.04(m,2H),1.69(d,J=9.8Hz,2H),1.57–1.42(m,2H).ESI-MS:C 21 H 24 N6O3[MH] - found 407.4.

[0084] Example 13. 4-Amino-6-(6-methoxypyridin-3-yl)-8-(tetrahydro-2H-pyran-4-yl)pterin-7(8H)-one (TOR015)

[0085] The synthesis method is similar to that of Example 1, except that the arylacetic acid methyl ester used is 2-(6-methoxypyridin-3-yl)acetic acid methyl ester, and the halide or methanesulfonyl compound used is tetrahydro-2H-pyran-4-yl methanesulfonate. 1H NMR(500MHz,DMSO-d6)δ9.33(s,1H),8.81–8.74(m,1H),8.31(s,1H),7.90(br s,1H),7.85(br s,1H),6.92(d,J=9.0Hz,1H),5.60(br s,1H),3.99(d,J=12.9Hz,2H),3.94(d,J=2.0Hz,3H),3.45(t,J=11.9Hz,2H),2.92(d,J=12.9Hz,2H),1.57(d,J=11.9Hz,2H).ESI-MS:C 17 H 18 N6O3[MH] - found 353.5.

[0086] Example 14. 4-Amino-8-butyl-6-(6-methoxypyridin-3-yl)pterin-7(8H)-one (TOR016)

[0087] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-methoxypyridin-3-yl)acetate, and the halide or methanesulfonyl compound used is iodobutane. 1 H NMR(500MHz,DMSO-d6)δ9.39(d,J=2.2Hz,1H),8.83(dd,J=8.8,2.2Hz,1H),8.32(s,1H),7.92(s,1H),7.86(s,1H),6.93(d,J=8.8H z,1H),4.29(t,J=7.6Hz,2H),3.95(d,J=1.3Hz,3H),1.66(p,J=7.6Hz,2H),1.37(q,J=7.6Hz,2H),0.94(t,J=7.4Hz,3H).ESI-MS:C 16 H 18 N6O2[M+Na] + found 349.4.

[0088] Example 15. 8-Isopropyl-4-(isopropylamino)-6-(6-methoxypyridin-3-yl)pterin-7(8H)-one (TOR017)

[0089] The synthesis method is similar to that of Example 1, except that the arylacetic acid methyl ester used is 2-(6-methoxypyridin-3-yl)acetic acid methyl ester, and the halide or methanesulfonyl compound used is 2-iodopropane. 1H NMR(500MHz,Chloroform-d)δ9.07(d,J=2.2Hz,1H),8.55(d,J=8.8Hz,1H),8.41(d,J=1.8Hz,1H),6.82(dd,J=8.8,1.8Hz,1H),6.45( d,J=8.3Hz,1H),5.86–5.76(m,1H),4.45(h,J=7.0Hz,1H),4.01(d,J=1.9Hz,3H),1.64(d,J=5.2Hz,6H),1.37–1.32(m,6H).ESI-MS:C 18 H 22 N6O2[M+Na] + found377.7.

[0090] Example 16. 4-Amino-8-(2-hydroxyethyl)-6-(6-methoxypyridin-3-yl)pterin-7(8H)-one (TOR022)

[0091] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-methoxypyridin-3-yl)acetate, and the halide or methanesulfonyl compound used is (2-bromoethoxy)(tert-butyl)dimethylsilane. 1 H NMR (500MHz, DMSO-d6) δ9.39(d,J=2.0Hz,1H),8.83(dd,J=8.9,2.1Hz,1H),8.30(d,J=1.4Hz,1H),7.91(br s,1H),7.86(br s,1H),6.93(d,J=8.8Hz,1H),4.84(t,J=6.1Hz,1H),4.41(t,J=6.6Hz,2H),3.95(d,J=1.5Hz,3H),3.67(q,J=6.5Hz,2H).ESI-MS:C 14 H 14 N6O3[MH] - found 313.4.

[0092] Example 17. 4-Amino-6-(2-methylbenzo[d]oxazol-5-yl)-8-(tetrahydro-2H-pyran-4-yl)pteridin-7(8H)-one (TOR023)

[0093] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-methylbenzo[d]oxazol-5-yl)acetate, and the halide or methanesulfonyl compound used is tetrahydro-2H-pyran-4-yl methanesulfonate. 1H NMR (500MHz, DMSO-d6) δ8.78(s,1H),8.49(d,J=8.7Hz,1H),8.32(s,1H),7.91(br s,1H),7.85(br s,1H),7.73(d,J=8.8Hz,1H),5.62(br s,1H),4.04–3.96(m,2H),3.46(t,J=11.9Hz,2H),2.98–2.92(m,2H),2.66(s,3H),1.59(d,J=12.3Hz,2H).ESI-MS:C 19 H 18 N6O3[M+Na] + found 401.5.

[0094] Example 18. 4-Amino-8-butyl-6-(2-methylbenzo[d]oxazol-5-yl)pteridin-7(8H)-one (TOR024)

[0095] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-methylbenzo[d]oxazol-5-yl)acetate, and the halide or methanesulfonyl compound used is iodobutane. 1 H NMR (500MHz, DMSO-d6) δ8.85(s,1H),8.56(d,J=8.7Hz,1H),8.32(d,J=1.6Hz,1H),7.95(br s,1H),7.87(br s,1H),7.73(d,J=8.7Hz,1H),4.31(t,J=7.7Hz,2H),2.66(d,J=1.6Hz,3H) ,1.68(p,J=7.7Hz,2H),1.38(h,J=7.7Hz,2H),1.00–0.88(m,3H).ESI-MS:C 18 H 18 N6O2[M+H] + found 351.3.

[0096] Example 19. 4-Amino-8-isopropyl-6-(2-methylbenzo[d]oxazol-5-yl)pteridin-7(8H)-one (TOR025)

[0097] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-methylbenzo[d]oxazol-5-yl)acetate, and the halide or methanesulfonyl compound used is 2-iodopropane. 1H NMR (500MHz, DMSO-d6) δ8.78(s,1H),8.50(d,J=8.6Hz,1H),8.30(d,J=1.9Hz,1H),7.88(br s,1H),7.82(br s,1H),7.74–7.67(m,1H),5.85–5.64(m,1H),2.66(d,J=1.8Hz,3H),1.58(dd,J=6.9,1.8Hz,6H).ESI-MS:C 17 H 16 N6O2[M+Na] + found 359.4.

[0098] Example 20. 4-Amino-8-(trans-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)pterin-7(8H)-one (TOR032)

[0099] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-methoxypyridin-3-yl)acetate, and the halide or methanesulfonyl compound used is cis-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)methanesulfonic acid cyclohexyl ester. 1 H NMR (500MHz, Methanol-d4) δ9.24(d,J=2.3Hz,1H),8.67(dd,J=8.8,2.3Hz,1H),8.28(s,1H),6.88(d,J=8.8Hz,1H),5.48(br s,1H),3.99(s,3H),3.68(t,J=4.8Hz,2H),3.62(t,J=4.9Hz,2H),3.52–3.46(m,1H),2.85(d ,J=12.5Hz,2H),2.24(d,J=12.5Hz,2H),1.75(d,J=12.6Hz,2H),1.51–1.40(m,2H).ESI-MS:C 20 H 24 N6O4[M+H] + found413.19.

[0100] Example 21. 4-Amino-8-(2-hydroxyethyl)-6-(2-methylbenzo[d]oxazol-5-yl)pteridin-7(8H)-one (TOR033)

[0101] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-methylbenzo[d]oxazol-5-yl)acetate, and the halide or methanesulfonyl compound used is (2-bromoethoxy)(tert-butyl)dimethylsilane. 1HNMR(500MHz,DMSO-d6)δ8.84(s,1H),8.55(d,J=8.7Hz,1H),8.30(s,1H),7.94(s,1H),7.86(s,1H),7 .73(d,J=8.7Hz,1H), 4.85(t,J=6.1Hz,1H), 4.43(t,J=6.7Hz,2H), 3.68(q,J=6.5Hz,2H), 2.65(s,3H).

[0102] Example 22. 4-Amino-8-(trans-4-(2-hydroxyethoxy)cyclohexyl)-6-(2-methylbenzo[d]oxazol-5-yl)pteridin-7(8H)-one (TOR034)

[0103] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-methylbenzo[d]oxazol-5-yl)acetate, and the halide or methanesulfonyl compound used is cis-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)methanesulfonic acid cyclohexyl ester.

[0104] Example 23. trans-4-(4-amino-6-(2-methylbenzo[d]oxazol-5-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid methyl ester (TOR035)

[0105] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-methylbenzo[d]oxazol-5-yl)acetate, and the last step of ester hydrolysis reaction is not performed.

[0106] Example 24. trans-4-(4-amino-6-(6-methoxypyridin-3-yl)-2-methyl-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR054)

[0107] The synthesis method is similar to that of Example 1, except that the starting material used is 2-methylpyrimidine-4,6-diamine, and the arylacetic acid methyl ester used is 2-(6-methoxypyridin-3-yl)acetic acid methyl ester. 1H NMR (500MHz, DMSO-d6) δ12.09(s,1H),9.29(s,1H),8.75(d,J=8.8Hz,1H),7.73(s,2H),6.89(d,J=8.8Hz,1H),5.32(s,1H),3.93(d,J= 1.7Hz, 3H), 2.72 (s, 2H), 2.43 (s, 3H), 2.27 (t, J = 12.5Hz, 1H), 2.06 (d, J = 13.0Hz, 2H), 1.69 (d, J = 12.2Hz, 2H), 1.46 (d, J = 12.3Hz, 2H).

[0108] Example 25. trans-4-(4-amino-6-(7-methoxy-1H-indol-2-yl)-2-methyl-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR055)

[0109] The synthesis method is similar to that of Example 1, except that the starting material used is 2-methylpyrimidine-4,6-diamine, and the methyl aryl acetate used is methyl 2-(7-methoxy-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ11.62(br s,1H),8.50(s,1H),7.77–7.67(m,2H),7.23(d,J=8.1Hz,1H),6.96(s,1H),6.77(d,J=7.7Hz,1H),5.32(br,1H),3.98(s,3H) ,2.74(br,2H),2.44(s,3H),2.29(t,J=12.6Hz,1H),2.07(d,J=13.0Hz,2H),1.69(d,J=12.1Hz,2H),1.47(d,J=13.6Hz,2H).

[0110] Example 26. trans-4-(4-amino-6-(2-methoxypyridin-4-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR056)

[0111] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-methoxypyridin-4-yl)acetate.

[0112] Example 27. trans-4-(4-amino-6-(4-cyanophenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR057)

[0113] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-cyanophenyl)acetate.

[0114] Example 28. trans-4-(4-amino-6-(6,7-dimethoxy-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR058)

[0115] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6,7-dimethoxy-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.12(s,1H),11.36(s,1H),8.53(s,1H),8.28(d,J=3 .1Hz,1H),7.85(s,1H),7.76(s,1H),7.35(dd,J=8.6,3.0Hz,1H),6.91(dd,J=8 .6,3.1Hz,1H),5.42–5.27(m,1H),3.95–3.83(m,6H),2.72(s,2H),2.32–2.24( m, 1H), 2.07 (d, J = 13.0Hz, 2H), 1.71 (d, J = 12.1Hz, 2H), 1.47 (d, J = 12.6Hz, 2H).

[0116] Example 29. trans-4-(4-amino-6-(4-(benzyloxy)-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR059)

[0117] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(benzyloxy)-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.12(br s,1H),11.70(s,1H),8.30(s,1H),8.06(s,1H),7.91(s,1H),7.78(d,J=2.1Hz,1H),7.55(d ,J=7.6Hz,2H),7.45(t,J=7.4Hz,2H),7.38(t,J=7.4Hz,1H),7.17(t,J=8.0Hz,1H),7.06(d, J=8.2Hz,1H),6.65(d,J=7.7Hz,1H),5.37(br,1H),5.26(s,2H),2.72(br,2H),2.28(t,J=12 .3Hz,1H),2.08(d,J=13.0Hz,2H),1.72(d,J=11.9Hz,2H),1.47(q,J=12.8Hz,2H).ESI-MS:C 28 H 26 N6O4[MH]- found 509.3.

[0118] Example 30. trans-4-(4-amino-6-(4-methoxy-3-nitrophenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR060)

[0119] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-methoxy-3-nitrophenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.11(br s,1H),9.09(d,J=2.3Hz,1H),8.87(d,J=8.9Hz,1H),8.31(br s,1H),8.02(br s,1H),7.88(s,1H),7.44(d,J=9.1Hz,1H),5.35(br s,1H),4.02(s,2H),2.70(d,J=13.0Hz,2H),2.28(t,J=13.0Hz,1H),2.07( d,J=12.9Hz,2H),1.72(d,J=12.2Hz,2H),1.48(q,J=13.1Hz,2H).ESI-MS:C 20 H 20 N6O6[MH] - found 439.4.

[0120] Example 31. trans-4-(4-amino-7-oxo-6-(quinolin-6-yl)pteridin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR061)

[0121] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(quinolin-6-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.12(br s,1H),9.24(s,1H),8.96(s,1H),8.85(s,1H),8.50(d,J=8.1Hz,1H),8.34(s,1H),8. 06(d,J=10.2Hz,1H),7.94(s,2H),7.60(s,1H),5.39(brs,1H),2.74(br,2H),2.29(br s,1H),2.09(br,2H),1.76(br,2H),1.49(br,2H).ESI-MS:C 22 H 20 N6O3[MH] - found415.2.

[0122] Example 32. trans-4-(4-amino-6-(3,4-dimethoxyphenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR062)

[0123] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(3,4-dimethoxyphenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.12(s,1H),8.29(s,1H),8.18(d,J=8.2Hz,1H),8.02(s,1H),7.79(s,2H),7.03(d,J=8.6Hz,1H),5.34(br s,1H),3.87(s,3H),3.84(s,3H),2.71(d,J=13.6Hz,2H),2.28(t,J=12.5Hz,1H ),2.07(d,J=13.1Hz,2H),1.71(d,J=12.1Hz,2H),1.54–1.43(m,2H).ESI-MS:C 21 H 23 N5O5[MH] - found 424.5.

[0124] Example 33. trans-4-(4-amino-6-(5,7-difluoro-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR063)

[0125] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(5,7-difluoro-1H-indol-2-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.06(s,1H),8.45(s,1H),8.31(s,1H),8.01(s,1H),7.81(s,1H),7.36(d,J=9.0Hz,1H),7.13(t,J=10.6H z,1H),5.33(br,1H),2.68(br,2H),2.34(br,1H),2.04(d,J=13.9Hz,4H),1.67(d,J=11.7Hz,2H),1.44(q,J=13.4Hz,2H).ESI-MS:C 21 H 18 F2N6O3[MH] - found 438.8.

[0126] Example 34. trans-4-(4-amino-6-(7-cyano-4-fluoro-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR064)

[0127] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(7-cyano-4-fluoro-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.28(s,1H),12.14(br s,1H),8.53(s,1H),8.34(s,1H),8.03(s,1H),7.93(s,1H),7.84(s,1H),7.10(t,J=8.9Hz,1H),5.38(br,1H ),2.72(br,2H),2.30(br,1H),2.09(d,J=13.0Hz,2H),1.78–1.71(m,2H),1.48(q,J=13.1Hz,2H).ESI-MS:C 22 H 18 FN7O3[MH] - found 446.1.

[0128] Example 35. trans-4-(4-amino-6-(2-(2,5-dimethyl-1H-pyrrol-1-yl)benzo[d]thiazol-6-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR065)

[0129] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(2-(2,5-dimethyl-1H-pyrrol-1-yl)benzo[d]thiazol-6-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.14(br s,1H),9.28(s,1H),8.73(d,J=8.7Hz,1H),8.33(d,J=2.0Hz,1H),8.08(d,J=8.7Hz,1H),7.93(s,2H),5.99(d,J=2.1Hz,2H),5.38(br s,1H),2.72(br,2H),2.33(s,6H),2.27(t,J=12.9Hz,1H),2.09(d,J=13.0Hz,2H),1.76–1.70(m,2H),1.49(q,J=13.1Hz,2H).ESI-MS:C 26 H 25 N7O3S[MH] - found 514.4.

[0130] Example 36. trans-4-(4-amino-6-(4-hydroxy-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR066)

[0131] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-hydroxy-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.14(s,1H),11.54(s,1H),9.65(s,1H),8.29(s,1H),8.07(s,1H),7.89 (s,1H),7.86(s,1H),7.04(t,J=8.1Hz,1H),6.88(d,J=8.1Hz,1H),6.38(d,J=7.6Hz,1H),5.37(br s,1H),2.73(br,2H),2.28(t,J=11.8Hz,1H),2.09(d,J=12.8Hz,2H),1.73(d,J=12.1Hz,2H),1.49(q,J=13.0Hz,2H).ESI-MS:C 21 H 20 N6O4[MH] - found 419.2.

[0132] Example 37. trans-4-(4-amino-6-(2-aminobenzo[d]thiazol-6-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR067)

[0133] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-aminobenzo[d]thiazol-6-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ8.87(s,1H),8.50(s,1H),8.47(d,J=8.7Hz,1H),8.28(s,1H),7.79(s,3H),7.36(d,J=8.6Hz,1H),5 .33(br,1H),2.64(br,2H),2.01(d,J=13.1Hz,2H),1.90(t,J=13.0Hz,1H),1.61(br,2H),1.40(q,J=13.6Hz,2H).ESI-MS:C 20 H 19 N7O3S[MH] - found 436.0.

[0134] Example 38. trans-4-(4-amino-6-(3-amino-4-methoxyphenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR068)

[0135] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(3-amino-4-methoxyphenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.14(br s,1H),8.27(s,1H),7.82(s,1H),7.76(d,J=8.8Hz,2H),7.77(br s,1H),7.49(brs,1H),6.87(d,J=8.5Hz,1H),5.33(br s,1H),4.70(br s,2H),3.84(s,3H),2.69(d,J=13.0Hz,2H),2.26(t,J=12.6Hz,1H),2.06(d,J=13.0Hz,2H),1.72–1.66(m,2H),1.46(q,J=13.0Hz,2H).ESI-MS:C 20 H 22 N6O4[MH] - found409.1.

[0136] Example 39. trans-4-(4-amino-6-(4-carbamoylphenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR069)

[0137] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-carbamoylphenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ8.55(d,J=8.1Hz,2H),8.28(s,1H),7.96(d,J=8.2Hz,2H),5.32(s ,1H),2.18(d,J=8.5Hz,1H),2.01(s,4H),1.60(d,J=12.6Hz,2H),1.44(d,J=12.5Hz,2H).

[0138] Example 40. trans-4-(4-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR070)

[0139] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(4-methylpiperazin-1-yl)phenyl)acetate. 1H NMR(500MHz,DMSO-d6)δ8.43(d,J=8.6Hz,2H),8.25(s,1H),7.68(s,2H),6.97(d,J=8.7Hz,2H),5.32(s,1H) ,3.17(s,2H),2.69(s,4H),2.27(s,4H),2.11–1.94(m,4H),1.69(d,J=12.0Hz,3H),1.46(q,J=11.9Hz,3H).

[0140] Example 41. trans-4-(4-amino-6-(1H-indazol-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR071)

[0141] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(1H-indazol-3-yl)acetate.

[0142] Example 42. trans-4-(4-amino-6-(4-morpholinophenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR072)

[0143] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-morpholinophenyl)acetate. 1 HNMR(500MHz,DMSO-d6)δ12.08(s,1H),8.45(d,J=8.5Hz,2H),8.25(s,1H),7.69(s,2H),6.98(d,J=8.5Hz,2H),5.32(s,1H),3.76(t,J=4.6Hz,4H), 3.25(t,J=4.7Hz,4H),2.69(d,J=13.4Hz,2H),2.26(t,J=12.5Hz,1H),2. 09–2.03(m,2H),1.69(d,J=12.3Hz,2H),1.46(d,J=13.8Hz,2H).ESI-MS:C 23 H 26 N6O4[M+H] + found 451.21.

[0144] Example 43. trans-4-(4-amino-6-(5-methoxypyridin-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR077)

[0145] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(5-methoxypyridin-2-yl)acetate. 1H NMR (500MHz, DMSO-d6) δ12.15(br s,1H),8.39(s,1H),8.31(s,1H),8.08(d,J=8.8Hz,1H),7.82(br s,1H),7.60(br s,1H),7.51(dd,J=8.8,2.9Hz,1H),5.32(br s,1H),3.91(s,3H),2.67(d,J=14.0Hz,2H),2.25(t,J=12.4Hz,1H),2.06( d,J=13.1Hz,2H),1.71(d,J=12.3Hz,2H),1.46(q,J=13.1Hz,2H).ESI-MS:C 19 H 20 N6O4[MH] - found395.2.

[0146] Example 44. trans-4-(6-(4-acetylaminophenyl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR078)

[0147] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-acetamidophenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.12(s,1H),10.14(s,1H),8.45(d,J=8.4Hz,2H),8.28(s,1H),7.77(s,2H),7.66(d,J=8.4Hz,2H),5.33 (s,1H),2.69(d,J=12.0Hz,2H),2.26(t,J=12.5Hz,1H),2.08(s,3H),2.05(s,2H),1.70(d,J=12.1Hz,2H),1.46(q,J=12.9Hz,2H).

[0148] Example 45. trans-4-(6-(7-acetylamino-1H-indol-2-yl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR079)

[0149] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(7-acetylamino-1H-indol-2-yl)acetate. 1H NMR(500MHz,DMSO-d6)δ12.14(s,1H),11.20(s,1H),9.88(s,1H),8.32(s,1H),8.0 0(s,1H),7.81(s,1H),7.78(s,1H),7.53(d,J=7.6Hz,1H),7.44(d,J=7.9Hz,1H),7 .00(t,J=7.8Hz,1H),5.38(s,1H),2.73(s,2H),2.29(t,J=12.8Hz,1H),2.20(s,3H ),2.09(d,J=13.0Hz,2H),1.74(d,J=12.0Hz,2H),1.49(q,J=13.0Hz,2H).ESI-MS:C 23 H 23 N7O4[M+H] + found462.19.

[0150] Example 46. trans-4-(4-amino-6-(7-hydroxy-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR087)

[0151] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(7-hydroxy-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.14(s,1H),11.52(s,1H),9.84(s,1H),8.51(s,1H),8. 29(s,1H),7.84(s,1H),7.73(d,J=2.2Hz,1H),7.10(d,J=7.9Hz,1H),6.83(t,J=7. 7Hz,1H),6.63(d,J=7.5Hz,1H),5.37(s,1H),2.73(br,2H),2.28(t,J=12.5Hz,1H) ,2.08(d,J=12.9Hz,2H),1.72(d,J=12.1Hz,2H),1.48(q,J=13.4Hz,2H).ESI-MS:C 21 H 20 N6O4[MH] - found 419.5.

[0152] Example 47. trans-4-(4-amino-6-(7-(benzyloxy)-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR088)

[0153] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(7-(benzyloxy)-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.14(br s,1H),11.67(s,1H),8.64(s,1H),8.29(s,1H),7.85(s,1H),7.80(d,J=2.4Hz,1H),7.55(d,J=7.5Hz,2H),7.40(t,J=7.3 Hz,2H),7.32(t,J=7.6Hz,1H),7.23(d,J=7.9Hz,1H),6.90(t,J=8.0Hz,1H),6.80(d,J=7.5Hz,1H),5.42(s,2H),5.33(br s,1H),2.73(br,2H),2.28(t,J=12.8Hz,1H),2.08(d,J=13.1Hz,2H),1.73(d,J=12.1Hz,2H),1.48(q,J=12.4Hz,2H).ESI-MS:C 28 H 26 N6O4[MH] - found 509.3.

[0154] Example 48. trans-4-(4-amino-7-oxo-6-(6-(pyrrolidin-1-yl)pyridin-3-yl)pteridin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR089)

[0155] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-(pyrrolidin-1-yl)pyridin-3-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ9.37(s,1H),9.15(s,1H),8.33(s,1H),8.17(s,1H),7.98(s,1H),7.15(s,1H),5.36(br s,1H),3.68(s,4H),2.69(br,2H),2.29(t,J=12.3Hz,1H),2.07(s,6H),1.71(d,J=12.1Hz,2H),1.47(q,J=12.7Hz,2H).ESI-MS:C 22 H 25 N7O3[MH] - found434.7.

[0156] Example 49. trans-4-(4-amino-6-(6-morpholinopyridin-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR090)

[0157] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-morpholinopyridin-3-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ9.33 (s, 1H), 8.68 (d, J = 8.8Hz, 1H), 8.26 (s, 1H), 7.76 (br s,2H),6.89(d,J=9.3Hz,1H),5.33(br,1H),3.72(s,4H),3.60(s,4H),2.76–2.62(m,2H),2.27(t,J= 12.1Hz,1H),2.06(d,J=12.9Hz,2H),1.70(d,J=12.1Hz,2H),1.46(q,J=13.2,12.7Hz,2H).ESI-MS:C 22 H 25 N7O4[MH] - found 450.5.

[0158] Example 50. trans-4-(4-amino-6-(7-bromo-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR091)

[0159] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(7-bromo-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.14(br s,1H),11.24(s,1H),8.70(s,1H),8.31(s,1H),7.97(s,1H),7.95(s,1H),7 .72(d,J=7.9Hz,1H),7.48(d,J=7.6Hz,1H),7.02(t,J=7.7Hz,1H),5.38(br s,1H),2.73(br,2H),2.29(t,J=12.4Hz,1H),2.08(d,J=13.1Hz,2H),1.83–1.65(m,2H),1.48(q,J=13.1Hz,2H).ESI-MS:C 21 H 19 BrN6O3[MH] - found 481.0.

[0160] Example 51. trans-4-(4-amino-6-(6-nitro-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR094)

[0161] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-nitro-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.49(s,1H),12.16(br s,1H),8.35(s,2H),8.18(s,1H),8.08(s,1H),7.93(d,J=9.0Hz,1H),7.89(d,J=8.8Hz,1H),7.86(s,1H),5.38(b rs,1H),2.72(br,2H),2.29(br,1H),2.09(d,J=12.7Hz,2H),1.74(d,J=12.3Hz,2H),1.57–1.43(m,2H).ESI-MS:C 21 H 19 N7O5[MH] - found 448.2.

[0162] Example 52. trans-4-(4-amino-6-(6-aminopyridin-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR095)

[0163] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-aminopyridin-3-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.14(br s,1H),9.19(s,1H),8.53(d,J=8.9Hz,1H),8.25(s,1H),7.71(s,2H),6.53(s,2H),6.50(d,J=9.0Hz,1H),5.33(br s,1H),2.69(d,J=12.7Hz,2H),2.27(t,J=12.2Hz,1H),2.06(d,J=12.9Hz,2H),1.69(d,J=11.5Hz,2H),1.46(q,J=13.0Hz,2H).ESI-MS:C 18 H 19 N7O3[MH] - found 380.1.

[0164] Example 53. trans-4-(4-amino-6-(4-hydroxy-6-methyl-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR096)

[0165] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-hydroxy-6-methyl-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.15(br s,1H),11.39(s,1H),9.58(s,1H),8.28(d,J=2.5Hz,1H),8.05(s,1H),7.87(s,1H),7.81(s,1H),6.67(s,1H),6.22(s,1H),5.36(br s,1H),2.72(br,2H),2.34(s,3H),2.32–2.25(m,1H),2.08(d,J=13.0Hz,2H),1.78–1.65(m,2H),1.48(q,J=13.1Hz,2H).ESI-MS:C 22 H 22 N6O4[MH] - found 433.6.

[0166] Example 54. trans-4-(4-amino-6-(5-chloro-3a,7a-dihydro-1H-indol-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR097)

[0167] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(5-chloro-1H-indol-3-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.15(br s,1H),11.98(s,1H),8.85(s,1H),8.56(s,1H),8.30(s,1H),7.79(br,1H),7.52(d,J=8.6Hz,1H),7.25(d,J=8.6Hz,1H),6.96(br ,1H),5.41(br,1H),2.74(br,2H),2.29(t,J=12.9Hz,1H),2.08(d,J=13.0Hz,2H),1.73(d,J=11.5Hz,2H),1.49(q,J=12.9Hz,2H).

[0168] Example 55. trans-4-(4-amino-6-(4-(3-nitrobenzamido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR098)

[0169] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-nitrobenzamido)phenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ10.79(s,1H),8.83(s,1H),8.55(d,J=8.5Hz,2H),8.46(t,J=9.0Hz,2H),8.29(s,1H),7.91(d,J=8.5Hz,2H),7.87(t,J=8.0H z,1H),7.82(s,2H),5.41–5.28(m,1H),2.69(d,J=11.7Hz,2H),2.23(s,1H ), 2.06 (d, J = 12.8Hz, 2H), 1.70 (d, J = 11.9Hz, 2H), 1.46 (q, J = 12.1Hz, 2H).

[0170] Example 56. trans-4-(4-amino-6-(4-((3-nitrophenyl)carbamoyl)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR099)

[0171] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-((3-nitrophenyl)carbamoyl)phenyl)acetate.

[0172] Example 57. trans-4-(4-amino-6-(6-amino-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR106)

[0173] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(6-amino-1H-indol-2-yl)acetate. 1 H NMR (500MHz, Methanol-d4) δ8.25(s,1H),7.72(s,1H),7.25(d,J=8.5Hz,1H),7.15(d,J=8.6Hz,1H),6.79(s,1H),5.51(br s,1H),2.90(br,2H),2.44(t,J=12.9Hz,1H),2.20(d,J=11.3Hz,2H),1.81(d,J=12.5Hz,2H),1.66(q,J=14.1Hz,2H).ESI-MS:C 21 H 21N7O3[MH] - found 418.2.

[0174] Example 58. trans-4-(4-amino-6-(7-hydroxy-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid methyl ester (TOR107)

[0175] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(7-hydroxy-1H-indol-2-yl)acetate, and the final ester hydrolysis reaction is omitted. 1 H NMR (500MHz, Methanol-d4) δ8.27(s,1H),7.79(s,1H),7.15(d,J=8.0Hz,1H),6.87(t,J=7.8Hz,1H),6.64(d,J=7.5Hz,1H),5.53(br s,1H),3.72(s,3H),2.90(br,2H),2.52(t,J=12.7Hz,1H),2.19(d,J=13.4Hz,2H),1.82(d,J=12.6Hz,2H),1.66(q,J=13.6Hz,3H).ESI-MS:C 22 H 22 N6O4[MH] - found 433.2.

[0176] Example 59. trans-4-(4-amino-6-(6-amino-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid methyl ester (TOR108)

[0177] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-amino-1H-indol-2-yl)acetate, and the final ester hydrolysis reaction is omitted. 1 H NMR(500MHz,Chloroform-d)δ9.70(br s,1H),8.33(s,1H),7.71(s,1H),7.48(d,J=8.7Hz,1H),6.65(s,1H),6.58(d,J=8.7Hz,1H),5.47(br,1H),3.71(s,3H),2.84(br,2H),2.50(br s,1H),2.18(d,J=13.2Hz,2H),1.84–1.77(m,2H),1.69(q,J=13.7Hz,2H).ESI-MS:C 22 H 23 N7O3[M+H] + found 434.5.

[0178] Example 60. trans-4-(6-(5-acetylamino-1H-indol-2-yl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR109)

[0179] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(5-acetylamino-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ11.63(s,1H),9.82(s,1H),8.32(d,J=2.6Hz,1H),8.16(s,1H),8.00(s,1H),7.95(s,1H),7.67(s,1H),7.37(s,2H),5.36(br s,1H),2.72(br,2H),2.30(t,J=12.8Hz,1H),2.08(d,J=13.2Hz,2H),2.04(s,3H),1.73(d,J=12.1Hz,2H),1.48(q,J=13.2Hz,2H).ESI-MS:C 23 H 23 N7O4[MH] - found 460.3.

[0180] Example 61. trans-4-(4-amino-6-(4-hydroxy-6-methyl-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid methyl ester (TOR110)

[0181] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-hydroxy-6-methyl-1H-indol-2-yl)acetate, and the final ester hydrolysis reaction is omitted. 1 H NMR(500MHz,Chloroform-d)δ9.98(br s,1H),8.35(s,1H),7.80(s,1H),6.80(s,1H),6.36(s,1H),5.51(br,2H),3.71(s,3H),2.83(br,2H),2.51( t,J=12.6Hz,1H),2.41(s,3H),2.19(d,J=13.8Hz,2H),1.80(d,J=12.3Hz,2H),1.78–1.64(m,2H).ESI-MS:C 23 H 24 N6O4[M+H] + found 449.7.

[0182] Example 62. trans-4-(6-(6-acetylaminopyridin-3-yl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR111)

[0183] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-acetylaminopyridin-3-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.16(br s,1H),10.77(s,1H),9.42(s,1H),8.84(d,J=8.8Hz,1H),8.31(d,J=3.6Hz,1H),7.35(s,1H),7.23–7.15(m, 2H),5.33(br,1H),2.27(br,2H),2.14(d,J=4.0Hz,2H),2.06(s,3H),1.71(br,2H),1.47(br,2H).ESI-MS:C 20 H 21 N7O4[MH] - found 422.4.

[0184] Example 63. trans-4-(6-(5-acetylamino-1H-indol-2-yl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid methyl ester (TOR112)

[0185] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(5-acetylamino-1H-indol-2-yl)acetate, and the final ester hydrolysis reaction is omitted. 1 H NMR(500MHz,Chloroform-d)δ10.29(s,1H),8.39(s,1H),7.92(s,1H),7.69(s,1H),7.40(d,J=9.1Hz,1H),7.32(d,J=9.1Hz,1H),7.21( s,1H),5.37(s,1H),3.51(s,3H),2.86(br,2H),2.53(s,1H),2.24(s,3H),2.03(br,2H),1.84(br,2H),1.72(d,J=12.9Hz,2H).ESI-MS:C 24 H 25 N7O4[M+H] + found 476.3.

[0186] Example 64. trans-4-(4-amino-6-(7-hydroxy-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carbonitrile (TOR113)

[0187] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(7-hydroxy-1H-indol-2-yl)acetate, and the halide or methanesulfonyl compound used is cis-4-cyanocyclohexyl methanesulfonate. 1 H NMR(500MHz,DMSO-d6)δ11.52(s,1H),9.84(s,1H),8.52(s,1H),8.28(s,1H),7.86(s,1H),7.7 2(d,J=2.1Hz,1H),7.10(d,J=8.1Hz,1H),6.83(t,J=7.7Hz,1H),6.63(d,J=7.5Hz,1H),5.40(br s,1H),2.73(br,2H),2.19(d,J=12.1Hz,2H),2.03–1.95(m,1H),1.76–1.68(m,4H).ESI-MS:C 21 H 19 N7O2[MH] - found 399.7.

[0188] Example 65. trans-4-(4-amino-6-(5-(ethylcarbamoyl)-7-methoxy-1H-indol-2-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR114)

[0189] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(5-(ethylcarbamoyl)-7-methoxy-1H-indol-2-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.25(s,1H),12.09–11.93(m,1H),8.66(s,1H),8.30(s,1H),8 .02(d,J=11.2Hz,1H),7.90(s,2H),7.31(s,1H),5.45–5.25(m,1H),4.33(q,J=7.4Hz,1H ),4.05(d,J=3.5Hz,3H),2.71(s,2H),2.35–2.25(m,1H),2.07(d,J=12.7Hz,2H),1.99( d, J=13.7Hz, 1H), 1.72 (d, J=12.0Hz, 2H), 1.47 (q, J=13.1Hz, 2H), 1.35 (t, J=7.9Hz, 2H).

[0190] Example 66. trans-4-(4-amino-6-(4-((3-aminophenyl)carbamoyl)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR115)

[0191] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-((3-aminophenyl)carbamoyl)phenyl)acetate.

[0192] Example 67. trans-4-(4-amino-6-(4-(3-aminobenzamido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR116)

[0193] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-aminobenzamido)phenyl)acetate.

[0194] Example 68. 8-(trans-4-(1H-tetrazol-5-yl)cyclohexyl)-4-amino-6-(7-(benzyloxy)-1H-indol-2-yl)pterin-7(8H)-one (TOR117)

[0195] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(7-(benzyloxy)-1H-indol-2-yl)acetate, and the halide or methanesulfonyl compound used is cis-4-(1H-tetrazol-5-yl)cyclohexyl methanesulfonate. 1 H NMR (500MHz, DMSO-d6) δ11.69(s,1H),8.66(s,1H),8.31(s,1H),7.87(s,1H),7.81(d,J=2.1Hz, 1H),7.56(d,J=7.5Hz,2H),7.40(t,J=7.5Hz,2H),7.32(t,J=7.5Hz,1H),7.23(d,J=7.9Hz,1H), 6.90(t,J=7.8Hz,1H),6.81(d,J=7.8Hz,1H),5.49(br,1H),5.42(s,2H),3.11(t,J=12.6Hz,1H) ,2.23(d,J=13.0Hz,2H),2.04–1.96(m,2H),1.83(d,J=12.2Hz,2H),1.76–1.69(m,2H).ESI-MS:C 28 H 26 N 10 O2[MH] - found 533.4.

[0196] Example 69. trans-4-(4-amino-7-oxo-6-(4-(3-phenylureido)phenyl)pteridin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR118)

[0197] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-phenylureido)phenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.14(s,1H),9.01(s,1H),8.81(s,1H),8.47(d,J=8.5Hz,2H),8.28(s,1H),7.77( br,2H),7.55(d,J=8.6Hz,2H),7.48(d,J=8.0Hz,2H),7.30(t,J=7.7Hz,2H),7.00(t,J=7.4Hz,1H),5.35(br s,1H),2.71(d,J=13.8Hz,2H),2.28(t,J=12.6Hz,1H),2.07(d,J=12.9Hz,2H),1.71(d,J=12.0Hz,2H),1.58–1.41(m,2H).ESI-MS:C 26 H 25 N7O4[MH] - found 498.4.

[0198] Example 70. trans-4-(4-amino-6-(imidazo[1,2-a]pyridin-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR119)

[0199] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(imidazo[1,2-a]pyridin-3-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.15(br s,1H),9.99(d,J=7.0Hz,1H),9.05(s,1H),8.32(s,1H),7.83(d,J=8.9Hz,1H),7.60(t,J=7.9Hz,1H),7.26(t,J=6.9Hz,1H),5.44(br ,1H),2.74(br,2H),2.31(t,J=12.3Hz,1H),2.09(d,J=12.8Hz,2H),1.74(d,J=12.2Hz,2H),1.49(dt,J=15.0,11.4Hz,2H).ESI-MS:C 20 H 19 N7O3[MH] - found 404.3.

[0200] Example 71. trans-4-(4-amino-6-(2-cyano-1H-indol-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR120)

[0201] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(2-cyano-1H-indol-3-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.99(s,1H),12.14(br s,1H),8.35(s,1H),8.10(d,J=8.3Hz,1H),7.96(br s,1H),7.52(d,J=8.4Hz,1H),7.41(t,J=7.7Hz,1H),7.26(t,J=7.6Hz,1H),7.17(br s,1H),5.37(br s,1H),2.70(d,J=13.0Hz,2H),2.29(t,J=12.6Hz,1H),2.08(d,J=13.0Hz,2H),1.76(d,J=12.3Hz,2H),1.49(q,J=12.5,12.1Hz,2H).ESI-MS:C 22 H 19 N7O3[MH] - found 428.2.

[0202] Example 72. trans-4-(4-amino-6-(4-hydroxyphenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR121)

[0203] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-hydroxyphenyl)acetate. 1 HNMR(500MHz,DMSO-d6)δ12.14(br s,1H),9.97(s,1H),8.39(d,J=8.6Hz,2H),8.27(s,1H),7.72(d,J=20.4Hz,2H),6.83(d,J=8.7Hz,2H),5.33(br s,1H),2.69(d,J=12.8Hz,2H),2.27(ddd,J=12.6,8.8,3.6Hz,1H),2.13–2.03 (m,2H),1.69(dd,J=12.9,3.9Hz,2H),1.46(qd,J=13.3,3.6Hz,2H).ESI-MS:C 19 H 19 N5O4[MH] -found 380.3.

[0204] Example 73. trans-4-(6-(4-acetylamino-3-fluorophenyl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR122)

[0205] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-acetylamino-3-fluorophenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.14(s,1H),9.93(s,1H),8.47(dd,J=13.4,2.0Hz,1H),8.41(dd,J=8.7,1.9Hz,1H),8.30(s,1H),8.10(t,J=8.5Hz,1H),7.97(br s,1H),7.87(br s,1H),5.34(br s,1H),2.73–2.65(m,2H),2.27(t,J=12.3Hz,1H),2.14(s,3H),2.07(d,J =12.9Hz,2H),1.78–1.65(m,2H),1.47(dt,J=13.8,10.9Hz,2H).ESI-MS:C 21 H 21 FN6O4[MH] - found439.2.

[0206] Example 74. N-(4-(4-amino-8-(trans-4-cyanocyclohexyl)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)acetamide (TOR123)

[0207] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-acetamidophenyl)acetate, and the halide or methanesulfonyl compound used is cis-4-cyanocyclohexyl methanesulfonate. 1 H NMR(500MHz,Chloroform-d)δ8.36(s,1H),8.25(d,J=8.5Hz,2H),7.62(d,J=8.4Hz,2H),7.29(s,1H),5.48(br,1H) ,2.82(d,J=13.3Hz,2H),2.60(t,J=12.4Hz,1H),2.30(d,J=13.1Hz,2H),2.22(s,3H),1.87–1.76(m,4H).ESI-MS:C 21 H 21 N7O2[M+H] + found 404.7.

[0208] Example 75. N-(4-(8-(trans-4-(1H-tetrazol-5-yl)cyclohexyl)-4-amino-7-oxo-7,8-dihydropteridin-6-yl)phenyl)acetamide (TOR124)

[0209] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-acetylaminophenyl)acetate, and the halide or methanesulfonyl compound used is cis-4-(1H-tetrazol-5-yl)cyclohexyl methanesulfonate. 1 H NMR (500MHz, DMSO-d6) δ10.18(s,1H),8.48(d,J=8.5Hz,2H),8.30(s,1H),7.81(d,J=18.2Hz,2H),7.68(d,J=8.6Hz,2H),5.46(br,1 H),3.09(t,J=12.5Hz,1H),2.92–2.85(m,2H),2.25–2.17(m,2H),2.09(s,3H),1.81(d,J=12.2Hz,2H),1.78–1.63(m,2H).ESI-MS:C 21 H 22 N 10 O2[MH] - found445.3.

[0210] Example 76. trans-4-(6-(4-(3-acetamidobenzamido)phenyl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR125)

[0211] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-acetamidobenzamido)phenyl)acetate. 1H NMR(500MHz,DMSO-d6)δ12.14(s,1H),10.45(s,1H),10.16(s,1H),8.52(d,J=8.6Hz,2H),8.29( s,1H),8.11(d,J=2.0Hz,1H),7.89(d,J=8.6Hz,2H),7.83(s,1H),7.82–7.77(m,2H),7.65(d,J= 7.7Hz,1H),7.46(t,J=7.9Hz,1H),5.33(d,J=12.7Hz,1H),2.70(d,J=14.1Hz,2H),2.27(dd,J=1 3.9,10.3Hz,1H),2.08(s,3H),2.06(s,2H),1.71(d,J=11.9Hz,2H),1.52–1.42(m,2H).ESI-MS:C 28 H 27 N7O5[M+H] + found 542.27.

[0212] Example 77. trans-4-(4-amino-6-(4-(2,4-difluorobenzamido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR126)

[0213] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(2,4-difluorobenzamido)phenyl)acetate.

[0214] Example 78. trans-4-(4-amino-6-(4-(3-methoxybenzamido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR127)

[0215] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-methoxybenzamido)phenyl)acetate. 1H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.43(s,1H),8.55(d,J=8.8Hz,2H),8.31(s,1H),7.9 2(d,J=8.9Hz,2H),7.82(s,2H),7.60(d,J=7.7Hz,1H),7.55(t,J=2.3Hz,1H),7.49(t,J=7.9 Hz,1H),7.20(dd,J=8.1,2.6Hz,1H),5.36(d,J=12.1Hz,1H),3.88(s,3H),2.73(d,J=13.4Hz ,2H),2.30(t,J=12.3Hz,1H),2.09(d,J=12.5Hz,2H),1.78–1.69(m,2H),1.56–1.41(m,2H).

[0216] Example 79. trans-4-(4-amino-6-(4-(4-(dimethylamino)benzamido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR128)

[0217] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(4-(dimethylamino)benzamido)phenyl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.17(s,1H),10.07(s,1H),8.50(d,J=8.7Hz,2H), 8.28(s,1H),7.90(dd,J=8.7,5.8Hz,4H),7.80(s,2H),6.78(d,J=8.7Hz,2H) ,5.34(d,J=16.1Hz,1H),3.01(s,6H),2.77–2.63(m,2H),2.26(t,J=12.1Hz, 1H), 2.07 (d, J = 12.8Hz, 2H), 1.71 (d, J = 11.8Hz, 2H), 1.46 (q, J = 13.2Hz, 2H).

[0218] Example 80. trans-4-(4-amino-6-(4-(nicotinamido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR129)

[0219] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(nicotinamido)phenyl)acetate. 1H NMR(500MHz,DMSO-d6)δ12.15(s,1H),10.67(s,1H),9.16(s,1H),8.79(s,1H),8.54(d ,J=8.8Hz,2H),8.35(d,J=8.1Hz,1H),8.29(s,1H),7.90(d,J=8.7Hz,2H),7.83(s,2H) ,7.60(dd,J=8.0,4.8Hz,1H),5.32(s,1H),2.70(d,J=13.1Hz,2H),2.27(t,J=12.4Hz, 1H), 2.07(d,J=12.8Hz,2H),1.71(d,J=12.0Hz,2H),1.47(h,J=10.5Hz,2H).ESI-MS:C 25 H 23 N7O4[M+H] + ,found 486.18.

[0220] Example 81. trans-4-(4-amino-6-(benzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR130)

[0221] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(benzofuran-3-yl)acetate. 1 HNMR(500MHz,DMSO-d6)δ12.16(s,1H),9.22(s,1H),8.71(d,J=7.2Hz,1H),8.36(s,1H),8.00(br s,1H),7.69(d,J=7.6Hz,1H),7.47–7.42(m,3H),7.31(br s,1H),5.43(br,1H),2.73(br,2H),2.29(t,J=12.5Hz,1H),2.09(d,J=13.0Hz,2H),1.75(d,J=11.2Hz,2H),1.60–1.38(m,2H).ESI-MS:C 21 H 19 N5O4[M+H] + found 406.16.

[0222] Example 82. trans-4-(4-amino-6-(4-((4-methylphenyl)sulfonamido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR131)

[0223] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-((4-methylphenyl)sulfonamido)phenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.13(br s,1H),10.55(s,1H),8.34(d,J=8.6Hz,2H),8.27(s,1H),7.79(br s,1H),7.73(br s,1H),7.71(d,J=8.1Hz,2H),7.37(d,J=8.0Hz,2H),7.17(d,J=8.6Hz,2H),5.31(br,1H),2.66(d,J=13.1Hz,2H),2.34(s,3H) ,2.25(dd,J=14.1,10.7Hz,1H),2.05(d,J=12.9Hz,2H),1.67(d,J=12.0Hz,2H),1.55–1.38(m,2H).ESI-MS:C26H26N6O5S[MH] - found 533.3.

[0224] Example 83. trans-4-(4-amino-6-(4-(3-ethylureido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR132)

[0225] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-ethylureido)phenyl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.14(br s,1H),8.89(s,1H),8.42(d,J=8.6Hz,2H),8.27(s,1H),7.75(br,2H),7.48 (d,J=8.6Hz,2H),6.32(t,J=5.7Hz,1H),5.34(br,1H),3.13(p,J=7.1Hz,2H) ,2.70(d,J=12.6Hz,2H),2.27(t,J=12.5Hz,1H),2.06(d,J=12.8Hz,2H),1.7 0(d,J=12.1Hz,2H),1.46(q,J=12.7Hz,2H),1.07(t,J=7.2Hz,3H).ESI-MS:C 22 H 25 N7O4[MH] - found 450.1.

[0226] Example 84. trans-4-(6-(4-acetylamino-2-fluorophenyl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR134)

[0227] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-acetylamino-2-fluorophenyl)acetate. 1 H NMR (500MHz, DMSO-d6) δ10.43(br s,1H),9.03(s,1H),8.43(d,J=8.5Hz,1H),8.34(s,1H),7.96(br s,1H),7.22(br s,1H),7.01(s,1H),6.91(d,J=8.6Hz,1H),5.39(br s,1H),2.64(br,2H),2.00(d,J=9.0Hz,2H),1.88(br s, 1H), 1.63 (d, J = 11.6Hz, 2H), 1.39 (d, J = 13.4Hz, 2H).

[0228] Example 85. trans-4-(6-(3-acetylamino-4-chlorophenyl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR135)

[0229] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(3-acetylamino-4-chlorophenyl)acetate.

[0230] Example 86. trans-4-(4-amino-7-oxo-6-(4-(3-(trifluoromethyl)benzamido)phenyl)pteridin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR136)

[0231] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-(trifluoromethyl)benzamido)phenyl)acetate.

[0232] Example 87. trans-4-(6-(3-acetylaminophenyl)-4-amino-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR137)

[0233] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(3-acetamidophenyl)acetate. 1H NMR(500MHz,DMSO-d6)δ12.15(s,1H),10.06(s,1H),8.39(t,J=2.1Hz,1H),8.3 0(d,J=2.1Hz,1H),7.98(d,J=7.9Hz,1H),7.87(d,J=8.4Hz,2H),7.65(s,1H),7. 38(td,J=7.9,2.2Hz,1H),5.33(d,J=13.1Hz,1H),2.74–2.59(m,2H),2.25(t,J =12.4Hz, 1H), 2.06 (d, J = 2.0Hz, 5H), 1.71 (d, J = 12.1Hz, 2H), 1.51–1.40 (m, 2H).

[0234] Example 88. trans-4-(4-amino-7-oxo-6-(4-pentanoylaminophenyl)pterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR138)

[0235] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-pentanoylaminophenyl)acetate.

[0236] Example 89. trans-4-(4-amino-6-(6-fluoro-1H-indol-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR139)

[0237] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(6-fluoro-1H-indol-3-yl)acetate.

[0238] Example 90. trans-4-(4-amino-7-oxo-6-(4-(3-((4-trifluoromethyl)phenyl)ureido)phenyl)pteridin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR140)

[0239] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-((4-trifluoromethyl)phenyl)ureido)phenyl)acetate. 1H NMR (500MHz, DMSO-d6) δ12.13(s,1H),9.28(s,1H),9.18(s,1H),8.50–8.44(m,2H),8.28(d,J=3.8Hz,1H),7.78(s,2H),7.67(q,J=8.7Hz,4H), 7.58–7.54(m,2H),5.33(d,J=10.5Hz,1H),2.77–2.62(m,2H),2.31–2.2 3(m,1H),2.06(d,J=12.7Hz,2H),1.75–1.66(m,2H),1.51–1.42(m,2H).

[0240] Example 91. N-(4-(4-amino-8-(trans-4-cyanocyclohexyl)-7-oxo-7,8-dihydropteridin-6-yl)-2-fluorophenyl)acetamide (TOR141)

[0241] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(4-acetylamino-3-fluorophenyl)acetate, and the halide or methanesulfonyl compound used is cis-4-cyanocyclohexyl methanesulfonate. 1 H NMR (500MHz, DMSO-d6) δ9.93 (s, 1H), 8.46 (d, J = 13.4Hz, 1H), 8.40 (d, J = 8.8Hz, 1H),8.29(s,1H),8.10(s,1H),7.98(s,1H),7.88(s,1H),5.36(br,1H),2.76(br s,1H),2.66(d,J=13.6Hz,2H),2.18(d,J=11.9Hz,2H),2.14(s,3H),1.75–1.62(m,4H).ESI-MS:C 21 H 20 FN7O2[M+H] + found 422.5.

[0242] Example 92. trans-4-(4-amino-6-(4-(3-(4-chloro-(3-trifluoromethyl)phenyl)ureido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR142)

[0243] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-(4-chloro-(3-trifluoromethyl)phenyl)ureido)phenyl)acetate. 1H NMR(500MHz,DMSO-d6)δ12.11(s,1H),9.51(s,1H),9.34(s,1H),8.47(d,J=8.5Hz ,2H),8.28(s,1H),8.12(d,J=2.5Hz,1H),7.78(s,2H),7.69–7.60(m,2H),7.56(d, J=8.5Hz,2H),5.39–5.28(m,1H),2.69(d,J=12.9Hz,2H),2.27(dd,J=14.1,10.6Hz ,1H),2.06(d,J=12.7Hz,2H),1.70(d,J=11.8Hz,2H),1.49–1.44(m,2H).ESI-MS:C 27 H 23 ClF3N7O4[M+H] + found 602.24.

[0244] Example 93. 1-(4-(4-amino-8-isopropyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-3-phenylurea (TOR143)

[0245] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-phenylureido)phenyl)acetate, and the halide or methanesulfonyl compound used is 2-iodopropane. 1 H NMR(500MHz,Chloroform-d)δ8.38(s,1H),8.26(d,J=8.5Hz,2H),7.46(d,J=8.6Hz,2H), 7.37(d,J=5.2Hz,3H),7.16(s,1H),6.78(s,1H),6.65(s,1H),5.43(s,1H),1.25(s,6H).

[0246] Example 94. 1-(4-(4-amino-8-cyclohexyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-3-phenylurea (TOR144)

[0247] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-phenylureido)phenyl)acetate, and the halide or mesylate compound used is cyclohexyl methanesulfonate. 1H NMR(500MHz,Chloroform-d)δ8.38(s,1H),8.26(d,J=8.5Hz,2H),7.48(d,J=8.7Hz,2H),7.41–7. 33(m,4H),7.14(t,J=7.0Hz,1H),6.98(s,1H),6.84(s,1H),5.86–5.77(m,1H),0.92–0.79(m,8H).

[0248] Example 95. 1-(4-(4-amino-8-butyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-3-phenylurea (TOR145)

[0249] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-phenylureido)phenyl)acetate, and the halide or methanesulfonyl compound used is iodobutane. 1 H NMR(500MHz,DMSO-d6)δ9.17(s,1H),8.96(s,1H),8.53(d,J=8.9Hz,2H),8.29(s,1H),7.80(s,2H),7.59–7.54(m,2H),7.50–7.45(m,2H) ),7.29(t,J=7.9Hz,2H),6.98(t,J=7.3Hz,1H),4.32–4.25(m,2H),1.64(q,J=7.6Hz,2H),1.36(q,J=7.4Hz,2H),0.93(t,J=7.3Hz,3H).

[0250] Example 96. 1-(4-(4-amino-8-isopropyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-3-(2-methoxyphenyl)urea (TOR146)

[0251] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-(2-methoxyphenyl)ureido)phenyl)acetate, and the halide or methanesulfonyl compound used is 2-iodopropane. 1H NMR(500MHz,Chloroform-d)δ8.37(s,1H),8.25(dd,J=8.9,1.9Hz,2H),8.09(dd,J=8.0,1.8Hz,1H),7.53–7.45(m,2H),7.34(s,1H),7.23( s,1H),7.02(td,J=7.8,1.8Hz,1H),6.97(t,J=7.7Hz,1H),6.88(d,J=8.1Hz,1H),5.81(p,J=6.9Hz,1H),3.83(s,3H),1.64(d,J=6.6Hz,6H).

[0252] Example 97. 1-(4-(4-amino-8-isopropyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-3-(4-methoxyphenyl)urea (TOR147)

[0253] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-(4-methoxyphenyl)ureido)phenyl)acetate, and the halide or methanesulfonyl compound used is 2-iodopropane. 1 H NMR (500MHz, DMSO-d6) δ8.88(s,1H),8.55(s,1H),8.47(d,J=8.9Hz,2H),8.27(s,1H),7.74(s,2H),7.53(d, J=8.7Hz,2H),7.40–7.34(m,2H),6.91–6.85(m,2H),5.74–5.67(m,1H),3.72(s,3H),1.56(d,J=6.9Hz,6H).

[0254] Example 98. 1-(4-(4-amino-8-isopropyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-3-(4-fluorophenyl)urea (TOR148)

[0255] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-(4-fluorophenyl)ureido)phenyl)acetate, and the halide or methanesulfonyl compound used is 2-iodopropane. 1 H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.79(s,1H),8.47(d,J=8.8Hz,2H),8.27(s,1H),7.75(s,2H),7.5 4(d,J=8.7Hz,2H),7.51–7.46(m,2H),7.14(t,J=8.9Hz,2H),5.74–5.68(m,1H),1.56(d,J=6.9Hz,6H).

[0256] Example 99. 1-(4-(4-amino-8-isopropyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-3-(2,4-difluorophenyl)urea (TOR149)

[0257] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-(2,4-difluorophenyl)ureido)phenyl)acetate, and the halide or methanesulfonyl compound used is 2-iodopropane.

[0258] Example 100. 1-(4-(4-amino-8-isopropyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-3-(4-cyanophenyl)urea (TOR150)

[0259] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-(4-cyanophenyl)ureido)phenyl)acetate, and the halide or methanesulfonyl compound used is 2-iodopropane. 1 H NMR(500MHz,DMSO-d6)δ9.33(s,1H),9.15(s,1H),8.41(s,1H),8.29(d,J=8.7Hz,2H),7.93(s,2H),7.75(d ,J=8.7Hz,2H),7.66(d,J=8.7Hz,2H),7.61(d,J=8.7Hz,2H),5.54(p,J=6.1Hz,1H),1.45(d,J=6.3Hz,6H).

[0260] Example 101. 4-Amino-6-(6-hydroxybenzofuran-3-yl)-8-isopropylpteridin-7(8H)-one (TOR151)

[0261] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(6-hydroxybenzofuran-3-yl)acetate, and the halide or methanesulfonyl compound used is 2-iodopropane.

[0262] Example 102. 1-(4-(4-amino-8-isopropyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-3-cyclohexylurea (TOR152)

[0263] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-cyclohexylureido)phenyl)acetate, and the halide or methanesulfonyl compound used is 2-iodopropane. 1H NMR(500MHz,DMSO-d6)δ8.59(s,1H),8.46–8.40(m,2H),8.26(s,1H),7.72(s,2H),7.48–7.41(m,2H),6.17(d,J=7.8Hz,1H),5.75–5. 67(m,1H),3.53–3.42(m,1H),1.85–1.76(m,2H),1.71–1.62(m,2H),1.55(d,J=7.0Hz,6H),1.35–1.27(m,2H),1.18(q,J=10.0Hz,4H).

[0264] Example 103. trans-4-(4-amino-6-(4-(3-cyclohexylureido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR153)

[0265] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-cyclohexylureido)phenyl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.13(s,1H),8.59(s,1H),8.42(d,J=8.9Hz,2H),8.26(s,1H),7.73 (s,2H),7.48–7.42(m,2H),6.18(d,J=7.8Hz,1H),5.32(t,J=4.8Hz,1H),3.52–3.46(m,1H), 2.68(s,2H),2.25(d,J=13.0Hz,1H),2.06(d,J=12.8Hz,2H),2.01–1.95(m,2H),1.81(d,J=1 1.9Hz,2H),1.68(t,J=12.1Hz,4H),1.46(d,J=11.4Hz,2H),1.30(t,J=12.2Hz,4H).ESI-MS:C 26 H 31 N7O4[M+H] + found 506.29.

[0266] Example 104. trans-4-(4-amino-6-(5-bromobenzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR154)

[0267] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(5-bromobenzofuran-3-yl)acetate.

[0268] Example 105. trans-4-(4-amino-6-(5-fluoro-6-hydroxybenzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR155)

[0269] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(5-fluoro-6-hydroxybenzofuran-3-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ12.13(s,1H)10.15(s,1H),9.07(s,1H),8.33(s,1H),8.30(d,J=11.0Hz,1H),7.85(s,1H),7.52(s,1H),7.20(d,J= 7.2Hz,1H),5.40(s,1H),2.70(s,2H),2.27(t,J=12.3Hz,1H),2.07(d,J=12.7Hz,2H),1.72(d,J=12.0Hz,2H),1.51–1.40(m,2H).ESI-MS:C 21 H 18 FN5O5[M+H] + found 440.14.

[0270] Example 106. trans-4-(4-amino-6-(4-(3-(4-fluorophenyl)ureido)phenyl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR156)

[0271] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(4-(3-(4-fluorophenyl)ureido)phenyl)acetate. 1 H NMR(500MHz,DMSO-d6)δ8.94(s,1H),8.77(s,1H),8.46(d,J=8.8Hz,2H),8.2 7(s,1H),7.75(s,2H),7.54(d,J=8.8Hz,2H),7.50–7.46(m,2H),7.13(t,J=8 .9Hz,2H),5.38–5.31(m,1H),2.76–2.65(m,2H),2.40(d,J=12.1Hz,1H),2.0 7(d,J=12.7Hz,2H),1.71(d,J=12.1Hz,2H),1.49(q,J=13.1Hz,2H).ESI-MS:C 26 H 24 FN7O4[M+H] + found 518.25.

[0272] Example 107. trans-4-(4-amino-6-(7-chloro-6-hydroxybenzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR157)

[0273] The synthesis method is similar to that of Example 1, except that the methyl aryl acetate used is methyl 2-(7-chloro-6-hydroxybenzofuran-3-yl)acetate. 1 H NMR (500MHz, DMSO-d6) δ8.31(s,1H),7.37(dd,J=8.7,2.4Hz,1H),7.26(d,J=8.8Hz,1H),6.89(dd,J=8.6,2.3Hz,1H),5.42(s, 1H),2.46–2.38(m,2H),2.29(tt,J=11.9,7.1Hz,2H),2.16(d,J=12.1Hz,2H),2.07–1.99(m,1H),1.68–1.59(m,2H).ESI-MS:C 21 H 18 ClN5O5[M+H] + found 456.11.

[0274] Example 108. trans-4-(4-amino-6-(6-(2-amino-2-oxoethoxy)benzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR158)

[0275] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(6-(2-amino-2-oxoethoxy)benzofuran-3-yl)acetate. 1 H NMR(500MHz,DMSO-d6)δ12.15(s,1H),9.11(s,1H),8.58(d,J=8.7Hz,1H),8.3 4(s,1H),7.95(s,2H),7.61(s,1H),7.43(s,1H),7.28(d,J=2.3Hz,1H),7.07(d d,J=8.7,2.3Hz,1H),5.41(s,1H),4.52(s,2H),2.71(s,2H),2.27(d,J=12.9H z, 1H), 2.07 (d, J = 12.9Hz, 2H), 1.73 (d, J = 11.9Hz, 2H), 1.48 (d, J = 13.7Hz, 2H).

[0276] Example 109. trans-4-(4-amino-6-(6-(cyanomethoxy)benzofuran-3-yl)-7-oxopterin-8(7H)-yl)cyclohexane-1-carboxylic acid (TOR159)

[0277] The synthesis method is similar to that of Example 1, except that the methyl arylacetate used is methyl 2-(6-(cyanomethoxy)benzofuran-3-yl)acetate. 1 H NMR (500MHz, DMSO-d6)) δ9.11(s,1H),8.58(d,J=8.6Hz,1H),8.34(s,1H),7.61(s,1H),7.43(s,1H),7.28(d,J=2.3Hz,1H),7.07(d,J=8.8Hz ,1H),5.39(s,1H),4.52(s,2H),2.70(s,2H),2.26(d,J=12.8Hz,1H),2.07(d,J=13.3Hz,2H),1.73(d,J=12.1Hz,2H),1.47(d,J=14.1Hz,2H).

[0278] Effect test:

[0279] In vitro mTOR kinase inhibition assay

[0280] First, prepare 1× kinase buffer containing 50 mM HEPES (pH 7.5), 1 mM EGTA, and 0.01% Tween-20. Prepare a 10 mM stock solution of the test compound in DMSO. Serially dilute the compound in DMSO to a maximum concentration of 10 μM, for a total of 10 concentrations.

[0281] Transfer the diluted compound to a 384-well plate, and prepare a control group without compound and a control group without kinase. Add 1×kinase buffer to mTOR to prepare the kinase solution, take 2.5μL and add it to the 384-well plate and vortex to mix. Also prepare 1×kinase reaction buffer containing ULight-4E-BP1 peptide and ATP substrate, take 5μL and add it to the 384-well plate to start the reaction. After reacting at room temperature for 30 minutes, prepare a buffer containing EDTA and Eu-anti-phospho-4E-BP1 antibody, take 10μL and add it to the 384-well plate, and incubate at 20°C for 60 minutes. Read the 384-well plate and calculate the statistical data to calculate the inhibition rate of the compound on mTOR kinase. Substitute the inhibition rate and the corresponding concentration into GraphPadPrism software for curve fitting to calculate the IC 50 value.

[0282] The results of the mTOR kinase inhibition assay are shown in Table 1. A is <1 nM, B is 1 nM to 10 nM, C is 10 nM to 100 nM, and D is >100 nM. As shown in Table 1, the compounds described herein all effectively inhibit mTOR kinase and exhibit good inhibitory activity. Compared to the clinical drug candidates OSI-027 and PF-04691502, several compounds described herein exhibit superior mTOR inhibitory activity compared to the positive controls OSI-027 and PF-04691502.

[0283] Table 1. In vitro inhibitory activity of target compounds against mTOR kinase

[0284]

[0285] Tumor cell proliferation inhibition test

[0286] Culture conditions: RPMI 1640 medium (GIBCO), 90% + FBS 10%, 37°C, 5% CO2.

[0287] (1) Cell plating: Prepare cell suspension. The plating density of T-47D is 1×10 5 cells / mL, 100 μL / well, culture overnight at 37°C in 5% CO2.

[0288] (2) On the second day, replace the medium and add the compound in a gradient dilution. Remove the medium from the 96-well plate and add 100 μL / well of the compound diluted in the medium. The starting concentration of the compound is 100 μM, and the compound is diluted 3-fold for a total of 10 concentrations.

[0289] (3) Incubate the culture plate in an incubator at 37°C and 5% CO2 for 48 hours.

[0290] (4) According to the instructions of the CCK8 kit (GLPBIO, GK10001), 10 μL of CCK-8 solution was added to each well and incubated in an incubator at 37°C for approximately 3 h.

[0291] (5) Plate reading: Measure the absorbance at a wavelength of 450 nm using a detector. Calculate the IC using GraphPad Prism software. 50 .

[0292] The results of in vitro antitumor activity are shown in Table 2. As shown in Table 2, the compounds of the present invention have good inhibitory activity against the proliferation of MCF-7 cells and Hs578T cells. These results indicate that the compounds of the present invention have positive and predictable clinical application value in anti-proliferative diseases, especially anti-tumor effects.

[0293] Table 2. In vitro antitumor activity of target compounds

[0294]

[0295] In vitro hepatic microsomal metabolic stability

[0296] The reaction solution ratio is: 0.1 M potassium phosphate buffer (pH 7.45), 3.3 mM MgCl2, 1.2 mM NADPH, 0.2 mg / mL human or mouse liver microsomes, and 1 μM test compound.

[0297] Preheat liver microsomes at 37°C for 5 minutes, then add the test compound and NADPH. Remove 100 μL of the reaction mixture at 0, 5, 10, 20, and 30 minutes, add 200 μL of cold acetonitrile containing 100 ng / mL internal standard, vortex the sample for 5 minutes, and transfer the supernatant to a 96-well plate for LC-MS / MS analysis.

[0298] The results of the in vitro liver microsome metabolic stability experiment are shown in Table 3. As shown in Table 3, the compounds of the present invention have good metabolic stability in mouse liver microsomes and human liver microsomes.

[0299] Table 3. Metabolic stability of liver microsomes

[0300]

[0301]

[0302] In vivo toxicology / safety studies of compounds

[0303] Female BALB / c mice, 5-6 weeks old and weighing approximately 18-20 g, were purchased from Guangdong Yaojiekang Biotechnology Co., Ltd. The mice were housed and maintained at the Laboratory Animal Center of the Guangzhou Institutes of Biomedicine and Health (GIBH). Experiments were conducted in accordance with the regulations of the Laboratory Animal Welfare and Ethics Committee.

[0304] Each mouse was injected subcutaneously in the right groin with HGC-27 tumor cells (5×10 6 ) 0.1 ml of the mixture was added to induce tumor growth. Once the tumors became palpable, the animals were randomly divided into four groups and the mice were orally dosed daily. The control group was treated with saline containing 2% dimethyl sulfoxide and 10% polyethylene glycol-15 hydroxystearate (Solutol). The experimental groups were administered the compounds PF-04691502 (10 mg / kg), TOR133 (30 mg / kg), and TOR133 (60 mg / kg) dissolved in the control solution. Dosing was done once daily for 18 consecutive days. At the end of the experiment, the mice were euthanized and tissues such as liver, kidney, and lung were harvested.

[0305] Liver, kidney, and lung tissues were fixed with 4% paraformaldehyde for 24 hours. Subsequently, each tissue was dehydrated through a gradient of ethanol (100% → 70% → water), cleared with xylene, and embedded in paraffin. The paraffin-embedded tissues were cut into 4-micron-thick sections, dewaxed with xylene, and rehydrated through a gradient of ethanol (100% → 70% → water). The sections were stained with hematoxylin for 5 minutes and eosin for 2 minutes, and then coverslipped with mounting medium. The stained tissues were observed and imaged microscopically.

[0306] The results are as follows Figure 1 As shown, H&E staining histopathological analysis showed that in the group treated with PF-04691502, significant drug-induced liver injury occurred, characterized by sinusoidal stenosis and hepatocyte vacuolation, suggesting inflammation-mediated interstitial proliferation and fatty or vesicular degeneration. In addition, PF-04691502 also caused severe lung damage, manifested as extensive structural distortion, including destruction of alveolar septa, collapse of alveolar spaces, and significant interstitial fibrosis with collagen deposition. Correspondingly, the compound TOR133 did not cause significant morphological and pathological changes in liver, kidney, or lung tissue at higher drug concentrations, indicating that the compound of the present application has lower toxicity.

[0307] The applicant declares that the present invention illustrates the pteridone compounds and their applications through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent replacement of raw materials for the products of the present invention, addition of auxiliary ingredients, and selection of specific methods, etc., are all within the scope of protection and disclosure of the present invention.

[0308] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0309] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A pteridinone compound, characterized in that The structure of the pteridinone compound is shown in Formula I: Among them, R 1 is selected from substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C12 heteroaryl; R 2 Any one selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, or substituted or unsubstituted C3-C12 cycloalkyl; the carbon atoms in the C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or C3-C12 cycloalkyl are independently unsubstituted or at least one carbon atom is replaced by any one of O, S, or N; R 3 、R 4 Independently selected from substituted or unsubstituted C1-C6 alkyl.

2. The pteridone compound according to claim 1, characterized in that The substituted substituent is selected from any one of halogen, hydroxyl, acyl, carboxyl, amino, nitro, thiol, aldehyde, C1-C6 alkoxy, C6-C20 aryl, C3-C20 heteroaryl, C1-C6 alkyl, C3-C12 cycloalkyl, amide or cyano.

3. The pteridinone compound according to claim 1 or 2, characterized in that The R 1 Selected from any one of the following groups: Preferably, the R 2 Selected from any one of the following groups:

4. The pteridinone compound according to any one of claims 1 to 3, characterized in that The R 3 、R 4 Independently selected from C1-C6 alkyl, preferably methyl, ethyl, n-propyl or isopropyl.

5. The pteridinone compound according to any one of claims 1 to 4, characterized in that The pteridinone compound is selected from any one of the compounds with the following structures:

6. Use of the pteridinone compound according to any one of claims 1 to 5 in the preparation of an mTOR inhibitor.

7. Use of a pteridinone compound according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or preventing diseases involving the mTOR signaling pathway.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the pteridinone compound according to any one of claims 1 to 5.

9. Use of the pteridinone compound according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or preventing tumors.

10. The use according to claim 9, characterized in that The tumors include colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, cervical cancer, esophageal cancer, gallbladder cancer, malignant glioma, myeloproliferative disease, leukemia or lymphoma.

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